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Oxybutynin rapidly quells hot flashes
SAN ANTONIO – because of a history of or concern about breast cancer, suggests a phase 3 double-blind randomized controlled trial.
Managing hot flashes in breast cancer survivors is important for ensuring their adherence to endocrine therapy, as about a third fail to complete the recommended 5- to 7-year course, in part because of side effects, Roberto A. Leon-Ferre, MD, of the Mayo Clinic, Rochester, Minn., reported at the San Antonio Breast Cancer Symposium
But many survivors cannot use estrogen because of hormone receptor–positive disease, and currently used nonhormonal alternatives have drawbacks. “Some of these agents interfere with the metabolic activation of tamoxifen, for example. There is also the association, unfortunately, of the taboo of taking antidepressants or anticonvulsants when you don’t have those diagnoses,” he said. In addition, a variety of nonpharmacologic options, such as black cohosh and vitamin E, have not proved any more effective than placebo.
The 150 women enrolled in the trial, ACCRU study SC-1603, were experiencing frequent, bothersome hot flashes and had a history of or concern about breast cancer. The 6-week reduction in a hot flash score capturing both frequency and severity was about 30% with placebo, 65% with oxybutynin 2.5 mg b.i.d., and 80% with oxybutynin 5 mg b.i.d. (P less than .01 across groups and for each dose vs. placebo), with a difference emerging within 2 weeks. “These doses are on the lower end of the currently used doses for urinary incontinence,” Dr. Leon-Ferre noted, with that range extending up to 20 mg daily.
The oxybutynin groups also had significantly greater reductions in hot flash frequency alone and improvements in measures of quality of life such as sleep, work, and relations. The drug was well tolerated, with expected main side effects of dry mouth and difficulty urinating.
Despite the potential pitfalls of cross-trial comparisons, the magnitude of benefit with oxybutynin appeared to exceed that previously reported with clonidine, fluoxetine, citalopram, venlafaxine, and pregabalin, according to Dr. Leon-Ferre.
“Oxybutynin significantly improves hot flash frequency and severity. The use of oxybutynin, more importantly, is associated with a positive impact in several quality of life metrics. And toxicity was acceptable,” he said. “While the two oxybutynin doses were not formally compared, 5 mg twice daily appears to be more effective.”
Treatment considerations
“What is your current strategy for using this variety of drugs?” asked SABCS codirector and press conference moderator C. Kent Osborne, MD, director of the Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston. “Also, acupuncture has been shown to work in several randomized trials,” he noted.
“Before this study, we had been primarily using citalopram or venlafaxine as our first drug intervention. We typically favored venlafaxine for patients who are taking tamoxifen due to the concern about interaction with the CYP2D6 inhibitors,” Dr. Leon-Ferre replied. Oxybutynin is an attractive alternative here because patients can stop it abruptly if they want, whereas venlafaxine may require a lengthy period of tapering and weaning.
His institution doesn’t have a structured acupuncture program. “We do have acupuncturists, but they have to follow a specific program, it’s not any acupuncture. But we often recommend that patients pursue it if they have access to it,” he explained. “With the results of this particular study, we have become more keen on using oxybutynin. As a matter of fact, many of the patients who enrolled in this study decided to continue [or start] it after it had been revealed whether they were taking it or the placebo.”
As with all therapies, it is important to match the therapy to the patient, Dr. Leon-Ferre cautioned. “I can tell you that we have been using oxybutynin, but one has to be cautious about which patients to select for this because this is an anticholinergic drug. We were very careful about not including patients who had taken other potent anticholinergic drugs because these medications can lead to confusion episodes and altered mental status, particularly in more elderly patients and patients who suffer from polypharmacy and take many medications that start interacting with each other.” Another contraindication is urinary retention.
It is also noteworthy that women in the trial received just 6 weeks of oxybutynin therapy, as there has been some concern that extended use of anticholinergics can lead to memory issues.
“With those caveats, I think that if we have an informed decision, we could prescribe oxybutynin to patients,” Dr. Leon-Ferre said. “But ideally, I would say try to use it for a shorter rather than longer period of time.”
Study details
The women randomized in ACCRU study SC-1603 had had hot flashes for at least 30 days and were experiencing at least 28 of them each week. Concurrent stable-dose antidepressants, gabapentin, and pregabalin were allowed, whereas concurrent potent anticholinergics were not. Two-thirds of the women were on tamoxifen or an aromatase inhibitor.
In addition to the dramatic reduction in hot flash scores seen with oxybutynin, the drug was associated with marked reductions in hot flash frequency: 30% with placebo versus 60% with oxybutynin 2.5 mg b.i.d. and 75% with oxybutynin 5 mg b.i.d. (P less than .01 across groups and for each dose compared with placebo), Dr. Leon-Ferre reported.
Most of the 10 domains on the Hot Flash-Related Daily Interference Scale were significantly more improved with both doses of oxybutynin relative to placebo. The exceptions were mood and life enjoyment, which were significantly more improved only with the higher dose, and concentration and sexuality, which were not significantly more improved with either dose.
Both doses of oxybutynin were overall well tolerated, according to Dr. Leon-Ferre. Each was associated with higher incidence of dry mouth, abdominal pain, and difficulty urinating relative to placebo, as expected from what is known about the drug. The higher dose had a greater incidence of dry eyes, episodes of confusion, diarrhea, and headache.
Dr. Leon-Ferre disclosed that he had no conflicts of interest. The study was funded by the Breast Cancer Research Foundation.
SOURCE: Leon-Ferre RA et al. SABCS 2018 Abstract GS6-02.
SAN ANTONIO – because of a history of or concern about breast cancer, suggests a phase 3 double-blind randomized controlled trial.
Managing hot flashes in breast cancer survivors is important for ensuring their adherence to endocrine therapy, as about a third fail to complete the recommended 5- to 7-year course, in part because of side effects, Roberto A. Leon-Ferre, MD, of the Mayo Clinic, Rochester, Minn., reported at the San Antonio Breast Cancer Symposium
But many survivors cannot use estrogen because of hormone receptor–positive disease, and currently used nonhormonal alternatives have drawbacks. “Some of these agents interfere with the metabolic activation of tamoxifen, for example. There is also the association, unfortunately, of the taboo of taking antidepressants or anticonvulsants when you don’t have those diagnoses,” he said. In addition, a variety of nonpharmacologic options, such as black cohosh and vitamin E, have not proved any more effective than placebo.
