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FDA Expands Repotrectinib Label to All NTRK Gene Fusion+ Solid Tumors
The approval is a label expansion for the tyrosine kinase inhibitor (TKI), which received initial clearance in November 2023 for locally advanced or metastatic ROS1-positive non–small cell lung cancer.
NTRK gene fusions are genetic abnormalities wherein part of the NTRK gene fuses with an unrelated gene. The abnormal gene can then produce an oncogenic protein. Although rare, these mutations are found in many cancer types.
The approval, for adult and pediatric patients aged 12 years or older, was based on the single-arm open-label TRIDENT-1 trial in 88 adults with locally advanced or metastatic NTRK gene fusion solid tumors.
In the 40 patients who were TKI-naive, the overall response rate was 58%, and the median duration of response was not estimable. In the 48 patients who had a TKI previously, the overall response rate was 50% and median duration of response was 9.9 months.
In 20% or more of participants, treatment caused dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.
Labeling warns of central nervous system reactions, interstitial lung disease/pneumonitis, hepatotoxicity, myalgia with creatine phosphokinase elevation, hyperuricemia, bone fractures, and embryo-fetal toxicity.
The recommended dose is 160 mg orally once daily for 14 days then increased to 160 mg twice daily until disease progression or unacceptable toxicity.
Sixty 40-mg capsules cost around $7,644, according to drugs.com.
A version of this article appeared on Medscape.com.
The approval is a label expansion for the tyrosine kinase inhibitor (TKI), which received initial clearance in November 2023 for locally advanced or metastatic ROS1-positive non–small cell lung cancer.
NTRK gene fusions are genetic abnormalities wherein part of the NTRK gene fuses with an unrelated gene. The abnormal gene can then produce an oncogenic protein. Although rare, these mutations are found in many cancer types.
The approval, for adult and pediatric patients aged 12 years or older, was based on the single-arm open-label TRIDENT-1 trial in 88 adults with locally advanced or metastatic NTRK gene fusion solid tumors.
In the 40 patients who were TKI-naive, the overall response rate was 58%, and the median duration of response was not estimable. In the 48 patients who had a TKI previously, the overall response rate was 50% and median duration of response was 9.9 months.
In 20% or more of participants, treatment caused dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.
Labeling warns of central nervous system reactions, interstitial lung disease/pneumonitis, hepatotoxicity, myalgia with creatine phosphokinase elevation, hyperuricemia, bone fractures, and embryo-fetal toxicity.
The recommended dose is 160 mg orally once daily for 14 days then increased to 160 mg twice daily until disease progression or unacceptable toxicity.
Sixty 40-mg capsules cost around $7,644, according to drugs.com.
A version of this article appeared on Medscape.com.
The approval is a label expansion for the tyrosine kinase inhibitor (TKI), which received initial clearance in November 2023 for locally advanced or metastatic ROS1-positive non–small cell lung cancer.
NTRK gene fusions are genetic abnormalities wherein part of the NTRK gene fuses with an unrelated gene. The abnormal gene can then produce an oncogenic protein. Although rare, these mutations are found in many cancer types.
The approval, for adult and pediatric patients aged 12 years or older, was based on the single-arm open-label TRIDENT-1 trial in 88 adults with locally advanced or metastatic NTRK gene fusion solid tumors.
In the 40 patients who were TKI-naive, the overall response rate was 58%, and the median duration of response was not estimable. In the 48 patients who had a TKI previously, the overall response rate was 50% and median duration of response was 9.9 months.
In 20% or more of participants, treatment caused dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.
Labeling warns of central nervous system reactions, interstitial lung disease/pneumonitis, hepatotoxicity, myalgia with creatine phosphokinase elevation, hyperuricemia, bone fractures, and embryo-fetal toxicity.
The recommended dose is 160 mg orally once daily for 14 days then increased to 160 mg twice daily until disease progression or unacceptable toxicity.
Sixty 40-mg capsules cost around $7,644, according to drugs.com.
A version of this article appeared on Medscape.com.
Ovarian Cancer Risk Doubled by Estrogen-Only HRT
Two decades after the landmark Women’s Health Initiative (WHI) changed the way clinicians thought about hormone therapy and cancer, new findings suggest this national health study is "the gift that keeps on giving."
Estrogen and progesterone together, meanwhile, did not increase ovarian cancer risk, and significantly reduced the risk of endometrial cancer. Rowan T. Chlebowski, MD, PhD, of The Lundquist Institute in Torrance, California, presented these results from the latest WHI findings, at the annual meeting of the American Society of Clinical Oncology in Chicago.
Dr. Chlebowski and his colleagues conducted an analysis from two randomized, placebo-controlled trials, which between 1993 and 1998 enrolled nearly 28,000 postmenopausal women aged 50-79 years without prior cancer from 40 centers across the United States. (The full WHI effort involved a total cohort of 161,000 patients, and included an observational study and two other non-drug trials.)
In one of the hormone therapy trials, 17,000 women with a uterus at baseline were randomized to combined equine estrogen plus medroxyprogesterone acetate, or placebo. In the other trial, about 11,000 women with prior hysterectomy were randomized to daily estrogen alone or placebo. Both trials were stopped early: the estrogen-only trial due to an increased stroke risk, and the combined therapy trial due to findings of increased breast cancer and cardiovascular risk.
Mean exposure to hormone therapy was 5.6 years for the combined therapy trial and 7.2 years for estrogen alone trial.
Ovarian Cancer Incidence Doubles with Estrogen
At 20 years’ follow up, with mortality information available for nearly the full cohort, Dr. Chlebowski and his colleagues could determine that ovarian cancer incidence doubled among women who had taken estrogen alone (hazard ratio = 2.04; 95% CI 1.14-3.65; P = .01), a difference that reached statistical significance at 12 years’ follow up. Ovarian cancer mortality was also significantly increased (HR = 2.79 95% CI 1.30-5.99, P = .006). Absolute numbers were small, however, with 35 cases of ovarian cancer compared with 17 in the placebo group.
Combined therapy recipients saw no increased risk for ovarian cancer and significantly lower endometrial cancer incidence (106 cases vs. 140 HR = 0.72; 95% CI, 0.56-0.92; P = .01).
Conjugated equine estrogen, Dr. Chlebowski said during his presentation at the meeting, “was introduced in US clinical practice in 1943 and used for over half a century, yet the question about hormone therapy’s influence on endometrial and ovarian cancer remains unsettled. Endometrial cancer and ovarian cancer are the fourth and fifth leading causes of cancer deaths in women ... and there’s some discordant findings from observational studies.”
Care of Ovarian Cancer Survivors Should Change
The new findings should prompt practice and guideline changes regarding the use of estrogen alone in ovarian cancer survivors, Dr. Chlebowski said.
In an interview, oncologist Eleonora Teplinsky, MD, of Valley-Mount Sinai Comprehensive Cancer Care in Paramus, New Jersey, said that apart from this subgroup of ovarian cancer survivors, the findings would not likely have much impact on how clinicians and patients approach hormone replacement therapy today.
“Twenty years ago the Women’s Health Initiative showed that hormone replacement therapy increases breast cancer risk, and everyone stopped taking HRT. And now people pushing back on it and saying wait a second – it was the estrogen plus progesterone that increased breast cancer, not estrogen alone. And now we’ve got these newer [estrogen] formulations.
“Yes, there’s a little bit of an increased risk [for ovarian cancer]. Patients should be aware. They should know the symptoms of ovarian cancer. But if they have indications and have been recommended HRT, this is not something that we would advise them against because of this very slightly increased risk,” Dr. Teplinsky said.
Oncologist Allison Kurian, MD of Stanford University in Stanford, California, who specializes in breast cancer, also noted that the duration of hormone treatment, treatment timing relative to age of menopause onset, and commonly used estrogen preparations had indeed changed since the time the WHI trials were conducted, making it harder to generalize the findings to current practice. Nonetheless, she argued, they still have real significance.
“WHI is an incredibly complex but also incredibly valuable resource,” said Dr. Kurian, who has conducted studies using WHI data. “The first big results came out in 2002, and we’re still learning from it. These are randomized trials, which offer the strongest form of scientific evidence that exists. So whenever we see results from this study, we have to take note of them,” she said.
Because the WHI trials had shown combined therapy, not estrogen alone, to be associated with breast cancer risk, clinicians have felt reassured over the years about using estrogen alone.
“You can’t give it to a person unless they have their uterus removed, because we know it will cause uterine cancer if the uterus is in place. But if the uterus is removed, the feeling was that you can give estrogen alone. I think the new piece that is going to get everyone’s attention is this signal for ovarian cancer.”
Something else the new findings show, Dr. Kurian said, is that WHI is “the gift that keeps on giving,” even after decades. “Some of the participants had a relatively short-term exposure to HRT. They took a medication for just a little while. But you didn’t see the effects until you followed people 12 years. So we’re now going to be a little more worried about ovarian cancer in this setting than we used to be. And that’s going to be something we’re all going to keep an eye on and think twice about in terms of talking to patients.”
These results help demonstrate what happens when a society invests in science on a national scale, Dr. Kurian said. “Here we have a really long-term, incredibly informative study that keeps generating knowledge to help women.”
When the WHI began, it “really was the first time that people decided it was important to systematically study women at midlife. It was a remarkable thing then that society got mobilized to do this, and we’re still seeing the benefits.”
Dr. Chlebowski disclosed receiving consulting or advisory fees from Pfizer. Dr. Teplinsky and Dr. Kurian disclosed no financial conflicts of interest.
Two decades after the landmark Women’s Health Initiative (WHI) changed the way clinicians thought about hormone therapy and cancer, new findings suggest this national health study is "the gift that keeps on giving."
Estrogen and progesterone together, meanwhile, did not increase ovarian cancer risk, and significantly reduced the risk of endometrial cancer. Rowan T. Chlebowski, MD, PhD, of The Lundquist Institute in Torrance, California, presented these results from the latest WHI findings, at the annual meeting of the American Society of Clinical Oncology in Chicago.
Dr. Chlebowski and his colleagues conducted an analysis from two randomized, placebo-controlled trials, which between 1993 and 1998 enrolled nearly 28,000 postmenopausal women aged 50-79 years without prior cancer from 40 centers across the United States. (The full WHI effort involved a total cohort of 161,000 patients, and included an observational study and two other non-drug trials.)
In one of the hormone therapy trials, 17,000 women with a uterus at baseline were randomized to combined equine estrogen plus medroxyprogesterone acetate, or placebo. In the other trial, about 11,000 women with prior hysterectomy were randomized to daily estrogen alone or placebo. Both trials were stopped early: the estrogen-only trial due to an increased stroke risk, and the combined therapy trial due to findings of increased breast cancer and cardiovascular risk.
Mean exposure to hormone therapy was 5.6 years for the combined therapy trial and 7.2 years for estrogen alone trial.
Ovarian Cancer Incidence Doubles with Estrogen
At 20 years’ follow up, with mortality information available for nearly the full cohort, Dr. Chlebowski and his colleagues could determine that ovarian cancer incidence doubled among women who had taken estrogen alone (hazard ratio = 2.04; 95% CI 1.14-3.65; P = .01), a difference that reached statistical significance at 12 years’ follow up. Ovarian cancer mortality was also significantly increased (HR = 2.79 95% CI 1.30-5.99, P = .006). Absolute numbers were small, however, with 35 cases of ovarian cancer compared with 17 in the placebo group.
Combined therapy recipients saw no increased risk for ovarian cancer and significantly lower endometrial cancer incidence (106 cases vs. 140 HR = 0.72; 95% CI, 0.56-0.92; P = .01).
Conjugated equine estrogen, Dr. Chlebowski said during his presentation at the meeting, “was introduced in US clinical practice in 1943 and used for over half a century, yet the question about hormone therapy’s influence on endometrial and ovarian cancer remains unsettled. Endometrial cancer and ovarian cancer are the fourth and fifth leading causes of cancer deaths in women ... and there’s some discordant findings from observational studies.”
Care of Ovarian Cancer Survivors Should Change
The new findings should prompt practice and guideline changes regarding the use of estrogen alone in ovarian cancer survivors, Dr. Chlebowski said.
In an interview, oncologist Eleonora Teplinsky, MD, of Valley-Mount Sinai Comprehensive Cancer Care in Paramus, New Jersey, said that apart from this subgroup of ovarian cancer survivors, the findings would not likely have much impact on how clinicians and patients approach hormone replacement therapy today.
“Twenty years ago the Women’s Health Initiative showed that hormone replacement therapy increases breast cancer risk, and everyone stopped taking HRT. And now people pushing back on it and saying wait a second – it was the estrogen plus progesterone that increased breast cancer, not estrogen alone. And now we’ve got these newer [estrogen] formulations.
“Yes, there’s a little bit of an increased risk [for ovarian cancer]. Patients should be aware. They should know the symptoms of ovarian cancer. But if they have indications and have been recommended HRT, this is not something that we would advise them against because of this very slightly increased risk,” Dr. Teplinsky said.
Oncologist Allison Kurian, MD of Stanford University in Stanford, California, who specializes in breast cancer, also noted that the duration of hormone treatment, treatment timing relative to age of menopause onset, and commonly used estrogen preparations had indeed changed since the time the WHI trials were conducted, making it harder to generalize the findings to current practice. Nonetheless, she argued, they still have real significance.
“WHI is an incredibly complex but also incredibly valuable resource,” said Dr. Kurian, who has conducted studies using WHI data. “The first big results came out in 2002, and we’re still learning from it. These are randomized trials, which offer the strongest form of scientific evidence that exists. So whenever we see results from this study, we have to take note of them,” she said.
Because the WHI trials had shown combined therapy, not estrogen alone, to be associated with breast cancer risk, clinicians have felt reassured over the years about using estrogen alone.
“You can’t give it to a person unless they have their uterus removed, because we know it will cause uterine cancer if the uterus is in place. But if the uterus is removed, the feeling was that you can give estrogen alone. I think the new piece that is going to get everyone’s attention is this signal for ovarian cancer.”
Something else the new findings show, Dr. Kurian said, is that WHI is “the gift that keeps on giving,” even after decades. “Some of the participants had a relatively short-term exposure to HRT. They took a medication for just a little while. But you didn’t see the effects until you followed people 12 years. So we’re now going to be a little more worried about ovarian cancer in this setting than we used to be. And that’s going to be something we’re all going to keep an eye on and think twice about in terms of talking to patients.”
These results help demonstrate what happens when a society invests in science on a national scale, Dr. Kurian said. “Here we have a really long-term, incredibly informative study that keeps generating knowledge to help women.”
When the WHI began, it “really was the first time that people decided it was important to systematically study women at midlife. It was a remarkable thing then that society got mobilized to do this, and we’re still seeing the benefits.”
Dr. Chlebowski disclosed receiving consulting or advisory fees from Pfizer. Dr. Teplinsky and Dr. Kurian disclosed no financial conflicts of interest.
Two decades after the landmark Women’s Health Initiative (WHI) changed the way clinicians thought about hormone therapy and cancer, new findings suggest this national health study is "the gift that keeps on giving."
Estrogen and progesterone together, meanwhile, did not increase ovarian cancer risk, and significantly reduced the risk of endometrial cancer. Rowan T. Chlebowski, MD, PhD, of The Lundquist Institute in Torrance, California, presented these results from the latest WHI findings, at the annual meeting of the American Society of Clinical Oncology in Chicago.
Dr. Chlebowski and his colleagues conducted an analysis from two randomized, placebo-controlled trials, which between 1993 and 1998 enrolled nearly 28,000 postmenopausal women aged 50-79 years without prior cancer from 40 centers across the United States. (The full WHI effort involved a total cohort of 161,000 patients, and included an observational study and two other non-drug trials.)
In one of the hormone therapy trials, 17,000 women with a uterus at baseline were randomized to combined equine estrogen plus medroxyprogesterone acetate, or placebo. In the other trial, about 11,000 women with prior hysterectomy were randomized to daily estrogen alone or placebo. Both trials were stopped early: the estrogen-only trial due to an increased stroke risk, and the combined therapy trial due to findings of increased breast cancer and cardiovascular risk.
Mean exposure to hormone therapy was 5.6 years for the combined therapy trial and 7.2 years for estrogen alone trial.
Ovarian Cancer Incidence Doubles with Estrogen
At 20 years’ follow up, with mortality information available for nearly the full cohort, Dr. Chlebowski and his colleagues could determine that ovarian cancer incidence doubled among women who had taken estrogen alone (hazard ratio = 2.04; 95% CI 1.14-3.65; P = .01), a difference that reached statistical significance at 12 years’ follow up. Ovarian cancer mortality was also significantly increased (HR = 2.79 95% CI 1.30-5.99, P = .006). Absolute numbers were small, however, with 35 cases of ovarian cancer compared with 17 in the placebo group.
Combined therapy recipients saw no increased risk for ovarian cancer and significantly lower endometrial cancer incidence (106 cases vs. 140 HR = 0.72; 95% CI, 0.56-0.92; P = .01).
Conjugated equine estrogen, Dr. Chlebowski said during his presentation at the meeting, “was introduced in US clinical practice in 1943 and used for over half a century, yet the question about hormone therapy’s influence on endometrial and ovarian cancer remains unsettled. Endometrial cancer and ovarian cancer are the fourth and fifth leading causes of cancer deaths in women ... and there’s some discordant findings from observational studies.”
Care of Ovarian Cancer Survivors Should Change
The new findings should prompt practice and guideline changes regarding the use of estrogen alone in ovarian cancer survivors, Dr. Chlebowski said.
