TBD Meeting (3274-21)

Supplementation with omega-3 polyunsaturated fatty acids (PUFA) leads to gut microbial changes that may protect against inflammation, according to a new analysis of obese and overweight, postmenopausal women who participated in a weight loss trial.

The study was presented by Katherine Cook, PhD, during a poster session at the San Antonio Breast Cancer Symposium. Dr. Cook is a researcher at Wake Forest University, Winston-Salem, N.C.

Obesity increases risk of breast cancer, but it also alters the composition of the gut microbiome. Obesity is associated with a greater frequency of Firmicute bacteria phyla, compared with Bacteroidetes phyla, while abnormally low ratios are associated with inflammatory bowel disease.

In mice, the researchers previously showed that diet can lead to changes in the microbiome of both the gut and the breast. They conducted fecal transplants between mice who were fed normal or high-fat diets (HFD), and then used a chemical carcinogenesis model to investigate the impact on tumor outcomes. They observed changes in the microbiota populations in both the gut and the mammary glands when mice fed a normal diet received fecal transplants from HFD mice. On the other hand, when HFD mice received fecal transplants from mice with normal diets, the transplants countered the increase in serum lipopolysaccharide levels associated with HFD. In vitro models showed that microbiota from HFD mice also altered the epithelial permeability of breast tissue, and infection of breast cancer cells with HFD microbiota led to greater proliferation.

The researchers also examined breast cancer tissue from women who received omega-3 PUFA supplements or placebo before undergoing primary tumor resection, and found that there were differences in the proportional abundance of specific microbes between tumor and adjacent normal tissue, with the former having excess of Lachnospiraceae and Ruminococcus. The finding suggests that these bacteria may grow better in a tumor microenvironment, and could play a role in breast cancer cell signaling. The supplements altered the microbiota of both normal and breast cancer tissue.

In the study presented at SABCS, the researchers analyzed fecal samples from 34 obese and overweight postmenopausal women involved in a weight-loss trial, who received 3.25 g/day of omega-3 PUFA supplements or placebo combined with calorie restriction and exercise. They performed metagenomic sequencing from the fecal samples at baseline and 6 months to determine microbiome populations.

Women who experienced weight loss, with or without omega-3 PUFA supplementation, had a decline in the abundance of Firmicutes phyla – a group linked to inflammation risk – as a percentage of overall bacterial phyla. The researchers found a similar trend among women who received omega-3 PUFA, regardless of how much weight they lost. At the species level, those who received supplements had higher proportional abundance of Phocaeicola massiliensis and reduced proportions of Faecalibacterium prausnitzii, R. lactaris, Blautia obeum, and Dorea formicigenerans (P < .05).

Weight loss combined with supplementation also seemed to affect gut microbiota, with subjects who lost more than 10% of their body weight and received omega-3 PUFA supplements having elevated Bacteriodetes and reduced Firmicutes, compared with all other groups (P < .05).

At 6 months, the researchers grouped women by mean body fat composition, and found both positive and negative correlations among different bacterial species. Finally, the researchers looked at serum levels of the inflammatory cytokines interleukin-6, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor–alpha at 6 months. Women with elevated levels of at least two cytokines had higher levels of two species of mucin-degrading bacteria. Levels of MCP-1 alone also correlated with greater proportions of mucin-degrading bacteria (P < .05).

The authors concluded that increasing omega-3 PUFA uptake to about 2% of total daily calorie intake could push the gut microbiome in a direction that improves intestinal permeability parameters and reduces chronic inflammation. These changes could lead to a reduction in the risk for postmenopausal breast cancer.

The study was funded by the Breast Cancer Research Foundation.

Supplementation with omega-3 polyunsaturated fatty acids (PUFA) leads to gut microbial changes that may protect against inflammation, according to a new analysis of obese and overweight, postmenopausal women who participated in a weight loss trial.

The study was presented by Katherine Cook, PhD, during a poster session at the San Antonio Breast Cancer Symposium. Dr. Cook is a researcher at Wake Forest University, Winston-Salem, N.C.

Obesity increases risk of breast cancer, but it also alters the composition of the gut microbiome. Obesity is associated with a greater frequency of Firmicute bacteria phyla, compared with Bacteroidetes phyla, while abnormally low ratios are associated with inflammatory bowel disease.

In mice, the researchers previously showed that diet can lead to changes in the microbiome of both the gut and the breast. They conducted fecal transplants between mice who were fed normal or high-fat diets (HFD), and then used a chemical carcinogenesis model to investigate the impact on tumor outcomes. They observed changes in the microbiota populations in both the gut and the mammary glands when mice fed a normal diet received fecal transplants from HFD mice. On the other hand, when HFD mice received fecal transplants from mice with normal diets, the transplants countered the increase in serum lipopolysaccharide levels associated with HFD. In vitro models showed that microbiota from HFD mice also altered the epithelial permeability of breast tissue, and infection of breast cancer cells with HFD microbiota led to greater proliferation.

The researchers also examined breast cancer tissue from women who received omega-3 PUFA supplements or placebo before undergoing primary tumor resection, and found that there were differences in the proportional abundance of specific microbes between tumor and adjacent normal tissue, with the former having excess of Lachnospiraceae and Ruminococcus. The finding suggests that these bacteria may grow better in a tumor microenvironment, and could play a role in breast cancer cell signaling. The supplements altered the microbiota of both normal and breast cancer tissue.

In the study presented at SABCS, the researchers analyzed fecal samples from 34 obese and overweight postmenopausal women involved in a weight-loss trial, who received 3.25 g/day of omega-3 PUFA supplements or placebo combined with calorie restriction and exercise. They performed metagenomic sequencing from the fecal samples at baseline and 6 months to determine microbiome populations.

Women who experienced weight loss, with or without omega-3 PUFA supplementation, had a decline in the abundance of Firmicutes phyla – a group linked to inflammation risk – as a percentage of overall bacterial phyla. The researchers found a similar trend among women who received omega-3 PUFA, regardless of how much weight they lost. At the species level, those who received supplements had higher proportional abundance of Phocaeicola massiliensis and reduced proportions of Faecalibacterium prausnitzii, R. lactaris, Blautia obeum, and Dorea formicigenerans (P < .05).

Weight loss combined with supplementation also seemed to affect gut microbiota, with subjects who lost more than 10% of their body weight and received omega-3 PUFA supplements having elevated Bacteriodetes and reduced Firmicutes, compared with all other groups (P < .05).

At 6 months, the researchers grouped women by mean body fat composition, and found both positive and negative correlations among different bacterial species. Finally, the researchers looked at serum levels of the inflammatory cytokines interleukin-6, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor–alpha at 6 months. Women with elevated levels of at least two cytokines had higher levels of two species of mucin-degrading bacteria. Levels of MCP-1 alone also correlated with greater proportions of mucin-degrading bacteria (P < .05).

The authors concluded that increasing omega-3 PUFA uptake to about 2% of total daily calorie intake could push the gut microbiome in a direction that improves intestinal permeability parameters and reduces chronic inflammation. These changes could lead to a reduction in the risk for postmenopausal breast cancer.

The study was funded by the Breast Cancer Research Foundation.

Supplementation with omega-3 polyunsaturated fatty acids (PUFA) leads to gut microbial changes that may protect against inflammation, according to a new analysis of obese and overweight, postmenopausal women who participated in a weight loss trial.

The study was presented by Katherine Cook, PhD, during a poster session at the San Antonio Breast Cancer Symposium. Dr. Cook is a researcher at Wake Forest University, Winston-Salem, N.C.

Obesity increases risk of breast cancer, but it also alters the composition of the gut microbiome. Obesity is associated with a greater frequency of Firmicute bacteria phyla, compared with Bacteroidetes phyla, while abnormally low ratios are associated with inflammatory bowel disease.

In mice, the researchers previously showed that diet can lead to changes in the microbiome of both the gut and the breast. They conducted fecal transplants between mice who were fed normal or high-fat diets (HFD), and then used a chemical carcinogenesis model to investigate the impact on tumor outcomes. They observed changes in the microbiota populations in both the gut and the mammary glands when mice fed a normal diet received fecal transplants from HFD mice. On the other hand, when HFD mice received fecal transplants from mice with normal diets, the transplants countered the increase in serum lipopolysaccharide levels associated with HFD. In vitro models showed that microbiota from HFD mice also altered the epithelial permeability of breast tissue, and infection of breast cancer cells with HFD microbiota led to greater proliferation.

The researchers also examined breast cancer tissue from women who received omega-3 PUFA supplements or placebo before undergoing primary tumor resection, and found that there were differences in the proportional abundance of specific microbes between tumor and adjacent normal tissue, with the former having excess of Lachnospiraceae and Ruminococcus. The finding suggests that these bacteria may grow better in a tumor microenvironment, and could play a role in breast cancer cell signaling. The supplements altered the microbiota of both normal and breast cancer tissue.

In the study presented at SABCS, the researchers analyzed fecal samples from 34 obese and overweight postmenopausal women involved in a weight-loss trial, who received 3.25 g/day of omega-3 PUFA supplements or placebo combined with calorie restriction and exercise. They performed metagenomic sequencing from the fecal samples at baseline and 6 months to determine microbiome populations.

Women who experienced weight loss, with or without omega-3 PUFA supplementation, had a decline in the abundance of Firmicutes phyla – a group linked to inflammation risk – as a percentage of overall bacterial phyla. The researchers found a similar trend among women who received omega-3 PUFA, regardless of how much weight they lost. At the species level, those who received supplements had higher proportional abundance of Phocaeicola massiliensis and reduced proportions of Faecalibacterium prausnitzii, R. lactaris, Blautia obeum, and Dorea formicigenerans (P < .05).

Weight loss combined with supplementation also seemed to affect gut microbiota, with subjects who lost more than 10% of their body weight and received omega-3 PUFA supplements having elevated Bacteriodetes and reduced Firmicutes, compared with all other groups (P < .05).

At 6 months, the researchers grouped women by mean body fat composition, and found both positive and negative correlations among different bacterial species. Finally, the researchers looked at serum levels of the inflammatory cytokines interleukin-6, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor–alpha at 6 months. Women with elevated levels of at least two cytokines had higher levels of two species of mucin-degrading bacteria. Levels of MCP-1 alone also correlated with greater proportions of mucin-degrading bacteria (P < .05).

The authors concluded that increasing omega-3 PUFA uptake to about 2% of total daily calorie intake could push the gut microbiome in a direction that improves intestinal permeability parameters and reduces chronic inflammation. These changes could lead to a reduction in the risk for postmenopausal breast cancer.

The study was funded by the Breast Cancer Research Foundation.

SAN ANTONIO – Sedative-hypnotic medications, such as benzodiazepines and nonbenzodiazepine sedative-hypnotics commonly used to treat chemotherapy-related nausea, anxiety, and insomnia in women being treated for breast cancer, put women at high risk of dependency after chemotherapy treatment, shows a new study.

While benzodiazepines and nonbenzodiazepine sedative-hypnotics are effective for these indications, misuse and increased health care utilization can ensue from their prolonged use, said Jacob C. Cogan, MD, a fellow in oncology/hematology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York. Dr. Cogan recently presented the results of the study at the San Antonio Breast Cancer Symposium.

The study included patients with breast cancer who received adjuvant chemotherapy between 2008 and 2017. Prescriptions for sedatives were divided into three periods: 365 days prior to chemotherapy to the start of chemotherapy (period one); start of chemotherapy to 90 days after the end of chemotherapy (period two); and 90-365 days after chemotherapy (period three). Patients who filled at least one benzodiazepine prescription in period two and patients who filled at least two benzodiazepine in period three were classified as new persistent benzodiazepine users. The same definitions were then used for nonbenzodiazepine sedative-hypnotics.

Among 17,532 benzodiazepine-naive patients (mean age, 57 years) and 21,863 nonbenzodiazepine sedative-hypnotic drug–naive patients (mean age, 56 years) who received adjuvant chemotherapy for breast cancer, lumpectomies were performed for a small majority (56.6% benzodiazepine naive, 55.1% nonbenzodiazepine sedative-hypnotics naive) versus mastectomy, and about half of patients received less than 4 months of chemotherapy (48.0% benzodiazepine naive, 48.6% nonbenzodiazepine sedative-hypnotics naive). Among benzodiazepine-naive patients, 4,447 (25.4%) filled at least one benzodiazepine prescription during chemotherapy, and 2,160 (9.9%) filled at least one nonbenzodiazepine sedative-hypnotic prescription during chemotherapy. The rate of new persistent benzodiazepine use after initial exposure during chemotherapy was 26.8% (n = 1,192). Similarly, 33.8% (n = 730) of nonbenzodiazepine sedative-hypnotics users became new persistent users. In addition, 115 patients became new persistent users of both types of sedative-hypnotics.

New persistent benzodiazepine use was associated with several characteristics: age 50-65 (odds ratio, 1.23; P = .01) and age greater than 65 (OR, 1.38, P = .005) relative to age less than 49; as well as Medicaid insurance, relative to commercial and Medicare insurance (OR, 1.68; P < .0001). Both new persistent benzodiazepine and nonbenzodiazepine sedative-hypnotics use was associated with chemotherapy duration of less than 4 months relative to 4 or more months of chemotherapy (OR, 1.17; P = .03 for benzodiazepines; OR, 1.58; P < .0001 for nonbenzodiazepine sedative-hypnotics).

It is not clear why shorter chemotherapy duration is associated with more new persistent use, Dr. Cogan said. “It may be that, paradoxically, a shorter duration of treatment could lead to more anxiety about recurrence. These patients may need closer monitoring of mental health symptoms and earlier referral for psychological services.”

Dr. Cogan said that providers should take steps to ensure that benzodiazepines and nonbenzodiazepine sedatives are used appropriately, which includes tapering dosages and, when appropriate, encouraging nonpharmacologic strategies.

There were no funding or other conflicts of interest associated with this study.

SAN ANTONIO – Sedative-hypnotic medications, such as benzodiazepines and nonbenzodiazepine sedative-hypnotics commonly used to treat chemotherapy-related nausea, anxiety, and insomnia in women being treated for breast cancer, put women at high risk of dependency after chemotherapy treatment, shows a new study.

While benzodiazepines and nonbenzodiazepine sedative-hypnotics are effective for these indications, misuse and increased health care utilization can ensue from their prolonged use, said Jacob C. Cogan, MD, a fellow in oncology/hematology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York. Dr. Cogan recently presented the results of the study at the San Antonio Breast Cancer Symposium.

The study included patients with breast cancer who received adjuvant chemotherapy between 2008 and 2017. Prescriptions for sedatives were divided into three periods: 365 days prior to chemotherapy to the start of chemotherapy (period one); start of chemotherapy to 90 days after the end of chemotherapy (period two); and 90-365 days after chemotherapy (period three). Patients who filled at least one benzodiazepine prescription in period two and patients who filled at least two benzodiazepine in period three were classified as new persistent benzodiazepine users. The same definitions were then used for nonbenzodiazepine sedative-hypnotics.

