Advanced and Metastatic Breast Cancer

Treatment options for patients with cancer that is detected at a late stage are severely limited, which usually leads to an unfavorable prognosis for such patients. Indeed, the options available for patients with metastatic solid cancers are scarcely curative. Therefore, early diagnosis of neoplasia remains a fundamental mainstay for improving outcomes for cancer patients.

Histopathology is the current gold standard for cancer diagnosis. Biopsy is an invasive procedure that provides physicians with further samples to test but that furnishes limited information concerning tumor heterogeneity. Biopsy specimens are usually obtained only when there is clinical evidence of neoplasia, which significantly limits their usefulness in early diagnosis.

Around 20 years ago, it was discovered that the presence of circulating tumor cells (CTC) in patients with metastatic breast cancer who were about to begin a new line of treatment was predictive of overall and progression-free survival. The prognostic value of CTC was independent of the line of treatment (first or second) and was greater than that of the site of metastasis, the type of therapy, and the time to metastasis after complete primary resection. These results support the idea that the presence of CTC could be used to modify the system for staging advanced disease.

Since then, research into liquid biopsy assays has expanded rapidly, and many biomarkers have been studied in various body fluids for their usefulness in assessing solid tumors.
 

Liquid vs. tissue

Liquid biopsy is a minimally invasive tool that is easy to use. It is employed to detect cancer, to assess treatment response, or to monitor disease progression. Liquid biopsy produces test material from primary and metastatic (or micrometastatic) sites and provides a more heterogeneous picture of the entire tumor cell population, compared with specimens obtained with tissue biopsy.

Metastasis

The notion that metastatic lesions are formed from cancer cells that have disseminated from advanced primary tumors has been substantially revised following the identification of disseminated tumor cells (DTC) in the bone marrow of patients with early-stage disease. These results have led researchers to no longer view cancer metastasis as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as metastasizing cells assume new phenotypes while abandoning older behaviors.

The initiation of metastasis is not simply a cell-autonomous event but is heavily influenced by complex tissue microenvironments. Although colonization of distant tissues by DTC is an extremely inefficient process, at times, relatively numerous CTC can be detected in the blood of cancer patients (> 1,000 CTC/mL of blood plasma), whereas the number of clinically detectable metastases is disproportionately low, confirming that tumor cell diffusion can happen at an early stage but usually occurs later on.
 

Early dissemination

Little is currently known about the preference of cancer subtypes for distinct tissues or about the receptiveness of a tissue as a metastatic site. What endures as one of the most confounding clinical phenomena is that patients may undergo tumor resection and remain apparently disease free for months, years, and even decades, only to experience relapse and be diagnosed with late-stage metastatic disease. This course may be a result of cell seeding from minimal residual disease after resection of the primary tumor or of preexisting clinically undetectable micrometastases. It may also arise from early disseminated cells that remain dormant and resistant to therapy until they suddenly reawaken to initiate proliferation into clinically detectable macrometastases.

Dormant DTC could be the main reason for delayed detection of metastases. It is thought that around 40% of patients with prostate cancer who undergo radical prostatectomy present with biochemical recurrence, suggesting that it is likely that hidden DTC or micrometastases are present at the time of the procedure. The finding is consistent with the detection of DTC many years after tumor resection, suggesting they were released before surgical treatment. Nevertheless, research into tumor cell dormancy is limited, owing to the invasive and technically challenging nature of obtaining DTC samples, which are predominantly taken from the bone marrow.
 

CTC metastases

Cancer cells can undergo epithelial-to-mesenchymal transition to facilitate their detachment from the primary tumor and intravasation into the blood circulation (step 1). Dissemination of cancer cells from the primary tumor into circulation can involve either single cells or cell clusters containing multiple CTC as well as immune cells and platelets, known as microemboli. CTC that can survive in circulation (step 2) can exit the bloodstream (step 3) and establish metastatic tumors (step 4), or they can enter dormancy and reside in distant organs, such as the bone marrow.

Use in practice

CTC were discovered over a century ago, but only in recent years has technology been sufficiently advanced to study CTC and to assess their usefulness as biomarkers. Recent evidence suggests that not only do the number of CTC increase during sleep and rest phases but also that these CTC are better able to metastasize, compared to those generated during periods of wakefulness or activity.

CTC clusters (microemboli) are defined as groups of two or more CTC. They can consist of CTC alone (homotypic) or can include various stromal cells, such as cancer-associated fibroblasts or platelets and immune cells (heterotypic). CTC clusters (with or without leukocytes) seem to have greater metastatic capacity, compared with individual CTC.

A multitude of characteristics can be measured in CTC, including genetics and epigenetics, as well as protein levels, which might help in understanding many processes involved in the formation of metastases.

Quantitative assessment of CTC could indicate tumor burden in patients with aggressive cancers, as has been seen in patients with primary lung cancer.
 

Early cancer diagnosis

Early research into CTC didn’t explore their usefulness in diagnosing early-stage tumors because it was thought that CTC were characteristic of advanced-stage disease. This hypothesis was later rejected following evidence of local intravascular invasion of very early cancer cells, even over a period of several hours. This feature may allow CTC to be detected before the clinical diagnosis of cancer.

CTC have been detected in various neoplastic conditions: in breast cancer, seen in 20% of patients with stage I disease, in 26.8% with stage II disease, and 26.7% with stage III disease; in nonmetastatic colorectal cancer, including stage I and II disease; and in prostate cancer, seen in over 50% of patients with localized disease.

The presence of CTC has been proven to be an unfavorable prognostic predictor of overall survival among patients with early-stage non–small cell lung cancer. It distinguishes patients with pancreatic ductal adenocarcinoma from those with noncancerous pancreatic diseases with a sensitivity of 75% and a specificity of 96.3%.

CTC positivity scoring (appropriately defined), combined with serum prostate-specific antigen level, was predictive of a biopsy diagnosis of clinically significant prostate cancer.

All these data support the utility of CTC in early cancer diagnosis. Their link with metastases, and thus with aggressive tumors, gives them an advantage over other (noninvasive or minimally invasive) biomarkers in the early identification of invasive tumors for therapeutic intervention with better cure rates.
 

This article was translated from Univadis Italy. A version appeared on Medscape.com.

Treatment options for patients with cancer that is detected at a late stage are severely limited, which usually leads to an unfavorable prognosis for such patients. Indeed, the options available for patients with metastatic solid cancers are scarcely curative. Therefore, early diagnosis of neoplasia remains a fundamental mainstay for improving outcomes for cancer patients.

Histopathology is the current gold standard for cancer diagnosis. Biopsy is an invasive procedure that provides physicians with further samples to test but that furnishes limited information concerning tumor heterogeneity. Biopsy specimens are usually obtained only when there is clinical evidence of neoplasia, which significantly limits their usefulness in early diagnosis.

Around 20 years ago, it was discovered that the presence of circulating tumor cells (CTC) in patients with metastatic breast cancer who were about to begin a new line of treatment was predictive of overall and progression-free survival. The prognostic value of CTC was independent of the line of treatment (first or second) and was greater than that of the site of metastasis, the type of therapy, and the time to metastasis after complete primary resection. These results support the idea that the presence of CTC could be used to modify the system for staging advanced disease.

Since then, research into liquid biopsy assays has expanded rapidly, and many biomarkers have been studied in various body fluids for their usefulness in assessing solid tumors.
 

Liquid vs. tissue

Liquid biopsy is a minimally invasive tool that is easy to use. It is employed to detect cancer, to assess treatment response, or to monitor disease progression. Liquid biopsy produces test material from primary and metastatic (or micrometastatic) sites and provides a more heterogeneous picture of the entire tumor cell population, compared with specimens obtained with tissue biopsy.

Metastasis

The notion that metastatic lesions are formed from cancer cells that have disseminated from advanced primary tumors has been substantially revised following the identification of disseminated tumor cells (DTC) in the bone marrow of patients with early-stage disease. These results have led researchers to no longer view cancer metastasis as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as metastasizing cells assume new phenotypes while abandoning older behaviors.

The initiation of metastasis is not simply a cell-autonomous event but is heavily influenced by complex tissue microenvironments. Although colonization of distant tissues by DTC is an extremely inefficient process, at times, relatively numerous CTC can be detected in the blood of cancer patients (> 1,000 CTC/mL of blood plasma), whereas the number of clinically detectable metastases is disproportionately low, confirming that tumor cell diffusion can happen at an early stage but usually occurs later on.
 

Early dissemination

Little is currently known about the preference of cancer subtypes for distinct tissues or about the receptiveness of a tissue as a metastatic site. What endures as one of the most confounding clinical phenomena is that patients may undergo tumor resection and remain apparently disease free for months, years, and even decades, only to experience relapse and be diagnosed with late-stage metastatic disease. This course may be a result of cell seeding from minimal residual disease after resection of the primary tumor or of preexisting clinically undetectable micrometastases. It may also arise from early disseminated cells that remain dormant and resistant to therapy until they suddenly reawaken to initiate proliferation into clinically detectable macrometastases.

Dormant DTC could be the main reason for delayed detection of metastases. It is thought that around 40% of patients with prostate cancer who undergo radical prostatectomy present with biochemical recurrence, suggesting that it is likely that hidden DTC or micrometastases are present at the time of the procedure. The finding is consistent with the detection of DTC many years after tumor resection, suggesting they were released before surgical treatment. Nevertheless, research into tumor cell dormancy is limited, owing to the invasive and technically challenging nature of obtaining DTC samples, which are predominantly taken from the bone marrow.
 

CTC metastases

Cancer cells can undergo epithelial-to-mesenchymal transition to facilitate their detachment from the primary tumor and intravasation into the blood circulation (step 1). Dissemination of cancer cells from the primary tumor into circulation can involve either single cells or cell clusters containing multiple CTC as well as immune cells and platelets, known as microemboli. CTC that can survive in circulation (step 2) can exit the bloodstream (step 3) and establish metastatic tumors (step 4), or they can enter dormancy and reside in distant organs, such as the bone marrow.

Use in practice

CTC were discovered over a century ago, but only in recent years has technology been sufficiently advanced to study CTC and to assess their usefulness as biomarkers. Recent evidence suggests that not only do the number of CTC increase during sleep and rest phases but also that these CTC are better able to metastasize, compared to those generated during periods of wakefulness or activity.

CTC clusters (microemboli) are defined as groups of two or more CTC. They can consist of CTC alone (homotypic) or can include various stromal cells, such as cancer-associated fibroblasts or platelets and immune cells (heterotypic). CTC clusters (with or without leukocytes) seem to have greater metastatic capacity, compared with individual CTC.

A multitude of characteristics can be measured in CTC, including genetics and epigenetics, as well as protein levels, which might help in understanding many processes involved in the formation of metastases.

Quantitative assessment of CTC could indicate tumor burden in patients with aggressive cancers, as has been seen in patients with primary lung cancer.
 

Early cancer diagnosis

Early research into CTC didn’t explore their usefulness in diagnosing early-stage tumors because it was thought that CTC were characteristic of advanced-stage disease. This hypothesis was later rejected following evidence of local intravascular invasion of very early cancer cells, even over a period of several hours. This feature may allow CTC to be detected before the clinical diagnosis of cancer.

CTC have been detected in various neoplastic conditions: in breast cancer, seen in 20% of patients with stage I disease, in 26.8% with stage II disease, and 26.7% with stage III disease; in nonmetastatic colorectal cancer, including stage I and II disease; and in prostate cancer, seen in over 50% of patients with localized disease.

The presence of CTC has been proven to be an unfavorable prognostic predictor of overall survival among patients with early-stage non–small cell lung cancer. It distinguishes patients with pancreatic ductal adenocarcinoma from those with noncancerous pancreatic diseases with a sensitivity of 75% and a specificity of 96.3%.

CTC positivity scoring (appropriately defined), combined with serum prostate-specific antigen level, was predictive of a biopsy diagnosis of clinically significant prostate cancer.

All these data support the utility of CTC in early cancer diagnosis. Their link with metastases, and thus with aggressive tumors, gives them an advantage over other (noninvasive or minimally invasive) biomarkers in the early identification of invasive tumors for therapeutic intervention with better cure rates.
 

This article was translated from Univadis Italy. A version appeared on Medscape.com.

Treatment options for patients with cancer that is detected at a late stage are severely limited, which usually leads to an unfavorable prognosis for such patients. Indeed, the options available for patients with metastatic solid cancers are scarcely curative. Therefore, early diagnosis of neoplasia remains a fundamental mainstay for improving outcomes for cancer patients.

Histopathology is the current gold standard for cancer diagnosis. Biopsy is an invasive procedure that provides physicians with further samples to test but that furnishes limited information concerning tumor heterogeneity. Biopsy specimens are usually obtained only when there is clinical evidence of neoplasia, which significantly limits their usefulness in early diagnosis.

Around 20 years ago, it was discovered that the presence of circulating tumor cells (CTC) in patients with metastatic breast cancer who were about to begin a new line of treatment was predictive of overall and progression-free survival. The prognostic value of CTC was independent of the line of treatment (first or second) and was greater than that of the site of metastasis, the type of therapy, and the time to metastasis after complete primary resection. These results support the idea that the presence of CTC could be used to modify the system for staging advanced disease.

Since then, research into liquid biopsy assays has expanded rapidly, and many biomarkers have been studied in various body fluids for their usefulness in assessing solid tumors.
 

Liquid vs. tissue

Liquid biopsy is a minimally invasive tool that is easy to use. It is employed to detect cancer, to assess treatment response, or to monitor disease progression. Liquid biopsy produces test material from primary and metastatic (or micrometastatic) sites and provides a more heterogeneous picture of the entire tumor cell population, compared with specimens obtained with tissue biopsy.

Metastasis

The notion that metastatic lesions are formed from cancer cells that have disseminated from advanced primary tumors has been substantially revised following the identification of disseminated tumor cells (DTC) in the bone marrow of patients with early-stage disease. These results have led researchers to no longer view cancer metastasis as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as metastasizing cells assume new phenotypes while abandoning older behaviors.

The initiation of metastasis is not simply a cell-autonomous event but is heavily influenced by complex tissue microenvironments. Although colonization of distant tissues by DTC is an extremely inefficient process, at times, relatively numerous CTC can be detected in the blood of cancer patients (> 1,000 CTC/mL of blood plasma), whereas the number of clinically detectable metastases is disproportionately low, confirming that tumor cell diffusion can happen at an early stage but usually occurs later on.
 

Early dissemination

Little is currently known about the preference of cancer subtypes for distinct tissues or about the receptiveness of a tissue as a metastatic site. What endures as one of the most confounding clinical phenomena is that patients may undergo tumor resection and remain apparently disease free for months, years, and even decades, only to experience relapse and be diagnosed with late-stage metastatic disease. This course may be a result of cell seeding from minimal residual disease after resection of the primary tumor or of preexisting clinically undetectable micrometastases. It may also arise from early disseminated cells that remain dormant and resistant to therapy until they suddenly reawaken to initiate proliferation into clinically detectable macrometastases.

Dormant DTC could be the main reason for delayed detection of metastases. It is thought that around 40% of patients with prostate cancer who undergo radical prostatectomy present with biochemical recurrence, suggesting that it is likely that hidden DTC or micrometastases are present at the time of the procedure. The finding is consistent with the detection of DTC many years after tumor resection, suggesting they were released before surgical treatment. Nevertheless, research into tumor cell dormancy is limited, owing to the invasive and technically challenging nature of obtaining DTC samples, which are predominantly taken from the bone marrow.
 

CTC metastases

Cancer cells can undergo epithelial-to-mesenchymal transition to facilitate their detachment from the primary tumor and intravasation into the blood circulation (step 1). Dissemination of cancer cells from the primary tumor into circulation can involve either single cells or cell clusters containing multiple CTC as well as immune cells and platelets, known as microemboli. CTC that can survive in circulation (step 2) can exit the bloodstream (step 3) and establish metastatic tumors (step 4), or they can enter dormancy and reside in distant organs, such as the bone marrow.

Use in practice

CTC were discovered over a century ago, but only in recent years has technology been sufficiently advanced to study CTC and to assess their usefulness as biomarkers. Recent evidence suggests that not only do the number of CTC increase during sleep and rest phases but also that these CTC are better able to metastasize, compared to those generated during periods of wakefulness or activity.

CTC clusters (microemboli) are defined as groups of two or more CTC. They can consist of CTC alone (homotypic) or can include various stromal cells, such as cancer-associated fibroblasts or platelets and immune cells (heterotypic). CTC clusters (with or without leukocytes) seem to have greater metastatic capacity, compared with individual CTC.

A multitude of characteristics can be measured in CTC, including genetics and epigenetics, as well as protein levels, which might help in understanding many processes involved in the formation of metastases.

Quantitative assessment of CTC could indicate tumor burden in patients with aggressive cancers, as has been seen in patients with primary lung cancer.
 

Early cancer diagnosis

Early research into CTC didn’t explore their usefulness in diagnosing early-stage tumors because it was thought that CTC were characteristic of advanced-stage disease. This hypothesis was later rejected following evidence of local intravascular invasion of very early cancer cells, even over a period of several hours. This feature may allow CTC to be detected before the clinical diagnosis of cancer.

CTC have been detected in various neoplastic conditions: in breast cancer, seen in 20% of patients with stage I disease, in 26.8% with stage II disease, and 26.7% with stage III disease; in nonmetastatic colorectal cancer, including stage I and II disease; and in prostate cancer, seen in over 50% of patients with localized disease.

The presence of CTC has been proven to be an unfavorable prognostic predictor of overall survival among patients with early-stage non–small cell lung cancer. It distinguishes patients with pancreatic ductal adenocarcinoma from those with noncancerous pancreatic diseases with a sensitivity of 75% and a specificity of 96.3%.

CTC positivity scoring (appropriately defined), combined with serum prostate-specific antigen level, was predictive of a biopsy diagnosis of clinically significant prostate cancer.

All these data support the utility of CTC in early cancer diagnosis. Their link with metastases, and thus with aggressive tumors, gives them an advantage over other (noninvasive or minimally invasive) biomarkers in the early identification of invasive tumors for therapeutic intervention with better cure rates.
 

This article was translated from Univadis Italy. A version appeared on Medscape.com.

This transcript has been edited for clarity.

Dr. Partridge: We’re here today to have a conversation about the unique or age-specific issues that face our young patients and survivors with breast cancer.

Olivia, let’s get started. What kinds of things do we need to think about when we’re seeing a young patient in clinic, beyond the usual things we think about for patients with breast cancer?

Dr. Pagani: The idea of selecting age as a determinant of care of young women is because they have specific issues, which are different from older, premenopausal patients but also older patients in general. We need to take care of many things, which can go from their job, family, fertility, and all these things are specific to these women and can impact their treatment, survivorship issues, side effects, and long-term problems. It’s a different world, compared with other patients with breast cancer.

Dr. Partridge: One of the areas that you and I have been very deep in the weeds in is the fertility issues. That’s obviously one of the things that’s pretty age-specific. There are some new data around that that we’re excited about. What do we think about when we think about trying to have a pregnancy or not after a breast cancer diagnosis?

Dr. Pagani: Yeah. I think it’s great times for that because we succeeded in building up a very important trial, which broke a taboo that was there for many, many decades: You had breast cancer so forget your pregnancy desire.

Despite many retrospective data from many groups that suggested pregnancy after breast cancer was not detrimental, there were so many obstacles for these women to address their pregnancy desire. I think we succeeded in explaining and showing in a quite solid way that if you desire a baby after breast cancer, you can try to have him or her.

Dr. Partridge: This was called the POSITIVE trial, with early findings published in the New England Journal of Medicine this past year, which was very exciting. Let’s dig a little deeper into that. Is this relevant for all patients with breast cancer or select patients with breast cancer who want to get pregnant?

Dr. Pagani: The accrual of the trial was open to all patients with stage I-III disease, but the majority of the patients were low risk, which means that the majority were node negative with small tumors. I think, so far, we can say that in low-risk women, pregnancy after breast cancer can be discussed and planned.

Summarizing, I think the evidence is for low-risk patients with early breast cancer. A minority had huge tumors or node-positive disease.

Dr. Partridge: It’s nice to be able to have these data to say a temporary interruption of endocrine therapy – not coming off forever, getting back on – was not associated with any worsening in terms of their breast cancer events in the future, which is great news for the women who are diagnosed when they’re trying to get pregnant and build their families or not having completed their families. It’s been fantastic.