In an interview, oncologist Eleonora Teplinsky, MD, of Valley-Mount Sinai Comprehensive Cancer Care in Paramus, New Jersey, said that apart from this subgroup of ovarian cancer survivors, the findings would not likely have much impact on how clinicians and patients approach hormone replacement therapy today.
“Twenty years ago the Women’s Health Initiative showed that hormone replacement therapy increases breast cancer risk, and everyone stopped taking HRT. And now people pushing back on it and saying wait a second – it was the estrogen plus progesterone that increased breast cancer, not estrogen alone. And now we’ve got these newer [estrogen] formulations.
“Yes, there’s a little bit of an increased risk [for ovarian cancer]. Patients should be aware. They should know the symptoms of ovarian cancer. But if they have indications and have been recommended HRT, this is not something that we would advise them against because of this very slightly increased risk,” Dr. Teplinsky said.
Oncologist Allison Kurian, MD of Stanford University in Stanford, California, who specializes in breast cancer, also noted that the duration of hormone treatment, treatment timing relative to age of menopause onset, and commonly used estrogen preparations had indeed changed since the time the WHI trials were conducted, making it harder to generalize the findings to current practice. Nonetheless, she argued, they still have real significance.
“WHI is an incredibly complex but also incredibly valuable resource,” said Dr. Kurian, who has conducted studies using WHI data. “The first big results came out in 2002, and we’re still learning from it. These are randomized trials, which offer the strongest form of scientific evidence that exists. So whenever we see results from this study, we have to take note of them,” she said.
Because the WHI trials had shown combined therapy, not estrogen alone, to be associated with breast cancer risk, clinicians have felt reassured over the years about using estrogen alone.
“You can’t give it to a person unless they have their uterus removed, because we know it will cause uterine cancer if the uterus is in place. But if the uterus is removed, the feeling was that you can give estrogen alone. I think the new piece that is going to get everyone’s attention is this signal for ovarian cancer.”
Something else the new findings show, Dr. Kurian said, is that WHI is “the gift that keeps on giving,” even after decades. “Some of the participants had a relatively short-term exposure to HRT. They took a medication for just a little while. But you didn’t see the effects until you followed people 12 years. So we’re now going to be a little more worried about ovarian cancer in this setting than we used to be. And that’s going to be something we’re all going to keep an eye on and think twice about in terms of talking to patients.”
These results help demonstrate what happens when a society invests in science on a national scale, Dr. Kurian said. “Here we have a really long-term, incredibly informative study that keeps generating knowledge to help women.”
When the WHI began, it “really was the first time that people decided it was important to systematically study women at midlife. It was a remarkable thing then that society got mobilized to do this, and we’re still seeing the benefits.”
Dr. Chlebowski disclosed receiving consulting or advisory fees from Pfizer. Dr. Teplinsky and Dr. Kurian disclosed no financial conflicts of interest.
FROM ASCO 2024
Are Children Born Through ART at Higher Risk for Cancer?
The results of a large French study comparing the cancer risk in children conceived through assisted reproductive technology (ART) with that of naturally conceived children were published recently in JAMA Network Open. This study is one of the largest to date on this subject: It included 8,526,306 children born in France between 2010 and 2021, of whom 260,236 (3%) were conceived through ART, and followed them up to a median age of 6.7 years.
Motivations for the Study
ART (including artificial insemination, in vitro fertilization [IVF], or intracytoplasmic sperm injection [ICSI] with fresh or frozen embryo transfer) accounts for about 1 in 30 births in France. However, limited and heterogeneous data have suggested an increased risk for certain health disorders, including cancer, among children conceived through ART. Therefore, a large-scale evaluation of cancer risk in these children is important.
No Overall Increase
In all, 9256 children developed cancer, including 292 who were conceived through ART. Thus, Nevertheless, a slight increase in the risk for leukemia was observed in children conceived through IVF or ICSI. The investigators observed approximately one additional case for every 5000 newborns conceived through IVF or ICSI who reached age 10 years.
Epidemiological monitoring should be continued to better evaluate long-term risks and see whether the risk for leukemia is confirmed. If it is, then it will be useful to investigate the mechanisms related to ART techniques or the fertility disorders of parents that could lead to an increased risk for leukemia.
This story was translated from Univadis France, which is part of the Medscape Professional Network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
The results of a large French study comparing the cancer risk in children conceived through assisted reproductive technology (ART) with that of naturally conceived children were published recently in JAMA Network Open. This study is one of the largest to date on this subject: It included 8,526,306 children born in France between 2010 and 2021, of whom 260,236 (3%) were conceived through ART, and followed them up to a median age of 6.7 years.
Motivations for the Study
ART (including artificial insemination, in vitro fertilization [IVF], or intracytoplasmic sperm injection [ICSI] with fresh or frozen embryo transfer) accounts for about 1 in 30 births in France. However, limited and heterogeneous data have suggested an increased risk for certain health disorders, including cancer, among children conceived through ART. Therefore, a large-scale evaluation of cancer risk in these children is important.
No Overall Increase
In all, 9256 children developed cancer, including 292 who were conceived through ART. Thus, Nevertheless, a slight increase in the risk for leukemia was observed in children conceived through IVF or ICSI. The investigators observed approximately one additional case for every 5000 newborns conceived through IVF or ICSI who reached age 10 years.
Epidemiological monitoring should be continued to better evaluate long-term risks and see whether the risk for leukemia is confirmed. If it is, then it will be useful to investigate the mechanisms related to ART techniques or the fertility disorders of parents that could lead to an increased risk for leukemia.
This story was translated from Univadis France, which is part of the Medscape Professional Network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
The results of a large French study comparing the cancer risk in children conceived through assisted reproductive technology (ART) with that of naturally conceived children were published recently in JAMA Network Open. This study is one of the largest to date on this subject: It included 8,526,306 children born in France between 2010 and 2021, of whom 260,236 (3%) were conceived through ART, and followed them up to a median age of 6.7 years.
Motivations for the Study
ART (including artificial insemination, in vitro fertilization [IVF], or intracytoplasmic sperm injection [ICSI] with fresh or frozen embryo transfer) accounts for about 1 in 30 births in France. However, limited and heterogeneous data have suggested an increased risk for certain health disorders, including cancer, among children conceived through ART. Therefore, a large-scale evaluation of cancer risk in these children is important.
No Overall Increase
In all, 9256 children developed cancer, including 292 who were conceived through ART. Thus, Nevertheless, a slight increase in the risk for leukemia was observed in children conceived through IVF or ICSI. The investigators observed approximately one additional case for every 5000 newborns conceived through IVF or ICSI who reached age 10 years.
Epidemiological monitoring should be continued to better evaluate long-term risks and see whether the risk for leukemia is confirmed. If it is, then it will be useful to investigate the mechanisms related to ART techniques or the fertility disorders of parents that could lead to an increased risk for leukemia.
This story was translated from Univadis France, which is part of the Medscape Professional Network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
About 20% of Breast Cancer Survivors Gain Excess Weight
BOSTON — Nearly one in five breast cancer survivors will gain more than 10% of their body weight in the 6 years following their diagnosis, according to new research presented at ENDO 2024, the annual meeting of the Endocrine Society.
Younger age and lower weight at diagnosis were the strongest predictors of this excessive weight gain over time.
“Weight gain is a common concern after breast cancer diagnosis and treatment,” said Maria Daniela Hurtado Andrade, MD, PhD, of the Mayo Clinic in Jacksonville, Florida, who led the research. “This weight gain in breast cancer survivor increases breast cancer recurrence and mortality, increases cardiovascular disease and mortality, and also increases all-cause mortality.”
Previous studies have found an association between breast cancer survivorship and weight gain, but the reported incidences of weight gain — and the amounts gained — have been highly variable, she added.
In the study, researchers used the Mayo Clinic Breast Cancer Registry to identify 4575 breast cancer survivors and tracked their weight over the course of 6 years following cancer diagnosis. These patients were age-matched to women in the general population selected from the Rochester Epidemiology Project, which contains the medical records of residents of 27 counties in Minnesota and Wisconsin. All controls had no history of cancer or bariatric surgery.
Nearly all patients and controls were White (97%); at breast cancer diagnosis, patients were on average 58 years of age and weighed 76 kg (165.5 lb). Controls had similar ages and baseline weights.
At 6 years following breast cancer diagnosis, average weight gain was modest: Breast cancer survivors gained 1.6% of their body weight, compared with 0.7% in controls (P = .004).
However, 18% of breast cancer survivors had gained at least 10% of their body weight over that time. By comparison, 8% of controls experienced this excessive weight gain during that same time frame (P < .0001). The same trend was observed for 15% and 20% weight gain.
After adjustment for confounding factors, younger age at breast cancer diagnosis and lower baseline weight were the strongest predictors of more than 10% weight gain. BRCA2 mutation and use of systemic chemotherapy treatment were also associated with excessive weight gain.
Several factors could be driving weight gain in these patients, said Zeynep Madak-Erdogan, PhD, at the University of Illinois Urbana-Champaign, who was not involved with the research. Her work focuses on how diet and nutrition affect hormone action in postmenopausal women and breast cancer survivors. Certain therapies can induce temporary or permanent menopause in patients, “and this early menopause might shift balance of estrogens and cause increased weight gain,” she said. Along the same lines, endocrine therapies can also affect estrogen production.
Stress and exhaustion from treatment — especially compounded by the two previous factors — are also likely culprits in weight gain, she continued.
“These findings highlight importance of lifestyle interventions,” added Dr. Madak-Erdogan. “In addition to changes in the diet (increased vegetable, fruit, [and] whole grain intake; reduction in saturated fats, alcohol, [and] sweetened beverage consumption), survivors should be consulted on importance of regular exercise.”
“These data clearly show we must consider weight changes in breast cancer survivors, and we must find ways of instituting strategies to mitigate these weight gains,” Dr. Hurtado Andrade said. “These women have a lot to think of when they have a breast cancer diagnosis, so we also must find ways of instituting these measures in a way that doesn’t increase the burden of their health.”
Dr. Hurtado Andrade has received research funding from the National Institutes of Health and by Phenomix Sciences. She also is a consultant for Novo Nordisk. These three organizations were not involved with this study. Dr. Madak-Erdogan had no disclosures.
A version of this article first appeared on Medscape.com.
BOSTON — Nearly one in five breast cancer survivors will gain more than 10% of their body weight in the 6 years following their diagnosis, according to new research presented at ENDO 2024, the annual meeting of the Endocrine Society.
Younger age and lower weight at diagnosis were the strongest predictors of this excessive weight gain over time.
“Weight gain is a common concern after breast cancer diagnosis and treatment,” said Maria Daniela Hurtado Andrade, MD, PhD, of the Mayo Clinic in Jacksonville, Florida, who led the research. “This weight gain in breast cancer survivor increases breast cancer recurrence and mortality, increases cardiovascular disease and mortality, and also increases all-cause mortality.”
Previous studies have found an association between breast cancer survivorship and weight gain, but the reported incidences of weight gain — and the amounts gained — have been highly variable, she added.
In the study, researchers used the Mayo Clinic Breast Cancer Registry to identify 4575 breast cancer survivors and tracked their weight over the course of 6 years following cancer diagnosis. These patients were age-matched to women in the general population selected from the Rochester Epidemiology Project, which contains the medical records of residents of 27 counties in Minnesota and Wisconsin. All controls had no history of cancer or bariatric surgery.
Nearly all patients and controls were White (97%); at breast cancer diagnosis, patients were on average 58 years of age and weighed 76 kg (165.5 lb). Controls had similar ages and baseline weights.
At 6 years following breast cancer diagnosis, average weight gain was modest: Breast cancer survivors gained 1.6% of their body weight, compared with 0.7% in controls (P = .004).
However, 18% of breast cancer survivors had gained at least 10% of their body weight over that time. By comparison, 8% of controls experienced this excessive weight gain during that same time frame (P < .0001). The same trend was observed for 15% and 20% weight gain.
After adjustment for confounding factors, younger age at breast cancer diagnosis and lower baseline weight were the strongest predictors of more than 10% weight gain. BRCA2 mutation and use of systemic chemotherapy treatment were also associated with excessive weight gain.
Several factors could be driving weight gain in these patients, said Zeynep Madak-Erdogan, PhD, at the University of Illinois Urbana-Champaign, who was not involved with the research. Her work focuses on how diet and nutrition affect hormone action in postmenopausal women and breast cancer survivors. Certain therapies can induce temporary or permanent menopause in patients, “and this early menopause might shift balance of estrogens and cause increased weight gain,” she said. Along the same lines, endocrine therapies can also affect estrogen production.
Stress and exhaustion from treatment — especially compounded by the two previous factors — are also likely culprits in weight gain, she continued.
“These findings highlight importance of lifestyle interventions,” added Dr. Madak-Erdogan. “In addition to changes in the diet (increased vegetable, fruit, [and] whole grain intake; reduction in saturated fats, alcohol, [and] sweetened beverage consumption), survivors should be consulted on importance of regular exercise.”
“These data clearly show we must consider weight changes in breast cancer survivors, and we must find ways of instituting strategies to mitigate these weight gains,” Dr. Hurtado Andrade said. “These women have a lot to think of when they have a breast cancer diagnosis, so we also must find ways of instituting these measures in a way that doesn’t increase the burden of their health.”
Dr. Hurtado Andrade has received research funding from the National Institutes of Health and by Phenomix Sciences. She also is a consultant for Novo Nordisk. These three organizations were not involved with this study. Dr. Madak-Erdogan had no disclosures.
A version of this article first appeared on Medscape.com.
BOSTON — Nearly one in five breast cancer survivors will gain more than 10% of their body weight in the 6 years following their diagnosis, according to new research presented at ENDO 2024, the annual meeting of the Endocrine Society.
Younger age and lower weight at diagnosis were the strongest predictors of this excessive weight gain over time.
“Weight gain is a common concern after breast cancer diagnosis and treatment,” said Maria Daniela Hurtado Andrade, MD, PhD, of the Mayo Clinic in Jacksonville, Florida, who led the research. “This weight gain in breast cancer survivor increases breast cancer recurrence and mortality, increases cardiovascular disease and mortality, and also increases all-cause mortality.”
Previous studies have found an association between breast cancer survivorship and weight gain, but the reported incidences of weight gain — and the amounts gained — have been highly variable, she added.
In the study, researchers used the Mayo Clinic Breast Cancer Registry to identify 4575 breast cancer survivors and tracked their weight over the course of 6 years following cancer diagnosis. These patients were age-matched to women in the general population selected from the Rochester Epidemiology Project, which contains the medical records of residents of 27 counties in Minnesota and Wisconsin. All controls had no history of cancer or bariatric surgery.
Nearly all patients and controls were White (97%); at breast cancer diagnosis, patients were on average 58 years of age and weighed 76 kg (165.5 lb). Controls had similar ages and baseline weights.
At 6 years following breast cancer diagnosis, average weight gain was modest: Breast cancer survivors gained 1.6% of their body weight, compared with 0.7% in controls (P = .004).
However, 18% of breast cancer survivors had gained at least 10% of their body weight over that time. By comparison, 8% of controls experienced this excessive weight gain during that same time frame (P < .0001). The same trend was observed for 15% and 20% weight gain.
After adjustment for confounding factors, younger age at breast cancer diagnosis and lower baseline weight were the strongest predictors of more than 10% weight gain. BRCA2 mutation and use of systemic chemotherapy treatment were also associated with excessive weight gain.
Several factors could be driving weight gain in these patients, said Zeynep Madak-Erdogan, PhD, at the University of Illinois Urbana-Champaign, who was not involved with the research. Her work focuses on how diet and nutrition affect hormone action in postmenopausal women and breast cancer survivors. Certain therapies can induce temporary or permanent menopause in patients, “and this early menopause might shift balance of estrogens and cause increased weight gain,” she said. Along the same lines, endocrine therapies can also affect estrogen production.
Stress and exhaustion from treatment — especially compounded by the two previous factors — are also likely culprits in weight gain, she continued.
“These findings highlight importance of lifestyle interventions,” added Dr. Madak-Erdogan. “In addition to changes in the diet (increased vegetable, fruit, [and] whole grain intake; reduction in saturated fats, alcohol, [and] sweetened beverage consumption), survivors should be consulted on importance of regular exercise.”
“These data clearly show we must consider weight changes in breast cancer survivors, and we must find ways of instituting strategies to mitigate these weight gains,” Dr. Hurtado Andrade said. “These women have a lot to think of when they have a breast cancer diagnosis, so we also must find ways of instituting these measures in a way that doesn’t increase the burden of their health.”
Dr. Hurtado Andrade has received research funding from the National Institutes of Health and by Phenomix Sciences. She also is a consultant for Novo Nordisk. These three organizations were not involved with this study. Dr. Madak-Erdogan had no disclosures.
A version of this article first appeared on Medscape.com.
FROM ENDO 2024
T-DXd Moves Toward First Line for HER2-Low Metastatic BC
HER2-low cancers express levels of human epidermal growth factor receptor 2 that are below standard thresholds for HER2-positive immunohistochemistry. In 2022, results from the DESTINY-Breast04 trial showed T-DXd (Enhertu, AstraZeneca) to be an effective second-line chemotherapy in patients with HER2-low metastatic breast cancer.
The highly awaited new findings, from the manufacturer-sponsored, open-label Phase 3 DESTINY-Breast06 trial, were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.
The findings not only definitively establish a role for T-DXd earlier in the treatment sequence for HER2-low cancers, they also suggest benefit in a group of patients designated for the purposes of this trial to be HER2-ultralow. These patients have cancers with only faintly detectable HER2 expression on currently used assays (J Clin Oncol 42, 2024 [suppl 17; abstr LBA 1000]).