Among 17,532 benzodiazepine-naive patients (mean age, 57 years) and 21,863 nonbenzodiazepine sedative-hypnotic drug–naive patients (mean age, 56 years) who received adjuvant chemotherapy for breast cancer, lumpectomies were performed for a small majority (56.6% benzodiazepine naive, 55.1% nonbenzodiazepine sedative-hypnotics naive) versus mastectomy, and about half of patients received less than 4 months of chemotherapy (48.0% benzodiazepine naive, 48.6% nonbenzodiazepine sedative-hypnotics naive). Among benzodiazepine-naive patients, 4,447 (25.4%) filled at least one benzodiazepine prescription during chemotherapy, and 2,160 (9.9%) filled at least one nonbenzodiazepine sedative-hypnotic prescription during chemotherapy. The rate of new persistent benzodiazepine use after initial exposure during chemotherapy was 26.8% (n = 1,192). Similarly, 33.8% (n = 730) of nonbenzodiazepine sedative-hypnotics users became new persistent users. In addition, 115 patients became new persistent users of both types of sedative-hypnotics.

New persistent benzodiazepine use was associated with several characteristics: age 50-65 (odds ratio, 1.23; P = .01) and age greater than 65 (OR, 1.38, P = .005) relative to age less than 49; as well as Medicaid insurance, relative to commercial and Medicare insurance (OR, 1.68; P < .0001). Both new persistent benzodiazepine and nonbenzodiazepine sedative-hypnotics use was associated with chemotherapy duration of less than 4 months relative to 4 or more months of chemotherapy (OR, 1.17; P = .03 for benzodiazepines; OR, 1.58; P < .0001 for nonbenzodiazepine sedative-hypnotics).

It is not clear why shorter chemotherapy duration is associated with more new persistent use, Dr. Cogan said. “It may be that, paradoxically, a shorter duration of treatment could lead to more anxiety about recurrence. These patients may need closer monitoring of mental health symptoms and earlier referral for psychological services.”

Dr. Cogan said that providers should take steps to ensure that benzodiazepines and nonbenzodiazepine sedatives are used appropriately, which includes tapering dosages and, when appropriate, encouraging nonpharmacologic strategies.

There were no funding or other conflicts of interest associated with this study.

SAN ANTONIO – Sedative-hypnotic medications, such as benzodiazepines and nonbenzodiazepine sedative-hypnotics commonly used to treat chemotherapy-related nausea, anxiety, and insomnia in women being treated for breast cancer, put women at high risk of dependency after chemotherapy treatment, shows a new study.

While benzodiazepines and nonbenzodiazepine sedative-hypnotics are effective for these indications, misuse and increased health care utilization can ensue from their prolonged use, said Jacob C. Cogan, MD, a fellow in oncology/hematology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York. Dr. Cogan recently presented the results of the study at the San Antonio Breast Cancer Symposium.

The study included patients with breast cancer who received adjuvant chemotherapy between 2008 and 2017. Prescriptions for sedatives were divided into three periods: 365 days prior to chemotherapy to the start of chemotherapy (period one); start of chemotherapy to 90 days after the end of chemotherapy (period two); and 90-365 days after chemotherapy (period three). Patients who filled at least one benzodiazepine prescription in period two and patients who filled at least two benzodiazepine in period three were classified as new persistent benzodiazepine users. The same definitions were then used for nonbenzodiazepine sedative-hypnotics.

Among 17,532 benzodiazepine-naive patients (mean age, 57 years) and 21,863 nonbenzodiazepine sedative-hypnotic drug–naive patients (mean age, 56 years) who received adjuvant chemotherapy for breast cancer, lumpectomies were performed for a small majority (56.6% benzodiazepine naive, 55.1% nonbenzodiazepine sedative-hypnotics naive) versus mastectomy, and about half of patients received less than 4 months of chemotherapy (48.0% benzodiazepine naive, 48.6% nonbenzodiazepine sedative-hypnotics naive). Among benzodiazepine-naive patients, 4,447 (25.4%) filled at least one benzodiazepine prescription during chemotherapy, and 2,160 (9.9%) filled at least one nonbenzodiazepine sedative-hypnotic prescription during chemotherapy. The rate of new persistent benzodiazepine use after initial exposure during chemotherapy was 26.8% (n = 1,192). Similarly, 33.8% (n = 730) of nonbenzodiazepine sedative-hypnotics users became new persistent users. In addition, 115 patients became new persistent users of both types of sedative-hypnotics.

New persistent benzodiazepine use was associated with several characteristics: age 50-65 (odds ratio, 1.23; P = .01) and age greater than 65 (OR, 1.38, P = .005) relative to age less than 49; as well as Medicaid insurance, relative to commercial and Medicare insurance (OR, 1.68; P < .0001). Both new persistent benzodiazepine and nonbenzodiazepine sedative-hypnotics use was associated with chemotherapy duration of less than 4 months relative to 4 or more months of chemotherapy (OR, 1.17; P = .03 for benzodiazepines; OR, 1.58; P < .0001 for nonbenzodiazepine sedative-hypnotics).

It is not clear why shorter chemotherapy duration is associated with more new persistent use, Dr. Cogan said. “It may be that, paradoxically, a shorter duration of treatment could lead to more anxiety about recurrence. These patients may need closer monitoring of mental health symptoms and earlier referral for psychological services.”

Dr. Cogan said that providers should take steps to ensure that benzodiazepines and nonbenzodiazepine sedatives are used appropriately, which includes tapering dosages and, when appropriate, encouraging nonpharmacologic strategies.

There were no funding or other conflicts of interest associated with this study.

Final results from a large phase 3 trial confirm no benefit to adding palbociclib (Ibrance) to endocrine therapy in early hormone receptor (HR)–positive, HER2-negative breast cancer.

Two years of adjuvant palbociclib added to endocrine therapy failed to improve invasive disease-free survival or any other efficacy endpoint in patients with stage II-III HR-positive, HER2-negative breast cancer.

“These definitive findings from the PALLAS trial, already indicated by an interim analysis, are surprising given the established efficacy of palbociclib and other CDK4/6i [inhibitors] in advanced breast cancer,” according to lead author Michael Gnant, MD, professor in the department of surgery, Medical University of Vienna, and colleagues.

The results from the PALLAS trial were presented Dec. 7 at the San Antonio Breast Cancer Symposium and simultaneously published in the Journal of Clinical Oncology.

At a median follow-up of 31 months and at the final protocol-defined analysis, invasive disease-free survival events occurred in 253 (8.8%) of 2,884 patients who received the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor plus endocrine therapy and in 263 (9.1%) of 2,877 patients who received endocrine therapy alone. At 4 years, invasive disease-free survival rates were similar in the palbociclib group (84.2%) and standard treatment group (84.5%).
 

Caught by surprise

Studies have shown that combining CDK4/6 inhibitors and endocrine therapy prolongs progression-free survival (PFS) and overall survival in metastatic HR-positive, HER2-negative breast cancer, with good tolerability.

“CDK4/6 inhibitors have markedly changed outcomes in the metastatic setting and are now standard of care,” said Dr. Gnant, who presented the recent findings at SABCS. “It seem[ed] only logical to try to transfer these benefits to the curative setting of early breast cancer.”

But in 2020, palbociclib manufacturer Pfizer issued a press release noting that the PALLAS trial was unlikely to show a statistically significant improvement in the primary endpoint of invasive disease-free survival.

The results “caught many of us by surprise,” Kathy D. Miller, MD, codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University, Indianapolis, wrote in response to this announcement.

The trial was based on strong science and incredibly positive results in the metastatic setting but did not meet its primary endpoint when incorporated into the adjuvant setting, Dr. Miller noted in a Medscape blog. “That is certainly not the result we had hoped for, and it’s not the result many of us were expecting.”

Dr. Miller emphasized that “more than anything else, this trial reminds us of the absolute necessity of putting our ideas to the test and doing appropriately powered, appropriately controlled, and well-conducted randomized trials.”

The PALLAS trial enrolled 5,796 patients from 406 centers in 21 countries worldwide over a 3-year period, with 5,761 included in the intention-to-treat population.

Participants were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone for at least 5 years.

Dr. Gnant and colleagues found that the primary endpoint – invasive disease-free survival – did not differ significantly different between the two treatment groups (hazard ratio, 0.96; P = .65). Secondary endpoints in the palbociclib versus no-palbociclib groups were also similar: 4-year survival rates for invasive breast cancer-free survival were 85.4% versus 86%, distant recurrence-free survival was 86.2% versus 87.8%, locoregional recurrence-free survival was 96.8% versus 95.4%, and overall survival was 93.8% versus 95.2%.

The main side effect of palbociclib was neutropenia, but there were no new safety signals, Dr. Gnant explained. He noted, however, that the rates of palbociclib discontinuation were monitored closely and were substantial. At 1 year, 30% of patients discontinued palbociclib and by 24 months, 45% had stopped.
 

Not the final word?

An interim analysis of the phase 3 monarchE trial did not align with the PALLAS trial.

The monarchE trial found that adding the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy for 2 years significantly reduced the risk of early recurrence, compared with endocrine therapy alone in the same patient populations – those with early HR-positive, HER2-negative breast cancer. The researchers reported the combination was associated with a 25% relative risk reduction of invasive disease-free survival (HR, 0.75; P =.0096).

The research was presented at the ESMO Virtual Congress 2020 and simultaneously published in the Journal of Clinical Oncology.

Dr. Miller speculated how about how these two drugs that look so similar in the metastatic setting have given such different results in the adjuvant setting. One potential reason is pure chance.

“Any study, no matter how many zeros in the P value, could be simply the play of chance,” she said in an interview. “And that is true for negative and positive studies.”

The fault could also lie in the study design. “Remember, these are agents that we think of as reversing endocrine resistance and extending the benefit of hormone therapy,” she pointed out. “And yet we looked at very early results. Perhaps the study design was just wrong for palbociclib.”

Yet another possibility: The relative potency of those two CDK4/6 inhibitors could differ. “In a metastatic setting, that did not seem to affect effectiveness, but it clearly affected the toxicity profile. Perhaps in the adjuvant setting, those differences really do drive differences in efficacy,” she said.

Dr. Gnant also speculated that differences in the treatment schedules for the two drugs, as abemaciclib is taken continuously without a break, could potentially explain the different efficacies in the early breast cancer setting.

He called for long-term follow up, saying it’s essential for comprehensively examining outcomes in HR-positive luminal breast cancers.

“Ongoing analyses in the Trans-PALLAS translational and clinical science program, with almost 6,000 tumor blocks and tens of thousands of blood samples, will improve understanding of CD4/6 inhibition as well as contemporary management of HR-positive, HER2-negative breast cancer,” Dr. Gnant said.

The trial was funded by Pfizer, who provided study drug and financial support. In addition, the academic organizations ABCSG and AFT supported the trial by providing human resources. Dr. Gnant reported employment at Sandoz; receiving honoraria from Amgen, Novartis, AstraZeneca, Lilly; and consulting or advisory roles at Daiichi Sankyo, Veracyte, Tolmar¸ LifeBrain, and Lilly.

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

Final results from a large phase 3 trial confirm no benefit to adding palbociclib (Ibrance) to endocrine therapy in early hormone receptor (HR)–positive, HER2-negative breast cancer.

Two years of adjuvant palbociclib added to endocrine therapy failed to improve invasive disease-free survival or any other efficacy endpoint in patients with stage II-III HR-positive, HER2-negative breast cancer.

“These definitive findings from the PALLAS trial, already indicated by an interim analysis, are surprising given the established efficacy of palbociclib and other CDK4/6i [inhibitors] in advanced breast cancer,” according to lead author Michael Gnant, MD, professor in the department of surgery, Medical University of Vienna, and colleagues.

The results from the PALLAS trial were presented Dec. 7 at the San Antonio Breast Cancer Symposium and simultaneously published in the Journal of Clinical Oncology.

At a median follow-up of 31 months and at the final protocol-defined analysis, invasive disease-free survival events occurred in 253 (8.8%) of 2,884 patients who received the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor plus endocrine therapy and in 263 (9.1%) of 2,877 patients who received endocrine therapy alone. At 4 years, invasive disease-free survival rates were similar in the palbociclib group (84.2%) and standard treatment group (84.5%).
 

Caught by surprise

Studies have shown that combining CDK4/6 inhibitors and endocrine therapy prolongs progression-free survival (PFS) and overall survival in metastatic HR-positive, HER2-negative breast cancer, with good tolerability.

“CDK4/6 inhibitors have markedly changed outcomes in the metastatic setting and are now standard of care,” said Dr. Gnant, who presented the recent findings at SABCS. “It seem[ed] only logical to try to transfer these benefits to the curative setting of early breast cancer.”

But in 2020, palbociclib manufacturer Pfizer issued a press release noting that the PALLAS trial was unlikely to show a statistically significant improvement in the primary endpoint of invasive disease-free survival.

The results “caught many of us by surprise,” Kathy D. Miller, MD, codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University, Indianapolis, wrote in response to this announcement.

The trial was based on strong science and incredibly positive results in the metastatic setting but did not meet its primary endpoint when incorporated into the adjuvant setting, Dr. Miller noted in a Medscape blog. “That is certainly not the result we had hoped for, and it’s not the result many of us were expecting.”

Dr. Miller emphasized that “more than anything else, this trial reminds us of the absolute necessity of putting our ideas to the test and doing appropriately powered, appropriately controlled, and well-conducted randomized trials.”

The PALLAS trial enrolled 5,796 patients from 406 centers in 21 countries worldwide over a 3-year period, with 5,761 included in the intention-to-treat population.

Participants were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone for at least 5 years.

Dr. Gnant and colleagues found that the primary endpoint – invasive disease-free survival – did not differ significantly different between the two treatment groups (hazard ratio, 0.96; P = .65). Secondary endpoints in the palbociclib versus no-palbociclib groups were also similar: 4-year survival rates for invasive breast cancer-free survival were 85.4% versus 86%, distant recurrence-free survival was 86.2% versus 87.8%, locoregional recurrence-free survival was 96.8% versus 95.4%, and overall survival was 93.8% versus 95.2%.

The main side effect of palbociclib was neutropenia, but there were no new safety signals, Dr. Gnant explained. He noted, however, that the rates of palbociclib discontinuation were monitored closely and were substantial. At 1 year, 30% of patients discontinued palbociclib and by 24 months, 45% had stopped.
 

Not the final word?

An interim analysis of the phase 3 monarchE trial did not align with the PALLAS trial.

The monarchE trial found that adding the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy for 2 years significantly reduced the risk of early recurrence, compared with endocrine therapy alone in the same patient populations – those with early HR-positive, HER2-negative breast cancer. The researchers reported the combination was associated with a 25% relative risk reduction of invasive disease-free survival (HR, 0.75; P =.0096).

The research was presented at the ESMO Virtual Congress 2020 and simultaneously published in the Journal of Clinical Oncology.

Dr. Miller speculated how about how these two drugs that look so similar in the metastatic setting have given such different results in the adjuvant setting. One potential reason is pure chance.

“Any study, no matter how many zeros in the P value, could be simply the play of chance,” she said in an interview. “And that is true for negative and positive studies.”

The fault could also lie in the study design. “Remember, these are agents that we think of as reversing endocrine resistance and extending the benefit of hormone therapy,” she pointed out. “And yet we looked at very early results. Perhaps the study design was just wrong for palbociclib.”

Yet another possibility: The relative potency of those two CDK4/6 inhibitors could differ. “In a metastatic setting, that did not seem to affect effectiveness, but it clearly affected the toxicity profile. Perhaps in the adjuvant setting, those differences really do drive differences in efficacy,” she said.

Dr. Gnant also speculated that differences in the treatment schedules for the two drugs, as abemaciclib is taken continuously without a break, could potentially explain the different efficacies in the early breast cancer setting.