What about for our patients with advanced disease who come in, and we’re treating them more to try and manage the cancer and improve their survival and quality of life, but cure may not be the goal. How do we manage the fertility issues for them?

Dr. Pagani: This is, I think, still an open issue despite overall survival for many women with advanced disease, especially HER2 positive or endocrine responsive; it is improving and it’s getting better and better. There are few women with oligometastatic disease that can be cured.

We are not yet there. At the Advanced Breast Cancer conference, we started to open the door to say that fertility should be discussed with patients with advanced breast cancer as well. We cannot recommend to patients with advanced breast cancer to pursue a pregnancy.

We have no data. For sure, this needs to be taken into account and discussed openly with all the patients who desire to discuss this.

Dr. Partridge: Yes. To help people to either grieve their losses or find alternative ways to build their family, I think, is something that we focus on.

How to optimize the plan of care for young patients

Dr. Partridge: Shifting gears into the psychosocial, we know that our young women of all stages have a harder time adjusting to a breast cancer diagnosis for good reason. It’s not normative at all to be dealing with a lot of the slings and arrows that our young women deal with at the age that they do. How do you manage that in your clinic, Olivia?

Dr. Pagani: Well, I think it’s always tough. One of the problems, which is also true for early breast cancer in general, which I think is common to you as well, is that in our society many women get breast cancer before even having thought of their family planning. That’s many of them in our reality.

In other countries, maybe they have already two to three children. In our countries, they are aged 30-35 years with no children, no stable relationship, and then are faced with all these things, and their pregnancy desire can be blown up because they understand there is no time, especially if they are metastatic. This can be devastating.

We are not very good at that yet. I think we need to develop better tools, better competence, and knowledge to support them to this extent as well.

Dr. Partridge: I know that whether people want kids or not, the diagnosis of breast cancer has financial toxicity and the inconvenience of going through this kind of experience while managing a busy life. Many of our patients, especially our young patients, are trying to develop their careers, to graduate from schools, and to grow a nest egg. They’re not retired yet, on average.

I agree that we have a large amount of work to do. The one thing I try and do is always bring in our social workers and our psychosocial supportive care providers for our young patients; not that I don’t bring them in for everybody that needs them, but our young patients on average seem to need them a little bit more just because it can be just so hard on them from a psychosocial and emotional standpoint, don’t you think?

Dr. Pagani: Yes, I think so. Do you have any specific program going on at Harvard?

Dr. Partridge: We do. We’ve built a program for young women that focuses on their unique and specific needs that capitalizes on groups that are already there. We have a social work department. We just have smoothed the pathway, and we send our young people in there more quickly and have some dedicated support groups and one-to-one interventions where patients can guide other young patients. We’ve built out the supportive care for these young patients and programming.

The other big area we’ve developed that’s not unique to young age but certainly enhanced in our young patients is genetics. We have a big genetic component at our cancer center. The young patients, more so than any other group, need to have the genetic counseling and the genetic testing not only to know about future risks and about their families but also to inform their treatment decisions these days. Do you want to comment on that?

Dr. Pagani: Yes, of course. Genetic counseling, especially for the most common BRCA1 and BRCA2, can change their local treatment (e.g., bilateral mastectomy instead of conservative surgery) but they have also to take care of their ovaries. They need to think of prophylactic oophorectomy, which makes fertility and pregnancy even more complicated. For them, it’s much more complex to address everything.

I think it’s really very complex, and I think we need a better understanding of all the nuances. Sometimes, we really do not consider, as you mentioned, that not every woman desires to have a baby.

The occurrence of breast cancer can wake up a desire that was not conscious but becomes conscious because you feel that you will not be able to do that. With the social support, the psychological support, and support groups – we have a very strong breast cancer support group for younger women — they could face these things. The young women support group was supportive of the POSITIVE trial: they helped to develop and financed a video, which was very helpful to promote POSITIVE.

I think that having a relationship or a network between patients, health professionals, social workers, and psychologists can help everyone, including those who want to become mothers, those who cannot, and those who do not want to.

Dr. Partridge: I think that’s great, Olivia. I think you rounded it out by just shining a light on these issues for our young patients and elevating it to being okay to talk about these issues. I think historically, it’s been: “You’ve got breast cancer, forget about this. We just need to get you to a better survival.”

We’re increasingly recognizing for patients of all ages, but particularly our young patients, that just surviving through breast cancer or cancer in general is not enough. We need to help people live the best and fullest life possible in their survivorship.
 

Education and communication: Key aspects moving forward

Dr. Pagani: I think another issue we need really to improve is health professional competence and knowledge. After you presented the POSITIVE trial in San Antonio, I had many calls with patients. They told me, “Well, I had this information, but my gynecologist, my oncologist, or my general practitioner still discouraged me.” This is a great barrier.

I think we need to do more to teach the health professionals. Otherwise, what we do is never enough because it will be blocked. They are scared and they do not want to go against their doctors. I think this is a very big conflict.

Dr. Partridge: That’s a really important point, and I appreciate you bringing it up. We as clinicians and educators who are building the research base need to really get it out there.

Dr. Pagani is a professor at the University of Geneva. Dr. Partridge is professor of medicine at Harvard Medical School and vice chair of clinical oncology at Dana-Farber Cancer Institute, both in Boston. Dr. Pagani reported conflicts of interest with PRIME, Roche, Eli Lilly, Novartis, Takeda, Pfizer, and Debiopharm. Dr. Partridge reported no conflicts of interest.
 

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Dr. Partridge: We’re here today to have a conversation about the unique or age-specific issues that face our young patients and survivors with breast cancer.

Olivia, let’s get started. What kinds of things do we need to think about when we’re seeing a young patient in clinic, beyond the usual things we think about for patients with breast cancer?

Dr. Pagani: The idea of selecting age as a determinant of care of young women is because they have specific issues, which are different from older, premenopausal patients but also older patients in general. We need to take care of many things, which can go from their job, family, fertility, and all these things are specific to these women and can impact their treatment, survivorship issues, side effects, and long-term problems. It’s a different world, compared with other patients with breast cancer.

Dr. Partridge: One of the areas that you and I have been very deep in the weeds in is the fertility issues. That’s obviously one of the things that’s pretty age-specific. There are some new data around that that we’re excited about. What do we think about when we think about trying to have a pregnancy or not after a breast cancer diagnosis?

Dr. Pagani: Yeah. I think it’s great times for that because we succeeded in building up a very important trial, which broke a taboo that was there for many, many decades: You had breast cancer so forget your pregnancy desire.

Despite many retrospective data from many groups that suggested pregnancy after breast cancer was not detrimental, there were so many obstacles for these women to address their pregnancy desire. I think we succeeded in explaining and showing in a quite solid way that if you desire a baby after breast cancer, you can try to have him or her.

Dr. Partridge: This was called the POSITIVE trial, with early findings published in the New England Journal of Medicine this past year, which was very exciting. Let’s dig a little deeper into that. Is this relevant for all patients with breast cancer or select patients with breast cancer who want to get pregnant?

Dr. Pagani: The accrual of the trial was open to all patients with stage I-III disease, but the majority of the patients were low risk, which means that the majority were node negative with small tumors. I think, so far, we can say that in low-risk women, pregnancy after breast cancer can be discussed and planned.

Summarizing, I think the evidence is for low-risk patients with early breast cancer. A minority had huge tumors or node-positive disease.

Dr. Partridge: It’s nice to be able to have these data to say a temporary interruption of endocrine therapy – not coming off forever, getting back on – was not associated with any worsening in terms of their breast cancer events in the future, which is great news for the women who are diagnosed when they’re trying to get pregnant and build their families or not having completed their families. It’s been fantastic.

What about for our patients with advanced disease who come in, and we’re treating them more to try and manage the cancer and improve their survival and quality of life, but cure may not be the goal. How do we manage the fertility issues for them?

Dr. Pagani: This is, I think, still an open issue despite overall survival for many women with advanced disease, especially HER2 positive or endocrine responsive; it is improving and it’s getting better and better. There are few women with oligometastatic disease that can be cured.

We are not yet there. At the Advanced Breast Cancer conference, we started to open the door to say that fertility should be discussed with patients with advanced breast cancer as well. We cannot recommend to patients with advanced breast cancer to pursue a pregnancy.

We have no data. For sure, this needs to be taken into account and discussed openly with all the patients who desire to discuss this.

Dr. Partridge: Yes. To help people to either grieve their losses or find alternative ways to build their family, I think, is something that we focus on.

How to optimize the plan of care for young patients

Dr. Partridge: Shifting gears into the psychosocial, we know that our young women of all stages have a harder time adjusting to a breast cancer diagnosis for good reason. It’s not normative at all to be dealing with a lot of the slings and arrows that our young women deal with at the age that they do. How do you manage that in your clinic, Olivia?

Dr. Pagani: Well, I think it’s always tough. One of the problems, which is also true for early breast cancer in general, which I think is common to you as well, is that in our society many women get breast cancer before even having thought of their family planning. That’s many of them in our reality.

In other countries, maybe they have already two to three children. In our countries, they are aged 30-35 years with no children, no stable relationship, and then are faced with all these things, and their pregnancy desire can be blown up because they understand there is no time, especially if they are metastatic. This can be devastating.

We are not very good at that yet. I think we need to develop better tools, better competence, and knowledge to support them to this extent as well.

Dr. Partridge: I know that whether people want kids or not, the diagnosis of breast cancer has financial toxicity and the inconvenience of going through this kind of experience while managing a busy life. Many of our patients, especially our young patients, are trying to develop their careers, to graduate from schools, and to grow a nest egg. They’re not retired yet, on average.

I agree that we have a large amount of work to do. The one thing I try and do is always bring in our social workers and our psychosocial supportive care providers for our young patients; not that I don’t bring them in for everybody that needs them, but our young patients on average seem to need them a little bit more just because it can be just so hard on them from a psychosocial and emotional standpoint, don’t you think?

Dr. Pagani: Yes, I think so. Do you have any specific program going on at Harvard?

Dr. Partridge: We do. We’ve built a program for young women that focuses on their unique and specific needs that capitalizes on groups that are already there. We have a social work department. We just have smoothed the pathway, and we send our young people in there more quickly and have some dedicated support groups and one-to-one interventions where patients can guide other young patients. We’ve built out the supportive care for these young patients and programming.

The other big area we’ve developed that’s not unique to young age but certainly enhanced in our young patients is genetics. We have a big genetic component at our cancer center. The young patients, more so than any other group, need to have the genetic counseling and the genetic testing not only to know about future risks and about their families but also to inform their treatment decisions these days. Do you want to comment on that?

Dr. Pagani: Yes, of course. Genetic counseling, especially for the most common BRCA1 and BRCA2, can change their local treatment (e.g., bilateral mastectomy instead of conservative surgery) but they have also to take care of their ovaries. They need to think of prophylactic oophorectomy, which makes fertility and pregnancy even more complicated. For them, it’s much more complex to address everything.

I think it’s really very complex, and I think we need a better understanding of all the nuances. Sometimes, we really do not consider, as you mentioned, that not every woman desires to have a baby.

The occurrence of breast cancer can wake up a desire that was not conscious but becomes conscious because you feel that you will not be able to do that. With the social support, the psychological support, and support groups – we have a very strong breast cancer support group for younger women — they could face these things. The young women support group was supportive of the POSITIVE trial: they helped to develop and financed a video, which was very helpful to promote POSITIVE.

I think that having a relationship or a network between patients, health professionals, social workers, and psychologists can help everyone, including those who want to become mothers, those who cannot, and those who do not want to.

Dr. Partridge: I think that’s great, Olivia. I think you rounded it out by just shining a light on these issues for our young patients and elevating it to being okay to talk about these issues. I think historically, it’s been: “You’ve got breast cancer, forget about this. We just need to get you to a better survival.”

We’re increasingly recognizing for patients of all ages, but particularly our young patients, that just surviving through breast cancer or cancer in general is not enough. We need to help people live the best and fullest life possible in their survivorship.
 

Education and communication: Key aspects moving forward

Dr. Pagani: I think another issue we need really to improve is health professional competence and knowledge. After you presented the POSITIVE trial in San Antonio, I had many calls with patients. They told me, “Well, I had this information, but my gynecologist, my oncologist, or my general practitioner still discouraged me.” This is a great barrier.

I think we need to do more to teach the health professionals. Otherwise, what we do is never enough because it will be blocked. They are scared and they do not want to go against their doctors. I think this is a very big conflict.

Dr. Partridge: That’s a really important point, and I appreciate you bringing it up. We as clinicians and educators who are building the research base need to really get it out there.

Dr. Pagani is a professor at the University of Geneva. Dr. Partridge is professor of medicine at Harvard Medical School and vice chair of clinical oncology at Dana-Farber Cancer Institute, both in Boston. Dr. Pagani reported conflicts of interest with PRIME, Roche, Eli Lilly, Novartis, Takeda, Pfizer, and Debiopharm. Dr. Partridge reported no conflicts of interest.
 

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Dr. Partridge: We’re here today to have a conversation about the unique or age-specific issues that face our young patients and survivors with breast cancer.

Olivia, let’s get started. What kinds of things do we need to think about when we’re seeing a young patient in clinic, beyond the usual things we think about for patients with breast cancer?

Dr. Pagani: The idea of selecting age as a determinant of care of young women is because they have specific issues, which are different from older, premenopausal patients but also older patients in general. We need to take care of many things, which can go from their job, family, fertility, and all these things are specific to these women and can impact their treatment, survivorship issues, side effects, and long-term problems. It’s a different world, compared with other patients with breast cancer.

Dr. Partridge: One of the areas that you and I have been very deep in the weeds in is the fertility issues. That’s obviously one of the things that’s pretty age-specific. There are some new data around that that we’re excited about. What do we think about when we think about trying to have a pregnancy or not after a breast cancer diagnosis?

Dr. Pagani: Yeah. I think it’s great times for that because we succeeded in building up a very important trial, which broke a taboo that was there for many, many decades: You had breast cancer so forget your pregnancy desire.

Despite many retrospective data from many groups that suggested pregnancy after breast cancer was not detrimental, there were so many obstacles for these women to address their pregnancy desire. I think we succeeded in explaining and showing in a quite solid way that if you desire a baby after breast cancer, you can try to have him or her.

Dr. Partridge: This was called the POSITIVE trial, with early findings published in the New England Journal of Medicine this past year, which was very exciting. Let’s dig a little deeper into that. Is this relevant for all patients with breast cancer or select patients with breast cancer who want to get pregnant?

Dr. Pagani: The accrual of the trial was open to all patients with stage I-III disease, but the majority of the patients were low risk, which means that the majority were node negative with small tumors. I think, so far, we can say that in low-risk women, pregnancy after breast cancer can be discussed and planned.

Summarizing, I think the evidence is for low-risk patients with early breast cancer. A minority had huge tumors or node-positive disease.

Dr. Partridge: It’s nice to be able to have these data to say a temporary interruption of endocrine therapy – not coming off forever, getting back on – was not associated with any worsening in terms of their breast cancer events in the future, which is great news for the women who are diagnosed when they’re trying to get pregnant and build their families or not having completed their families. It’s been fantastic.

What about for our patients with advanced disease who come in, and we’re treating them more to try and manage the cancer and improve their survival and quality of life, but cure may not be the goal. How do we manage the fertility issues for them?

Dr. Pagani: This is, I think, still an open issue despite overall survival for many women with advanced disease, especially HER2 positive or endocrine responsive; it is improving and it’s getting better and better. There are few women with oligometastatic disease that can be cured.

We are not yet there. At the Advanced Breast Cancer conference, we started to open the door to say that fertility should be discussed with patients with advanced breast cancer as well. We cannot recommend to patients with advanced breast cancer to pursue a pregnancy.

We have no data. For sure, this needs to be taken into account and discussed openly with all the patients who desire to discuss this.

Dr. Partridge: Yes. To help people to either grieve their losses or find alternative ways to build their family, I think, is something that we focus on.

How to optimize the plan of care for young patients

Dr. Partridge: Shifting gears into the psychosocial, we know that our young women of all stages have a harder time adjusting to a breast cancer diagnosis for good reason. It’s not normative at all to be dealing with a lot of the slings and arrows that our young women deal with at the age that they do. How do you manage that in your clinic, Olivia?

Dr. Pagani: Well, I think it’s always tough. One of the problems, which is also true for early breast cancer in general, which I think is common to you as well, is that in our society many women get breast cancer before even having thought of their family planning. That’s many of them in our reality.

In other countries, maybe they have already two to three children. In our countries, they are aged 30-35 years with no children, no stable relationship, and then are faced with all these things, and their pregnancy desire can be blown up because they understand there is no time, especially if they are metastatic. This can be devastating.

We are not very good at that yet. I think we need to develop better tools, better competence, and knowledge to support them to this extent as well.

Dr. Partridge: I know that whether people want kids or not, the diagnosis of breast cancer has financial toxicity and the inconvenience of going through this kind of experience while managing a busy life. Many of our patients, especially our young patients, are trying to develop their careers, to graduate from schools, and to grow a nest egg. They’re not retired yet, on average.

I agree that we have a large amount of work to do. The one thing I try and do is always bring in our social workers and our psychosocial supportive care providers for our young patients; not that I don’t bring them in for everybody that needs them, but our young patients on average seem to need them a little bit more just because it can be just so hard on them from a psychosocial and emotional standpoint, don’t you think?

Dr. Pagani: Yes, I think so. Do you have any specific program going on at Harvard?

Dr. Partridge: We do. We’ve built a program for young women that focuses on their unique and specific needs that capitalizes on groups that are already there. We have a social work department. We just have smoothed the pathway, and we send our young people in there more quickly and have some dedicated support groups and one-to-one interventions where patients can guide other young patients. We’ve built out the supportive care for these young patients and programming.

The other big area we’ve developed that’s not unique to young age but certainly enhanced in our young patients is genetics. We have a big genetic component at our cancer center. The young patients, more so than any other group, need to have the genetic counseling and the genetic testing not only to know about future risks and about their families but also to inform their treatment decisions these days. Do you want to comment on that?

Dr. Pagani: Yes, of course. Genetic counseling, especially for the most common BRCA1 and BRCA2, can change their local treatment (e.g., bilateral mastectomy instead of conservative surgery) but they have also to take care of their ovaries. They need to think of prophylactic oophorectomy, which makes fertility and pregnancy even more complicated. For them, it’s much more complex to address everything.

I think it’s really very complex, and I think we need a better understanding of all the nuances. Sometimes, we really do not consider, as you mentioned, that not every woman desires to have a baby.

The occurrence of breast cancer can wake up a desire that was not conscious but becomes conscious because you feel that you will not be able to do that. With the social support, the psychological support, and support groups – we have a very strong breast cancer support group for younger women — they could face these things. The young women support group was supportive of the POSITIVE trial: they helped to develop and financed a video, which was very helpful to promote POSITIVE.

I think that having a relationship or a network between patients, health professionals, social workers, and psychologists can help everyone, including those who want to become mothers, those who cannot, and those who do not want to.

Dr. Partridge: I think that’s great, Olivia. I think you rounded it out by just shining a light on these issues for our young patients and elevating it to being okay to talk about these issues. I think historically, it’s been: “You’ve got breast cancer, forget about this. We just need to get you to a better survival.”

We’re increasingly recognizing for patients of all ages, but particularly our young patients, that just surviving through breast cancer or cancer in general is not enough. We need to help people live the best and fullest life possible in their survivorship.
 

Education and communication: Key aspects moving forward

Dr. Pagani: I think another issue we need really to improve is health professional competence and knowledge. After you presented the POSITIVE trial in San Antonio, I had many calls with patients. They told me, “Well, I had this information, but my gynecologist, my oncologist, or my general practitioner still discouraged me.” This is a great barrier.

I think we need to do more to teach the health professionals. Otherwise, what we do is never enough because it will be blocked. They are scared and they do not want to go against their doctors. I think this is a very big conflict.

Dr. Partridge: That’s a really important point, and I appreciate you bringing it up. We as clinicians and educators who are building the research base need to really get it out there.

Dr. Pagani is a professor at the University of Geneva. Dr. Partridge is professor of medicine at Harvard Medical School and vice chair of clinical oncology at Dana-Farber Cancer Institute, both in Boston. Dr. Pagani reported conflicts of interest with PRIME, Roche, Eli Lilly, Novartis, Takeda, Pfizer, and Debiopharm. Dr. Partridge reported no conflicts of interest.
 

A version of this article first appeared on Medscape.com.

