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WDC: Frequent light activity breaks from prolonged sitting have metabolic benefits
VANCOUVER – Taking frequent 5-minute breaks from prolonged sitting to stand or walk at a leisurely pace improved the metabolic response to a meal in heavy postmenopausal women with dysglycemia in a randomized trial reported at the World Diabetes Congress.
The incremental area under the curve for glucose levels after a meal was 34% lower with standing breaks and 28% lower with light walking breaks, compared with uninterrupted, prolonged sitting. Moreover, these benefits persisted into the next day.
Findings were similar for levels of insulin (20% and 37% reductions in response) and for the suppression of nonesterified fatty acids (33% and 47% reductions in response).
“The results of this trial provide new experimental evidence that simply breaking up sedentary behavior appears to have quite an acute positive effect in overweight or obese women with a high risk of type 2 diabetes, and it may last for at least 24 hours after the initial activity stimulus,” commented first author Joseph Henson, Ph.D., a research associate at the Diabetes Research Centre at the University of Leicester in England.
“This simple behavioral approach could inform future public health interventions aimed at improving the metabolic profile of dysglycemic individuals if we are able to prove this in large numbers and also in men,” he added.
“I think as a proof of principle, this study was fascinating,” commented session comoderator Dr. Robert E. Ratner, professor of medicine at Georgetown University and senior research scientist at the MedStar Health Research Institute, Washington, as well as chief scientific and medical officer of the American Diabetes Association.
However, the uninterrupted sitting condition was not realistic, he noted in an interview. “The bottom line is that none of us are escorted to the lavatory by wheelchairs, so the control situation is somewhat limited. But I think that it points out that all of us need to sit less and move more.”
A session attendee noted that the findings for simple standing and with regard to the persistence of the effects over time were somewhat surprising.
The “difference I would have thought previously would have been driven by energy expenditure. So I would have said individuals would have to get up and move in order to see a difference,” Dr. Henson acknowledged. “But we were noticing that [benefit] even with standing. So maybe there is something happening at the level of the muscle, which is inducing the responses.”
As for the persistence of the metabolic benefit, more research will be needed, he said. In particular, studies should assess exactly how long it lasts.
“I think the main conclusion is, simply put, that you can break sitting time with anything, whether it’s standing or walking, and you are likely to get some sort of effect,” Dr. Henson said. Also, individuals should “try and use a stepped approach, so going from sitting to standing, and from standing to walking. The more you move, the better the health outcomes will be.”
Women were eligible for the trial if they were overweight or obese, postmenopausal, aged 50-75 years, and had impaired glucose tolerance or a glycated hemoglobin level of 5.7%-6.4%. “These characteristics are really important because these are the sorts of individuals who are likely to be identified and referred into relevant diabetes prevention programs,” Dr. Henson commented. In addition, the women had to be sedentary, engaging in less than 150 minutes of regular purposeful activity each week.
They each participated in two of three activities on separate days: unbroken prolonged sitting for 7.5 hours (interrupted only by trips to the restroom by wheelchair); prolonged sitting, broken up with 5-minute bouts of standing every 30 minutes; and prolonged sitting, broken up with 5-minute bouts of light-intensity walking (up to 2.5 mph) on a treadmill every 30 minutes.
Midway through each day, the women were given a high-fat meal. Serial blood samples were collected throughout the day for measurement of cardiometabolic markers.
Study results, reported at the congress and recently published (Diabetes Care. 2015 Dec 1. doi: 10.2337/dc15-1240), showed that the incremental area under the curve was 5.3 mmol/L per hour with unbroken prolonged sitting, but it was lower at 3.5 mmol/L per hour with standing breaks and 3.8 mmol/L per hour with sitting breaks (P less than .05 for each difference vs. sitting).
Respective values were 548.2, 437.2, and 347.9 mU/L per hour for insulin levels (P less than .05 for each difference vs. sitting), and –1.5, –1.0, and –0.8 mmol/L per hour for suppression of nonesterified fatty acid levels (P less than .05 for each difference vs. sitting).
In contrast, neither type of activity break significantly affected the triglyceride response to a meal or altered blood pressure, according to Dr. Henson, who disclosed that he received support for the presentation from the International Diabetes Federation–American Diabetes Association.
VANCOUVER – Taking frequent 5-minute breaks from prolonged sitting to stand or walk at a leisurely pace improved the metabolic response to a meal in heavy postmenopausal women with dysglycemia in a randomized trial reported at the World Diabetes Congress.
The incremental area under the curve for glucose levels after a meal was 34% lower with standing breaks and 28% lower with light walking breaks, compared with uninterrupted, prolonged sitting. Moreover, these benefits persisted into the next day.
Findings were similar for levels of insulin (20% and 37% reductions in response) and for the suppression of nonesterified fatty acids (33% and 47% reductions in response).
“The results of this trial provide new experimental evidence that simply breaking up sedentary behavior appears to have quite an acute positive effect in overweight or obese women with a high risk of type 2 diabetes, and it may last for at least 24 hours after the initial activity stimulus,” commented first author Joseph Henson, Ph.D., a research associate at the Diabetes Research Centre at the University of Leicester in England.
“This simple behavioral approach could inform future public health interventions aimed at improving the metabolic profile of dysglycemic individuals if we are able to prove this in large numbers and also in men,” he added.
“I think as a proof of principle, this study was fascinating,” commented session comoderator Dr. Robert E. Ratner, professor of medicine at Georgetown University and senior research scientist at the MedStar Health Research Institute, Washington, as well as chief scientific and medical officer of the American Diabetes Association.
However, the uninterrupted sitting condition was not realistic, he noted in an interview. “The bottom line is that none of us are escorted to the lavatory by wheelchairs, so the control situation is somewhat limited. But I think that it points out that all of us need to sit less and move more.”
A session attendee noted that the findings for simple standing and with regard to the persistence of the effects over time were somewhat surprising.
The “difference I would have thought previously would have been driven by energy expenditure. So I would have said individuals would have to get up and move in order to see a difference,” Dr. Henson acknowledged. “But we were noticing that [benefit] even with standing. So maybe there is something happening at the level of the muscle, which is inducing the responses.”
As for the persistence of the metabolic benefit, more research will be needed, he said. In particular, studies should assess exactly how long it lasts.
“I think the main conclusion is, simply put, that you can break sitting time with anything, whether it’s standing or walking, and you are likely to get some sort of effect,” Dr. Henson said. Also, individuals should “try and use a stepped approach, so going from sitting to standing, and from standing to walking. The more you move, the better the health outcomes will be.”
Women were eligible for the trial if they were overweight or obese, postmenopausal, aged 50-75 years, and had impaired glucose tolerance or a glycated hemoglobin level of 5.7%-6.4%. “These characteristics are really important because these are the sorts of individuals who are likely to be identified and referred into relevant diabetes prevention programs,” Dr. Henson commented. In addition, the women had to be sedentary, engaging in less than 150 minutes of regular purposeful activity each week.
They each participated in two of three activities on separate days: unbroken prolonged sitting for 7.5 hours (interrupted only by trips to the restroom by wheelchair); prolonged sitting, broken up with 5-minute bouts of standing every 30 minutes; and prolonged sitting, broken up with 5-minute bouts of light-intensity walking (up to 2.5 mph) on a treadmill every 30 minutes.
Midway through each day, the women were given a high-fat meal. Serial blood samples were collected throughout the day for measurement of cardiometabolic markers.
Study results, reported at the congress and recently published (Diabetes Care. 2015 Dec 1. doi: 10.2337/dc15-1240), showed that the incremental area under the curve was 5.3 mmol/L per hour with unbroken prolonged sitting, but it was lower at 3.5 mmol/L per hour with standing breaks and 3.8 mmol/L per hour with sitting breaks (P less than .05 for each difference vs. sitting).
Respective values were 548.2, 437.2, and 347.9 mU/L per hour for insulin levels (P less than .05 for each difference vs. sitting), and –1.5, –1.0, and –0.8 mmol/L per hour for suppression of nonesterified fatty acid levels (P less than .05 for each difference vs. sitting).
In contrast, neither type of activity break significantly affected the triglyceride response to a meal or altered blood pressure, according to Dr. Henson, who disclosed that he received support for the presentation from the International Diabetes Federation–American Diabetes Association.
VANCOUVER – Taking frequent 5-minute breaks from prolonged sitting to stand or walk at a leisurely pace improved the metabolic response to a meal in heavy postmenopausal women with dysglycemia in a randomized trial reported at the World Diabetes Congress.
The incremental area under the curve for glucose levels after a meal was 34% lower with standing breaks and 28% lower with light walking breaks, compared with uninterrupted, prolonged sitting. Moreover, these benefits persisted into the next day.
Findings were similar for levels of insulin (20% and 37% reductions in response) and for the suppression of nonesterified fatty acids (33% and 47% reductions in response).
“The results of this trial provide new experimental evidence that simply breaking up sedentary behavior appears to have quite an acute positive effect in overweight or obese women with a high risk of type 2 diabetes, and it may last for at least 24 hours after the initial activity stimulus,” commented first author Joseph Henson, Ph.D., a research associate at the Diabetes Research Centre at the University of Leicester in England.
“This simple behavioral approach could inform future public health interventions aimed at improving the metabolic profile of dysglycemic individuals if we are able to prove this in large numbers and also in men,” he added.
“I think as a proof of principle, this study was fascinating,” commented session comoderator Dr. Robert E. Ratner, professor of medicine at Georgetown University and senior research scientist at the MedStar Health Research Institute, Washington, as well as chief scientific and medical officer of the American Diabetes Association.
However, the uninterrupted sitting condition was not realistic, he noted in an interview. “The bottom line is that none of us are escorted to the lavatory by wheelchairs, so the control situation is somewhat limited. But I think that it points out that all of us need to sit less and move more.”
A session attendee noted that the findings for simple standing and with regard to the persistence of the effects over time were somewhat surprising.
The “difference I would have thought previously would have been driven by energy expenditure. So I would have said individuals would have to get up and move in order to see a difference,” Dr. Henson acknowledged. “But we were noticing that [benefit] even with standing. So maybe there is something happening at the level of the muscle, which is inducing the responses.”
As for the persistence of the metabolic benefit, more research will be needed, he said. In particular, studies should assess exactly how long it lasts.
“I think the main conclusion is, simply put, that you can break sitting time with anything, whether it’s standing or walking, and you are likely to get some sort of effect,” Dr. Henson said. Also, individuals should “try and use a stepped approach, so going from sitting to standing, and from standing to walking. The more you move, the better the health outcomes will be.”
Women were eligible for the trial if they were overweight or obese, postmenopausal, aged 50-75 years, and had impaired glucose tolerance or a glycated hemoglobin level of 5.7%-6.4%. “These characteristics are really important because these are the sorts of individuals who are likely to be identified and referred into relevant diabetes prevention programs,” Dr. Henson commented. In addition, the women had to be sedentary, engaging in less than 150 minutes of regular purposeful activity each week.
They each participated in two of three activities on separate days: unbroken prolonged sitting for 7.5 hours (interrupted only by trips to the restroom by wheelchair); prolonged sitting, broken up with 5-minute bouts of standing every 30 minutes; and prolonged sitting, broken up with 5-minute bouts of light-intensity walking (up to 2.5 mph) on a treadmill every 30 minutes.