The 150 women enrolled in the trial, ACCRU study SC-1603, were experiencing frequent, bothersome hot flashes and had a history of or concern about breast cancer. The 6-week reduction in a hot flash score capturing both frequency and severity was about 30% with placebo, 65% with oxybutynin 2.5 mg b.i.d., and 80% with oxybutynin 5 mg b.i.d. (P less than .01 across groups and for each dose vs. placebo), with a difference emerging within 2 weeks. “These doses are on the lower end of the currently used doses for urinary incontinence,” Dr. Leon-Ferre noted, with that range extending up to 20 mg daily.
The oxybutynin groups also had significantly greater reductions in hot flash frequency alone and improvements in measures of quality of life such as sleep, work, and relations. The drug was well tolerated, with expected main side effects of dry mouth and difficulty urinating.
Despite the potential pitfalls of cross-trial comparisons, the magnitude of benefit with oxybutynin appeared to exceed that previously reported with clonidine, fluoxetine, citalopram, venlafaxine, and pregabalin, according to Dr. Leon-Ferre.
“Oxybutynin significantly improves hot flash frequency and severity. The use of oxybutynin, more importantly, is associated with a positive impact in several quality of life metrics. And toxicity was acceptable,” he said. “While the two oxybutynin doses were not formally compared, 5 mg twice daily appears to be more effective.”
Treatment considerations
“What is your current strategy for using this variety of drugs?” asked SABCS codirector and press conference moderator C. Kent Osborne, MD, director of the Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston. “Also, acupuncture has been shown to work in several randomized trials,” he noted.
“Before this study, we had been primarily using citalopram or venlafaxine as our first drug intervention. We typically favored venlafaxine for patients who are taking tamoxifen due to the concern about interaction with the CYP2D6 inhibitors,” Dr. Leon-Ferre replied. Oxybutynin is an attractive alternative here because patients can stop it abruptly if they want, whereas venlafaxine may require a lengthy period of tapering and weaning.
His institution doesn’t have a structured acupuncture program. “We do have acupuncturists, but they have to follow a specific program, it’s not any acupuncture. But we often recommend that patients pursue it if they have access to it,” he explained. “With the results of this particular study, we have become more keen on using oxybutynin. As a matter of fact, many of the patients who enrolled in this study decided to continue [or start] it after it had been revealed whether they were taking it or the placebo.”
As with all therapies, it is important to match the therapy to the patient, Dr. Leon-Ferre cautioned. “I can tell you that we have been using oxybutynin, but one has to be cautious about which patients to select for this because this is an anticholinergic drug. We were very careful about not including patients who had taken other potent anticholinergic drugs because these medications can lead to confusion episodes and altered mental status, particularly in more elderly patients and patients who suffer from polypharmacy and take many medications that start interacting with each other.” Another contraindication is urinary retention.
It is also noteworthy that women in the trial received just 6 weeks of oxybutynin therapy, as there has been some concern that extended use of anticholinergics can lead to memory issues.
“With those caveats, I think that if we have an informed decision, we could prescribe oxybutynin to patients,” Dr. Leon-Ferre said. “But ideally, I would say try to use it for a shorter rather than longer period of time.”
Study details
The women randomized in ACCRU study SC-1603 had had hot flashes for at least 30 days and were experiencing at least 28 of them each week. Concurrent stable-dose antidepressants, gabapentin, and pregabalin were allowed, whereas concurrent potent anticholinergics were not. Two-thirds of the women were on tamoxifen or an aromatase inhibitor.
In addition to the dramatic reduction in hot flash scores seen with oxybutynin, the drug was associated with marked reductions in hot flash frequency: 30% with placebo versus 60% with oxybutynin 2.5 mg b.i.d. and 75% with oxybutynin 5 mg b.i.d. (P less than .01 across groups and for each dose compared with placebo), Dr. Leon-Ferre reported.
Most of the 10 domains on the Hot Flash-Related Daily Interference Scale were significantly more improved with both doses of oxybutynin relative to placebo. The exceptions were mood and life enjoyment, which were significantly more improved only with the higher dose, and concentration and sexuality, which were not significantly more improved with either dose.
Both doses of oxybutynin were overall well tolerated, according to Dr. Leon-Ferre. Each was associated with higher incidence of dry mouth, abdominal pain, and difficulty urinating relative to placebo, as expected from what is known about the drug. The higher dose had a greater incidence of dry eyes, episodes of confusion, diarrhea, and headache.
Dr. Leon-Ferre disclosed that he had no conflicts of interest. The study was funded by the Breast Cancer Research Foundation.
SOURCE: Leon-Ferre RA et al. SABCS 2018 Abstract GS6-02.
SAN ANTONIO – because of a history of or concern about breast cancer, suggests a phase 3 double-blind randomized controlled trial.
Managing hot flashes in breast cancer survivors is important for ensuring their adherence to endocrine therapy, as about a third fail to complete the recommended 5- to 7-year course, in part because of side effects, Roberto A. Leon-Ferre, MD, of the Mayo Clinic, Rochester, Minn., reported at the San Antonio Breast Cancer Symposium
But many survivors cannot use estrogen because of hormone receptor–positive disease, and currently used nonhormonal alternatives have drawbacks. “Some of these agents interfere with the metabolic activation of tamoxifen, for example. There is also the association, unfortunately, of the taboo of taking antidepressants or anticonvulsants when you don’t have those diagnoses,” he said. In addition, a variety of nonpharmacologic options, such as black cohosh and vitamin E, have not proved any more effective than placebo.
The 150 women enrolled in the trial, ACCRU study SC-1603, were experiencing frequent, bothersome hot flashes and had a history of or concern about breast cancer. The 6-week reduction in a hot flash score capturing both frequency and severity was about 30% with placebo, 65% with oxybutynin 2.5 mg b.i.d., and 80% with oxybutynin 5 mg b.i.d. (P less than .01 across groups and for each dose vs. placebo), with a difference emerging within 2 weeks. “These doses are on the lower end of the currently used doses for urinary incontinence,” Dr. Leon-Ferre noted, with that range extending up to 20 mg daily.