New national data on the occurrence of triple-negative breast cancer (TNBC) among different racial groups confirms that the disease is more common among Black women nationwide. A state-by-state analysis in the study, published online  in JAMA Oncology, shows that these trends persist at the state level.

The analysis revealed that incidence rate ratios of TNBC were significantly higher among Black women, compared with White women, in all states with data on this population. Rates ranged from a low of 1.38 in Colorado to a high of 2.32 in Delaware.

The state-level disparities highlight gaps in physicians’ understanding of how social factors contribute to disparities in TNBC risk and the need “to develop effective preventative measures,” the study authors explain.

“We’ve realized for a long time that Black women have a higher incidence of TNBC. This is related to the genetic signature of the cancer. So that is not at all surprising,” said Arnold M. Baskies, MD, past chairman of the national board of directors of the American Cancer Society, Atlanta, who was not involved in the research. However, “the variance of TNBC among women from state to state is somewhat surprising.”

Existing research shows that TNBC is diagnosed more frequently among non-Hispanic Black women than among other populations in the United States, but it’s unclear whether these racial and ethnic disparities differ at the state level.

The authors identified 133,579 women with TNBC from the U.S. Cancer Statistics Public Use Research Database whose conditions were diagnosed from January 2015 through the end of December 2019. Most patients (64.5%) were White, 21.5% were Black, nearly 10% were Hispanic, 3.7% were Asian or Pacific Islander, and 0.6% were American Indian or Alaska Native. States with fewer than 30 cases were excluded, as was Nevada, owing to concerns regarding data quality. That left eight states for American Indian or Alaska Natives, 22 for Asian or Pacific Islanders, 35 for Hispanic women, 38 for Black women, and 50 for White women.

Overall, the incidence ratios of TNBC were highest among Black women (IR, 25.2 per 100,000), followed by White women (IR, 12.9 per 100,000), American Indian or Alaska Native women (IR, 11.2 per 100,000), Hispanic women (IR, 11.1 per 100,000 women), and Asian or Pacific Islander (IR, 9.0 per 100,000) women.

The authors also uncovered significant state-by-state variations in TNBC incidence by racial and ethnic groups. The lowest IR rates occurred among Asian or Pacific Islander women in Oregon and Pennsylvania – fewer than 7 per 100,000 women – and the highest occurred among Black women in Delaware, Missouri, Louisiana, and Mississippi – more than 29 per 100,000 women.

In the 38 states for which data on Black women were available, IR rates were significantly higher among Black women in all 38, compared with White women. The IR rates ranged from a low of 1.38 (IR, 17.4 per 100 000 women) in Colorado to a high of 2.32 (IR, 32.0 per 100 000 women) in Delaware.

While genetics play a role in TNBC risk, “the substantial geographic variation we found within each racial and ethnic group is highly suggestive that there are structural, environmental, and social factors at play in determining women’s risk of TNBC,” said lead study author Hyuna Sung, PhD, senior principal scientist and cancer epidemiologist at the American Cancer Society, Atlanta.

Existing evidence indicates that Black and White women living in socioeconomically disadvantaged neighborhoods are at higher risk of developing more aggressive subtypes of breast cancer, Dr. Sung said. Another factor, Dr. Sung and co-authors note, is breastfeeding. Across races, women who breastfeed have lower rates of TNBC.

Getting more definitive answers as to what causes differences in TNBC rates across states and what strategies can help reduce these disparities will be difficult and requires more research. “We really need to do a better job at researching and treating TNBC to improve health care equality for all women,” Dr. Baskies said. “The mortality rates from this cancer are high, and we rely heavily on surgery and toxic chemotherapy to treat it.”

Dr. Sung agreed, noting that “the observed state variation in TNBC rates merits further studies with risk factor data at multiple levels to better understand the associations of social exposures with the risk of TNBC.”

In states such as Louisiana and Mississippi, which are known to have a disproportionately higher burden of many types of cancers, “addressing barriers to access to preventive care and empowering public health efforts to promote a healthy living environment are the best policy prescription that could be deduced from our results,” Dr. Sung concluded.

Dr. Baskies is on the board of directors of Anixa Biosciences, which is currently conducting a clinical trial of a TNBC vaccine at the Cleveland Clinic. Dr. Sung has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New national data on the occurrence of triple-negative breast cancer (TNBC) among different racial groups confirms that the disease is more common among Black women nationwide. A state-by-state analysis in the study, published online  in JAMA Oncology, shows that these trends persist at the state level.

The analysis revealed that incidence rate ratios of TNBC were significantly higher among Black women, compared with White women, in all states with data on this population. Rates ranged from a low of 1.38 in Colorado to a high of 2.32 in Delaware.

The state-level disparities highlight gaps in physicians’ understanding of how social factors contribute to disparities in TNBC risk and the need “to develop effective preventative measures,” the study authors explain.

“We’ve realized for a long time that Black women have a higher incidence of TNBC. This is related to the genetic signature of the cancer. So that is not at all surprising,” said Arnold M. Baskies, MD, past chairman of the national board of directors of the American Cancer Society, Atlanta, who was not involved in the research. However, “the variance of TNBC among women from state to state is somewhat surprising.”

Existing research shows that TNBC is diagnosed more frequently among non-Hispanic Black women than among other populations in the United States, but it’s unclear whether these racial and ethnic disparities differ at the state level.

The authors identified 133,579 women with TNBC from the U.S. Cancer Statistics Public Use Research Database whose conditions were diagnosed from January 2015 through the end of December 2019. Most patients (64.5%) were White, 21.5% were Black, nearly 10% were Hispanic, 3.7% were Asian or Pacific Islander, and 0.6% were American Indian or Alaska Native. States with fewer than 30 cases were excluded, as was Nevada, owing to concerns regarding data quality. That left eight states for American Indian or Alaska Natives, 22 for Asian or Pacific Islanders, 35 for Hispanic women, 38 for Black women, and 50 for White women.

Overall, the incidence ratios of TNBC were highest among Black women (IR, 25.2 per 100,000), followed by White women (IR, 12.9 per 100,000), American Indian or Alaska Native women (IR, 11.2 per 100,000), Hispanic women (IR, 11.1 per 100,000 women), and Asian or Pacific Islander (IR, 9.0 per 100,000) women.

The authors also uncovered significant state-by-state variations in TNBC incidence by racial and ethnic groups. The lowest IR rates occurred among Asian or Pacific Islander women in Oregon and Pennsylvania – fewer than 7 per 100,000 women – and the highest occurred among Black women in Delaware, Missouri, Louisiana, and Mississippi – more than 29 per 100,000 women.

In the 38 states for which data on Black women were available, IR rates were significantly higher among Black women in all 38, compared with White women. The IR rates ranged from a low of 1.38 (IR, 17.4 per 100 000 women) in Colorado to a high of 2.32 (IR, 32.0 per 100 000 women) in Delaware.

While genetics play a role in TNBC risk, “the substantial geographic variation we found within each racial and ethnic group is highly suggestive that there are structural, environmental, and social factors at play in determining women’s risk of TNBC,” said lead study author Hyuna Sung, PhD, senior principal scientist and cancer epidemiologist at the American Cancer Society, Atlanta.

Existing evidence indicates that Black and White women living in socioeconomically disadvantaged neighborhoods are at higher risk of developing more aggressive subtypes of breast cancer, Dr. Sung said. Another factor, Dr. Sung and co-authors note, is breastfeeding. Across races, women who breastfeed have lower rates of TNBC.

Getting more definitive answers as to what causes differences in TNBC rates across states and what strategies can help reduce these disparities will be difficult and requires more research. “We really need to do a better job at researching and treating TNBC to improve health care equality for all women,” Dr. Baskies said. “The mortality rates from this cancer are high, and we rely heavily on surgery and toxic chemotherapy to treat it.”

Dr. Sung agreed, noting that “the observed state variation in TNBC rates merits further studies with risk factor data at multiple levels to better understand the associations of social exposures with the risk of TNBC.”

In states such as Louisiana and Mississippi, which are known to have a disproportionately higher burden of many types of cancers, “addressing barriers to access to preventive care and empowering public health efforts to promote a healthy living environment are the best policy prescription that could be deduced from our results,” Dr. Sung concluded.

Dr. Baskies is on the board of directors of Anixa Biosciences, which is currently conducting a clinical trial of a TNBC vaccine at the Cleveland Clinic. Dr. Sung has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New national data on the occurrence of triple-negative breast cancer (TNBC) among different racial groups confirms that the disease is more common among Black women nationwide. A state-by-state analysis in the study, published online  in JAMA Oncology, shows that these trends persist at the state level.

The analysis revealed that incidence rate ratios of TNBC were significantly higher among Black women, compared with White women, in all states with data on this population. Rates ranged from a low of 1.38 in Colorado to a high of 2.32 in Delaware.

The state-level disparities highlight gaps in physicians’ understanding of how social factors contribute to disparities in TNBC risk and the need “to develop effective preventative measures,” the study authors explain.

“We’ve realized for a long time that Black women have a higher incidence of TNBC. This is related to the genetic signature of the cancer. So that is not at all surprising,” said Arnold M. Baskies, MD, past chairman of the national board of directors of the American Cancer Society, Atlanta, who was not involved in the research. However, “the variance of TNBC among women from state to state is somewhat surprising.”

Existing research shows that TNBC is diagnosed more frequently among non-Hispanic Black women than among other populations in the United States, but it’s unclear whether these racial and ethnic disparities differ at the state level.

The authors identified 133,579 women with TNBC from the U.S. Cancer Statistics Public Use Research Database whose conditions were diagnosed from January 2015 through the end of December 2019. Most patients (64.5%) were White, 21.5% were Black, nearly 10% were Hispanic, 3.7% were Asian or Pacific Islander, and 0.6% were American Indian or Alaska Native. States with fewer than 30 cases were excluded, as was Nevada, owing to concerns regarding data quality. That left eight states for American Indian or Alaska Natives, 22 for Asian or Pacific Islanders, 35 for Hispanic women, 38 for Black women, and 50 for White women.

Overall, the incidence ratios of TNBC were highest among Black women (IR, 25.2 per 100,000), followed by White women (IR, 12.9 per 100,000), American Indian or Alaska Native women (IR, 11.2 per 100,000), Hispanic women (IR, 11.1 per 100,000 women), and Asian or Pacific Islander (IR, 9.0 per 100,000) women.

The authors also uncovered significant state-by-state variations in TNBC incidence by racial and ethnic groups. The lowest IR rates occurred among Asian or Pacific Islander women in Oregon and Pennsylvania – fewer than 7 per 100,000 women – and the highest occurred among Black women in Delaware, Missouri, Louisiana, and Mississippi – more than 29 per 100,000 women.

In the 38 states for which data on Black women were available, IR rates were significantly higher among Black women in all 38, compared with White women. The IR rates ranged from a low of 1.38 (IR, 17.4 per 100 000 women) in Colorado to a high of 2.32 (IR, 32.0 per 100 000 women) in Delaware.

While genetics play a role in TNBC risk, “the substantial geographic variation we found within each racial and ethnic group is highly suggestive that there are structural, environmental, and social factors at play in determining women’s risk of TNBC,” said lead study author Hyuna Sung, PhD, senior principal scientist and cancer epidemiologist at the American Cancer Society, Atlanta.

Existing evidence indicates that Black and White women living in socioeconomically disadvantaged neighborhoods are at higher risk of developing more aggressive subtypes of breast cancer, Dr. Sung said. Another factor, Dr. Sung and co-authors note, is breastfeeding. Across races, women who breastfeed have lower rates of TNBC.

Getting more definitive answers as to what causes differences in TNBC rates across states and what strategies can help reduce these disparities will be difficult and requires more research. “We really need to do a better job at researching and treating TNBC to improve health care equality for all women,” Dr. Baskies said. “The mortality rates from this cancer are high, and we rely heavily on surgery and toxic chemotherapy to treat it.”

Dr. Sung agreed, noting that “the observed state variation in TNBC rates merits further studies with risk factor data at multiple levels to better understand the associations of social exposures with the risk of TNBC.”

In states such as Louisiana and Mississippi, which are known to have a disproportionately higher burden of many types of cancers, “addressing barriers to access to preventive care and empowering public health efforts to promote a healthy living environment are the best policy prescription that could be deduced from our results,” Dr. Sung concluded.

Dr. Baskies is on the board of directors of Anixa Biosciences, which is currently conducting a clinical trial of a TNBC vaccine at the Cleveland Clinic. Dr. Sung has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Although breast cancer occurs less frequently in Black women, compared with White women, they have a much higher risk of dying from the disease.

In the United States, age-adjusted breast cancer mortality between 2014 and 2018 was approximately 40% higher among Black women than among non-Hispanic White women.

This mortality gap likely reflects the fact that Black women face substantial barriers to obtaining timely, high-quality medical care, compared with White women, lead author Ismail Jatoi, MD, PhD, University of Texas Health Science Center, San Antonio, and colleagues suggest in a recent opinion piece.

The article was published online  in The New England Journal of Medicine.

When the team examined the statistics for breast cancer mortality, they found a surprise: The mortality gap between races only dates back to 1980.

Prior to 1980, mortality from breast cancer among Black women was slightly lower than White women, Dr. Jatoi and colleagues point out.

That year was a turning point in breast cancer management, as in 1980, both mammography screening and adjuvant endocrine therapy became available.

This was also when the mortality gap between the races started to show up.

It was disparities in access to the two new interventions that precipitated the divergence, as the authors suggest. Why this occurred is fairly self-evident, they comment.

“Black women are more likely than White women to lack health insurance or to have inadequate coverage, which has limited their access to mammography screening and adversely affected therapeutic decisionmaking,” researchers point out.

Moreover, both mammography screening and endocrine therapy primarily benefit patients with hormone receptor (HR)-positive breast cancer, which is equally common in Black and White patients. However, Black women have a 65% higher rate of HR-negative cancers than White women – and HR-negative tumors are often detected during the interval between mammography screening exams as palpable cancers.

Black women also have an 81% higher rate of triple-negative breast cancer, so they have benefited less from mammography screening and adjuvant endocrine therapy, both of which favor the detection and treatment of HR-positive breast cancer, the authors emphasize.

Some have suggested that the excess HR-negative breast cancer in Black women might be explained by hereditary factors. Yet as Dr. Jatoi and colleagues point out, the incidence of HR-negative breast cancer has actually been falling across all races in the United States since 1992.

However, the declines have been slower among Black women, and reductions in its incidence have been smaller among White women living in less affluent regions of the United States compared with White women from more affluent regions.

These patterns suggest that social determinants of health influence not only access to and quality of health care but also the development of HR-negative breast cancers, as the authors observe.

“If all people with breast cancer benefited equally from effective medical interventions, racial differences in mortality for individual tumor subtypes would largely reflect differences in incidence,” Dr. Jatoi and colleagues continue.

Yet the statistics show that the substantial racial disparities in mortality for both HR-positive and HR-negative cancers between Black and White women cannot be explained by differences in the incidence of either tumor alone, they write.

For example, mortality for HR-positive breast cancer is 19% higher among Black women than among White women, yet the incidence of HR-positive breast cancer is 22% lower among Black women.

Similarly, mortality from HR-negative breast cancer is over twice as high among Black women as it is among White women – a substantially larger disparity, compared with the 65% relative difference in the incidence of HR-negative breast cancer between the two races.

“Universal health care coverage could reduce disparities in treatment for cancers of all subtypes, including triple-negative breast cancer,” Dr. Jatoi and colleagues emphasize.

“Ensuring universal access to high-quality medical care can substantially narrow the racial disparity in U.S. breast-cancer mortality,” they conclude. 

The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Although breast cancer occurs less frequently in Black women, compared with White women, they have a much higher risk of dying from the disease.

In the United States, age-adjusted breast cancer mortality between 2014 and 2018 was approximately 40% higher among Black women than among non-Hispanic White women.

This mortality gap likely reflects the fact that Black women face substantial barriers to obtaining timely, high-quality medical care, compared with White women, lead author Ismail Jatoi, MD, PhD, University of Texas Health Science Center, San Antonio, and colleagues suggest in a recent opinion piece.

The article was published online  in The New England Journal of Medicine.

When the team examined the statistics for breast cancer mortality, they found a surprise: The mortality gap between races only dates back to 1980.

Prior to 1980, mortality from breast cancer among Black women was slightly lower than White women, Dr. Jatoi and colleagues point out.

That year was a turning point in breast cancer management, as in 1980, both mammography screening and adjuvant endocrine therapy became available.

This was also when the mortality gap between the races started to show up.

It was disparities in access to the two new interventions that precipitated the divergence, as the authors suggest. Why this occurred is fairly self-evident, they comment.

“Black women are more likely than White women to lack health insurance or to have inadequate coverage, which has limited their access to mammography screening and adversely affected therapeutic decisionmaking,” researchers point out.

Moreover, both mammography screening and endocrine therapy primarily benefit patients with hormone receptor (HR)-positive breast cancer, which is equally common in Black and White patients. However, Black women have a 65% higher rate of HR-negative cancers than White women – and HR-negative tumors are often detected during the interval between mammography screening exams as palpable cancers.

Black women also have an 81% higher rate of triple-negative breast cancer, so they have benefited less from mammography screening and adjuvant endocrine therapy, both of which favor the detection and treatment of HR-positive breast cancer, the authors emphasize.

Some have suggested that the excess HR-negative breast cancer in Black women might be explained by hereditary factors. Yet as Dr. Jatoi and colleagues point out, the incidence of HR-negative breast cancer has actually been falling across all races in the United States since 1992.

However, the declines have been slower among Black women, and reductions in its incidence have been smaller among White women living in less affluent regions of the United States compared with White women from more affluent regions.

These patterns suggest that social determinants of health influence not only access to and quality of health care but also the development of HR-negative breast cancers, as the authors observe.

“If all people with breast cancer benefited equally from effective medical interventions, racial differences in mortality for individual tumor subtypes would largely reflect differences in incidence,” Dr. Jatoi and colleagues continue.

Yet the statistics show that the substantial racial disparities in mortality for both HR-positive and HR-negative cancers between Black and White women cannot be explained by differences in the incidence of either tumor alone, they write.

For example, mortality for HR-positive breast cancer is 19% higher among Black women than among White women, yet the incidence of HR-positive breast cancer is 22% lower among Black women.

Similarly, mortality from HR-negative breast cancer is over twice as high among Black women as it is among White women – a substantially larger disparity, compared with the 65% relative difference in the incidence of HR-negative breast cancer between the two races.

“Universal health care coverage could reduce disparities in treatment for cancers of all subtypes, including triple-negative breast cancer,” Dr. Jatoi and colleagues emphasize.

“Ensuring universal access to high-quality medical care can substantially narrow the racial disparity in U.S. breast-cancer mortality,” they conclude. 

The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Although breast cancer occurs less frequently in Black women, compared with White women, they have a much higher risk of dying from the disease.

In the United States, age-adjusted breast cancer mortality between 2014 and 2018 was approximately 40% higher among Black women than among non-Hispanic White women.

This mortality gap likely reflects the fact that Black women face substantial barriers to obtaining timely, high-quality medical care, compared with White women, lead author Ismail Jatoi, MD, PhD, University of Texas Health Science Center, San Antonio, and colleagues suggest in a recent opinion piece.

The article was published online  in The New England Journal of Medicine.

When the team examined the statistics for breast cancer mortality, they found a surprise: The mortality gap between races only dates back to 1980.

Prior to 1980, mortality from breast cancer among Black women was slightly lower than White women, Dr. Jatoi and colleagues point out.

That year was a turning point in breast cancer management, as in 1980, both mammography screening and adjuvant endocrine therapy became available.

This was also when the mortality gap between the races started to show up.

It was disparities in access to the two new interventions that precipitated the divergence, as the authors suggest. Why this occurred is fairly self-evident, they comment.

“Black women are more likely than White women to lack health insurance or to have inadequate coverage, which has limited their access to mammography screening and adversely affected therapeutic decisionmaking,” researchers point out.

Moreover, both mammography screening and endocrine therapy primarily benefit patients with hormone receptor (HR)-positive breast cancer, which is equally common in Black and White patients. However, Black women have a 65% higher rate of HR-negative cancers than White women – and HR-negative tumors are often detected during the interval between mammography screening exams as palpable cancers.

Black women also have an 81% higher rate of triple-negative breast cancer, so they have benefited less from mammography screening and adjuvant endocrine therapy, both of which favor the detection and treatment of HR-positive breast cancer, the authors emphasize.