Midway through each day, the women were given a high-fat meal. Serial blood samples were collected throughout the day for measurement of cardiometabolic markers.
Study results, reported at the congress and recently published (Diabetes Care. 2015 Dec 1. doi: 10.2337/dc15-1240), showed that the incremental area under the curve was 5.3 mmol/L per hour with unbroken prolonged sitting, but it was lower at 3.5 mmol/L per hour with standing breaks and 3.8 mmol/L per hour with sitting breaks (P less than .05 for each difference vs. sitting).
Respective values were 548.2, 437.2, and 347.9 mU/L per hour for insulin levels (P less than .05 for each difference vs. sitting), and –1.5, –1.0, and –0.8 mmol/L per hour for suppression of nonesterified fatty acid levels (P less than .05 for each difference vs. sitting).
In contrast, neither type of activity break significantly affected the triglyceride response to a meal or altered blood pressure, according to Dr. Henson, who disclosed that he received support for the presentation from the International Diabetes Federation–American Diabetes Association.
AT THE WORLD DIABETES CONGRESS
Key clinical point: Breaking up prolonged sitting with short bouts of either standing or walking blunts the postprandial metabolic response in women at elevated risk for diabetes.
Major finding: The glucose response after a meal was 34% lower with standing breaks and 28% lower with walking breaks as compared with unbroken prolonged sitting.
Data source: A randomized trial among 30 sedentary, overweight or obese postmenopausal women with dysglycemia.
Disclosures: Dr. Henson disclosed that he received support for the presentation from the International Diabetes Federation–American Diabetes Association.
ESR1 mutations linked with poorer survival from ER-positive breast cancer
SAN ANTONIO – Women with estrogen receptor–positive advanced breast cancer who have common mutations of the estrogen receptor 1 (ESR1) gene detectable in plasma cell–free DNA have poorer overall survival, according to data presented at the San Antonio Breast Cancer Symposium.
Investigators led by Dr. Sarat Chandarlapaty, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York, analyzed archival baseline plasma samples from 541 patients enrolled in the BOLERO-2 trial, which evaluated addition of everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin). They specifically looked for the D538G and Y537S mutations of the ESR1 gene, the two most commonly seen mutations in this setting and ones that lead to activation of the receptor even in the absence of estrogen.
Overall, nearly 29% of the women had either or both mutations, he reported in a session and related press briefing. “We think that is almost certainly an underestimate of the mutation rate, because there will be some other mutations … that we didn’t assay for here,” he commented. Of note, this prevalence using plasma was sharply higher than that found when analysis was instead performed on archival tumor tissue.
Patients with these ESR1 mutations had a 40% higher risk of death than counterparts who did not have them. And those with the D538G mutation (but not those with the Y537S mutation) had better progression-free survival if they were given everolimus.
“Patients with different mutations might end up having different responses to therapies in the future, and I think that’s what we are looking for in future research,” Dr. Chandarlapaty commented.
Press briefing moderator and codirector of the San Antonio Breast Cancer Symposium, Dr. Carlos L. Arteaga, a professor of medicine at Vanderbilt University, Nashville, Tenn., and director of the Breast Cancer Program, noted the high rate of discordance in mutation prevalence between the tumor tissue and the plasma. “Can you speculate about the reasons for that discordance?” he asked.
There are three possible explanations, Dr. Chandarlapaty replied. The archival tumor was often the primary tumor, whereas plasma samples were collected in the metastatic setting. Also, the tumor tissue was often obtained before any aromatase inhibitor therapy, which precipitates a low-estrogen environment that may promote emergence of resistance mutations. Finally, mutations detected in plasma likely reflect a summation of all mutations in the body in different sites. “I think for all these reasons, plasma may have certain advantages, especially for this alteration,” he said.
In the session, attendee Dr. Daniel F. Hayes of the University of Michigan Health System in Ann Arbor wondered whether the plasma samples were treated in any special way before the mutational testing.
“This trial started before we recognized the importance of plasma tumor DNA, so I’m pretty certain these samples were not handled in a way that we all believe they should be. The reason I’m asking this question is that if you did something special, the rest of us would love to know what it is because we are all sitting on samples like this that I’ve been told are worthless, but maybe I’m wrong,” he elaborated.
The plasma samples were collected in a routine manner, without any consideration of future genomic analysis and mutational testing, according to Dr. Chandarlapaty. “These were collected as a regular spin … and frozen at –70 [degrees],” he said. And they were stored that way, in some cases for many years, at various global sites. The investigators simply performed an additional hard spin before analyzing the samples. “So I think it does tell us that some of these archival samples that we have in our freezers may be usable for this type of analysis,” he said.
Attendee Dr. Eric P. Winer of the Dana-Farber Cancer Institute in Boston said, “So on Monday morning, people can’t go home and order circulating tumor DNA in most centers. What studies need to be done and how long do you think it will be before this is something we should consider?”
Efforts are under way to try to rapidly make these assays available in the clinic, according to Dr. Chandarlapaty. “Actually, there are some that are not in the CLIA lab but sort of are available by different vendors,” he said. Additional studies still needed include validation of the observed findings in other cohorts, among others.
BOLERO-2 tested addition of the mTOR inhibitor everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin) in postmenopausal women with metastatic or locally advanced estrogen receptor–positive, HER2-negative breast cancer that had progressed despite treatment with other aromatase inhibitors.
Dr. Chandarlapaty and colleagues detected the D538G mutation in 15.3% of patients, the Y537S mutation in 7.8%, and both in 5.5% patients, for an overall prevalence of 28.8%.
In a subset of cases having both cell-free DNA and archival tumor tissue, the proportion of cases having these mutations was much higher in the former (28.4% vs. 1.3%).
Subgroup analyses showed mutations were more common for patients who had received prior aromatase therapy in the metastatic setting versus only in the adjuvant setting (P for difference less than .001).
In the study sample as a whole, median overall survival was 32.1 months with neither ESR1 mutation, 26.0 months with only the D538G mutation, 20.0 months with only the Y537S mutation, and 15.2 months with both. Compared with patients having neither mutation, patients having either or both had an increased risk of death (hazard ratio, 1.40), as did those having the D538G mutation (1.25), the Y537S mutation (2.31), and both (1.77).
Additionally, exploratory analyses showed that adding everolimus to exemestane more than doubled median progression-free survival for patients with neither mutation (8.5 vs. 3.9 months; hazard ratio, 0.40) and for those with a D538G mutation (5.8 vs. 2.7 months; hazard ratio, 0.34). In contrast and unexpectedly, adding this drug did not improve the outcome for patients with a Y537S mutation.
Numbers of patients in the Y537S group were small, and a clear explanation for lack of benefit in that group is lacking, Dr. Chandarlapaty cautioned. “But it does tell us the biology, and what we need to do going forward in the clinic is look at these mutations not just as a whole, but individually, and ask how do they impact therapies that we are developing going forward,” he said.
SAN ANTONIO – Women with estrogen receptor–positive advanced breast cancer who have common mutations of the estrogen receptor 1 (ESR1) gene detectable in plasma cell–free DNA have poorer overall survival, according to data presented at the San Antonio Breast Cancer Symposium.
Investigators led by Dr. Sarat Chandarlapaty, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York, analyzed archival baseline plasma samples from 541 patients enrolled in the BOLERO-2 trial, which evaluated addition of everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin). They specifically looked for the D538G and Y537S mutations of the ESR1 gene, the two most commonly seen mutations in this setting and ones that lead to activation of the receptor even in the absence of estrogen.
Overall, nearly 29% of the women had either or both mutations, he reported in a session and related press briefing. “We think that is almost certainly an underestimate of the mutation rate, because there will be some other mutations … that we didn’t assay for here,” he commented. Of note, this prevalence using plasma was sharply higher than that found when analysis was instead performed on archival tumor tissue.
Patients with these ESR1 mutations had a 40% higher risk of death than counterparts who did not have them. And those with the D538G mutation (but not those with the Y537S mutation) had better progression-free survival if they were given everolimus.
“Patients with different mutations might end up having different responses to therapies in the future, and I think that’s what we are looking for in future research,” Dr. Chandarlapaty commented.
Press briefing moderator and codirector of the San Antonio Breast Cancer Symposium, Dr. Carlos L. Arteaga, a professor of medicine at Vanderbilt University, Nashville, Tenn., and director of the Breast Cancer Program, noted the high rate of discordance in mutation prevalence between the tumor tissue and the plasma. “Can you speculate about the reasons for that discordance?” he asked.
There are three possible explanations, Dr. Chandarlapaty replied. The archival tumor was often the primary tumor, whereas plasma samples were collected in the metastatic setting. Also, the tumor tissue was often obtained before any aromatase inhibitor therapy, which precipitates a low-estrogen environment that may promote emergence of resistance mutations. Finally, mutations detected in plasma likely reflect a summation of all mutations in the body in different sites. “I think for all these reasons, plasma may have certain advantages, especially for this alteration,” he said.
In the session, attendee Dr. Daniel F. Hayes of the University of Michigan Health System in Ann Arbor wondered whether the plasma samples were treated in any special way before the mutational testing.
“This trial started before we recognized the importance of plasma tumor DNA, so I’m pretty certain these samples were not handled in a way that we all believe they should be. The reason I’m asking this question is that if you did something special, the rest of us would love to know what it is because we are all sitting on samples like this that I’ve been told are worthless, but maybe I’m wrong,” he elaborated.
The plasma samples were collected in a routine manner, without any consideration of future genomic analysis and mutational testing, according to Dr. Chandarlapaty. “These were collected as a regular spin … and frozen at –70 [degrees],” he said. And they were stored that way, in some cases for many years, at various global sites. The investigators simply performed an additional hard spin before analyzing the samples. “So I think it does tell us that some of these archival samples that we have in our freezers may be usable for this type of analysis,” he said.
Attendee Dr. Eric P. Winer of the Dana-Farber Cancer Institute in Boston said, “So on Monday morning, people can’t go home and order circulating tumor DNA in most centers. What studies need to be done and how long do you think it will be before this is something we should consider?”
Efforts are under way to try to rapidly make these assays available in the clinic, according to Dr. Chandarlapaty. “Actually, there are some that are not in the CLIA lab but sort of are available by different vendors,” he said. Additional studies still needed include validation of the observed findings in other cohorts, among others.
BOLERO-2 tested addition of the mTOR inhibitor everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin) in postmenopausal women with metastatic or locally advanced estrogen receptor–positive, HER2-negative breast cancer that had progressed despite treatment with other aromatase inhibitors.
Dr. Chandarlapaty and colleagues detected the D538G mutation in 15.3% of patients, the Y537S mutation in 7.8%, and both in 5.5% patients, for an overall prevalence of 28.8%.
In a subset of cases having both cell-free DNA and archival tumor tissue, the proportion of cases having these mutations was much higher in the former (28.4% vs. 1.3%).
Subgroup analyses showed mutations were more common for patients who had received prior aromatase therapy in the metastatic setting versus only in the adjuvant setting (P for difference less than .001).