The oxybutynin groups also had significantly greater reductions in hot flash frequency alone and improvements in measures of quality of life such as sleep, work, and relations. The drug was well tolerated, with expected main side effects of dry mouth and difficulty urinating.
Despite the potential pitfalls of cross-trial comparisons, the magnitude of benefit with oxybutynin appeared to exceed that previously reported with clonidine, fluoxetine, citalopram, venlafaxine, and pregabalin, according to Dr. Leon-Ferre.
“Oxybutynin significantly improves hot flash frequency and severity. The use of oxybutynin, more importantly, is associated with a positive impact in several quality of life metrics. And toxicity was acceptable,” he said. “While the two oxybutynin doses were not formally compared, 5 mg twice daily appears to be more effective.”
Treatment considerations
“What is your current strategy for using this variety of drugs?” asked SABCS codirector and press conference moderator C. Kent Osborne, MD, director of the Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston. “Also, acupuncture has been shown to work in several randomized trials,” he noted.
“Before this study, we had been primarily using citalopram or venlafaxine as our first drug intervention. We typically favored venlafaxine for patients who are taking tamoxifen due to the concern about interaction with the CYP2D6 inhibitors,” Dr. Leon-Ferre replied. Oxybutynin is an attractive alternative here because patients can stop it abruptly if they want, whereas venlafaxine may require a lengthy period of tapering and weaning.
His institution doesn’t have a structured acupuncture program. “We do have acupuncturists, but they have to follow a specific program, it’s not any acupuncture. But we often recommend that patients pursue it if they have access to it,” he explained. “With the results of this particular study, we have become more keen on using oxybutynin. As a matter of fact, many of the patients who enrolled in this study decided to continue [or start] it after it had been revealed whether they were taking it or the placebo.”
As with all therapies, it is important to match the therapy to the patient, Dr. Leon-Ferre cautioned. “I can tell you that we have been using oxybutynin, but one has to be cautious about which patients to select for this because this is an anticholinergic drug. We were very careful about not including patients who had taken other potent anticholinergic drugs because these medications can lead to confusion episodes and altered mental status, particularly in more elderly patients and patients who suffer from polypharmacy and take many medications that start interacting with each other.” Another contraindication is urinary retention.
It is also noteworthy that women in the trial received just 6 weeks of oxybutynin therapy, as there has been some concern that extended use of anticholinergics can lead to memory issues.
“With those caveats, I think that if we have an informed decision, we could prescribe oxybutynin to patients,” Dr. Leon-Ferre said. “But ideally, I would say try to use it for a shorter rather than longer period of time.”
Study details
The women randomized in ACCRU study SC-1603 had had hot flashes for at least 30 days and were experiencing at least 28 of them each week. Concurrent stable-dose antidepressants, gabapentin, and pregabalin were allowed, whereas concurrent potent anticholinergics were not. Two-thirds of the women were on tamoxifen or an aromatase inhibitor.
In addition to the dramatic reduction in hot flash scores seen with oxybutynin, the drug was associated with marked reductions in hot flash frequency: 30% with placebo versus 60% with oxybutynin 2.5 mg b.i.d. and 75% with oxybutynin 5 mg b.i.d. (P less than .01 across groups and for each dose compared with placebo), Dr. Leon-Ferre reported.
Most of the 10 domains on the Hot Flash-Related Daily Interference Scale were significantly more improved with both doses of oxybutynin relative to placebo. The exceptions were mood and life enjoyment, which were significantly more improved only with the higher dose, and concentration and sexuality, which were not significantly more improved with either dose.
Both doses of oxybutynin were overall well tolerated, according to Dr. Leon-Ferre. Each was associated with higher incidence of dry mouth, abdominal pain, and difficulty urinating relative to placebo, as expected from what is known about the drug. The higher dose had a greater incidence of dry eyes, episodes of confusion, diarrhea, and headache.
Dr. Leon-Ferre disclosed that he had no conflicts of interest. The study was funded by the Breast Cancer Research Foundation.
SOURCE: Leon-Ferre RA et al. SABCS 2018 Abstract GS6-02.
REPORTING FROM SABCS 2018
Partial- and whole-breast irradiation very close in efficacy
SAN ANTONIO – , suggests a phase 3, randomized, controlled trial conducted by NRG Oncology.
At a median follow-up of 10.2 years, the trial was unable to refute the hypothesis that the partial technique was inferior in terms of ipsilateral breast tumor recurrences; however, the difference between techniques in this outcome was an absolute 0.7%, lead investigator Frank Vicini, MD, principal investigator at the MHP Radiation Oncology Institute/21st Century Oncology in Pontiac, Mich., reported in a session and press conference at the San Antonio Breast Cancer Symposium. The difference in recurrence-free interval was significant but likewise small, at 1.6%, and other efficacy outcomes were similar.
Meanwhile, the groups had low, statistically indistinguishable rates of grade 3-5 toxicities and second cancers. The investigators are still analyzing quality of life and cosmesis outcomes.
“This was the largest trial ever looking at partial-breast [irradiation] in a very diverse group of patients. Even though we weren’t able to demonstrate equivalence, it’s nice to see that in this large population of patients with extended follow-up, the differences are quite small,” Dr. Vicini said. “Because the differences for both ipsilateral breast tumor recurrence and recurrence-free interval were very small, partial-breast irradiation may be an acceptable alternative to whole-breast irradiation for a proportion of women who are undergoing breast-conserving surgery.”
Implications for practice and research
SABCS codirector and press conference moderator Virginia Kaklamani, MD, leader of the breast cancer program at UT Health San Antonio, asked how the findings have influenced his practice.
“This trial is over 15 years old now, and a lot of these techniques have been refined. But we are offering partial-breast irradiation to our patients,” Dr. Vicini replied. “There are a lot of competing ways to do radiation now; probably the biggest competing way is to do 3 weeks of whole-breast irradiation. But for those patients who have transportation issues and more elderly patients, we try to offer partial-breast irradiation, within the guidelines of ASTRO [American Society for Therapeutic Radiology and Oncology].”