In a separate set of findings also presented at ASCO, from the randomized phase 1B open-label study, DESTINY-Breast07, T-Dxd showed efficacy in previously untreated HER2-positive metastatic breast cancer patients both alone and in combination with the monoclonal antibody pertuzumab (Perjeta, Genentech).
DESTINY-Breast06 Methods and Results
The DESTINY-Breast06 findings were presented by lead investigator Guiseppe Curigliano, MD, PhD, of the University of Milan and European Institute of Oncology. Dr. Curigliano and his colleagues randomized 866 patients with metastatic breast cancer: 436 to intravenous T-Dxd and 430 to the investigator’s choice of capecitabine, nab-paclitaxel, or paclitaxel chemotherapy. The investigators chose capecitabine 60% of the time.
Most patients had cancers classed as HER2 low (immunohistochemistry 1+ or 2+), while 153 had cancers classed by investigators as HER2-ultralow (IHC 0 with membrane staining or IHC under 1+). Patients enrolled in the study were those whose disease had progressed after endocrine therapy with or without targeted therapy. Patients’ median age was between 57 and 58, and all were chemotherapy-naive in the metastatic breast cancer setting.
The main outcome of the study was median progression-free survival in the HER2-low group. T-Dxd was seen improving progression-free survival, with median 13.2 months vs. 8.1 months (hazard ratio, 0.62; 95% confidence interval, 0.51-0.74; P < .0001). In the intention-to-treat population, which included the HER2 ultralow patients, the benefit was the same (HR, 0.63; 95% CI, 0.53-0.75; P < .0001). This suggested that T-DXd is also effective in these patients, and it will be extremely important going forward to identify the lowest level of HER2 expression in metastatic breast cancers that can still benefit from therapy with T-DxD, Dr. Curigliano said.
Overall survival could not be assessed in the study cohort because complete data were not yet available, Dr. Curigliano said. However, trends pointed to an advantage for T-DXd, and tumor response rates were markedly higher with T-DXd: 57% compared with 31% for standard chemotherapy in the full cohort.
Serious treatment-emergent adverse events were more common in the T-Dxd–treated patients, with 11% of that arm developing drug-related interstitial lung disease, and three patients dying of it. Five patients in the T-DXd arm died of adverse events deemed treatment-related, and none died from treatment-related adverse events in the standard chemotherapy arm. Altogether 11 patients died in the T-DXd arm and 6 in the chemotherapy arm.
Clinical Implications of DESTINY-Breast06
The DESTINY-Breast06 data show that “we have to again change how we think about HER2 expression. Even very low levels of HER2 expression matter, and they can be leveraged to improve the treatment for our patients,” said Ian Krop, MD, PhD, of the Yale Cancer Center in New Haven, Connecticut, during the session where the results were presented.
But T-DXd may not be an appropriate first choice for all patients, especially given the safety concerns associated with T-DXd, he continued. With overall survival and quality-of-life data still lacking, clinicians will have to determine on a case-by-case basis who should get T-DXd in the first line.
“For patients who have symptomatic metastatic disease, who need a response to address those symptoms, those in whom you think chemotherapy may not work as well because they had, for example, a short recurrence interval after their adjuvant chemotherapy — using T-DXd in that first-line setting makes perfect sense to take advantage of the substantially higher response rate compared to chemo,” Dr. Krop said. “But for patients who have asymptomatic low burdens of disease, it seems very reasonable to consider using a well-tolerated chemotherapy like capecitabine in the first line, and then using T-DXd in the second line.”
In an interview, Erica Mayer, MD, of the Dana Farber Cancer Institute in Boston, Massachusetts, said patient choice will also matter in determining whether T-DXd is a first-line option. The known toxicity of T-DXd was underscored by the latest findings, she noted, while capecitabine, one of the chemotherapy choices in the control arm of the study, “really reflects what the majority of breast cancer doctors tend to offer, both because of the efficacy of the drug, but also because it’s oral, it’s well tolerated, and you don’t lose your hair.”
DESTINY-Breast07 Results
The DESTINY-Breast07 findings, from a Phase 1B open-label trial measuring safety and tolerability, were presented by Fabrice Andre, MD, PhD, of Université Paris Saclay in Paris, France. Dr. Andre and his colleagues presented the first data comparing T-DXd monotherapy and T-DXd with pertuzumab — a monoclonal antibody targeting HER2 — as a first-line treatment in patients with HER2-overexpressing (immunohistochemistry 3 and above) metastatic breast cancer. (J Clin Oncol 42, 2024 [suppl 16; abstr 1009]).
Current first-line standard of care for these patients is pertuzumab, trastuzumab, and docetaxel, based on results from the 2015 CLEOPATRA trial. T-DXd is currently approved as a second-line treatment.
Dr. Andre and his colleagues randomized 75 patients to monotherapy with T-DXd and 50 to combined therapy, with a median follow-up of 2 years.
After 1 year of treatment, combination of T-DXd and pertuzumab was seen to be associated with a progression-free survival of 89% at 1 year (80% CI, 81.9-93.9), compared with 80% in patients treated with T-DXd alone (80% CI, 73.7-86.1). Objective tumor response rate was 84% for the combined therapy at 12 weeks, with 20% of patients seeing a complete response, compared with 76% and 8%, respectively, for monotherapy.
As in the DESTINY-Breast06 trial, adverse events were high, with interstitial lung disease seen in 9% of patients in the monotherapy group and in 14% of the combined-therapy patients, although no treatment-related deaths occurred.
A randomized phase 3 trial, DESTINY Breast09, will now compare the monotherapy and the combined therapy with standard care.
T-DXd has seen a rapidly expanding role in treating breast and other solid tumors. The DESTINY Breast06 findings will move up its place in the treatment algorithm for metastatic breast cancer, “allowing us to now offer T-DXd as the first chemotherapy choice for patients who are making that transition to chemotherapy over many of the traditional provider choices that we previously have offered,” Dr. Mayer said.
The results “support the use of not only this specific agent, but also the concept of antibody drug conjugates as a very effective way to treat malignancy,” she added.
Dr. Curigliano reported receiving speaker’s fees, research funding, and other support from AstraZeneca and Daiichi Sankyo, among other companies, as did most of his co-authors, of whom three were AstraZeneca employees. Dr. Fabrice disclosed receiving research funding, travel compensation, and/or advisory fees from AstraZeneca and other entities, as did several of his co-authors. Two of his co-authors were employed by AstraZeneca and Roche, manufacturers of the study drugs. Dr. Krop and Dr. Mayer disclosed relationships with AstraZeneca and others.
HER2-low cancers express levels of human epidermal growth factor receptor 2 that are below standard thresholds for HER2-positive immunohistochemistry. In 2022, results from the DESTINY-Breast04 trial showed T-DXd (Enhertu, AstraZeneca) to be an effective second-line chemotherapy in patients with HER2-low metastatic breast cancer.
The highly awaited new findings, from the manufacturer-sponsored, open-label Phase 3 DESTINY-Breast06 trial, were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.
The findings not only definitively establish a role for T-DXd earlier in the treatment sequence for HER2-low cancers, they also suggest benefit in a group of patients designated for the purposes of this trial to be HER2-ultralow. These patients have cancers with only faintly detectable HER2 expression on currently used assays (J Clin Oncol 42, 2024 [suppl 17; abstr LBA 1000]).
In a separate set of findings also presented at ASCO, from the randomized phase 1B open-label study, DESTINY-Breast07, T-Dxd showed efficacy in previously untreated HER2-positive metastatic breast cancer patients both alone and in combination with the monoclonal antibody pertuzumab (Perjeta, Genentech).
DESTINY-Breast06 Methods and Results
The DESTINY-Breast06 findings were presented by lead investigator Guiseppe Curigliano, MD, PhD, of the University of Milan and European Institute of Oncology. Dr. Curigliano and his colleagues randomized 866 patients with metastatic breast cancer: 436 to intravenous T-Dxd and 430 to the investigator’s choice of capecitabine, nab-paclitaxel, or paclitaxel chemotherapy. The investigators chose capecitabine 60% of the time.
Most patients had cancers classed as HER2 low (immunohistochemistry 1+ or 2+), while 153 had cancers classed by investigators as HER2-ultralow (IHC 0 with membrane staining or IHC under 1+). Patients enrolled in the study were those whose disease had progressed after endocrine therapy with or without targeted therapy. Patients’ median age was between 57 and 58, and all were chemotherapy-naive in the metastatic breast cancer setting.
The main outcome of the study was median progression-free survival in the HER2-low group. T-Dxd was seen improving progression-free survival, with median 13.2 months vs. 8.1 months (hazard ratio, 0.62; 95% confidence interval, 0.51-0.74; P < .0001). In the intention-to-treat population, which included the HER2 ultralow patients, the benefit was the same (HR, 0.63; 95% CI, 0.53-0.75; P < .0001). This suggested that T-DXd is also effective in these patients, and it will be extremely important going forward to identify the lowest level of HER2 expression in metastatic breast cancers that can still benefit from therapy with T-DxD, Dr. Curigliano said.
Overall survival could not be assessed in the study cohort because complete data were not yet available, Dr. Curigliano said. However, trends pointed to an advantage for T-DXd, and tumor response rates were markedly higher with T-DXd: 57% compared with 31% for standard chemotherapy in the full cohort.
Serious treatment-emergent adverse events were more common in the T-Dxd–treated patients, with 11% of that arm developing drug-related interstitial lung disease, and three patients dying of it. Five patients in the T-DXd arm died of adverse events deemed treatment-related, and none died from treatment-related adverse events in the standard chemotherapy arm. Altogether 11 patients died in the T-DXd arm and 6 in the chemotherapy arm.
Clinical Implications of DESTINY-Breast06
The DESTINY-Breast06 data show that “we have to again change how we think about HER2 expression. Even very low levels of HER2 expression matter, and they can be leveraged to improve the treatment for our patients,” said Ian Krop, MD, PhD, of the Yale Cancer Center in New Haven, Connecticut, during the session where the results were presented.
But T-DXd may not be an appropriate first choice for all patients, especially given the safety concerns associated with T-DXd, he continued. With overall survival and quality-of-life data still lacking, clinicians will have to determine on a case-by-case basis who should get T-DXd in the first line.
“For patients who have symptomatic metastatic disease, who need a response to address those symptoms, those in whom you think chemotherapy may not work as well because they had, for example, a short recurrence interval after their adjuvant chemotherapy — using T-DXd in that first-line setting makes perfect sense to take advantage of the substantially higher response rate compared to chemo,” Dr. Krop said. “But for patients who have asymptomatic low burdens of disease, it seems very reasonable to consider using a well-tolerated chemotherapy like capecitabine in the first line, and then using T-DXd in the second line.”
In an interview, Erica Mayer, MD, of the Dana Farber Cancer Institute in Boston, Massachusetts, said patient choice will also matter in determining whether T-DXd is a first-line option. The known toxicity of T-DXd was underscored by the latest findings, she noted, while capecitabine, one of the chemotherapy choices in the control arm of the study, “really reflects what the majority of breast cancer doctors tend to offer, both because of the efficacy of the drug, but also because it’s oral, it’s well tolerated, and you don’t lose your hair.”
DESTINY-Breast07 Results
The DESTINY-Breast07 findings, from a Phase 1B open-label trial measuring safety and tolerability, were presented by Fabrice Andre, MD, PhD, of Université Paris Saclay in Paris, France. Dr. Andre and his colleagues presented the first data comparing T-DXd monotherapy and T-DXd with pertuzumab — a monoclonal antibody targeting HER2 — as a first-line treatment in patients with HER2-overexpressing (immunohistochemistry 3 and above) metastatic breast cancer. (J Clin Oncol 42, 2024 [suppl 16; abstr 1009]).
Current first-line standard of care for these patients is pertuzumab, trastuzumab, and docetaxel, based on results from the 2015 CLEOPATRA trial. T-DXd is currently approved as a second-line treatment.
Dr. Andre and his colleagues randomized 75 patients to monotherapy with T-DXd and 50 to combined therapy, with a median follow-up of 2 years.
After 1 year of treatment, combination of T-DXd and pertuzumab was seen to be associated with a progression-free survival of 89% at 1 year (80% CI, 81.9-93.9), compared with 80% in patients treated with T-DXd alone (80% CI, 73.7-86.1). Objective tumor response rate was 84% for the combined therapy at 12 weeks, with 20% of patients seeing a complete response, compared with 76% and 8%, respectively, for monotherapy.
As in the DESTINY-Breast06 trial, adverse events were high, with interstitial lung disease seen in 9% of patients in the monotherapy group and in 14% of the combined-therapy patients, although no treatment-related deaths occurred.
A randomized phase 3 trial, DESTINY Breast09, will now compare the monotherapy and the combined therapy with standard care.
T-DXd has seen a rapidly expanding role in treating breast and other solid tumors. The DESTINY Breast06 findings will move up its place in the treatment algorithm for metastatic breast cancer, “allowing us to now offer T-DXd as the first chemotherapy choice for patients who are making that transition to chemotherapy over many of the traditional provider choices that we previously have offered,” Dr. Mayer said.
The results “support the use of not only this specific agent, but also the concept of antibody drug conjugates as a very effective way to treat malignancy,” she added.
Dr. Curigliano reported receiving speaker’s fees, research funding, and other support from AstraZeneca and Daiichi Sankyo, among other companies, as did most of his co-authors, of whom three were AstraZeneca employees. Dr. Fabrice disclosed receiving research funding, travel compensation, and/or advisory fees from AstraZeneca and other entities, as did several of his co-authors. Two of his co-authors were employed by AstraZeneca and Roche, manufacturers of the study drugs. Dr. Krop and Dr. Mayer disclosed relationships with AstraZeneca and others.
HER2-low cancers express levels of human epidermal growth factor receptor 2 that are below standard thresholds for HER2-positive immunohistochemistry. In 2022, results from the DESTINY-Breast04 trial showed T-DXd (Enhertu, AstraZeneca) to be an effective second-line chemotherapy in patients with HER2-low metastatic breast cancer.
The highly awaited new findings, from the manufacturer-sponsored, open-label Phase 3 DESTINY-Breast06 trial, were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.
The findings not only definitively establish a role for T-DXd earlier in the treatment sequence for HER2-low cancers, they also suggest benefit in a group of patients designated for the purposes of this trial to be HER2-ultralow. These patients have cancers with only faintly detectable HER2 expression on currently used assays (J Clin Oncol 42, 2024 [suppl 17; abstr LBA 1000]).
In a separate set of findings also presented at ASCO, from the randomized phase 1B open-label study, DESTINY-Breast07, T-Dxd showed efficacy in previously untreated HER2-positive metastatic breast cancer patients both alone and in combination with the monoclonal antibody pertuzumab (Perjeta, Genentech).
DESTINY-Breast06 Methods and Results
The DESTINY-Breast06 findings were presented by lead investigator Guiseppe Curigliano, MD, PhD, of the University of Milan and European Institute of Oncology. Dr. Curigliano and his colleagues randomized 866 patients with metastatic breast cancer: 436 to intravenous T-Dxd and 430 to the investigator’s choice of capecitabine, nab-paclitaxel, or paclitaxel chemotherapy. The investigators chose capecitabine 60% of the time.
Most patients had cancers classed as HER2 low (immunohistochemistry 1+ or 2+), while 153 had cancers classed by investigators as HER2-ultralow (IHC 0 with membrane staining or IHC under 1+). Patients enrolled in the study were those whose disease had progressed after endocrine therapy with or without targeted therapy. Patients’ median age was between 57 and 58, and all were chemotherapy-naive in the metastatic breast cancer setting.
The main outcome of the study was median progression-free survival in the HER2-low group. T-Dxd was seen improving progression-free survival, with median 13.2 months vs. 8.1 months (hazard ratio, 0.62; 95% confidence interval, 0.51-0.74; P < .0001). In the intention-to-treat population, which included the HER2 ultralow patients, the benefit was the same (HR, 0.63; 95% CI, 0.53-0.75; P < .0001). This suggested that T-DXd is also effective in these patients, and it will be extremely important going forward to identify the lowest level of HER2 expression in metastatic breast cancers that can still benefit from therapy with T-DxD, Dr. Curigliano said.
Overall survival could not be assessed in the study cohort because complete data were not yet available, Dr. Curigliano said. However, trends pointed to an advantage for T-DXd, and tumor response rates were markedly higher with T-DXd: 57% compared with 31% for standard chemotherapy in the full cohort.
Serious treatment-emergent adverse events were more common in the T-Dxd–treated patients, with 11% of that arm developing drug-related interstitial lung disease, and three patients dying of it. Five patients in the T-DXd arm died of adverse events deemed treatment-related, and none died from treatment-related adverse events in the standard chemotherapy arm. Altogether 11 patients died in the T-DXd arm and 6 in the chemotherapy arm.
Clinical Implications of DESTINY-Breast06
The DESTINY-Breast06 data show that “we have to again change how we think about HER2 expression. Even very low levels of HER2 expression matter, and they can be leveraged to improve the treatment for our patients,” said Ian Krop, MD, PhD, of the Yale Cancer Center in New Haven, Connecticut, during the session where the results were presented.
But T-DXd may not be an appropriate first choice for all patients, especially given the safety concerns associated with T-DXd, he continued. With overall survival and quality-of-life data still lacking, clinicians will have to determine on a case-by-case basis who should get T-DXd in the first line.