In the study sample as a whole, median overall survival was 32.1 months with neither ESR1 mutation, 26.0 months with only the D538G mutation, 20.0 months with only the Y537S mutation, and 15.2 months with both. Compared with patients having neither mutation, patients having either or both had an increased risk of death (hazard ratio, 1.40), as did those having the D538G mutation (1.25), the Y537S mutation (2.31), and both (1.77).
Additionally, exploratory analyses showed that adding everolimus to exemestane more than doubled median progression-free survival for patients with neither mutation (8.5 vs. 3.9 months; hazard ratio, 0.40) and for those with a D538G mutation (5.8 vs. 2.7 months; hazard ratio, 0.34). In contrast and unexpectedly, adding this drug did not improve the outcome for patients with a Y537S mutation.
Numbers of patients in the Y537S group were small, and a clear explanation for lack of benefit in that group is lacking, Dr. Chandarlapaty cautioned. “But it does tell us the biology, and what we need to do going forward in the clinic is look at these mutations not just as a whole, but individually, and ask how do they impact therapies that we are developing going forward,” he said.
SAN ANTONIO – Women with estrogen receptor–positive advanced breast cancer who have common mutations of the estrogen receptor 1 (ESR1) gene detectable in plasma cell–free DNA have poorer overall survival, according to data presented at the San Antonio Breast Cancer Symposium.
Investigators led by Dr. Sarat Chandarlapaty, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York, analyzed archival baseline plasma samples from 541 patients enrolled in the BOLERO-2 trial, which evaluated addition of everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin). They specifically looked for the D538G and Y537S mutations of the ESR1 gene, the two most commonly seen mutations in this setting and ones that lead to activation of the receptor even in the absence of estrogen.
Overall, nearly 29% of the women had either or both mutations, he reported in a session and related press briefing. “We think that is almost certainly an underestimate of the mutation rate, because there will be some other mutations … that we didn’t assay for here,” he commented. Of note, this prevalence using plasma was sharply higher than that found when analysis was instead performed on archival tumor tissue.
Patients with these ESR1 mutations had a 40% higher risk of death than counterparts who did not have them. And those with the D538G mutation (but not those with the Y537S mutation) had better progression-free survival if they were given everolimus.
“Patients with different mutations might end up having different responses to therapies in the future, and I think that’s what we are looking for in future research,” Dr. Chandarlapaty commented.
Press briefing moderator and codirector of the San Antonio Breast Cancer Symposium, Dr. Carlos L. Arteaga, a professor of medicine at Vanderbilt University, Nashville, Tenn., and director of the Breast Cancer Program, noted the high rate of discordance in mutation prevalence between the tumor tissue and the plasma. “Can you speculate about the reasons for that discordance?” he asked.
There are three possible explanations, Dr. Chandarlapaty replied. The archival tumor was often the primary tumor, whereas plasma samples were collected in the metastatic setting. Also, the tumor tissue was often obtained before any aromatase inhibitor therapy, which precipitates a low-estrogen environment that may promote emergence of resistance mutations. Finally, mutations detected in plasma likely reflect a summation of all mutations in the body in different sites. “I think for all these reasons, plasma may have certain advantages, especially for this alteration,” he said.
In the session, attendee Dr. Daniel F. Hayes of the University of Michigan Health System in Ann Arbor wondered whether the plasma samples were treated in any special way before the mutational testing.
“This trial started before we recognized the importance of plasma tumor DNA, so I’m pretty certain these samples were not handled in a way that we all believe they should be. The reason I’m asking this question is that if you did something special, the rest of us would love to know what it is because we are all sitting on samples like this that I’ve been told are worthless, but maybe I’m wrong,” he elaborated.
The plasma samples were collected in a routine manner, without any consideration of future genomic analysis and mutational testing, according to Dr. Chandarlapaty. “These were collected as a regular spin … and frozen at –70 [degrees],” he said. And they were stored that way, in some cases for many years, at various global sites. The investigators simply performed an additional hard spin before analyzing the samples. “So I think it does tell us that some of these archival samples that we have in our freezers may be usable for this type of analysis,” he said.
Attendee Dr. Eric P. Winer of the Dana-Farber Cancer Institute in Boston said, “So on Monday morning, people can’t go home and order circulating tumor DNA in most centers. What studies need to be done and how long do you think it will be before this is something we should consider?”
Efforts are under way to try to rapidly make these assays available in the clinic, according to Dr. Chandarlapaty. “Actually, there are some that are not in the CLIA lab but sort of are available by different vendors,” he said. Additional studies still needed include validation of the observed findings in other cohorts, among others.
BOLERO-2 tested addition of the mTOR inhibitor everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin) in postmenopausal women with metastatic or locally advanced estrogen receptor–positive, HER2-negative breast cancer that had progressed despite treatment with other aromatase inhibitors.
Dr. Chandarlapaty and colleagues detected the D538G mutation in 15.3% of patients, the Y537S mutation in 7.8%, and both in 5.5% patients, for an overall prevalence of 28.8%.
In a subset of cases having both cell-free DNA and archival tumor tissue, the proportion of cases having these mutations was much higher in the former (28.4% vs. 1.3%).
Subgroup analyses showed mutations were more common for patients who had received prior aromatase therapy in the metastatic setting versus only in the adjuvant setting (P for difference less than .001).
In the study sample as a whole, median overall survival was 32.1 months with neither ESR1 mutation, 26.0 months with only the D538G mutation, 20.0 months with only the Y537S mutation, and 15.2 months with both. Compared with patients having neither mutation, patients having either or both had an increased risk of death (hazard ratio, 1.40), as did those having the D538G mutation (1.25), the Y537S mutation (2.31), and both (1.77).
Additionally, exploratory analyses showed that adding everolimus to exemestane more than doubled median progression-free survival for patients with neither mutation (8.5 vs. 3.9 months; hazard ratio, 0.40) and for those with a D538G mutation (5.8 vs. 2.7 months; hazard ratio, 0.34). In contrast and unexpectedly, adding this drug did not improve the outcome for patients with a Y537S mutation.
Numbers of patients in the Y537S group were small, and a clear explanation for lack of benefit in that group is lacking, Dr. Chandarlapaty cautioned. “But it does tell us the biology, and what we need to do going forward in the clinic is look at these mutations not just as a whole, but individually, and ask how do they impact therapies that we are developing going forward,” he said.
AT SABCS 2015
Key clinical point: Women with estrogen receptor–positive advanced breast cancer who have an ESR1 mutation are at increased risk for death.
Major finding: Median overall survival was 32.1 months with neither ESR1 mutation, 26.0 months with only the D538G mutation, 20.0 months with only the Y537S mutation, and 15.2 months with both mutations.
Data source: An exploratory analysis of plasma cell–free DNA from 541 patients in a phase III trial evaluating everolimus plus exemestane (BOLERO-2 trial).
Disclosures: Dr. Chandarlapaty disclosed that he receives consulting fees from Chugai, Foresite Capital, and Oncothyreon, and receives grant support from Novartis. The study was supported by Novartis and the Memorial Sloan Kettering Cancer Center’s Center for Metastasis Research.
New agents effectively target CLL’s molecular Achilles
SAN FRANCISCO – Novel targeted agents offer more options for treating chronic lymphocytic leukemia (CLL), and if properly leveraged, may be able to shorten the time on treatment, improving acceptability to patients and possibly reducing treatment costs, according to Dr. William G. Wierda.
BTK inhibitors
Agents that inhibit Bruton tyrosine kinase (BTK) block signaling through the B-cell receptor in CLL, triggering apoptosis, said Dr. Wierda, professor and medical director, department of leukemia, division of cancer medicine, at the University of Texas MD Anderson Cancer Center in Houston. One such agent, ibrutinib (Imbruvica), is approved by the Food and Drug Administration for treatment of relapsed CLL and for treatment of newly diagnosed CLL having 17p deletion, a high-risk factor.
Results from RESONATE-2, a randomized trial comparing ibrutinib with chlorambucil as frontline therapy in older adults with CLL or small lymphocytic lymphoma, will be reported later this year. “We don’t know the details of that publicly yet, but we do know from a press release that it is a positive trial and showed improvement in outcomes for ibrutinib-treated patients. With that data, we will likely have an expanded label for ibrutinib into the frontline setting, at least for the elderly population,” he said at the NCCN Annual Congress: Hematologic Malignancies.
Longer-term data, collected 3 years after patients started ibrutinib monotherapy, have been very good, with overall response rates of 90% in those with relapsed or refractory disease and 87% in those with treatment-naive disease (ASCO 2014. Abstract 7014). “The last time I saw these data updated, the complete remission portions have increased. So as patients remain on the treatment, responses do improve,” Dr. Wierda noted. Complete remission rates now are about 14% and 24%, respectively. Median progression-free survival has not been reached in either group.
Data from the randomized RESONATE trial, which led to ibrutinib’s approval in relapsed CLL, showed benefit relative to ofatumumab across subgroups, including patients who had disease that was refractory to purine analogs, who had the 17p deletion and who had received at least three prior regimens (ASCO 2014. Abstract LBA7008).
The main grade 3 or 4 toxicity of ibrutinib in patients with CLL is infections, but atrial fibrillation and bleeding/hemorrhage are each seen in about 5% of patients. “The trials all excluded patients on warfarin, so we do not recommend treating patients with ibrutinib who are on warfarin,” Dr. Wierda commented. “If patients are anticoagulated on warfarin and we want to put them on ibrutinib, I will usually switch them over to something like Xarelto [rivaroxaban],” he said. Toxicity generally declines with longer treatment.
Discontinuations because of toxicity or Richter transformation usually occur within the first 18 months (JAMA Oncol. 2015;1[1]:80-7). “The concerning [point] for me though is the patients who develop refractory disease. … The incidence starts to go up significantly as you go out beyond 30 or 36 months,” he said. “We are reviewing our data right now to see if we make a similar observation. But that suggests to me that the longer the patients stay on treatment, the more at risk they are for progressing and developing refractory disease.”
The HELIOS trial tested addition of ibrutinib to bendamustine (Treanda) and rituximab (Rituxan) (ASCO 2015. Abstract LBA7005). Results showed superior progression-free survival with the three-drug combination. “But the question that always comes up when this data is presented is, well, how would it compare with ibrutinib monotherapy? Until that question for me is adequately addressed … I would probably be inclined to give patients ibrutinib monotherapy over the combination,” Dr. Wierda said.
Trials are testing a wide range of other combinations. “To me, this suggests that we really don’t have a direction or a rational strategy for combinations with these agents. … Right now, I’m excited about combining ibrutinib with venetoclax. … They seem clinically complementary, and there is some laboratory data that suggests as well that there will be a complementary mechanism of action.”
PI3 kinase inhibitors
Inhibitors of PI3 kinase also block signaling through the B-cell receptor. In this drug class, idelalisib (Zydelig) is approved for treating relapsed CLL in combination with rituximab.
The phase III trial establishing efficacy of this combination showed that it improved both progression-free and overall survival over rituximab alone (ASH 2014. Abstract 330). Median progression-free survival was 19.4 months. There was similar benefit across various subgroups, including patients with 17p deletion or an unmutated IGHV gene, another high-risk factor.