Some of the women enrolled had risk factors that fall outside those guidelines, for example, higher-grade tumors or axillary node involvement, he acknowledged. “We tried to do exploratory analyses to look at whether certain patients did better with whole-breast irradiation or not, and we weren’t able to really pick out any group of patients that had better or worse outcome based on those criteria,” he said. “We have yet to look at the quality indices for radiation therapy, in other words, how much the breast actually needs to be treated. But at the present time, I would just suggest sticking with the ASTRO guidelines.”
It is noteworthy that likely the most important endpoints, disease-free and overall survival, did not differ between groups, according to Dr. Vicini. “Certainly, a recurrence is still an important event for a patient, so our goal is to always limit that as much as possible,” he said. “But putting it into perspective, does a 0.7% higher risk of recurrence [matter] when you know the survival rates are the same? That’s what patients and doctors need to take into consideration. This is a pretty dramatic difference in treatment [duration], 6 weeks, down to 1 week or less. There have been many studies looking at quality of life and, as you can imagine, quality of life is better” with the shorter therapy.
The trial’s results can also inform statistical planning of future trials, according to Dr. Kaklamani. “It’s important when we design the trials to look at clinically meaningful differences because we don’t want to harm our patients, but at the same time, we are also harming them by giving them more treatment. So if you are designing a trial where a 0.7% difference is statistically significant, you probably would have been able to get away with many fewer patients and a difference of 1.5% or 2% not being significant, and I think everybody would be happy with that.”
Study details
Dr. Vicini and colleagues enrolled in their trial 4,216 women with stage 0-II breast cancer who had undergone lumpectomy. They were randomized to whole-breast irradiation (5-6 weeks of radiation therapy at that time) or partial-breast irradiation using one of three techniques (3D conformal external beam radiation completed in 5 days, interstitial brachytherapy completed in 5 days, or device-based brachytherapy).
The hazard ratio for ipsilateral breast tumor recurrence (invasive or DCIS) as a first recurrence with partial-breast irradiation versus whole-breast irradiation was 1.22, with the upper bound of the 90% confidence interval (0.94-1.58) falling just outside the predefined range to declare the two modalities equivalent (0.667-1.5), Dr. Vicini reported. However, the absolute difference in the 10-year cumulative incidence of ipsilateral breast tumor recurrences was merely 0.7% (4.6% vs. 3.9%).
The 10-year recurrence-free interval was inferior with partial-breast irradiation (hazard ratio, 1.33; P = .02), but the absolute difference was again small at 1.6% (91.8% vs 93.4%). The partial- and whole-breast irradiation groups were statistically indistinguishable on distant disease-free interval (96.7% vs 97.1%; HR, 1.31; P = .15) and overall survival (90.6% vs. 91.3%; HR, 1.10; P = .35).
Dr. Vicini disclosed that he is a research advisor for ImpediMed. The study was sponsored by the National Cancer Institute.
SOURCE: Vicini FA et al. SABCS 2018, Abstract GS4-04,
SAN ANTONIO – , suggests a phase 3, randomized, controlled trial conducted by NRG Oncology.
At a median follow-up of 10.2 years, the trial was unable to refute the hypothesis that the partial technique was inferior in terms of ipsilateral breast tumor recurrences; however, the difference between techniques in this outcome was an absolute 0.7%, lead investigator Frank Vicini, MD, principal investigator at the MHP Radiation Oncology Institute/21st Century Oncology in Pontiac, Mich., reported in a session and press conference at the San Antonio Breast Cancer Symposium. The difference in recurrence-free interval was significant but likewise small, at 1.6%, and other efficacy outcomes were similar.
Meanwhile, the groups had low, statistically indistinguishable rates of grade 3-5 toxicities and second cancers. The investigators are still analyzing quality of life and cosmesis outcomes.
“This was the largest trial ever looking at partial-breast [irradiation] in a very diverse group of patients. Even though we weren’t able to demonstrate equivalence, it’s nice to see that in this large population of patients with extended follow-up, the differences are quite small,” Dr. Vicini said. “Because the differences for both ipsilateral breast tumor recurrence and recurrence-free interval were very small, partial-breast irradiation may be an acceptable alternative to whole-breast irradiation for a proportion of women who are undergoing breast-conserving surgery.”
Implications for practice and research
SABCS codirector and press conference moderator Virginia Kaklamani, MD, leader of the breast cancer program at UT Health San Antonio, asked how the findings have influenced his practice.
“This trial is over 15 years old now, and a lot of these techniques have been refined. But we are offering partial-breast irradiation to our patients,” Dr. Vicini replied. “There are a lot of competing ways to do radiation now; probably the biggest competing way is to do 3 weeks of whole-breast irradiation. But for those patients who have transportation issues and more elderly patients, we try to offer partial-breast irradiation, within the guidelines of ASTRO [American Society for Therapeutic Radiology and Oncology].”
Some of the women enrolled had risk factors that fall outside those guidelines, for example, higher-grade tumors or axillary node involvement, he acknowledged. “We tried to do exploratory analyses to look at whether certain patients did better with whole-breast irradiation or not, and we weren’t able to really pick out any group of patients that had better or worse outcome based on those criteria,” he said. “We have yet to look at the quality indices for radiation therapy, in other words, how much the breast actually needs to be treated. But at the present time, I would just suggest sticking with the ASTRO guidelines.”
It is noteworthy that likely the most important endpoints, disease-free and overall survival, did not differ between groups, according to Dr. Vicini. “Certainly, a recurrence is still an important event for a patient, so our goal is to always limit that as much as possible,” he said. “But putting it into perspective, does a 0.7% higher risk of recurrence [matter] when you know the survival rates are the same? That’s what patients and doctors need to take into consideration. This is a pretty dramatic difference in treatment [duration], 6 weeks, down to 1 week or less. There have been many studies looking at quality of life and, as you can imagine, quality of life is better” with the shorter therapy.
The trial’s results can also inform statistical planning of future trials, according to Dr. Kaklamani. “It’s important when we design the trials to look at clinically meaningful differences because we don’t want to harm our patients, but at the same time, we are also harming them by giving them more treatment. So if you are designing a trial where a 0.7% difference is statistically significant, you probably would have been able to get away with many fewer patients and a difference of 1.5% or 2% not being significant, and I think everybody would be happy with that.”