Some have suggested that the excess HR-negative breast cancer in Black women might be explained by hereditary factors. Yet as Dr. Jatoi and colleagues point out, the incidence of HR-negative breast cancer has actually been falling across all races in the United States since 1992.

However, the declines have been slower among Black women, and reductions in its incidence have been smaller among White women living in less affluent regions of the United States compared with White women from more affluent regions.

These patterns suggest that social determinants of health influence not only access to and quality of health care but also the development of HR-negative breast cancers, as the authors observe.

“If all people with breast cancer benefited equally from effective medical interventions, racial differences in mortality for individual tumor subtypes would largely reflect differences in incidence,” Dr. Jatoi and colleagues continue.

Yet the statistics show that the substantial racial disparities in mortality for both HR-positive and HR-negative cancers between Black and White women cannot be explained by differences in the incidence of either tumor alone, they write.

For example, mortality for HR-positive breast cancer is 19% higher among Black women than among White women, yet the incidence of HR-positive breast cancer is 22% lower among Black women.

Similarly, mortality from HR-negative breast cancer is over twice as high among Black women as it is among White women – a substantially larger disparity, compared with the 65% relative difference in the incidence of HR-negative breast cancer between the two races.

“Universal health care coverage could reduce disparities in treatment for cancers of all subtypes, including triple-negative breast cancer,” Dr. Jatoi and colleagues emphasize.

“Ensuring universal access to high-quality medical care can substantially narrow the racial disparity in U.S. breast-cancer mortality,” they conclude. 

The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Breast cancer has replaced lung cancer as the leading cause of cancer-related death among Black women, but lung cancer remains the leading cause of cancer death in Black men, according to a new report from the American Cancer Society (ACS).

Lung cancer remains the second most commonly diagnosed cancer in both Black women and Black men.

These are among the key findings of the report, Cancer Statistics for African American/Black People 2022 – a triannual compilation of U.S. data on cancer incidence, mortality, survival, screening, and risk factors for Black people – and it marks a major shift as of 2019.

“African American/Black people have a disproportionately high cancer burden compared to other population groups. According to the report, the risk of cancer death for Black individuals remains 19% higher for men and 12% higher for women compared to White individuals,” the ACS says in a statement.

“The gap for breast cancer is more alarming,” it adds. “Black women are 41% more likely to die from breast cancer than White women despite a lower risk of being diagnosed with the disease.”

The new report, published online on Feb. 10 in CA: A Cancer Journal for Clinicians, also notes the following:

An estimated 224,080 new cancer cases and 73,680 cancer deaths will occur among Black people in 2022.

Over the past 5 data years, Black women had an 8% lower overall cancer incidence than White women but 12% higher mortality; Black men have 6% higher cancer incidence than White men but 19% higher cancer mortality.

Prostate cancer mortality among Black men decreased by 1.3% per year from 2015 to 2019 despite a 5% increase in the diagnosis of distant-stage prostate cancer annually since 2012, but the decline was slower than the 5% per year decline from 2010 to 2014.

The overall cancer mortality gap between Black and White people is narrowing. This is due to a steeper drop in prostate, lung, and other smoking-related cancers among Black people.

Colorectal cancer incidence and mortality rates are 21% and 44% higher, respectively, in Black men in comparison with White men and 18% and 31% higher, respectively, in Black women in comparison with White women.

The reasons for the disparities are complex but “largely stem from less access to high-quality care and optimal treatment as a repercussion of long-standing institutional racism,” the report concludes.

“We must address structural racism as a public health issue to close the gaps and advance health equity,” Tawana Thomas-Johnson, senior vice president and chief diversity officer at the ACS, said in the press release.

A version of this article first appeared on Medscape.com.

Breast cancer has replaced lung cancer as the leading cause of cancer-related death among Black women, but lung cancer remains the leading cause of cancer death in Black men, according to a new report from the American Cancer Society (ACS).

Lung cancer remains the second most commonly diagnosed cancer in both Black women and Black men.

These are among the key findings of the report, Cancer Statistics for African American/Black People 2022 – a triannual compilation of U.S. data on cancer incidence, mortality, survival, screening, and risk factors for Black people – and it marks a major shift as of 2019.

“African American/Black people have a disproportionately high cancer burden compared to other population groups. According to the report, the risk of cancer death for Black individuals remains 19% higher for men and 12% higher for women compared to White individuals,” the ACS says in a statement.

“The gap for breast cancer is more alarming,” it adds. “Black women are 41% more likely to die from breast cancer than White women despite a lower risk of being diagnosed with the disease.”

The new report, published online on Feb. 10 in CA: A Cancer Journal for Clinicians, also notes the following:

An estimated 224,080 new cancer cases and 73,680 cancer deaths will occur among Black people in 2022.

Over the past 5 data years, Black women had an 8% lower overall cancer incidence than White women but 12% higher mortality; Black men have 6% higher cancer incidence than White men but 19% higher cancer mortality.

Prostate cancer mortality among Black men decreased by 1.3% per year from 2015 to 2019 despite a 5% increase in the diagnosis of distant-stage prostate cancer annually since 2012, but the decline was slower than the 5% per year decline from 2010 to 2014.

The overall cancer mortality gap between Black and White people is narrowing. This is due to a steeper drop in prostate, lung, and other smoking-related cancers among Black people.

Colorectal cancer incidence and mortality rates are 21% and 44% higher, respectively, in Black men in comparison with White men and 18% and 31% higher, respectively, in Black women in comparison with White women.

The reasons for the disparities are complex but “largely stem from less access to high-quality care and optimal treatment as a repercussion of long-standing institutional racism,” the report concludes.

“We must address structural racism as a public health issue to close the gaps and advance health equity,” Tawana Thomas-Johnson, senior vice president and chief diversity officer at the ACS, said in the press release.

A version of this article first appeared on Medscape.com.

Breast cancer has replaced lung cancer as the leading cause of cancer-related death among Black women, but lung cancer remains the leading cause of cancer death in Black men, according to a new report from the American Cancer Society (ACS).

Lung cancer remains the second most commonly diagnosed cancer in both Black women and Black men.

These are among the key findings of the report, Cancer Statistics for African American/Black People 2022 – a triannual compilation of U.S. data on cancer incidence, mortality, survival, screening, and risk factors for Black people – and it marks a major shift as of 2019.

“African American/Black people have a disproportionately high cancer burden compared to other population groups. According to the report, the risk of cancer death for Black individuals remains 19% higher for men and 12% higher for women compared to White individuals,” the ACS says in a statement.

“The gap for breast cancer is more alarming,” it adds. “Black women are 41% more likely to die from breast cancer than White women despite a lower risk of being diagnosed with the disease.”

The new report, published online on Feb. 10 in CA: A Cancer Journal for Clinicians, also notes the following:

An estimated 224,080 new cancer cases and 73,680 cancer deaths will occur among Black people in 2022.

Over the past 5 data years, Black women had an 8% lower overall cancer incidence than White women but 12% higher mortality; Black men have 6% higher cancer incidence than White men but 19% higher cancer mortality.

Prostate cancer mortality among Black men decreased by 1.3% per year from 2015 to 2019 despite a 5% increase in the diagnosis of distant-stage prostate cancer annually since 2012, but the decline was slower than the 5% per year decline from 2010 to 2014.

The overall cancer mortality gap between Black and White people is narrowing. This is due to a steeper drop in prostate, lung, and other smoking-related cancers among Black people.

Colorectal cancer incidence and mortality rates are 21% and 44% higher, respectively, in Black men in comparison with White men and 18% and 31% higher, respectively, in Black women in comparison with White women.

The reasons for the disparities are complex but “largely stem from less access to high-quality care and optimal treatment as a repercussion of long-standing institutional racism,” the report concludes.

“We must address structural racism as a public health issue to close the gaps and advance health equity,” Tawana Thomas-Johnson, senior vice president and chief diversity officer at the ACS, said in the press release.

A version of this article first appeared on Medscape.com.

Recalls and false-positives for breast imaging patients were significantly more likely when the results were read by less-experienced radiologists who had worked more hours that day, based on data from more than 97,000 screening mammograms.

Psychology literature has shown the impact of fatigue on performance in a range of settings, and previous studies have shown that radiologists’ performances are more accurate earlier in their shifts compared to later-shift performance, write Michael H. Bernstein, PhD, and colleagues at Brown University, Providence, R.I., in a study published online Jan. 11 in Radiology.

The effect of time of day on performance may be greater for more detailed imaging modalities that are more “cognitively taxing,” and the effect may be greater in less-experienced radiologists, but the impact of time and experience on overall patient recall and false-positive rates has not been well-studied, the researchers said.

In the retrospective review, the researchers identified 97,671 screening mammograms read by 18 radiologists at one of 12 community sites between Jan. 2018 and Dec. 2019. The researchers analyzed the results by type of image, either standard digital mammography (DM) or the more complex digital breast tomosynthesis (DBT). The researchers separated radiologists into two groups: those with at least 5 post-training years of experience and those with less than 5 post-training years of experience. A total of nine radiologists fell into each category.

Overall, the recall rates were significantly different and higher for DM versus DBT (10.2% vs. 9.0%; P = .006). The false-positive (FP) rate also differed significantly and was higher for DM versus DBT (9.8% vs. 8.6%; P = .004).

The odds of recall increased by 11.5% with each hour of reading time for radiologists with less than 5 post-training years of experience for both DBT (odds ratio, 1.12) and DM (OR, 1.09). For the more experienced radiologists, the odds of recall increased by 1.6% for each hour of reading time for DBT but decreased by 0.1% for DM, with no significant difference.

Similarly, the odds of an FP result increased by 12.1% for DBT and 9% for DM per hour of reading time for radiologists with less experience. For more experienced radiologists, the odds of an FP increased by 1.6% for DBT but decreased by 1.1% for DM per hour of reading time.

Cancer detection (defined as true-positive, or TP) was not higher for DM across time, the researchers note. However, “DBT achieved a higher TP rate than DM regardless of the time of day; this shows that for DBT to maintain a constant and superior TP rate relative to DM, radiologists’ FP rates had to go up as the day went on,” they write. “That is, although DBT achieves a superior TP rate, more junior radiologists appeared to compensate for their fatigue later in the day when using DBT by recalling a broader range of mammograms, more of which were FP findings.”

The researchers caution that their findings were limited by several factors, including the study’s retrospective design and the lack of randomization of the imaging technology, patients, and time of day, which prohibit conclusions regarding causality. Other limitations included the consideration of time of day without the ability to use hours since the start of a clinical shift and the use of a 5-year mark to indicate experience without accounting for work volume.

However, the stronger impact of a time-of-day effect for more junior radiologists agrees with findings from other studies, the researchers add. More empirical research is needed, and the researchers propose a longitudinal study of how time of day affects radiologists as they gain experience, as well as experimental studies to test strategies for mitigating the time-of-day effect observed in the current study.
 

Scheduled breaks may reduce impact of fatigue

“Digital breast tomosynthesis is increasingly used in clinical practice and takes significantly longer to interpret compared with digital mammography,” said corresponding author Ana P. Lourenco, MD, in an interview. “Radiologists interpret hundreds of images for each screening digital breast tomosynthesis exam, compared with four images for each screening digital mammogram exam; this may certainly contribute to radiologist fatigue.”

“I found it interesting that there was a difference based on years of experience of the radiologist, but I was not surprised that recall rate increased later in the day, as some of us had anecdotally noted this in our clinical practice,” Dr. Lourenco said. In fact, the idea to conduct the study was prompted by a conversation with her statistician colleagues “about how I subjectively felt like my own recall rate increased at the end of the day.”

Ways to counteract the impact of fatigue could include intermittent breaks to refocus attention, said Dr. Lourenco. “Potential barriers would include imaging volumes and attending to patients in the breast imaging center,” she said. “If we can show that decreasing fatigue improves mammography performance metrics, then this may encourage practices to support such interventions.”

However, “more research that includes a larger number of radiologists, wider range of imaging interpretation experience, perhaps even experimental studies comparing metrics for radiologists reading with scheduled breaks versus without such breaks would be of interest,” Dr. Lourenco said.
 

Fatigue in health care goes beyond radiology

“Due primarily to staffing shortages and increased volume and complexity of patients, burnout and fatigue of all medical personnel, not just physicians, have become hallmarks of modern health care delivery in the United States, and this has been exacerbated by COVID-19 and other societal factors,” said Jeffrey C. Weinreb, MD, professor of radiology and biomedical imaging at Yale University, New Haven, Conn., in an interview.

Previous studies have documented the fact that radiologists are among the specialists most affected by burnout and fatigue, and it has an impact on their performance, Dr. Weinreb said. The current study is important because it tries to pinpoint the key variables that are responsible for fatigue, so resources can be directed to effect change, he said.

Dr. Weinreb said he was not particularly surprised by the study findings. “Diagnostic mammography is a high-volume repetitive enterprise, so it would have been surprising if radiologist experience and time of day had no effect on performance and recall rate,” he said. “As most radiologists will attest based on personal experience, human beings get tired and lose some level of cognition over the course of a long, intense workday,” he added.

“I am a bit surprised that less experienced radiologists were more likely to recommend additional imaging at a higher rate when interpreting DBT but not for DM and only later in the day,” Dr. Weinreb noted. “The authors suggest that this could be due to the increased number of images that are viewed with DBT and the different ways experienced and less experienced radiologists process the information. However, there could be other explanations, such as differences in volumes or differences in ages.”

“Reducing the study volumes per radiologist is one obvious solution to reducing fatigue, but it will not be practical in many practices,” said Dr. Weinreb. “The important work of interpreting diagnostic mammograms needs to continue and grow. Without an increase in radiologist mammographers in the labor pool, this is not going to happen any time soon.”

Instead, “more immediate obvious solutions to radiologist fatigue in clinical practice include more frequent breaks during the workday, which would include walking around and not looking at a computer or cell phone screen, fewer images per study, report templates, streamlined workflow, more variety in daily work, and AI assistance for interpretation and reporting,” said Dr. Weinreb. Using nonradiologists when possible to relieve some of the burden could be considered, “but this is a complex and politically charged issue,” he noted.

Radiology is a well-compensated specialty, but further increasing compensation would help to mitigate burnout, said Dr. Weinreb. However, “perhaps even more important is making certain that the efforts of individual radiologists are appreciated and recognized,” he said.

As for additional research needs, “mammographers are not the only radiologists experiencing fatigue, but the most critical contributing factors for other types of imaging exams and subspecialities may not be identical,” Dr. Weinreb emphasized. “Data for other radiologists, similar to that provided by this study for diagnostic mammography, could be useful.

“An additional area of research could address the issue of individual radiologist circadian rhythms,” said Dr. Weinreb. “Perhaps we could rigorously determine whom amongst us is a ‘morning person’ versus one who performs equally well or better later in the day and use this information for radiologist scheduling,” he said. “Finally, once we know the key factors affecting performance for each type of exam and subspecialty, studies of possible incremental and combined benefits of various interventions would be needed.”

The study received no outside funding. The researchers and Dr. Weinreb have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Recalls and false-positives for breast imaging patients were significantly more likely when the results were read by less-experienced radiologists who had worked more hours that day, based on data from more than 97,000 screening mammograms.

Psychology literature has shown the impact of fatigue on performance in a range of settings, and previous studies have shown that radiologists’ performances are more accurate earlier in their shifts compared to later-shift performance, write Michael H. Bernstein, PhD, and colleagues at Brown University, Providence, R.I., in a study published online Jan. 11 in Radiology.

The effect of time of day on performance may be greater for more detailed imaging modalities that are more “cognitively taxing,” and the effect may be greater in less-experienced radiologists, but the impact of time and experience on overall patient recall and false-positive rates has not been well-studied, the researchers said.

In the retrospective review, the researchers identified 97,671 screening mammograms read by 18 radiologists at one of 12 community sites between Jan. 2018 and Dec. 2019. The researchers analyzed the results by type of image, either standard digital mammography (DM) or the more complex digital breast tomosynthesis (DBT). The researchers separated radiologists into two groups: those with at least 5 post-training years of experience and those with less than 5 post-training years of experience. A total of nine radiologists fell into each category.

Overall, the recall rates were significantly different and higher for DM versus DBT (10.2% vs. 9.0%; P = .006). The false-positive (FP) rate also differed significantly and was higher for DM versus DBT (9.8% vs. 8.6%; P = .004).

The odds of recall increased by 11.5% with each hour of reading time for radiologists with less than 5 post-training years of experience for both DBT (odds ratio, 1.12) and DM (OR, 1.09). For the more experienced radiologists, the odds of recall increased by 1.6% for each hour of reading time for DBT but decreased by 0.1% for DM, with no significant difference.

Similarly, the odds of an FP result increased by 12.1% for DBT and 9% for DM per hour of reading time for radiologists with less experience. For more experienced radiologists, the odds of an FP increased by 1.6% for DBT but decreased by 1.1% for DM per hour of reading time.

Cancer detection (defined as true-positive, or TP) was not higher for DM across time, the researchers note. However, “DBT achieved a higher TP rate than DM regardless of the time of day; this shows that for DBT to maintain a constant and superior TP rate relative to DM, radiologists’ FP rates had to go up as the day went on,” they write. “That is, although DBT achieves a superior TP rate, more junior radiologists appeared to compensate for their fatigue later in the day when using DBT by recalling a broader range of mammograms, more of which were FP findings.”

The researchers caution that their findings were limited by several factors, including the study’s retrospective design and the lack of randomization of the imaging technology, patients, and time of day, which prohibit conclusions regarding causality. Other limitations included the consideration of time of day without the ability to use hours since the start of a clinical shift and the use of a 5-year mark to indicate experience without accounting for work volume.

However, the stronger impact of a time-of-day effect for more junior radiologists agrees with findings from other studies, the researchers add. More empirical research is needed, and the researchers propose a longitudinal study of how time of day affects radiologists as they gain experience, as well as experimental studies to test strategies for mitigating the time-of-day effect observed in the current study.
 

Scheduled breaks may reduce impact of fatigue

“Digital breast tomosynthesis is increasingly used in clinical practice and takes significantly longer to interpret compared with digital mammography,” said corresponding author Ana P. Lourenco, MD, in an interview. “Radiologists interpret hundreds of images for each screening digital breast tomosynthesis exam, compared with four images for each screening digital mammogram exam; this may certainly contribute to radiologist fatigue.”

“I found it interesting that there was a difference based on years of experience of the radiologist, but I was not surprised that recall rate increased later in the day, as some of us had anecdotally noted this in our clinical practice,” Dr. Lourenco said. In fact, the idea to conduct the study was prompted by a conversation with her statistician colleagues “about how I subjectively felt like my own recall rate increased at the end of the day.”

Ways to counteract the impact of fatigue could include intermittent breaks to refocus attention, said Dr. Lourenco. “Potential barriers would include imaging volumes and attending to patients in the breast imaging center,” she said. “If we can show that decreasing fatigue improves mammography performance metrics, then this may encourage practices to support such interventions.”

However, “more research that includes a larger number of radiologists, wider range of imaging interpretation experience, perhaps even experimental studies comparing metrics for radiologists reading with scheduled breaks versus without such breaks would be of interest,” Dr. Lourenco said.
 

Fatigue in health care goes beyond radiology

“Due primarily to staffing shortages and increased volume and complexity of patients, burnout and fatigue of all medical personnel, not just physicians, have become hallmarks of modern health care delivery in the United States, and this has been exacerbated by COVID-19 and other societal factors,” said Jeffrey C. Weinreb, MD, professor of radiology and biomedical imaging at Yale University, New Haven, Conn., in an interview.

Previous studies have documented the fact that radiologists are among the specialists most affected by burnout and fatigue, and it has an impact on their performance, Dr. Weinreb said. The current study is important because it tries to pinpoint the key variables that are responsible for fatigue, so resources can be directed to effect change, he said.

Dr. Weinreb said he was not particularly surprised by the study findings. “Diagnostic mammography is a high-volume repetitive enterprise, so it would have been surprising if radiologist experience and time of day had no effect on performance and recall rate,” he said. “As most radiologists will attest based on personal experience, human beings get tired and lose some level of cognition over the course of a long, intense workday,” he added.

“I am a bit surprised that less experienced radiologists were more likely to recommend additional imaging at a higher rate when interpreting DBT but not for DM and only later in the day,” Dr. Weinreb noted. “The authors suggest that this could be due to the increased number of images that are viewed with DBT and the different ways experienced and less experienced radiologists process the information. However, there could be other explanations, such as differences in volumes or differences in ages.”