One of the main toxicities of idelalisib, elevation of liver function test results, typically occurs early and is usually not treatment limiting. Colitis occurs with two predominant patterns: early onset and late onset. “The early colitis in my experience hasn’t necessarily been treatment limiting. We can usually get those patients through their diarrhea [by] withholding the drug; sometimes we’ll give budesonide, and can restart the drug at a lower dose,” Dr. Wierda said. “It’s the late colitis that we have difficulty with – colitis that occurs after patients have been on 3 months, 6 months. And in my experience, those patients have had more severe colitis, and it’s been more treatment limiting.”
Ongoing trials are testing idelalisib in combinations for CLL as well. “Certainly, there’s a number of strategies, and as with ibrutinib, it’s difficult for me to identify a rational combination or a clear combination that I think is going to be superior or a significant advance,” he said. Trials are also testing other PI3 kinase inhibitors, such as duvelisib (IPI-145), now in a phase III registration trial in patients with relapsed or refractory disease.
BCL-2 inhibitors
The investigational agent venetoclax (formerly ABT-199/GDC-199) inhibits BCL-2, which is overexpressed in CLL and renders the cells resistant to apoptosis. It has advanced to a pair of phase III trials, one testing it when combined with rituximab and the other when combined with obinutuzumab (Gazyva).
When used as monotherapy for patients with relapsed disease, venetoclax achieved an overall response rate of 77% and a complete response rate of 23% (EHA 2014. Abstract S702). Benefit was similar among high-risk groups, including patients with the 17p deletion or fludarabine-refractory disease. With a median follow-up of 5.3 months, median progression-free survival for patients treated at the full dose has not been reached.
In earlier trials, venetoclax was associated with a problematic tumor lysis syndrome, according to Dr. Wierda. But that issue has largely been resolved by starting at a low dose and escalating gradually to a full dose; in the trial, it was seen in 7% of patients. The most common grade 3 or 4 adverse event was neutropenia, seen in 33% of patients; however, this toxicity can usually be managed with growth factors and dose reduction, he said.
The combination of venetoclax with rituximab in relapsed CLL yields an 88% overall response rate and a 31% complete response rate (ASH 2014. Abstract 325). Respective values were 78% and 22% in patients with 17p deletion. Moreover, some patients were found to have become negative for minimal residual disease on the combination, although it was not systematically assessed, Dr. Wierda noted.
“Venetoclax is a drug we will hear more about. … It has activity. I think it has a future in treating CLL, and it will be approved in time,” he said.
Leveraging targeted therapies
These new targeted agents, and others in the pipeline, could potentially be leveraged in several ways to improve CLL treatment strategies, according to Dr. Wierda.
Importantly, if ibrutinib becomes approved for universal frontline therapy, a large share of patients are likely to achieve partial remission. “We know if patients are in partial remission, you can’t really stop their treatment on ibrutinib; they will progress. And there was some data reported at ASH [American Society of Hematology] this past year that patients who were on a lower dose or patients who had dose interruption did poorer,” he said. Furthermore, most patients don’t like to be on treatment indefinitely.
“So we’re working on trials to expand our options for consolidation strategies in patients who have been on ibrutinib. We are trying to push them over into a complete remission by adding additional agents,” he explained.
For example, an ongoing trial is testing addition of nivolumab (Opdivo), an immune checkpoint inhibitor, in patients who have been on ibrutinib for at least 9 months and still have a partial remission. “The strategy with that is to try to consolidate them and to get them into a deep remission, where we can have a discussion about holding their treatment or stopping their treatment, or at least to the point where we are comfortable doing that,” he said.
Dr. Wierda disclosed that he has various relationships with AbbVie, Ascerta, Celgene, Emergent BioSolutions, Genentech, Genzyme, Gilead Sciences, GlaxoSmithKline, Juno Therapeutics, Karyopharm, Kite Pharma, Merck, Novartis Pharmaceuticals, Pharmacyclics, Roche Laboratories, and Sanofi-Aventis U.S.
SAN FRANCISCO – Novel targeted agents offer more options for treating chronic lymphocytic leukemia (CLL), and if properly leveraged, may be able to shorten the time on treatment, improving acceptability to patients and possibly reducing treatment costs, according to Dr. William G. Wierda.
BTK inhibitors
Agents that inhibit Bruton tyrosine kinase (BTK) block signaling through the B-cell receptor in CLL, triggering apoptosis, said Dr. Wierda, professor and medical director, department of leukemia, division of cancer medicine, at the University of Texas MD Anderson Cancer Center in Houston. One such agent, ibrutinib (Imbruvica), is approved by the Food and Drug Administration for treatment of relapsed CLL and for treatment of newly diagnosed CLL having 17p deletion, a high-risk factor.
Results from RESONATE-2, a randomized trial comparing ibrutinib with chlorambucil as frontline therapy in older adults with CLL or small lymphocytic lymphoma, will be reported later this year. “We don’t know the details of that publicly yet, but we do know from a press release that it is a positive trial and showed improvement in outcomes for ibrutinib-treated patients. With that data, we will likely have an expanded label for ibrutinib into the frontline setting, at least for the elderly population,” he said at the NCCN Annual Congress: Hematologic Malignancies.
Longer-term data, collected 3 years after patients started ibrutinib monotherapy, have been very good, with overall response rates of 90% in those with relapsed or refractory disease and 87% in those with treatment-naive disease (ASCO 2014. Abstract 7014). “The last time I saw these data updated, the complete remission portions have increased. So as patients remain on the treatment, responses do improve,” Dr. Wierda noted. Complete remission rates now are about 14% and 24%, respectively. Median progression-free survival has not been reached in either group.
Data from the randomized RESONATE trial, which led to ibrutinib’s approval in relapsed CLL, showed benefit relative to ofatumumab across subgroups, including patients who had disease that was refractory to purine analogs, who had the 17p deletion and who had received at least three prior regimens (ASCO 2014. Abstract LBA7008).
The main grade 3 or 4 toxicity of ibrutinib in patients with CLL is infections, but atrial fibrillation and bleeding/hemorrhage are each seen in about 5% of patients. “The trials all excluded patients on warfarin, so we do not recommend treating patients with ibrutinib who are on warfarin,” Dr. Wierda commented. “If patients are anticoagulated on warfarin and we want to put them on ibrutinib, I will usually switch them over to something like Xarelto [rivaroxaban],” he said. Toxicity generally declines with longer treatment.
Discontinuations because of toxicity or Richter transformation usually occur within the first 18 months (JAMA Oncol. 2015;1[1]:80-7). “The concerning [point] for me though is the patients who develop refractory disease. … The incidence starts to go up significantly as you go out beyond 30 or 36 months,” he said. “We are reviewing our data right now to see if we make a similar observation. But that suggests to me that the longer the patients stay on treatment, the more at risk they are for progressing and developing refractory disease.”
The HELIOS trial tested addition of ibrutinib to bendamustine (Treanda) and rituximab (Rituxan) (ASCO 2015. Abstract LBA7005). Results showed superior progression-free survival with the three-drug combination. “But the question that always comes up when this data is presented is, well, how would it compare with ibrutinib monotherapy? Until that question for me is adequately addressed … I would probably be inclined to give patients ibrutinib monotherapy over the combination,” Dr. Wierda said.
Trials are testing a wide range of other combinations. “To me, this suggests that we really don’t have a direction or a rational strategy for combinations with these agents. … Right now, I’m excited about combining ibrutinib with venetoclax. … They seem clinically complementary, and there is some laboratory data that suggests as well that there will be a complementary mechanism of action.”
PI3 kinase inhibitors
Inhibitors of PI3 kinase also block signaling through the B-cell receptor. In this drug class, idelalisib (Zydelig) is approved for treating relapsed CLL in combination with rituximab.
The phase III trial establishing efficacy of this combination showed that it improved both progression-free and overall survival over rituximab alone (ASH 2014. Abstract 330). Median progression-free survival was 19.4 months. There was similar benefit across various subgroups, including patients with 17p deletion or an unmutated IGHV gene, another high-risk factor.
One of the main toxicities of idelalisib, elevation of liver function test results, typically occurs early and is usually not treatment limiting. Colitis occurs with two predominant patterns: early onset and late onset. “The early colitis in my experience hasn’t necessarily been treatment limiting. We can usually get those patients through their diarrhea [by] withholding the drug; sometimes we’ll give budesonide, and can restart the drug at a lower dose,” Dr. Wierda said. “It’s the late colitis that we have difficulty with – colitis that occurs after patients have been on 3 months, 6 months. And in my experience, those patients have had more severe colitis, and it’s been more treatment limiting.”
Ongoing trials are testing idelalisib in combinations for CLL as well. “Certainly, there’s a number of strategies, and as with ibrutinib, it’s difficult for me to identify a rational combination or a clear combination that I think is going to be superior or a significant advance,” he said. Trials are also testing other PI3 kinase inhibitors, such as duvelisib (IPI-145), now in a phase III registration trial in patients with relapsed or refractory disease.
BCL-2 inhibitors
The investigational agent venetoclax (formerly ABT-199/GDC-199) inhibits BCL-2, which is overexpressed in CLL and renders the cells resistant to apoptosis. It has advanced to a pair of phase III trials, one testing it when combined with rituximab and the other when combined with obinutuzumab (Gazyva).
When used as monotherapy for patients with relapsed disease, venetoclax achieved an overall response rate of 77% and a complete response rate of 23% (EHA 2014. Abstract S702). Benefit was similar among high-risk groups, including patients with the 17p deletion or fludarabine-refractory disease. With a median follow-up of 5.3 months, median progression-free survival for patients treated at the full dose has not been reached.
In earlier trials, venetoclax was associated with a problematic tumor lysis syndrome, according to Dr. Wierda. But that issue has largely been resolved by starting at a low dose and escalating gradually to a full dose; in the trial, it was seen in 7% of patients. The most common grade 3 or 4 adverse event was neutropenia, seen in 33% of patients; however, this toxicity can usually be managed with growth factors and dose reduction, he said.
The combination of venetoclax with rituximab in relapsed CLL yields an 88% overall response rate and a 31% complete response rate (ASH 2014. Abstract 325). Respective values were 78% and 22% in patients with 17p deletion. Moreover, some patients were found to have become negative for minimal residual disease on the combination, although it was not systematically assessed, Dr. Wierda noted.
“Venetoclax is a drug we will hear more about. … It has activity. I think it has a future in treating CLL, and it will be approved in time,” he said.
Leveraging targeted therapies
These new targeted agents, and others in the pipeline, could potentially be leveraged in several ways to improve CLL treatment strategies, according to Dr. Wierda.
Importantly, if ibrutinib becomes approved for universal frontline therapy, a large share of patients are likely to achieve partial remission. “We know if patients are in partial remission, you can’t really stop their treatment on ibrutinib; they will progress. And there was some data reported at ASH [American Society of Hematology] this past year that patients who were on a lower dose or patients who had dose interruption did poorer,” he said. Furthermore, most patients don’t like to be on treatment indefinitely.
“So we’re working on trials to expand our options for consolidation strategies in patients who have been on ibrutinib. We are trying to push them over into a complete remission by adding additional agents,” he explained.