He called for long-term follow up, saying it’s essential for comprehensively examining outcomes in HR-positive luminal breast cancers.

“Ongoing analyses in the Trans-PALLAS translational and clinical science program, with almost 6,000 tumor blocks and tens of thousands of blood samples, will improve understanding of CD4/6 inhibition as well as contemporary management of HR-positive, HER2-negative breast cancer,” Dr. Gnant said.

The trial was funded by Pfizer, who provided study drug and financial support. In addition, the academic organizations ABCSG and AFT supported the trial by providing human resources. Dr. Gnant reported employment at Sandoz; receiving honoraria from Amgen, Novartis, AstraZeneca, Lilly; and consulting or advisory roles at Daiichi Sankyo, Veracyte, Tolmar¸ LifeBrain, and Lilly.

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

Final results from a large phase 3 trial confirm no benefit to adding palbociclib (Ibrance) to endocrine therapy in early hormone receptor (HR)–positive, HER2-negative breast cancer.

Two years of adjuvant palbociclib added to endocrine therapy failed to improve invasive disease-free survival or any other efficacy endpoint in patients with stage II-III HR-positive, HER2-negative breast cancer.

“These definitive findings from the PALLAS trial, already indicated by an interim analysis, are surprising given the established efficacy of palbociclib and other CDK4/6i [inhibitors] in advanced breast cancer,” according to lead author Michael Gnant, MD, professor in the department of surgery, Medical University of Vienna, and colleagues.

The results from the PALLAS trial were presented Dec. 7 at the San Antonio Breast Cancer Symposium and simultaneously published in the Journal of Clinical Oncology.

At a median follow-up of 31 months and at the final protocol-defined analysis, invasive disease-free survival events occurred in 253 (8.8%) of 2,884 patients who received the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor plus endocrine therapy and in 263 (9.1%) of 2,877 patients who received endocrine therapy alone. At 4 years, invasive disease-free survival rates were similar in the palbociclib group (84.2%) and standard treatment group (84.5%).
 

Caught by surprise

Studies have shown that combining CDK4/6 inhibitors and endocrine therapy prolongs progression-free survival (PFS) and overall survival in metastatic HR-positive, HER2-negative breast cancer, with good tolerability.

“CDK4/6 inhibitors have markedly changed outcomes in the metastatic setting and are now standard of care,” said Dr. Gnant, who presented the recent findings at SABCS. “It seem[ed] only logical to try to transfer these benefits to the curative setting of early breast cancer.”

But in 2020, palbociclib manufacturer Pfizer issued a press release noting that the PALLAS trial was unlikely to show a statistically significant improvement in the primary endpoint of invasive disease-free survival.

The results “caught many of us by surprise,” Kathy D. Miller, MD, codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University, Indianapolis, wrote in response to this announcement.

The trial was based on strong science and incredibly positive results in the metastatic setting but did not meet its primary endpoint when incorporated into the adjuvant setting, Dr. Miller noted in a Medscape blog. “That is certainly not the result we had hoped for, and it’s not the result many of us were expecting.”

Dr. Miller emphasized that “more than anything else, this trial reminds us of the absolute necessity of putting our ideas to the test and doing appropriately powered, appropriately controlled, and well-conducted randomized trials.”

The PALLAS trial enrolled 5,796 patients from 406 centers in 21 countries worldwide over a 3-year period, with 5,761 included in the intention-to-treat population.

Participants were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone for at least 5 years.

Dr. Gnant and colleagues found that the primary endpoint – invasive disease-free survival – did not differ significantly different between the two treatment groups (hazard ratio, 0.96; P = .65). Secondary endpoints in the palbociclib versus no-palbociclib groups were also similar: 4-year survival rates for invasive breast cancer-free survival were 85.4% versus 86%, distant recurrence-free survival was 86.2% versus 87.8%, locoregional recurrence-free survival was 96.8% versus 95.4%, and overall survival was 93.8% versus 95.2%.

The main side effect of palbociclib was neutropenia, but there were no new safety signals, Dr. Gnant explained. He noted, however, that the rates of palbociclib discontinuation were monitored closely and were substantial. At 1 year, 30% of patients discontinued palbociclib and by 24 months, 45% had stopped.
 

Not the final word?

An interim analysis of the phase 3 monarchE trial did not align with the PALLAS trial.

The monarchE trial found that adding the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy for 2 years significantly reduced the risk of early recurrence, compared with endocrine therapy alone in the same patient populations – those with early HR-positive, HER2-negative breast cancer. The researchers reported the combination was associated with a 25% relative risk reduction of invasive disease-free survival (HR, 0.75; P =.0096).

The research was presented at the ESMO Virtual Congress 2020 and simultaneously published in the Journal of Clinical Oncology.

Dr. Miller speculated how about how these two drugs that look so similar in the metastatic setting have given such different results in the adjuvant setting. One potential reason is pure chance.

“Any study, no matter how many zeros in the P value, could be simply the play of chance,” she said in an interview. “And that is true for negative and positive studies.”

The fault could also lie in the study design. “Remember, these are agents that we think of as reversing endocrine resistance and extending the benefit of hormone therapy,” she pointed out. “And yet we looked at very early results. Perhaps the study design was just wrong for palbociclib.”

Yet another possibility: The relative potency of those two CDK4/6 inhibitors could differ. “In a metastatic setting, that did not seem to affect effectiveness, but it clearly affected the toxicity profile. Perhaps in the adjuvant setting, those differences really do drive differences in efficacy,” she said.

Dr. Gnant also speculated that differences in the treatment schedules for the two drugs, as abemaciclib is taken continuously without a break, could potentially explain the different efficacies in the early breast cancer setting.

He called for long-term follow up, saying it’s essential for comprehensively examining outcomes in HR-positive luminal breast cancers.

“Ongoing analyses in the Trans-PALLAS translational and clinical science program, with almost 6,000 tumor blocks and tens of thousands of blood samples, will improve understanding of CD4/6 inhibition as well as contemporary management of HR-positive, HER2-negative breast cancer,” Dr. Gnant said.

The trial was funded by Pfizer, who provided study drug and financial support. In addition, the academic organizations ABCSG and AFT supported the trial by providing human resources. Dr. Gnant reported employment at Sandoz; receiving honoraria from Amgen, Novartis, AstraZeneca, Lilly; and consulting or advisory roles at Daiichi Sankyo, Veracyte, Tolmar¸ LifeBrain, and Lilly.

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

The thresholds for genomic instability scores in triple-negative breast cancer (TNBC) are similar to those in ovarian cancer but different from in estrogen receptor–positive (ER+) breast cancer, which could eventually be used to help guide treatment decisions, suggests an analysis of trial data.

More than 1,000 patients with TNBC, ER+ breast cancer, or ovarian cancer from five cohorts were examined for genomic instability scores (GIS) and the presence of BRCA deficiency, which showed that, while GIS was similar in BRCA-deficient TNBC and ovarian cancer, it was significantly different in ER+ breast cancer.

The analysis, presented at the San Antonio Breast Cancer Symposium, showed that the genomic instability scores threshold, which could be used to dictate a patient’s treatment, should be lower for ER+ breast cancer than for TNBC.

“This indicates that different GIS thresholds are appropriate for breast cancer subtypes, and that the GIS threshold developed for ovarian caner is not appropriate for ER+ breast cancer,” said lead author Kirsten Timms, PhD, from Myriad Genetics.

This, she noted, is “consistent with the fact that ovarian cancer and TNBC are known to have similar molecular signatures.”

The researchers suggest that the “more inclusive” thresholds assessed in the study should be examined in further studies “to determine whether these cutoffs are associated with a benefit from treatment with DNA-targeting agents,” such as poly (ADP-ribose) polymerase (PARP) inhibitors.

Thomas P. Slavin, MD, chief medical officer at Myriad Genetics, said in an interview that there is “not a one size fits all” for GIS thresholds.

“When you look at ER+ breast cancer you see we need a different cutoff because it’s probably not as driven by homologous recombination deficiency [HRD], as least as a whole, compared to the other two,” he said. “There’s a little less genomic instability.”

He continued that their results suggest around half of TNBC patients have a GIS score that indicates the presence of significant HRD, which is “spot on for what we see with ovarian cancer” and “those people should respond pretty well to PARP-inhibitor therapies,” which is currently being investigated in clinical trials.

“But even in the ER+ group, when we look at the thresholds we used in this research, still about a third have what looks like a substantial amount of HRD, so that’s a huge biomarker,” Dr. Slavin said.

He explained that the importance of their score is that, rather than looking for the causes of HRD, they are looking for the consequences.

“We don’t know all the causes of why, all of a sudden, a tumor cell looks like it can’t replicate through homologous combination [but] what this test does is it says: ‘We don’t really care what the cause is ... we can just look at the genomic scarring and the consequences.’ ”

Elena Provenzano, MD, CRUK Therapeutic Discovery Laboratories, Cambridge (England) University Hospitals NHS Foundation Trust, who was not involved in the study, said in an interview it is “interesting work.”

“We have a personalized breast cancer program here in Cambridge and we’re running trials where we use PARP inhibitors and platinum-based therapy, and what we’re using to make these sorts of decisions is COSMIC mutational signatures associated with genetic instability. And I guess we also look at the total mutational burden,” Dr. Provenzano said.

She continued that the GIS is one of several ways of measuring HRD. “So the question is how it compares with the other measures that are being used to assess whether or not patients are suitable for PARP inhibitor and platinum-based therapy.”

Dr. Provenzano underlined that it has been known since the “early 2000s” that breast cancer is a group of different diseases. “Even within those categories there’s quite a lot of tumor types,” so it “makes sense you need to adjust the threshold slightly for it to become relevant to types of breast cancer.”

She added that the “holy grail in oncology is this concept of personalized medicine, so all these tests help us make sure that the right patient is getting the right treatment.

“At the moment TNBC is often getting treated in a similar way, although we know that there are different biological subtypes, so while there’s a significant group that falls into this BRCA-deficient group that are going to respond to PARPs there are other types that don’t.

“So these sorts of tests help us decide which subset are going to help us the most, and for the others ones we potentially need to identify other treatments as being optimal,” Dr. Provenzano said.

Previous studies have shown that HR-deficient tumors may benefit from treatment with DNA-damaging agents, and that tools such as the three-biomarker GIS can be used to identify HR deficiency.

The Food and Drug Administration has already approved a GIS threshold for identifying HR deficiency in ovarian cancer of 42, which was set as the 5th percentile for BRCA-deficient tumors. However, a recent published in Molecular Cancer Research, and a second published on MDPI Open Access Journals, indicated that a lower, first percentile, cutoff of at least 33 was associated with improved outcomes after platinum-based treatment.

As TNBC is known to have a similar molecular profile to ovarian cancer, the researchers investigated whether it has a different GIS threshold to that in ER+ breast cancer, gathering data on patients newly diagnosed with ovarian cancer, TNBC, or ER+ breast cancer from across five cohorts.

They included 127 ovarian cancer patients from Nature, 434 ovarian cancer, 44 TNBC, and 213 ER+ breast cancer patients from The Cancer Genome Atlas, 55 TNBC and 112 ER+ breast cancer patients from Breast Cancer Research, 19 TNBC and 25 ER+ breast cancer patients from TBCRC 008, and 56 ER+ breast cancer patients from OlympiAD.

GIS was defined as a combination of loss of heterozygosity, telomeric-allellic imbalance, and large-scale state transitions, identified through next-generation sequencing, and GIS distributions were compared between cancer types and subtypes.

The team also determined the presence of BRCA deficiency, finding that, among BRCA deficient tumors, the GIS distribution among patients with ER+ breast cancer was significantly different from that seen in both ovarian cancer (P = 9.6 x 10^–5) and TNBC (P = 2.1 x 10^–4).

The first percentile of a normal distribution of BRCA-deficient ER+ breast cancers indicated a GIS threshold of 24, with 45.1% of all ER+ tumors at or above this threshold found to be GIS positive. This translated into 98.7% of BRCA-deficient tumors and 32.7% that were BRCA intact.

The results also showed, however, that the GIS distribution for TNBC was not significantly different from that seen in ovarian cancer (P = .72), with the threshold of at least 33 Identifying 64.4% of TNBC tumors as GIS positive. This equated to 100% of BRCA-deficient tumors and 41.7% that were BRCA intact.

Dr. Timms and Dr. Slavin are employed by Myriad Genetics, who funded the study.

The thresholds for genomic instability scores in triple-negative breast cancer (TNBC) are similar to those in ovarian cancer but different from in estrogen receptor–positive (ER+) breast cancer, which could eventually be used to help guide treatment decisions, suggests an analysis of trial data.

More than 1,000 patients with TNBC, ER+ breast cancer, or ovarian cancer from five cohorts were examined for genomic instability scores (GIS) and the presence of BRCA deficiency, which showed that, while GIS was similar in BRCA-deficient TNBC and ovarian cancer, it was significantly different in ER+ breast cancer.

The analysis, presented at the San Antonio Breast Cancer Symposium, showed that the genomic instability scores threshold, which could be used to dictate a patient’s treatment, should be lower for ER+ breast cancer than for TNBC.

“This indicates that different GIS thresholds are appropriate for breast cancer subtypes, and that the GIS threshold developed for ovarian caner is not appropriate for ER+ breast cancer,” said lead author Kirsten Timms, PhD, from Myriad Genetics.

This, she noted, is “consistent with the fact that ovarian cancer and TNBC are known to have similar molecular signatures.”

The researchers suggest that the “more inclusive” thresholds assessed in the study should be examined in further studies “to determine whether these cutoffs are associated with a benefit from treatment with DNA-targeting agents,” such as poly (ADP-ribose) polymerase (PARP) inhibitors.

Thomas P. Slavin, MD, chief medical officer at Myriad Genetics, said in an interview that there is “not a one size fits all” for GIS thresholds.

“When you look at ER+ breast cancer you see we need a different cutoff because it’s probably not as driven by homologous recombination deficiency [HRD], as least as a whole, compared to the other two,” he said. “There’s a little less genomic instability.”

He continued that their results suggest around half of TNBC patients have a GIS score that indicates the presence of significant HRD, which is “spot on for what we see with ovarian cancer” and “those people should respond pretty well to PARP-inhibitor therapies,” which is currently being investigated in clinical trials.

“But even in the ER+ group, when we look at the thresholds we used in this research, still about a third have what looks like a substantial amount of HRD, so that’s a huge biomarker,” Dr. Slavin said.

He explained that the importance of their score is that, rather than looking for the causes of HRD, they are looking for the consequences.

“We don’t know all the causes of why, all of a sudden, a tumor cell looks like it can’t replicate through homologous combination [but] what this test does is it says: ‘We don’t really care what the cause is ... we can just look at the genomic scarring and the consequences.’ ”

Elena Provenzano, MD, CRUK Therapeutic Discovery Laboratories, Cambridge (England) University Hospitals NHS Foundation Trust, who was not involved in the study, said in an interview it is “interesting work.”

“We have a personalized breast cancer program here in Cambridge and we’re running trials where we use PARP inhibitors and platinum-based therapy, and what we’re using to make these sorts of decisions is COSMIC mutational signatures associated with genetic instability. And I guess we also look at the total mutational burden,” Dr. Provenzano said.

She continued that the GIS is one of several ways of measuring HRD. “So the question is how it compares with the other measures that are being used to assess whether or not patients are suitable for PARP inhibitor and platinum-based therapy.”

