M. Alexander Otto, PA, MMS

The US Food and Drug Administration (FDA) has approved the gene therapy fidanacogene elaparvovec (Beqvez) for adults with hemophilia B, a rare bleeding disorder that affects almost 4 in 100,000 US men.

Patients are eligible for a one-time infusion of Pfizer’s gene therapy if they are currently using clotting factor IX prophylaxis therapy; have current or historical life-threatening hemorrhages; or have repeated, serious spontaneous bleeding episodes. 

Beqvez is the second gene therapy the agency has approved for hemophilia B, a deficiency in clotting factor IX because of a faulty gene that occurs mostly in males. The FDA approved the first gene therapy, etranacogene dezaparvovec (Hemgenix), in November 2022. 

Both therapies deliver a functional copy of the factor IX gene to liver cells via a viral vector. 

Pfizer said the list price of Beqvez will be $3.5 million — the same price as Hemgenix. The argument for this hefty price tag is that these gene therapies offer the possibility of a cure whereas ongoing factor IX infusions can cost more than $20 million over a patient’s lifetime. Uptake of Hemgenix, however, has been slow, given the cost and concerns about the therapy’s durability and safety.

Beqvez was approved on the basis of the phase 3 BENEGENE-2 trial in 45 men with moderate to severe hemophilia B. These men had been on factor IX prophylaxis for at least 6 months and had tested negative for antibodies against the viral delivery vector. 

The annualized bleeding rate fell from a mean of 4.5 events during the pretreatment period of at least 6 months to a mean of 2.5 events between week 12 and data cutoff (median, 1.8 years of follow-up), according to Pfizer’s press release. Overall, bleeding events were eliminated in 60% of patients who received the one-time infusion vs 29% of patients on factor IX prophylaxis therapy.

Overall, Pfizer reported that the gene therapy was “generally well-tolerated,” with an increase in transaminases reported as the most common adverse event. No deaths, serious infusion reactions, thrombotic events, or development of factor IX antibodies occurred. 

Pfizer has said it will continue to monitor patients to assess the therapy’s long-term durability and safety over a 15-year period.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved the gene therapy fidanacogene elaparvovec (Beqvez) for adults with hemophilia B, a rare bleeding disorder that affects almost 4 in 100,000 US men.

Patients are eligible for a one-time infusion of Pfizer’s gene therapy if they are currently using clotting factor IX prophylaxis therapy; have current or historical life-threatening hemorrhages; or have repeated, serious spontaneous bleeding episodes. 

Beqvez is the second gene therapy the agency has approved for hemophilia B, a deficiency in clotting factor IX because of a faulty gene that occurs mostly in males. The FDA approved the first gene therapy, etranacogene dezaparvovec (Hemgenix), in November 2022. 

Both therapies deliver a functional copy of the factor IX gene to liver cells via a viral vector. 

Pfizer said the list price of Beqvez will be $3.5 million — the same price as Hemgenix. The argument for this hefty price tag is that these gene therapies offer the possibility of a cure whereas ongoing factor IX infusions can cost more than $20 million over a patient’s lifetime. Uptake of Hemgenix, however, has been slow, given the cost and concerns about the therapy’s durability and safety.

Beqvez was approved on the basis of the phase 3 BENEGENE-2 trial in 45 men with moderate to severe hemophilia B. These men had been on factor IX prophylaxis for at least 6 months and had tested negative for antibodies against the viral delivery vector. 

The annualized bleeding rate fell from a mean of 4.5 events during the pretreatment period of at least 6 months to a mean of 2.5 events between week 12 and data cutoff (median, 1.8 years of follow-up), according to Pfizer’s press release. Overall, bleeding events were eliminated in 60% of patients who received the one-time infusion vs 29% of patients on factor IX prophylaxis therapy.

Overall, Pfizer reported that the gene therapy was “generally well-tolerated,” with an increase in transaminases reported as the most common adverse event. No deaths, serious infusion reactions, thrombotic events, or development of factor IX antibodies occurred. 

Pfizer has said it will continue to monitor patients to assess the therapy’s long-term durability and safety over a 15-year period.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved the gene therapy fidanacogene elaparvovec (Beqvez) for adults with hemophilia B, a rare bleeding disorder that affects almost 4 in 100,000 US men.

Patients are eligible for a one-time infusion of Pfizer’s gene therapy if they are currently using clotting factor IX prophylaxis therapy; have current or historical life-threatening hemorrhages; or have repeated, serious spontaneous bleeding episodes. 

Beqvez is the second gene therapy the agency has approved for hemophilia B, a deficiency in clotting factor IX because of a faulty gene that occurs mostly in males. The FDA approved the first gene therapy, etranacogene dezaparvovec (Hemgenix), in November 2022. 

Both therapies deliver a functional copy of the factor IX gene to liver cells via a viral vector. 

Pfizer said the list price of Beqvez will be $3.5 million — the same price as Hemgenix. The argument for this hefty price tag is that these gene therapies offer the possibility of a cure whereas ongoing factor IX infusions can cost more than $20 million over a patient’s lifetime. Uptake of Hemgenix, however, has been slow, given the cost and concerns about the therapy’s durability and safety.

Beqvez was approved on the basis of the phase 3 BENEGENE-2 trial in 45 men with moderate to severe hemophilia B. These men had been on factor IX prophylaxis for at least 6 months and had tested negative for antibodies against the viral delivery vector. 

The annualized bleeding rate fell from a mean of 4.5 events during the pretreatment period of at least 6 months to a mean of 2.5 events between week 12 and data cutoff (median, 1.8 years of follow-up), according to Pfizer’s press release. Overall, bleeding events were eliminated in 60% of patients who received the one-time infusion vs 29% of patients on factor IX prophylaxis therapy.

Overall, Pfizer reported that the gene therapy was “generally well-tolerated,” with an increase in transaminases reported as the most common adverse event. No deaths, serious infusion reactions, thrombotic events, or development of factor IX antibodies occurred. 

Pfizer has said it will continue to monitor patients to assess the therapy’s long-term durability and safety over a 15-year period.

A version of this article appeared on Medscape.com.

SAN DIEGO — When should patients with advanced or metastatic non–small cell lung cancer receive osimertinib plus platinum-based chemotherapy in the frontline setting and when is osimertinib enough on its own?

That is a question brewing among some oncologists now that the US Food and Drug Administration (FDA) has approved osimertinib (Tagrisso, AstraZeneca) for both indications in patients with epidermal growth factor receptor (EGFR) mutations.

An answer began to emerge in research presented at the American Association for Cancer Research annual meeting.

An exploratory analysis of the FLAURA2 trial found that, when patients have EGFR mutations on baseline circulating tumor DNA (ctDNA) testing, the combination treatment can extend progression-free survival (PFS). In this patient group, those receiving osimertinib alongside pemetrexed plus cisplatin or carboplatin had a 9-month PFS advantage compared with those who received osimertinib alone.

Conversely, when patients do not have EGFR mutations following baseline ctDNA testing, osimertinib alone appears to offer similar PFS outcomes to the combination therapy, but with less toxicity.

“Baseline detection of plasma EGFR mutations may identify a subgroup of patients who derive most benefit from the addition of platinum-pemetrexed to osimertinib as first-line treatment of EGFR-mutated advance non–small cell lung cancer,” investigator Pasi A. Jänne, MD, PhD, a lung cancer oncologist at the Dana-Farber Cancer Institute, Boston, said during his presentation.

The FLAURA2 trial randomized 557 patients equally to daily osimertinib either alone or with pemetrexed plus cisplatin or carboplatin every 3 weeks for four cycles followed by pemetrexed every 3 weeks until disease progression or unacceptable toxicity.

Patients were tested for Ex19del or L858R EGFR mutations at baseline and at 3 and 6 weeks; baseline mutations were found in 73% of evaluable patients.

In patients with baseline mutations, the median PFS was 24.8 months with the combination therapy vs 13.9 months with osimertinib alone (hazard ratio [HR], 0.60).

In patients without baseline mutations, the median PFS was similar in both groups — 33.3 months with the combination vs 30.3 months with monotherapy (HR, 0.93; 95% CI, 0.51-1.72).

The investigators also found that having baseline mutations was associated with worse outcomes regardless of study arm, and mutation clearance was associated with improved outcomes. Clearance occurred more quickly among patients receiving the combination treatment, but almost 90% of patients in both arms cleared their mutations by week 6.

“As we move forward and think about which of our patients we would treat with the combination ... the presence of baseline EGFR mutations in ctDNA may be one of the features that goes into the conversation,” Dr. Jänne said.

Study discussant Marina Chiara Garassino, MD, a thoracic oncologist at the University of Chicago, agreed that this trial can help oncologists make this kind of treatment decision.

Patients with baseline EGFR mutations also tended to have larger tumors, more brain metastases, and worse performance scores; the combination therapy makes sense when such factors are present in patients with baseline EGFR mutations, Dr. Garassino said.

The wrinkle in the findings is that the study used digital droplet polymerase chain reaction (Biodesix) to test for EGFR mutations, which is not commonly used. Clinicians often use next-generation sequencing, which is less sensitive and can lead to false negatives.

It makes it difficult to know how to apply the findings to everyday practice, but Janne hopes a study will be done to correlate next-generation sequencing detection with outcomes.

The study was funded by AstraZeneca, maker of osimertinib, and researchers included AstraZeneca employees. Dr. Jänne is a consultant for and reported research funding from the company. He is a co-inventor on an EGFR mutations patent. Dr. Garassino is also an AstraZeneca consultant and reported institutional financial interests in the company.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — When should patients with advanced or metastatic non–small cell lung cancer receive osimertinib plus platinum-based chemotherapy in the frontline setting and when is osimertinib enough on its own?

That is a question brewing among some oncologists now that the US Food and Drug Administration (FDA) has approved osimertinib (Tagrisso, AstraZeneca) for both indications in patients with epidermal growth factor receptor (EGFR) mutations.

An answer began to emerge in research presented at the American Association for Cancer Research annual meeting.

An exploratory analysis of the FLAURA2 trial found that, when patients have EGFR mutations on baseline circulating tumor DNA (ctDNA) testing, the combination treatment can extend progression-free survival (PFS). In this patient group, those receiving osimertinib alongside pemetrexed plus cisplatin or carboplatin had a 9-month PFS advantage compared with those who received osimertinib alone.

Conversely, when patients do not have EGFR mutations following baseline ctDNA testing, osimertinib alone appears to offer similar PFS outcomes to the combination therapy, but with less toxicity.

“Baseline detection of plasma EGFR mutations may identify a subgroup of patients who derive most benefit from the addition of platinum-pemetrexed to osimertinib as first-line treatment of EGFR-mutated advance non–small cell lung cancer,” investigator Pasi A. Jänne, MD, PhD, a lung cancer oncologist at the Dana-Farber Cancer Institute, Boston, said during his presentation.

The FLAURA2 trial randomized 557 patients equally to daily osimertinib either alone or with pemetrexed plus cisplatin or carboplatin every 3 weeks for four cycles followed by pemetrexed every 3 weeks until disease progression or unacceptable toxicity.

Patients were tested for Ex19del or L858R EGFR mutations at baseline and at 3 and 6 weeks; baseline mutations were found in 73% of evaluable patients.

In patients with baseline mutations, the median PFS was 24.8 months with the combination therapy vs 13.9 months with osimertinib alone (hazard ratio [HR], 0.60).

In patients without baseline mutations, the median PFS was similar in both groups — 33.3 months with the combination vs 30.3 months with monotherapy (HR, 0.93; 95% CI, 0.51-1.72).

The investigators also found that having baseline mutations was associated with worse outcomes regardless of study arm, and mutation clearance was associated with improved outcomes. Clearance occurred more quickly among patients receiving the combination treatment, but almost 90% of patients in both arms cleared their mutations by week 6.