For example, an ongoing trial is testing addition of nivolumab (Opdivo), an immune checkpoint inhibitor, in patients who have been on ibrutinib for at least 9 months and still have a partial remission. “The strategy with that is to try to consolidate them and to get them into a deep remission, where we can have a discussion about holding their treatment or stopping their treatment, or at least to the point where we are comfortable doing that,” he said.
Dr. Wierda disclosed that he has various relationships with AbbVie, Ascerta, Celgene, Emergent BioSolutions, Genentech, Genzyme, Gilead Sciences, GlaxoSmithKline, Juno Therapeutics, Karyopharm, Kite Pharma, Merck, Novartis Pharmaceuticals, Pharmacyclics, Roche Laboratories, and Sanofi-Aventis U.S.
SAN FRANCISCO – Novel targeted agents offer more options for treating chronic lymphocytic leukemia (CLL), and if properly leveraged, may be able to shorten the time on treatment, improving acceptability to patients and possibly reducing treatment costs, according to Dr. William G. Wierda.
BTK inhibitors
Agents that inhibit Bruton tyrosine kinase (BTK) block signaling through the B-cell receptor in CLL, triggering apoptosis, said Dr. Wierda, professor and medical director, department of leukemia, division of cancer medicine, at the University of Texas MD Anderson Cancer Center in Houston. One such agent, ibrutinib (Imbruvica), is approved by the Food and Drug Administration for treatment of relapsed CLL and for treatment of newly diagnosed CLL having 17p deletion, a high-risk factor.
Results from RESONATE-2, a randomized trial comparing ibrutinib with chlorambucil as frontline therapy in older adults with CLL or small lymphocytic lymphoma, will be reported later this year. “We don’t know the details of that publicly yet, but we do know from a press release that it is a positive trial and showed improvement in outcomes for ibrutinib-treated patients. With that data, we will likely have an expanded label for ibrutinib into the frontline setting, at least for the elderly population,” he said at the NCCN Annual Congress: Hematologic Malignancies.
Longer-term data, collected 3 years after patients started ibrutinib monotherapy, have been very good, with overall response rates of 90% in those with relapsed or refractory disease and 87% in those with treatment-naive disease (ASCO 2014. Abstract 7014). “The last time I saw these data updated, the complete remission portions have increased. So as patients remain on the treatment, responses do improve,” Dr. Wierda noted. Complete remission rates now are about 14% and 24%, respectively. Median progression-free survival has not been reached in either group.
Data from the randomized RESONATE trial, which led to ibrutinib’s approval in relapsed CLL, showed benefit relative to ofatumumab across subgroups, including patients who had disease that was refractory to purine analogs, who had the 17p deletion and who had received at least three prior regimens (ASCO 2014. Abstract LBA7008).
The main grade 3 or 4 toxicity of ibrutinib in patients with CLL is infections, but atrial fibrillation and bleeding/hemorrhage are each seen in about 5% of patients. “The trials all excluded patients on warfarin, so we do not recommend treating patients with ibrutinib who are on warfarin,” Dr. Wierda commented. “If patients are anticoagulated on warfarin and we want to put them on ibrutinib, I will usually switch them over to something like Xarelto [rivaroxaban],” he said. Toxicity generally declines with longer treatment.
Discontinuations because of toxicity or Richter transformation usually occur within the first 18 months (JAMA Oncol. 2015;1[1]:80-7). “The concerning [point] for me though is the patients who develop refractory disease. … The incidence starts to go up significantly as you go out beyond 30 or 36 months,” he said. “We are reviewing our data right now to see if we make a similar observation. But that suggests to me that the longer the patients stay on treatment, the more at risk they are for progressing and developing refractory disease.”
The HELIOS trial tested addition of ibrutinib to bendamustine (Treanda) and rituximab (Rituxan) (ASCO 2015. Abstract LBA7005). Results showed superior progression-free survival with the three-drug combination. “But the question that always comes up when this data is presented is, well, how would it compare with ibrutinib monotherapy? Until that question for me is adequately addressed … I would probably be inclined to give patients ibrutinib monotherapy over the combination,” Dr. Wierda said.
Trials are testing a wide range of other combinations. “To me, this suggests that we really don’t have a direction or a rational strategy for combinations with these agents. … Right now, I’m excited about combining ibrutinib with venetoclax. … They seem clinically complementary, and there is some laboratory data that suggests as well that there will be a complementary mechanism of action.”
PI3 kinase inhibitors
Inhibitors of PI3 kinase also block signaling through the B-cell receptor. In this drug class, idelalisib (Zydelig) is approved for treating relapsed CLL in combination with rituximab.
The phase III trial establishing efficacy of this combination showed that it improved both progression-free and overall survival over rituximab alone (ASH 2014. Abstract 330). Median progression-free survival was 19.4 months. There was similar benefit across various subgroups, including patients with 17p deletion or an unmutated IGHV gene, another high-risk factor.
One of the main toxicities of idelalisib, elevation of liver function test results, typically occurs early and is usually not treatment limiting. Colitis occurs with two predominant patterns: early onset and late onset. “The early colitis in my experience hasn’t necessarily been treatment limiting. We can usually get those patients through their diarrhea [by] withholding the drug; sometimes we’ll give budesonide, and can restart the drug at a lower dose,” Dr. Wierda said. “It’s the late colitis that we have difficulty with – colitis that occurs after patients have been on 3 months, 6 months. And in my experience, those patients have had more severe colitis, and it’s been more treatment limiting.”
Ongoing trials are testing idelalisib in combinations for CLL as well. “Certainly, there’s a number of strategies, and as with ibrutinib, it’s difficult for me to identify a rational combination or a clear combination that I think is going to be superior or a significant advance,” he said. Trials are also testing other PI3 kinase inhibitors, such as duvelisib (IPI-145), now in a phase III registration trial in patients with relapsed or refractory disease.
BCL-2 inhibitors
The investigational agent venetoclax (formerly ABT-199/GDC-199) inhibits BCL-2, which is overexpressed in CLL and renders the cells resistant to apoptosis. It has advanced to a pair of phase III trials, one testing it when combined with rituximab and the other when combined with obinutuzumab (Gazyva).
When used as monotherapy for patients with relapsed disease, venetoclax achieved an overall response rate of 77% and a complete response rate of 23% (EHA 2014. Abstract S702). Benefit was similar among high-risk groups, including patients with the 17p deletion or fludarabine-refractory disease. With a median follow-up of 5.3 months, median progression-free survival for patients treated at the full dose has not been reached.
In earlier trials, venetoclax was associated with a problematic tumor lysis syndrome, according to Dr. Wierda. But that issue has largely been resolved by starting at a low dose and escalating gradually to a full dose; in the trial, it was seen in 7% of patients. The most common grade 3 or 4 adverse event was neutropenia, seen in 33% of patients; however, this toxicity can usually be managed with growth factors and dose reduction, he said.
The combination of venetoclax with rituximab in relapsed CLL yields an 88% overall response rate and a 31% complete response rate (ASH 2014. Abstract 325). Respective values were 78% and 22% in patients with 17p deletion. Moreover, some patients were found to have become negative for minimal residual disease on the combination, although it was not systematically assessed, Dr. Wierda noted.
“Venetoclax is a drug we will hear more about. … It has activity. I think it has a future in treating CLL, and it will be approved in time,” he said.
Leveraging targeted therapies
These new targeted agents, and others in the pipeline, could potentially be leveraged in several ways to improve CLL treatment strategies, according to Dr. Wierda.
Importantly, if ibrutinib becomes approved for universal frontline therapy, a large share of patients are likely to achieve partial remission. “We know if patients are in partial remission, you can’t really stop their treatment on ibrutinib; they will progress. And there was some data reported at ASH [American Society of Hematology] this past year that patients who were on a lower dose or patients who had dose interruption did poorer,” he said. Furthermore, most patients don’t like to be on treatment indefinitely.
“So we’re working on trials to expand our options for consolidation strategies in patients who have been on ibrutinib. We are trying to push them over into a complete remission by adding additional agents,” he explained.
For example, an ongoing trial is testing addition of nivolumab (Opdivo), an immune checkpoint inhibitor, in patients who have been on ibrutinib for at least 9 months and still have a partial remission. “The strategy with that is to try to consolidate them and to get them into a deep remission, where we can have a discussion about holding their treatment or stopping their treatment, or at least to the point where we are comfortable doing that,” he said.
Dr. Wierda disclosed that he has various relationships with AbbVie, Ascerta, Celgene, Emergent BioSolutions, Genentech, Genzyme, Gilead Sciences, GlaxoSmithKline, Juno Therapeutics, Karyopharm, Kite Pharma, Merck, Novartis Pharmaceuticals, Pharmacyclics, Roche Laboratories, and Sanofi-Aventis U.S.
EXPERT ANALYSIS FROM NCCN ANNUAL CONGRESS: HEMATOLOGIC MALIGNANCIES
TH3RESA: T-DM1 prolongs survival in heavily pretreated HER2-positive breast cancer
SAN ANTONIO – The antibody–drug conjugate trastuzumab emtansine (T-DM1) is safe and efficacious for treating heavily pretreated HER2-positive metastatic breast cancer, according to data from the randomized phase III TH3RESA trial reported at the San Antonio Breast Cancer Symposium.
“T-DM1 demonstrated a clinically meaningful and statistically significant improvement in overall survival, compared to treatment of physician’s choice in patients with HER2-positive metastatic breast cancer previously treated with a taxane, trastuzumab, and lapatinib,” first author Dr. Hans Wildiers, professor of medical oncology at KU Leuven (Belgium), commented in a related press briefing. “This result was reached despite about 50% crossover and about 80% of patients in the control arm receiving trastuzumab-containing regimens,” he said.
T-DM1 is approved by the Food and Drug Administration for the treatment of less heavily pretreated advanced disease on the basis of findings from the EMILIA trial. In that trial (the results of which were updated at the symposium), T-DM1 outperformed the combination of lapatinib and capecitabine.
“The TH3RESA results together with the EMILIA overall survival benefit … further solidify the role of T-DM1 in the treatment of previously treated HER2-positive advanced breast cancer,” Dr. Wildiers said.
Press briefing moderator Dr. C. Kent Osborne, professor of medicine and molecular and cellular biology and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, asked about the durability of the T-DM1 benefit: “What is the longest patients who are still in remission have been on study?”
About a quarter of patients were still on the trial as of the data cutoff for the analysis, signifying longer-term benefit, according to Dr. Wildiers.
“Just to put this in perspective, we used to think, and still do in a way, that HER2-positive breast cancer was one of the more aggressive forms of the disease, and we hated to see a patient who would come in with a HER2-positive tumor,” Dr. Osborne commented. “Now with our treatments, based on the HER2 and the identification of targeted therapy, it’s actually turned out to be a good tumor to have. And this is just another example of the effectiveness of this drug.”
The 602 patients enrolled in TH3RESA had to have received at least two prior HER2-directed therapies for their advanced disease, although the majority had received four or more. They were randomized 2:1 to T-DM1 (brand name Kadcyla) or a treatment of the physician’s choice as a control.
The study was amended part way through when the EMILIA results became available so that patients in the control arm could cross over to T-DM1 at the time of progression, and about half did so.
The results of the second interim overall survival analysis reported at the symposium showed that T-DM1 prolonged overall survival by almost 7 months, compared with a treatment of the physician’s choice: 22.7 months vs.15.8 months (hazard ratio, 0.68; P = .0007).