“Reducing the study volumes per radiologist is one obvious solution to reducing fatigue, but it will not be practical in many practices,” said Dr. Weinreb. “The important work of interpreting diagnostic mammograms needs to continue and grow. Without an increase in radiologist mammographers in the labor pool, this is not going to happen any time soon.”

Instead, “more immediate obvious solutions to radiologist fatigue in clinical practice include more frequent breaks during the workday, which would include walking around and not looking at a computer or cell phone screen, fewer images per study, report templates, streamlined workflow, more variety in daily work, and AI assistance for interpretation and reporting,” said Dr. Weinreb. Using nonradiologists when possible to relieve some of the burden could be considered, “but this is a complex and politically charged issue,” he noted.

Radiology is a well-compensated specialty, but further increasing compensation would help to mitigate burnout, said Dr. Weinreb. However, “perhaps even more important is making certain that the efforts of individual radiologists are appreciated and recognized,” he said.

As for additional research needs, “mammographers are not the only radiologists experiencing fatigue, but the most critical contributing factors for other types of imaging exams and subspecialities may not be identical,” Dr. Weinreb emphasized. “Data for other radiologists, similar to that provided by this study for diagnostic mammography, could be useful.

“An additional area of research could address the issue of individual radiologist circadian rhythms,” said Dr. Weinreb. “Perhaps we could rigorously determine whom amongst us is a ‘morning person’ versus one who performs equally well or better later in the day and use this information for radiologist scheduling,” he said. “Finally, once we know the key factors affecting performance for each type of exam and subspecialty, studies of possible incremental and combined benefits of various interventions would be needed.”

The study received no outside funding. The researchers and Dr. Weinreb have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Recalls and false-positives for breast imaging patients were significantly more likely when the results were read by less-experienced radiologists who had worked more hours that day, based on data from more than 97,000 screening mammograms.

Psychology literature has shown the impact of fatigue on performance in a range of settings, and previous studies have shown that radiologists’ performances are more accurate earlier in their shifts compared to later-shift performance, write Michael H. Bernstein, PhD, and colleagues at Brown University, Providence, R.I., in a study published online Jan. 11 in Radiology.

The effect of time of day on performance may be greater for more detailed imaging modalities that are more “cognitively taxing,” and the effect may be greater in less-experienced radiologists, but the impact of time and experience on overall patient recall and false-positive rates has not been well-studied, the researchers said.

In the retrospective review, the researchers identified 97,671 screening mammograms read by 18 radiologists at one of 12 community sites between Jan. 2018 and Dec. 2019. The researchers analyzed the results by type of image, either standard digital mammography (DM) or the more complex digital breast tomosynthesis (DBT). The researchers separated radiologists into two groups: those with at least 5 post-training years of experience and those with less than 5 post-training years of experience. A total of nine radiologists fell into each category.

Overall, the recall rates were significantly different and higher for DM versus DBT (10.2% vs. 9.0%; P = .006). The false-positive (FP) rate also differed significantly and was higher for DM versus DBT (9.8% vs. 8.6%; P = .004).

The odds of recall increased by 11.5% with each hour of reading time for radiologists with less than 5 post-training years of experience for both DBT (odds ratio, 1.12) and DM (OR, 1.09). For the more experienced radiologists, the odds of recall increased by 1.6% for each hour of reading time for DBT but decreased by 0.1% for DM, with no significant difference.

Similarly, the odds of an FP result increased by 12.1% for DBT and 9% for DM per hour of reading time for radiologists with less experience. For more experienced radiologists, the odds of an FP increased by 1.6% for DBT but decreased by 1.1% for DM per hour of reading time.

Cancer detection (defined as true-positive, or TP) was not higher for DM across time, the researchers note. However, “DBT achieved a higher TP rate than DM regardless of the time of day; this shows that for DBT to maintain a constant and superior TP rate relative to DM, radiologists’ FP rates had to go up as the day went on,” they write. “That is, although DBT achieves a superior TP rate, more junior radiologists appeared to compensate for their fatigue later in the day when using DBT by recalling a broader range of mammograms, more of which were FP findings.”

The researchers caution that their findings were limited by several factors, including the study’s retrospective design and the lack of randomization of the imaging technology, patients, and time of day, which prohibit conclusions regarding causality. Other limitations included the consideration of time of day without the ability to use hours since the start of a clinical shift and the use of a 5-year mark to indicate experience without accounting for work volume.

However, the stronger impact of a time-of-day effect for more junior radiologists agrees with findings from other studies, the researchers add. More empirical research is needed, and the researchers propose a longitudinal study of how time of day affects radiologists as they gain experience, as well as experimental studies to test strategies for mitigating the time-of-day effect observed in the current study.
 

Scheduled breaks may reduce impact of fatigue

“Digital breast tomosynthesis is increasingly used in clinical practice and takes significantly longer to interpret compared with digital mammography,” said corresponding author Ana P. Lourenco, MD, in an interview. “Radiologists interpret hundreds of images for each screening digital breast tomosynthesis exam, compared with four images for each screening digital mammogram exam; this may certainly contribute to radiologist fatigue.”

“I found it interesting that there was a difference based on years of experience of the radiologist, but I was not surprised that recall rate increased later in the day, as some of us had anecdotally noted this in our clinical practice,” Dr. Lourenco said. In fact, the idea to conduct the study was prompted by a conversation with her statistician colleagues “about how I subjectively felt like my own recall rate increased at the end of the day.”

Ways to counteract the impact of fatigue could include intermittent breaks to refocus attention, said Dr. Lourenco. “Potential barriers would include imaging volumes and attending to patients in the breast imaging center,” she said. “If we can show that decreasing fatigue improves mammography performance metrics, then this may encourage practices to support such interventions.”

However, “more research that includes a larger number of radiologists, wider range of imaging interpretation experience, perhaps even experimental studies comparing metrics for radiologists reading with scheduled breaks versus without such breaks would be of interest,” Dr. Lourenco said.
 

Fatigue in health care goes beyond radiology

“Due primarily to staffing shortages and increased volume and complexity of patients, burnout and fatigue of all medical personnel, not just physicians, have become hallmarks of modern health care delivery in the United States, and this has been exacerbated by COVID-19 and other societal factors,” said Jeffrey C. Weinreb, MD, professor of radiology and biomedical imaging at Yale University, New Haven, Conn., in an interview.

Previous studies have documented the fact that radiologists are among the specialists most affected by burnout and fatigue, and it has an impact on their performance, Dr. Weinreb said. The current study is important because it tries to pinpoint the key variables that are responsible for fatigue, so resources can be directed to effect change, he said.

Dr. Weinreb said he was not particularly surprised by the study findings. “Diagnostic mammography is a high-volume repetitive enterprise, so it would have been surprising if radiologist experience and time of day had no effect on performance and recall rate,” he said. “As most radiologists will attest based on personal experience, human beings get tired and lose some level of cognition over the course of a long, intense workday,” he added.

“I am a bit surprised that less experienced radiologists were more likely to recommend additional imaging at a higher rate when interpreting DBT but not for DM and only later in the day,” Dr. Weinreb noted. “The authors suggest that this could be due to the increased number of images that are viewed with DBT and the different ways experienced and less experienced radiologists process the information. However, there could be other explanations, such as differences in volumes or differences in ages.”

“Reducing the study volumes per radiologist is one obvious solution to reducing fatigue, but it will not be practical in many practices,” said Dr. Weinreb. “The important work of interpreting diagnostic mammograms needs to continue and grow. Without an increase in radiologist mammographers in the labor pool, this is not going to happen any time soon.”

Instead, “more immediate obvious solutions to radiologist fatigue in clinical practice include more frequent breaks during the workday, which would include walking around and not looking at a computer or cell phone screen, fewer images per study, report templates, streamlined workflow, more variety in daily work, and AI assistance for interpretation and reporting,” said Dr. Weinreb. Using nonradiologists when possible to relieve some of the burden could be considered, “but this is a complex and politically charged issue,” he noted.

Radiology is a well-compensated specialty, but further increasing compensation would help to mitigate burnout, said Dr. Weinreb. However, “perhaps even more important is making certain that the efforts of individual radiologists are appreciated and recognized,” he said.

As for additional research needs, “mammographers are not the only radiologists experiencing fatigue, but the most critical contributing factors for other types of imaging exams and subspecialities may not be identical,” Dr. Weinreb emphasized. “Data for other radiologists, similar to that provided by this study for diagnostic mammography, could be useful.

“An additional area of research could address the issue of individual radiologist circadian rhythms,” said Dr. Weinreb. “Perhaps we could rigorously determine whom amongst us is a ‘morning person’ versus one who performs equally well or better later in the day and use this information for radiologist scheduling,” he said. “Finally, once we know the key factors affecting performance for each type of exam and subspecialty, studies of possible incremental and combined benefits of various interventions would be needed.”

The study received no outside funding. The researchers and Dr. Weinreb have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Recent therapeutic advances in HER2-positive metastatic breast cancer (MBC) have begun to reshape the treatment landscape for patients. Since late 2019, the U.S. Food and Drug Administration (FDA) has approved a handful of novel agents for HER2-positive MBC — most notably, the antibody-drug conjugate (ADC) trastuzumab deruxtecan in December 2019 and the tyrosine kinase inhibitors (TKIs) tucatinib and neratinib in 2020. According to the National Cancer Institute›s Surveillance, Epidemiology, and End Results (SEER) program, the 5-year survival rate for patients with advanced disease was already on the rise between 2004 and 2018, and the introduction of these new therapeutic options has continued to improve patients’ survival odds.
 

“I’ve been involved in the HER2 space for a long time and have watched the field evolve,” said Adam Brufsky, MD, PhD, associate chief in the division of hematology/oncology and co-director of the Comprehensive Breast Cancer Center at the University of Pittsburgh School of Medicine. “The fact that we’re now talking about fourth- and fifth-line therapies for HER2-positive MBC represents a major advance in the management of these patients.”

breast_cancer_illust_web.jpg

Oncologists are still building on this progress, focusing on designing more targeted therapies as well as studying different combinations of available agents. The main goal of treatment, experts say, is to prolong patients’ systemic response and prevent recurrences, especially in the brain. This news organization spoke to Dr. Brufksy and others about promising agents and therapeutic strategies on the horizon to treat HER2-positive MBC.

Inside emerging ADCs

Because many patients develop resistance to trastuzumab emtansine (T-DM1) — the first FDA-approved ADC in breast cancer — researchers have focused on developing the next generation of ADCs with more potent payloads, different linkers, and distinct mechanisms of action, according to Sayeh Lavasani, MD, MS, a medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

The second-generation ADC trastuzumab deruxtecan showed “really dramatic” results in HER2-positive MBC, demonstrating progression-free survival of 16 months, remarked Kevin Kalinsky, MD, acting associate professor in the department of hematology and medical oncology at Emory University School of Medicine in Atlanta and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University. “These outcomes further changed how we treat patients with metastatic disease and prompted considerable excitement over the potential to develop novel ADCs to treat HER2-positive MBC.”

Most recently, two investigational ADCs — trastuzumab duocarmazine (SYD985) and ARX788 — have stood out. The FDA granted fast-track designations to trastuzumab duocarmazine in January 2018 and ARX788 in January 2021. Trastuzumab duocarmazine, the furthest along the pipeline, has shown promising results so far. In June 2021, Netherlands-based biopharmaceutical company Byondis reported preliminary phase 3 data from the TULIP trial. The open-label, randomized phase 3 study enrolled 436 patients with HER2-positive locally advanced or metastatic disease that had progressed on previous anti-HER2 regimens. The company shared early results that trastuzumab duocarmazine achieved its progression-free survival primary endpoint, marking a significant improvement over physician’s choice of chemotherapy, and promised more detailed results to come later this year.

Although only in early-phase trials, ARX788 has also shown robust anti-HER2 activity as well as low toxicity in HER2-positive tumors, according to recent data. The findings from two phase 1 studies, presented at the June 2021 virtual American Society for Clinical Oncology meeting (abstract 1038), revealed an overall response rate of 74% in the breast cancer cohort, but the investigators acknowledged it was too early to report median progression-free survival outcomes. Preclinical data also showed activity in HER2-low and T-DM1–resistant tumors.

Despite the encouraging initial findings, Dr. Kalinsky remains cautiously optimistic about long-term outcomes for both ADCs. “These data are hot off the press, but it’s too soon to know how these two ADCs and others in the pipeline will measure up to approved therapies,” he commented. As experts learn more about the efficacy of these novel ADCs, Dr. Brufsky would also like to better understand resistance mechanisms and how to integrate these agents into current treatment strategies. “The cellular biology of HER2-positive MBC is complicated, and many factors in these tumor cells affect where ADCs are released, how resistance develops, and whether or not resistance to one ADC applies to others,” Dr. Brufsky remarked. “As we gather more data, we’ll understand resistance mechanisms better and begin to figure out where to go with treatment sequencing.”

TKIs and beyond

In addition to ADCs, TKIs continue to make their mark in the targeted HER2 therapeutic space. The approvals of tucatinib and neratinib last year represented an important advance in treating HER2-positive MBC, particularly for patients with brain metastases. The HER2CLIMB trial, for instance, found that tucatinib combined with trastuzumab and capecitabine had a 4.5-month overall survival advantage compared with placebo (21.9 vs 17.4) and a median progression-free survival advantage of 5.4 months in patients with active brain metastases (9.5 vs 4.1) and 8.3 months in patients with stable metastases (13.9 vs 5.6).

Given this progress, experts are looking to add new TKIs to the armamentarium. In particular, pyrotinib — already approved in China for treating HER2-positive MBC — has demonstrated significantly longer progression-free survival compared with a standard TKI, lapatinib. The phase 3 PHOEBE trial results, published in The Lancet in early 2021, found a median progression-free survival of 12.5 months in patients randomly assigned to receive pyrotinib plus capecitabine compared with 6.8 months in those receiving lapatinib plus capecitabine. The investigators also reported “manageable toxicity”; diarrhea was the most common grade 3 adverse event, occurring in 31% of the pyrotinib group vs. 8% of the lapatinib group, and overall serious adverse events occurred in 10% of patients receiving pyrotinib vs. 8% of those receiving lapatinib.

More recent data on pyrotinib come from the phase 2 PERMEATE trial, which focused on the safety and efficacy of the agent in patients with advanced disease and brain metastases. The investigators, who presented their findings at the 2021 virtual ASCO meeting (abstract 1037), reported that radiation therapy–naive patients receiving pyrotinib plus capecitabine had an overall response rate of 74.6% in the central nervous system. Patients experiencing progression after whole-brain or stereotactic radiation therapy, however, had a comparatively lower overall response rate of 42.1%.

Similarly, median progression-free survival was much higher in the radiation therapy–naive patients (12.1 vs 5.6 months in the radiation therapy cohort). Similar to the PHOEBE trial, the most common grade 3 adverse event was diarrhea (23.1%), followed by decreased neutrophil and white blood cell counts (12.8% for both), anemia (9%), and hand-foot syndrome (7.7%). The main question for Dr. Kalinsky is how well pyrotinib will ultimately stack up to tucatinib and neratinib. “Pyrotinib — like neratinib — was shown to be superior to lapatinib plus capecitabine , but its role may be limited by its gastrointestinal toxicity,” he said. In addition to research focused on expanding the selection of novel ADCs and TKIs, researchers are also exploring new combinations of approved treatments and whether these combinations can be used earlier in treatment sequencing.

Take the CompassHER2 trials. The ongoing phase 3 trial in patients with high-risk HER2-positive breast cancer and residual disease will explore whether tucatinib plus T-DM1 compared with T-DM1 alone improves overall survival and recurrence-free survival and prevents brain metastases. Another possibility currently under investigation is pairing tucatinib and trastuzumab deruxtecan, instead of T-DM1. “Overall, it’s exciting that we are increasing the number of therapeutic options and combinations,” commented Debu Tripathy, MD, professor and chairman in the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. “Having more choices allows us to tailor therapies to manage resistance and prolong patients’ responses.”

Curbing brain metastasis, according to Dr. Brufksy, is particularly important, and experts need to explore the extent to which ADCs can penetrate the blood-brain barrier. Already, a subgroup analysis of the DESTINY-Breast01 trial found that trastuzumab deruxtecan appeared to be active in patients with brain metastases. Investigators reported an overall response rate of 58.3% and a median progression-free survival of 18.1 months — results in line with those in the general study cohort — but the study population did not include patients with untreated or progressive brain metastases. A phase 2 study currently under way will examine whether patients with HER2-positive and HER2-low breast cancer who have untreated or progressive brain metastases respond to trastuzumab deruxtecan as well. Ultimately, Dr. Brufksy hopes the recent successes with preventing brain metastases in pediatric acute lymphoblastic leukemia (ALL) foreshadow what›s to come in HER2-positive MBC.

“When we figured out how to treat brain metastases prophylactically in childhood ALL, we saw a huge improvement in the cure rate, which is ultimately my vision for HER2-positive disease,” Dr. Brufsky remarked. “Are there cures for HER2-positive MBC on the horizon? We don’t know yet, but the field has really exploded in recent years.”

A version of this article first appeared on Medscape.com.

Recent therapeutic advances in HER2-positive metastatic breast cancer (MBC) have begun to reshape the treatment landscape for patients. Since late 2019, the U.S. Food and Drug Administration (FDA) has approved a handful of novel agents for HER2-positive MBC — most notably, the antibody-drug conjugate (ADC) trastuzumab deruxtecan in December 2019 and the tyrosine kinase inhibitors (TKIs) tucatinib and neratinib in 2020. According to the National Cancer Institute›s Surveillance, Epidemiology, and End Results (SEER) program, the 5-year survival rate for patients with advanced disease was already on the rise between 2004 and 2018, and the introduction of these new therapeutic options has continued to improve patients’ survival odds.
 

“I’ve been involved in the HER2 space for a long time and have watched the field evolve,” said Adam Brufsky, MD, PhD, associate chief in the division of hematology/oncology and co-director of the Comprehensive Breast Cancer Center at the University of Pittsburgh School of Medicine. “The fact that we’re now talking about fourth- and fifth-line therapies for HER2-positive MBC represents a major advance in the management of these patients.”

breast_cancer_illust_web.jpg

Oncologists are still building on this progress, focusing on designing more targeted therapies as well as studying different combinations of available agents. The main goal of treatment, experts say, is to prolong patients’ systemic response and prevent recurrences, especially in the brain. This news organization spoke to Dr. Brufksy and others about promising agents and therapeutic strategies on the horizon to treat HER2-positive MBC.

Inside emerging ADCs

Because many patients develop resistance to trastuzumab emtansine (T-DM1) — the first FDA-approved ADC in breast cancer — researchers have focused on developing the next generation of ADCs with more potent payloads, different linkers, and distinct mechanisms of action, according to Sayeh Lavasani, MD, MS, a medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

The second-generation ADC trastuzumab deruxtecan showed “really dramatic” results in HER2-positive MBC, demonstrating progression-free survival of 16 months, remarked Kevin Kalinsky, MD, acting associate professor in the department of hematology and medical oncology at Emory University School of Medicine in Atlanta and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University. “These outcomes further changed how we treat patients with metastatic disease and prompted considerable excitement over the potential to develop novel ADCs to treat HER2-positive MBC.”

Most recently, two investigational ADCs — trastuzumab duocarmazine (SYD985) and ARX788 — have stood out. The FDA granted fast-track designations to trastuzumab duocarmazine in January 2018 and ARX788 in January 2021. Trastuzumab duocarmazine, the furthest along the pipeline, has shown promising results so far. In June 2021, Netherlands-based biopharmaceutical company Byondis reported preliminary phase 3 data from the TULIP trial. The open-label, randomized phase 3 study enrolled 436 patients with HER2-positive locally advanced or metastatic disease that had progressed on previous anti-HER2 regimens. The company shared early results that trastuzumab duocarmazine achieved its progression-free survival primary endpoint, marking a significant improvement over physician’s choice of chemotherapy, and promised more detailed results to come later this year.

Although only in early-phase trials, ARX788 has also shown robust anti-HER2 activity as well as low toxicity in HER2-positive tumors, according to recent data. The findings from two phase 1 studies, presented at the June 2021 virtual American Society for Clinical Oncology meeting (abstract 1038), revealed an overall response rate of 74% in the breast cancer cohort, but the investigators acknowledged it was too early to report median progression-free survival outcomes. Preclinical data also showed activity in HER2-low and T-DM1–resistant tumors.