Dr. Provenzano underlined that it has been known since the “early 2000s” that breast cancer is a group of different diseases. “Even within those categories there’s quite a lot of tumor types,” so it “makes sense you need to adjust the threshold slightly for it to become relevant to types of breast cancer.”

She added that the “holy grail in oncology is this concept of personalized medicine, so all these tests help us make sure that the right patient is getting the right treatment.

“At the moment TNBC is often getting treated in a similar way, although we know that there are different biological subtypes, so while there’s a significant group that falls into this BRCA-deficient group that are going to respond to PARPs there are other types that don’t.

“So these sorts of tests help us decide which subset are going to help us the most, and for the others ones we potentially need to identify other treatments as being optimal,” Dr. Provenzano said.

Previous studies have shown that HR-deficient tumors may benefit from treatment with DNA-damaging agents, and that tools such as the three-biomarker GIS can be used to identify HR deficiency.

The Food and Drug Administration has already approved a GIS threshold for identifying HR deficiency in ovarian cancer of 42, which was set as the 5th percentile for BRCA-deficient tumors. However, a recent published in Molecular Cancer Research, and a second published on MDPI Open Access Journals, indicated that a lower, first percentile, cutoff of at least 33 was associated with improved outcomes after platinum-based treatment.

As TNBC is known to have a similar molecular profile to ovarian cancer, the researchers investigated whether it has a different GIS threshold to that in ER+ breast cancer, gathering data on patients newly diagnosed with ovarian cancer, TNBC, or ER+ breast cancer from across five cohorts.

They included 127 ovarian cancer patients from Nature, 434 ovarian cancer, 44 TNBC, and 213 ER+ breast cancer patients from The Cancer Genome Atlas, 55 TNBC and 112 ER+ breast cancer patients from Breast Cancer Research, 19 TNBC and 25 ER+ breast cancer patients from TBCRC 008, and 56 ER+ breast cancer patients from OlympiAD.

GIS was defined as a combination of loss of heterozygosity, telomeric-allellic imbalance, and large-scale state transitions, identified through next-generation sequencing, and GIS distributions were compared between cancer types and subtypes.

The team also determined the presence of BRCA deficiency, finding that, among BRCA deficient tumors, the GIS distribution among patients with ER+ breast cancer was significantly different from that seen in both ovarian cancer (P = 9.6 x 10^–5) and TNBC (P = 2.1 x 10^–4).

The first percentile of a normal distribution of BRCA-deficient ER+ breast cancers indicated a GIS threshold of 24, with 45.1% of all ER+ tumors at or above this threshold found to be GIS positive. This translated into 98.7% of BRCA-deficient tumors and 32.7% that were BRCA intact.

The results also showed, however, that the GIS distribution for TNBC was not significantly different from that seen in ovarian cancer (P = .72), with the threshold of at least 33 Identifying 64.4% of TNBC tumors as GIS positive. This equated to 100% of BRCA-deficient tumors and 41.7% that were BRCA intact.

Dr. Timms and Dr. Slavin are employed by Myriad Genetics, who funded the study.

The thresholds for genomic instability scores in triple-negative breast cancer (TNBC) are similar to those in ovarian cancer but different from in estrogen receptor–positive (ER+) breast cancer, which could eventually be used to help guide treatment decisions, suggests an analysis of trial data.

More than 1,000 patients with TNBC, ER+ breast cancer, or ovarian cancer from five cohorts were examined for genomic instability scores (GIS) and the presence of BRCA deficiency, which showed that, while GIS was similar in BRCA-deficient TNBC and ovarian cancer, it was significantly different in ER+ breast cancer.

The analysis, presented at the San Antonio Breast Cancer Symposium, showed that the genomic instability scores threshold, which could be used to dictate a patient’s treatment, should be lower for ER+ breast cancer than for TNBC.

“This indicates that different GIS thresholds are appropriate for breast cancer subtypes, and that the GIS threshold developed for ovarian caner is not appropriate for ER+ breast cancer,” said lead author Kirsten Timms, PhD, from Myriad Genetics.

This, she noted, is “consistent with the fact that ovarian cancer and TNBC are known to have similar molecular signatures.”

The researchers suggest that the “more inclusive” thresholds assessed in the study should be examined in further studies “to determine whether these cutoffs are associated with a benefit from treatment with DNA-targeting agents,” such as poly (ADP-ribose) polymerase (PARP) inhibitors.

Thomas P. Slavin, MD, chief medical officer at Myriad Genetics, said in an interview that there is “not a one size fits all” for GIS thresholds.

“When you look at ER+ breast cancer you see we need a different cutoff because it’s probably not as driven by homologous recombination deficiency [HRD], as least as a whole, compared to the other two,” he said. “There’s a little less genomic instability.”

He continued that their results suggest around half of TNBC patients have a GIS score that indicates the presence of significant HRD, which is “spot on for what we see with ovarian cancer” and “those people should respond pretty well to PARP-inhibitor therapies,” which is currently being investigated in clinical trials.

“But even in the ER+ group, when we look at the thresholds we used in this research, still about a third have what looks like a substantial amount of HRD, so that’s a huge biomarker,” Dr. Slavin said.

He explained that the importance of their score is that, rather than looking for the causes of HRD, they are looking for the consequences.

“We don’t know all the causes of why, all of a sudden, a tumor cell looks like it can’t replicate through homologous combination [but] what this test does is it says: ‘We don’t really care what the cause is ... we can just look at the genomic scarring and the consequences.’ ”

Elena Provenzano, MD, CRUK Therapeutic Discovery Laboratories, Cambridge (England) University Hospitals NHS Foundation Trust, who was not involved in the study, said in an interview it is “interesting work.”

“We have a personalized breast cancer program here in Cambridge and we’re running trials where we use PARP inhibitors and platinum-based therapy, and what we’re using to make these sorts of decisions is COSMIC mutational signatures associated with genetic instability. And I guess we also look at the total mutational burden,” Dr. Provenzano said.

She continued that the GIS is one of several ways of measuring HRD. “So the question is how it compares with the other measures that are being used to assess whether or not patients are suitable for PARP inhibitor and platinum-based therapy.”

Dr. Provenzano underlined that it has been known since the “early 2000s” that breast cancer is a group of different diseases. “Even within those categories there’s quite a lot of tumor types,” so it “makes sense you need to adjust the threshold slightly for it to become relevant to types of breast cancer.”

She added that the “holy grail in oncology is this concept of personalized medicine, so all these tests help us make sure that the right patient is getting the right treatment.

“At the moment TNBC is often getting treated in a similar way, although we know that there are different biological subtypes, so while there’s a significant group that falls into this BRCA-deficient group that are going to respond to PARPs there are other types that don’t.

“So these sorts of tests help us decide which subset are going to help us the most, and for the others ones we potentially need to identify other treatments as being optimal,” Dr. Provenzano said.

Previous studies have shown that HR-deficient tumors may benefit from treatment with DNA-damaging agents, and that tools such as the three-biomarker GIS can be used to identify HR deficiency.

The Food and Drug Administration has already approved a GIS threshold for identifying HR deficiency in ovarian cancer of 42, which was set as the 5th percentile for BRCA-deficient tumors. However, a recent published in Molecular Cancer Research, and a second published on MDPI Open Access Journals, indicated that a lower, first percentile, cutoff of at least 33 was associated with improved outcomes after platinum-based treatment.

As TNBC is known to have a similar molecular profile to ovarian cancer, the researchers investigated whether it has a different GIS threshold to that in ER+ breast cancer, gathering data on patients newly diagnosed with ovarian cancer, TNBC, or ER+ breast cancer from across five cohorts.

They included 127 ovarian cancer patients from Nature, 434 ovarian cancer, 44 TNBC, and 213 ER+ breast cancer patients from The Cancer Genome Atlas, 55 TNBC and 112 ER+ breast cancer patients from Breast Cancer Research, 19 TNBC and 25 ER+ breast cancer patients from TBCRC 008, and 56 ER+ breast cancer patients from OlympiAD.

GIS was defined as a combination of loss of heterozygosity, telomeric-allellic imbalance, and large-scale state transitions, identified through next-generation sequencing, and GIS distributions were compared between cancer types and subtypes.

The team also determined the presence of BRCA deficiency, finding that, among BRCA deficient tumors, the GIS distribution among patients with ER+ breast cancer was significantly different from that seen in both ovarian cancer (P = 9.6 x 10^–5) and TNBC (P = 2.1 x 10^–4).

The first percentile of a normal distribution of BRCA-deficient ER+ breast cancers indicated a GIS threshold of 24, with 45.1% of all ER+ tumors at or above this threshold found to be GIS positive. This translated into 98.7% of BRCA-deficient tumors and 32.7% that were BRCA intact.

The results also showed, however, that the GIS distribution for TNBC was not significantly different from that seen in ovarian cancer (P = .72), with the threshold of at least 33 Identifying 64.4% of TNBC tumors as GIS positive. This equated to 100% of BRCA-deficient tumors and 41.7% that were BRCA intact.

Dr. Timms and Dr. Slavin are employed by Myriad Genetics, who funded the study.

Meeting the treatment needs of the nearly 50% of women with metastatic breast cancer in British Columbia who could benefit from continued access to HER2 suppression would cost the province at least $68,000 more per patient, given the changing treatment landscape, an analysis of outcomes and pharmacy data suggests.

The current funding policy in British Columbia restricts patients to two lines of HER2-directed therapy for metastatic breast cancer, but accessing continued HER2 suppression has become more complex as novel agents have emerged, Emily Jackson, MD, and colleagues explained (in poster PD8-09) at the San Antonio Breast Cancer Symposium.

Continuing HER2 suppression has improved progression free survival (PFS) and overall survival (OS), but the financial implications of adapting funding policies to “reflect increasing lines of proven HER2 treatment” are unclear, they noted.

Drug funding is provided through the provincial government, but it can take months – and sometimes years – from when a drug is approved by Health Canada and when provincial protocols are approved and funding is made available, Dr. Jackson, co-chief resident (PGY5) at BC Cancer, Vancouver, said in an interview.

During that “lag time,” the province is negotiating drug prices with pharmaceutical companies and determining “which patients are eligible and under which circumstances,” she said.

To assess the potential costs, the investigators analyzed data from the BC Cancer outcomes unit, which collects clinical and outcome information on 85% of all patients diagnosed with breast cancer in the province. Information on therapy use was obtained from the BC Cancer pharmacy database.

Of 230 patients who received any HER2 treatment for metastatic breast cancer dispensed by BC Cancer between 2013 and 2018, 112 (49%) were eligible to continue beyond their second line of therapy.

“Of these, 86 patients accessed continued HER2-directed therapy, while 26 were eligible but unable to access continued HER2Rx,” they reported, noting that “the remaining 51% (n = 118) were not eligible for consideration of further HER2Rx due to either stable disease (n = 61) or deterioration precluding treatment (n = 57).”

At median follow-up of 42.2 months, the median number of lines of therapy in the entire study population was three. The median number of cycles in those who received HER2-directed therapy beyond second-line therapy was 33.

The median overall survival was 37.5 months for those who were eligible but did not continue HER2, compared with 57.9 months for those who did continue, they found.

The overall survival difference was not statistically significant (P = .13), but this was likely due to the small number of patients included in the initial analysis, Dr. Jackson said, noting that the finding is “hypothesis generating,” and should be further assessed.

Notably, most patients who continued HER2 therapy did so through pharmaceutical company compassionate access programs or clinical trials, she said.

The “conservative estimated cost per cycle of HER2Rx” was based on currently available trastuzumab biosimilars, and the potential financial implications were calculated based on the current cost of commonly used third-line therapies.

The findings demonstrate that most patients access continued treatment despite prohibitive funding policies, and suggest that significant increases in cost per patient can be expected if funding policies don’t evolve to meet treatment needs, they concluded, noting that “if these trends in survival continue we would expect an additional cost of $68,000 per patient over current costs.

“As the cost of novel therapies are likely to be higher than currently available biosimilars, there will be significant implications for both private payer and public payer healthcare systems,” they added.

A larger, more comprehensive analysis of the data is planned, said Dr. Jackson, who did not disclose any funding or other conflicts of interest associated with this study.

sworcester@mdedge.com

Meeting the treatment needs of the nearly 50% of women with metastatic breast cancer in British Columbia who could benefit from continued access to HER2 suppression would cost the province at least $68,000 more per patient, given the changing treatment landscape, an analysis of outcomes and pharmacy data suggests.

The current funding policy in British Columbia restricts patients to two lines of HER2-directed therapy for metastatic breast cancer, but accessing continued HER2 suppression has become more complex as novel agents have emerged, Emily Jackson, MD, and colleagues explained (in poster PD8-09) at the San Antonio Breast Cancer Symposium.

Continuing HER2 suppression has improved progression free survival (PFS) and overall survival (OS), but the financial implications of adapting funding policies to “reflect increasing lines of proven HER2 treatment” are unclear, they noted.

Drug funding is provided through the provincial government, but it can take months – and sometimes years – from when a drug is approved by Health Canada and when provincial protocols are approved and funding is made available, Dr. Jackson, co-chief resident (PGY5) at BC Cancer, Vancouver, said in an interview.

During that “lag time,” the province is negotiating drug prices with pharmaceutical companies and determining “which patients are eligible and under which circumstances,” she said.

To assess the potential costs, the investigators analyzed data from the BC Cancer outcomes unit, which collects clinical and outcome information on 85% of all patients diagnosed with breast cancer in the province. Information on therapy use was obtained from the BC Cancer pharmacy database.

Of 230 patients who received any HER2 treatment for metastatic breast cancer dispensed by BC Cancer between 2013 and 2018, 112 (49%) were eligible to continue beyond their second line of therapy.

“Of these, 86 patients accessed continued HER2-directed therapy, while 26 were eligible but unable to access continued HER2Rx,” they reported, noting that “the remaining 51% (n = 118) were not eligible for consideration of further HER2Rx due to either stable disease (n = 61) or deterioration precluding treatment (n = 57).”

At median follow-up of 42.2 months, the median number of lines of therapy in the entire study population was three. The median number of cycles in those who received HER2-directed therapy beyond second-line therapy was 33.

The median overall survival was 37.5 months for those who were eligible but did not continue HER2, compared with 57.9 months for those who did continue, they found.

The overall survival difference was not statistically significant (P = .13), but this was likely due to the small number of patients included in the initial analysis, Dr. Jackson said, noting that the finding is “hypothesis generating,” and should be further assessed.

Notably, most patients who continued HER2 therapy did so through pharmaceutical company compassionate access programs or clinical trials, she said.

The “conservative estimated cost per cycle of HER2Rx” was based on currently available trastuzumab biosimilars, and the potential financial implications were calculated based on the current cost of commonly used third-line therapies.

The findings demonstrate that most patients access continued treatment despite prohibitive funding policies, and suggest that significant increases in cost per patient can be expected if funding policies don’t evolve to meet treatment needs, they concluded, noting that “if these trends in survival continue we would expect an additional cost of $68,000 per patient over current costs.

“As the cost of novel therapies are likely to be higher than currently available biosimilars, there will be significant implications for both private payer and public payer healthcare systems,” they added.

A larger, more comprehensive analysis of the data is planned, said Dr. Jackson, who did not disclose any funding or other conflicts of interest associated with this study.

sworcester@mdedge.com

Meeting the treatment needs of the nearly 50% of women with metastatic breast cancer in British Columbia who could benefit from continued access to HER2 suppression would cost the province at least $68,000 more per patient, given the changing treatment landscape, an analysis of outcomes and pharmacy data suggests.