“For patients who have symptomatic metastatic disease, who need a response to address those symptoms, those in whom you think chemotherapy may not work as well because they had, for example, a short recurrence interval after their adjuvant chemotherapy — using T-DXd in that first-line setting makes perfect sense to take advantage of the substantially higher response rate compared to chemo,” Dr. Krop said. “But for patients who have asymptomatic low burdens of disease, it seems very reasonable to consider using a well-tolerated chemotherapy like capecitabine in the first line, and then using T-DXd in the second line.”
In an interview, Erica Mayer, MD, of the Dana Farber Cancer Institute in Boston, Massachusetts, said patient choice will also matter in determining whether T-DXd is a first-line option. The known toxicity of T-DXd was underscored by the latest findings, she noted, while capecitabine, one of the chemotherapy choices in the control arm of the study, “really reflects what the majority of breast cancer doctors tend to offer, both because of the efficacy of the drug, but also because it’s oral, it’s well tolerated, and you don’t lose your hair.”
DESTINY-Breast07 Results
The DESTINY-Breast07 findings, from a Phase 1B open-label trial measuring safety and tolerability, were presented by Fabrice Andre, MD, PhD, of Université Paris Saclay in Paris, France. Dr. Andre and his colleagues presented the first data comparing T-DXd monotherapy and T-DXd with pertuzumab — a monoclonal antibody targeting HER2 — as a first-line treatment in patients with HER2-overexpressing (immunohistochemistry 3 and above) metastatic breast cancer. (J Clin Oncol 42, 2024 [suppl 16; abstr 1009]).
Current first-line standard of care for these patients is pertuzumab, trastuzumab, and docetaxel, based on results from the 2015 CLEOPATRA trial. T-DXd is currently approved as a second-line treatment.
Dr. Andre and his colleagues randomized 75 patients to monotherapy with T-DXd and 50 to combined therapy, with a median follow-up of 2 years.
After 1 year of treatment, combination of T-DXd and pertuzumab was seen to be associated with a progression-free survival of 89% at 1 year (80% CI, 81.9-93.9), compared with 80% in patients treated with T-DXd alone (80% CI, 73.7-86.1). Objective tumor response rate was 84% for the combined therapy at 12 weeks, with 20% of patients seeing a complete response, compared with 76% and 8%, respectively, for monotherapy.
As in the DESTINY-Breast06 trial, adverse events were high, with interstitial lung disease seen in 9% of patients in the monotherapy group and in 14% of the combined-therapy patients, although no treatment-related deaths occurred.
A randomized phase 3 trial, DESTINY Breast09, will now compare the monotherapy and the combined therapy with standard care.
T-DXd has seen a rapidly expanding role in treating breast and other solid tumors. The DESTINY Breast06 findings will move up its place in the treatment algorithm for metastatic breast cancer, “allowing us to now offer T-DXd as the first chemotherapy choice for patients who are making that transition to chemotherapy over many of the traditional provider choices that we previously have offered,” Dr. Mayer said.
The results “support the use of not only this specific agent, but also the concept of antibody drug conjugates as a very effective way to treat malignancy,” she added.
Dr. Curigliano reported receiving speaker’s fees, research funding, and other support from AstraZeneca and Daiichi Sankyo, among other companies, as did most of his co-authors, of whom three were AstraZeneca employees. Dr. Fabrice disclosed receiving research funding, travel compensation, and/or advisory fees from AstraZeneca and other entities, as did several of his co-authors. Two of his co-authors were employed by AstraZeneca and Roche, manufacturers of the study drugs. Dr. Krop and Dr. Mayer disclosed relationships with AstraZeneca and others.
FROM ASCO
Anti-Müllerian Hormone Predicts Chemo Benefits in BC
The new findings also show that women with low baseline anti-Müllerian hormone (AMH) of less than 10 pg/mL do not benefit from chemotherapy. In fact, AMH levels were a better predictor of chemotherapy benefit than self-reported premenopausal status, age, and other hormone levels.
“We may be overtreating some of our patients” with invasive breast cancer and low AMH levels, Kevin Kalinsky, MD, of the Winship Cancer Institute of Emory University, Atlanta, said in a presentation at the annual meeting of the American Society of Clinical Oncology (ASCO).
The potential implication of the study is that clinicians may be able to stop giving chemotherapy to a subset of breast cancer patients who will not benefit from it, he said in the presentation.
New Analysis Singles Out AMH Levels
In a new analysis of data from the RxPONDER trial, Dr. Kalinsky shared data from 1,016 patients who were younger than 55 years of age and self-reported as premenopausal.
The original RxPONDER trial (also known as SWOG S1007) was a randomized, phase 3 trial designed to evaluate the benefit of endocrine therapy (ET) alone vs. ET plus chemotherapy in patients with hormone receptor positive and human epidermal growth factor receptor 2 negative (HR+/HER2-) invasive breast cancer and low recurrence scores (25 or less with genomic testing by Oncotype DX), Dr. Kalinsky said in his presentation.
The researchers found no improvement in invasive disease-free survival (IDFS) with the addition of chemotherapy to ET overall, but significant IDFS improvement occurred with added chemotherapy to ET in the subgroup of self-reported premenopausal women (hazard ratio 0.60).
To better identify the impact of menopausal status on patients who would benefit or not benefit from chemotherapy in the new analysis, the researchers assessed baseline serum samples of serum estradiol, progesterone, follicular stimulating hormone(FSH), luteinizing hormone, AMH, and inhibin B.
The primary outcomes were associations of these markers (continuous and dichotomized) with IDFS and distant relapse-free survival with prognosis and prediction of chemotherapy benefit, based on Cox regression analysis.
Of the six markers analyzed, only AMH showed an association with chemotherapy benefits. “AMH is more stable and reliable during the menstrual cycle” compared to other hormones such as FSH and estradiol. Also, AMH levels ≥ 10 pg/mL are considered a standard cutoff to define normal ovarian reserve, Dr. Kalinsky said in his presentation.
A total of 209 patients (21%) had low AMH (less than 10 pg/mL) and were considered postmenopausal, and 806 (79%) were considered premenopausal, with AMH levels of 10 pg/mL or higher.
Chemotherapy plus ET was significantly more beneficial than ET alone in the premenopausal patients with AMH levels ≥ 10 pg/mL (hazard ratio 0.48), Dr. Kalinsky said. By contrast, no chemotherapy benefit was seen in the patients deemed postmenopausal, with low AMH levels (HR 1.21).
In the patients with AMH of 10 pg/mL or higher, the absolute 5-year IDFS benefit of chemotherapy was 7.8%, compared to no notable difference for those with low AMH levels.
Similarly, 5-year DRFS with chemotherapy in patients with AMH of 10 pg/mL or higher was 4.4% (HR 0.41), with no benefit for those with low AMH (HR 1.50).
The findings were limited by the post hoc design and lack of longitudinal data, Dr. Kalinsky said.
During the question-and-answer session, Dr. Kalinsky said that he hoped the data could be incorporated into a clinical model “to further refine patients who need chemotherapy or don’t.” The results suggest that the reproductive hormone AMH can be used to identify premenopausal women with HR+/HER2- invasive breast cancer and intermediate risk based on oncotype scores who would likely benefit from chemotherapy, while those with lower AMH who could forgo it, Dr. Kalinsky concluded.
AMH May Ultimately Inform Chemotherapy Choices
The findings are “thoughtful and intriguing” and may inform which patients benefit from adjuvant chemotherapy and which may not, said Lisa A. Carey, MD, of Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, who served as discussant for the abstract.
Dr. Carey noted as a caveat that AMH is not currently recommended by the American College of Obstetricians and Gynecologists for menopause prediction. However, AMH is “a very credible biomarker of ovarian reserve,” she said in her presentation.
As for clinical implications, the lack of chemotherapy benefit in patients with low AMH at baseline suggests that at least part of the benefits of chemotherapy come from ovarian suppression, Dr. Carey said.
Current assessments of menopausal status are often crude, she noted, and AMH may be helpful when menopausal status is clinically unclear.
Dr. Carey agreed the findings were limited by the post hoc design, and longitudinal data are needed. However, the clinical implications are real if the results are validated, she said, and longitudinal data will be explored in the currently enrolling NRG BR009 OFSET trial.
Clinical Challenges of Menopausal Status
Since the original RxPONDER showed a benefit of chemotherapy for premenopausal women, but not for postmenopausal women with the same low recurrence score, the medical oncology community has worked to determine how much of the benefit seen was related to the ovarian suppression associated with chemotherapy, Megan Kruse, MD, of the Cleveland Clinic, said in an interview.
“Determining a woman’s menopausal status can be challenging in the clinic, as many women have had hysterectomy but have intact ovaries or may have significantly irregular periods, which can lead to confusion about the best endocrine therapy to recommend and how to categorize risk when it comes to Oncotype DX testing,” said Dr. Kruse. She was not involved in the RxPONDER study, but commented on the study in a podcast for ASCO Daily News in advance of the ASCO meeting.
“I was surprised that only AMH showed an association with chemotherapy benefit, as we often obtain estradiol/FSH levels in clinic to try to help with the menopausal assessment,” Dr. Kruse said in an interview. However, in clinical practice, the data may help discuss systemic therapy in patients who are near clinical menopause and trying to decide whether the potential added benefit of chemotherapy is worth the associated toxicity, she said.
“My hope is that new data allow for a more informed, individualized decision-making process,” she added.
Potential barriers to incorporate AMH into chemotherapy decisions in clinical practice include the need for insurance coverage for AMH levels, Dr. Kruse said in an interview. “The [AMH] levels also can be dynamic, so checking one point in time and making such a significant clinical decision based on one level is also a bit concerning,” she said.
Looking ahead, Dr. Kruse emphasized the need to complete the NRG BR-009 OFSET trial. That trial is designed to answer the question of whether adjuvant chemotherapy added to ovarian suppression (OS) plus ET is superior to OS plus ET for premenopausal women with early stage high-risk node negative or 1-3 lymph nodes positive breast cancer with an RS score of 25 or lower, she said.
“This extra analysis of the RxPONDER trial helps to further understand how premenopausal women may best benefit from adjuvant treatments,” Malinda T. West, MD, of the University of Wisconsin, Madison, said in an interview. The new study is important because it shows the ability of serum AMH to help predict ovarian reserve and imminent menopause, said Dr. West, who was not involved in the study.
In clinical practice, the study provides further insight into how premenopausal women may benefit from added chemotherapy and the role of ovarian suppression, Dr. West said.
The study was supported by the Breast Cancer Research Foundation, the National Institutes of Health/National Institute of General Medical Sciences/National Cancer Institute, Exact Sciences Corporation (previously Genomic Health), and the Hope Foundation for Cancer Research.
Dr. Kalinsky disclosed that immediate family members are employed by EQRx and GRAIL, with stock or other ownership interests in these companies. He disclosed consulting or advisory roles with 4D Pharma, AstraZeneca, Cullinan Oncology, Daiichi Sankyo/AstraZeneca, eFFECTOR Therapeutics, Genentech/Roche, Immunomedics, Lilly, Menarini Silicon Biosystems, Merck, Mersana, Myovant Sciences, Novartis, Oncosec, Prelude Therapeutics, Puma Biotechnology, RayzeBio, Seagen, and Takeda. Dr. Kalinsky further disclosed research funding to his institution from Ascentage Pharma, AstraZeneca, Daiichi Sankyo, Genentech/Roche, Lilly, Novartis, and Seagen, and relationships with Genentech and Immunomedics.
Dr. Carey disclosed research funding to her institution from AstraZeneca, Genentech/Roche, Gilead Sciences, Lilly, NanoString Technologies, Novartis, Seagen, and Veracyte. She disclosed an uncompensated relationship with Seagen, and uncompensated relationships between her institution and Genentech/Roche, GlaxoSmithKline, Lilly, and Novartis.
Dr. Kruse disclosed consulting or advisory roles with Novartis Oncology, Puma Biotechnology, Immunomedics, Eisai, Seattle Genetics, and Lilly.
Dr. West had no financial conflicts to disclose.
The new findings also show that women with low baseline anti-Müllerian hormone (AMH) of less than 10 pg/mL do not benefit from chemotherapy. In fact, AMH levels were a better predictor of chemotherapy benefit than self-reported premenopausal status, age, and other hormone levels.
“We may be overtreating some of our patients” with invasive breast cancer and low AMH levels, Kevin Kalinsky, MD, of the Winship Cancer Institute of Emory University, Atlanta, said in a presentation at the annual meeting of the American Society of Clinical Oncology (ASCO).
The potential implication of the study is that clinicians may be able to stop giving chemotherapy to a subset of breast cancer patients who will not benefit from it, he said in the presentation.
New Analysis Singles Out AMH Levels
In a new analysis of data from the RxPONDER trial, Dr. Kalinsky shared data from 1,016 patients who were younger than 55 years of age and self-reported as premenopausal.
The original RxPONDER trial (also known as SWOG S1007) was a randomized, phase 3 trial designed to evaluate the benefit of endocrine therapy (ET) alone vs. ET plus chemotherapy in patients with hormone receptor positive and human epidermal growth factor receptor 2 negative (HR+/HER2-) invasive breast cancer and low recurrence scores (25 or less with genomic testing by Oncotype DX), Dr. Kalinsky said in his presentation.
The researchers found no improvement in invasive disease-free survival (IDFS) with the addition of chemotherapy to ET overall, but significant IDFS improvement occurred with added chemotherapy to ET in the subgroup of self-reported premenopausal women (hazard ratio 0.60).
To better identify the impact of menopausal status on patients who would benefit or not benefit from chemotherapy in the new analysis, the researchers assessed baseline serum samples of serum estradiol, progesterone, follicular stimulating hormone(FSH), luteinizing hormone, AMH, and inhibin B.
The primary outcomes were associations of these markers (continuous and dichotomized) with IDFS and distant relapse-free survival with prognosis and prediction of chemotherapy benefit, based on Cox regression analysis.
Of the six markers analyzed, only AMH showed an association with chemotherapy benefits. “AMH is more stable and reliable during the menstrual cycle” compared to other hormones such as FSH and estradiol. Also, AMH levels ≥ 10 pg/mL are considered a standard cutoff to define normal ovarian reserve, Dr. Kalinsky said in his presentation.
A total of 209 patients (21%) had low AMH (less than 10 pg/mL) and were considered postmenopausal, and 806 (79%) were considered premenopausal, with AMH levels of 10 pg/mL or higher.
Chemotherapy plus ET was significantly more beneficial than ET alone in the premenopausal patients with AMH levels ≥ 10 pg/mL (hazard ratio 0.48), Dr. Kalinsky said. By contrast, no chemotherapy benefit was seen in the patients deemed postmenopausal, with low AMH levels (HR 1.21).
In the patients with AMH of 10 pg/mL or higher, the absolute 5-year IDFS benefit of chemotherapy was 7.8%, compared to no notable difference for those with low AMH levels.
Similarly, 5-year DRFS with chemotherapy in patients with AMH of 10 pg/mL or higher was 4.4% (HR 0.41), with no benefit for those with low AMH (HR 1.50).
The findings were limited by the post hoc design and lack of longitudinal data, Dr. Kalinsky said.
During the question-and-answer session, Dr. Kalinsky said that he hoped the data could be incorporated into a clinical model “to further refine patients who need chemotherapy or don’t.” The results suggest that the reproductive hormone AMH can be used to identify premenopausal women with HR+/HER2- invasive breast cancer and intermediate risk based on oncotype scores who would likely benefit from chemotherapy, while those with lower AMH who could forgo it, Dr. Kalinsky concluded.
AMH May Ultimately Inform Chemotherapy Choices
The findings are “thoughtful and intriguing” and may inform which patients benefit from adjuvant chemotherapy and which may not, said Lisa A. Carey, MD, of Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, who served as discussant for the abstract.
Dr. Carey noted as a caveat that AMH is not currently recommended by the American College of Obstetricians and Gynecologists for menopause prediction. However, AMH is “a very credible biomarker of ovarian reserve,” she said in her presentation.
As for clinical implications, the lack of chemotherapy benefit in patients with low AMH at baseline suggests that at least part of the benefits of chemotherapy come from ovarian suppression, Dr. Carey said.
Current assessments of menopausal status are often crude, she noted, and AMH may be helpful when menopausal status is clinically unclear.
Dr. Carey agreed the findings were limited by the post hoc design, and longitudinal data are needed. However, the clinical implications are real if the results are validated, she said, and longitudinal data will be explored in the currently enrolling NRG BR009 OFSET trial.
Clinical Challenges of Menopausal Status
Since the original RxPONDER showed a benefit of chemotherapy for premenopausal women, but not for postmenopausal women with the same low recurrence score, the medical oncology community has worked to determine how much of the benefit seen was related to the ovarian suppression associated with chemotherapy, Megan Kruse, MD, of the Cleveland Clinic, said in an interview.
“Determining a woman’s menopausal status can be challenging in the clinic, as many women have had hysterectomy but have intact ovaries or may have significantly irregular periods, which can lead to confusion about the best endocrine therapy to recommend and how to categorize risk when it comes to Oncotype DX testing,” said Dr. Kruse. She was not involved in the RxPONDER study, but commented on the study in a podcast for ASCO Daily News in advance of the ASCO meeting.
“I was surprised that only AMH showed an association with chemotherapy benefit, as we often obtain estradiol/FSH levels in clinic to try to help with the menopausal assessment,” Dr. Kruse said in an interview. However, in clinical practice, the data may help discuss systemic therapy in patients who are near clinical menopause and trying to decide whether the potential added benefit of chemotherapy is worth the associated toxicity, she said.
“My hope is that new data allow for a more informed, individualized decision-making process,” she added.