“Subgroup analysis showed no clear differences in different subgroups, except for a possible trend toward greater benefit for patients outside the United States,” Dr. Wildiers commented, while cautioning that numbers of patients were small and that finding shouldn’t be overinterpreted.
The overall survival benefit was similar when patients in the control arm were censored at the time of progression and crossing over to T-DM1 (22.7 vs. 15.6 months; HR, 0.58; P = .0002).
Patients were on therapy about twice as long with T-DM1 as with the treatment of a physician’s choice (7.9 vs. 4.1 months). Even so, the agent had a favorable safety profile, he said.
The control group had higher rates of grade 3 or worse diarrhea (4.3% vs. 0.7%), neutropenia (15.8% vs. 2.5%), and febrile neutropenia (3.8% vs. 0.2%). The T-DM1 group had a higher rate of grade 3 or worse thrombocytopenia (6.0% vs. 2.7%). Reductions in ejection fraction were rare overall and no more common with T-DM1 than in the control arm, according to Dr. Wildiers.
Quality of life was not assessed in the trial. However, that outcome can be inferred from others, according to Dr. Osborne.
“You could estimate the difference in quality of life by looking at the side effects of the treatment, and this treatment [T-DM1] had far fewer side effects,” he said. “Most of the side effects come from the cancer anyway at this stage, and if you are putting patients into remission and they are staying there for long periods of time, those symptoms are markedly improved.”
SAN ANTONIO – The antibody–drug conjugate trastuzumab emtansine (T-DM1) is safe and efficacious for treating heavily pretreated HER2-positive metastatic breast cancer, according to data from the randomized phase III TH3RESA trial reported at the San Antonio Breast Cancer Symposium.
“T-DM1 demonstrated a clinically meaningful and statistically significant improvement in overall survival, compared to treatment of physician’s choice in patients with HER2-positive metastatic breast cancer previously treated with a taxane, trastuzumab, and lapatinib,” first author Dr. Hans Wildiers, professor of medical oncology at KU Leuven (Belgium), commented in a related press briefing. “This result was reached despite about 50% crossover and about 80% of patients in the control arm receiving trastuzumab-containing regimens,” he said.
T-DM1 is approved by the Food and Drug Administration for the treatment of less heavily pretreated advanced disease on the basis of findings from the EMILIA trial. In that trial (the results of which were updated at the symposium), T-DM1 outperformed the combination of lapatinib and capecitabine.
“The TH3RESA results together with the EMILIA overall survival benefit … further solidify the role of T-DM1 in the treatment of previously treated HER2-positive advanced breast cancer,” Dr. Wildiers said.
Press briefing moderator Dr. C. Kent Osborne, professor of medicine and molecular and cellular biology and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, asked about the durability of the T-DM1 benefit: “What is the longest patients who are still in remission have been on study?”
About a quarter of patients were still on the trial as of the data cutoff for the analysis, signifying longer-term benefit, according to Dr. Wildiers.
“Just to put this in perspective, we used to think, and still do in a way, that HER2-positive breast cancer was one of the more aggressive forms of the disease, and we hated to see a patient who would come in with a HER2-positive tumor,” Dr. Osborne commented. “Now with our treatments, based on the HER2 and the identification of targeted therapy, it’s actually turned out to be a good tumor to have. And this is just another example of the effectiveness of this drug.”
The 602 patients enrolled in TH3RESA had to have received at least two prior HER2-directed therapies for their advanced disease, although the majority had received four or more. They were randomized 2:1 to T-DM1 (brand name Kadcyla) or a treatment of the physician’s choice as a control.
The study was amended part way through when the EMILIA results became available so that patients in the control arm could cross over to T-DM1 at the time of progression, and about half did so.
The results of the second interim overall survival analysis reported at the symposium showed that T-DM1 prolonged overall survival by almost 7 months, compared with a treatment of the physician’s choice: 22.7 months vs.15.8 months (hazard ratio, 0.68; P = .0007).
“Subgroup analysis showed no clear differences in different subgroups, except for a possible trend toward greater benefit for patients outside the United States,” Dr. Wildiers commented, while cautioning that numbers of patients were small and that finding shouldn’t be overinterpreted.
The overall survival benefit was similar when patients in the control arm were censored at the time of progression and crossing over to T-DM1 (22.7 vs. 15.6 months; HR, 0.58; P = .0002).
Patients were on therapy about twice as long with T-DM1 as with the treatment of a physician’s choice (7.9 vs. 4.1 months). Even so, the agent had a favorable safety profile, he said.
The control group had higher rates of grade 3 or worse diarrhea (4.3% vs. 0.7%), neutropenia (15.8% vs. 2.5%), and febrile neutropenia (3.8% vs. 0.2%). The T-DM1 group had a higher rate of grade 3 or worse thrombocytopenia (6.0% vs. 2.7%). Reductions in ejection fraction were rare overall and no more common with T-DM1 than in the control arm, according to Dr. Wildiers.
Quality of life was not assessed in the trial. However, that outcome can be inferred from others, according to Dr. Osborne.
“You could estimate the difference in quality of life by looking at the side effects of the treatment, and this treatment [T-DM1] had far fewer side effects,” he said. “Most of the side effects come from the cancer anyway at this stage, and if you are putting patients into remission and they are staying there for long periods of time, those symptoms are markedly improved.”
SAN ANTONIO – The antibody–drug conjugate trastuzumab emtansine (T-DM1) is safe and efficacious for treating heavily pretreated HER2-positive metastatic breast cancer, according to data from the randomized phase III TH3RESA trial reported at the San Antonio Breast Cancer Symposium.
“T-DM1 demonstrated a clinically meaningful and statistically significant improvement in overall survival, compared to treatment of physician’s choice in patients with HER2-positive metastatic breast cancer previously treated with a taxane, trastuzumab, and lapatinib,” first author Dr. Hans Wildiers, professor of medical oncology at KU Leuven (Belgium), commented in a related press briefing. “This result was reached despite about 50% crossover and about 80% of patients in the control arm receiving trastuzumab-containing regimens,” he said.
T-DM1 is approved by the Food and Drug Administration for the treatment of less heavily pretreated advanced disease on the basis of findings from the EMILIA trial. In that trial (the results of which were updated at the symposium), T-DM1 outperformed the combination of lapatinib and capecitabine.
“The TH3RESA results together with the EMILIA overall survival benefit … further solidify the role of T-DM1 in the treatment of previously treated HER2-positive advanced breast cancer,” Dr. Wildiers said.
Press briefing moderator Dr. C. Kent Osborne, professor of medicine and molecular and cellular biology and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, asked about the durability of the T-DM1 benefit: “What is the longest patients who are still in remission have been on study?”
About a quarter of patients were still on the trial as of the data cutoff for the analysis, signifying longer-term benefit, according to Dr. Wildiers.
“Just to put this in perspective, we used to think, and still do in a way, that HER2-positive breast cancer was one of the more aggressive forms of the disease, and we hated to see a patient who would come in with a HER2-positive tumor,” Dr. Osborne commented. “Now with our treatments, based on the HER2 and the identification of targeted therapy, it’s actually turned out to be a good tumor to have. And this is just another example of the effectiveness of this drug.”
The 602 patients enrolled in TH3RESA had to have received at least two prior HER2-directed therapies for their advanced disease, although the majority had received four or more. They were randomized 2:1 to T-DM1 (brand name Kadcyla) or a treatment of the physician’s choice as a control.
The study was amended part way through when the EMILIA results became available so that patients in the control arm could cross over to T-DM1 at the time of progression, and about half did so.
The results of the second interim overall survival analysis reported at the symposium showed that T-DM1 prolonged overall survival by almost 7 months, compared with a treatment of the physician’s choice: 22.7 months vs.15.8 months (hazard ratio, 0.68; P = .0007).
“Subgroup analysis showed no clear differences in different subgroups, except for a possible trend toward greater benefit for patients outside the United States,” Dr. Wildiers commented, while cautioning that numbers of patients were small and that finding shouldn’t be overinterpreted.
The overall survival benefit was similar when patients in the control arm were censored at the time of progression and crossing over to T-DM1 (22.7 vs. 15.6 months; HR, 0.58; P = .0002).
Patients were on therapy about twice as long with T-DM1 as with the treatment of a physician’s choice (7.9 vs. 4.1 months). Even so, the agent had a favorable safety profile, he said.
The control group had higher rates of grade 3 or worse diarrhea (4.3% vs. 0.7%), neutropenia (15.8% vs. 2.5%), and febrile neutropenia (3.8% vs. 0.2%). The T-DM1 group had a higher rate of grade 3 or worse thrombocytopenia (6.0% vs. 2.7%). Reductions in ejection fraction were rare overall and no more common with T-DM1 than in the control arm, according to Dr. Wildiers.
Quality of life was not assessed in the trial. However, that outcome can be inferred from others, according to Dr. Osborne.
“You could estimate the difference in quality of life by looking at the side effects of the treatment, and this treatment [T-DM1] had far fewer side effects,” he said. “Most of the side effects come from the cancer anyway at this stage, and if you are putting patients into remission and they are staying there for long periods of time, those symptoms are markedly improved.”
AT SABCS 2015
Key clinical point: T-DM1 is safe and efficacious for treating heavily pretreated HER2-positive breast cancer.
Major finding: The median overall survival was 22.7 months with T-DM1 vs. 15.8 months with the treatment of a physician’s choice.
Data source: A randomized phase III trial in 602 patients with heavily pretreated HER2-positive breast cancer (TH3RESA trial).
Disclosures: Dr. Wildiers disclosed that his institution has received compensation from Roche for lectures he has presented at national meetings and for consulting work, as well as an unrestricted research grant for academic research. The trial was supported by Roche.
Premenopausal women with luminal A tumors may be able to skip chemo
SAN ANTONIO – Adjuvant chemotherapy does not improve outcomes in premenopausal women with luminal A breast cancer, suggests a prospective-retrospective study using samples from the 77B randomized trial of the Danish Breast Cancer Cooperative Group (DBCG).
Researchers led by Dr. Torsten O. Nielsen, professor of pathology at the University of British Columbia, Vancouver, performed immunohistochemical intrinsic subtyping on tissue microarrays from 709 participants in the trial, which began in 1977.
The women in the trial had high-risk features – positive axillary lymph nodes or tumors greater than 5 cm – and were treated with mastectomy, axillary node dissection, and radiation therapy, but no endocrine therapy. They were randomized to cyclophosphamide-based chemotherapy or no chemotherapy.
Results of the new study, reported in a session and press briefing at the San Antonio Breast Cancer Symposium, showed that patients with luminal A tumors did not see any improvement in 10-year invasive disease–free survival from chemotherapy versus no chemotherapy. In contrast, patients with other subtypes had a halving of the risk of events.
“Women with luminal A breast cancers derive no benefit from chemotherapy – even premenopausal, node positive, and no endocrine therapy,” Dr. Nielsen said. “You might expect that this would be a particularly difficult set of patients [in which to find a group that was] lacking benefit from chemotherapy. Nonetheless, we did find that group.”