Despite the encouraging initial findings, Dr. Kalinsky remains cautiously optimistic about long-term outcomes for both ADCs. “These data are hot off the press, but it’s too soon to know how these two ADCs and others in the pipeline will measure up to approved therapies,” he commented. As experts learn more about the efficacy of these novel ADCs, Dr. Brufsky would also like to better understand resistance mechanisms and how to integrate these agents into current treatment strategies. “The cellular biology of HER2-positive MBC is complicated, and many factors in these tumor cells affect where ADCs are released, how resistance develops, and whether or not resistance to one ADC applies to others,” Dr. Brufsky remarked. “As we gather more data, we’ll understand resistance mechanisms better and begin to figure out where to go with treatment sequencing.”

TKIs and beyond

In addition to ADCs, TKIs continue to make their mark in the targeted HER2 therapeutic space. The approvals of tucatinib and neratinib last year represented an important advance in treating HER2-positive MBC, particularly for patients with brain metastases. The HER2CLIMB trial, for instance, found that tucatinib combined with trastuzumab and capecitabine had a 4.5-month overall survival advantage compared with placebo (21.9 vs 17.4) and a median progression-free survival advantage of 5.4 months in patients with active brain metastases (9.5 vs 4.1) and 8.3 months in patients with stable metastases (13.9 vs 5.6).

Given this progress, experts are looking to add new TKIs to the armamentarium. In particular, pyrotinib — already approved in China for treating HER2-positive MBC — has demonstrated significantly longer progression-free survival compared with a standard TKI, lapatinib. The phase 3 PHOEBE trial results, published in The Lancet in early 2021, found a median progression-free survival of 12.5 months in patients randomly assigned to receive pyrotinib plus capecitabine compared with 6.8 months in those receiving lapatinib plus capecitabine. The investigators also reported “manageable toxicity”; diarrhea was the most common grade 3 adverse event, occurring in 31% of the pyrotinib group vs. 8% of the lapatinib group, and overall serious adverse events occurred in 10% of patients receiving pyrotinib vs. 8% of those receiving lapatinib.

More recent data on pyrotinib come from the phase 2 PERMEATE trial, which focused on the safety and efficacy of the agent in patients with advanced disease and brain metastases. The investigators, who presented their findings at the 2021 virtual ASCO meeting (abstract 1037), reported that radiation therapy–naive patients receiving pyrotinib plus capecitabine had an overall response rate of 74.6% in the central nervous system. Patients experiencing progression after whole-brain or stereotactic radiation therapy, however, had a comparatively lower overall response rate of 42.1%.

Similarly, median progression-free survival was much higher in the radiation therapy–naive patients (12.1 vs 5.6 months in the radiation therapy cohort). Similar to the PHOEBE trial, the most common grade 3 adverse event was diarrhea (23.1%), followed by decreased neutrophil and white blood cell counts (12.8% for both), anemia (9%), and hand-foot syndrome (7.7%). The main question for Dr. Kalinsky is how well pyrotinib will ultimately stack up to tucatinib and neratinib. “Pyrotinib — like neratinib — was shown to be superior to lapatinib plus capecitabine , but its role may be limited by its gastrointestinal toxicity,” he said. In addition to research focused on expanding the selection of novel ADCs and TKIs, researchers are also exploring new combinations of approved treatments and whether these combinations can be used earlier in treatment sequencing.

Take the CompassHER2 trials. The ongoing phase 3 trial in patients with high-risk HER2-positive breast cancer and residual disease will explore whether tucatinib plus T-DM1 compared with T-DM1 alone improves overall survival and recurrence-free survival and prevents brain metastases. Another possibility currently under investigation is pairing tucatinib and trastuzumab deruxtecan, instead of T-DM1. “Overall, it’s exciting that we are increasing the number of therapeutic options and combinations,” commented Debu Tripathy, MD, professor and chairman in the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. “Having more choices allows us to tailor therapies to manage resistance and prolong patients’ responses.”

Curbing brain metastasis, according to Dr. Brufksy, is particularly important, and experts need to explore the extent to which ADCs can penetrate the blood-brain barrier. Already, a subgroup analysis of the DESTINY-Breast01 trial found that trastuzumab deruxtecan appeared to be active in patients with brain metastases. Investigators reported an overall response rate of 58.3% and a median progression-free survival of 18.1 months — results in line with those in the general study cohort — but the study population did not include patients with untreated or progressive brain metastases. A phase 2 study currently under way will examine whether patients with HER2-positive and HER2-low breast cancer who have untreated or progressive brain metastases respond to trastuzumab deruxtecan as well. Ultimately, Dr. Brufksy hopes the recent successes with preventing brain metastases in pediatric acute lymphoblastic leukemia (ALL) foreshadow what›s to come in HER2-positive MBC.

“When we figured out how to treat brain metastases prophylactically in childhood ALL, we saw a huge improvement in the cure rate, which is ultimately my vision for HER2-positive disease,” Dr. Brufsky remarked. “Are there cures for HER2-positive MBC on the horizon? We don’t know yet, but the field has really exploded in recent years.”

A version of this article first appeared on Medscape.com.

Recent therapeutic advances in HER2-positive metastatic breast cancer (MBC) have begun to reshape the treatment landscape for patients. Since late 2019, the U.S. Food and Drug Administration (FDA) has approved a handful of novel agents for HER2-positive MBC — most notably, the antibody-drug conjugate (ADC) trastuzumab deruxtecan in December 2019 and the tyrosine kinase inhibitors (TKIs) tucatinib and neratinib in 2020. According to the National Cancer Institute›s Surveillance, Epidemiology, and End Results (SEER) program, the 5-year survival rate for patients with advanced disease was already on the rise between 2004 and 2018, and the introduction of these new therapeutic options has continued to improve patients’ survival odds.
 

“I’ve been involved in the HER2 space for a long time and have watched the field evolve,” said Adam Brufsky, MD, PhD, associate chief in the division of hematology/oncology and co-director of the Comprehensive Breast Cancer Center at the University of Pittsburgh School of Medicine. “The fact that we’re now talking about fourth- and fifth-line therapies for HER2-positive MBC represents a major advance in the management of these patients.”

breast_cancer_illust_web.jpg

Oncologists are still building on this progress, focusing on designing more targeted therapies as well as studying different combinations of available agents. The main goal of treatment, experts say, is to prolong patients’ systemic response and prevent recurrences, especially in the brain. This news organization spoke to Dr. Brufksy and others about promising agents and therapeutic strategies on the horizon to treat HER2-positive MBC.

Inside emerging ADCs

Because many patients develop resistance to trastuzumab emtansine (T-DM1) — the first FDA-approved ADC in breast cancer — researchers have focused on developing the next generation of ADCs with more potent payloads, different linkers, and distinct mechanisms of action, according to Sayeh Lavasani, MD, MS, a medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

The second-generation ADC trastuzumab deruxtecan showed “really dramatic” results in HER2-positive MBC, demonstrating progression-free survival of 16 months, remarked Kevin Kalinsky, MD, acting associate professor in the department of hematology and medical oncology at Emory University School of Medicine in Atlanta and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University. “These outcomes further changed how we treat patients with metastatic disease and prompted considerable excitement over the potential to develop novel ADCs to treat HER2-positive MBC.”

Most recently, two investigational ADCs — trastuzumab duocarmazine (SYD985) and ARX788 — have stood out. The FDA granted fast-track designations to trastuzumab duocarmazine in January 2018 and ARX788 in January 2021. Trastuzumab duocarmazine, the furthest along the pipeline, has shown promising results so far. In June 2021, Netherlands-based biopharmaceutical company Byondis reported preliminary phase 3 data from the TULIP trial. The open-label, randomized phase 3 study enrolled 436 patients with HER2-positive locally advanced or metastatic disease that had progressed on previous anti-HER2 regimens. The company shared early results that trastuzumab duocarmazine achieved its progression-free survival primary endpoint, marking a significant improvement over physician’s choice of chemotherapy, and promised more detailed results to come later this year.

Although only in early-phase trials, ARX788 has also shown robust anti-HER2 activity as well as low toxicity in HER2-positive tumors, according to recent data. The findings from two phase 1 studies, presented at the June 2021 virtual American Society for Clinical Oncology meeting (abstract 1038), revealed an overall response rate of 74% in the breast cancer cohort, but the investigators acknowledged it was too early to report median progression-free survival outcomes. Preclinical data also showed activity in HER2-low and T-DM1–resistant tumors.

Despite the encouraging initial findings, Dr. Kalinsky remains cautiously optimistic about long-term outcomes for both ADCs. “These data are hot off the press, but it’s too soon to know how these two ADCs and others in the pipeline will measure up to approved therapies,” he commented. As experts learn more about the efficacy of these novel ADCs, Dr. Brufsky would also like to better understand resistance mechanisms and how to integrate these agents into current treatment strategies. “The cellular biology of HER2-positive MBC is complicated, and many factors in these tumor cells affect where ADCs are released, how resistance develops, and whether or not resistance to one ADC applies to others,” Dr. Brufsky remarked. “As we gather more data, we’ll understand resistance mechanisms better and begin to figure out where to go with treatment sequencing.”

TKIs and beyond

In addition to ADCs, TKIs continue to make their mark in the targeted HER2 therapeutic space. The approvals of tucatinib and neratinib last year represented an important advance in treating HER2-positive MBC, particularly for patients with brain metastases. The HER2CLIMB trial, for instance, found that tucatinib combined with trastuzumab and capecitabine had a 4.5-month overall survival advantage compared with placebo (21.9 vs 17.4) and a median progression-free survival advantage of 5.4 months in patients with active brain metastases (9.5 vs 4.1) and 8.3 months in patients with stable metastases (13.9 vs 5.6).

Given this progress, experts are looking to add new TKIs to the armamentarium. In particular, pyrotinib — already approved in China for treating HER2-positive MBC — has demonstrated significantly longer progression-free survival compared with a standard TKI, lapatinib. The phase 3 PHOEBE trial results, published in The Lancet in early 2021, found a median progression-free survival of 12.5 months in patients randomly assigned to receive pyrotinib plus capecitabine compared with 6.8 months in those receiving lapatinib plus capecitabine. The investigators also reported “manageable toxicity”; diarrhea was the most common grade 3 adverse event, occurring in 31% of the pyrotinib group vs. 8% of the lapatinib group, and overall serious adverse events occurred in 10% of patients receiving pyrotinib vs. 8% of those receiving lapatinib.

More recent data on pyrotinib come from the phase 2 PERMEATE trial, which focused on the safety and efficacy of the agent in patients with advanced disease and brain metastases. The investigators, who presented their findings at the 2021 virtual ASCO meeting (abstract 1037), reported that radiation therapy–naive patients receiving pyrotinib plus capecitabine had an overall response rate of 74.6% in the central nervous system. Patients experiencing progression after whole-brain or stereotactic radiation therapy, however, had a comparatively lower overall response rate of 42.1%.

Similarly, median progression-free survival was much higher in the radiation therapy–naive patients (12.1 vs 5.6 months in the radiation therapy cohort). Similar to the PHOEBE trial, the most common grade 3 adverse event was diarrhea (23.1%), followed by decreased neutrophil and white blood cell counts (12.8% for both), anemia (9%), and hand-foot syndrome (7.7%). The main question for Dr. Kalinsky is how well pyrotinib will ultimately stack up to tucatinib and neratinib. “Pyrotinib — like neratinib — was shown to be superior to lapatinib plus capecitabine , but its role may be limited by its gastrointestinal toxicity,” he said. In addition to research focused on expanding the selection of novel ADCs and TKIs, researchers are also exploring new combinations of approved treatments and whether these combinations can be used earlier in treatment sequencing.

Take the CompassHER2 trials. The ongoing phase 3 trial in patients with high-risk HER2-positive breast cancer and residual disease will explore whether tucatinib plus T-DM1 compared with T-DM1 alone improves overall survival and recurrence-free survival and prevents brain metastases. Another possibility currently under investigation is pairing tucatinib and trastuzumab deruxtecan, instead of T-DM1. “Overall, it’s exciting that we are increasing the number of therapeutic options and combinations,” commented Debu Tripathy, MD, professor and chairman in the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. “Having more choices allows us to tailor therapies to manage resistance and prolong patients’ responses.”

Curbing brain metastasis, according to Dr. Brufksy, is particularly important, and experts need to explore the extent to which ADCs can penetrate the blood-brain barrier. Already, a subgroup analysis of the DESTINY-Breast01 trial found that trastuzumab deruxtecan appeared to be active in patients with brain metastases. Investigators reported an overall response rate of 58.3% and a median progression-free survival of 18.1 months — results in line with those in the general study cohort — but the study population did not include patients with untreated or progressive brain metastases. A phase 2 study currently under way will examine whether patients with HER2-positive and HER2-low breast cancer who have untreated or progressive brain metastases respond to trastuzumab deruxtecan as well. Ultimately, Dr. Brufksy hopes the recent successes with preventing brain metastases in pediatric acute lymphoblastic leukemia (ALL) foreshadow what›s to come in HER2-positive MBC.

“When we figured out how to treat brain metastases prophylactically in childhood ALL, we saw a huge improvement in the cure rate, which is ultimately my vision for HER2-positive disease,” Dr. Brufsky remarked. “Are there cures for HER2-positive MBC on the horizon? We don’t know yet, but the field has really exploded in recent years.”

A version of this article first appeared on Medscape.com.

Identifying the molecular features of metastatic breast cancer (MBC) offers a real-time window into a patient’s treatment options as well as the potential to follow the disease as it evolves over time.
 

Tissue biopsy remains the gold standard for characterizing tumor biology and guiding therapeutic decisions, but liquid biopsies — blood analyses that allow oncologists to detect circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in the blood — are increasingly demonstrating their value. Last year, the U.S. Food and Drug Administration (FDA) approved two liquid biopsy tests, Guardant360 CDx and FoundationOne Liquid CDx, that can identify more than 300 cancer-related genes in the blood. In 2019, the FDA also approved the first companion diagnostic test, therascreen, to pinpoint PIK3CA gene mutations in patients’ ctDNA and determine whether patients should receive the PI3K inhibitor alpelisib along with fulvestrant.

Here’s an overview of how liquid biopsy is being used in monitoring MBC progression and treatment — and what some oncologists think of it.

What we do and don’t know

“Identifying a patient’s targetable mutations, most notably PIK3CA mutations, is currently the main use of liquid biopsy,” said Pedram Razavi, MD, PhD, a medical oncologist who leads the liquid biopsy program for breast cancer at Memorial Sloan Kettering (MSK) Cancer Center in New York City. “Patients who come to MSK are offered a tumor and liquid biopsy at the time of metastatic diagnosis as part of the standard of care.”

Liquid and tissue biopsy analyses can provide a more complete picture of a patient’s condition. Whereas tissue biopsy allows oncologists to target a more saturated sample of the cancer ecosystem and a wider array of biomarkers, liquid biopsy offers important advantages as well, including a less invasive way to sequence a sample, monitor patients’ treatment response, or track tumor evolution. Liquid biopsy also provides a bigger picture view of tumor heterogeneity by pooling information from many tumor locations as opposed to one.

But, cautioned Yuan Yuan, MD, PhD, liquid biopsy technology is not always sensitive enough to detect CTCs, ctDNA, or all relevant mutations. “When you collect a small tube of blood, you’re essentially trying to catch a small fish in a big sea and wading through a lot of background noise,” said Dr. Yuan, medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County. “The results may be hard to interpret or come back inconclusive.”

And although emerging data suggest that liquid biopsy provides important insights about tumor dynamics — including mapping disease progression, predicting survival, and even detecting signs of cancer recurrence before metastasis develops — the tool has limited utility in clinical practice outside of identifying sensitivity to various therapies or drugs.

“Right now, a lot of research is being done to understand how to use CTC and ctDNA in particular as a means of surveillance in breast cancer, but we’re still in the beginning stages of applying that outside of clinical trials,” said Joseph A. Sparano, MD, deputy director of the Tisch Cancer Institute and chief of the division of hematology and medical oncology, Icahn School of Medicine at Mount Sinai, New York City.

Personalizing treatment

The companion diagnostic test therascreen marked the beginning stages of using liquid biopsy to match treatments to genetic abnormalities in MBC. The SOLAR-1 phase 3 trial, which led to the approval of alpelisib and therascreen, found that the PI3K inhibitor plus fulvestrant almost doubled progression-free survival (PFS) (11 months vs 5.7 months in placebo-fulvestrant group) in patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer.

More recent studies have shown that liquid biopsy tests can also identify ESR1 mutations and predict responses to inhibitors that target AKT1 and HER2. Investigators presenting at the 2021 American Society of Clinical Oncology meeting reported that next-generation sequencing of ctDNA in patients with HR-positive MBC, HER-positive MBC, or triple-negative breast cancer detected ESR1 mutations in 14% of patients (71 of 501). Moreover, ESR1 mutations were found only in HR-positive patients who had already received endocrine therapy. (The study also examined PIK3CA mutations, which occurred in about one third of patients). A more in-depth look revealed that ESR1 mutations were strongly associated with liver and bone metastases and that mutations along specific codons negatively affected overall survival (OS) and PFS: codons 537 and 538 for OS and codons 380 and 536 for PFS.

According to Debasish Tripathy, MD, professor and chairman of the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, in addition to tumor sequencing, “liquid biopsy has become a great research tool to track patients in real time and predict, for instance, who will respond to a treatment and identify emerging resistance.”

In terms of predicting responses to treatment, the plasmaMATCH trial assessed ctDNA in 1,034 patients with advanced breast cancer for mutations in ESR1, HER2, and AKT1 using digital droplet polymerase chain reaction (PCR) and Guardant360. Results showed that 357 (34.5%) of these patients had potentially targetable aberrations, including 222 patients with ESR1 mutations, 36 patients with HER2 mutations, and 30 patients with AKT1 mutations.

Agreement between digital droplet PCR and Guardant360 testing was 96%-99%, and liquid biopsy showed 93% sensitivity compared with tumor samples. The investigators also used liquid biopsy findings to match patients’ mutations to targeted treatments: fulvestrant for those with ESR1 mutations, neratinib for HER2 (ERBB2) mutations, and the selective AKT inhibitor capivasertib for estrogen receptor–positive tumors with AKT1 mutations.

Overall, the investigators concluded that ctDNA testing offers “accurate tumor genotyping” in line with tissue-based testing and is ready for routine clinical practice to identify common as well as rare genetic alterations, such as HER2 and AKT1 mutations, that affect only about 5% of patients with advanced disease.

Predicting survival and recurrence

A particularly promising area for liquid biopsy is its usefulness in helping to predict survival outcomes and monitor patients for early signs of recurrence before metastasis occurs. But the data to support this are still in their infancy.

A highly cited study, published over 15 years ago in the New England Journal of Medicine, found that patients with MBC who had five or more CTCs per 7.5 mL of whole blood before receiving first-line therapy exhibited significantly shorter median PFS (2.7 vs 7.0 months) and OS (10 vs > 18 months) compared with patients with fewer than five CTCs. Subsequent analyses performed more than a decade later, including a meta-analysis published last year, helped validate these early findings that levels of CTCs detected in the blood independently and strongly predicted PFS and OS in patients with MBC.

In addition, ctDNA can provide important information about patients’ survival odds. In a retrospective study published last year, investigators tracked changes in ctDNA in 291 plasma samples from 84 patients with locally advanced breast cancer who participated in the I-SPY trial. Patients who remained ctDNA-positive after 3 weeks of neoadjuvant chemotherapy were significantly more likely to have residual disease after completing their treatment compared with patients who cleared ctDNA at that early stage (83% for those with nonpathologic complete response vs 52%). Notably, the presence of ctDNA between therapy initiation and completion was associated with a significantly greater risk for metastatic recurrence, whereas clearance of ctDNA after neoadjuvant therapy was linked to improved survival.

“The study is important because it highlights how tracking circulating ctDNA status in neoadjuvant-treated breast cancer can expose a patient’s risk for distant metastasis,” said Dr. Yuan. But, she added, “I think the biggest attraction of liquid biopsy will be the ability to detect molecular disease even before imaging can, and identify who has a high risk for recurrence.”

Dr. Razavi agreed that the potential to prevent metastasis by finding minimal residual disease (MRD) is the most exciting area of liquid biopsy research. “If we can find tumor DNA early before tumors have a chance to establish themselves, we could potentially change the trajectory of the disease for patients,” he said.