Potential barriers to incorporate AMH into chemotherapy decisions in clinical practice include the need for insurance coverage for AMH levels, Dr. Kruse said in an interview. “The [AMH] levels also can be dynamic, so checking one point in time and making such a significant clinical decision based on one level is also a bit concerning,” she said.
Looking ahead, Dr. Kruse emphasized the need to complete the NRG BR-009 OFSET trial. That trial is designed to answer the question of whether adjuvant chemotherapy added to ovarian suppression (OS) plus ET is superior to OS plus ET for premenopausal women with early stage high-risk node negative or 1-3 lymph nodes positive breast cancer with an RS score of 25 or lower, she said.
“This extra analysis of the RxPONDER trial helps to further understand how premenopausal women may best benefit from adjuvant treatments,” Malinda T. West, MD, of the University of Wisconsin, Madison, said in an interview. The new study is important because it shows the ability of serum AMH to help predict ovarian reserve and imminent menopause, said Dr. West, who was not involved in the study.
In clinical practice, the study provides further insight into how premenopausal women may benefit from added chemotherapy and the role of ovarian suppression, Dr. West said.
The study was supported by the Breast Cancer Research Foundation, the National Institutes of Health/National Institute of General Medical Sciences/National Cancer Institute, Exact Sciences Corporation (previously Genomic Health), and the Hope Foundation for Cancer Research.
Dr. Kalinsky disclosed that immediate family members are employed by EQRx and GRAIL, with stock or other ownership interests in these companies. He disclosed consulting or advisory roles with 4D Pharma, AstraZeneca, Cullinan Oncology, Daiichi Sankyo/AstraZeneca, eFFECTOR Therapeutics, Genentech/Roche, Immunomedics, Lilly, Menarini Silicon Biosystems, Merck, Mersana, Myovant Sciences, Novartis, Oncosec, Prelude Therapeutics, Puma Biotechnology, RayzeBio, Seagen, and Takeda. Dr. Kalinsky further disclosed research funding to his institution from Ascentage Pharma, AstraZeneca, Daiichi Sankyo, Genentech/Roche, Lilly, Novartis, and Seagen, and relationships with Genentech and Immunomedics.
Dr. Carey disclosed research funding to her institution from AstraZeneca, Genentech/Roche, Gilead Sciences, Lilly, NanoString Technologies, Novartis, Seagen, and Veracyte. She disclosed an uncompensated relationship with Seagen, and uncompensated relationships between her institution and Genentech/Roche, GlaxoSmithKline, Lilly, and Novartis.
Dr. Kruse disclosed consulting or advisory roles with Novartis Oncology, Puma Biotechnology, Immunomedics, Eisai, Seattle Genetics, and Lilly.
Dr. West had no financial conflicts to disclose.
The new findings also show that women with low baseline anti-Müllerian hormone (AMH) of less than 10 pg/mL do not benefit from chemotherapy. In fact, AMH levels were a better predictor of chemotherapy benefit than self-reported premenopausal status, age, and other hormone levels.
“We may be overtreating some of our patients” with invasive breast cancer and low AMH levels, Kevin Kalinsky, MD, of the Winship Cancer Institute of Emory University, Atlanta, said in a presentation at the annual meeting of the American Society of Clinical Oncology (ASCO).
The potential implication of the study is that clinicians may be able to stop giving chemotherapy to a subset of breast cancer patients who will not benefit from it, he said in the presentation.
New Analysis Singles Out AMH Levels
In a new analysis of data from the RxPONDER trial, Dr. Kalinsky shared data from 1,016 patients who were younger than 55 years of age and self-reported as premenopausal.
The original RxPONDER trial (also known as SWOG S1007) was a randomized, phase 3 trial designed to evaluate the benefit of endocrine therapy (ET) alone vs. ET plus chemotherapy in patients with hormone receptor positive and human epidermal growth factor receptor 2 negative (HR+/HER2-) invasive breast cancer and low recurrence scores (25 or less with genomic testing by Oncotype DX), Dr. Kalinsky said in his presentation.
The researchers found no improvement in invasive disease-free survival (IDFS) with the addition of chemotherapy to ET overall, but significant IDFS improvement occurred with added chemotherapy to ET in the subgroup of self-reported premenopausal women (hazard ratio 0.60).
To better identify the impact of menopausal status on patients who would benefit or not benefit from chemotherapy in the new analysis, the researchers assessed baseline serum samples of serum estradiol, progesterone, follicular stimulating hormone(FSH), luteinizing hormone, AMH, and inhibin B.
The primary outcomes were associations of these markers (continuous and dichotomized) with IDFS and distant relapse-free survival with prognosis and prediction of chemotherapy benefit, based on Cox regression analysis.
Of the six markers analyzed, only AMH showed an association with chemotherapy benefits. “AMH is more stable and reliable during the menstrual cycle” compared to other hormones such as FSH and estradiol. Also, AMH levels ≥ 10 pg/mL are considered a standard cutoff to define normal ovarian reserve, Dr. Kalinsky said in his presentation.
A total of 209 patients (21%) had low AMH (less than 10 pg/mL) and were considered postmenopausal, and 806 (79%) were considered premenopausal, with AMH levels of 10 pg/mL or higher.
Chemotherapy plus ET was significantly more beneficial than ET alone in the premenopausal patients with AMH levels ≥ 10 pg/mL (hazard ratio 0.48), Dr. Kalinsky said. By contrast, no chemotherapy benefit was seen in the patients deemed postmenopausal, with low AMH levels (HR 1.21).
In the patients with AMH of 10 pg/mL or higher, the absolute 5-year IDFS benefit of chemotherapy was 7.8%, compared to no notable difference for those with low AMH levels.
Similarly, 5-year DRFS with chemotherapy in patients with AMH of 10 pg/mL or higher was 4.4% (HR 0.41), with no benefit for those with low AMH (HR 1.50).
The findings were limited by the post hoc design and lack of longitudinal data, Dr. Kalinsky said.
During the question-and-answer session, Dr. Kalinsky said that he hoped the data could be incorporated into a clinical model “to further refine patients who need chemotherapy or don’t.” The results suggest that the reproductive hormone AMH can be used to identify premenopausal women with HR+/HER2- invasive breast cancer and intermediate risk based on oncotype scores who would likely benefit from chemotherapy, while those with lower AMH who could forgo it, Dr. Kalinsky concluded.
AMH May Ultimately Inform Chemotherapy Choices
The findings are “thoughtful and intriguing” and may inform which patients benefit from adjuvant chemotherapy and which may not, said Lisa A. Carey, MD, of Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, who served as discussant for the abstract.
Dr. Carey noted as a caveat that AMH is not currently recommended by the American College of Obstetricians and Gynecologists for menopause prediction. However, AMH is “a very credible biomarker of ovarian reserve,” she said in her presentation.
As for clinical implications, the lack of chemotherapy benefit in patients with low AMH at baseline suggests that at least part of the benefits of chemotherapy come from ovarian suppression, Dr. Carey said.
Current assessments of menopausal status are often crude, she noted, and AMH may be helpful when menopausal status is clinically unclear.
Dr. Carey agreed the findings were limited by the post hoc design, and longitudinal data are needed. However, the clinical implications are real if the results are validated, she said, and longitudinal data will be explored in the currently enrolling NRG BR009 OFSET trial.
Clinical Challenges of Menopausal Status
Since the original RxPONDER showed a benefit of chemotherapy for premenopausal women, but not for postmenopausal women with the same low recurrence score, the medical oncology community has worked to determine how much of the benefit seen was related to the ovarian suppression associated with chemotherapy, Megan Kruse, MD, of the Cleveland Clinic, said in an interview.
“Determining a woman’s menopausal status can be challenging in the clinic, as many women have had hysterectomy but have intact ovaries or may have significantly irregular periods, which can lead to confusion about the best endocrine therapy to recommend and how to categorize risk when it comes to Oncotype DX testing,” said Dr. Kruse. She was not involved in the RxPONDER study, but commented on the study in a podcast for ASCO Daily News in advance of the ASCO meeting.
“I was surprised that only AMH showed an association with chemotherapy benefit, as we often obtain estradiol/FSH levels in clinic to try to help with the menopausal assessment,” Dr. Kruse said in an interview. However, in clinical practice, the data may help discuss systemic therapy in patients who are near clinical menopause and trying to decide whether the potential added benefit of chemotherapy is worth the associated toxicity, she said.
“My hope is that new data allow for a more informed, individualized decision-making process,” she added.
Potential barriers to incorporate AMH into chemotherapy decisions in clinical practice include the need for insurance coverage for AMH levels, Dr. Kruse said in an interview. “The [AMH] levels also can be dynamic, so checking one point in time and making such a significant clinical decision based on one level is also a bit concerning,” she said.
Looking ahead, Dr. Kruse emphasized the need to complete the NRG BR-009 OFSET trial. That trial is designed to answer the question of whether adjuvant chemotherapy added to ovarian suppression (OS) plus ET is superior to OS plus ET for premenopausal women with early stage high-risk node negative or 1-3 lymph nodes positive breast cancer with an RS score of 25 or lower, she said.
“This extra analysis of the RxPONDER trial helps to further understand how premenopausal women may best benefit from adjuvant treatments,” Malinda T. West, MD, of the University of Wisconsin, Madison, said in an interview. The new study is important because it shows the ability of serum AMH to help predict ovarian reserve and imminent menopause, said Dr. West, who was not involved in the study.
In clinical practice, the study provides further insight into how premenopausal women may benefit from added chemotherapy and the role of ovarian suppression, Dr. West said.
The study was supported by the Breast Cancer Research Foundation, the National Institutes of Health/National Institute of General Medical Sciences/National Cancer Institute, Exact Sciences Corporation (previously Genomic Health), and the Hope Foundation for Cancer Research.
Dr. Kalinsky disclosed that immediate family members are employed by EQRx and GRAIL, with stock or other ownership interests in these companies. He disclosed consulting or advisory roles with 4D Pharma, AstraZeneca, Cullinan Oncology, Daiichi Sankyo/AstraZeneca, eFFECTOR Therapeutics, Genentech/Roche, Immunomedics, Lilly, Menarini Silicon Biosystems, Merck, Mersana, Myovant Sciences, Novartis, Oncosec, Prelude Therapeutics, Puma Biotechnology, RayzeBio, Seagen, and Takeda. Dr. Kalinsky further disclosed research funding to his institution from Ascentage Pharma, AstraZeneca, Daiichi Sankyo, Genentech/Roche, Lilly, Novartis, and Seagen, and relationships with Genentech and Immunomedics.
Dr. Carey disclosed research funding to her institution from AstraZeneca, Genentech/Roche, Gilead Sciences, Lilly, NanoString Technologies, Novartis, Seagen, and Veracyte. She disclosed an uncompensated relationship with Seagen, and uncompensated relationships between her institution and Genentech/Roche, GlaxoSmithKline, Lilly, and Novartis.
Dr. Kruse disclosed consulting or advisory roles with Novartis Oncology, Puma Biotechnology, Immunomedics, Eisai, Seattle Genetics, and Lilly.
Dr. West had no financial conflicts to disclose.
FROM ASCO 2024
Should ER-Low Breast Cancer Patients Be Offered Endocrine Therapy?
For women with early-stage estrogen-receptor positive breast cancer, adjuvant endocrine therapy is known to decrease the likelihood of recurrence and improve survival, while omitting the therapy is associated with a higher risk of death.
For that reason, current guidelines, including those from the National Comprehensive Cancer Network, recommend adjuvant endocrine therapy (AET) for patients with estrogen-receptor positive (ER+) breast cancers.
But these and other guidelines do not make recommendations for a class of tumors deemed estrogen receptor low positive, often referred to as “ER-low,” a category in which ER is seen expressed in between 1% and 10% of cells. This is because benefits of endocrine therapy have not been demonstrated in patients with ER-low disease.
The findings showed that omitting endocrine therapy after surgery and chemotherapy was associated with a 25% higher chance of death within 3 years in ER-low patients.
Endocrine therapy, the investigators say, should therefore be offered to all patients with ER-low cancers, at least until it can be determined which subgroups are most likely to benefit.
How Was the Study Conducted?
Grace M. Choong, MD, of the Mayo Clinic in Rochester, Minnesota, and her colleagues, looked at 2018-2020 data from the National Cancer Database for more than 350,000 female patients with stages 1-3, ER+ breast cancer. From among these they identified about 7000 patients with ER-low cancers who had undergone adjuvant or neoadjuvant chemotherapy.
“We specifically wanted to focus on those treated with chemotherapy as these patients have a higher risk of recurrence in our short interval follow-up,” Dr. Choong said during her presentation.
Patients’ median age was 55 years, and three-quarters of them were White. Their tumors were more likely to be HER2-negative (65%), PR-negative (73%), have higher Ki-67 expression, and have a higher clinical stage (73% grade III).
Forty-two percent of patients did not undergo AET as part of their treatment regimen, with various tumor factors seen associated with AET omission. At a median 3 years of follow-up, 586 patients had died. After the researchers controlled for age, comorbidities, year of diagnosis, tumor factors, and pathologic stage, the effect of omitting AET still resulted in significantly worse survival: (HR 1.25, 95% CI: 1.05-1.48, P = .01).
Mortality was driven by patients with residual disease after neoadjuvant chemotherapy, who comprised nearly half the study cohort. In these patients, omission of endocrine therapy was associated with a 27% higher risk of death (HR 1.27, 1.10-1.58). However, for those with a complete pathological response following chemotherapy, omission of endocrine therapy was not associated with a higher risk of death (HR 1.06; 0.62-1.80).
The investigators noted several limitations of their study, including a retrospective design and no information available on recurrence or the duration of endocrine therapy.
Why Is Endocrine Therapy So Frequently Omitted in This Patient Group?
Matthew P. Goetz, MD, of the Mayo Clinic, the study’s corresponding author, said in an interview that in Sweden, for example, ER-low patients are explicitly not offered endocrine therapy based on Swedish guidelines.
In other settings, he said, it is unclear what is happening.
“Are patients refusing it? Do physicians not even offer it because they think there is no value? We do not have that granular detail, but our data right now suggests a physician should be having this conversation with patients,” he said.
Which ER-Low Patients Are Likely To Benefit?
The findings apply mostly to patients with residual disease after chemotherapy, and underlying biological factors are likely the reason, Dr. Goetz said.
ER-low patients are a heterogeneous group, he explained.
“In genomic profiling, where we look at the underlying biology of these cancers, most of the ER-low cancers are considered the basal subtype of triple negative breast cancer. Those patients should have absolutely zero benefit from endocrine therapy. But there is another group, referred to as the luminal group, which comprises anywhere from 20% to 30% of the ER-low patients.”
Dr. Goetz said he expects to find that this latter group are the patients benefiting from endocrine therapy when they have residual disease.
“We are not yet at the point of saying to patients, ‘you have residual disease after chemotherapy. Let’s check your tumor to see if it is the basal or luminal subtype.’ But that is something that we are planning to look into. What is most important right now is that clinicians be aware of these data, and that there is a suggestion that omitting endocrine therapy may have detrimental effects on survival in this subgroup of patients.”
Are the Findings Compelling Enough To Change Clinical Practice Right Away?
In an interview about the findings, Eric Winer, MD, of the Yale Cancer Center in New Haven, Connecticut, cautioned that due to the retrospective study design, “we don’t know how doctors made decisions about who got endocrine therapy and who didn’t.”
The patients with the worst tumors tended not to get endocrine therapy, Dr. Winer noted, and despite attempts to adjust for this, “in any large data set like this, unlike in a randomized trial, you just can’t control for all the bias.”
What Should Doctors Tell Patients?
“In the setting of significant side effects from endocrine therapy, we’re still less certain about the benefits of endocrine therapy here than in somebody with an ER-high tumor,” Dr. Winer cautioned.
Nonetheless, he said, the new findings certainly suggest that there may be a benefit for endocrine therapy in patients with ER-low tumors, and doctors should make this known to patients. “It may not be the strongest evidence, but it’s evidence,” he said. “This is very much a question to be raised between the doctor and the patient.”
Dr. Choong and colleagues’ study was funded by a Mayo Clinic Breast Cancer SPORE grant. Dr. Goetz reported consulting fees and research support from pharmaceutical manufacturers, including AstraZeneca, Pfizer, Lilly, and Novartis. Dr. Choong and Dr. Winer reported no financial conflicts of interest.
For women with early-stage estrogen-receptor positive breast cancer, adjuvant endocrine therapy is known to decrease the likelihood of recurrence and improve survival, while omitting the therapy is associated with a higher risk of death.
For that reason, current guidelines, including those from the National Comprehensive Cancer Network, recommend adjuvant endocrine therapy (AET) for patients with estrogen-receptor positive (ER+) breast cancers.
But these and other guidelines do not make recommendations for a class of tumors deemed estrogen receptor low positive, often referred to as “ER-low,” a category in which ER is seen expressed in between 1% and 10% of cells. This is because benefits of endocrine therapy have not been demonstrated in patients with ER-low disease.
The findings showed that omitting endocrine therapy after surgery and chemotherapy was associated with a 25% higher chance of death within 3 years in ER-low patients.
Endocrine therapy, the investigators say, should therefore be offered to all patients with ER-low cancers, at least until it can be determined which subgroups are most likely to benefit.
How Was the Study Conducted?
Grace M. Choong, MD, of the Mayo Clinic in Rochester, Minnesota, and her colleagues, looked at 2018-2020 data from the National Cancer Database for more than 350,000 female patients with stages 1-3, ER+ breast cancer. From among these they identified about 7000 patients with ER-low cancers who had undergone adjuvant or neoadjuvant chemotherapy.
“We specifically wanted to focus on those treated with chemotherapy as these patients have a higher risk of recurrence in our short interval follow-up,” Dr. Choong said during her presentation.