The current funding policy in British Columbia restricts patients to two lines of HER2-directed therapy for metastatic breast cancer, but accessing continued HER2 suppression has become more complex as novel agents have emerged, Emily Jackson, MD, and colleagues explained (in poster PD8-09) at the San Antonio Breast Cancer Symposium.

Continuing HER2 suppression has improved progression free survival (PFS) and overall survival (OS), but the financial implications of adapting funding policies to “reflect increasing lines of proven HER2 treatment” are unclear, they noted.

Drug funding is provided through the provincial government, but it can take months – and sometimes years – from when a drug is approved by Health Canada and when provincial protocols are approved and funding is made available, Dr. Jackson, co-chief resident (PGY5) at BC Cancer, Vancouver, said in an interview.

During that “lag time,” the province is negotiating drug prices with pharmaceutical companies and determining “which patients are eligible and under which circumstances,” she said.

To assess the potential costs, the investigators analyzed data from the BC Cancer outcomes unit, which collects clinical and outcome information on 85% of all patients diagnosed with breast cancer in the province. Information on therapy use was obtained from the BC Cancer pharmacy database.

Of 230 patients who received any HER2 treatment for metastatic breast cancer dispensed by BC Cancer between 2013 and 2018, 112 (49%) were eligible to continue beyond their second line of therapy.

“Of these, 86 patients accessed continued HER2-directed therapy, while 26 were eligible but unable to access continued HER2Rx,” they reported, noting that “the remaining 51% (n = 118) were not eligible for consideration of further HER2Rx due to either stable disease (n = 61) or deterioration precluding treatment (n = 57).”

At median follow-up of 42.2 months, the median number of lines of therapy in the entire study population was three. The median number of cycles in those who received HER2-directed therapy beyond second-line therapy was 33.

The median overall survival was 37.5 months for those who were eligible but did not continue HER2, compared with 57.9 months for those who did continue, they found.

The overall survival difference was not statistically significant (P = .13), but this was likely due to the small number of patients included in the initial analysis, Dr. Jackson said, noting that the finding is “hypothesis generating,” and should be further assessed.

Notably, most patients who continued HER2 therapy did so through pharmaceutical company compassionate access programs or clinical trials, she said.

The “conservative estimated cost per cycle of HER2Rx” was based on currently available trastuzumab biosimilars, and the potential financial implications were calculated based on the current cost of commonly used third-line therapies.

The findings demonstrate that most patients access continued treatment despite prohibitive funding policies, and suggest that significant increases in cost per patient can be expected if funding policies don’t evolve to meet treatment needs, they concluded, noting that “if these trends in survival continue we would expect an additional cost of $68,000 per patient over current costs.

“As the cost of novel therapies are likely to be higher than currently available biosimilars, there will be significant implications for both private payer and public payer healthcare systems,” they added.

A larger, more comprehensive analysis of the data is planned, said Dr. Jackson, who did not disclose any funding or other conflicts of interest associated with this study.

sworcester@mdedge.com

A new model based on data from the Breast Cancer Surveillance Consortium (BCSC) suggests that overdiagnosis of screen-detected breast cancer is less frequent than estimates from excess-incidence studies, but the model also takes into account indolent tumors and produced a higher estimate than previous models that didn’t consider this factor.

“There is a pronounced lack of consensus of the true rate of overdiagnosis in the contemporary U.S. mammography practice. This uncertainty about the extent of overdiagnosis is a problem for the development of guidelines and policies. By overcoming shortcomings of previous studies, we produced a defensible estimate of overdiagnosis in contemporary U.S. mammography practice. About one in seven screen-detected cancers in women (between 50 and 74 years) undergoing biennial screening will be overdiagnosed, and about one in three overdiagnosed cancers are attributed to the detection of nonprogressive cancers,” said Marc D. Ryser, PhD, in an interview. Dr. Ryser is an expert in mathematical and statistical modeling in population health science at Duke University, Durham, N.C. He presented the results of the model at the 2021 San Antonio Breast Cancer Symposium.

Previous models have come up with estimates ranging from 0% to 54%, but the heterogeneity makes them difficult to compare. “They differ in study populations, estimation methods and their definitions of overdiagnosis,” Dr. Ryser said.

There are two general ways to estimate overdiagnosis. One is a model-based approach that works out the tumor latency using models of disease natural history and clinical data, and then uses that to predict overdiagnosis. But these models may not account or indolent tumors, or tumors that would not likely cause death during the patient’s lifetime, and the assumptions behind the models can be opaque. On the other hand, the excess-incidence strategy compares incidence in screened versus unscreened populations and assumes that excess cancers in the screened group is caused by overdiagnosis, but this can be affected by bias.

To get around these limitations, Dr. Ryser’s group used a model-based approach, but also allowed for indolent tumors. They ensured transparency of the underlying assumptions of the model, and took advantage of a contemporary, high-quality data source in the BCSC.

They used individual mammography screening and breast cancer diagnosis records from 35,986 women aged 50-74 years, who were first screened between 2000 and 2018. To estimate overdiagnosis caused by indolent tumors, they used the risk of non–breast cancer mortality from age cohort–adjusted annual mortality risks. There were a total 82,677 screens and 718 cases of breast cancer diagnosed. 3.6% of detected tumor were indolent (95% credible interval, 0.2%-13.8%). The predicted overdiagnosis rate for a biennial screening program was 15.3% (95% prediction interval, 9.7%-25.2%). 6.0% of overdiagnosis was projected to be caused by indolent tumors (95% PI, 0.2%-19.0%) that don’t progress at all, and 9.3% to tumors that would progress, but not fast enough to cause mortality during the individual’s lifetime. An annual screening program had a predicted overdiagnosis rate of 14.6% (95% PI, 9.4%-23.9%).

Dr. Ryser identified some specific studies that used the same definition of overdiagnosis as his group used, and compared them with the 15.3% incidence that his group determined. Excess-incidence studies produced higher estimates, while modeling studies produced lower estimates.

The model did not distinguish between ductal carcinoma in situ and invasive cancers, and it did not account for patient race and breast density.

The study was funded by the National Institutes of Health. Dr. Ryser has no relevant financial disclosures.

A new model based on data from the Breast Cancer Surveillance Consortium (BCSC) suggests that overdiagnosis of screen-detected breast cancer is less frequent than estimates from excess-incidence studies, but the model also takes into account indolent tumors and produced a higher estimate than previous models that didn’t consider this factor.

“There is a pronounced lack of consensus of the true rate of overdiagnosis in the contemporary U.S. mammography practice. This uncertainty about the extent of overdiagnosis is a problem for the development of guidelines and policies. By overcoming shortcomings of previous studies, we produced a defensible estimate of overdiagnosis in contemporary U.S. mammography practice. About one in seven screen-detected cancers in women (between 50 and 74 years) undergoing biennial screening will be overdiagnosed, and about one in three overdiagnosed cancers are attributed to the detection of nonprogressive cancers,” said Marc D. Ryser, PhD, in an interview. Dr. Ryser is an expert in mathematical and statistical modeling in population health science at Duke University, Durham, N.C. He presented the results of the model at the 2021 San Antonio Breast Cancer Symposium.

Previous models have come up with estimates ranging from 0% to 54%, but the heterogeneity makes them difficult to compare. “They differ in study populations, estimation methods and their definitions of overdiagnosis,” Dr. Ryser said.

There are two general ways to estimate overdiagnosis. One is a model-based approach that works out the tumor latency using models of disease natural history and clinical data, and then uses that to predict overdiagnosis. But these models may not account or indolent tumors, or tumors that would not likely cause death during the patient’s lifetime, and the assumptions behind the models can be opaque. On the other hand, the excess-incidence strategy compares incidence in screened versus unscreened populations and assumes that excess cancers in the screened group is caused by overdiagnosis, but this can be affected by bias.

To get around these limitations, Dr. Ryser’s group used a model-based approach, but also allowed for indolent tumors. They ensured transparency of the underlying assumptions of the model, and took advantage of a contemporary, high-quality data source in the BCSC.

They used individual mammography screening and breast cancer diagnosis records from 35,986 women aged 50-74 years, who were first screened between 2000 and 2018. To estimate overdiagnosis caused by indolent tumors, they used the risk of non–breast cancer mortality from age cohort–adjusted annual mortality risks. There were a total 82,677 screens and 718 cases of breast cancer diagnosed. 3.6% of detected tumor were indolent (95% credible interval, 0.2%-13.8%). The predicted overdiagnosis rate for a biennial screening program was 15.3% (95% prediction interval, 9.7%-25.2%). 6.0% of overdiagnosis was projected to be caused by indolent tumors (95% PI, 0.2%-19.0%) that don’t progress at all, and 9.3% to tumors that would progress, but not fast enough to cause mortality during the individual’s lifetime. An annual screening program had a predicted overdiagnosis rate of 14.6% (95% PI, 9.4%-23.9%).

Dr. Ryser identified some specific studies that used the same definition of overdiagnosis as his group used, and compared them with the 15.3% incidence that his group determined. Excess-incidence studies produced higher estimates, while modeling studies produced lower estimates.

The model did not distinguish between ductal carcinoma in situ and invasive cancers, and it did not account for patient race and breast density.

The study was funded by the National Institutes of Health. Dr. Ryser has no relevant financial disclosures.

A new model based on data from the Breast Cancer Surveillance Consortium (BCSC) suggests that overdiagnosis of screen-detected breast cancer is less frequent than estimates from excess-incidence studies, but the model also takes into account indolent tumors and produced a higher estimate than previous models that didn’t consider this factor.

“There is a pronounced lack of consensus of the true rate of overdiagnosis in the contemporary U.S. mammography practice. This uncertainty about the extent of overdiagnosis is a problem for the development of guidelines and policies. By overcoming shortcomings of previous studies, we produced a defensible estimate of overdiagnosis in contemporary U.S. mammography practice. About one in seven screen-detected cancers in women (between 50 and 74 years) undergoing biennial screening will be overdiagnosed, and about one in three overdiagnosed cancers are attributed to the detection of nonprogressive cancers,” said Marc D. Ryser, PhD, in an interview. Dr. Ryser is an expert in mathematical and statistical modeling in population health science at Duke University, Durham, N.C. He presented the results of the model at the 2021 San Antonio Breast Cancer Symposium.

Previous models have come up with estimates ranging from 0% to 54%, but the heterogeneity makes them difficult to compare. “They differ in study populations, estimation methods and their definitions of overdiagnosis,” Dr. Ryser said.

There are two general ways to estimate overdiagnosis. One is a model-based approach that works out the tumor latency using models of disease natural history and clinical data, and then uses that to predict overdiagnosis. But these models may not account or indolent tumors, or tumors that would not likely cause death during the patient’s lifetime, and the assumptions behind the models can be opaque. On the other hand, the excess-incidence strategy compares incidence in screened versus unscreened populations and assumes that excess cancers in the screened group is caused by overdiagnosis, but this can be affected by bias.

To get around these limitations, Dr. Ryser’s group used a model-based approach, but also allowed for indolent tumors. They ensured transparency of the underlying assumptions of the model, and took advantage of a contemporary, high-quality data source in the BCSC.

They used individual mammography screening and breast cancer diagnosis records from 35,986 women aged 50-74 years, who were first screened between 2000 and 2018. To estimate overdiagnosis caused by indolent tumors, they used the risk of non–breast cancer mortality from age cohort–adjusted annual mortality risks. There were a total 82,677 screens and 718 cases of breast cancer diagnosed. 3.6% of detected tumor were indolent (95% credible interval, 0.2%-13.8%). The predicted overdiagnosis rate for a biennial screening program was 15.3% (95% prediction interval, 9.7%-25.2%). 6.0% of overdiagnosis was projected to be caused by indolent tumors (95% PI, 0.2%-19.0%) that don’t progress at all, and 9.3% to tumors that would progress, but not fast enough to cause mortality during the individual’s lifetime. An annual screening program had a predicted overdiagnosis rate of 14.6% (95% PI, 9.4%-23.9%).

Dr. Ryser identified some specific studies that used the same definition of overdiagnosis as his group used, and compared them with the 15.3% incidence that his group determined. Excess-incidence studies produced higher estimates, while modeling studies produced lower estimates.

The model did not distinguish between ductal carcinoma in situ and invasive cancers, and it did not account for patient race and breast density.

The study was funded by the National Institutes of Health. Dr. Ryser has no relevant financial disclosures.

Among women with breast cancer being treated with aromatase inhibitors (AI), supplementation with vitamin D and calcium protected against bone loss after 5 years, according to results from a prospective cohort study in Brazil. The study found no difference in bone mineral density outcomes at 5 years between women with hormone receptor–positive cancers treated with aromatase inhibitors (AIG) and triple negative or HER-2 positive patients who were treated with another therapy (CG).

Courtesy Renata Flores

About two-thirds of women with breast cancer have tumors that are positive for hormone receptors, and so are often treated with endocrine therapy such as selective estrogen receptor modulators or AI. However, there are concerns that AI treatment may lead to a loss of bone mineral density and impacts on quality of life. This loss is influenced by a range of factors, including body weight, physical activity, smoking, alcohol consumption, corticosteroid use, calcium in the diet, and circulating levels of vitamin D.

Vitamin D helps to regulate absorption of calcium and phosphorus, ensuring that their plasma concentrations are high enough for adequate bone health. But vitamin D deficiency is a common problem, even in tropical areas such as Brazil. “It is high in the general population and especially in postmenopausal breast cancer patients. Thus, vitamin D and calcium supplementation has an impact on these women’s lives,” said lead author Marcelo Antonini, MD, who presented the study (abstract P1-13-04) at the San Antonio Breast Cancer Symposium. He is a researcher at Hospital Servidor Publico Estadual in São Paulo, Brazil.

Although the findings are encouraging, more work needs to be done before it leads to a change in practice. “Larger studies must be carried out to prove this theory; however, in noncancer patients we have already well established the benefits of vitamin D and calcium supplementation,” Dr. Antonini said in an interview

The researchers examined women before the start of treatment, at 6 months, and at 5 years. Those with vitamin D levels below 30 ng/mL received 7,000 IU/day for 8 weeks, followed by a 1,000 IU/day maintenance dose. Subjects with osteopenia received a calcium supplement (500 mg calcium carbonate), and those with osteoporosis received 4 mg zoledronic acid (Zometa, Novartis).

There were 140 patients in both the AIG and CG groups. The average age was 65 years. Sixty-four percent of the AIG group and 71% of the CG group were vitamin D deficient at baseline. At 5 years, the frequencies were 17% and 16%, respectively. Both groups showed significant declines in bone mineral density in the femoral neck and femur at both 6 months and 5 years, but there was no significant difference between them. There was no significant difference between the two groups with respect to bone density loss in the spine.

The study is limited by the fact that it was conducted at a single center and had a small population size.

Another prospective observational study, published earlier this year, looked at vitamin D supplementation in 741 patients (mean age 61.9 years) being treated with aromatase inhibitors, whose baseline vitamin D levels were less 30 ng/mL. They received 16,000 IU dose of oral calcifediol every 2 weeks. At 3 months, individuals who achieved vitamin D levels of 40 ng/mL or higher were less likely to have joint pain (P < .05). At 12 months, data from 473 patients showed that for every 10-ng/mL increase in serum vitamin D at 3 months, there was a reduction in loss of bone marrow density in the lumbar spine (adjusted beta = +0.177%, P < .05), though there were no associations between vitamin D levels and BMD of the femur or total hip.