“As we move forward and think about which of our patients we would treat with the combination ... the presence of baseline EGFR mutations in ctDNA may be one of the features that goes into the conversation,” Dr. Jänne said.

Study discussant Marina Chiara Garassino, MD, a thoracic oncologist at the University of Chicago, agreed that this trial can help oncologists make this kind of treatment decision.

Patients with baseline EGFR mutations also tended to have larger tumors, more brain metastases, and worse performance scores; the combination therapy makes sense when such factors are present in patients with baseline EGFR mutations, Dr. Garassino said.

The wrinkle in the findings is that the study used digital droplet polymerase chain reaction (Biodesix) to test for EGFR mutations, which is not commonly used. Clinicians often use next-generation sequencing, which is less sensitive and can lead to false negatives.

It makes it difficult to know how to apply the findings to everyday practice, but Janne hopes a study will be done to correlate next-generation sequencing detection with outcomes.

The study was funded by AstraZeneca, maker of osimertinib, and researchers included AstraZeneca employees. Dr. Jänne is a consultant for and reported research funding from the company. He is a co-inventor on an EGFR mutations patent. Dr. Garassino is also an AstraZeneca consultant and reported institutional financial interests in the company.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — When should patients with advanced or metastatic non–small cell lung cancer receive osimertinib plus platinum-based chemotherapy in the frontline setting and when is osimertinib enough on its own?

That is a question brewing among some oncologists now that the US Food and Drug Administration (FDA) has approved osimertinib (Tagrisso, AstraZeneca) for both indications in patients with epidermal growth factor receptor (EGFR) mutations.

An answer began to emerge in research presented at the American Association for Cancer Research annual meeting.

An exploratory analysis of the FLAURA2 trial found that, when patients have EGFR mutations on baseline circulating tumor DNA (ctDNA) testing, the combination treatment can extend progression-free survival (PFS). In this patient group, those receiving osimertinib alongside pemetrexed plus cisplatin or carboplatin had a 9-month PFS advantage compared with those who received osimertinib alone.

Conversely, when patients do not have EGFR mutations following baseline ctDNA testing, osimertinib alone appears to offer similar PFS outcomes to the combination therapy, but with less toxicity.

“Baseline detection of plasma EGFR mutations may identify a subgroup of patients who derive most benefit from the addition of platinum-pemetrexed to osimertinib as first-line treatment of EGFR-mutated advance non–small cell lung cancer,” investigator Pasi A. Jänne, MD, PhD, a lung cancer oncologist at the Dana-Farber Cancer Institute, Boston, said during his presentation.

The FLAURA2 trial randomized 557 patients equally to daily osimertinib either alone or with pemetrexed plus cisplatin or carboplatin every 3 weeks for four cycles followed by pemetrexed every 3 weeks until disease progression or unacceptable toxicity.

Patients were tested for Ex19del or L858R EGFR mutations at baseline and at 3 and 6 weeks; baseline mutations were found in 73% of evaluable patients.

In patients with baseline mutations, the median PFS was 24.8 months with the combination therapy vs 13.9 months with osimertinib alone (hazard ratio [HR], 0.60).

In patients without baseline mutations, the median PFS was similar in both groups — 33.3 months with the combination vs 30.3 months with monotherapy (HR, 0.93; 95% CI, 0.51-1.72).

The investigators also found that having baseline mutations was associated with worse outcomes regardless of study arm, and mutation clearance was associated with improved outcomes. Clearance occurred more quickly among patients receiving the combination treatment, but almost 90% of patients in both arms cleared their mutations by week 6.

“As we move forward and think about which of our patients we would treat with the combination ... the presence of baseline EGFR mutations in ctDNA may be one of the features that goes into the conversation,” Dr. Jänne said.

Study discussant Marina Chiara Garassino, MD, a thoracic oncologist at the University of Chicago, agreed that this trial can help oncologists make this kind of treatment decision.

Patients with baseline EGFR mutations also tended to have larger tumors, more brain metastases, and worse performance scores; the combination therapy makes sense when such factors are present in patients with baseline EGFR mutations, Dr. Garassino said.

The wrinkle in the findings is that the study used digital droplet polymerase chain reaction (Biodesix) to test for EGFR mutations, which is not commonly used. Clinicians often use next-generation sequencing, which is less sensitive and can lead to false negatives.

It makes it difficult to know how to apply the findings to everyday practice, but Janne hopes a study will be done to correlate next-generation sequencing detection with outcomes.

The study was funded by AstraZeneca, maker of osimertinib, and researchers included AstraZeneca employees. Dr. Jänne is a consultant for and reported research funding from the company. He is a co-inventor on an EGFR mutations patent. Dr. Garassino is also an AstraZeneca consultant and reported institutional financial interests in the company.
 

A version of this article appeared on Medscape.com.

There have been many attempts to use immunotherapy to improve outcomes in pancreatic cancer, but they haven’t worked out.

The trials, however, have focused on adding immune checkpoint inhibitors to chemotherapy in metastatic disease, leaving open the question of whether immunotherapy might have a role in the neoadjuvant setting before surgery.

In the first study to test the hypothesis, Zev A. Wainberg, MD, a gastrointestinal medical oncologist at the University of California Los Angeles, reported promising results at the American Association for Cancer Research annual meeting.

The small, single arm pilot study included 28 patients with borderline resectable pancreatic cancer, meaning that tumors had some degree of vascular involvement. About 20% of pancreatic tumors are borderline resectable, Dr. Wainberg said.

Patients received 480 mg of nivolumab intravenously every 4 weeks plus mFOLFIRINOX chemotherapy (oxaliplatin, irinotecan, leucovorin, and 5-fluorouracil) on days 1 and 15 of the 28-day cycle.

Patients who downstaged to resectable disease after three cycles went on to surgery; if not, treatment continued for another 3 months. The median number of cycles was 5.5, and almost all patients completed at least 3.

Overall, 19 of the 22 patients who proceeded to surgery (86%) had a pathologic response to neoadjuvant treatment with nivolumab: 2 complete responses, 2 near-complete responses, and 15 partial responses.

Among patients receiving surgery, 21 had R0 resections, meaning negative surgical margins with no tumor left behind. This is key because R0 resections predict longer survival, and “every effort should be made to achieve” this outcome, Dr. Wainberg said. The remaining patient had an R1 resection.

Median progression-free survival was 21.9 months among all patients and 27.3 months among the 22 patients who had resections.

Median overall survival was 34.6 months across the entire group and 44 months among those who had surgery. Overall, 82% of patients were alive at 12 months, and 77% were alive at 18 months.

The study outcomes, especially among the surgery cohort, stand in contrast to those observed in patients who receive the current standard neoadjuvant regimen for borderline resectable pancreatic cancer, mFOLFIRINOX alone, with studies finding a median overall survival of 29.8 months.

Adding nivolumab to neoadjuvant treatment also did not increase side effects. More than half of patients had grade 3 or worse adverse events, but they were all related to mFOLFIRINOX. There were no significant surgical complications, including no grade 2 or higher fistulas.

“We are very pleased” with the outcomes, Dr. Wainberg said. “We need to be studying [immune checkpoint inhibitors] earlier on in both borderline and locally advanced disease. Pancreatic cancer needs all the help it can get to engage immunity.”

Moderator Alice Ho, MD, a radiation oncologist at Duke University in Durham, North Carolina, called the R0 resection rate “stunning” in a “field that very much needs improvements and advancements.”

Dr. Ho also noted that the trial raises “a lot of interesting questions.”

For instance, why exactly is the addition of nivolumab seemingly improving outcomes?

The combination neoadjuvant therapy appeared to increase tertiary lymphoid structures, plasma cells, and CD4+ T cells — all indications that immunotherapy is having a positive impact — but the treatment also seemed to upregulate pathways for adenosine, an immunosuppressant associated with worse responses to checkpoint blockade.

A larger study is already in the works. In addition to a PD-1 blocker and mFOLFIRINOX, patients will receive a CD73 inhibitor to block adenosine production, Dr. Wainberg said.

Bristol Myers Squibb (BMS) provided the nivolumab used in the study. Dr. Wainberg is a consultant for and reported research funding from BMS and other companies. Dr. Ho had no relevant disclosures.
 

A version of this article appeared on Medscape.com.

There have been many attempts to use immunotherapy to improve outcomes in pancreatic cancer, but they haven’t worked out.

The trials, however, have focused on adding immune checkpoint inhibitors to chemotherapy in metastatic disease, leaving open the question of whether immunotherapy might have a role in the neoadjuvant setting before surgery.

In the first study to test the hypothesis, Zev A. Wainberg, MD, a gastrointestinal medical oncologist at the University of California Los Angeles, reported promising results at the American Association for Cancer Research annual meeting.

The small, single arm pilot study included 28 patients with borderline resectable pancreatic cancer, meaning that tumors had some degree of vascular involvement. About 20% of pancreatic tumors are borderline resectable, Dr. Wainberg said.

Patients received 480 mg of nivolumab intravenously every 4 weeks plus mFOLFIRINOX chemotherapy (oxaliplatin, irinotecan, leucovorin, and 5-fluorouracil) on days 1 and 15 of the 28-day cycle.

Patients who downstaged to resectable disease after three cycles went on to surgery; if not, treatment continued for another 3 months. The median number of cycles was 5.5, and almost all patients completed at least 3.

Overall, 19 of the 22 patients who proceeded to surgery (86%) had a pathologic response to neoadjuvant treatment with nivolumab: 2 complete responses, 2 near-complete responses, and 15 partial responses.

Among patients receiving surgery, 21 had R0 resections, meaning negative surgical margins with no tumor left behind. This is key because R0 resections predict longer survival, and “every effort should be made to achieve” this outcome, Dr. Wainberg said. The remaining patient had an R1 resection.

Median progression-free survival was 21.9 months among all patients and 27.3 months among the 22 patients who had resections.

Median overall survival was 34.6 months across the entire group and 44 months among those who had surgery. Overall, 82% of patients were alive at 12 months, and 77% were alive at 18 months.

The study outcomes, especially among the surgery cohort, stand in contrast to those observed in patients who receive the current standard neoadjuvant regimen for borderline resectable pancreatic cancer, mFOLFIRINOX alone, with studies finding a median overall survival of 29.8 months.

Adding nivolumab to neoadjuvant treatment also did not increase side effects. More than half of patients had grade 3 or worse adverse events, but they were all related to mFOLFIRINOX. There were no significant surgical complications, including no grade 2 or higher fistulas.

“We are very pleased” with the outcomes, Dr. Wainberg said. “We need to be studying [immune checkpoint inhibitors] earlier on in both borderline and locally advanced disease. Pancreatic cancer needs all the help it can get to engage immunity.”

Moderator Alice Ho, MD, a radiation oncologist at Duke University in Durham, North Carolina, called the R0 resection rate “stunning” in a “field that very much needs improvements and advancements.”

Dr. Ho also noted that the trial raises “a lot of interesting questions.”

For instance, why exactly is the addition of nivolumab seemingly improving outcomes?

The combination neoadjuvant therapy appeared to increase tertiary lymphoid structures, plasma cells, and CD4+ T cells — all indications that immunotherapy is having a positive impact — but the treatment also seemed to upregulate pathways for adenosine, an immunosuppressant associated with worse responses to checkpoint blockade.

A larger study is already in the works. In addition to a PD-1 blocker and mFOLFIRINOX, patients will receive a CD73 inhibitor to block adenosine production, Dr. Wainberg said.

Bristol Myers Squibb (BMS) provided the nivolumab used in the study. Dr. Wainberg is a consultant for and reported research funding from BMS and other companies. Dr. Ho had no relevant disclosures.
 

A version of this article appeared on Medscape.com.

There have been many attempts to use immunotherapy to improve outcomes in pancreatic cancer, but they haven’t worked out.