Patients’ median age was 55 years, and three-quarters of them were White. Their tumors were more likely to be HER2-negative (65%), PR-negative (73%), have higher Ki-67 expression, and have a higher clinical stage (73% grade III).
Forty-two percent of patients did not undergo AET as part of their treatment regimen, with various tumor factors seen associated with AET omission. At a median 3 years of follow-up, 586 patients had died. After the researchers controlled for age, comorbidities, year of diagnosis, tumor factors, and pathologic stage, the effect of omitting AET still resulted in significantly worse survival: (HR 1.25, 95% CI: 1.05-1.48, P = .01).
Mortality was driven by patients with residual disease after neoadjuvant chemotherapy, who comprised nearly half the study cohort. In these patients, omission of endocrine therapy was associated with a 27% higher risk of death (HR 1.27, 1.10-1.58). However, for those with a complete pathological response following chemotherapy, omission of endocrine therapy was not associated with a higher risk of death (HR 1.06; 0.62-1.80).
The investigators noted several limitations of their study, including a retrospective design and no information available on recurrence or the duration of endocrine therapy.
Why Is Endocrine Therapy So Frequently Omitted in This Patient Group?
Matthew P. Goetz, MD, of the Mayo Clinic, the study’s corresponding author, said in an interview that in Sweden, for example, ER-low patients are explicitly not offered endocrine therapy based on Swedish guidelines.
In other settings, he said, it is unclear what is happening.
“Are patients refusing it? Do physicians not even offer it because they think there is no value? We do not have that granular detail, but our data right now suggests a physician should be having this conversation with patients,” he said.
Which ER-Low Patients Are Likely To Benefit?
The findings apply mostly to patients with residual disease after chemotherapy, and underlying biological factors are likely the reason, Dr. Goetz said.
ER-low patients are a heterogeneous group, he explained.
“In genomic profiling, where we look at the underlying biology of these cancers, most of the ER-low cancers are considered the basal subtype of triple negative breast cancer. Those patients should have absolutely zero benefit from endocrine therapy. But there is another group, referred to as the luminal group, which comprises anywhere from 20% to 30% of the ER-low patients.”
Dr. Goetz said he expects to find that this latter group are the patients benefiting from endocrine therapy when they have residual disease.
“We are not yet at the point of saying to patients, ‘you have residual disease after chemotherapy. Let’s check your tumor to see if it is the basal or luminal subtype.’ But that is something that we are planning to look into. What is most important right now is that clinicians be aware of these data, and that there is a suggestion that omitting endocrine therapy may have detrimental effects on survival in this subgroup of patients.”
Are the Findings Compelling Enough To Change Clinical Practice Right Away?
In an interview about the findings, Eric Winer, MD, of the Yale Cancer Center in New Haven, Connecticut, cautioned that due to the retrospective study design, “we don’t know how doctors made decisions about who got endocrine therapy and who didn’t.”
The patients with the worst tumors tended not to get endocrine therapy, Dr. Winer noted, and despite attempts to adjust for this, “in any large data set like this, unlike in a randomized trial, you just can’t control for all the bias.”
What Should Doctors Tell Patients?
“In the setting of significant side effects from endocrine therapy, we’re still less certain about the benefits of endocrine therapy here than in somebody with an ER-high tumor,” Dr. Winer cautioned.
Nonetheless, he said, the new findings certainly suggest that there may be a benefit for endocrine therapy in patients with ER-low tumors, and doctors should make this known to patients. “It may not be the strongest evidence, but it’s evidence,” he said. “This is very much a question to be raised between the doctor and the patient.”
Dr. Choong and colleagues’ study was funded by a Mayo Clinic Breast Cancer SPORE grant. Dr. Goetz reported consulting fees and research support from pharmaceutical manufacturers, including AstraZeneca, Pfizer, Lilly, and Novartis. Dr. Choong and Dr. Winer reported no financial conflicts of interest.
For women with early-stage estrogen-receptor positive breast cancer, adjuvant endocrine therapy is known to decrease the likelihood of recurrence and improve survival, while omitting the therapy is associated with a higher risk of death.
For that reason, current guidelines, including those from the National Comprehensive Cancer Network, recommend adjuvant endocrine therapy (AET) for patients with estrogen-receptor positive (ER+) breast cancers.
But these and other guidelines do not make recommendations for a class of tumors deemed estrogen receptor low positive, often referred to as “ER-low,” a category in which ER is seen expressed in between 1% and 10% of cells. This is because benefits of endocrine therapy have not been demonstrated in patients with ER-low disease.
The findings showed that omitting endocrine therapy after surgery and chemotherapy was associated with a 25% higher chance of death within 3 years in ER-low patients.
Endocrine therapy, the investigators say, should therefore be offered to all patients with ER-low cancers, at least until it can be determined which subgroups are most likely to benefit.
How Was the Study Conducted?
Grace M. Choong, MD, of the Mayo Clinic in Rochester, Minnesota, and her colleagues, looked at 2018-2020 data from the National Cancer Database for more than 350,000 female patients with stages 1-3, ER+ breast cancer. From among these they identified about 7000 patients with ER-low cancers who had undergone adjuvant or neoadjuvant chemotherapy.
“We specifically wanted to focus on those treated with chemotherapy as these patients have a higher risk of recurrence in our short interval follow-up,” Dr. Choong said during her presentation.
Patients’ median age was 55 years, and three-quarters of them were White. Their tumors were more likely to be HER2-negative (65%), PR-negative (73%), have higher Ki-67 expression, and have a higher clinical stage (73% grade III).
Forty-two percent of patients did not undergo AET as part of their treatment regimen, with various tumor factors seen associated with AET omission. At a median 3 years of follow-up, 586 patients had died. After the researchers controlled for age, comorbidities, year of diagnosis, tumor factors, and pathologic stage, the effect of omitting AET still resulted in significantly worse survival: (HR 1.25, 95% CI: 1.05-1.48, P = .01).
Mortality was driven by patients with residual disease after neoadjuvant chemotherapy, who comprised nearly half the study cohort. In these patients, omission of endocrine therapy was associated with a 27% higher risk of death (HR 1.27, 1.10-1.58). However, for those with a complete pathological response following chemotherapy, omission of endocrine therapy was not associated with a higher risk of death (HR 1.06; 0.62-1.80).
The investigators noted several limitations of their study, including a retrospective design and no information available on recurrence or the duration of endocrine therapy.
Why Is Endocrine Therapy So Frequently Omitted in This Patient Group?
Matthew P. Goetz, MD, of the Mayo Clinic, the study’s corresponding author, said in an interview that in Sweden, for example, ER-low patients are explicitly not offered endocrine therapy based on Swedish guidelines.
In other settings, he said, it is unclear what is happening.
“Are patients refusing it? Do physicians not even offer it because they think there is no value? We do not have that granular detail, but our data right now suggests a physician should be having this conversation with patients,” he said.
Which ER-Low Patients Are Likely To Benefit?
The findings apply mostly to patients with residual disease after chemotherapy, and underlying biological factors are likely the reason, Dr. Goetz said.
ER-low patients are a heterogeneous group, he explained.
“In genomic profiling, where we look at the underlying biology of these cancers, most of the ER-low cancers are considered the basal subtype of triple negative breast cancer. Those patients should have absolutely zero benefit from endocrine therapy. But there is another group, referred to as the luminal group, which comprises anywhere from 20% to 30% of the ER-low patients.”
Dr. Goetz said he expects to find that this latter group are the patients benefiting from endocrine therapy when they have residual disease.
“We are not yet at the point of saying to patients, ‘you have residual disease after chemotherapy. Let’s check your tumor to see if it is the basal or luminal subtype.’ But that is something that we are planning to look into. What is most important right now is that clinicians be aware of these data, and that there is a suggestion that omitting endocrine therapy may have detrimental effects on survival in this subgroup of patients.”
Are the Findings Compelling Enough To Change Clinical Practice Right Away?
In an interview about the findings, Eric Winer, MD, of the Yale Cancer Center in New Haven, Connecticut, cautioned that due to the retrospective study design, “we don’t know how doctors made decisions about who got endocrine therapy and who didn’t.”
The patients with the worst tumors tended not to get endocrine therapy, Dr. Winer noted, and despite attempts to adjust for this, “in any large data set like this, unlike in a randomized trial, you just can’t control for all the bias.”
What Should Doctors Tell Patients?
“In the setting of significant side effects from endocrine therapy, we’re still less certain about the benefits of endocrine therapy here than in somebody with an ER-high tumor,” Dr. Winer cautioned.
Nonetheless, he said, the new findings certainly suggest that there may be a benefit for endocrine therapy in patients with ER-low tumors, and doctors should make this known to patients. “It may not be the strongest evidence, but it’s evidence,” he said. “This is very much a question to be raised between the doctor and the patient.”
Dr. Choong and colleagues’ study was funded by a Mayo Clinic Breast Cancer SPORE grant. Dr. Goetz reported consulting fees and research support from pharmaceutical manufacturers, including AstraZeneca, Pfizer, Lilly, and Novartis. Dr. Choong and Dr. Winer reported no financial conflicts of interest.
FROM ASCO 2024
Abemaciclib Plus Fulvestrant Improves Survival in Advanced Breast Cancer
Disease progression is common in these patients, for whom first-line treatment is cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors plus endocrine therapy, Kevin Kalinsky, MD, of the Winship Cancer Institute of Emory University, Atlanta, said in a presentation at the American Society of Clinical Oncology (ASCO) annual meeting.
A need exists for additional targeted therapies for patients with advanced hormone receptor (HR)+, HER2- breast cancer whose tumors have progressed on endocrine therapy plus a CDK4/6 inhibitor, he said.
Data on the benefits of continuing CDK4/6 inhibitor therapy after progression have been mixed in phase 2 trials, Dr. Kalinsky noted in his presentation. Abemaciclib, an oral CDK4/6 inhibitor, has shown more selectivity for CDK 4 than CDK 6, and is approved in combination with fulvestrant or an aromatase inhibitor for advanced breast cancer, he said.
In a phase 3 study known as postMONARCH, the researchers randomized 182 patients to abemaciclib plus fulvestrant and 186 to placebo plus fulvestrant. The primary endpoint was progression-free survival (PFS) based on investigator assessment; secondary endpoints included PFS based on blinded independent central review (BICR), objective response rate (ORR), and safety.
The PFS rates at 6 months were 50% and 37% for the abemaciclib and placebo arms, respectively.
In the primary analysis, abemaciclib led to a 27% reduction in risk of investigator-assessed progression-free survival events compared with the placebo (117 vs. 141 events, hazard ratio 0.73, P = 0.02).
The study population included men and pre- and postmenopausal women with advanced HR+, HER2- breast cancer and progression after initial CDK4/6 plus endocrine therapy from 96 centers in 16 countries, enrolled between March 2022 and June 2023. The median age of the patients in the abemaciclib and placebo groups was 58 years and 61 years, respectively. Patients underwent scans every 8 weeks for the first 12 months, then every 12 weeks. Most of the patients were enrolled immediately after CDK4/6i + ET as initial therapy for advanced breast cancer. The most common previous CDK4/6 inhibitor therapy was palbociclib (59%), followed by ribociclib (33%) and abemaciclib (8%).
Secondary Endpoints Also Favor Abemaciclib
The effects in favor of abemaciclib were consistent across subgroups, regardless of the presence or absence of baseline genetic mutations (ESR1 or PIK3CA), Dr. Kalinsky said in his presentation.
Overall response rate was significantly improved in the abemaciclib group compared with the placebo group in patients with measurable disease (17% vs. 7%) and PFS according to BICR also significantly improved (HR 0.55).
The magnitude of benefit was less in the subgroup of patients with visceral metastases, Dr. Kalinsky noted.
“Safety was consistent with what is known about the abemaciclib profile,” he added. Six percent of abemaciclib patients discontinued treatment because of adverse events.
The study is the first phase 3 trial to show improvement with CDK4/6 inhibition therapy with a combination of abemaciclib and fulvestrant and offers a new option for patients with HR+, HER2- advanced breast cancer not selected for biomarker status, Dr. Kalinsky concluded.
Data Support Switching CDK Inhibitors in Absence of Mutations
Switching CDK inhibitors to abemaciclib plus endocrine therapy significantly prolonged progression-free survival compared with endocrine therapy alone, with especially pronounced improvement in those without visceral metastases and those with longer durations of first-line CKD4/6 inhibitor therapy, said Ruth O’Regan, MD, of the University of Rochester, New York, who served as the discussant for the new research.
Dr. Regan referenced the improvement with abemaciclib in the BICR, a technique used to identify potential bias introduced by the assessment of local investigators. This can result in more favorable PFS on a treatment arm as seen in this study, but its use generally does not impact overall trial results, she said.
In the context of other studies involving switching CDK 4/6 inhibitors post-progression, the difference of 0.7 months in PFS between the abemaciclib and placebo groups was less than the 2.5 months difference seen in the MAINTAIN trial and the 1.3 months difference seen in the PALMIRA trial, Dr. O’Regan said in her presentation. Conversely, in the PACE trial, the intervention group did worse (4.6 months) than the control group in terms of the PFS (4.8 months), she said. Overall, the results of the postMONARCH trial support the use abemaciclib in patients with no actionable genetic mutation, she said.
In a question-and-answer session, Dr. Kalinsky was asked whether clinicians should still bother with genetic testing, since patients in the current study showed benefits regardless of the presence or absence of a mutation.
“I would still recommend that we check for mutations,” he emphasized. The current study “is one chapter in a much larger book,” and the field continues to evolve, he said.
A Clinician’s Take
“Currently, no standard second-line treatment after progression on first line CDK4/6 inhibitor plus endocrine therapy exists,” Malinda T. West, MD, of the University of Wisconsin, Madison, said in an interview. “Using a different CDK4/6 inhibitor after progression on a first CDK4/6 inhibitor has mixed data,” she said.
“If benefit with a second CDK4/6 inhibitor is confirmed, it may represent an additional low toxicity, chemotherapy-sparing regimen,” she noted.
Earlier data from the MAINTAIN trial had shown benefit with using ribociclib after progression on a primarily first line palbociclib, though other trials looking at use of palbociclib after progression on CDK 4/6 inhibitor [including the PACE and PALMIRA trials] had not, she said.
Overall, the results from postMONARCH support that switching the CDK4/6 inhibitor at progression to ribociclib or abemaciclib may be another treatment option, and reasonable for patients who don’t have other actionable mutations, Dr. West told this news organization.
The study was supported by Eli Lilly. Dr. Kalinsky disclosed that immediate family members are employed by EQRx and GRAIL, with stock or other ownership interests in these companies. He disclosed consulting or advisory roles with 4D Pharma; AstraZeneca; Cullinan Oncology; Daiichi Sankyo/AstraZeneca; eFFECTOR Therapeutics; Genentech/Roche; Immunomedics; Lilly; Menarini Silicon Biosystems; Merck; Mersana; Myovant Sciences; Novartis; Oncosec; Prelude Therapeutics; Puma Biotechnology; RayzeBio; Seagen; and Takeda. Dr. Kalinsky further disclosed research funding to his institution from Ascentage Pharma; AstraZeneca; Daiichi Sankyo; Genentech/Roche; Lilly; Novartis; and Seagen, and relationships with Genentech and Immunomedics.
Dr. O’Regan disclosed honoraria from AstraZeneca/MedImmune; bioTheranostics; Gilead Sciences; Novartis; Pfizer; Puma Biotechnology; and Seagen, serving as a consultant or adviser for AstraZeneca/MedImmune; bioTheranostics; Lilly; Novartis; Puma Biotechnology; and Seagen, and funding to her institution from Novartis and Puma Biotechnology.
Dr. West, who was not involved in the new research or other studies mentioned in this article, had no financial conflicts to disclose.
Disease progression is common in these patients, for whom first-line treatment is cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors plus endocrine therapy, Kevin Kalinsky, MD, of the Winship Cancer Institute of Emory University, Atlanta, said in a presentation at the American Society of Clinical Oncology (ASCO) annual meeting.
A need exists for additional targeted therapies for patients with advanced hormone receptor (HR)+, HER2- breast cancer whose tumors have progressed on endocrine therapy plus a CDK4/6 inhibitor, he said.
Data on the benefits of continuing CDK4/6 inhibitor therapy after progression have been mixed in phase 2 trials, Dr. Kalinsky noted in his presentation. Abemaciclib, an oral CDK4/6 inhibitor, has shown more selectivity for CDK 4 than CDK 6, and is approved in combination with fulvestrant or an aromatase inhibitor for advanced breast cancer, he said.
In a phase 3 study known as postMONARCH, the researchers randomized 182 patients to abemaciclib plus fulvestrant and 186 to placebo plus fulvestrant. The primary endpoint was progression-free survival (PFS) based on investigator assessment; secondary endpoints included PFS based on blinded independent central review (BICR), objective response rate (ORR), and safety.
The PFS rates at 6 months were 50% and 37% for the abemaciclib and placebo arms, respectively.
In the primary analysis, abemaciclib led to a 27% reduction in risk of investigator-assessed progression-free survival events compared with the placebo (117 vs. 141 events, hazard ratio 0.73, P = 0.02).
The study population included men and pre- and postmenopausal women with advanced HR+, HER2- breast cancer and progression after initial CDK4/6 plus endocrine therapy from 96 centers in 16 countries, enrolled between March 2022 and June 2023. The median age of the patients in the abemaciclib and placebo groups was 58 years and 61 years, respectively. Patients underwent scans every 8 weeks for the first 12 months, then every 12 weeks. Most of the patients were enrolled immediately after CDK4/6i + ET as initial therapy for advanced breast cancer. The most common previous CDK4/6 inhibitor therapy was palbociclib (59%), followed by ribociclib (33%) and abemaciclib (8%).