Study details
Dr. Vicini and colleagues enrolled in their trial 4,216 women with stage 0-II breast cancer who had undergone lumpectomy. They were randomized to whole-breast irradiation (5-6 weeks of radiation therapy at that time) or partial-breast irradiation using one of three techniques (3D conformal external beam radiation completed in 5 days, interstitial brachytherapy completed in 5 days, or device-based brachytherapy).
The hazard ratio for ipsilateral breast tumor recurrence (invasive or DCIS) as a first recurrence with partial-breast irradiation versus whole-breast irradiation was 1.22, with the upper bound of the 90% confidence interval (0.94-1.58) falling just outside the predefined range to declare the two modalities equivalent (0.667-1.5), Dr. Vicini reported. However, the absolute difference in the 10-year cumulative incidence of ipsilateral breast tumor recurrences was merely 0.7% (4.6% vs. 3.9%).
The 10-year recurrence-free interval was inferior with partial-breast irradiation (hazard ratio, 1.33; P = .02), but the absolute difference was again small at 1.6% (91.8% vs 93.4%). The partial- and whole-breast irradiation groups were statistically indistinguishable on distant disease-free interval (96.7% vs 97.1%; HR, 1.31; P = .15) and overall survival (90.6% vs. 91.3%; HR, 1.10; P = .35).
Dr. Vicini disclosed that he is a research advisor for ImpediMed. The study was sponsored by the National Cancer Institute.
SOURCE: Vicini FA et al. SABCS 2018, Abstract GS4-04,
SAN ANTONIO – , suggests a phase 3, randomized, controlled trial conducted by NRG Oncology.
At a median follow-up of 10.2 years, the trial was unable to refute the hypothesis that the partial technique was inferior in terms of ipsilateral breast tumor recurrences; however, the difference between techniques in this outcome was an absolute 0.7%, lead investigator Frank Vicini, MD, principal investigator at the MHP Radiation Oncology Institute/21st Century Oncology in Pontiac, Mich., reported in a session and press conference at the San Antonio Breast Cancer Symposium. The difference in recurrence-free interval was significant but likewise small, at 1.6%, and other efficacy outcomes were similar.
Meanwhile, the groups had low, statistically indistinguishable rates of grade 3-5 toxicities and second cancers. The investigators are still analyzing quality of life and cosmesis outcomes.
“This was the largest trial ever looking at partial-breast [irradiation] in a very diverse group of patients. Even though we weren’t able to demonstrate equivalence, it’s nice to see that in this large population of patients with extended follow-up, the differences are quite small,” Dr. Vicini said. “Because the differences for both ipsilateral breast tumor recurrence and recurrence-free interval were very small, partial-breast irradiation may be an acceptable alternative to whole-breast irradiation for a proportion of women who are undergoing breast-conserving surgery.”
Implications for practice and research
SABCS codirector and press conference moderator Virginia Kaklamani, MD, leader of the breast cancer program at UT Health San Antonio, asked how the findings have influenced his practice.
“This trial is over 15 years old now, and a lot of these techniques have been refined. But we are offering partial-breast irradiation to our patients,” Dr. Vicini replied. “There are a lot of competing ways to do radiation now; probably the biggest competing way is to do 3 weeks of whole-breast irradiation. But for those patients who have transportation issues and more elderly patients, we try to offer partial-breast irradiation, within the guidelines of ASTRO [American Society for Therapeutic Radiology and Oncology].”
Some of the women enrolled had risk factors that fall outside those guidelines, for example, higher-grade tumors or axillary node involvement, he acknowledged. “We tried to do exploratory analyses to look at whether certain patients did better with whole-breast irradiation or not, and we weren’t able to really pick out any group of patients that had better or worse outcome based on those criteria,” he said. “We have yet to look at the quality indices for radiation therapy, in other words, how much the breast actually needs to be treated. But at the present time, I would just suggest sticking with the ASTRO guidelines.”
It is noteworthy that likely the most important endpoints, disease-free and overall survival, did not differ between groups, according to Dr. Vicini. “Certainly, a recurrence is still an important event for a patient, so our goal is to always limit that as much as possible,” he said. “But putting it into perspective, does a 0.7% higher risk of recurrence [matter] when you know the survival rates are the same? That’s what patients and doctors need to take into consideration. This is a pretty dramatic difference in treatment [duration], 6 weeks, down to 1 week or less. There have been many studies looking at quality of life and, as you can imagine, quality of life is better” with the shorter therapy.
The trial’s results can also inform statistical planning of future trials, according to Dr. Kaklamani. “It’s important when we design the trials to look at clinically meaningful differences because we don’t want to harm our patients, but at the same time, we are also harming them by giving them more treatment. So if you are designing a trial where a 0.7% difference is statistically significant, you probably would have been able to get away with many fewer patients and a difference of 1.5% or 2% not being significant, and I think everybody would be happy with that.”
Study details
Dr. Vicini and colleagues enrolled in their trial 4,216 women with stage 0-II breast cancer who had undergone lumpectomy. They were randomized to whole-breast irradiation (5-6 weeks of radiation therapy at that time) or partial-breast irradiation using one of three techniques (3D conformal external beam radiation completed in 5 days, interstitial brachytherapy completed in 5 days, or device-based brachytherapy).
The hazard ratio for ipsilateral breast tumor recurrence (invasive or DCIS) as a first recurrence with partial-breast irradiation versus whole-breast irradiation was 1.22, with the upper bound of the 90% confidence interval (0.94-1.58) falling just outside the predefined range to declare the two modalities equivalent (0.667-1.5), Dr. Vicini reported. However, the absolute difference in the 10-year cumulative incidence of ipsilateral breast tumor recurrences was merely 0.7% (4.6% vs. 3.9%).
The 10-year recurrence-free interval was inferior with partial-breast irradiation (hazard ratio, 1.33; P = .02), but the absolute difference was again small at 1.6% (91.8% vs 93.4%). The partial- and whole-breast irradiation groups were statistically indistinguishable on distant disease-free interval (96.7% vs 97.1%; HR, 1.31; P = .15) and overall survival (90.6% vs. 91.3%; HR, 1.10; P = .35).
Dr. Vicini disclosed that he is a research advisor for ImpediMed. The study was sponsored by the National Cancer Institute.