It is unclear whether the findings are robust enough to change practice, he said. “The community has to decide if it is enough evidence. Technically, this is level 2 evidence. If you feel that there is another trial that’s very well matched and [has] similar results, you might consider it level 1 evidence.”
Press briefing moderator Dr. Virginia Kaklamani, professor of medicine, University of Texas, San Antonio, noted that the recently closed RxPONDER trial used OncoType DX to randomize low-risk women to chemotherapy versus no chemotherapy and should shed more light on this issue in the contemporary treatment era.
“But this data kind of confirms what we believe, that you probably don’t need chemotherapy for those patients. So this is another step, and for me, it gives me a little more confidence in my premenopausal women – because I was pretty confident in my postmenopausal women – but in my premenopausal women, to not push chemotherapy,” she said.
“This is clearly part of a body of evidence that’s building up and may be one of the themes of the conference here, that we can probably back off on the aggressiveness of our treatments and still achieve the same results,” Dr. Nielsen agreed, noting there have been similar trends in surgery and radiation therapy. “And this is where we want to be in cancer research. We cure a lot of women with breast cancer now.”
Still, the final decision rests with the patient and physician, he acknowledged. When asked about the likely reluctance of some premenopausal women with luminal A tumors to forgo chemotherapy, he replied, “It’s a woman’s choice, I think. Most oncologists would support that, although they would provide the evidence that you were probably being overtreated.”
In the session where the data were presented, attendee Dr. Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy asked, “Did you look at the prognostic role of amenorrhea in this specific subgroup of patients? I think you should do that in the context of the luminal A patients who received adjuvant chemotherapy.”
Dr. Nielsen agreed that this information is important. If that analysis has not already been done by DBCG, “it’s something we can do as an exploratory study,” he said.
Attendee Dr. Steven Vogl, an oncologist at Montefiore Medical Center in New York, noted that a positive trial with a negative subgroup finding, as in this case, presents a quandary for oncologists. Also, the study had relatively few patients with luminal A disease who did not get chemotherapy, and the cyclophosphamide likely did confer some benefit by inducing amenorrhea.
“So I will go home saying, ‘Small numbers, old study. I don’t know what it means,’ ” he said. “Convince me I should do something about it.”
“This is the best we can do because we are looking at old studies that are randomized,” Dr. Nielsen replied, noting that the trial’s no-chemotherapy arms were closed early because of lack of benefit. “We prespecified quite a stringent statistical test with the interaction test, which is hard to meet, and it did achieve that because there absolutely was no sign of benefit in those patients.”
The issue of whether adjuvant chemotherapy provides benefit in early breast cancer was settled back in the 1980s, he noted when introducing the study. “Since that time, it’s been unethical to randomize women in those settings to no chemotherapy. Most of the studies have been different types of chemotherapies as choices.”
In contrast, participants in the 77B trial were randomized to two adjuvant chemotherapy arms (cyclophosphamide alone or cyclophosphamide, methotrexate, and fluorouracil) and two nonchemotherapy arms (levamisole or no agent). Main findings showed that chemotherapy improved 10-year invasive disease–free survival (Cancer. 2010;116:2081-9).
According to results of the subtyping, which Dr. Nielsen and colleagues performed in a central lab, 26% of the tumors were of luminal A subtype, meaning they were estrogen receptor positive and HER2 negative, had a low proliferation index (13% or fewer cells staining for Ki67), and had high progesterone receptor expression (more than 20% of cells staining) (J Clin Oncol. 2013;31:203-9).
These patients did not derive significant benefit from chemotherapy. In contrast, patients with other subtypes (luminal B, HER2E, or triple negative) had a marked benefit (hazard ratio, 0.50; 95% CI, 0.38-0.66; P less than .001).
The heterogeneity in treatment impact between luminal A and non–luminal A subtypes was statistically significant (interaction test P = .048). Analyses also showed a similar trend for the endpoint of 25-year overall survival.
Discussing study caveats, Dr. Nielsen acknowledged that immunohistochemistry scoring can be subjective. “Currently, we are trying to get the original [tissue] blocks. Isolating RNA for gene profile analysis is another way to identify the subtypes,” he explained.
SAN ANTONIO – Adjuvant chemotherapy does not improve outcomes in premenopausal women with luminal A breast cancer, suggests a prospective-retrospective study using samples from the 77B randomized trial of the Danish Breast Cancer Cooperative Group (DBCG).
Researchers led by Dr. Torsten O. Nielsen, professor of pathology at the University of British Columbia, Vancouver, performed immunohistochemical intrinsic subtyping on tissue microarrays from 709 participants in the trial, which began in 1977.
The women in the trial had high-risk features – positive axillary lymph nodes or tumors greater than 5 cm – and were treated with mastectomy, axillary node dissection, and radiation therapy, but no endocrine therapy. They were randomized to cyclophosphamide-based chemotherapy or no chemotherapy.
Results of the new study, reported in a session and press briefing at the San Antonio Breast Cancer Symposium, showed that patients with luminal A tumors did not see any improvement in 10-year invasive disease–free survival from chemotherapy versus no chemotherapy. In contrast, patients with other subtypes had a halving of the risk of events.
“Women with luminal A breast cancers derive no benefit from chemotherapy – even premenopausal, node positive, and no endocrine therapy,” Dr. Nielsen said. “You might expect that this would be a particularly difficult set of patients [in which to find a group that was] lacking benefit from chemotherapy. Nonetheless, we did find that group.”
It is unclear whether the findings are robust enough to change practice, he said. “The community has to decide if it is enough evidence. Technically, this is level 2 evidence. If you feel that there is another trial that’s very well matched and [has] similar results, you might consider it level 1 evidence.”
Press briefing moderator Dr. Virginia Kaklamani, professor of medicine, University of Texas, San Antonio, noted that the recently closed RxPONDER trial used OncoType DX to randomize low-risk women to chemotherapy versus no chemotherapy and should shed more light on this issue in the contemporary treatment era.
“But this data kind of confirms what we believe, that you probably don’t need chemotherapy for those patients. So this is another step, and for me, it gives me a little more confidence in my premenopausal women – because I was pretty confident in my postmenopausal women – but in my premenopausal women, to not push chemotherapy,” she said.
“This is clearly part of a body of evidence that’s building up and may be one of the themes of the conference here, that we can probably back off on the aggressiveness of our treatments and still achieve the same results,” Dr. Nielsen agreed, noting there have been similar trends in surgery and radiation therapy. “And this is where we want to be in cancer research. We cure a lot of women with breast cancer now.”
Still, the final decision rests with the patient and physician, he acknowledged. When asked about the likely reluctance of some premenopausal women with luminal A tumors to forgo chemotherapy, he replied, “It’s a woman’s choice, I think. Most oncologists would support that, although they would provide the evidence that you were probably being overtreated.”
In the session where the data were presented, attendee Dr. Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy asked, “Did you look at the prognostic role of amenorrhea in this specific subgroup of patients? I think you should do that in the context of the luminal A patients who received adjuvant chemotherapy.”
Dr. Nielsen agreed that this information is important. If that analysis has not already been done by DBCG, “it’s something we can do as an exploratory study,” he said.
Attendee Dr. Steven Vogl, an oncologist at Montefiore Medical Center in New York, noted that a positive trial with a negative subgroup finding, as in this case, presents a quandary for oncologists. Also, the study had relatively few patients with luminal A disease who did not get chemotherapy, and the cyclophosphamide likely did confer some benefit by inducing amenorrhea.
“So I will go home saying, ‘Small numbers, old study. I don’t know what it means,’ ” he said. “Convince me I should do something about it.”
“This is the best we can do because we are looking at old studies that are randomized,” Dr. Nielsen replied, noting that the trial’s no-chemotherapy arms were closed early because of lack of benefit. “We prespecified quite a stringent statistical test with the interaction test, which is hard to meet, and it did achieve that because there absolutely was no sign of benefit in those patients.”
The issue of whether adjuvant chemotherapy provides benefit in early breast cancer was settled back in the 1980s, he noted when introducing the study. “Since that time, it’s been unethical to randomize women in those settings to no chemotherapy. Most of the studies have been different types of chemotherapies as choices.”
In contrast, participants in the 77B trial were randomized to two adjuvant chemotherapy arms (cyclophosphamide alone or cyclophosphamide, methotrexate, and fluorouracil) and two nonchemotherapy arms (levamisole or no agent). Main findings showed that chemotherapy improved 10-year invasive disease–free survival (Cancer. 2010;116:2081-9).
According to results of the subtyping, which Dr. Nielsen and colleagues performed in a central lab, 26% of the tumors were of luminal A subtype, meaning they were estrogen receptor positive and HER2 negative, had a low proliferation index (13% or fewer cells staining for Ki67), and had high progesterone receptor expression (more than 20% of cells staining) (J Clin Oncol. 2013;31:203-9).
These patients did not derive significant benefit from chemotherapy. In contrast, patients with other subtypes (luminal B, HER2E, or triple negative) had a marked benefit (hazard ratio, 0.50; 95% CI, 0.38-0.66; P less than .001).
The heterogeneity in treatment impact between luminal A and non–luminal A subtypes was statistically significant (interaction test P = .048). Analyses also showed a similar trend for the endpoint of 25-year overall survival.
Discussing study caveats, Dr. Nielsen acknowledged that immunohistochemistry scoring can be subjective. “Currently, we are trying to get the original [tissue] blocks. Isolating RNA for gene profile analysis is another way to identify the subtypes,” he explained.
SAN ANTONIO – Adjuvant chemotherapy does not improve outcomes in premenopausal women with luminal A breast cancer, suggests a prospective-retrospective study using samples from the 77B randomized trial of the Danish Breast Cancer Cooperative Group (DBCG).
Researchers led by Dr. Torsten O. Nielsen, professor of pathology at the University of British Columbia, Vancouver, performed immunohistochemical intrinsic subtyping on tissue microarrays from 709 participants in the trial, which began in 1977.
The women in the trial had high-risk features – positive axillary lymph nodes or tumors greater than 5 cm – and were treated with mastectomy, axillary node dissection, and radiation therapy, but no endocrine therapy. They were randomized to cyclophosphamide-based chemotherapy or no chemotherapy.
Results of the new study, reported in a session and press briefing at the San Antonio Breast Cancer Symposium, showed that patients with luminal A tumors did not see any improvement in 10-year invasive disease–free survival from chemotherapy versus no chemotherapy. In contrast, patients with other subtypes had a halving of the risk of events.
“Women with luminal A breast cancers derive no benefit from chemotherapy – even premenopausal, node positive, and no endocrine therapy,” Dr. Nielsen said. “You might expect that this would be a particularly difficult set of patients [in which to find a group that was] lacking benefit from chemotherapy. Nonetheless, we did find that group.”
It is unclear whether the findings are robust enough to change practice, he said. “The community has to decide if it is enough evidence. Technically, this is level 2 evidence. If you feel that there is another trial that’s very well matched and [has] similar results, you might consider it level 1 evidence.”
Press briefing moderator Dr. Virginia Kaklamani, professor of medicine, University of Texas, San Antonio, noted that the recently closed RxPONDER trial used OncoType DX to randomize low-risk women to chemotherapy versus no chemotherapy and should shed more light on this issue in the contemporary treatment era.