Several studies suggest that monitoring patients’ ctDNA levels after neoadjuvant treatment and surgery may help predict their risk for relapse and progression to metastatic disease. A 2015 analysis, which followed 20 patients with breast cancer after surgery, found that ctDNA monitoring accurately differentiated those who ultimately developed metastatic disease from those who didn’t (sensitivity, 93%; specificity, 100%) and detected metastatic disease 11 months earlier, on average, than imaging did. Another 2015 study found that the presence of ctDNA in plasma after neoadjuvant chemotherapy and surgery predicted metastatic relapse a median of almost 8 months before clinical detection. Other recent data show the power of ultrasensitive blood tests to detect MRD and potentially find metastatic disease early.

Although an increasing number of studies show that ctDNA and CTCs are prognostic for breast cancer recurrence, a major question remains: For patients with ctDNA or CTCs but no overt disease after imaging, will initiating therapy prevent or delay the development of metastatic disease?

“We still have to do those clinical trials to determine whether detecting MRD and treating patients early actually positively affects their survival and quality of life,” Dr. Razavi said.

Identifying the molecular features of metastatic breast cancer (MBC) offers a real-time window into a patient’s treatment options as well as the potential to follow the disease as it evolves over time.
 

Tissue biopsy remains the gold standard for characterizing tumor biology and guiding therapeutic decisions, but liquid biopsies — blood analyses that allow oncologists to detect circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in the blood — are increasingly demonstrating their value. Last year, the U.S. Food and Drug Administration (FDA) approved two liquid biopsy tests, Guardant360 CDx and FoundationOne Liquid CDx, that can identify more than 300 cancer-related genes in the blood. In 2019, the FDA also approved the first companion diagnostic test, therascreen, to pinpoint PIK3CA gene mutations in patients’ ctDNA and determine whether patients should receive the PI3K inhibitor alpelisib along with fulvestrant.

Here’s an overview of how liquid biopsy is being used in monitoring MBC progression and treatment — and what some oncologists think of it.

What we do and don’t know

“Identifying a patient’s targetable mutations, most notably PIK3CA mutations, is currently the main use of liquid biopsy,” said Pedram Razavi, MD, PhD, a medical oncologist who leads the liquid biopsy program for breast cancer at Memorial Sloan Kettering (MSK) Cancer Center in New York City. “Patients who come to MSK are offered a tumor and liquid biopsy at the time of metastatic diagnosis as part of the standard of care.”

Liquid and tissue biopsy analyses can provide a more complete picture of a patient’s condition. Whereas tissue biopsy allows oncologists to target a more saturated sample of the cancer ecosystem and a wider array of biomarkers, liquid biopsy offers important advantages as well, including a less invasive way to sequence a sample, monitor patients’ treatment response, or track tumor evolution. Liquid biopsy also provides a bigger picture view of tumor heterogeneity by pooling information from many tumor locations as opposed to one.

But, cautioned Yuan Yuan, MD, PhD, liquid biopsy technology is not always sensitive enough to detect CTCs, ctDNA, or all relevant mutations. “When you collect a small tube of blood, you’re essentially trying to catch a small fish in a big sea and wading through a lot of background noise,” said Dr. Yuan, medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County. “The results may be hard to interpret or come back inconclusive.”

And although emerging data suggest that liquid biopsy provides important insights about tumor dynamics — including mapping disease progression, predicting survival, and even detecting signs of cancer recurrence before metastasis develops — the tool has limited utility in clinical practice outside of identifying sensitivity to various therapies or drugs.

“Right now, a lot of research is being done to understand how to use CTC and ctDNA in particular as a means of surveillance in breast cancer, but we’re still in the beginning stages of applying that outside of clinical trials,” said Joseph A. Sparano, MD, deputy director of the Tisch Cancer Institute and chief of the division of hematology and medical oncology, Icahn School of Medicine at Mount Sinai, New York City.

Personalizing treatment

The companion diagnostic test therascreen marked the beginning stages of using liquid biopsy to match treatments to genetic abnormalities in MBC. The SOLAR-1 phase 3 trial, which led to the approval of alpelisib and therascreen, found that the PI3K inhibitor plus fulvestrant almost doubled progression-free survival (PFS) (11 months vs 5.7 months in placebo-fulvestrant group) in patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer.

More recent studies have shown that liquid biopsy tests can also identify ESR1 mutations and predict responses to inhibitors that target AKT1 and HER2. Investigators presenting at the 2021 American Society of Clinical Oncology meeting reported that next-generation sequencing of ctDNA in patients with HR-positive MBC, HER-positive MBC, or triple-negative breast cancer detected ESR1 mutations in 14% of patients (71 of 501). Moreover, ESR1 mutations were found only in HR-positive patients who had already received endocrine therapy. (The study also examined PIK3CA mutations, which occurred in about one third of patients). A more in-depth look revealed that ESR1 mutations were strongly associated with liver and bone metastases and that mutations along specific codons negatively affected overall survival (OS) and PFS: codons 537 and 538 for OS and codons 380 and 536 for PFS.

According to Debasish Tripathy, MD, professor and chairman of the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, in addition to tumor sequencing, “liquid biopsy has become a great research tool to track patients in real time and predict, for instance, who will respond to a treatment and identify emerging resistance.”

In terms of predicting responses to treatment, the plasmaMATCH trial assessed ctDNA in 1,034 patients with advanced breast cancer for mutations in ESR1, HER2, and AKT1 using digital droplet polymerase chain reaction (PCR) and Guardant360. Results showed that 357 (34.5%) of these patients had potentially targetable aberrations, including 222 patients with ESR1 mutations, 36 patients with HER2 mutations, and 30 patients with AKT1 mutations.

Agreement between digital droplet PCR and Guardant360 testing was 96%-99%, and liquid biopsy showed 93% sensitivity compared with tumor samples. The investigators also used liquid biopsy findings to match patients’ mutations to targeted treatments: fulvestrant for those with ESR1 mutations, neratinib for HER2 (ERBB2) mutations, and the selective AKT inhibitor capivasertib for estrogen receptor–positive tumors with AKT1 mutations.

Overall, the investigators concluded that ctDNA testing offers “accurate tumor genotyping” in line with tissue-based testing and is ready for routine clinical practice to identify common as well as rare genetic alterations, such as HER2 and AKT1 mutations, that affect only about 5% of patients with advanced disease.

Predicting survival and recurrence

A particularly promising area for liquid biopsy is its usefulness in helping to predict survival outcomes and monitor patients for early signs of recurrence before metastasis occurs. But the data to support this are still in their infancy.

A highly cited study, published over 15 years ago in the New England Journal of Medicine, found that patients with MBC who had five or more CTCs per 7.5 mL of whole blood before receiving first-line therapy exhibited significantly shorter median PFS (2.7 vs 7.0 months) and OS (10 vs > 18 months) compared with patients with fewer than five CTCs. Subsequent analyses performed more than a decade later, including a meta-analysis published last year, helped validate these early findings that levels of CTCs detected in the blood independently and strongly predicted PFS and OS in patients with MBC.

In addition, ctDNA can provide important information about patients’ survival odds. In a retrospective study published last year, investigators tracked changes in ctDNA in 291 plasma samples from 84 patients with locally advanced breast cancer who participated in the I-SPY trial. Patients who remained ctDNA-positive after 3 weeks of neoadjuvant chemotherapy were significantly more likely to have residual disease after completing their treatment compared with patients who cleared ctDNA at that early stage (83% for those with nonpathologic complete response vs 52%). Notably, the presence of ctDNA between therapy initiation and completion was associated with a significantly greater risk for metastatic recurrence, whereas clearance of ctDNA after neoadjuvant therapy was linked to improved survival.

“The study is important because it highlights how tracking circulating ctDNA status in neoadjuvant-treated breast cancer can expose a patient’s risk for distant metastasis,” said Dr. Yuan. But, she added, “I think the biggest attraction of liquid biopsy will be the ability to detect molecular disease even before imaging can, and identify who has a high risk for recurrence.”

Dr. Razavi agreed that the potential to prevent metastasis by finding minimal residual disease (MRD) is the most exciting area of liquid biopsy research. “If we can find tumor DNA early before tumors have a chance to establish themselves, we could potentially change the trajectory of the disease for patients,” he said.

Several studies suggest that monitoring patients’ ctDNA levels after neoadjuvant treatment and surgery may help predict their risk for relapse and progression to metastatic disease. A 2015 analysis, which followed 20 patients with breast cancer after surgery, found that ctDNA monitoring accurately differentiated those who ultimately developed metastatic disease from those who didn’t (sensitivity, 93%; specificity, 100%) and detected metastatic disease 11 months earlier, on average, than imaging did. Another 2015 study found that the presence of ctDNA in plasma after neoadjuvant chemotherapy and surgery predicted metastatic relapse a median of almost 8 months before clinical detection. Other recent data show the power of ultrasensitive blood tests to detect MRD and potentially find metastatic disease early.

Although an increasing number of studies show that ctDNA and CTCs are prognostic for breast cancer recurrence, a major question remains: For patients with ctDNA or CTCs but no overt disease after imaging, will initiating therapy prevent or delay the development of metastatic disease?

“We still have to do those clinical trials to determine whether detecting MRD and treating patients early actually positively affects their survival and quality of life,” Dr. Razavi said.

Identifying the molecular features of metastatic breast cancer (MBC) offers a real-time window into a patient’s treatment options as well as the potential to follow the disease as it evolves over time.
 

Tissue biopsy remains the gold standard for characterizing tumor biology and guiding therapeutic decisions, but liquid biopsies — blood analyses that allow oncologists to detect circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in the blood — are increasingly demonstrating their value. Last year, the U.S. Food and Drug Administration (FDA) approved two liquid biopsy tests, Guardant360 CDx and FoundationOne Liquid CDx, that can identify more than 300 cancer-related genes in the blood. In 2019, the FDA also approved the first companion diagnostic test, therascreen, to pinpoint PIK3CA gene mutations in patients’ ctDNA and determine whether patients should receive the PI3K inhibitor alpelisib along with fulvestrant.

Here’s an overview of how liquid biopsy is being used in monitoring MBC progression and treatment — and what some oncologists think of it.

What we do and don’t know

“Identifying a patient’s targetable mutations, most notably PIK3CA mutations, is currently the main use of liquid biopsy,” said Pedram Razavi, MD, PhD, a medical oncologist who leads the liquid biopsy program for breast cancer at Memorial Sloan Kettering (MSK) Cancer Center in New York City. “Patients who come to MSK are offered a tumor and liquid biopsy at the time of metastatic diagnosis as part of the standard of care.”

Liquid and tissue biopsy analyses can provide a more complete picture of a patient’s condition. Whereas tissue biopsy allows oncologists to target a more saturated sample of the cancer ecosystem and a wider array of biomarkers, liquid biopsy offers important advantages as well, including a less invasive way to sequence a sample, monitor patients’ treatment response, or track tumor evolution. Liquid biopsy also provides a bigger picture view of tumor heterogeneity by pooling information from many tumor locations as opposed to one.

But, cautioned Yuan Yuan, MD, PhD, liquid biopsy technology is not always sensitive enough to detect CTCs, ctDNA, or all relevant mutations. “When you collect a small tube of blood, you’re essentially trying to catch a small fish in a big sea and wading through a lot of background noise,” said Dr. Yuan, medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County. “The results may be hard to interpret or come back inconclusive.”

And although emerging data suggest that liquid biopsy provides important insights about tumor dynamics — including mapping disease progression, predicting survival, and even detecting signs of cancer recurrence before metastasis develops — the tool has limited utility in clinical practice outside of identifying sensitivity to various therapies or drugs.

“Right now, a lot of research is being done to understand how to use CTC and ctDNA in particular as a means of surveillance in breast cancer, but we’re still in the beginning stages of applying that outside of clinical trials,” said Joseph A. Sparano, MD, deputy director of the Tisch Cancer Institute and chief of the division of hematology and medical oncology, Icahn School of Medicine at Mount Sinai, New York City.

Personalizing treatment

The companion diagnostic test therascreen marked the beginning stages of using liquid biopsy to match treatments to genetic abnormalities in MBC. The SOLAR-1 phase 3 trial, which led to the approval of alpelisib and therascreen, found that the PI3K inhibitor plus fulvestrant almost doubled progression-free survival (PFS) (11 months vs 5.7 months in placebo-fulvestrant group) in patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer.

More recent studies have shown that liquid biopsy tests can also identify ESR1 mutations and predict responses to inhibitors that target AKT1 and HER2. Investigators presenting at the 2021 American Society of Clinical Oncology meeting reported that next-generation sequencing of ctDNA in patients with HR-positive MBC, HER-positive MBC, or triple-negative breast cancer detected ESR1 mutations in 14% of patients (71 of 501). Moreover, ESR1 mutations were found only in HR-positive patients who had already received endocrine therapy. (The study also examined PIK3CA mutations, which occurred in about one third of patients). A more in-depth look revealed that ESR1 mutations were strongly associated with liver and bone metastases and that mutations along specific codons negatively affected overall survival (OS) and PFS: codons 537 and 538 for OS and codons 380 and 536 for PFS.

According to Debasish Tripathy, MD, professor and chairman of the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, in addition to tumor sequencing, “liquid biopsy has become a great research tool to track patients in real time and predict, for instance, who will respond to a treatment and identify emerging resistance.”

In terms of predicting responses to treatment, the plasmaMATCH trial assessed ctDNA in 1,034 patients with advanced breast cancer for mutations in ESR1, HER2, and AKT1 using digital droplet polymerase chain reaction (PCR) and Guardant360. Results showed that 357 (34.5%) of these patients had potentially targetable aberrations, including 222 patients with ESR1 mutations, 36 patients with HER2 mutations, and 30 patients with AKT1 mutations.

Agreement between digital droplet PCR and Guardant360 testing was 96%-99%, and liquid biopsy showed 93% sensitivity compared with tumor samples. The investigators also used liquid biopsy findings to match patients’ mutations to targeted treatments: fulvestrant for those with ESR1 mutations, neratinib for HER2 (ERBB2) mutations, and the selective AKT inhibitor capivasertib for estrogen receptor–positive tumors with AKT1 mutations.

Overall, the investigators concluded that ctDNA testing offers “accurate tumor genotyping” in line with tissue-based testing and is ready for routine clinical practice to identify common as well as rare genetic alterations, such as HER2 and AKT1 mutations, that affect only about 5% of patients with advanced disease.

Predicting survival and recurrence

A particularly promising area for liquid biopsy is its usefulness in helping to predict survival outcomes and monitor patients for early signs of recurrence before metastasis occurs. But the data to support this are still in their infancy.

A highly cited study, published over 15 years ago in the New England Journal of Medicine, found that patients with MBC who had five or more CTCs per 7.5 mL of whole blood before receiving first-line therapy exhibited significantly shorter median PFS (2.7 vs 7.0 months) and OS (10 vs > 18 months) compared with patients with fewer than five CTCs. Subsequent analyses performed more than a decade later, including a meta-analysis published last year, helped validate these early findings that levels of CTCs detected in the blood independently and strongly predicted PFS and OS in patients with MBC.

In addition, ctDNA can provide important information about patients’ survival odds. In a retrospective study published last year, investigators tracked changes in ctDNA in 291 plasma samples from 84 patients with locally advanced breast cancer who participated in the I-SPY trial. Patients who remained ctDNA-positive after 3 weeks of neoadjuvant chemotherapy were significantly more likely to have residual disease after completing their treatment compared with patients who cleared ctDNA at that early stage (83% for those with nonpathologic complete response vs 52%). Notably, the presence of ctDNA between therapy initiation and completion was associated with a significantly greater risk for metastatic recurrence, whereas clearance of ctDNA after neoadjuvant therapy was linked to improved survival.

“The study is important because it highlights how tracking circulating ctDNA status in neoadjuvant-treated breast cancer can expose a patient’s risk for distant metastasis,” said Dr. Yuan. But, she added, “I think the biggest attraction of liquid biopsy will be the ability to detect molecular disease even before imaging can, and identify who has a high risk for recurrence.”

Dr. Razavi agreed that the potential to prevent metastasis by finding minimal residual disease (MRD) is the most exciting area of liquid biopsy research. “If we can find tumor DNA early before tumors have a chance to establish themselves, we could potentially change the trajectory of the disease for patients,” he said.

Several studies suggest that monitoring patients’ ctDNA levels after neoadjuvant treatment and surgery may help predict their risk for relapse and progression to metastatic disease. A 2015 analysis, which followed 20 patients with breast cancer after surgery, found that ctDNA monitoring accurately differentiated those who ultimately developed metastatic disease from those who didn’t (sensitivity, 93%; specificity, 100%) and detected metastatic disease 11 months earlier, on average, than imaging did. Another 2015 study found that the presence of ctDNA in plasma after neoadjuvant chemotherapy and surgery predicted metastatic relapse a median of almost 8 months before clinical detection. Other recent data show the power of ultrasensitive blood tests to detect MRD and potentially find metastatic disease early.

Although an increasing number of studies show that ctDNA and CTCs are prognostic for breast cancer recurrence, a major question remains: For patients with ctDNA or CTCs but no overt disease after imaging, will initiating therapy prevent or delay the development of metastatic disease?

“We still have to do those clinical trials to determine whether detecting MRD and treating patients early actually positively affects their survival and quality of life,” Dr. Razavi said.

Identifying biomarkers in metastatic breast cancer (MBC) has become an integral part of choosing treatments and understanding disease progression. The American Society of Clinical Oncology Clinical Practice Guideline, published in 2015, recommends an initial biopsy to confirm estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) status as well as repeat biopsies to watch for receptor status changes over time.
 

“Decisions concerning the initiation of systemic therapy or selection of systemic therapy for metastatic breast cancer should be guided by ER, PR, and HER2 status in conjunction with clinical evaluation, judgment, and the patient’s goals for care,” according to the guideline authors.Along with tumor subtypes, experts continue to identify a host of other actionable targets that can shape treatment decisions. This news organization reached out to Kelly McCann, MD, PhD, a hematologist and oncologist in the department of medicine at the David Geffen School of Medicine, University of California, Los Angeles, to explore the role biomarker testing plays in managing MBC.

Question: How important is biomarker testing in guiding MBC treatments? Is there a standard or recommended process?

Dr. McCann: Biomarker testing is essential to breast cancer treatment and the development of targeted therapies. Oncologists typically identify a tumor’s canonical biomarkers — ER, PR, and HER2 — using immunohistochemistry or fluorescence in situ hybridization (FISH) testing and then try to match the tumor biology to drugs that target that subtype.

McGann_Kelly_LA_web.JPG

For tumors that lack canonical biomarkers — for example, triple-negative breast cancer (TNBC) — I send the tumor tissue for next-generation sequencing at the time of metastatic diagnosis to identify a wider range of potential targets or oncogenic drivers, such as somatic or germline mutations in homologous recombination repair genes ( BRCA1, BRCA2, and PALB2 ) or mutations in the PI3K/AKT/mTOR pathway.

In our attempts to define tumor biology and design a treatment strategy, two additional issues quickly arise. First, tumors are heterogeneous from the start. Second, tumors evolve.

Let’s start with how we define or subtype a tumor. Would you walk us through this process?

Defining a breast tumor can be tricky because these cancers often don’t fit neatly into predefined categories. Let’s take the estrogen receptor. In clinical trials, we need to define the cutoff for what constitutes ER-positive MBC or TNBC. Some trials define ER-positive as 1% or greater, others define it as 10% or greater.

But is a PR- and HER2-negative tumor with 1% or even 5% ER expression really ER-positive in the biological or prognostic sense? Probably not. A tumor with less than 10% ER expression, for instance, will actually behave like a triple-negative tumor. Instead of choosing a regimen targeting the ER-positive cells, I’ll lean more toward cytotoxic chemotherapy, the standard treatment for TNBC.

Tumors may have multiple drivers as well. What are some aberrations in addition to the main subtypes?

Tumors also often harbor more than one targetable driver. For instance, PIK3CA gene mutations are present in about 40% of hormone receptor–positive, HER2-negative tumors. Activating mutations in ESR1 develop in anywhere from 10% to 50% of MBCs as a resistance mechanism to estrogen deprivation therapy, conferring estrogen independence to the cells. Activating mutations in ERBB2, which essentially turns HER2 into an active receptor, are found in 2%-4% of breast cancers, including ER-positive, HER2-mutant breast cancers, and are enriched in lobular breast cancers, which are typically ER positive, HER2 negative.

What about tumor evolution, given the growing body of evidence that biomarker status in MBC can change over time?