“Our results suggest that optimal levels of vitamin D are associated with a reduced risk of joint pain related to AI treatment. A target threshold (of vitamin D) levels was set at 40 ng/mL to significantly reduce the increase in joint pain. The authors noted that this threshold is well above the goal of 20 ng/mL recommended by the 2010 Institute of Medicine report.

The study did not receive external funding. Dr. Antonini has no relevant financial disclosures.

Among women with breast cancer being treated with aromatase inhibitors (AI), supplementation with vitamin D and calcium protected against bone loss after 5 years, according to results from a prospective cohort study in Brazil. The study found no difference in bone mineral density outcomes at 5 years between women with hormone receptor–positive cancers treated with aromatase inhibitors (AIG) and triple negative or HER-2 positive patients who were treated with another therapy (CG).

Courtesy Renata Flores

About two-thirds of women with breast cancer have tumors that are positive for hormone receptors, and so are often treated with endocrine therapy such as selective estrogen receptor modulators or AI. However, there are concerns that AI treatment may lead to a loss of bone mineral density and impacts on quality of life. This loss is influenced by a range of factors, including body weight, physical activity, smoking, alcohol consumption, corticosteroid use, calcium in the diet, and circulating levels of vitamin D.

Vitamin D helps to regulate absorption of calcium and phosphorus, ensuring that their plasma concentrations are high enough for adequate bone health. But vitamin D deficiency is a common problem, even in tropical areas such as Brazil. “It is high in the general population and especially in postmenopausal breast cancer patients. Thus, vitamin D and calcium supplementation has an impact on these women’s lives,” said lead author Marcelo Antonini, MD, who presented the study (abstract P1-13-04) at the San Antonio Breast Cancer Symposium. He is a researcher at Hospital Servidor Publico Estadual in São Paulo, Brazil.

Although the findings are encouraging, more work needs to be done before it leads to a change in practice. “Larger studies must be carried out to prove this theory; however, in noncancer patients we have already well established the benefits of vitamin D and calcium supplementation,” Dr. Antonini said in an interview

The researchers examined women before the start of treatment, at 6 months, and at 5 years. Those with vitamin D levels below 30 ng/mL received 7,000 IU/day for 8 weeks, followed by a 1,000 IU/day maintenance dose. Subjects with osteopenia received a calcium supplement (500 mg calcium carbonate), and those with osteoporosis received 4 mg zoledronic acid (Zometa, Novartis).

There were 140 patients in both the AIG and CG groups. The average age was 65 years. Sixty-four percent of the AIG group and 71% of the CG group were vitamin D deficient at baseline. At 5 years, the frequencies were 17% and 16%, respectively. Both groups showed significant declines in bone mineral density in the femoral neck and femur at both 6 months and 5 years, but there was no significant difference between them. There was no significant difference between the two groups with respect to bone density loss in the spine.

The study is limited by the fact that it was conducted at a single center and had a small population size.

Another prospective observational study, published earlier this year, looked at vitamin D supplementation in 741 patients (mean age 61.9 years) being treated with aromatase inhibitors, whose baseline vitamin D levels were less 30 ng/mL. They received 16,000 IU dose of oral calcifediol every 2 weeks. At 3 months, individuals who achieved vitamin D levels of 40 ng/mL or higher were less likely to have joint pain (P < .05). At 12 months, data from 473 patients showed that for every 10-ng/mL increase in serum vitamin D at 3 months, there was a reduction in loss of bone marrow density in the lumbar spine (adjusted beta = +0.177%, P < .05), though there were no associations between vitamin D levels and BMD of the femur or total hip.

“Our results suggest that optimal levels of vitamin D are associated with a reduced risk of joint pain related to AI treatment. A target threshold (of vitamin D) levels was set at 40 ng/mL to significantly reduce the increase in joint pain. The authors noted that this threshold is well above the goal of 20 ng/mL recommended by the 2010 Institute of Medicine report.

The study did not receive external funding. Dr. Antonini has no relevant financial disclosures.

Among women with breast cancer being treated with aromatase inhibitors (AI), supplementation with vitamin D and calcium protected against bone loss after 5 years, according to results from a prospective cohort study in Brazil. The study found no difference in bone mineral density outcomes at 5 years between women with hormone receptor–positive cancers treated with aromatase inhibitors (AIG) and triple negative or HER-2 positive patients who were treated with another therapy (CG).

Courtesy Renata Flores

About two-thirds of women with breast cancer have tumors that are positive for hormone receptors, and so are often treated with endocrine therapy such as selective estrogen receptor modulators or AI. However, there are concerns that AI treatment may lead to a loss of bone mineral density and impacts on quality of life. This loss is influenced by a range of factors, including body weight, physical activity, smoking, alcohol consumption, corticosteroid use, calcium in the diet, and circulating levels of vitamin D.

Vitamin D helps to regulate absorption of calcium and phosphorus, ensuring that their plasma concentrations are high enough for adequate bone health. But vitamin D deficiency is a common problem, even in tropical areas such as Brazil. “It is high in the general population and especially in postmenopausal breast cancer patients. Thus, vitamin D and calcium supplementation has an impact on these women’s lives,” said lead author Marcelo Antonini, MD, who presented the study (abstract P1-13-04) at the San Antonio Breast Cancer Symposium. He is a researcher at Hospital Servidor Publico Estadual in São Paulo, Brazil.

Although the findings are encouraging, more work needs to be done before it leads to a change in practice. “Larger studies must be carried out to prove this theory; however, in noncancer patients we have already well established the benefits of vitamin D and calcium supplementation,” Dr. Antonini said in an interview

The researchers examined women before the start of treatment, at 6 months, and at 5 years. Those with vitamin D levels below 30 ng/mL received 7,000 IU/day for 8 weeks, followed by a 1,000 IU/day maintenance dose. Subjects with osteopenia received a calcium supplement (500 mg calcium carbonate), and those with osteoporosis received 4 mg zoledronic acid (Zometa, Novartis).

There were 140 patients in both the AIG and CG groups. The average age was 65 years. Sixty-four percent of the AIG group and 71% of the CG group were vitamin D deficient at baseline. At 5 years, the frequencies were 17% and 16%, respectively. Both groups showed significant declines in bone mineral density in the femoral neck and femur at both 6 months and 5 years, but there was no significant difference between them. There was no significant difference between the two groups with respect to bone density loss in the spine.

The study is limited by the fact that it was conducted at a single center and had a small population size.

Another prospective observational study, published earlier this year, looked at vitamin D supplementation in 741 patients (mean age 61.9 years) being treated with aromatase inhibitors, whose baseline vitamin D levels were less 30 ng/mL. They received 16,000 IU dose of oral calcifediol every 2 weeks. At 3 months, individuals who achieved vitamin D levels of 40 ng/mL or higher were less likely to have joint pain (P < .05). At 12 months, data from 473 patients showed that for every 10-ng/mL increase in serum vitamin D at 3 months, there was a reduction in loss of bone marrow density in the lumbar spine (adjusted beta = +0.177%, P < .05), though there were no associations between vitamin D levels and BMD of the femur or total hip.

“Our results suggest that optimal levels of vitamin D are associated with a reduced risk of joint pain related to AI treatment. A target threshold (of vitamin D) levels was set at 40 ng/mL to significantly reduce the increase in joint pain. The authors noted that this threshold is well above the goal of 20 ng/mL recommended by the 2010 Institute of Medicine report.

The study did not receive external funding. Dr. Antonini has no relevant financial disclosures.

Adjuvant treatment with metformin did not improve outcomes in most patients with early breast cancer, according to new findings from a randomized controlled trial.

In the primary analysis, the addition of metformin to standard therapy in moderate/high-risk hormone receptor positive or negative breast cancer did not improve invasive disease–free survival (IDFS), overall survival, or other breast outcomes, explained lead author Pamela J. Goodwin, MD, FRCPC, professor of medicine at the University of Toronto. “Metformin should not be used as breast cancer treatment in this population.”

However, an exploratory analysis suggested that metformin may have a beneficial effect in women with HER2-positive breast cancer, Dr. Goodwin noted.

In this subset, IDFS was improved in patients who received metformin (hazard ratio, 0.64; P = .03), as was overall survival (HR, 0.53; P = .04).

The findings were presented at the San Antonio Breast Cancer Symposium.

“This trial arose from the observation that obesity is associated with poor breast cancer outcomes, and insulin levels are higher in obesity and may be more strongly associated with breast cancer outcomes than obesity,” said Dr. Goodwin.

Metformin was used because of its ability to promote modest weight loss and lower insulin by about 15%-20% in nondiabetic breast cancer survivors. It has also shown anticancer effects in preclinical studies. “In some window of opportunity neoadjuvant studies, it has been shown to reduce Ki67 in breast cancer cells,” she said. “And in preclinical in vitro and in vivo research, it slows growth of breast cancer.”

In addition, emerging evidence from observational studies suggests that the use of metformin to treat diabetes in breast cancer patients may be associated with better outcomes, strengthening the rationale for the study.

The negative results in breast cancer follow recent reports of negative findings in lung cancer, when metformin was found to be ineffective when used alongside chemotherapy in locally advanced lung cancer, as reported by this news organization.
 

No benefit seen

Metformin was compared to placebo in the phase 3 CCTG MA.32 trial, conducted in 3,649 patients aged 18-74 years with T1-3 N0-3 M0 breast cancer. All patients were treated with standard therapy and were randomized to receive metformin 850 mg twice daily for 5 years or placebo.

In 2016, “futility was declared in ER/PR-negative patients” after a second interim analysis conducted at 29.6 months’ median follow-up, Dr. Goodwin noted. The intervention was stopped in that group, although blinding and follow-up continued.

After that, the study’s primary analysis focused on the 2,533 ER/PR-positive patients (mean age, 52.7 years; mean body mass index, 28.8; approx. 60% postmenopausal).

Just over half of these patients had T2 tumor stage, and most disease was grade 2 or 3.

In addition, 16.5% (of metformin) and 17.4% (of placebo) patients had HER2-positive disease, with the majority (97%) of all HER2 patients receiving trastuzumab.

There was no difference between the two groups in IDFS events, occurring in 18.5% of patients receiving metformin and 18.3% who received placebo, with most (75.6%) events due to breast cancer (HR, 1.01; P = .92).

There were 131 deaths in the metformin arm and 119 in the placebo arm, with most (75.8%) of the deaths related to breast cancer (HR, 1.10; P = .47).

Other breast cancer outcomes had similar results, including distant disease-free survival (HR, 0.99; P = .94) and breast cancer–free interval (HR, 0.98; P = .87), both of which showed no advantage for metformin.
 

Possible HER2 advantage

However, the exploratory analysis suggested there may be an advantage for patients with HER2-positive disease, but primarily those who had at least one C allele of a prespecified ATM associated rs11212617 SNP. These patients achieved a higher pathologic complete response rate with metformin than that of those without the allele.

There were 620 patients with HER2-positive disease analyzed, with 99.4% receiving chemotherapy and 96.5% receiving trastuzumab. There were 99 IDFS events, and 47 OS events.

In the entire HER2-positive cohort, patients who received metformin had fewer IDFS events (HR, 0.64; P = .026) compared with the placebo arm. Mortality was lower with metformin (HR for overall survival, 0.53; P = .038).

“Subjects with HER2-positive breast cancer, notably those with at least one C allele of the ATM-associated rs11212617 SNP, experienced improved IDFS and overall survival with metformin,” Dr. Goodwin concluded. “However, no P-value ‘spend’ was allocated to this comparison. As a result, it requires replication in a prospective trial focusing on the HER2-positive population.”
 

More research?

Stephanie Bernik, MD, chief of breast surgery, Mount Sinai West, and associate professor of breast surgery, Icahn School of Medicine at Mount Sinai, New York, was approached by this news organization for an independent comment.

“It has long been known that obesity, which often correlates with diabetes, increases a woman’s risk of breast cancer,” she said.

“This study tried to show that using a medication that helps control insulin levels, even in those without diabetes, might decrease one’s risk of breast cancer,” she said. “Unfortunately, using metformin had no effect on outcomes in this study, even though it has shown promise in other studies. Perhaps more research needs to be carried out to try to pinpoint which mechanisms of action, if any, might be helpful to combat cancer in those with and without diabetes.”

The study was funded by the Canadian Cancer Trials Group, Cancer Therapy Evaluation Program, Breast Cancer Researcher Foundation, Susan G. Komen for the Cure, Canadian Cancer Society, Apotex, Swiss Cancer Research, and the Canadian Breast Cancer Foundation. Dr. Goodwin has no disclosures.

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

Adjuvant treatment with metformin did not improve outcomes in most patients with early breast cancer, according to new findings from a randomized controlled trial.

In the primary analysis, the addition of metformin to standard therapy in moderate/high-risk hormone receptor positive or negative breast cancer did not improve invasive disease–free survival (IDFS), overall survival, or other breast outcomes, explained lead author Pamela J. Goodwin, MD, FRCPC, professor of medicine at the University of Toronto. “Metformin should not be used as breast cancer treatment in this population.”

However, an exploratory analysis suggested that metformin may have a beneficial effect in women with HER2-positive breast cancer, Dr. Goodwin noted.

In this subset, IDFS was improved in patients who received metformin (hazard ratio, 0.64; P = .03), as was overall survival (HR, 0.53; P = .04).

The findings were presented at the San Antonio Breast Cancer Symposium.

“This trial arose from the observation that obesity is associated with poor breast cancer outcomes, and insulin levels are higher in obesity and may be more strongly associated with breast cancer outcomes than obesity,” said Dr. Goodwin.

Metformin was used because of its ability to promote modest weight loss and lower insulin by about 15%-20% in nondiabetic breast cancer survivors. It has also shown anticancer effects in preclinical studies. “In some window of opportunity neoadjuvant studies, it has been shown to reduce Ki67 in breast cancer cells,” she said. “And in preclinical in vitro and in vivo research, it slows growth of breast cancer.”

In addition, emerging evidence from observational studies suggests that the use of metformin to treat diabetes in breast cancer patients may be associated with better outcomes, strengthening the rationale for the study.

The negative results in breast cancer follow recent reports of negative findings in lung cancer, when metformin was found to be ineffective when used alongside chemotherapy in locally advanced lung cancer, as reported by this news organization.
 

No benefit seen

Metformin was compared to placebo in the phase 3 CCTG MA.32 trial, conducted in 3,649 patients aged 18-74 years with T1-3 N0-3 M0 breast cancer. All patients were treated with standard therapy and were randomized to receive metformin 850 mg twice daily for 5 years or placebo.

In 2016, “futility was declared in ER/PR-negative patients” after a second interim analysis conducted at 29.6 months’ median follow-up, Dr. Goodwin noted. The intervention was stopped in that group, although blinding and follow-up continued.

After that, the study’s primary analysis focused on the 2,533 ER/PR-positive patients (mean age, 52.7 years; mean body mass index, 28.8; approx. 60% postmenopausal).

Just over half of these patients had T2 tumor stage, and most disease was grade 2 or 3.

In addition, 16.5% (of metformin) and 17.4% (of placebo) patients had HER2-positive disease, with the majority (97%) of all HER2 patients receiving trastuzumab.