Secondary Endpoints Also Favor Abemaciclib
The effects in favor of abemaciclib were consistent across subgroups, regardless of the presence or absence of baseline genetic mutations (ESR1 or PIK3CA), Dr. Kalinsky said in his presentation.
Overall response rate was significantly improved in the abemaciclib group compared with the placebo group in patients with measurable disease (17% vs. 7%) and PFS according to BICR also significantly improved (HR 0.55).
The magnitude of benefit was less in the subgroup of patients with visceral metastases, Dr. Kalinsky noted.
“Safety was consistent with what is known about the abemaciclib profile,” he added. Six percent of abemaciclib patients discontinued treatment because of adverse events.
The study is the first phase 3 trial to show improvement with CDK4/6 inhibition therapy with a combination of abemaciclib and fulvestrant and offers a new option for patients with HR+, HER2- advanced breast cancer not selected for biomarker status, Dr. Kalinsky concluded.
Data Support Switching CDK Inhibitors in Absence of Mutations
Switching CDK inhibitors to abemaciclib plus endocrine therapy significantly prolonged progression-free survival compared with endocrine therapy alone, with especially pronounced improvement in those without visceral metastases and those with longer durations of first-line CKD4/6 inhibitor therapy, said Ruth O’Regan, MD, of the University of Rochester, New York, who served as the discussant for the new research.
Dr. Regan referenced the improvement with abemaciclib in the BICR, a technique used to identify potential bias introduced by the assessment of local investigators. This can result in more favorable PFS on a treatment arm as seen in this study, but its use generally does not impact overall trial results, she said.
In the context of other studies involving switching CDK 4/6 inhibitors post-progression, the difference of 0.7 months in PFS between the abemaciclib and placebo groups was less than the 2.5 months difference seen in the MAINTAIN trial and the 1.3 months difference seen in the PALMIRA trial, Dr. O’Regan said in her presentation. Conversely, in the PACE trial, the intervention group did worse (4.6 months) than the control group in terms of the PFS (4.8 months), she said. Overall, the results of the postMONARCH trial support the use abemaciclib in patients with no actionable genetic mutation, she said.
In a question-and-answer session, Dr. Kalinsky was asked whether clinicians should still bother with genetic testing, since patients in the current study showed benefits regardless of the presence or absence of a mutation.
“I would still recommend that we check for mutations,” he emphasized. The current study “is one chapter in a much larger book,” and the field continues to evolve, he said.
A Clinician’s Take
“Currently, no standard second-line treatment after progression on first line CDK4/6 inhibitor plus endocrine therapy exists,” Malinda T. West, MD, of the University of Wisconsin, Madison, said in an interview. “Using a different CDK4/6 inhibitor after progression on a first CDK4/6 inhibitor has mixed data,” she said.
“If benefit with a second CDK4/6 inhibitor is confirmed, it may represent an additional low toxicity, chemotherapy-sparing regimen,” she noted.
Earlier data from the MAINTAIN trial had shown benefit with using ribociclib after progression on a primarily first line palbociclib, though other trials looking at use of palbociclib after progression on CDK 4/6 inhibitor [including the PACE and PALMIRA trials] had not, she said.
Overall, the results from postMONARCH support that switching the CDK4/6 inhibitor at progression to ribociclib or abemaciclib may be another treatment option, and reasonable for patients who don’t have other actionable mutations, Dr. West told this news organization.
The study was supported by Eli Lilly. Dr. Kalinsky disclosed that immediate family members are employed by EQRx and GRAIL, with stock or other ownership interests in these companies. He disclosed consulting or advisory roles with 4D Pharma; AstraZeneca; Cullinan Oncology; Daiichi Sankyo/AstraZeneca; eFFECTOR Therapeutics; Genentech/Roche; Immunomedics; Lilly; Menarini Silicon Biosystems; Merck; Mersana; Myovant Sciences; Novartis; Oncosec; Prelude Therapeutics; Puma Biotechnology; RayzeBio; Seagen; and Takeda. Dr. Kalinsky further disclosed research funding to his institution from Ascentage Pharma; AstraZeneca; Daiichi Sankyo; Genentech/Roche; Lilly; Novartis; and Seagen, and relationships with Genentech and Immunomedics.
Dr. O’Regan disclosed honoraria from AstraZeneca/MedImmune; bioTheranostics; Gilead Sciences; Novartis; Pfizer; Puma Biotechnology; and Seagen, serving as a consultant or adviser for AstraZeneca/MedImmune; bioTheranostics; Lilly; Novartis; Puma Biotechnology; and Seagen, and funding to her institution from Novartis and Puma Biotechnology.
Dr. West, who was not involved in the new research or other studies mentioned in this article, had no financial conflicts to disclose.
Disease progression is common in these patients, for whom first-line treatment is cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors plus endocrine therapy, Kevin Kalinsky, MD, of the Winship Cancer Institute of Emory University, Atlanta, said in a presentation at the American Society of Clinical Oncology (ASCO) annual meeting.
A need exists for additional targeted therapies for patients with advanced hormone receptor (HR)+, HER2- breast cancer whose tumors have progressed on endocrine therapy plus a CDK4/6 inhibitor, he said.
Data on the benefits of continuing CDK4/6 inhibitor therapy after progression have been mixed in phase 2 trials, Dr. Kalinsky noted in his presentation. Abemaciclib, an oral CDK4/6 inhibitor, has shown more selectivity for CDK 4 than CDK 6, and is approved in combination with fulvestrant or an aromatase inhibitor for advanced breast cancer, he said.
In a phase 3 study known as postMONARCH, the researchers randomized 182 patients to abemaciclib plus fulvestrant and 186 to placebo plus fulvestrant. The primary endpoint was progression-free survival (PFS) based on investigator assessment; secondary endpoints included PFS based on blinded independent central review (BICR), objective response rate (ORR), and safety.
The PFS rates at 6 months were 50% and 37% for the abemaciclib and placebo arms, respectively.
In the primary analysis, abemaciclib led to a 27% reduction in risk of investigator-assessed progression-free survival events compared with the placebo (117 vs. 141 events, hazard ratio 0.73, P = 0.02).
The study population included men and pre- and postmenopausal women with advanced HR+, HER2- breast cancer and progression after initial CDK4/6 plus endocrine therapy from 96 centers in 16 countries, enrolled between March 2022 and June 2023. The median age of the patients in the abemaciclib and placebo groups was 58 years and 61 years, respectively. Patients underwent scans every 8 weeks for the first 12 months, then every 12 weeks. Most of the patients were enrolled immediately after CDK4/6i + ET as initial therapy for advanced breast cancer. The most common previous CDK4/6 inhibitor therapy was palbociclib (59%), followed by ribociclib (33%) and abemaciclib (8%).
Secondary Endpoints Also Favor Abemaciclib
The effects in favor of abemaciclib were consistent across subgroups, regardless of the presence or absence of baseline genetic mutations (ESR1 or PIK3CA), Dr. Kalinsky said in his presentation.
Overall response rate was significantly improved in the abemaciclib group compared with the placebo group in patients with measurable disease (17% vs. 7%) and PFS according to BICR also significantly improved (HR 0.55).
The magnitude of benefit was less in the subgroup of patients with visceral metastases, Dr. Kalinsky noted.
“Safety was consistent with what is known about the abemaciclib profile,” he added. Six percent of abemaciclib patients discontinued treatment because of adverse events.
The study is the first phase 3 trial to show improvement with CDK4/6 inhibition therapy with a combination of abemaciclib and fulvestrant and offers a new option for patients with HR+, HER2- advanced breast cancer not selected for biomarker status, Dr. Kalinsky concluded.
Data Support Switching CDK Inhibitors in Absence of Mutations
Switching CDK inhibitors to abemaciclib plus endocrine therapy significantly prolonged progression-free survival compared with endocrine therapy alone, with especially pronounced improvement in those without visceral metastases and those with longer durations of first-line CKD4/6 inhibitor therapy, said Ruth O’Regan, MD, of the University of Rochester, New York, who served as the discussant for the new research.
Dr. Regan referenced the improvement with abemaciclib in the BICR, a technique used to identify potential bias introduced by the assessment of local investigators. This can result in more favorable PFS on a treatment arm as seen in this study, but its use generally does not impact overall trial results, she said.
In the context of other studies involving switching CDK 4/6 inhibitors post-progression, the difference of 0.7 months in PFS between the abemaciclib and placebo groups was less than the 2.5 months difference seen in the MAINTAIN trial and the 1.3 months difference seen in the PALMIRA trial, Dr. O’Regan said in her presentation. Conversely, in the PACE trial, the intervention group did worse (4.6 months) than the control group in terms of the PFS (4.8 months), she said. Overall, the results of the postMONARCH trial support the use abemaciclib in patients with no actionable genetic mutation, she said.
In a question-and-answer session, Dr. Kalinsky was asked whether clinicians should still bother with genetic testing, since patients in the current study showed benefits regardless of the presence or absence of a mutation.
“I would still recommend that we check for mutations,” he emphasized. The current study “is one chapter in a much larger book,” and the field continues to evolve, he said.
A Clinician’s Take
“Currently, no standard second-line treatment after progression on first line CDK4/6 inhibitor plus endocrine therapy exists,” Malinda T. West, MD, of the University of Wisconsin, Madison, said in an interview. “Using a different CDK4/6 inhibitor after progression on a first CDK4/6 inhibitor has mixed data,” she said.
“If benefit with a second CDK4/6 inhibitor is confirmed, it may represent an additional low toxicity, chemotherapy-sparing regimen,” she noted.
Earlier data from the MAINTAIN trial had shown benefit with using ribociclib after progression on a primarily first line palbociclib, though other trials looking at use of palbociclib after progression on CDK 4/6 inhibitor [including the PACE and PALMIRA trials] had not, she said.
Overall, the results from postMONARCH support that switching the CDK4/6 inhibitor at progression to ribociclib or abemaciclib may be another treatment option, and reasonable for patients who don’t have other actionable mutations, Dr. West told this news organization.
The study was supported by Eli Lilly. Dr. Kalinsky disclosed that immediate family members are employed by EQRx and GRAIL, with stock or other ownership interests in these companies. He disclosed consulting or advisory roles with 4D Pharma; AstraZeneca; Cullinan Oncology; Daiichi Sankyo/AstraZeneca; eFFECTOR Therapeutics; Genentech/Roche; Immunomedics; Lilly; Menarini Silicon Biosystems; Merck; Mersana; Myovant Sciences; Novartis; Oncosec; Prelude Therapeutics; Puma Biotechnology; RayzeBio; Seagen; and Takeda. Dr. Kalinsky further disclosed research funding to his institution from Ascentage Pharma; AstraZeneca; Daiichi Sankyo; Genentech/Roche; Lilly; Novartis; and Seagen, and relationships with Genentech and Immunomedics.
Dr. O’Regan disclosed honoraria from AstraZeneca/MedImmune; bioTheranostics; Gilead Sciences; Novartis; Pfizer; Puma Biotechnology; and Seagen, serving as a consultant or adviser for AstraZeneca/MedImmune; bioTheranostics; Lilly; Novartis; Puma Biotechnology; and Seagen, and funding to her institution from Novartis and Puma Biotechnology.
Dr. West, who was not involved in the new research or other studies mentioned in this article, had no financial conflicts to disclose.
FROM ASCO 2024
Bariatric Surgery May Reduce Breast Cancer Risk for Some
TOPLINE:
.
METHODOLOGY:
- Previous research suggests that bariatric surgery is associated with a lower risk for cancer in people with obesity, as well as female-specific cancers in women with obesity, especially those with higher baseline insulin levels. But there is a need for large prospective studies with more detailed patient information.
- The current secondary analysis included 2867 matched women (mean age, 48 years) from a prospective nonrandomized Swedish trial, which recruited men and women who had obesity between 1987 and 2001.
- Overall, 1420 women underwent bariatric surgery, and 1447 received usual care.
- Median baseline insulin levels were 15.8 μIU/L. In the surgery group, 68.3% of patients had vertical banded gastroplasty, 18.3% underwent gastric banding, and 13.4% underwent gastric bypass.
- The main outcome was breast cancer incidence, as identified from Swedish National Cancer Registry.
TAKEAWAY:
- Over a median follow-up of 23.9 years, 66 breast cancer events occurred in the surgery group and 88 in the usual care group (P = .02).
- Bariatric surgery was associated with a 33% lower risk for breast cancer (adjusted hazard ratio [aHR], 0.67), after excluding cases that occurred within the first 3 years (to account for any undiagnosed breast cancer at baseline) and adjusting for age, body mass index, alcohol, and smoking status.
- Looking at the menopausal status at baseline, bariatric surgery was associated with a reduced risk for breast cancer in premenopausal women (aHR, 0.64) but not postmenopausal women (aHR, 0.84; 95% CI, 0.49-1.45; P = .54).
- Bariatric surgery was also associated with a lower risk for breast cancer in women with baseline insulin levels above the median (aHR, 0.55) than in those with baseline insulin levels below the median (aHR, 1.01).
IN PRACTICE:
“The surgical treatment benefit was predominantly seen in women with hyperinsulinemia, suggesting insulin may be used as a predictor of treatment effect,” the authors wrote. Authors of an accompanying editorial, however, cautioned that “it is not known if insulin levels or insulin resistance are true biomarkers of breast cancer risk in patients with obesity undergoing bariatric surgery” and urged further research into underlying biological mechanisms.
SOURCE:
This study, led by Felipe M. Kristensson, MD, from Institute of Medicine, Department of Molecular and Clinical Medicine, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden, was published online in JAMA Surgery. The accompanying editorial was led by Swati A. Kulkarni, MD, of the Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago.
LIMITATIONS:
The study was not randomized. Breast cancer was not a predefined outcome of the main trial. Most patients underwent vertical banded gastroplasty, which is rarely used and could limit applicability of the results; however, vertical banded gastroplasty results in weight loss similar to that observed after sleeve gastrectomy. Follow-up values for insulin and insulin resistance were not available. The researchers noted significant differences in 12 out of 17 baseline characteristics between the two groups, including a larger proportion of postmenopausal women in the usual care group.
DISCLOSURES:
This study was supported by the Swedish state, Swedish Research Council, the Health & Medical Care Committee of the Region Västra Götaland, and the Adlerbert Research Foundation. The authors did not report any conflicts of interest.
A version of this article appeared on Medscape.com.
TOPLINE:
.
METHODOLOGY:
- Previous research suggests that bariatric surgery is associated with a lower risk for cancer in people with obesity, as well as female-specific cancers in women with obesity, especially those with higher baseline insulin levels. But there is a need for large prospective studies with more detailed patient information.
- The current secondary analysis included 2867 matched women (mean age, 48 years) from a prospective nonrandomized Swedish trial, which recruited men and women who had obesity between 1987 and 2001.
- Overall, 1420 women underwent bariatric surgery, and 1447 received usual care.
- Median baseline insulin levels were 15.8 μIU/L. In the surgery group, 68.3% of patients had vertical banded gastroplasty, 18.3% underwent gastric banding, and 13.4% underwent gastric bypass.
- The main outcome was breast cancer incidence, as identified from Swedish National Cancer Registry.
TAKEAWAY:
- Over a median follow-up of 23.9 years, 66 breast cancer events occurred in the surgery group and 88 in the usual care group (P = .02).
- Bariatric surgery was associated with a 33% lower risk for breast cancer (adjusted hazard ratio [aHR], 0.67), after excluding cases that occurred within the first 3 years (to account for any undiagnosed breast cancer at baseline) and adjusting for age, body mass index, alcohol, and smoking status.
- Looking at the menopausal status at baseline, bariatric surgery was associated with a reduced risk for breast cancer in premenopausal women (aHR, 0.64) but not postmenopausal women (aHR, 0.84; 95% CI, 0.49-1.45; P = .54).
- Bariatric surgery was also associated with a lower risk for breast cancer in women with baseline insulin levels above the median (aHR, 0.55) than in those with baseline insulin levels below the median (aHR, 1.01).
IN PRACTICE:
“The surgical treatment benefit was predominantly seen in women with hyperinsulinemia, suggesting insulin may be used as a predictor of treatment effect,” the authors wrote. Authors of an accompanying editorial, however, cautioned that “it is not known if insulin levels or insulin resistance are true biomarkers of breast cancer risk in patients with obesity undergoing bariatric surgery” and urged further research into underlying biological mechanisms.
SOURCE:
This study, led by Felipe M. Kristensson, MD, from Institute of Medicine, Department of Molecular and Clinical Medicine, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden, was published online in JAMA Surgery. The accompanying editorial was led by Swati A. Kulkarni, MD, of the Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago.
LIMITATIONS:
The study was not randomized. Breast cancer was not a predefined outcome of the main trial. Most patients underwent vertical banded gastroplasty, which is rarely used and could limit applicability of the results; however, vertical banded gastroplasty results in weight loss similar to that observed after sleeve gastrectomy. Follow-up values for insulin and insulin resistance were not available. The researchers noted significant differences in 12 out of 17 baseline characteristics between the two groups, including a larger proportion of postmenopausal women in the usual care group.
DISCLOSURES:
This study was supported by the Swedish state, Swedish Research Council, the Health & Medical Care Committee of the Region Västra Götaland, and the Adlerbert Research Foundation. The authors did not report any conflicts of interest.
A version of this article appeared on Medscape.com.
TOPLINE:
.