Patients with MBC often have several active areas of cancer, and these areas will evolve differently. During each line of treatment, some metastases will develop resistance and others won’t. For instance, if my patient’s liver metastases start to grow, I will change therapy immediately. If, however, a single bone metastasis begins to grow and the liver metastases have responded well, I might consider local therapy — such as radiation — to target that bone metastasis, though this particular approach hasn’t been formally studied.

Ultimately, we can expect tumors to change over time as they become more biologically aggressive or resistant to current therapy. The most common biomarker change is probably loss of ER or PR expression, but the frequency of ER, PR, or HER2 biomarker changes is still not well understood.

Resistance mutations can also happen. When, for instance, activating mutations in ESR1 occur, the estrogen receptor becomes independent of estrogen and tumors then develop resistance to endocrine therapies. We see a similar problem arise in metastatic prostate cancer. With chronic testosterone deprivation, eventually the androgen receptor evolves to become independent of testosterone in a stage known as castrate-resistant prostate cancer.

Which biomarkers or combinations of biomarkers can be paired with an approved treatment?

We have a range of treatments targeting ER-positive and HER2-positive MBC in particular. For tumors harboring additional targetable mutations, preliminary data suggest that HER2-targeted tyrosine kinase inhibitors (TKIs), such as tucatinib and neratinib, are effective against activating mutations in ERBB2.

The PI3K inhibitor alpelisib in combination with fulvestrant has been approved for patients with ER-positive, HER2-negative MBC and mutations in PIK3CA. The mTOR inhibitor everolimus plus exemestane is an option for patients with ER-positive, HER2-negative. And for those with activating mutations in ESR1, I switch patients to a selective estrogen receptor degrader, such as fulvestrant.

PARP inhibitors, including olaparib or talazoparib, target metastatic HR-positive disease or TNBC with deleterious germline BRCA1 or BRCA2 mutations. Sacituzumab govitecan has been approved for treating metastatic TNBC and targets the cell surface protein TROP2, expressed in almost 90% of TNBC tumors.

What targets, on the other hand, are less informative for treatment choice?

When we order next-generation sequencing, we also will get a list of possible targets for which there are currently no therapeutic options, but there may be in the future. I find this knowledge is helpful. For example, an activating mutation in KRAS tells me that the cancer has a very strong oncogenic driver that I won›t be able to target. I know that activating KRAS mutations in lung cancer and colon cancer portend a poorer prognosis, which helps me to prepare the patient and family.

Atezolizumab in combination with paclitaxel has been FDA-approved for PD-L1 TNBC in the first-line setting, though data show that immune checkpoint inhibitors may be effective even without PD-L1 expression. Although cell surface protein TROP2 has emerged as a target in recent years, its expression is so common in TNBC that confirmatory testing for TROP2 expression is not required to prescribe sacituzumab govitecan.

What factors do you weigh when selecting among the large number of tests available for tumor testing?

We have many biomarker tests available, but the National Comprehensive Cancer Network does not have guidelines for tumor genetics testing in breast cancer. That means insurance does not have to cover the cost, and many companies don’t. Ultimately, though, drug companies and some testing companies have an incentive to cover the cost themselves because a companion diagnostic might be linked to their drug — therascreen PIK3CA RGQ PCR kit for alpelisib, for instance.

I tend not to use a companion diagnostic test because I want more information with a wider panel. The tumor tests I often use are FoundationOne CDx, Caris Molecular Intelligence, and Tempus. I use Tempus because their financial aid is very generous and almost all of my patients qualify to be tested for less than $100. For germline genetic testing, Invitae, Myriad, and Color are also options. Invitae and Color are about $250 out of pocket without insurance. Many academic centers have their own gene panels as well. 

How far have we come in identifying biomarkers in MBC?

Targeted treatment for breast cancer has advanced significantly since doing my PhD research in cancer biology about 15 years ago. Of course, targeted therapies for ER-positive and HER2-amplified cancers were available at that point, but many more have been developed. The most significant advance has been the development of efficient and affordable genome sequencing, which has led to these large panels and identification of therapeutic targets. We’ve also expanded our knowledge of genetic predispositions for breast cancer beyond BRCA1 and BRCA2, which not only allows us to preemptively advise patients and their families about cancer risks and recommendations for cancer screening, but also to select a therapy to target a cancer’s DNA repair deficits.

I feel that we are in an exciting discovery phase in oncology. We currently rely on biomarkers to manage MBC and will continue to refine our strategies and develop more effective drug therapies as we identify more oncogenic drivers, tumor-specific proteins, and cancer cell vulnerabilities.

Identifying biomarkers in metastatic breast cancer (MBC) has become an integral part of choosing treatments and understanding disease progression. The American Society of Clinical Oncology Clinical Practice Guideline, published in 2015, recommends an initial biopsy to confirm estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) status as well as repeat biopsies to watch for receptor status changes over time.
 

“Decisions concerning the initiation of systemic therapy or selection of systemic therapy for metastatic breast cancer should be guided by ER, PR, and HER2 status in conjunction with clinical evaluation, judgment, and the patient’s goals for care,” according to the guideline authors.Along with tumor subtypes, experts continue to identify a host of other actionable targets that can shape treatment decisions. This news organization reached out to Kelly McCann, MD, PhD, a hematologist and oncologist in the department of medicine at the David Geffen School of Medicine, University of California, Los Angeles, to explore the role biomarker testing plays in managing MBC.

Question: How important is biomarker testing in guiding MBC treatments? Is there a standard or recommended process?

Dr. McCann: Biomarker testing is essential to breast cancer treatment and the development of targeted therapies. Oncologists typically identify a tumor’s canonical biomarkers — ER, PR, and HER2 — using immunohistochemistry or fluorescence in situ hybridization (FISH) testing and then try to match the tumor biology to drugs that target that subtype.

McGann_Kelly_LA_web.JPG

For tumors that lack canonical biomarkers — for example, triple-negative breast cancer (TNBC) — I send the tumor tissue for next-generation sequencing at the time of metastatic diagnosis to identify a wider range of potential targets or oncogenic drivers, such as somatic or germline mutations in homologous recombination repair genes ( BRCA1, BRCA2, and PALB2 ) or mutations in the PI3K/AKT/mTOR pathway.

In our attempts to define tumor biology and design a treatment strategy, two additional issues quickly arise. First, tumors are heterogeneous from the start. Second, tumors evolve.

Let’s start with how we define or subtype a tumor. Would you walk us through this process?

Defining a breast tumor can be tricky because these cancers often don’t fit neatly into predefined categories. Let’s take the estrogen receptor. In clinical trials, we need to define the cutoff for what constitutes ER-positive MBC or TNBC. Some trials define ER-positive as 1% or greater, others define it as 10% or greater.

But is a PR- and HER2-negative tumor with 1% or even 5% ER expression really ER-positive in the biological or prognostic sense? Probably not. A tumor with less than 10% ER expression, for instance, will actually behave like a triple-negative tumor. Instead of choosing a regimen targeting the ER-positive cells, I’ll lean more toward cytotoxic chemotherapy, the standard treatment for TNBC.

Tumors may have multiple drivers as well. What are some aberrations in addition to the main subtypes?

Tumors also often harbor more than one targetable driver. For instance, PIK3CA gene mutations are present in about 40% of hormone receptor–positive, HER2-negative tumors. Activating mutations in ESR1 develop in anywhere from 10% to 50% of MBCs as a resistance mechanism to estrogen deprivation therapy, conferring estrogen independence to the cells. Activating mutations in ERBB2, which essentially turns HER2 into an active receptor, are found in 2%-4% of breast cancers, including ER-positive, HER2-mutant breast cancers, and are enriched in lobular breast cancers, which are typically ER positive, HER2 negative.

What about tumor evolution, given the growing body of evidence that biomarker status in MBC can change over time?

Patients with MBC often have several active areas of cancer, and these areas will evolve differently. During each line of treatment, some metastases will develop resistance and others won’t. For instance, if my patient’s liver metastases start to grow, I will change therapy immediately. If, however, a single bone metastasis begins to grow and the liver metastases have responded well, I might consider local therapy — such as radiation — to target that bone metastasis, though this particular approach hasn’t been formally studied.

Ultimately, we can expect tumors to change over time as they become more biologically aggressive or resistant to current therapy. The most common biomarker change is probably loss of ER or PR expression, but the frequency of ER, PR, or HER2 biomarker changes is still not well understood.

Resistance mutations can also happen. When, for instance, activating mutations in ESR1 occur, the estrogen receptor becomes independent of estrogen and tumors then develop resistance to endocrine therapies. We see a similar problem arise in metastatic prostate cancer. With chronic testosterone deprivation, eventually the androgen receptor evolves to become independent of testosterone in a stage known as castrate-resistant prostate cancer.

Which biomarkers or combinations of biomarkers can be paired with an approved treatment?

We have a range of treatments targeting ER-positive and HER2-positive MBC in particular. For tumors harboring additional targetable mutations, preliminary data suggest that HER2-targeted tyrosine kinase inhibitors (TKIs), such as tucatinib and neratinib, are effective against activating mutations in ERBB2.

The PI3K inhibitor alpelisib in combination with fulvestrant has been approved for patients with ER-positive, HER2-negative MBC and mutations in PIK3CA. The mTOR inhibitor everolimus plus exemestane is an option for patients with ER-positive, HER2-negative. And for those with activating mutations in ESR1, I switch patients to a selective estrogen receptor degrader, such as fulvestrant.

PARP inhibitors, including olaparib or talazoparib, target metastatic HR-positive disease or TNBC with deleterious germline BRCA1 or BRCA2 mutations. Sacituzumab govitecan has been approved for treating metastatic TNBC and targets the cell surface protein TROP2, expressed in almost 90% of TNBC tumors.

What targets, on the other hand, are less informative for treatment choice?

When we order next-generation sequencing, we also will get a list of possible targets for which there are currently no therapeutic options, but there may be in the future. I find this knowledge is helpful. For example, an activating mutation in KRAS tells me that the cancer has a very strong oncogenic driver that I won›t be able to target. I know that activating KRAS mutations in lung cancer and colon cancer portend a poorer prognosis, which helps me to prepare the patient and family.

Atezolizumab in combination with paclitaxel has been FDA-approved for PD-L1 TNBC in the first-line setting, though data show that immune checkpoint inhibitors may be effective even without PD-L1 expression. Although cell surface protein TROP2 has emerged as a target in recent years, its expression is so common in TNBC that confirmatory testing for TROP2 expression is not required to prescribe sacituzumab govitecan.

What factors do you weigh when selecting among the large number of tests available for tumor testing?

We have many biomarker tests available, but the National Comprehensive Cancer Network does not have guidelines for tumor genetics testing in breast cancer. That means insurance does not have to cover the cost, and many companies don’t. Ultimately, though, drug companies and some testing companies have an incentive to cover the cost themselves because a companion diagnostic might be linked to their drug — therascreen PIK3CA RGQ PCR kit for alpelisib, for instance.

I tend not to use a companion diagnostic test because I want more information with a wider panel. The tumor tests I often use are FoundationOne CDx, Caris Molecular Intelligence, and Tempus. I use Tempus because their financial aid is very generous and almost all of my patients qualify to be tested for less than $100. For germline genetic testing, Invitae, Myriad, and Color are also options. Invitae and Color are about $250 out of pocket without insurance. Many academic centers have their own gene panels as well. 

How far have we come in identifying biomarkers in MBC?

Targeted treatment for breast cancer has advanced significantly since doing my PhD research in cancer biology about 15 years ago. Of course, targeted therapies for ER-positive and HER2-amplified cancers were available at that point, but many more have been developed. The most significant advance has been the development of efficient and affordable genome sequencing, which has led to these large panels and identification of therapeutic targets. We’ve also expanded our knowledge of genetic predispositions for breast cancer beyond BRCA1 and BRCA2, which not only allows us to preemptively advise patients and their families about cancer risks and recommendations for cancer screening, but also to select a therapy to target a cancer’s DNA repair deficits.

I feel that we are in an exciting discovery phase in oncology. We currently rely on biomarkers to manage MBC and will continue to refine our strategies and develop more effective drug therapies as we identify more oncogenic drivers, tumor-specific proteins, and cancer cell vulnerabilities.

Identifying biomarkers in metastatic breast cancer (MBC) has become an integral part of choosing treatments and understanding disease progression. The American Society of Clinical Oncology Clinical Practice Guideline, published in 2015, recommends an initial biopsy to confirm estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) status as well as repeat biopsies to watch for receptor status changes over time.
 

“Decisions concerning the initiation of systemic therapy or selection of systemic therapy for metastatic breast cancer should be guided by ER, PR, and HER2 status in conjunction with clinical evaluation, judgment, and the patient’s goals for care,” according to the guideline authors.Along with tumor subtypes, experts continue to identify a host of other actionable targets that can shape treatment decisions. This news organization reached out to Kelly McCann, MD, PhD, a hematologist and oncologist in the department of medicine at the David Geffen School of Medicine, University of California, Los Angeles, to explore the role biomarker testing plays in managing MBC.

Question: How important is biomarker testing in guiding MBC treatments? Is there a standard or recommended process?

Dr. McCann: Biomarker testing is essential to breast cancer treatment and the development of targeted therapies. Oncologists typically identify a tumor’s canonical biomarkers — ER, PR, and HER2 — using immunohistochemistry or fluorescence in situ hybridization (FISH) testing and then try to match the tumor biology to drugs that target that subtype.

McGann_Kelly_LA_web.JPG

For tumors that lack canonical biomarkers — for example, triple-negative breast cancer (TNBC) — I send the tumor tissue for next-generation sequencing at the time of metastatic diagnosis to identify a wider range of potential targets or oncogenic drivers, such as somatic or germline mutations in homologous recombination repair genes ( BRCA1, BRCA2, and PALB2 ) or mutations in the PI3K/AKT/mTOR pathway.

In our attempts to define tumor biology and design a treatment strategy, two additional issues quickly arise. First, tumors are heterogeneous from the start. Second, tumors evolve.

Let’s start with how we define or subtype a tumor. Would you walk us through this process?

Defining a breast tumor can be tricky because these cancers often don’t fit neatly into predefined categories. Let’s take the estrogen receptor. In clinical trials, we need to define the cutoff for what constitutes ER-positive MBC or TNBC. Some trials define ER-positive as 1% or greater, others define it as 10% or greater.

But is a PR- and HER2-negative tumor with 1% or even 5% ER expression really ER-positive in the biological or prognostic sense? Probably not. A tumor with less than 10% ER expression, for instance, will actually behave like a triple-negative tumor. Instead of choosing a regimen targeting the ER-positive cells, I’ll lean more toward cytotoxic chemotherapy, the standard treatment for TNBC.

Tumors may have multiple drivers as well. What are some aberrations in addition to the main subtypes?

Tumors also often harbor more than one targetable driver. For instance, PIK3CA gene mutations are present in about 40% of hormone receptor–positive, HER2-negative tumors. Activating mutations in ESR1 develop in anywhere from 10% to 50% of MBCs as a resistance mechanism to estrogen deprivation therapy, conferring estrogen independence to the cells. Activating mutations in ERBB2, which essentially turns HER2 into an active receptor, are found in 2%-4% of breast cancers, including ER-positive, HER2-mutant breast cancers, and are enriched in lobular breast cancers, which are typically ER positive, HER2 negative.

What about tumor evolution, given the growing body of evidence that biomarker status in MBC can change over time?

Patients with MBC often have several active areas of cancer, and these areas will evolve differently. During each line of treatment, some metastases will develop resistance and others won’t. For instance, if my patient’s liver metastases start to grow, I will change therapy immediately. If, however, a single bone metastasis begins to grow and the liver metastases have responded well, I might consider local therapy — such as radiation — to target that bone metastasis, though this particular approach hasn’t been formally studied.

Ultimately, we can expect tumors to change over time as they become more biologically aggressive or resistant to current therapy. The most common biomarker change is probably loss of ER or PR expression, but the frequency of ER, PR, or HER2 biomarker changes is still not well understood.

Resistance mutations can also happen. When, for instance, activating mutations in ESR1 occur, the estrogen receptor becomes independent of estrogen and tumors then develop resistance to endocrine therapies. We see a similar problem arise in metastatic prostate cancer. With chronic testosterone deprivation, eventually the androgen receptor evolves to become independent of testosterone in a stage known as castrate-resistant prostate cancer.

Which biomarkers or combinations of biomarkers can be paired with an approved treatment?

We have a range of treatments targeting ER-positive and HER2-positive MBC in particular. For tumors harboring additional targetable mutations, preliminary data suggest that HER2-targeted tyrosine kinase inhibitors (TKIs), such as tucatinib and neratinib, are effective against activating mutations in ERBB2.

The PI3K inhibitor alpelisib in combination with fulvestrant has been approved for patients with ER-positive, HER2-negative MBC and mutations in PIK3CA. The mTOR inhibitor everolimus plus exemestane is an option for patients with ER-positive, HER2-negative. And for those with activating mutations in ESR1, I switch patients to a selective estrogen receptor degrader, such as fulvestrant.

PARP inhibitors, including olaparib or talazoparib, target metastatic HR-positive disease or TNBC with deleterious germline BRCA1 or BRCA2 mutations. Sacituzumab govitecan has been approved for treating metastatic TNBC and targets the cell surface protein TROP2, expressed in almost 90% of TNBC tumors.

What targets, on the other hand, are less informative for treatment choice?

When we order next-generation sequencing, we also will get a list of possible targets for which there are currently no therapeutic options, but there may be in the future. I find this knowledge is helpful. For example, an activating mutation in KRAS tells me that the cancer has a very strong oncogenic driver that I won›t be able to target. I know that activating KRAS mutations in lung cancer and colon cancer portend a poorer prognosis, which helps me to prepare the patient and family.

Atezolizumab in combination with paclitaxel has been FDA-approved for PD-L1 TNBC in the first-line setting, though data show that immune checkpoint inhibitors may be effective even without PD-L1 expression. Although cell surface protein TROP2 has emerged as a target in recent years, its expression is so common in TNBC that confirmatory testing for TROP2 expression is not required to prescribe sacituzumab govitecan.

What factors do you weigh when selecting among the large number of tests available for tumor testing?

We have many biomarker tests available, but the National Comprehensive Cancer Network does not have guidelines for tumor genetics testing in breast cancer. That means insurance does not have to cover the cost, and many companies don’t. Ultimately, though, drug companies and some testing companies have an incentive to cover the cost themselves because a companion diagnostic might be linked to their drug — therascreen PIK3CA RGQ PCR kit for alpelisib, for instance.

I tend not to use a companion diagnostic test because I want more information with a wider panel. The tumor tests I often use are FoundationOne CDx, Caris Molecular Intelligence, and Tempus. I use Tempus because their financial aid is very generous and almost all of my patients qualify to be tested for less than $100. For germline genetic testing, Invitae, Myriad, and Color are also options. Invitae and Color are about $250 out of pocket without insurance. Many academic centers have their own gene panels as well. 

How far have we come in identifying biomarkers in MBC?

Targeted treatment for breast cancer has advanced significantly since doing my PhD research in cancer biology about 15 years ago. Of course, targeted therapies for ER-positive and HER2-amplified cancers were available at that point, but many more have been developed. The most significant advance has been the development of efficient and affordable genome sequencing, which has led to these large panels and identification of therapeutic targets. We’ve also expanded our knowledge of genetic predispositions for breast cancer beyond BRCA1 and BRCA2, which not only allows us to preemptively advise patients and their families about cancer risks and recommendations for cancer screening, but also to select a therapy to target a cancer’s DNA repair deficits.

I feel that we are in an exciting discovery phase in oncology. We currently rely on biomarkers to manage MBC and will continue to refine our strategies and develop more effective drug therapies as we identify more oncogenic drivers, tumor-specific proteins, and cancer cell vulnerabilities.

Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.

Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.

While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.

“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”

Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
 

Two or more prior therapies for metastatic breast cancer

TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.

Longer PFS with trastuzumab duocarmazine

Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).

A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
 

Ocular toxicity

Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.

Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.

Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.

TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.

Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.

Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.

While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.

“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”

Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
 

Two or more prior therapies for metastatic breast cancer

TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.

Longer PFS with trastuzumab duocarmazine

Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).

A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
 

Ocular toxicity

Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.

Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.

Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.

TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.

Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.

Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.

While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.

“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”

Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
 

Two or more prior therapies for metastatic breast cancer

TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.

Longer PFS with trastuzumab duocarmazine

Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).

A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
 

Ocular toxicity

Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.

Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.

Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.

TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.