“But this data kind of confirms what we believe, that you probably don’t need chemotherapy for those patients. So this is another step, and for me, it gives me a little more confidence in my premenopausal women – because I was pretty confident in my postmenopausal women – but in my premenopausal women, to not push chemotherapy,” she said.
“This is clearly part of a body of evidence that’s building up and may be one of the themes of the conference here, that we can probably back off on the aggressiveness of our treatments and still achieve the same results,” Dr. Nielsen agreed, noting there have been similar trends in surgery and radiation therapy. “And this is where we want to be in cancer research. We cure a lot of women with breast cancer now.”
Still, the final decision rests with the patient and physician, he acknowledged. When asked about the likely reluctance of some premenopausal women with luminal A tumors to forgo chemotherapy, he replied, “It’s a woman’s choice, I think. Most oncologists would support that, although they would provide the evidence that you were probably being overtreated.”
In the session where the data were presented, attendee Dr. Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy asked, “Did you look at the prognostic role of amenorrhea in this specific subgroup of patients? I think you should do that in the context of the luminal A patients who received adjuvant chemotherapy.”
Dr. Nielsen agreed that this information is important. If that analysis has not already been done by DBCG, “it’s something we can do as an exploratory study,” he said.
Attendee Dr. Steven Vogl, an oncologist at Montefiore Medical Center in New York, noted that a positive trial with a negative subgroup finding, as in this case, presents a quandary for oncologists. Also, the study had relatively few patients with luminal A disease who did not get chemotherapy, and the cyclophosphamide likely did confer some benefit by inducing amenorrhea.
“So I will go home saying, ‘Small numbers, old study. I don’t know what it means,’ ” he said. “Convince me I should do something about it.”
“This is the best we can do because we are looking at old studies that are randomized,” Dr. Nielsen replied, noting that the trial’s no-chemotherapy arms were closed early because of lack of benefit. “We prespecified quite a stringent statistical test with the interaction test, which is hard to meet, and it did achieve that because there absolutely was no sign of benefit in those patients.”
The issue of whether adjuvant chemotherapy provides benefit in early breast cancer was settled back in the 1980s, he noted when introducing the study. “Since that time, it’s been unethical to randomize women in those settings to no chemotherapy. Most of the studies have been different types of chemotherapies as choices.”
In contrast, participants in the 77B trial were randomized to two adjuvant chemotherapy arms (cyclophosphamide alone or cyclophosphamide, methotrexate, and fluorouracil) and two nonchemotherapy arms (levamisole or no agent). Main findings showed that chemotherapy improved 10-year invasive disease–free survival (Cancer. 2010;116:2081-9).
According to results of the subtyping, which Dr. Nielsen and colleagues performed in a central lab, 26% of the tumors were of luminal A subtype, meaning they were estrogen receptor positive and HER2 negative, had a low proliferation index (13% or fewer cells staining for Ki67), and had high progesterone receptor expression (more than 20% of cells staining) (J Clin Oncol. 2013;31:203-9).
These patients did not derive significant benefit from chemotherapy. In contrast, patients with other subtypes (luminal B, HER2E, or triple negative) had a marked benefit (hazard ratio, 0.50; 95% CI, 0.38-0.66; P less than .001).
The heterogeneity in treatment impact between luminal A and non–luminal A subtypes was statistically significant (interaction test P = .048). Analyses also showed a similar trend for the endpoint of 25-year overall survival.
Discussing study caveats, Dr. Nielsen acknowledged that immunohistochemistry scoring can be subjective. “Currently, we are trying to get the original [tissue] blocks. Isolating RNA for gene profile analysis is another way to identify the subtypes,” he explained.
AT SABCS 2015
Key clinical point: Premenopausal women with luminal A breast cancer do not benefit from adjuvant cyclophosphamide-based chemotherapy.
Major finding: Chemotherapy improved 10-year invasive disease–free survival in women with non–luminal A tumors (hazard ratio, 0.50) but not in women with luminal A tumors.
Data source: A prospective-retrospective study assessing tumor intrinsic subtype among 709 patients with early breast cancer in an older randomized trial of chemotherapy (DBCG 77B trial).
Disclosures: Dr. Nielsen disclosed that he holds a patent for Bioclassifier, and that he consults for, receives royalties from, and is a speaker for NanoString. The Canadian Breast Cancer Foundation, the IM Daehnfeldt Foundation, and the Danish Research Council supported the study.
VIDEO: TH3RESA results further solidify role of T-DM1
SAN ANTONIO – Compared with a treatment of the physician’s choice, the antibody-drug conjugate trastuzumab emtansine (T-DM1) prolongs median overall survival by almost 7 months among women with heavily pretreated HER2-positive metastatic breast cancer, according to new data from the TH3RESA trial.
In an interview at the San Antonio Breast Cancer Symposium, Dr. Hans Wildiers, professor at Katholieke Universiteit Leuven, Belgium, discusses the findings and how they further solidify the role of T-DM1 in the treatment of advanced HER2-positive disease.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Compared with a treatment of the physician’s choice, the antibody-drug conjugate trastuzumab emtansine (T-DM1) prolongs median overall survival by almost 7 months among women with heavily pretreated HER2-positive metastatic breast cancer, according to new data from the TH3RESA trial.
In an interview at the San Antonio Breast Cancer Symposium, Dr. Hans Wildiers, professor at Katholieke Universiteit Leuven, Belgium, discusses the findings and how they further solidify the role of T-DM1 in the treatment of advanced HER2-positive disease.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Compared with a treatment of the physician’s choice, the antibody-drug conjugate trastuzumab emtansine (T-DM1) prolongs median overall survival by almost 7 months among women with heavily pretreated HER2-positive metastatic breast cancer, according to new data from the TH3RESA trial.
In an interview at the San Antonio Breast Cancer Symposium, Dr. Hans Wildiers, professor at Katholieke Universiteit Leuven, Belgium, discusses the findings and how they further solidify the role of T-DM1 in the treatment of advanced HER2-positive disease.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT SABCS 2015
VIDEO: Estrogen receptor gene mutations linked to poorer survival
SAN ANTONIO – Mutations of the estrogen receptor 1 (ESR1) gene are more common than previously thought in women with advanced estrogen receptor–positive breast cancer and are associated with poorer survival. In an interview at the San Antonio Breast Cancer Symposium, Dr. Sarat Chandarlapaty of Memorial Sloan Kettering Cancer Center, New York, discusses a mutational analysis of cell-free DNA in blood samples from the BOLERO-2 trial and how the findings may help refine therapeutic strategies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Mutations of the estrogen receptor 1 (ESR1) gene are more common than previously thought in women with advanced estrogen receptor–positive breast cancer and are associated with poorer survival. In an interview at the San Antonio Breast Cancer Symposium, Dr. Sarat Chandarlapaty of Memorial Sloan Kettering Cancer Center, New York, discusses a mutational analysis of cell-free DNA in blood samples from the BOLERO-2 trial and how the findings may help refine therapeutic strategies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Mutations of the estrogen receptor 1 (ESR1) gene are more common than previously thought in women with advanced estrogen receptor–positive breast cancer and are associated with poorer survival. In an interview at the San Antonio Breast Cancer Symposium, Dr. Sarat Chandarlapaty of Memorial Sloan Kettering Cancer Center, New York, discusses a mutational analysis of cell-free DNA in blood samples from the BOLERO-2 trial and how the findings may help refine therapeutic strategies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT SABCS 2015
VIDEO: Time to skip chemo for luminal A tumors?
SAN ANTONIO – Premenopausal women with luminal A tumors did not derive benefit from adjuvant cyclophosphamide-based chemotherapy.
In an interview, Dr. Torsten Nielsen, professor of pathology at the University of British Columbia in Vancouver, discusses the prospective-retrospective study and whether its findings will prompt patients with these tumors and their physicians to skip chemotherapy.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Premenopausal women with luminal A tumors did not derive benefit from adjuvant cyclophosphamide-based chemotherapy.
In an interview, Dr. Torsten Nielsen, professor of pathology at the University of British Columbia in Vancouver, discusses the prospective-retrospective study and whether its findings will prompt patients with these tumors and their physicians to skip chemotherapy.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Premenopausal women with luminal A tumors did not derive benefit from adjuvant cyclophosphamide-based chemotherapy.
In an interview, Dr. Torsten Nielsen, professor of pathology at the University of British Columbia in Vancouver, discusses the prospective-retrospective study and whether its findings will prompt patients with these tumors and their physicians to skip chemotherapy.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT SABCS 2015
VIDEO: APOBEC3B enzyme may limit tamoxifen efficacy
SAN ANTONIO – Patients with estrogen receptor–positive breast cancers who had up-regulation of the APOBEC3B enzyme – a DNA-mutating enzyme – had a shorter time to progression on tamoxifen. In addition, suppressing levels of the enzyme in a preclinical model reduced tamoxifen resistance. In an interview, Reuben Harris, Ph.D., professor in the department of biochemistry, molecular biology, and biophysics at the University of Minnesota, Minneapolis, discussed the study’s findings and what they mean for the conduct of clinical trials and for future research.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Patients with estrogen receptor–positive breast cancers who had up-regulation of the APOBEC3B enzyme – a DNA-mutating enzyme – had a shorter time to progression on tamoxifen. In addition, suppressing levels of the enzyme in a preclinical model reduced tamoxifen resistance. In an interview, Reuben Harris, Ph.D., professor in the department of biochemistry, molecular biology, and biophysics at the University of Minnesota, Minneapolis, discussed the study’s findings and what they mean for the conduct of clinical trials and for future research.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Patients with estrogen receptor–positive breast cancers who had up-regulation of the APOBEC3B enzyme – a DNA-mutating enzyme – had a shorter time to progression on tamoxifen. In addition, suppressing levels of the enzyme in a preclinical model reduced tamoxifen resistance. In an interview, Reuben Harris, Ph.D., professor in the department of biochemistry, molecular biology, and biophysics at the University of Minnesota, Minneapolis, discussed the study’s findings and what they mean for the conduct of clinical trials and for future research.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT SABCS 2015
VIDEO: Adjuvant capecitabine has role for residual disease after neoadjuvant therapy
SAN ANTONIO – Adjuvant capecitabine improved both disease-free and overall survival in women with HER2-negative breast cancer who had residual disease after neoadjuvant chemotherapy. In an interview, Dr. Masakazu Toi, a professor at Kyoto University Hospital, and founder and senior director of the Japan Breast Cancer Research Group, discusses the phase III CREATE-X trial and its implications for clinical care.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Adjuvant capecitabine improved both disease-free and overall survival in women with HER2-negative breast cancer who had residual disease after neoadjuvant chemotherapy. In an interview, Dr. Masakazu Toi, a professor at Kyoto University Hospital, and founder and senior director of the Japan Breast Cancer Research Group, discusses the phase III CREATE-X trial and its implications for clinical care.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Adjuvant capecitabine improved both disease-free and overall survival in women with HER2-negative breast cancer who had residual disease after neoadjuvant chemotherapy. In an interview, Dr. Masakazu Toi, a professor at Kyoto University Hospital, and founder and senior director of the Japan Breast Cancer Research Group, discusses the phase III CREATE-X trial and its implications for clinical care.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT SABCS 2015