There was no difference between the two groups in IDFS events, occurring in 18.5% of patients receiving metformin and 18.3% who received placebo, with most (75.6%) events due to breast cancer (HR, 1.01; P = .92).

There were 131 deaths in the metformin arm and 119 in the placebo arm, with most (75.8%) of the deaths related to breast cancer (HR, 1.10; P = .47).

Other breast cancer outcomes had similar results, including distant disease-free survival (HR, 0.99; P = .94) and breast cancer–free interval (HR, 0.98; P = .87), both of which showed no advantage for metformin.
 

Possible HER2 advantage

However, the exploratory analysis suggested there may be an advantage for patients with HER2-positive disease, but primarily those who had at least one C allele of a prespecified ATM associated rs11212617 SNP. These patients achieved a higher pathologic complete response rate with metformin than that of those without the allele.

There were 620 patients with HER2-positive disease analyzed, with 99.4% receiving chemotherapy and 96.5% receiving trastuzumab. There were 99 IDFS events, and 47 OS events.

In the entire HER2-positive cohort, patients who received metformin had fewer IDFS events (HR, 0.64; P = .026) compared with the placebo arm. Mortality was lower with metformin (HR for overall survival, 0.53; P = .038).

“Subjects with HER2-positive breast cancer, notably those with at least one C allele of the ATM-associated rs11212617 SNP, experienced improved IDFS and overall survival with metformin,” Dr. Goodwin concluded. “However, no P-value ‘spend’ was allocated to this comparison. As a result, it requires replication in a prospective trial focusing on the HER2-positive population.”
 

More research?

Stephanie Bernik, MD, chief of breast surgery, Mount Sinai West, and associate professor of breast surgery, Icahn School of Medicine at Mount Sinai, New York, was approached by this news organization for an independent comment.

“It has long been known that obesity, which often correlates with diabetes, increases a woman’s risk of breast cancer,” she said.

“This study tried to show that using a medication that helps control insulin levels, even in those without diabetes, might decrease one’s risk of breast cancer,” she said. “Unfortunately, using metformin had no effect on outcomes in this study, even though it has shown promise in other studies. Perhaps more research needs to be carried out to try to pinpoint which mechanisms of action, if any, might be helpful to combat cancer in those with and without diabetes.”

The study was funded by the Canadian Cancer Trials Group, Cancer Therapy Evaluation Program, Breast Cancer Researcher Foundation, Susan G. Komen for the Cure, Canadian Cancer Society, Apotex, Swiss Cancer Research, and the Canadian Breast Cancer Foundation. Dr. Goodwin has no disclosures.

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

Adjuvant treatment with metformin did not improve outcomes in most patients with early breast cancer, according to new findings from a randomized controlled trial.

In the primary analysis, the addition of metformin to standard therapy in moderate/high-risk hormone receptor positive or negative breast cancer did not improve invasive disease–free survival (IDFS), overall survival, or other breast outcomes, explained lead author Pamela J. Goodwin, MD, FRCPC, professor of medicine at the University of Toronto. “Metformin should not be used as breast cancer treatment in this population.”

However, an exploratory analysis suggested that metformin may have a beneficial effect in women with HER2-positive breast cancer, Dr. Goodwin noted.

In this subset, IDFS was improved in patients who received metformin (hazard ratio, 0.64; P = .03), as was overall survival (HR, 0.53; P = .04).

The findings were presented at the San Antonio Breast Cancer Symposium.

“This trial arose from the observation that obesity is associated with poor breast cancer outcomes, and insulin levels are higher in obesity and may be more strongly associated with breast cancer outcomes than obesity,” said Dr. Goodwin.

Metformin was used because of its ability to promote modest weight loss and lower insulin by about 15%-20% in nondiabetic breast cancer survivors. It has also shown anticancer effects in preclinical studies. “In some window of opportunity neoadjuvant studies, it has been shown to reduce Ki67 in breast cancer cells,” she said. “And in preclinical in vitro and in vivo research, it slows growth of breast cancer.”

In addition, emerging evidence from observational studies suggests that the use of metformin to treat diabetes in breast cancer patients may be associated with better outcomes, strengthening the rationale for the study.

The negative results in breast cancer follow recent reports of negative findings in lung cancer, when metformin was found to be ineffective when used alongside chemotherapy in locally advanced lung cancer, as reported by this news organization.
 

No benefit seen

Metformin was compared to placebo in the phase 3 CCTG MA.32 trial, conducted in 3,649 patients aged 18-74 years with T1-3 N0-3 M0 breast cancer. All patients were treated with standard therapy and were randomized to receive metformin 850 mg twice daily for 5 years or placebo.

In 2016, “futility was declared in ER/PR-negative patients” after a second interim analysis conducted at 29.6 months’ median follow-up, Dr. Goodwin noted. The intervention was stopped in that group, although blinding and follow-up continued.

After that, the study’s primary analysis focused on the 2,533 ER/PR-positive patients (mean age, 52.7 years; mean body mass index, 28.8; approx. 60% postmenopausal).

Just over half of these patients had T2 tumor stage, and most disease was grade 2 or 3.

In addition, 16.5% (of metformin) and 17.4% (of placebo) patients had HER2-positive disease, with the majority (97%) of all HER2 patients receiving trastuzumab.

There was no difference between the two groups in IDFS events, occurring in 18.5% of patients receiving metformin and 18.3% who received placebo, with most (75.6%) events due to breast cancer (HR, 1.01; P = .92).

There were 131 deaths in the metformin arm and 119 in the placebo arm, with most (75.8%) of the deaths related to breast cancer (HR, 1.10; P = .47).

Other breast cancer outcomes had similar results, including distant disease-free survival (HR, 0.99; P = .94) and breast cancer–free interval (HR, 0.98; P = .87), both of which showed no advantage for metformin.
 

Possible HER2 advantage

However, the exploratory analysis suggested there may be an advantage for patients with HER2-positive disease, but primarily those who had at least one C allele of a prespecified ATM associated rs11212617 SNP. These patients achieved a higher pathologic complete response rate with metformin than that of those without the allele.

There were 620 patients with HER2-positive disease analyzed, with 99.4% receiving chemotherapy and 96.5% receiving trastuzumab. There were 99 IDFS events, and 47 OS events.

In the entire HER2-positive cohort, patients who received metformin had fewer IDFS events (HR, 0.64; P = .026) compared with the placebo arm. Mortality was lower with metformin (HR for overall survival, 0.53; P = .038).

“Subjects with HER2-positive breast cancer, notably those with at least one C allele of the ATM-associated rs11212617 SNP, experienced improved IDFS and overall survival with metformin,” Dr. Goodwin concluded. “However, no P-value ‘spend’ was allocated to this comparison. As a result, it requires replication in a prospective trial focusing on the HER2-positive population.”
 

More research?

Stephanie Bernik, MD, chief of breast surgery, Mount Sinai West, and associate professor of breast surgery, Icahn School of Medicine at Mount Sinai, New York, was approached by this news organization for an independent comment.

“It has long been known that obesity, which often correlates with diabetes, increases a woman’s risk of breast cancer,” she said.

“This study tried to show that using a medication that helps control insulin levels, even in those without diabetes, might decrease one’s risk of breast cancer,” she said. “Unfortunately, using metformin had no effect on outcomes in this study, even though it has shown promise in other studies. Perhaps more research needs to be carried out to try to pinpoint which mechanisms of action, if any, might be helpful to combat cancer in those with and without diabetes.”

The study was funded by the Canadian Cancer Trials Group, Cancer Therapy Evaluation Program, Breast Cancer Researcher Foundation, Susan G. Komen for the Cure, Canadian Cancer Society, Apotex, Swiss Cancer Research, and the Canadian Breast Cancer Foundation. Dr. Goodwin has no disclosures.

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

Genomic profiling improves outcomes for patients with metastatic breast cancer as long as the alteration-drug match has good clinical trial evidence supporting its use, a new pooled analysis suggests.

“The message is very simple,” lead study author Fabrice Andre, MD, PhD, research director, Gustave Roussy Cancer Campus, Villejuif, France, told this news organization during a virtual press briefing. “If a genomic alteration is validated, it is useful to give targeted therapy, but if the genomic alteration is not validated, we should not give a targeted therapy.”

The study, which pooled results from phase 2 randomized trials SAFIR02-BREAST and SAFIR-P13K, was presented Dec. 7 in a virtual press briefing at the San Antonio Breast Cancer Symposium (SABCS) 2021.

The new analysis explored two key questions: Is genomic testing of a cancer effective? And how should oncologists interpret a genomic report?

A total of 1,462 patients with metastatic HER2-negative breast cancer underwent next-generation sequencing. After receiving six to eight cycles of chemotherapy, 238 patients (16%) were randomized to one of nine targeted therapies matched to the genomic alteration identified on testing or to maintenance chemotherapy.

Genomic alterations in the patients’ tumors were classified using the ESMO Scale of Actionability of Molecular Targets (ESCAT). A tier I ranking indicates that the alteration-drug match is associated with improved outcomes in clinical trials, while a tier II ranking means that the alteration-drug match is associated with antitumor activity but the magnitude of benefit remains unknown.

In an analysis of the overall trial population, Dr. Andre and colleagues found an improvement in progression-free survival in the targeted therapy group (median of 5.5 months) in comparison with the maintenance chemotherapy group (2.9 months), but the difference was not significant (P = .109).

In a subgroup of 115 patients presenting with I- or II-tier genomic alterations, median progression-free survival was 59% longer, at 9.1 months, among patients receiving targeted therapy, compared with 2.8 months in the maintenance chemotherapy group (hazard ratio, 0.41; P < .001).

In addition, the team carried out single-nucleotide polymorphism (SNP) array analyses on 926 patients. They identified 21 genes that were altered more frequently in the metastases compared with the primary tumors, and they observed that a high homologous recombination deficiency score in patients with BCRA 1 or 2 mutations was associated with a longer progression-free survival in patients treated with olaparib.

“We also identified a subset of patients who are resistant to CDK4/6 inhibitors who presented with CDK4 amplification, and this amplification is associated with overexpression,” Dr. Andre explained.

When asked whether most oncologists were using genomic profiling to tailor treatment for breast cancer patients, Dr. Andre said that multigene sequencing is now widely used.

“The issue is not so much whether we should use or not use genomics; the issue here is to force everyone to put the genomic alteration in the right context in terms of its level of evidence,” Dr. Andre told this news organization.

Oncologists may overinterpret the genomic activation identified and give a targeted therapy that is not validated, but “oncologists should not use genomic information when the target has not been previously validated in a therapeutic trial,” he added.

Virginia Kaklamani, MD, professor of medicine at the University of Texas Health Sciences Center in San Antonio, said in an interview that approximately 5 years ago, Dr. Andre was part of the first debate at the SABCS discussing whether oncologists should be conducting next-generation sequencing for their patients with breast cancer.

“At the time, [Dr.] Andre’s comment was that we should not be doing it,” recalled Dr. Kaklamani, who is also leader of the breast cancer program at the Mays Cancer Center at the University of Texas Health San Antonio MD Anderson. “At that point, I think it was clear that we did not have the data we needed to be able to use next-generation sequencing to change our clinical management.”

However, the evidence has evolved. “Based on this clinical trial, I think we now do have the data,” she said. “I think that [next-generation sequencing] is something we will be using more and more in practice and treating our patients based on [validated] genomic alterations.”

Dr. Andre has received grants or advisory board/speaker honoraria from Daiichi Sankyo, Roche, Pfizer, AstraZeneca, Lily, and Novartis. Dr. Kaklamani has served as a consultant for Puma, AstraZeneca, Athenex, and Immunomedics, has received research funding from Eisai, and has served as a speaker for Pfizer, Celgene, Genentech, and Genomic Health, among other companies.

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

Genomic profiling improves outcomes for patients with metastatic breast cancer as long as the alteration-drug match has good clinical trial evidence supporting its use, a new pooled analysis suggests.

“The message is very simple,” lead study author Fabrice Andre, MD, PhD, research director, Gustave Roussy Cancer Campus, Villejuif, France, told this news organization during a virtual press briefing. “If a genomic alteration is validated, it is useful to give targeted therapy, but if the genomic alteration is not validated, we should not give a targeted therapy.”

The study, which pooled results from phase 2 randomized trials SAFIR02-BREAST and SAFIR-P13K, was presented Dec. 7 in a virtual press briefing at the San Antonio Breast Cancer Symposium (SABCS) 2021.

The new analysis explored two key questions: Is genomic testing of a cancer effective? And how should oncologists interpret a genomic report?

A total of 1,462 patients with metastatic HER2-negative breast cancer underwent next-generation sequencing. After receiving six to eight cycles of chemotherapy, 238 patients (16%) were randomized to one of nine targeted therapies matched to the genomic alteration identified on testing or to maintenance chemotherapy.

Genomic alterations in the patients’ tumors were classified using the ESMO Scale of Actionability of Molecular Targets (ESCAT). A tier I ranking indicates that the alteration-drug match is associated with improved outcomes in clinical trials, while a tier II ranking means that the alteration-drug match is associated with antitumor activity but the magnitude of benefit remains unknown.

In an analysis of the overall trial population, Dr. Andre and colleagues found an improvement in progression-free survival in the targeted therapy group (median of 5.5 months) in comparison with the maintenance chemotherapy group (2.9 months), but the difference was not significant (P = .109).

In a subgroup of 115 patients presenting with I- or II-tier genomic alterations, median progression-free survival was 59% longer, at 9.1 months, among patients receiving targeted therapy, compared with 2.8 months in the maintenance chemotherapy group (hazard ratio, 0.41; P < .001).

In addition, the team carried out single-nucleotide polymorphism (SNP) array analyses on 926 patients. They identified 21 genes that were altered more frequently in the metastases compared with the primary tumors, and they observed that a high homologous recombination deficiency score in patients with BCRA 1 or 2 mutations was associated with a longer progression-free survival in patients treated with olaparib.

“We also identified a subset of patients who are resistant to CDK4/6 inhibitors who presented with CDK4 amplification, and this amplification is associated with overexpression,” Dr. Andre explained.

When asked whether most oncologists were using genomic profiling to tailor treatment for breast cancer patients, Dr. Andre said that multigene sequencing is now widely used.

“The issue is not so much whether we should use or not use genomics; the issue here is to force everyone to put the genomic alteration in the right context in terms of its level of evidence,” Dr. Andre told this news organization.

Oncologists may overinterpret the genomic activation identified and give a targeted therapy that is not validated, but “oncologists should not use genomic information when the target has not been previously validated in a therapeutic trial,” he added.

Virginia Kaklamani, MD, professor of medicine at the University of Texas Health Sciences Center in San Antonio, said in an interview that approximately 5 years ago, Dr. Andre was part of the first debate at the SABCS discussing whether oncologists should be conducting next-generation sequencing for their patients with breast cancer.

“At the time, [Dr.] Andre’s comment was that we should not be doing it,” recalled Dr. Kaklamani, who is also leader of the breast cancer program at the Mays Cancer Center at the University of Texas Health San Antonio MD Anderson. “At that point, I think it was clear that we did not have the data we needed to be able to use next-generation sequencing to change our clinical management.”

However, the evidence has evolved. “Based on this clinical trial, I think we now do have the data,” she said. “I think that [next-generation sequencing] is something we will be using more and more in practice and treating our patients based on [validated] genomic alterations.”