The trials, however, have focused on adding immune checkpoint inhibitors to chemotherapy in metastatic disease, leaving open the question of whether immunotherapy might have a role in the neoadjuvant setting before surgery.

In the first study to test the hypothesis, Zev A. Wainberg, MD, a gastrointestinal medical oncologist at the University of California Los Angeles, reported promising results at the American Association for Cancer Research annual meeting.

The small, single arm pilot study included 28 patients with borderline resectable pancreatic cancer, meaning that tumors had some degree of vascular involvement. About 20% of pancreatic tumors are borderline resectable, Dr. Wainberg said.

Patients received 480 mg of nivolumab intravenously every 4 weeks plus mFOLFIRINOX chemotherapy (oxaliplatin, irinotecan, leucovorin, and 5-fluorouracil) on days 1 and 15 of the 28-day cycle.

Patients who downstaged to resectable disease after three cycles went on to surgery; if not, treatment continued for another 3 months. The median number of cycles was 5.5, and almost all patients completed at least 3.

Overall, 19 of the 22 patients who proceeded to surgery (86%) had a pathologic response to neoadjuvant treatment with nivolumab: 2 complete responses, 2 near-complete responses, and 15 partial responses.

Among patients receiving surgery, 21 had R0 resections, meaning negative surgical margins with no tumor left behind. This is key because R0 resections predict longer survival, and “every effort should be made to achieve” this outcome, Dr. Wainberg said. The remaining patient had an R1 resection.

Median progression-free survival was 21.9 months among all patients and 27.3 months among the 22 patients who had resections.

Median overall survival was 34.6 months across the entire group and 44 months among those who had surgery. Overall, 82% of patients were alive at 12 months, and 77% were alive at 18 months.

The study outcomes, especially among the surgery cohort, stand in contrast to those observed in patients who receive the current standard neoadjuvant regimen for borderline resectable pancreatic cancer, mFOLFIRINOX alone, with studies finding a median overall survival of 29.8 months.

Adding nivolumab to neoadjuvant treatment also did not increase side effects. More than half of patients had grade 3 or worse adverse events, but they were all related to mFOLFIRINOX. There were no significant surgical complications, including no grade 2 or higher fistulas.

“We are very pleased” with the outcomes, Dr. Wainberg said. “We need to be studying [immune checkpoint inhibitors] earlier on in both borderline and locally advanced disease. Pancreatic cancer needs all the help it can get to engage immunity.”

Moderator Alice Ho, MD, a radiation oncologist at Duke University in Durham, North Carolina, called the R0 resection rate “stunning” in a “field that very much needs improvements and advancements.”

Dr. Ho also noted that the trial raises “a lot of interesting questions.”

For instance, why exactly is the addition of nivolumab seemingly improving outcomes?

The combination neoadjuvant therapy appeared to increase tertiary lymphoid structures, plasma cells, and CD4+ T cells — all indications that immunotherapy is having a positive impact — but the treatment also seemed to upregulate pathways for adenosine, an immunosuppressant associated with worse responses to checkpoint blockade.

A larger study is already in the works. In addition to a PD-1 blocker and mFOLFIRINOX, patients will receive a CD73 inhibitor to block adenosine production, Dr. Wainberg said.

Bristol Myers Squibb (BMS) provided the nivolumab used in the study. Dr. Wainberg is a consultant for and reported research funding from BMS and other companies. Dr. Ho had no relevant disclosures.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — A new blood test that combines cell-free DNA fragmentomes and protein biomarkers to screen for ovarian cancer shows promising results, according to an initial analysis. 

The test, under development by Delfi Diagnostics, “looks very sensitive for detecting ovarian cancer early,” said company founder and board member Victor E. Velculescu, MD, PhD, codirector of Cancer Genetics and Epigenetics at Johns Hopkins University, Baltimore. 

The assay uses machine learning to integrate cell-free DNA fragment patterns with concentrations of two ovarian cancer biomarkers — CA125 and HE4 — to detect tumors. 

While fragmentation patterns are organized in healthy people, they are chaotic in cancer and reveal both its presence and location, said Velculescu who presented the findings at the American Association for Cancer Research annual meeting.

The researchers tested the assay in 134 women with ovarian cancer, 204 women without cancer, and 203 women with benign adnexal masses. The approach identified 69% of stage 1 cancers, 76% of stage 2, 85% of stage 3, and 100% of stage 4 at a specificity of over 99% and an area under the curve (AUC) of 0.97.

The test identified 91% of high-grade serous ovarian cancers — the most common type of ovarian cancer.

The AUC for distinguishing benign masses from cancer was 0.87, with 60% of ovarian cancers detected at a specificity of 95%. 

“In the preoperative setting where lower specificity is acceptable, this approach may improve management of adnexal masses,” the investigators said in their abstract.

Dr. Velculescu cautioned that the report “is an initial analysis” and that his team is working on validating the finding on a larger scale in both average and high-risk women.

If validated, the test “could enable population-wide ovarian cancer screening,” he added.

Delfi recently launched a lung cancer screening blood test — FirstLook Lung— that also uses a “fragmentomics” approach to detect tumors. The company is hopeful it will reach the market with a similar test for ovarian cancer, but it’s not a certainty. 

With lung cancer, we know screening helps. For ovarian cancer, however, it’s unclear whether this will help or not, said Dr. Velculescu. But based on the study findings, but “we are now optimistic that this could make an impact. We have more work to do.” 

This presentation was one of many at the meeting about liquid biopsies using DNA, RNA, and proteins to detect cancer, including a new assay for pancreatic cancer, another cancer that like ovarian cancer is difficult to detect in the early stages. 

“This is the future,” said study moderator Roy S. Herbst, MD, PhD, chief of medical oncology at Yale University in New Haven, Connecticut. 

He called liquid biopsy “a great advance” in many oncology settings, including cancer screening because finding tumors early offers the best chance at cure. 

However, one of the main concerns about rolling out liquid biopsies for wide-scale cancer screening is the possibility that a test will come back positive, but no tumor will be seen on diagnostic imaging, said Herbst. It won’t be clear if the test was a false positive or if the patient has a brewing tumor that can’t be located and treated, a difficult situation for both patients and doctors. 

What to do in that situation is “a policy question that the entire country is asking now as liquid biopsies are moving forward,” he said. We are going to have to come together to figure it out and learn how to use these tests.

The work was funded by Delfi Diagnostics, the National Institutes of Health, and others. Dr. Velculescu, in addition to founding Delfi, holds patents on the technology. Dr. Herbst is a consultant, researcher, and/or holds stock in many companies, including AstraZeneca, Pfizer, and Checkpoint Therapeutics. 
 

A version of this article appeared on Medscape.com .

SAN DIEGO — A new blood test that combines cell-free DNA fragmentomes and protein biomarkers to screen for ovarian cancer shows promising results, according to an initial analysis. 

The test, under development by Delfi Diagnostics, “looks very sensitive for detecting ovarian cancer early,” said company founder and board member Victor E. Velculescu, MD, PhD, codirector of Cancer Genetics and Epigenetics at Johns Hopkins University, Baltimore. 

The assay uses machine learning to integrate cell-free DNA fragment patterns with concentrations of two ovarian cancer biomarkers — CA125 and HE4 — to detect tumors. 

While fragmentation patterns are organized in healthy people, they are chaotic in cancer and reveal both its presence and location, said Velculescu who presented the findings at the American Association for Cancer Research annual meeting.

The researchers tested the assay in 134 women with ovarian cancer, 204 women without cancer, and 203 women with benign adnexal masses. The approach identified 69% of stage 1 cancers, 76% of stage 2, 85% of stage 3, and 100% of stage 4 at a specificity of over 99% and an area under the curve (AUC) of 0.97.

The test identified 91% of high-grade serous ovarian cancers — the most common type of ovarian cancer.

The AUC for distinguishing benign masses from cancer was 0.87, with 60% of ovarian cancers detected at a specificity of 95%. 

“In the preoperative setting where lower specificity is acceptable, this approach may improve management of adnexal masses,” the investigators said in their abstract.

Dr. Velculescu cautioned that the report “is an initial analysis” and that his team is working on validating the finding on a larger scale in both average and high-risk women.

If validated, the test “could enable population-wide ovarian cancer screening,” he added.

Delfi recently launched a lung cancer screening blood test — FirstLook Lung— that also uses a “fragmentomics” approach to detect tumors. The company is hopeful it will reach the market with a similar test for ovarian cancer, but it’s not a certainty. 

With lung cancer, we know screening helps. For ovarian cancer, however, it’s unclear whether this will help or not, said Dr. Velculescu. But based on the study findings, but “we are now optimistic that this could make an impact. We have more work to do.” 

This presentation was one of many at the meeting about liquid biopsies using DNA, RNA, and proteins to detect cancer, including a new assay for pancreatic cancer, another cancer that like ovarian cancer is difficult to detect in the early stages. 

“This is the future,” said study moderator Roy S. Herbst, MD, PhD, chief of medical oncology at Yale University in New Haven, Connecticut. 

He called liquid biopsy “a great advance” in many oncology settings, including cancer screening because finding tumors early offers the best chance at cure. 

However, one of the main concerns about rolling out liquid biopsies for wide-scale cancer screening is the possibility that a test will come back positive, but no tumor will be seen on diagnostic imaging, said Herbst. It won’t be clear if the test was a false positive or if the patient has a brewing tumor that can’t be located and treated, a difficult situation for both patients and doctors. 

What to do in that situation is “a policy question that the entire country is asking now as liquid biopsies are moving forward,” he said. We are going to have to come together to figure it out and learn how to use these tests.

The work was funded by Delfi Diagnostics, the National Institutes of Health, and others. Dr. Velculescu, in addition to founding Delfi, holds patents on the technology. Dr. Herbst is a consultant, researcher, and/or holds stock in many companies, including AstraZeneca, Pfizer, and Checkpoint Therapeutics. 
 

A version of this article appeared on Medscape.com .

SAN DIEGO — A new blood test that combines cell-free DNA fragmentomes and protein biomarkers to screen for ovarian cancer shows promising results, according to an initial analysis. 

The test, under development by Delfi Diagnostics, “looks very sensitive for detecting ovarian cancer early,” said company founder and board member Victor E. Velculescu, MD, PhD, codirector of Cancer Genetics and Epigenetics at Johns Hopkins University, Baltimore. 

The assay uses machine learning to integrate cell-free DNA fragment patterns with concentrations of two ovarian cancer biomarkers — CA125 and HE4 — to detect tumors. 

While fragmentation patterns are organized in healthy people, they are chaotic in cancer and reveal both its presence and location, said Velculescu who presented the findings at the American Association for Cancer Research annual meeting.

The researchers tested the assay in 134 women with ovarian cancer, 204 women without cancer, and 203 women with benign adnexal masses. The approach identified 69% of stage 1 cancers, 76% of stage 2, 85% of stage 3, and 100% of stage 4 at a specificity of over 99% and an area under the curve (AUC) of 0.97.

The test identified 91% of high-grade serous ovarian cancers — the most common type of ovarian cancer.

The AUC for distinguishing benign masses from cancer was 0.87, with 60% of ovarian cancers detected at a specificity of 95%. 

“In the preoperative setting where lower specificity is acceptable, this approach may improve management of adnexal masses,” the investigators said in their abstract.

Dr. Velculescu cautioned that the report “is an initial analysis” and that his team is working on validating the finding on a larger scale in both average and high-risk women.

If validated, the test “could enable population-wide ovarian cancer screening,” he added.

Delfi recently launched a lung cancer screening blood test — FirstLook Lung— that also uses a “fragmentomics” approach to detect tumors. The company is hopeful it will reach the market with a similar test for ovarian cancer, but it’s not a certainty. 