SOURCE: Vicini FA et al. SABCS 2018, Abstract GS4-04,
REPORTING FROM SABCS 2018
Key clinical point: Partial- and whole-breast irradiation yield outcomes that are statistically nonequivalent but very similar.
Major finding: The hazard ratio for ipsilateral recurrences with partial- vs. whole-breast irradiation was 1.22, with the confidence interval falling just outside the range for equivalence, but the absolute difference in 10-year rate was just 0.7% (4.6% vs. 3.9%).
Study details: A phase 3, randomized, controlled trial among women who underwent lumpectomy for stage 0-II breast cancer, conducted by NRG Oncology (NSABP B-39/RTOG 0413).
Disclosures: Dr. Vicini disclosed that he is a research advisor for ImpediMed. The study was sponsored by the National Cancer Institute.
Source: Vicini FA et al. SABCS 2018, Abstract GS4-04.
CTC counts signal treatment choice in ER-positive/HER2-negative metastatic breast cancer
SAN ANTONIO – Circulating tumor cell (CTC) counts could serve as a standalone biomarker for determining which patients with newly diagnosed estrogen receptor–positive, HER2-negative metastatic breast cancer are at high risk and should receive first-line chemotherapy and which are at low risk and could safely receive upfront hormonal therapy.
In the phase 3 STIC CTC trial, there were no significant differences in the primary endpoint of progression-free survival (PFS) or a secondary endpoint of overall survival (OS) between patients whose treatments were assigned according to the clinicians’ judgment and those whose treatments were chosen based on CTC count, reported Francois-Clement Bidard, MD, PhD, from Institut Curie in St. Cloud, France.
“CTC count should or may be included in the decision algorithm for hormone receptor–positive, HER2-negative metastatic breast cancer patients,” he said at the San Antonio Breast Cancer Symposium.
The CTC investigators sought to compare CTC-driven clinical decisions with the clinicians choice for first-line therapy in 778 patients with hormone receptor–positive, HER2-negative breast cancer.
Patients were stratified by performance status (0-3), treatment center, and disease-free interval and were randomly assigned to receive therapy based on either the clinician’s judgment of the best course of therapy for each patient or to CTC count, with a cutoff of less than 5 CTC/7.5 mL indicating hormonal therapy and 5 CTC/7.5 mL or above indicating higher-risk disease requiring chemotherapy. In the clinician’s choice arm, the CTC reading was recorded but not implemented, and in the CTC arm, the clinician’s choice was dismissed.
The trial protocol did not specify a chemotherapy regimen, and patients initially assigned to chemotherapy were allowed to have maintenance hormonal therapy.
At 42 months of follow-up, median PFS in the CTC arm was 15.6 months, compared with 14.0 months in the clinician choice arm. The hazard ratio for PFS was 0.92 (90% confidence interval, 0.80-1.06), and the trial met its primary noninferiority endpoint with a prespecified noninferiority margin of 1.25.
The OS rate at 24 months in the CTC group was 82.1%, and in the clinician choice arm was 81.4% (nonsignificant).
Planned subgroup analyses in which the two decision methods were in agreement on whether a patient was at either low or high risk found no significant differences in either PFS or OS, showing that the CTC count complemented the prognostic estimate and isolated patients with either excellent or poor outcomes.
However, when the clinician rated the risk as low but the CTC count rated it as high (196 patients), PFS was significantly higher with CTC (HR, 0.62; P = .002). OS did not differ in this circumstance.
In an exploratory analysis combining all patients with discordant findings (clinician low/CTC high or vice versa), the investigators determined that chemotherapy would offer a significant advantage for both PFS (HR, 0.66; adjusted P = .001) and OS (HR, 0.65; adjusted P = .04).
Virginia Kaklamani, MD, leader of the breast cancer program at the University of Texas, San Antonio, who moderated a briefing where Dr. Bidard discussed the findings prior to presentation in a general session, said that she is not fully convinced that CTC counts can substitute for the clinician’s discretion. “I would probably want to see another study or some more data.”
She noted that for the patient population in this study clinicians today often prescribe cyclin-dependent kinase (CDK) 4/6 inhibitors in the first-line setting over conventional chemotherapy.
“But it is true that CDK 4/6 inhibitors, besides their cost, $10,000 a month, also are toxic to our patients. They cause neutropenias, increase infections, some diarrhea, so if there is a group I can potentially save from taking a CDK 4/6 inhibitor in the first-line setting I’d love to do that. In the metastatic setting what we’re trying to do for years is deescalate therapy, so the idea of giving chemotherapy instead of endocrine therapy is a little foreign to us,” Dr. Kaklamani said.
The strength of the study, however, is that it’s the first to show a survival benefit using CTCs as a diagnostic aid, she added.
Lisa A. Carey, MD, from the University of North Carolina at Chapel Hill, who was not involved in the study, said in an interview that the technology is promising, but not ready for prime time.
“To be honest, it didn’t appear to me that it helped very much, so that particular approach I don’t think is likely to have much benefit for patients. But the concept is an excellent one, and I do think that’s something we need to take home, that this is an area of an unmet need,” she said.
The study was funded by the National Cancer Institute of France, Institut Curie, and Menarini. Dr. Bidard reported receiving research funding and travel grants from Menarini. Dr. Kaklamani and Dr. Carey reported having no relevant conflicts of interest.
SOURCE: Bidard F-C et al. SABCS 2018, Abstract GS3-07.
SAN ANTONIO – Circulating tumor cell (CTC) counts could serve as a standalone biomarker for determining which patients with newly diagnosed estrogen receptor–positive, HER2-negative metastatic breast cancer are at high risk and should receive first-line chemotherapy and which are at low risk and could safely receive upfront hormonal therapy.
In the phase 3 STIC CTC trial, there were no significant differences in the primary endpoint of progression-free survival (PFS) or a secondary endpoint of overall survival (OS) between patients whose treatments were assigned according to the clinicians’ judgment and those whose treatments were chosen based on CTC count, reported Francois-Clement Bidard, MD, PhD, from Institut Curie in St. Cloud, France.
“CTC count should or may be included in the decision algorithm for hormone receptor–positive, HER2-negative metastatic breast cancer patients,” he said at the San Antonio Breast Cancer Symposium.
The CTC investigators sought to compare CTC-driven clinical decisions with the clinicians choice for first-line therapy in 778 patients with hormone receptor–positive, HER2-negative breast cancer.