Dr. Andre has received grants or advisory board/speaker honoraria from Daiichi Sankyo, Roche, Pfizer, AstraZeneca, Lily, and Novartis. Dr. Kaklamani has served as a consultant for Puma, AstraZeneca, Athenex, and Immunomedics, has received research funding from Eisai, and has served as a speaker for Pfizer, Celgene, Genentech, and Genomic Health, among other companies.

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

Genomic profiling improves outcomes for patients with metastatic breast cancer as long as the alteration-drug match has good clinical trial evidence supporting its use, a new pooled analysis suggests.

“The message is very simple,” lead study author Fabrice Andre, MD, PhD, research director, Gustave Roussy Cancer Campus, Villejuif, France, told this news organization during a virtual press briefing. “If a genomic alteration is validated, it is useful to give targeted therapy, but if the genomic alteration is not validated, we should not give a targeted therapy.”

The study, which pooled results from phase 2 randomized trials SAFIR02-BREAST and SAFIR-P13K, was presented Dec. 7 in a virtual press briefing at the San Antonio Breast Cancer Symposium (SABCS) 2021.

The new analysis explored two key questions: Is genomic testing of a cancer effective? And how should oncologists interpret a genomic report?

A total of 1,462 patients with metastatic HER2-negative breast cancer underwent next-generation sequencing. After receiving six to eight cycles of chemotherapy, 238 patients (16%) were randomized to one of nine targeted therapies matched to the genomic alteration identified on testing or to maintenance chemotherapy.

Genomic alterations in the patients’ tumors were classified using the ESMO Scale of Actionability of Molecular Targets (ESCAT). A tier I ranking indicates that the alteration-drug match is associated with improved outcomes in clinical trials, while a tier II ranking means that the alteration-drug match is associated with antitumor activity but the magnitude of benefit remains unknown.

In an analysis of the overall trial population, Dr. Andre and colleagues found an improvement in progression-free survival in the targeted therapy group (median of 5.5 months) in comparison with the maintenance chemotherapy group (2.9 months), but the difference was not significant (P = .109).

In a subgroup of 115 patients presenting with I- or II-tier genomic alterations, median progression-free survival was 59% longer, at 9.1 months, among patients receiving targeted therapy, compared with 2.8 months in the maintenance chemotherapy group (hazard ratio, 0.41; P < .001).

In addition, the team carried out single-nucleotide polymorphism (SNP) array analyses on 926 patients. They identified 21 genes that were altered more frequently in the metastases compared with the primary tumors, and they observed that a high homologous recombination deficiency score in patients with BCRA 1 or 2 mutations was associated with a longer progression-free survival in patients treated with olaparib.

“We also identified a subset of patients who are resistant to CDK4/6 inhibitors who presented with CDK4 amplification, and this amplification is associated with overexpression,” Dr. Andre explained.

When asked whether most oncologists were using genomic profiling to tailor treatment for breast cancer patients, Dr. Andre said that multigene sequencing is now widely used.

“The issue is not so much whether we should use or not use genomics; the issue here is to force everyone to put the genomic alteration in the right context in terms of its level of evidence,” Dr. Andre told this news organization.

Oncologists may overinterpret the genomic activation identified and give a targeted therapy that is not validated, but “oncologists should not use genomic information when the target has not been previously validated in a therapeutic trial,” he added.

Virginia Kaklamani, MD, professor of medicine at the University of Texas Health Sciences Center in San Antonio, said in an interview that approximately 5 years ago, Dr. Andre was part of the first debate at the SABCS discussing whether oncologists should be conducting next-generation sequencing for their patients with breast cancer.

“At the time, [Dr.] Andre’s comment was that we should not be doing it,” recalled Dr. Kaklamani, who is also leader of the breast cancer program at the Mays Cancer Center at the University of Texas Health San Antonio MD Anderson. “At that point, I think it was clear that we did not have the data we needed to be able to use next-generation sequencing to change our clinical management.”

However, the evidence has evolved. “Based on this clinical trial, I think we now do have the data,” she said. “I think that [next-generation sequencing] is something we will be using more and more in practice and treating our patients based on [validated] genomic alterations.”

Dr. Andre has received grants or advisory board/speaker honoraria from Daiichi Sankyo, Roche, Pfizer, AstraZeneca, Lily, and Novartis. Dr. Kaklamani has served as a consultant for Puma, AstraZeneca, Athenex, and Immunomedics, has received research funding from Eisai, and has served as a speaker for Pfizer, Celgene, Genentech, and Genomic Health, among other companies.

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

Interruption of 4-6 cyclin D-dependent kinase inhibitors (CDK4/6i) was associated with a high rate of progression among women with metastatic breast cancer, particularly those with liver metastases. The treatment interruptions occurred during the COVID-19 pandemic, out of concern that myelosuppression from the drugs might make patients more vulnerable to COVID-19 infection, and that other side effects might be confused with symptoms of COVID-19 infection.

The finding comes from a multicenter study presented by Sophie Martin, PhD, at the San Antonio Breast Cancer Symposium. Dr. Martin is a researcher at ICANS Institut de cancérologie Strasbourg Europe. The patient population had a complete or partial response, or stable disease complete for at least 6 months.

Although CDK4/6i combined with endocrine therapy has led to significant improvements in outcomes among metastatic HR-positive, HER-2-negative patients, the treatment can lead to chronic toxicities that may affect quality of life.

In its 2020 guidance on management of cancer patients during the COVID-19 pandemic, the European Society for Medical Oncology noted that cancer patients are at higher risk of severe symptoms and worse outcomes. However, it points out that there is no direct evidence that neutropenia caused CDK4/6i or poly-adenosine diphosphate ribose polymer inhibitors leads to an increase risk of COVID-19 infection.

The American Society for Clinical Oncology guidance for managing treatment of cancer patients in the context of COVID-19 also says there is little direct evidence to guide practice regarding therapies that may lead to immunosuppression. Therefore, the society recommends against changing or withholding those drugs. “The balance of potential harms that may result from delaying or interrupting treatment versus the potential benefits of possibly preventing or delaying COVID-19 infection is very uncertain,” the authors wrote.

There were 60 patients in the study, and the median age was 64 years. The average interruption period was 8 weeks. Twenty-two patients (37%) experienced radiological and/or clinical disease progression. Sixteen of the 22 (73%) restarted on CDK4/6I, while the remaining 4 patients initiated chemotherapy or targeted therapy. Two patients died during CDK4/6i treatment interruption. A univariate analysis found that the presence of liver metastases was associated with increased risk of progression during CDK4/6I withdrawal (odds ratio, 5.50; 95% confidence interval, 1.14-26.41).

There was also a trend toward greater likelihood of disease progression when the withdrawal period was 2 or more months (OR, 2.38), but the finding was not statistically significant. Although the study looked at treatment interruption due to the COVID-19 pandemic, the authors noted that the findings likely apply to other reasons for interruption, such as analgesic radiotherapy or programmed surgery.

Although the study authors advise against stopping CDK4/6i inhibitors, another small study conducted at a single German center suggested that treatment interruption might be an option in patients with stable disease. The authors examined elective CDK4/6i discontinuation among 22 patients with advanced, hormone receptor–positive, HER-2-negative breast cancer who had stable disease for at least 6 months with treatment regimens of CDK4/6i plus aromatase inhibitors or fulvestrant. After discontinuation of CDK4/6i but maintenance of endocrine therapy, 13 patients had stable disease, 8 had a partial response, and 1 had a complete response. After withdrawal, 5 patients had a local relapse and 1 experienced systemic progression. The patients restabilized with chemotherapy or retreatment with CDK4/6i.

“Discontinuation of CDK4/6 inhibitors seems to be safe in selected patients with metastatic HR-positive HER-2-negative breast cancer and prolonged disease control,” the authors wrote, although they noted that the results need to be backed up with prospective clinical trials.

Both studies had small sample sizes and were retrospective in nature.

One author on the COVID-19 study has received consulting fees from Lilly, Novartis, Pfizer, Daïchi, Seagen, and AstraZeneca. Authors of the German study have received honoraria from Iomedico, Novartis, Roche, AstraZeneca, Boehringer Ingelheim, Merck, Sanofi, and BMS.

Interruption of 4-6 cyclin D-dependent kinase inhibitors (CDK4/6i) was associated with a high rate of progression among women with metastatic breast cancer, particularly those with liver metastases. The treatment interruptions occurred during the COVID-19 pandemic, out of concern that myelosuppression from the drugs might make patients more vulnerable to COVID-19 infection, and that other side effects might be confused with symptoms of COVID-19 infection.

The finding comes from a multicenter study presented by Sophie Martin, PhD, at the San Antonio Breast Cancer Symposium. Dr. Martin is a researcher at ICANS Institut de cancérologie Strasbourg Europe. The patient population had a complete or partial response, or stable disease complete for at least 6 months.

Although CDK4/6i combined with endocrine therapy has led to significant improvements in outcomes among metastatic HR-positive, HER-2-negative patients, the treatment can lead to chronic toxicities that may affect quality of life.

In its 2020 guidance on management of cancer patients during the COVID-19 pandemic, the European Society for Medical Oncology noted that cancer patients are at higher risk of severe symptoms and worse outcomes. However, it points out that there is no direct evidence that neutropenia caused CDK4/6i or poly-adenosine diphosphate ribose polymer inhibitors leads to an increase risk of COVID-19 infection.

The American Society for Clinical Oncology guidance for managing treatment of cancer patients in the context of COVID-19 also says there is little direct evidence to guide practice regarding therapies that may lead to immunosuppression. Therefore, the society recommends against changing or withholding those drugs. “The balance of potential harms that may result from delaying or interrupting treatment versus the potential benefits of possibly preventing or delaying COVID-19 infection is very uncertain,” the authors wrote.

There were 60 patients in the study, and the median age was 64 years. The average interruption period was 8 weeks. Twenty-two patients (37%) experienced radiological and/or clinical disease progression. Sixteen of the 22 (73%) restarted on CDK4/6I, while the remaining 4 patients initiated chemotherapy or targeted therapy. Two patients died during CDK4/6i treatment interruption. A univariate analysis found that the presence of liver metastases was associated with increased risk of progression during CDK4/6I withdrawal (odds ratio, 5.50; 95% confidence interval, 1.14-26.41).

There was also a trend toward greater likelihood of disease progression when the withdrawal period was 2 or more months (OR, 2.38), but the finding was not statistically significant. Although the study looked at treatment interruption due to the COVID-19 pandemic, the authors noted that the findings likely apply to other reasons for interruption, such as analgesic radiotherapy or programmed surgery.

Although the study authors advise against stopping CDK4/6i inhibitors, another small study conducted at a single German center suggested that treatment interruption might be an option in patients with stable disease. The authors examined elective CDK4/6i discontinuation among 22 patients with advanced, hormone receptor–positive, HER-2-negative breast cancer who had stable disease for at least 6 months with treatment regimens of CDK4/6i plus aromatase inhibitors or fulvestrant. After discontinuation of CDK4/6i but maintenance of endocrine therapy, 13 patients had stable disease, 8 had a partial response, and 1 had a complete response. After withdrawal, 5 patients had a local relapse and 1 experienced systemic progression. The patients restabilized with chemotherapy or retreatment with CDK4/6i.

“Discontinuation of CDK4/6 inhibitors seems to be safe in selected patients with metastatic HR-positive HER-2-negative breast cancer and prolonged disease control,” the authors wrote, although they noted that the results need to be backed up with prospective clinical trials.

Both studies had small sample sizes and were retrospective in nature.

One author on the COVID-19 study has received consulting fees from Lilly, Novartis, Pfizer, Daïchi, Seagen, and AstraZeneca. Authors of the German study have received honoraria from Iomedico, Novartis, Roche, AstraZeneca, Boehringer Ingelheim, Merck, Sanofi, and BMS.

Interruption of 4-6 cyclin D-dependent kinase inhibitors (CDK4/6i) was associated with a high rate of progression among women with metastatic breast cancer, particularly those with liver metastases. The treatment interruptions occurred during the COVID-19 pandemic, out of concern that myelosuppression from the drugs might make patients more vulnerable to COVID-19 infection, and that other side effects might be confused with symptoms of COVID-19 infection.

The finding comes from a multicenter study presented by Sophie Martin, PhD, at the San Antonio Breast Cancer Symposium. Dr. Martin is a researcher at ICANS Institut de cancérologie Strasbourg Europe. The patient population had a complete or partial response, or stable disease complete for at least 6 months.

Although CDK4/6i combined with endocrine therapy has led to significant improvements in outcomes among metastatic HR-positive, HER-2-negative patients, the treatment can lead to chronic toxicities that may affect quality of life.

In its 2020 guidance on management of cancer patients during the COVID-19 pandemic, the European Society for Medical Oncology noted that cancer patients are at higher risk of severe symptoms and worse outcomes. However, it points out that there is no direct evidence that neutropenia caused CDK4/6i or poly-adenosine diphosphate ribose polymer inhibitors leads to an increase risk of COVID-19 infection.

The American Society for Clinical Oncology guidance for managing treatment of cancer patients in the context of COVID-19 also says there is little direct evidence to guide practice regarding therapies that may lead to immunosuppression. Therefore, the society recommends against changing or withholding those drugs. “The balance of potential harms that may result from delaying or interrupting treatment versus the potential benefits of possibly preventing or delaying COVID-19 infection is very uncertain,” the authors wrote.

There were 60 patients in the study, and the median age was 64 years. The average interruption period was 8 weeks. Twenty-two patients (37%) experienced radiological and/or clinical disease progression. Sixteen of the 22 (73%) restarted on CDK4/6I, while the remaining 4 patients initiated chemotherapy or targeted therapy. Two patients died during CDK4/6i treatment interruption. A univariate analysis found that the presence of liver metastases was associated with increased risk of progression during CDK4/6I withdrawal (odds ratio, 5.50; 95% confidence interval, 1.14-26.41).

There was also a trend toward greater likelihood of disease progression when the withdrawal period was 2 or more months (OR, 2.38), but the finding was not statistically significant. Although the study looked at treatment interruption due to the COVID-19 pandemic, the authors noted that the findings likely apply to other reasons for interruption, such as analgesic radiotherapy or programmed surgery.

Although the study authors advise against stopping CDK4/6i inhibitors, another small study conducted at a single German center suggested that treatment interruption might be an option in patients with stable disease. The authors examined elective CDK4/6i discontinuation among 22 patients with advanced, hormone receptor–positive, HER-2-negative breast cancer who had stable disease for at least 6 months with treatment regimens of CDK4/6i plus aromatase inhibitors or fulvestrant. After discontinuation of CDK4/6i but maintenance of endocrine therapy, 13 patients had stable disease, 8 had a partial response, and 1 had a complete response. After withdrawal, 5 patients had a local relapse and 1 experienced systemic progression. The patients restabilized with chemotherapy or retreatment with CDK4/6i.

“Discontinuation of CDK4/6 inhibitors seems to be safe in selected patients with metastatic HR-positive HER-2-negative breast cancer and prolonged disease control,” the authors wrote, although they noted that the results need to be backed up with prospective clinical trials.

Both studies had small sample sizes and were retrospective in nature.

One author on the COVID-19 study has received consulting fees from Lilly, Novartis, Pfizer, Daïchi, Seagen, and AstraZeneca. Authors of the German study have received honoraria from Iomedico, Novartis, Roche, AstraZeneca, Boehringer Ingelheim, Merck, Sanofi, and BMS.