METHODOLOGY:
- Previous research suggests that bariatric surgery is associated with a lower risk for cancer in people with obesity, as well as female-specific cancers in women with obesity, especially those with higher baseline insulin levels. But there is a need for large prospective studies with more detailed patient information.
- The current secondary analysis included 2867 matched women (mean age, 48 years) from a prospective nonrandomized Swedish trial, which recruited men and women who had obesity between 1987 and 2001.
- Overall, 1420 women underwent bariatric surgery, and 1447 received usual care.
- Median baseline insulin levels were 15.8 μIU/L. In the surgery group, 68.3% of patients had vertical banded gastroplasty, 18.3% underwent gastric banding, and 13.4% underwent gastric bypass.
- The main outcome was breast cancer incidence, as identified from Swedish National Cancer Registry.
TAKEAWAY:
- Over a median follow-up of 23.9 years, 66 breast cancer events occurred in the surgery group and 88 in the usual care group (P = .02).
- Bariatric surgery was associated with a 33% lower risk for breast cancer (adjusted hazard ratio [aHR], 0.67), after excluding cases that occurred within the first 3 years (to account for any undiagnosed breast cancer at baseline) and adjusting for age, body mass index, alcohol, and smoking status.
- Looking at the menopausal status at baseline, bariatric surgery was associated with a reduced risk for breast cancer in premenopausal women (aHR, 0.64) but not postmenopausal women (aHR, 0.84; 95% CI, 0.49-1.45; P = .54).
- Bariatric surgery was also associated with a lower risk for breast cancer in women with baseline insulin levels above the median (aHR, 0.55) than in those with baseline insulin levels below the median (aHR, 1.01).
IN PRACTICE:
“The surgical treatment benefit was predominantly seen in women with hyperinsulinemia, suggesting insulin may be used as a predictor of treatment effect,” the authors wrote. Authors of an accompanying editorial, however, cautioned that “it is not known if insulin levels or insulin resistance are true biomarkers of breast cancer risk in patients with obesity undergoing bariatric surgery” and urged further research into underlying biological mechanisms.
SOURCE:
This study, led by Felipe M. Kristensson, MD, from Institute of Medicine, Department of Molecular and Clinical Medicine, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden, was published online in JAMA Surgery. The accompanying editorial was led by Swati A. Kulkarni, MD, of the Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago.
LIMITATIONS:
The study was not randomized. Breast cancer was not a predefined outcome of the main trial. Most patients underwent vertical banded gastroplasty, which is rarely used and could limit applicability of the results; however, vertical banded gastroplasty results in weight loss similar to that observed after sleeve gastrectomy. Follow-up values for insulin and insulin resistance were not available. The researchers noted significant differences in 12 out of 17 baseline characteristics between the two groups, including a larger proportion of postmenopausal women in the usual care group.
DISCLOSURES:
This study was supported by the Swedish state, Swedish Research Council, the Health & Medical Care Committee of the Region Västra Götaland, and the Adlerbert Research Foundation. The authors did not report any conflicts of interest.
A version of this article appeared on Medscape.com.
Carefully Designing De-escalation Trials in Breast Cancer
Over the past few years, several new, highly effective treatment strategies have improved survival outcomes in patients with early breast cancer.
“We’ve been very fortunate” to see these advances, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, told attendees at the European Society of Medical Oncology (ESMO) Breast Cancer annual congress.
However, Dr. Tolaney noted, these new treatment approaches can come with big limitations — namely, potential overtreatment of some patients as well as short- and long-term toxicities, some of which can be life-threatening.
These caveats have prompted trials exploring strategies to de-escalate therapy, which essentially means providing the right amount of treatment to the right patient at the right time, said Dr. Tolaney. The goal is to “right-size” or “optimize therapy” to maintain strong outcomes while mitigating side effects.
she explained.
But, she added, de-escalation trials are “not a very attractive strategy to pharmaceutical companies” and can be challenging for researchers to conduct. These trials may, for instance, lack adequate sample sizes and sufficient statistical power, which can interfere with achieving clinically meaningful findings that may affect practice.
That is why carefully designing de-escalation trials is crucial, Dr. Tolaney said.
In her talk at ESMO Breast, Dr. Tolaney highlighted several strategies for designing these trials.
One strategy is to shorten the duration of therapy, said Dr. Tolaney.
This approach was explored in the PHARE and PERSEPHONE trials, which looked at 6 vs 12 months of trastuzumab in nonmetastatic breast cancer. Other trials, such as GeparNuevo and KEYNOTE-522, explored whether adjuvant checkpoint inhibitor therapy was needed, or could be skipped, following neoadjuvant therapy. This approach requires establishing noninferiority, or similar efficacy, between the standard of care and the shorter duration of therapy.
A second strategy is to remove part of the chemotherapy regimen, typically the most toxic agent, Dr. Tolaney continued.
Conducting a prospective, randomized trial exploring this approach in human epidermal growth factor receptor 2–positive (HER2+) early breast cancer, for example, would be difficult for a range of reasons, such as the need to enroll thousands of patients.
Dr. Tolaney and colleagues, however, designed a nonrandomized prospective study — the APT trial — with just over 400 patients to assess adjuvant paclitaxel plus trastuzumab in patients with node-negative HER2+ disease. The open-label, single-arm, phase 2 APT trial found that adjuvant paclitaxel and trastuzumab led to a 10-year recurrence-free interval of 96.3%, 10-year overall survival of 94.3%, and 10-year breast cancer–specific survival of 98.8%.
Outcomes with this adjuvant regimen were comparable to previous findings in historical controls who received doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab or docetaxel, carboplatin, and trastuzumab.
Dr. Tolaney concluded that given few events, “it’s unlikely we need to escalate therapy to do better for most patients,” and the APT regimen “can be considered a reasonable and appealing approach for the majority of patients” with node-negative HER2+ breast cancer.
“A single-arm design for a de-escalation study can be practice-changing but only if there are very few recurrences,” Dr. Tolaney said.
Substituting chemotherapy with a targeted, potentially less-toxic agent is a third de-escalation approach. The ATEMPT trial compared patients receiving trastuzumab emtansine (T-DM1) with those receiving paclitaxel plus trastuzumab followed by maintenance trastuzumab.
Investigators found that de-escalation with T-DM1 was associated with very few recurrences but similar rates of certain adverse events, including grade 2 or higher neurotoxicity, febrile neutropenia, and grade 4 or higher hematologic toxicity.
However, there are questions about how to define “less toxic,” Dr. Tolaney said. The trial found, for instance, that T-DM1 did have some advantages — patients reported better quality of life and experienced less alopecia and neurotoxicity, as well as a less severe impact on fertility.
Understanding the right endpoint to demonstrate less toxicity is critical, “as we start to think about how to replace standard chemotherapies with better targeted drugs,” she added.
The ATEMPT 2.0 trial, which is currently enrolling, will aim to answer some of these questions about defining and demonstrating less toxicity, she said.
Finally, some researchers are attempting to omit chemotherapy altogether with the help of biomarkers. The TAILORx trial, for instance, aimed to stratify patients with early-stage breast cancer by clinical risk factors combined with a 21-gene expression assay and found that adjuvant chemotherapy was not necessary in a large proportion of these women.
On the biomarker front, oncologists might be able to use ctDNA to guide decision-making and personalize therapy, Tolaney said. The presence of ctDNA is associated with an almost 100% likelihood of having a recurrence, whereas its absence suggests better outcomes, she explained.
Oncologists could use the presence or absence of ctDNA to guide next steps — assign patients to follow-up assessments when ctDNA is not present or to standard or experimental treatment when it is present. It may also be possible to leverage the presence of minimal residual disease to help direct treatment choices.
But ctDNA is currently not as perfect a predictor of outcome as it could be, she cautioned. “We need more sensitive assays [so] I’m not sure we’re quite ready to use lack of ctDNA to de-escalate treatment,” she said.
Dr. Tolaney declared relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, and other companies.
A version of this article appeared on Medscape.com .
Over the past few years, several new, highly effective treatment strategies have improved survival outcomes in patients with early breast cancer.
“We’ve been very fortunate” to see these advances, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, told attendees at the European Society of Medical Oncology (ESMO) Breast Cancer annual congress.
However, Dr. Tolaney noted, these new treatment approaches can come with big limitations — namely, potential overtreatment of some patients as well as short- and long-term toxicities, some of which can be life-threatening.
These caveats have prompted trials exploring strategies to de-escalate therapy, which essentially means providing the right amount of treatment to the right patient at the right time, said Dr. Tolaney. The goal is to “right-size” or “optimize therapy” to maintain strong outcomes while mitigating side effects.
she explained.
But, she added, de-escalation trials are “not a very attractive strategy to pharmaceutical companies” and can be challenging for researchers to conduct. These trials may, for instance, lack adequate sample sizes and sufficient statistical power, which can interfere with achieving clinically meaningful findings that may affect practice.
That is why carefully designing de-escalation trials is crucial, Dr. Tolaney said.
In her talk at ESMO Breast, Dr. Tolaney highlighted several strategies for designing these trials.
One strategy is to shorten the duration of therapy, said Dr. Tolaney.
This approach was explored in the PHARE and PERSEPHONE trials, which looked at 6 vs 12 months of trastuzumab in nonmetastatic breast cancer. Other trials, such as GeparNuevo and KEYNOTE-522, explored whether adjuvant checkpoint inhibitor therapy was needed, or could be skipped, following neoadjuvant therapy. This approach requires establishing noninferiority, or similar efficacy, between the standard of care and the shorter duration of therapy.
A second strategy is to remove part of the chemotherapy regimen, typically the most toxic agent, Dr. Tolaney continued.
Conducting a prospective, randomized trial exploring this approach in human epidermal growth factor receptor 2–positive (HER2+) early breast cancer, for example, would be difficult for a range of reasons, such as the need to enroll thousands of patients.
Dr. Tolaney and colleagues, however, designed a nonrandomized prospective study — the APT trial — with just over 400 patients to assess adjuvant paclitaxel plus trastuzumab in patients with node-negative HER2+ disease. The open-label, single-arm, phase 2 APT trial found that adjuvant paclitaxel and trastuzumab led to a 10-year recurrence-free interval of 96.3%, 10-year overall survival of 94.3%, and 10-year breast cancer–specific survival of 98.8%.
Outcomes with this adjuvant regimen were comparable to previous findings in historical controls who received doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab or docetaxel, carboplatin, and trastuzumab.
Dr. Tolaney concluded that given few events, “it’s unlikely we need to escalate therapy to do better for most patients,” and the APT regimen “can be considered a reasonable and appealing approach for the majority of patients” with node-negative HER2+ breast cancer.
“A single-arm design for a de-escalation study can be practice-changing but only if there are very few recurrences,” Dr. Tolaney said.
Substituting chemotherapy with a targeted, potentially less-toxic agent is a third de-escalation approach. The ATEMPT trial compared patients receiving trastuzumab emtansine (T-DM1) with those receiving paclitaxel plus trastuzumab followed by maintenance trastuzumab.
Investigators found that de-escalation with T-DM1 was associated with very few recurrences but similar rates of certain adverse events, including grade 2 or higher neurotoxicity, febrile neutropenia, and grade 4 or higher hematologic toxicity.
However, there are questions about how to define “less toxic,” Dr. Tolaney said. The trial found, for instance, that T-DM1 did have some advantages — patients reported better quality of life and experienced less alopecia and neurotoxicity, as well as a less severe impact on fertility.
Understanding the right endpoint to demonstrate less toxicity is critical, “as we start to think about how to replace standard chemotherapies with better targeted drugs,” she added.
The ATEMPT 2.0 trial, which is currently enrolling, will aim to answer some of these questions about defining and demonstrating less toxicity, she said.
Finally, some researchers are attempting to omit chemotherapy altogether with the help of biomarkers. The TAILORx trial, for instance, aimed to stratify patients with early-stage breast cancer by clinical risk factors combined with a 21-gene expression assay and found that adjuvant chemotherapy was not necessary in a large proportion of these women.
On the biomarker front, oncologists might be able to use ctDNA to guide decision-making and personalize therapy, Tolaney said. The presence of ctDNA is associated with an almost 100% likelihood of having a recurrence, whereas its absence suggests better outcomes, she explained.
Oncologists could use the presence or absence of ctDNA to guide next steps — assign patients to follow-up assessments when ctDNA is not present or to standard or experimental treatment when it is present. It may also be possible to leverage the presence of minimal residual disease to help direct treatment choices.
But ctDNA is currently not as perfect a predictor of outcome as it could be, she cautioned. “We need more sensitive assays [so] I’m not sure we’re quite ready to use lack of ctDNA to de-escalate treatment,” she said.
Dr. Tolaney declared relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, and other companies.
A version of this article appeared on Medscape.com .
Over the past few years, several new, highly effective treatment strategies have improved survival outcomes in patients with early breast cancer.
“We’ve been very fortunate” to see these advances, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, told attendees at the European Society of Medical Oncology (ESMO) Breast Cancer annual congress.
However, Dr. Tolaney noted, these new treatment approaches can come with big limitations — namely, potential overtreatment of some patients as well as short- and long-term toxicities, some of which can be life-threatening.
These caveats have prompted trials exploring strategies to de-escalate therapy, which essentially means providing the right amount of treatment to the right patient at the right time, said Dr. Tolaney. The goal is to “right-size” or “optimize therapy” to maintain strong outcomes while mitigating side effects.
she explained.
But, she added, de-escalation trials are “not a very attractive strategy to pharmaceutical companies” and can be challenging for researchers to conduct. These trials may, for instance, lack adequate sample sizes and sufficient statistical power, which can interfere with achieving clinically meaningful findings that may affect practice.
That is why carefully designing de-escalation trials is crucial, Dr. Tolaney said.
In her talk at ESMO Breast, Dr. Tolaney highlighted several strategies for designing these trials.
One strategy is to shorten the duration of therapy, said Dr. Tolaney.
This approach was explored in the PHARE and PERSEPHONE trials, which looked at 6 vs 12 months of trastuzumab in nonmetastatic breast cancer. Other trials, such as GeparNuevo and KEYNOTE-522, explored whether adjuvant checkpoint inhibitor therapy was needed, or could be skipped, following neoadjuvant therapy. This approach requires establishing noninferiority, or similar efficacy, between the standard of care and the shorter duration of therapy.
A second strategy is to remove part of the chemotherapy regimen, typically the most toxic agent, Dr. Tolaney continued.
Conducting a prospective, randomized trial exploring this approach in human epidermal growth factor receptor 2–positive (HER2+) early breast cancer, for example, would be difficult for a range of reasons, such as the need to enroll thousands of patients.
Dr. Tolaney and colleagues, however, designed a nonrandomized prospective study — the APT trial — with just over 400 patients to assess adjuvant paclitaxel plus trastuzumab in patients with node-negative HER2+ disease. The open-label, single-arm, phase 2 APT trial found that adjuvant paclitaxel and trastuzumab led to a 10-year recurrence-free interval of 96.3%, 10-year overall survival of 94.3%, and 10-year breast cancer–specific survival of 98.8%.
Outcomes with this adjuvant regimen were comparable to previous findings in historical controls who received doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab or docetaxel, carboplatin, and trastuzumab.
Dr. Tolaney concluded that given few events, “it’s unlikely we need to escalate therapy to do better for most patients,” and the APT regimen “can be considered a reasonable and appealing approach for the majority of patients” with node-negative HER2+ breast cancer.
“A single-arm design for a de-escalation study can be practice-changing but only if there are very few recurrences,” Dr. Tolaney said.
Substituting chemotherapy with a targeted, potentially less-toxic agent is a third de-escalation approach. The ATEMPT trial compared patients receiving trastuzumab emtansine (T-DM1) with those receiving paclitaxel plus trastuzumab followed by maintenance trastuzumab.
Investigators found that de-escalation with T-DM1 was associated with very few recurrences but similar rates of certain adverse events, including grade 2 or higher neurotoxicity, febrile neutropenia, and grade 4 or higher hematologic toxicity.
However, there are questions about how to define “less toxic,” Dr. Tolaney said. The trial found, for instance, that T-DM1 did have some advantages — patients reported better quality of life and experienced less alopecia and neurotoxicity, as well as a less severe impact on fertility.
Understanding the right endpoint to demonstrate less toxicity is critical, “as we start to think about how to replace standard chemotherapies with better targeted drugs,” she added.
The ATEMPT 2.0 trial, which is currently enrolling, will aim to answer some of these questions about defining and demonstrating less toxicity, she said.
Finally, some researchers are attempting to omit chemotherapy altogether with the help of biomarkers. The TAILORx trial, for instance, aimed to stratify patients with early-stage breast cancer by clinical risk factors combined with a 21-gene expression assay and found that adjuvant chemotherapy was not necessary in a large proportion of these women.
On the biomarker front, oncologists might be able to use ctDNA to guide decision-making and personalize therapy, Tolaney said. The presence of ctDNA is associated with an almost 100% likelihood of having a recurrence, whereas its absence suggests better outcomes, she explained.
Oncologists could use the presence or absence of ctDNA to guide next steps — assign patients to follow-up assessments when ctDNA is not present or to standard or experimental treatment when it is present. It may also be possible to leverage the presence of minimal residual disease to help direct treatment choices.
But ctDNA is currently not as perfect a predictor of outcome as it could be, she cautioned. “We need more sensitive assays [so] I’m not sure we’re quite ready to use lack of ctDNA to de-escalate treatment,” she said.
Dr. Tolaney declared relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, and other companies.
A version of this article appeared on Medscape.com .
FROM ESMO BREAST CANCER 2024