With lung cancer, we know screening helps. For ovarian cancer, however, it’s unclear whether this will help or not, said Dr. Velculescu. But based on the study findings, but “we are now optimistic that this could make an impact. We have more work to do.” 

This presentation was one of many at the meeting about liquid biopsies using DNA, RNA, and proteins to detect cancer, including a new assay for pancreatic cancer, another cancer that like ovarian cancer is difficult to detect in the early stages. 

“This is the future,” said study moderator Roy S. Herbst, MD, PhD, chief of medical oncology at Yale University in New Haven, Connecticut. 

He called liquid biopsy “a great advance” in many oncology settings, including cancer screening because finding tumors early offers the best chance at cure. 

However, one of the main concerns about rolling out liquid biopsies for wide-scale cancer screening is the possibility that a test will come back positive, but no tumor will be seen on diagnostic imaging, said Herbst. It won’t be clear if the test was a false positive or if the patient has a brewing tumor that can’t be located and treated, a difficult situation for both patients and doctors. 

What to do in that situation is “a policy question that the entire country is asking now as liquid biopsies are moving forward,” he said. We are going to have to come together to figure it out and learn how to use these tests.

The work was funded by Delfi Diagnostics, the National Institutes of Health, and others. Dr. Velculescu, in addition to founding Delfi, holds patents on the technology. Dr. Herbst is a consultant, researcher, and/or holds stock in many companies, including AstraZeneca, Pfizer, and Checkpoint Therapeutics. 
 

A version of this article appeared on Medscape.com .

Multitarget stool-based tests are showing promise for colorectal cancer (CRC) screening in average-risk individuals and could edge out the current standard fecal immunochemical test (FIT).

These new tests aren’t radical departures from the standard FIT. Like the standard test, the multitarget FIT uses antibodies to test for hemoglobin in stool samples. But these multitarget approaches take the standard FIT a step further by testing for additional DNA, RNA, or protein biomarkers associated with CRC to help improve early detection.

Currently, the US Preventive Services Task Force (USPSTF) recommends two FIT tests — standard FIT and stool FIT-DNA — as well as a third noninvasive CRC screening test, guaiac fecal occult blood test (gFOBT). gFOBT detects heme, a component of hemoglobin, through a chemical reaction.

But both standard FIT and stool FIT-DNA come with caveats. Compared to the standard test, FIT-DNA tends to be better at detecting traces of blood in the stool, and thus can uncover more instances of CRC or other advanced lesions. The flipside is that the DNA test also often leads to more false-positive findings.

In fact, the American College of Physicians does not recommend stool FIT-DNA for screening, citing issues such as cost — more than $600 per test vs about $30 for standard FIT — and the greater likelihood of false-positives compared with both standard FIT and gFOBT.

Given these trade-offs with current noninvasive screening options, developing a FIT option that can improve early detection of CRC and advanced precancerous lesions without increasing false-positives could make a big difference in outcomes. 

Three new noninvasive multitarget tests under investigation — an updated DNA-based test, Cologuard 2.0 (Exact Sciences; Madison, WI); an RNA-based test, ColoSense (Geneoscopy; St Louis, MO); and a protein-based test from CRCbioscreen (Amsterdam, the Netherlands) — may be able to do just that. 
 

Cologuard 2.0: Multitarget Stool DNA-Based Test

An updated version of the stool FIT-DNA is currently under development. Dubbed Next Generation Cologuard, or Cologuard 2.0, this multitarget test detects three novel methylated DNA markers along with fecal hemoglobin.

In a recent trial comparing Cologuard 2.0 vs standard FIT, 20,176 participants aged 40 years or older were screened with Cologuard 2.0 as well as standard FIT before they all also received a colonoscopy. The researchers compared findings with Cologuard 2.0 and standard FIT, which used a positivity cutoff ≥ 20 mcg hemoglobin/g feces. 

The researchers then assessed Cologuard 2.0’s sensitivity (a gauge of how well it detects disease that is truly present) and specificity (a measure of how well a test indicates the absence of disease when no disease is present) compared with standard FIT and the original Cologuard test.

Overall, Cologuard 2.0 demonstrated better sensitivity for CRC than did standard FIT (93.9% vs 67.3%, respectively) and for advanced precancerous lesions (43.4% vs 23.3%). The next-generation test, for instance, identified 92 of 98 participants with colonoscopy-confirmed CRC diagnoses vs 66 cases using standard FIT.

Compared with the original Cologuard, Cologuard 2.0’s sensitivity improved slightly for CRC, from 92% to 93.9%,; for advanced precancerous lesions, from 42% to 43.4%; and for high-grade dysplasia, from 69% to 75%. Specificity also improved with the latest version, from 87% to 90.6%. 

However, Cologuard 2.0’s specificity for advanced neoplasia was worse than that of standard FIT (90.6% vs 94.8%, respectively), which would increase the likelihood of false-positive findings.

Despite its lower specificity compared with standard FIT, Cologuard 2.0 has several advantages. The test can identify more people with CRC and advanced precancerous lesions than the standard test and can lead to fewer false-positives than the original Cologuard test.

Cologuard maker Exact Sciences has submitted trial data to the US Food and Drug Administration (FDA) for approval.
 

Multitarget Stool RNA-Based Test

ColoSense, an RNA-based stool test, looks for eight RNA biomarkers associated with CRC. 

The company says that RNA-based testing has an advantage over DNA biomarker assays, such as the currently marketed Cologuard test, because it isn›t subject to the age-related changes in DNA methylation that can throw off the results from DNA assays. 

Like Cologuard 2.0, Geneoscopy’s Colosense test is under review by the FDA.

The data Geneoscopy submitted to the FDA came from the CRC-PREVENT trial, which included 8920 participants who were screened with both ColoSense and standard FIT before all had a colonoscopy. The participants ranged in age from 45 to 90 years, with 22% between 45 and 50 years old, a population recently added to the USPSTF screening recommendations. 

ColoSense showed higher sensitivity than standard FIT for the presence of CRC (94% vs 78%, respectively) and advanced adenomas (46% vs 29%). In the group aged 45-50 years, the RNA-based test had a sensitivity of 100% for CRC, correctly identifying all five people with colonoscopy-confirmed CRC, and 45% for advanced adenomas.

However, ColoSense was less specific than standard FIT compared with negative colonoscopy findings (88% vs 96%, respectively) and negative findings for advanced lesions or CRC (85.5% vs 94.9%); thus, it was more likely to lead to false-positive results.

Overall, the investigators said ColoSense is comparable to Cologuard — its chief market rival — in terms of sensitivity for CRC and advanced adenomas but has higher sensitivity for colorectal neoplasia in people aged 50 years or younger.
 

Multitarget Protein-Based Test

The multitarget protein-based FIT uses antibodies to test for two additional proteins: calprotectin, an inflammatory marker associated with CRC, and serpin family F member 2, a protease inhibitor thought to be upregulated in colon cancer. 

A 2021 study of 1284 patients found that the sensitivity of the multitarget protein-based test was 42.9% for advanced neoplasias compared with 37.3% with standard FIT. Its specificity was similar to that of standard FIT, at 96.6% for advanced neoplasias. 

In a more recent report published in The Lancet Oncology, the team modeled three scenarios comparing the two FIT tests. These scenarios used different cutoff values for a test to be positive for CRC or an advanced lesion.

Overall, the analysis included stool samples from 13,187 patients aged 55-75 years who were in the Netherlands’ national CRC screening program. Stool samples were evaluated with both the multitarget test and the standard FIT, using a positivity cutoff ≥ 47 mcg hemoglobin/g feces. Colonoscopy data were available for only 1270 participants. 

In scenario 1, the multitarget test had a lower threshold for a positive test and consequently identified more precancerous lesions than the standard FIT (828 vs 354, respectively). The multitarget FIT identified a few more CRC cases: Of 29 colonoscopy-confirmed CRC cases, the multitarget FIT identified 26 vs 23 with standard FIT. 

But the multitarget FIT also had more than double the number of false-positives than the standard FIT (347 vs 161, respectively).

Perhaps the most telling comparison occurred in scenario 2, with both tests set at the same low positivity threshold to minimize false-positives.

As expected, the two tests had similar positivity rates for advanced lesions, with the multitarget test correctly identifying 22 of 29 people with CRC, one fewer than the standard test. The protein-based test identified slightly more people with advanced lesions (156 vs 136 with the standard test), leading to a higher sensitivity for advanced lesions. 

Most notably, the protein-based test resulted in fewer false-positives than did the standard test (295 vs 311, respectively) , resulting in a slightly higher specificity.

In this scenario, “a single screening round might not have the biggest impact on cancer incidence and mortality,” the authors said, but the higher detection rate would still accumulate over 20 years of testing. The authors estimated that, under this scenario, substituting the multitarget FIT for the standard test in the Netherlands’ CRC screening program could reduce CRC incidence by 5% and CRC mortality by 4%.

Gerrit Meijer, MD, PhD, a pathologist at the Netherlands Cancer Institute, and colleagues recently launched a company called CRCbioscreen to commercialize this multitarget FIT for large-scale programs. The company›s priority is to develop and validate a clinical-grade test to sell to federal governments with national screening programs, such as those throughout Europe, Australia, and Asia, Dr. Meijer told this news organization. Dr. Meijer expects this process will take about 4 years.

The test will be developed for the US market, but with no nationwide screening program in the United States, future availability will depend on interest from providers and institutions, noted Dr. Meijer, who is also chief scientific officer at CRCbioscreen.

Overall, these three new multitarget stool-based CRC screening tests could help catch more cancers and advanced precancerous lesions. And, if the tests have a high enough specificity, a negative test result could also allow people to forgo screening colonoscopy. 

Still, people with a positive FIT finding would require follow-up colonoscopy, but about 10% of patients decline colonoscopy following an abnormal FIT, Mark A. Lewis, MD, director of gastrointestinal oncology at Intermountain Health in Murray, Utah, told this news organization last year. That means that even if precancerous lesions and CRC are being caught earlier, treatment can’t be started unless people follow through with colonoscopy.

A version of this article appeared on Medscape.com.

Multitarget stool-based tests are showing promise for colorectal cancer (CRC) screening in average-risk individuals and could edge out the current standard fecal immunochemical test (FIT).

These new tests aren’t radical departures from the standard FIT. Like the standard test, the multitarget FIT uses antibodies to test for hemoglobin in stool samples. But these multitarget approaches take the standard FIT a step further by testing for additional DNA, RNA, or protein biomarkers associated with CRC to help improve early detection.

Currently, the US Preventive Services Task Force (USPSTF) recommends two FIT tests — standard FIT and stool FIT-DNA — as well as a third noninvasive CRC screening test, guaiac fecal occult blood test (gFOBT). gFOBT detects heme, a component of hemoglobin, through a chemical reaction.

But both standard FIT and stool FIT-DNA come with caveats. Compared to the standard test, FIT-DNA tends to be better at detecting traces of blood in the stool, and thus can uncover more instances of CRC or other advanced lesions. The flipside is that the DNA test also often leads to more false-positive findings.

In fact, the American College of Physicians does not recommend stool FIT-DNA for screening, citing issues such as cost — more than $600 per test vs about $30 for standard FIT — and the greater likelihood of false-positives compared with both standard FIT and gFOBT.

Given these trade-offs with current noninvasive screening options, developing a FIT option that can improve early detection of CRC and advanced precancerous lesions without increasing false-positives could make a big difference in outcomes. 

Three new noninvasive multitarget tests under investigation — an updated DNA-based test, Cologuard 2.0 (Exact Sciences; Madison, WI); an RNA-based test, ColoSense (Geneoscopy; St Louis, MO); and a protein-based test from CRCbioscreen (Amsterdam, the Netherlands) — may be able to do just that. 
 