Patients were stratified by performance status (0-3), treatment center, and disease-free interval and were randomly assigned to receive therapy based on either the clinician’s judgment of the best course of therapy for each patient or to CTC count, with a cutoff of less than 5 CTC/7.5 mL indicating hormonal therapy and 5 CTC/7.5 mL or above indicating higher-risk disease requiring chemotherapy. In the clinician’s choice arm, the CTC reading was recorded but not implemented, and in the CTC arm, the clinician’s choice was dismissed.
The trial protocol did not specify a chemotherapy regimen, and patients initially assigned to chemotherapy were allowed to have maintenance hormonal therapy.
At 42 months of follow-up, median PFS in the CTC arm was 15.6 months, compared with 14.0 months in the clinician choice arm. The hazard ratio for PFS was 0.92 (90% confidence interval, 0.80-1.06), and the trial met its primary noninferiority endpoint with a prespecified noninferiority margin of 1.25.
The OS rate at 24 months in the CTC group was 82.1%, and in the clinician choice arm was 81.4% (nonsignificant).
Planned subgroup analyses in which the two decision methods were in agreement on whether a patient was at either low or high risk found no significant differences in either PFS or OS, showing that the CTC count complemented the prognostic estimate and isolated patients with either excellent or poor outcomes.
However, when the clinician rated the risk as low but the CTC count rated it as high (196 patients), PFS was significantly higher with CTC (HR, 0.62; P = .002). OS did not differ in this circumstance.
In an exploratory analysis combining all patients with discordant findings (clinician low/CTC high or vice versa), the investigators determined that chemotherapy would offer a significant advantage for both PFS (HR, 0.66; adjusted P = .001) and OS (HR, 0.65; adjusted P = .04).
Virginia Kaklamani, MD, leader of the breast cancer program at the University of Texas, San Antonio, who moderated a briefing where Dr. Bidard discussed the findings prior to presentation in a general session, said that she is not fully convinced that CTC counts can substitute for the clinician’s discretion. “I would probably want to see another study or some more data.”
She noted that for the patient population in this study clinicians today often prescribe cyclin-dependent kinase (CDK) 4/6 inhibitors in the first-line setting over conventional chemotherapy.
“But it is true that CDK 4/6 inhibitors, besides their cost, $10,000 a month, also are toxic to our patients. They cause neutropenias, increase infections, some diarrhea, so if there is a group I can potentially save from taking a CDK 4/6 inhibitor in the first-line setting I’d love to do that. In the metastatic setting what we’re trying to do for years is deescalate therapy, so the idea of giving chemotherapy instead of endocrine therapy is a little foreign to us,” Dr. Kaklamani said.
The strength of the study, however, is that it’s the first to show a survival benefit using CTCs as a diagnostic aid, she added.
Lisa A. Carey, MD, from the University of North Carolina at Chapel Hill, who was not involved in the study, said in an interview that the technology is promising, but not ready for prime time.
“To be honest, it didn’t appear to me that it helped very much, so that particular approach I don’t think is likely to have much benefit for patients. But the concept is an excellent one, and I do think that’s something we need to take home, that this is an area of an unmet need,” she said.
The study was funded by the National Cancer Institute of France, Institut Curie, and Menarini. Dr. Bidard reported receiving research funding and travel grants from Menarini. Dr. Kaklamani and Dr. Carey reported having no relevant conflicts of interest.
SOURCE: Bidard F-C et al. SABCS 2018, Abstract GS3-07.
SAN ANTONIO – Circulating tumor cell (CTC) counts could serve as a standalone biomarker for determining which patients with newly diagnosed estrogen receptor–positive, HER2-negative metastatic breast cancer are at high risk and should receive first-line chemotherapy and which are at low risk and could safely receive upfront hormonal therapy.
In the phase 3 STIC CTC trial, there were no significant differences in the primary endpoint of progression-free survival (PFS) or a secondary endpoint of overall survival (OS) between patients whose treatments were assigned according to the clinicians’ judgment and those whose treatments were chosen based on CTC count, reported Francois-Clement Bidard, MD, PhD, from Institut Curie in St. Cloud, France.
“CTC count should or may be included in the decision algorithm for hormone receptor–positive, HER2-negative metastatic breast cancer patients,” he said at the San Antonio Breast Cancer Symposium.
The CTC investigators sought to compare CTC-driven clinical decisions with the clinicians choice for first-line therapy in 778 patients with hormone receptor–positive, HER2-negative breast cancer.
Patients were stratified by performance status (0-3), treatment center, and disease-free interval and were randomly assigned to receive therapy based on either the clinician’s judgment of the best course of therapy for each patient or to CTC count, with a cutoff of less than 5 CTC/7.5 mL indicating hormonal therapy and 5 CTC/7.5 mL or above indicating higher-risk disease requiring chemotherapy. In the clinician’s choice arm, the CTC reading was recorded but not implemented, and in the CTC arm, the clinician’s choice was dismissed.
The trial protocol did not specify a chemotherapy regimen, and patients initially assigned to chemotherapy were allowed to have maintenance hormonal therapy.
At 42 months of follow-up, median PFS in the CTC arm was 15.6 months, compared with 14.0 months in the clinician choice arm. The hazard ratio for PFS was 0.92 (90% confidence interval, 0.80-1.06), and the trial met its primary noninferiority endpoint with a prespecified noninferiority margin of 1.25.
The OS rate at 24 months in the CTC group was 82.1%, and in the clinician choice arm was 81.4% (nonsignificant).
Planned subgroup analyses in which the two decision methods were in agreement on whether a patient was at either low or high risk found no significant differences in either PFS or OS, showing that the CTC count complemented the prognostic estimate and isolated patients with either excellent or poor outcomes.
However, when the clinician rated the risk as low but the CTC count rated it as high (196 patients), PFS was significantly higher with CTC (HR, 0.62; P = .002). OS did not differ in this circumstance.
In an exploratory analysis combining all patients with discordant findings (clinician low/CTC high or vice versa), the investigators determined that chemotherapy would offer a significant advantage for both PFS (HR, 0.66; adjusted P = .001) and OS (HR, 0.65; adjusted P = .04).