Cologuard 2.0: Multitarget Stool DNA-Based Test

An updated version of the stool FIT-DNA is currently under development. Dubbed Next Generation Cologuard, or Cologuard 2.0, this multitarget test detects three novel methylated DNA markers along with fecal hemoglobin.

In a recent trial comparing Cologuard 2.0 vs standard FIT, 20,176 participants aged 40 years or older were screened with Cologuard 2.0 as well as standard FIT before they all also received a colonoscopy. The researchers compared findings with Cologuard 2.0 and standard FIT, which used a positivity cutoff ≥ 20 mcg hemoglobin/g feces. 

The researchers then assessed Cologuard 2.0’s sensitivity (a gauge of how well it detects disease that is truly present) and specificity (a measure of how well a test indicates the absence of disease when no disease is present) compared with standard FIT and the original Cologuard test.

Overall, Cologuard 2.0 demonstrated better sensitivity for CRC than did standard FIT (93.9% vs 67.3%, respectively) and for advanced precancerous lesions (43.4% vs 23.3%). The next-generation test, for instance, identified 92 of 98 participants with colonoscopy-confirmed CRC diagnoses vs 66 cases using standard FIT.

Compared with the original Cologuard, Cologuard 2.0’s sensitivity improved slightly for CRC, from 92% to 93.9%,; for advanced precancerous lesions, from 42% to 43.4%; and for high-grade dysplasia, from 69% to 75%. Specificity also improved with the latest version, from 87% to 90.6%. 

However, Cologuard 2.0’s specificity for advanced neoplasia was worse than that of standard FIT (90.6% vs 94.8%, respectively), which would increase the likelihood of false-positive findings.

Despite its lower specificity compared with standard FIT, Cologuard 2.0 has several advantages. The test can identify more people with CRC and advanced precancerous lesions than the standard test and can lead to fewer false-positives than the original Cologuard test.

Cologuard maker Exact Sciences has submitted trial data to the US Food and Drug Administration (FDA) for approval.
 

Multitarget Stool RNA-Based Test

ColoSense, an RNA-based stool test, looks for eight RNA biomarkers associated with CRC. 

The company says that RNA-based testing has an advantage over DNA biomarker assays, such as the currently marketed Cologuard test, because it isn›t subject to the age-related changes in DNA methylation that can throw off the results from DNA assays. 

Like Cologuard 2.0, Geneoscopy’s Colosense test is under review by the FDA.

The data Geneoscopy submitted to the FDA came from the CRC-PREVENT trial, which included 8920 participants who were screened with both ColoSense and standard FIT before all had a colonoscopy. The participants ranged in age from 45 to 90 years, with 22% between 45 and 50 years old, a population recently added to the USPSTF screening recommendations. 

ColoSense showed higher sensitivity than standard FIT for the presence of CRC (94% vs 78%, respectively) and advanced adenomas (46% vs 29%). In the group aged 45-50 years, the RNA-based test had a sensitivity of 100% for CRC, correctly identifying all five people with colonoscopy-confirmed CRC, and 45% for advanced adenomas.

However, ColoSense was less specific than standard FIT compared with negative colonoscopy findings (88% vs 96%, respectively) and negative findings for advanced lesions or CRC (85.5% vs 94.9%); thus, it was more likely to lead to false-positive results.

Overall, the investigators said ColoSense is comparable to Cologuard — its chief market rival — in terms of sensitivity for CRC and advanced adenomas but has higher sensitivity for colorectal neoplasia in people aged 50 years or younger.
 

Multitarget Protein-Based Test

The multitarget protein-based FIT uses antibodies to test for two additional proteins: calprotectin, an inflammatory marker associated with CRC, and serpin family F member 2, a protease inhibitor thought to be upregulated in colon cancer. 

A 2021 study of 1284 patients found that the sensitivity of the multitarget protein-based test was 42.9% for advanced neoplasias compared with 37.3% with standard FIT. Its specificity was similar to that of standard FIT, at 96.6% for advanced neoplasias. 

In a more recent report published in The Lancet Oncology, the team modeled three scenarios comparing the two FIT tests. These scenarios used different cutoff values for a test to be positive for CRC or an advanced lesion.

Overall, the analysis included stool samples from 13,187 patients aged 55-75 years who were in the Netherlands’ national CRC screening program. Stool samples were evaluated with both the multitarget test and the standard FIT, using a positivity cutoff ≥ 47 mcg hemoglobin/g feces. Colonoscopy data were available for only 1270 participants. 

In scenario 1, the multitarget test had a lower threshold for a positive test and consequently identified more precancerous lesions than the standard FIT (828 vs 354, respectively). The multitarget FIT identified a few more CRC cases: Of 29 colonoscopy-confirmed CRC cases, the multitarget FIT identified 26 vs 23 with standard FIT. 

But the multitarget FIT also had more than double the number of false-positives than the standard FIT (347 vs 161, respectively).

Perhaps the most telling comparison occurred in scenario 2, with both tests set at the same low positivity threshold to minimize false-positives.

As expected, the two tests had similar positivity rates for advanced lesions, with the multitarget test correctly identifying 22 of 29 people with CRC, one fewer than the standard test. The protein-based test identified slightly more people with advanced lesions (156 vs 136 with the standard test), leading to a higher sensitivity for advanced lesions. 

Most notably, the protein-based test resulted in fewer false-positives than did the standard test (295 vs 311, respectively) , resulting in a slightly higher specificity.

In this scenario, “a single screening round might not have the biggest impact on cancer incidence and mortality,” the authors said, but the higher detection rate would still accumulate over 20 years of testing. The authors estimated that, under this scenario, substituting the multitarget FIT for the standard test in the Netherlands’ CRC screening program could reduce CRC incidence by 5% and CRC mortality by 4%.

Gerrit Meijer, MD, PhD, a pathologist at the Netherlands Cancer Institute, and colleagues recently launched a company called CRCbioscreen to commercialize this multitarget FIT for large-scale programs. The company›s priority is to develop and validate a clinical-grade test to sell to federal governments with national screening programs, such as those throughout Europe, Australia, and Asia, Dr. Meijer told this news organization. Dr. Meijer expects this process will take about 4 years.

The test will be developed for the US market, but with no nationwide screening program in the United States, future availability will depend on interest from providers and institutions, noted Dr. Meijer, who is also chief scientific officer at CRCbioscreen.

Overall, these three new multitarget stool-based CRC screening tests could help catch more cancers and advanced precancerous lesions. And, if the tests have a high enough specificity, a negative test result could also allow people to forgo screening colonoscopy. 

Still, people with a positive FIT finding would require follow-up colonoscopy, but about 10% of patients decline colonoscopy following an abnormal FIT, Mark A. Lewis, MD, director of gastrointestinal oncology at Intermountain Health in Murray, Utah, told this news organization last year. That means that even if precancerous lesions and CRC are being caught earlier, treatment can’t be started unless people follow through with colonoscopy.

A version of this article appeared on Medscape.com.

Multitarget stool-based tests are showing promise for colorectal cancer (CRC) screening in average-risk individuals and could edge out the current standard fecal immunochemical test (FIT).

These new tests aren’t radical departures from the standard FIT. Like the standard test, the multitarget FIT uses antibodies to test for hemoglobin in stool samples. But these multitarget approaches take the standard FIT a step further by testing for additional DNA, RNA, or protein biomarkers associated with CRC to help improve early detection.

Currently, the US Preventive Services Task Force (USPSTF) recommends two FIT tests — standard FIT and stool FIT-DNA — as well as a third noninvasive CRC screening test, guaiac fecal occult blood test (gFOBT). gFOBT detects heme, a component of hemoglobin, through a chemical reaction.

But both standard FIT and stool FIT-DNA come with caveats. Compared to the standard test, FIT-DNA tends to be better at detecting traces of blood in the stool, and thus can uncover more instances of CRC or other advanced lesions. The flipside is that the DNA test also often leads to more false-positive findings.

In fact, the American College of Physicians does not recommend stool FIT-DNA for screening, citing issues such as cost — more than $600 per test vs about $30 for standard FIT — and the greater likelihood of false-positives compared with both standard FIT and gFOBT.

Given these trade-offs with current noninvasive screening options, developing a FIT option that can improve early detection of CRC and advanced precancerous lesions without increasing false-positives could make a big difference in outcomes. 

Three new noninvasive multitarget tests under investigation — an updated DNA-based test, Cologuard 2.0 (Exact Sciences; Madison, WI); an RNA-based test, ColoSense (Geneoscopy; St Louis, MO); and a protein-based test from CRCbioscreen (Amsterdam, the Netherlands) — may be able to do just that. 
 

Cologuard 2.0: Multitarget Stool DNA-Based Test

An updated version of the stool FIT-DNA is currently under development. Dubbed Next Generation Cologuard, or Cologuard 2.0, this multitarget test detects three novel methylated DNA markers along with fecal hemoglobin.

In a recent trial comparing Cologuard 2.0 vs standard FIT, 20,176 participants aged 40 years or older were screened with Cologuard 2.0 as well as standard FIT before they all also received a colonoscopy. The researchers compared findings with Cologuard 2.0 and standard FIT, which used a positivity cutoff ≥ 20 mcg hemoglobin/g feces. 

The researchers then assessed Cologuard 2.0’s sensitivity (a gauge of how well it detects disease that is truly present) and specificity (a measure of how well a test indicates the absence of disease when no disease is present) compared with standard FIT and the original Cologuard test.

Overall, Cologuard 2.0 demonstrated better sensitivity for CRC than did standard FIT (93.9% vs 67.3%, respectively) and for advanced precancerous lesions (43.4% vs 23.3%). The next-generation test, for instance, identified 92 of 98 participants with colonoscopy-confirmed CRC diagnoses vs 66 cases using standard FIT.

Compared with the original Cologuard, Cologuard 2.0’s sensitivity improved slightly for CRC, from 92% to 93.9%,; for advanced precancerous lesions, from 42% to 43.4%; and for high-grade dysplasia, from 69% to 75%. Specificity also improved with the latest version, from 87% to 90.6%. 

However, Cologuard 2.0’s specificity for advanced neoplasia was worse than that of standard FIT (90.6% vs 94.8%, respectively), which would increase the likelihood of false-positive findings.

Despite its lower specificity compared with standard FIT, Cologuard 2.0 has several advantages. The test can identify more people with CRC and advanced precancerous lesions than the standard test and can lead to fewer false-positives than the original Cologuard test.

Cologuard maker Exact Sciences has submitted trial data to the US Food and Drug Administration (FDA) for approval.
 

Multitarget Stool RNA-Based Test

ColoSense, an RNA-based stool test, looks for eight RNA biomarkers associated with CRC. 

The company says that RNA-based testing has an advantage over DNA biomarker assays, such as the currently marketed Cologuard test, because it isn›t subject to the age-related changes in DNA methylation that can throw off the results from DNA assays. 

Like Cologuard 2.0, Geneoscopy’s Colosense test is under review by the FDA.

The data Geneoscopy submitted to the FDA came from the CRC-PREVENT trial, which included 8920 participants who were screened with both ColoSense and standard FIT before all had a colonoscopy. The participants ranged in age from 45 to 90 years, with 22% between 45 and 50 years old, a population recently added to the USPSTF screening recommendations. 

ColoSense showed higher sensitivity than standard FIT for the presence of CRC (94% vs 78%, respectively) and advanced adenomas (46% vs 29%). In the group aged 45-50 years, the RNA-based test had a sensitivity of 100% for CRC, correctly identifying all five people with colonoscopy-confirmed CRC, and 45% for advanced adenomas.

However, ColoSense was less specific than standard FIT compared with negative colonoscopy findings (88% vs 96%, respectively) and negative findings for advanced lesions or CRC (85.5% vs 94.9%); thus, it was more likely to lead to false-positive results.

Overall, the investigators said ColoSense is comparable to Cologuard — its chief market rival — in terms of sensitivity for CRC and advanced adenomas but has higher sensitivity for colorectal neoplasia in people aged 50 years or younger.
 

Multitarget Protein-Based Test

The multitarget protein-based FIT uses antibodies to test for two additional proteins: calprotectin, an inflammatory marker associated with CRC, and serpin family F member 2, a protease inhibitor thought to be upregulated in colon cancer. 

A 2021 study of 1284 patients found that the sensitivity of the multitarget protein-based test was 42.9% for advanced neoplasias compared with 37.3% with standard FIT. Its specificity was similar to that of standard FIT, at 96.6% for advanced neoplasias. 

In a more recent report published in The Lancet Oncology, the team modeled three scenarios comparing the two FIT tests. These scenarios used different cutoff values for a test to be positive for CRC or an advanced lesion.

Overall, the analysis included stool samples from 13,187 patients aged 55-75 years who were in the Netherlands’ national CRC screening program. Stool samples were evaluated with both the multitarget test and the standard FIT, using a positivity cutoff ≥ 47 mcg hemoglobin/g feces. Colonoscopy data were available for only 1270 participants. 

In scenario 1, the multitarget test had a lower threshold for a positive test and consequently identified more precancerous lesions than the standard FIT (828 vs 354, respectively). The multitarget FIT identified a few more CRC cases: Of 29 colonoscopy-confirmed CRC cases, the multitarget FIT identified 26 vs 23 with standard FIT. 

But the multitarget FIT also had more than double the number of false-positives than the standard FIT (347 vs 161, respectively).

Perhaps the most telling comparison occurred in scenario 2, with both tests set at the same low positivity threshold to minimize false-positives.

As expected, the two tests had similar positivity rates for advanced lesions, with the multitarget test correctly identifying 22 of 29 people with CRC, one fewer than the standard test. The protein-based test identified slightly more people with advanced lesions (156 vs 136 with the standard test), leading to a higher sensitivity for advanced lesions. 

Most notably, the protein-based test resulted in fewer false-positives than did the standard test (295 vs 311, respectively) , resulting in a slightly higher specificity.

In this scenario, “a single screening round might not have the biggest impact on cancer incidence and mortality,” the authors said, but the higher detection rate would still accumulate over 20 years of testing. The authors estimated that, under this scenario, substituting the multitarget FIT for the standard test in the Netherlands’ CRC screening program could reduce CRC incidence by 5% and CRC mortality by 4%.

Gerrit Meijer, MD, PhD, a pathologist at the Netherlands Cancer Institute, and colleagues recently launched a company called CRCbioscreen to commercialize this multitarget FIT for large-scale programs. The company›s priority is to develop and validate a clinical-grade test to sell to federal governments with national screening programs, such as those throughout Europe, Australia, and Asia, Dr. Meijer told this news organization. Dr. Meijer expects this process will take about 4 years.

The test will be developed for the US market, but with no nationwide screening program in the United States, future availability will depend on interest from providers and institutions, noted Dr. Meijer, who is also chief scientific officer at CRCbioscreen.

Overall, these three new multitarget stool-based CRC screening tests could help catch more cancers and advanced precancerous lesions. And, if the tests have a high enough specificity, a negative test result could also allow people to forgo screening colonoscopy. 

Still, people with a positive FIT finding would require follow-up colonoscopy, but about 10% of patients decline colonoscopy following an abnormal FIT, Mark A. Lewis, MD, director of gastrointestinal oncology at Intermountain Health in Murray, Utah, told this news organization last year. That means that even if precancerous lesions and CRC are being caught earlier, treatment can’t be started unless people follow through with colonoscopy.

A version of this article appeared on Medscape.com.

SAN DIEGO — A liquid biopsy assay that combines a microRNA signature and a well-known biomarker for pancreatic cancer has demonstrated an accuracy of 97% for detecting stage I/II pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer.

It is quite encouraging to know we have a blood test that could potentially find this disease early, said Ajay Goel, PhD, a molecular diagnostics specialist at City of Hope in Duarte, California, who presented the findings at the annual meeting of the American Association for Cancer Research (AACR).

Dr. Goel and colleagues developed a signature for pancreatic cancer based on microRNAs identified in the exomes shed from pancreatic cancers and cell-free DNA markers found in the blood of patients with the disease.

Their initial assay tested blood samples for this signature in a training cohort of 252 people in Japan, approximately 60% of whom had pancreatic cancer. The rest were healthy controls. The assay was then tested in validation cohorts of 400 subjects, half with pancreatic cancer and half controls, in China and South Korea.

In both the initial and validation tests, the microRNA assay had an accuracy of about 90% for stage I/II pancreatic cancer, already far better than commercially available assays.

In an additional validation cohort in the United States with 139 patients with pancreatic cancer and 193 controls at six centers across the country, the researchers found that adding carbohydrate antigen 19-9 — a well-known marker of pancreatic cancer — to the assay boosted the test’s accuracy to 97%.

The test performed the same whether the tumor was in the head or tail of the pancreas.

“We are very excited about this data,” said Dr. Goel.

The technology was recently licensed to Pharus Diagnostics for commercial development, which will likely include a prospective screening trial, he told this news organization.

Because pancreatic cancer is fairly uncommon, Dr. Goel did not anticipate the test being used for general screening but rather for screening high-risk patients such as those with newly diagnosed type 2 diabetes, a family history of pancreatic cancer, or predisposing genetic mutations.

“It should be a very inexpensive test; it doesn’t cost us much to do in the lab,” he added.

Study moderator Ryan Corcoran, MD, PhD, a gastrointestinal (GI) oncologist at Massachusetts General Hospital, Boston, saw the potential.

“As a GI oncologist, I know how lethal and hard to treat pancreatic cancer is,” he said. A test that could reliably detect pancreatic cancer early, with an acceptable false-positive rate, would be extremely useful.

“The cure rate is many, many times higher,” if we detect it before it has a chance to spread, he explained.

In the meantime, Dr. Goel said there’s more work to be done.

Almost 4,000 subjects have been enrolled in ongoing validation efforts, and efforts are underway to use the test to screen thousands of banked blood samples from the PLCO, a prospective cancer screening trial in healthy subjects.

The researchers also want to see if the test can distinguish benign pancreatic cysts from ones that turn cancerous.

The idea is to find the earliest possible signs of this disease to see if we can find it not “at the moment of clinical diagnosis, but possibly 6 months, 1 year, 2 years earlier” than with radiologic imaging, Dr. Goel said.

The work was funded by the National Cancer Institute and others. Dr. Goel is a consultant for Pharus Diagnostics and Cellomics. Dr. Corcoran is a consultant for, has grants from, and/or holds stock in numerous companies, including Pfizer, Novartis, Eli Lilly, and Revolution Medicines.

A version of this article appeared on Medscape.com.

SAN DIEGO — A liquid biopsy assay that combines a microRNA signature and a well-known biomarker for pancreatic cancer has demonstrated an accuracy of 97% for detecting stage I/II pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer.

It is quite encouraging to know we have a blood test that could potentially find this disease early, said Ajay Goel, PhD, a molecular diagnostics specialist at City of Hope in Duarte, California, who presented the findings at the annual meeting of the American Association for Cancer Research (AACR).

Dr. Goel and colleagues developed a signature for pancreatic cancer based on microRNAs identified in the exomes shed from pancreatic cancers and cell-free DNA markers found in the blood of patients with the disease.

Their initial assay tested blood samples for this signature in a training cohort of 252 people in Japan, approximately 60% of whom had pancreatic cancer. The rest were healthy controls. The assay was then tested in validation cohorts of 400 subjects, half with pancreatic cancer and half controls, in China and South Korea.

In both the initial and validation tests, the microRNA assay had an accuracy of about 90% for stage I/II pancreatic cancer, already far better than commercially available assays.

In an additional validation cohort in the United States with 139 patients with pancreatic cancer and 193 controls at six centers across the country, the researchers found that adding carbohydrate antigen 19-9 — a well-known marker of pancreatic cancer — to the assay boosted the test’s accuracy to 97%.

The test performed the same whether the tumor was in the head or tail of the pancreas.

“We are very excited about this data,” said Dr. Goel.

The technology was recently licensed to Pharus Diagnostics for commercial development, which will likely include a prospective screening trial, he told this news organization.

Because pancreatic cancer is fairly uncommon, Dr. Goel did not anticipate the test being used for general screening but rather for screening high-risk patients such as those with newly diagnosed type 2 diabetes, a family history of pancreatic cancer, or predisposing genetic mutations.

“It should be a very inexpensive test; it doesn’t cost us much to do in the lab,” he added.

Study moderator Ryan Corcoran, MD, PhD, a gastrointestinal (GI) oncologist at Massachusetts General Hospital, Boston, saw the potential.

“As a GI oncologist, I know how lethal and hard to treat pancreatic cancer is,” he said. A test that could reliably detect pancreatic cancer early, with an acceptable false-positive rate, would be extremely useful.

“The cure rate is many, many times higher,” if we detect it before it has a chance to spread, he explained.

In the meantime, Dr. Goel said there’s more work to be done.

Almost 4,000 subjects have been enrolled in ongoing validation efforts, and efforts are underway to use the test to screen thousands of banked blood samples from the PLCO, a prospective cancer screening trial in healthy subjects.

The researchers also want to see if the test can distinguish benign pancreatic cysts from ones that turn cancerous.

The idea is to find the earliest possible signs of this disease to see if we can find it not “at the moment of clinical diagnosis, but possibly 6 months, 1 year, 2 years earlier” than with radiologic imaging, Dr. Goel said.

The work was funded by the National Cancer Institute and others. Dr. Goel is a consultant for Pharus Diagnostics and Cellomics. Dr. Corcoran is a consultant for, has grants from, and/or holds stock in numerous companies, including Pfizer, Novartis, Eli Lilly, and Revolution Medicines.

A version of this article appeared on Medscape.com.

SAN DIEGO — A liquid biopsy assay that combines a microRNA signature and a well-known biomarker for pancreatic cancer has demonstrated an accuracy of 97% for detecting stage I/II pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer.

It is quite encouraging to know we have a blood test that could potentially find this disease early, said Ajay Goel, PhD, a molecular diagnostics specialist at City of Hope in Duarte, California, who presented the findings at the annual meeting of the American Association for Cancer Research (AACR).

Dr. Goel and colleagues developed a signature for pancreatic cancer based on microRNAs identified in the exomes shed from pancreatic cancers and cell-free DNA markers found in the blood of patients with the disease.

Their initial assay tested blood samples for this signature in a training cohort of 252 people in Japan, approximately 60% of whom had pancreatic cancer. The rest were healthy controls. The assay was then tested in validation cohorts of 400 subjects, half with pancreatic cancer and half controls, in China and South Korea.

In both the initial and validation tests, the microRNA assay had an accuracy of about 90% for stage I/II pancreatic cancer, already far better than commercially available assays.

In an additional validation cohort in the United States with 139 patients with pancreatic cancer and 193 controls at six centers across the country, the researchers found that adding carbohydrate antigen 19-9 — a well-known marker of pancreatic cancer — to the assay boosted the test’s accuracy to 97%.

The test performed the same whether the tumor was in the head or tail of the pancreas.

“We are very excited about this data,” said Dr. Goel.

The technology was recently licensed to Pharus Diagnostics for commercial development, which will likely include a prospective screening trial, he told this news organization.

Because pancreatic cancer is fairly uncommon, Dr. Goel did not anticipate the test being used for general screening but rather for screening high-risk patients such as those with newly diagnosed type 2 diabetes, a family history of pancreatic cancer, or predisposing genetic mutations.

“It should be a very inexpensive test; it doesn’t cost us much to do in the lab,” he added.

Study moderator Ryan Corcoran, MD, PhD, a gastrointestinal (GI) oncologist at Massachusetts General Hospital, Boston, saw the potential.

“As a GI oncologist, I know how lethal and hard to treat pancreatic cancer is,” he said. A test that could reliably detect pancreatic cancer early, with an acceptable false-positive rate, would be extremely useful.

“The cure rate is many, many times higher,” if we detect it before it has a chance to spread, he explained.

In the meantime, Dr. Goel said there’s more work to be done.

Almost 4,000 subjects have been enrolled in ongoing validation efforts, and efforts are underway to use the test to screen thousands of banked blood samples from the PLCO, a prospective cancer screening trial in healthy subjects.

The researchers also want to see if the test can distinguish benign pancreatic cysts from ones that turn cancerous.

The idea is to find the earliest possible signs of this disease to see if we can find it not “at the moment of clinical diagnosis, but possibly 6 months, 1 year, 2 years earlier” than with radiologic imaging, Dr. Goel said.

The work was funded by the National Cancer Institute and others. Dr. Goel is a consultant for Pharus Diagnostics and Cellomics. Dr. Corcoran is a consultant for, has grants from, and/or holds stock in numerous companies, including Pfizer, Novartis, Eli Lilly, and Revolution Medicines.

A version of this article appeared on Medscape.com.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved idecabtagene vicleucel (ide-cel) (Abecma, Bristol-Myers Squibb/2seventy bio) for adults with relapsed or refractory multiple myeloma after two or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. 

The approval expands the chimeric antigen receptor (CAR) T-cell therapy’s indications to earlier lines of treatment after exposure to these other main therapy classes, Bristol Myers Squibb said in a press release. 

Approval was based on the KarMMa-3 trial, in which 254 patients were randomly assigned to ide-cel and 132 to investigators’ choice of standard regimens, consisting of combinations of daratumumab, dexamethasone, and other agents. 

After a median follow-up of 15.9 months, median progression-free survival was three times higher in the ide-cel arm: 13.3 months with the CAR T-cell therapy vs 4.4 months with standard treatment. Overall, 39% of patients on ide-cel had a complete response vs 5% on standard regimens. 

The approval includes a new recommended dose range of 300-510 x 106 CAR-positive T cells. 

Ide-cel carries a boxed warning for cytokine release syndrome, neurologic toxicities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, prolonged cytopenia, and secondary hematologic cancers. 

In trials, cytokine release syndrome occurred in 89% (310 of 349) of patients in the KarMMa-3 and KarMMa studies, which included grade 3 syndrome in 7% (23 of 349) and fatal cases in 0.9% (3 of 349) of patients.

A one-time treatment is over $500,000, according to drugs.com.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved idecabtagene vicleucel (ide-cel) (Abecma, Bristol-Myers Squibb/2seventy bio) for adults with relapsed or refractory multiple myeloma after two or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. 

The approval expands the chimeric antigen receptor (CAR) T-cell therapy’s indications to earlier lines of treatment after exposure to these other main therapy classes, Bristol Myers Squibb said in a press release. 

Approval was based on the KarMMa-3 trial, in which 254 patients were randomly assigned to ide-cel and 132 to investigators’ choice of standard regimens, consisting of combinations of daratumumab, dexamethasone, and other agents. 

After a median follow-up of 15.9 months, median progression-free survival was three times higher in the ide-cel arm: 13.3 months with the CAR T-cell therapy vs 4.4 months with standard treatment. Overall, 39% of patients on ide-cel had a complete response vs 5% on standard regimens. 

The approval includes a new recommended dose range of 300-510 x 106 CAR-positive T cells. 

Ide-cel carries a boxed warning for cytokine release syndrome, neurologic toxicities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, prolonged cytopenia, and secondary hematologic cancers. 

In trials, cytokine release syndrome occurred in 89% (310 of 349) of patients in the KarMMa-3 and KarMMa studies, which included grade 3 syndrome in 7% (23 of 349) and fatal cases in 0.9% (3 of 349) of patients.

A one-time treatment is over $500,000, according to drugs.com.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved idecabtagene vicleucel (ide-cel) (Abecma, Bristol-Myers Squibb/2seventy bio) for adults with relapsed or refractory multiple myeloma after two or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. 

The approval expands the chimeric antigen receptor (CAR) T-cell therapy’s indications to earlier lines of treatment after exposure to these other main therapy classes, Bristol Myers Squibb said in a press release. 

Approval was based on the KarMMa-3 trial, in which 254 patients were randomly assigned to ide-cel and 132 to investigators’ choice of standard regimens, consisting of combinations of daratumumab, dexamethasone, and other agents. 

After a median follow-up of 15.9 months, median progression-free survival was three times higher in the ide-cel arm: 13.3 months with the CAR T-cell therapy vs 4.4 months with standard treatment. Overall, 39% of patients on ide-cel had a complete response vs 5% on standard regimens. 

The approval includes a new recommended dose range of 300-510 x 106 CAR-positive T cells. 

Ide-cel carries a boxed warning for cytokine release syndrome, neurologic toxicities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, prolonged cytopenia, and secondary hematologic cancers. 

In trials, cytokine release syndrome occurred in 89% (310 of 349) of patients in the KarMMa-3 and KarMMa studies, which included grade 3 syndrome in 7% (23 of 349) and fatal cases in 0.9% (3 of 349) of patients.

A one-time treatment is over $500,000, according to drugs.com.

A version of this article appeared on Medscape.com.

TOPLINE:

Being positive for Helicobacter pylori is associated with a higher risk for colorectal cancer (CRC) incidence and CRC mortality, new data show; however, a 2-week course of antibiotics to eliminate the bacterial infection can reduce the risk of developing and dying from CRC.

METHODOLOGY:

• H pylori is a known cause of peptic ulcers and stomach cancer and has been classified as a group I carcinogen by the World Health Organization›s International Agency for Research on Cancer.
• Studies showed that H pylori increases the risk for gastric cancer and may increase the risk for CRC, but evidence supporting the CRC connection remains inconsistent.
• To investigate a possible H pylori-CRC link, investigators reviewed CRC incidence and mortality in a nationwide cohort of 812,736 veterans tested for H pylori at Veterans Health Administration facilities; of the 205,178 (25.2%) who tested positive for H pylori, 134,417 (34%) were treated.
• Patients were followed from their first H pylori test, and researchers tracked subsequent CRC diagnoses as well as CRC-related and non-CRC–related deaths.

TAKEAWAY:

• H pylori infection was associated with an 18% higher risk for CRC (adjusted hazard ratio [aHR], 1.18) and a 12% higher risk for CRC mortality (aHR, 1.12).
• Untreated patients had a 23% higher risk for CRC (aHR, 1.23) and a 40% higher risk for CRC mortality (aHR, 1.40) than treated individuals.
• Over the 15-year follow-up, receiving treatment for H pylori infection vs no treatment was associated with a lower risk of developing and dying from CRC (absolute risk reduction, 0.23%-0.35%). For context, among individuals receiving a screening colonoscopy, the invasive test was associated with a 0.84%-1.22% absolute risk reduction in CRC incidence and a 0.15-0.30% absolute risk reduction in CRC mortality.
• Excluding patients diagnosed with CRC within a year of H pylori testing did not change the associations in the study.

IN PRACTICE:

“We would like to highlight the potentially exciting clinical implications of these findings,” the authors of an accompanying editorial wrote. “Although the mechanistic connection between H pylori and colorectal cancer is not fully resolved,” the finding that eliminating H pylori “could reduce both gastric and colorectal cancers is incredibly potent and should be considered in clinical care for individuals at high risk for GI [gastrointestinal] cancers.”

SOURCE:

The work, led by Shailja C. Shah, MD, of the University of California San Diego, was published in the Journal of Clinical Oncology, alongside the accompanying editorial by Julia Butt, PhD, of the German Cancer Research Center, Heidelberg, Germany, and Meira Epplein, PhD, of Duke University in Durham, North Carolina.

LIMITATIONS:

The study was limited to US veterans, which means generalizability to other populations needed to be confirmed. There may have been differences in CRC risk factors between treated and untreated patients.

DISCLOSURES:

The work was funded by the Veterans Health Administration, the National Cancer Institute, and others. Investigators reported ties to numerous companies, including AstraZeneca, Novartis, Guardant Health, and Medscape Medical News, publisher of this article. The editorialists had no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Being positive for Helicobacter pylori is associated with a higher risk for colorectal cancer (CRC) incidence and CRC mortality, new data show; however, a 2-week course of antibiotics to eliminate the bacterial infection can reduce the risk of developing and dying from CRC.

METHODOLOGY:

• H pylori is a known cause of peptic ulcers and stomach cancer and has been classified as a group I carcinogen by the World Health Organization›s International Agency for Research on Cancer.
• Studies showed that H pylori increases the risk for gastric cancer and may increase the risk for CRC, but evidence supporting the CRC connection remains inconsistent.
• To investigate a possible H pylori-CRC link, investigators reviewed CRC incidence and mortality in a nationwide cohort of 812,736 veterans tested for H pylori at Veterans Health Administration facilities; of the 205,178 (25.2%) who tested positive for H pylori, 134,417 (34%) were treated.
• Patients were followed from their first H pylori test, and researchers tracked subsequent CRC diagnoses as well as CRC-related and non-CRC–related deaths.

TAKEAWAY:

• H pylori infection was associated with an 18% higher risk for CRC (adjusted hazard ratio [aHR], 1.18) and a 12% higher risk for CRC mortality (aHR, 1.12).
• Untreated patients had a 23% higher risk for CRC (aHR, 1.23) and a 40% higher risk for CRC mortality (aHR, 1.40) than treated individuals.
• Over the 15-year follow-up, receiving treatment for H pylori infection vs no treatment was associated with a lower risk of developing and dying from CRC (absolute risk reduction, 0.23%-0.35%). For context, among individuals receiving a screening colonoscopy, the invasive test was associated with a 0.84%-1.22% absolute risk reduction in CRC incidence and a 0.15-0.30% absolute risk reduction in CRC mortality.
• Excluding patients diagnosed with CRC within a year of H pylori testing did not change the associations in the study.

IN PRACTICE:

“We would like to highlight the potentially exciting clinical implications of these findings,” the authors of an accompanying editorial wrote. “Although the mechanistic connection between H pylori and colorectal cancer is not fully resolved,” the finding that eliminating H pylori “could reduce both gastric and colorectal cancers is incredibly potent and should be considered in clinical care for individuals at high risk for GI [gastrointestinal] cancers.”

SOURCE:

The work, led by Shailja C. Shah, MD, of the University of California San Diego, was published in the Journal of Clinical Oncology, alongside the accompanying editorial by Julia Butt, PhD, of the German Cancer Research Center, Heidelberg, Germany, and Meira Epplein, PhD, of Duke University in Durham, North Carolina.

LIMITATIONS:

The study was limited to US veterans, which means generalizability to other populations needed to be confirmed. There may have been differences in CRC risk factors between treated and untreated patients.

DISCLOSURES:

The work was funded by the Veterans Health Administration, the National Cancer Institute, and others. Investigators reported ties to numerous companies, including AstraZeneca, Novartis, Guardant Health, and Medscape Medical News, publisher of this article. The editorialists had no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Being positive for Helicobacter pylori is associated with a higher risk for colorectal cancer (CRC) incidence and CRC mortality, new data show; however, a 2-week course of antibiotics to eliminate the bacterial infection can reduce the risk of developing and dying from CRC.

METHODOLOGY:

• H pylori is a known cause of peptic ulcers and stomach cancer and has been classified as a group I carcinogen by the World Health Organization›s International Agency for Research on Cancer.
• Studies showed that H pylori increases the risk for gastric cancer and may increase the risk for CRC, but evidence supporting the CRC connection remains inconsistent.
• To investigate a possible H pylori-CRC link, investigators reviewed CRC incidence and mortality in a nationwide cohort of 812,736 veterans tested for H pylori at Veterans Health Administration facilities; of the 205,178 (25.2%) who tested positive for H pylori, 134,417 (34%) were treated.
• Patients were followed from their first H pylori test, and researchers tracked subsequent CRC diagnoses as well as CRC-related and non-CRC–related deaths.

TAKEAWAY:

• H pylori infection was associated with an 18% higher risk for CRC (adjusted hazard ratio [aHR], 1.18) and a 12% higher risk for CRC mortality (aHR, 1.12).
• Untreated patients had a 23% higher risk for CRC (aHR, 1.23) and a 40% higher risk for CRC mortality (aHR, 1.40) than treated individuals.
• Over the 15-year follow-up, receiving treatment for H pylori infection vs no treatment was associated with a lower risk of developing and dying from CRC (absolute risk reduction, 0.23%-0.35%). For context, among individuals receiving a screening colonoscopy, the invasive test was associated with a 0.84%-1.22% absolute risk reduction in CRC incidence and a 0.15-0.30% absolute risk reduction in CRC mortality.
• Excluding patients diagnosed with CRC within a year of H pylori testing did not change the associations in the study.

IN PRACTICE:

“We would like to highlight the potentially exciting clinical implications of these findings,” the authors of an accompanying editorial wrote. “Although the mechanistic connection between H pylori and colorectal cancer is not fully resolved,” the finding that eliminating H pylori “could reduce both gastric and colorectal cancers is incredibly potent and should be considered in clinical care for individuals at high risk for GI [gastrointestinal] cancers.”

SOURCE:

The work, led by Shailja C. Shah, MD, of the University of California San Diego, was published in the Journal of Clinical Oncology, alongside the accompanying editorial by Julia Butt, PhD, of the German Cancer Research Center, Heidelberg, Germany, and Meira Epplein, PhD, of Duke University in Durham, North Carolina.

LIMITATIONS:

The study was limited to US veterans, which means generalizability to other populations needed to be confirmed. There may have been differences in CRC risk factors between treated and untreated patients.

DISCLOSURES:

The work was funded by the Veterans Health Administration, the National Cancer Institute, and others. Investigators reported ties to numerous companies, including AstraZeneca, Novartis, Guardant Health, and Medscape Medical News, publisher of this article. The editorialists had no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Using polygenic risk scores along with positive family histories and breast cancer-associated gene mutations improves risk stratification for breast cancer screening.

METHODOLOGY:

A polygenic risk score — a measure of an individual’s risk for a disease based on the estimated effects of many genetic variants — is not typically included alongside family histories and pathogenic variants of genes, such as BRCA1 and PALB2, when assessing a woman’s risk for breast cancer and the need for earlier or more frequent screening.

To assess the potential for a polygenic risk score to improve breast cancer risk stratification, investigators in Finland used a nationwide genetic database to calculate polygenic risk score scores for 117,252 women and then linked the scores to their breast cancer outcomes, using the country’s nationwide mammography screening program, which screens women, ages 50-69 years, every 2 years.

The researchers evaluated the use of polygenic risk scores both alone and in combination with family histories and pathogenic variants — specifically, CHEK2 and PALB2 variants common in Finland.

The researchers also looked at how well polygenic risk scores predicted a person’s risk for any breast cancer as well as invasive, in situ, and bilateral at three timepoints: before, during, and after screening age.

TAKEAWAY:

Compared with a lower polygenic risk score (below 90%), a high polygenic risk score — a score in the top 10% — was associated with more than a twofold higher risk for any breast cancer before, during, and after screening age (hazard ratio [HR], 2.50, 2.38, and 2.11, respectively). Pathogenic variants and family histories led to similar risk assessments (HR, 3.13, 2.30, and 1.95, respectively, for pathogenic variants; HR, 1.97, 1.96, and 1.68, respectively, for family history).

A high polygenic risk score had a positive predictive value of 39.5% for a breast cancer diagnosis after a positive screening mammography, about the same as positive family history (35.5%) and pathogenic variants (35.9%). Combining a high polygenic risk score with a positive family history increased the positive predictive value to 44.6% and with pathogenic variant carriers increased the positive predictive value to 50.6%.

A high polygenic risk score was also associated with a twofold higher risk for interval breast cancer — a cancer diagnosed between screenings — and a higher risk for bilateral breast cancer during screening ages (HR, 4.71), suggesting that women with high scores may benefit from a shorter time interval between screenings or earlier screening, the researchers said.

Women with scores in the bottom 10% had a very low risk for both interval and screen-detected cancers. Those with negative family histories and no pathogenic variants did not reach the 2% cumulative incidence threshold for breast cancer screening until age 62 years, “suggesting opportunities for less frequent screens,” the researchers noted.

IN PRACTICE:

This study demonstrates the effectiveness of using a breast cancer polygenic risk score for risk stratification, “with optimal stratification reached through combining” this information with family history and pathogenic variants, the researchers concluded.

SOURCE:

The study, led by Nina Mars, MD, PhD, of the University of Helsinki, Helsinki, Finland, was published in the Journal of Clinical Oncology.

LIMITATIONS:

The work was limited largely to people with Finnish genetic ancestry. The benefits of including polygenic risk scores in screening programs need to be confirmed in clinical trials in areas with broader genetic ancestry; several trials are underway in the United States and elsewhere.

DISCLOSURES:

The study was funded by the European Union’s Horizon 2020 research and innovation program, the Cancer Foundation Finland, and others. The investigators didn’t have any relevant disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Using polygenic risk scores along with positive family histories and breast cancer-associated gene mutations improves risk stratification for breast cancer screening.

METHODOLOGY:

A polygenic risk score — a measure of an individual’s risk for a disease based on the estimated effects of many genetic variants — is not typically included alongside family histories and pathogenic variants of genes, such as BRCA1 and PALB2, when assessing a woman’s risk for breast cancer and the need for earlier or more frequent screening.

To assess the potential for a polygenic risk score to improve breast cancer risk stratification, investigators in Finland used a nationwide genetic database to calculate polygenic risk score scores for 117,252 women and then linked the scores to their breast cancer outcomes, using the country’s nationwide mammography screening program, which screens women, ages 50-69 years, every 2 years.

The researchers evaluated the use of polygenic risk scores both alone and in combination with family histories and pathogenic variants — specifically, CHEK2 and PALB2 variants common in Finland.

The researchers also looked at how well polygenic risk scores predicted a person’s risk for any breast cancer as well as invasive, in situ, and bilateral at three timepoints: before, during, and after screening age.

TAKEAWAY:

Compared with a lower polygenic risk score (below 90%), a high polygenic risk score — a score in the top 10% — was associated with more than a twofold higher risk for any breast cancer before, during, and after screening age (hazard ratio [HR], 2.50, 2.38, and 2.11, respectively). Pathogenic variants and family histories led to similar risk assessments (HR, 3.13, 2.30, and 1.95, respectively, for pathogenic variants; HR, 1.97, 1.96, and 1.68, respectively, for family history).

A high polygenic risk score had a positive predictive value of 39.5% for a breast cancer diagnosis after a positive screening mammography, about the same as positive family history (35.5%) and pathogenic variants (35.9%). Combining a high polygenic risk score with a positive family history increased the positive predictive value to 44.6% and with pathogenic variant carriers increased the positive predictive value to 50.6%.

A high polygenic risk score was also associated with a twofold higher risk for interval breast cancer — a cancer diagnosed between screenings — and a higher risk for bilateral breast cancer during screening ages (HR, 4.71), suggesting that women with high scores may benefit from a shorter time interval between screenings or earlier screening, the researchers said.

Women with scores in the bottom 10% had a very low risk for both interval and screen-detected cancers. Those with negative family histories and no pathogenic variants did not reach the 2% cumulative incidence threshold for breast cancer screening until age 62 years, “suggesting opportunities for less frequent screens,” the researchers noted.

IN PRACTICE:

This study demonstrates the effectiveness of using a breast cancer polygenic risk score for risk stratification, “with optimal stratification reached through combining” this information with family history and pathogenic variants, the researchers concluded.

SOURCE:

The study, led by Nina Mars, MD, PhD, of the University of Helsinki, Helsinki, Finland, was published in the Journal of Clinical Oncology.

LIMITATIONS:

The work was limited largely to people with Finnish genetic ancestry. The benefits of including polygenic risk scores in screening programs need to be confirmed in clinical trials in areas with broader genetic ancestry; several trials are underway in the United States and elsewhere.

DISCLOSURES:

The study was funded by the European Union’s Horizon 2020 research and innovation program, the Cancer Foundation Finland, and others. The investigators didn’t have any relevant disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Using polygenic risk scores along with positive family histories and breast cancer-associated gene mutations improves risk stratification for breast cancer screening.

METHODOLOGY:

A polygenic risk score — a measure of an individual’s risk for a disease based on the estimated effects of many genetic variants — is not typically included alongside family histories and pathogenic variants of genes, such as BRCA1 and PALB2, when assessing a woman’s risk for breast cancer and the need for earlier or more frequent screening.

To assess the potential for a polygenic risk score to improve breast cancer risk stratification, investigators in Finland used a nationwide genetic database to calculate polygenic risk score scores for 117,252 women and then linked the scores to their breast cancer outcomes, using the country’s nationwide mammography screening program, which screens women, ages 50-69 years, every 2 years.

The researchers evaluated the use of polygenic risk scores both alone and in combination with family histories and pathogenic variants — specifically, CHEK2 and PALB2 variants common in Finland.

The researchers also looked at how well polygenic risk scores predicted a person’s risk for any breast cancer as well as invasive, in situ, and bilateral at three timepoints: before, during, and after screening age.

TAKEAWAY:

Compared with a lower polygenic risk score (below 90%), a high polygenic risk score — a score in the top 10% — was associated with more than a twofold higher risk for any breast cancer before, during, and after screening age (hazard ratio [HR], 2.50, 2.38, and 2.11, respectively). Pathogenic variants and family histories led to similar risk assessments (HR, 3.13, 2.30, and 1.95, respectively, for pathogenic variants; HR, 1.97, 1.96, and 1.68, respectively, for family history).

A high polygenic risk score had a positive predictive value of 39.5% for a breast cancer diagnosis after a positive screening mammography, about the same as positive family history (35.5%) and pathogenic variants (35.9%). Combining a high polygenic risk score with a positive family history increased the positive predictive value to 44.6% and with pathogenic variant carriers increased the positive predictive value to 50.6%.

A high polygenic risk score was also associated with a twofold higher risk for interval breast cancer — a cancer diagnosed between screenings — and a higher risk for bilateral breast cancer during screening ages (HR, 4.71), suggesting that women with high scores may benefit from a shorter time interval between screenings or earlier screening, the researchers said.

Women with scores in the bottom 10% had a very low risk for both interval and screen-detected cancers. Those with negative family histories and no pathogenic variants did not reach the 2% cumulative incidence threshold for breast cancer screening until age 62 years, “suggesting opportunities for less frequent screens,” the researchers noted.

IN PRACTICE:

This study demonstrates the effectiveness of using a breast cancer polygenic risk score for risk stratification, “with optimal stratification reached through combining” this information with family history and pathogenic variants, the researchers concluded.

SOURCE:

The study, led by Nina Mars, MD, PhD, of the University of Helsinki, Helsinki, Finland, was published in the Journal of Clinical Oncology.

LIMITATIONS:

The work was limited largely to people with Finnish genetic ancestry. The benefits of including polygenic risk scores in screening programs need to be confirmed in clinical trials in areas with broader genetic ancestry; several trials are underway in the United States and elsewhere.

DISCLOSURES:

The study was funded by the European Union’s Horizon 2020 research and innovation program, the Cancer Foundation Finland, and others. The investigators didn’t have any relevant disclosures.

A version of this article appeared on Medscape.com.