Virginia Kaklamani, MD, leader of the breast cancer program at the University of Texas, San Antonio, who moderated a briefing where Dr. Bidard discussed the findings prior to presentation in a general session, said that she is not fully convinced that CTC counts can substitute for the clinician’s discretion. “I would probably want to see another study or some more data.”
She noted that for the patient population in this study clinicians today often prescribe cyclin-dependent kinase (CDK) 4/6 inhibitors in the first-line setting over conventional chemotherapy.
“But it is true that CDK 4/6 inhibitors, besides their cost, $10,000 a month, also are toxic to our patients. They cause neutropenias, increase infections, some diarrhea, so if there is a group I can potentially save from taking a CDK 4/6 inhibitor in the first-line setting I’d love to do that. In the metastatic setting what we’re trying to do for years is deescalate therapy, so the idea of giving chemotherapy instead of endocrine therapy is a little foreign to us,” Dr. Kaklamani said.
The strength of the study, however, is that it’s the first to show a survival benefit using CTCs as a diagnostic aid, she added.
Lisa A. Carey, MD, from the University of North Carolina at Chapel Hill, who was not involved in the study, said in an interview that the technology is promising, but not ready for prime time.
“To be honest, it didn’t appear to me that it helped very much, so that particular approach I don’t think is likely to have much benefit for patients. But the concept is an excellent one, and I do think that’s something we need to take home, that this is an area of an unmet need,” she said.
The study was funded by the National Cancer Institute of France, Institut Curie, and Menarini. Dr. Bidard reported receiving research funding and travel grants from Menarini. Dr. Kaklamani and Dr. Carey reported having no relevant conflicts of interest.
SOURCE: Bidard F-C et al. SABCS 2018, Abstract GS3-07.
REPORTING FROM SABCS 2018
Key clinical point: Patients assigned to therapy based on circulating tumor cell (CTC) counts or clinician choice had no significant differences in progression-free survival or overall survival.
Major finding: At 42 months of follow-up, median progression-free survival in the circulating tumor cell arm was 15.6 months versus 14.0 months in the clinician choice arm.
Study details: A randomized, phase 3 trial in 778 patients with previously untreated estrogen receptor–positive/HER2-negative metastatic breast cancer.
Disclosures: The study was funded by the National Cancer Institute of France, Institut Curie, and Menarini Silicon Biosystems. Dr. Bidard disclosed research funding and travel grants from Menarini. Dr. Kaklamani and Dr. Carey reported having no relevant conflicts of interest.
Source: Bidard F-C et al. SABCS 2018, Abstract GS3-07.
AMAROS: Radiation has edge for axillary treatment
SAN ANTONIO – For treatment of the axilla in women with early-stage breast cancer having a positive sentinel node, the risk-benefit calculus tilts toward radiation therapy over axillary lymph node dissection, finds an update of the phase 3, noninferiority, randomized AMAROS trial.
The trial’s previously reported 5-year results showed noninferiority of axillary radiation relative to axillary lymph node dissection (ALND) with respect to axillary recurrences, as well as less lymphedema (Lancet Oncol. 2014 Nov;15(12):1303-10). But the trial was criticized as being underpowered and having insufficient follow-up, according to principal investigator Emiel J. T. Rutgers, MD, PhD, of the Netherlands Cancer Institute in Amsterdam.
Now, at a median follow-up of 10 years, findings were basically the same, with few additional axillary recurrences having occurred in either group, he reported in a session and press conference at the San Antonio Breast Cancer Symposium. There was a nonsignificant difference in the very-low 10-year cumulative incidences of axillary recurrence, and no significant difference in other efficacy outcomes. Meanwhile, an update of the rate of lymphedema at 5 years continued to show that this treatment complication was about half as common with radiation.
The radiation therapy group did have a higher risk of second primaries, with an absolute difference of about 4%, mainly driven by more contralateral breast cancers. But it was unclear whether this difference was related to the radiation, according to Dr. Rutgers.
“Both axillary clearance and radiotherapy provide excellent, comparable locoregional control in patients who have a positive sentinel node in the axilla,” he summarized. “After 10 years [of follow-up], there is significantly less lymphedema after radiation therapy at 5 years, and therefore this can be considered a standard procedure.”
Putting data into practice
SABCS codirector and press conference moderator Virginia Kaklamani, MD, leader of the breast cancer program at University of Texas, San Antonio, wondered how Dr. Rutger’s institution has incorporated findings of the AMAROS trial and findings of the previously reported ACOSOG Z11 trial (JAMA. 2011;305:569-75).
They apply both, on a case-by-case basis, he replied. “If it’s limited node involvement in early breast cancer – and of course that’s subjective, we have some cutoffs for that – we do nothing if the sentinel node is positive. If it’s a larger tumor, high grade, lymphovascular invasion, and there are two positive sentinel nodes, then we irradiate the axilla according to the AMAROS trial. This is a discussion within our tumor board, of course, with the multidisciplinary team and together with the patient.”
Over the past 20 years, the percentage of women at his institute undergoing axillary clearance has fallen sharply, from about 75% to merely 3%, as a result of introduction of and growing evidence on sentinel node biopsy, advances in radiation therapy, and increased use of neoadjuvant chemotherapy, according to Dr. Rutgers. “At our institute, an axillary clearance in breast cancer is a rare operation for our residents. They have to go to the melanoma doctors to learn axillary clearance.” At the same time, the occurrence of lymph node metastases has remained unchanged at about 1% annually.
“This is really the beauty of this sort of deescalation in therapy, where you’re improving the morbidity of our patients – our patients have a better quality of life because they don’t have as much lymphedema – without compromising their outcomes. The chance of them having a local recurrence is very low,” Dr. Kaklamani commented. “So taking 20 and 30 and sometimes 40 lymph nodes out, like we used to do, isn’t needed anymore.”
Still, selecting the right patient for radiation is important, she cautioned, as the findings do not apply to those with a bulky lymph node, for example. “But the majority of patients we see with breast cancer have these small metastases to their axillas, if they do [have any], and in those cases, doing radiation, instead of doing more surgery or not doing anything, is very appropriate.”
Changing the standard in the United States has historically been slow. “It is the longer follow-ups from Z11, from AMAROS that are helping our surgeons cut back on the amount of surgery that they are doing,” Dr. Kaklamani maintained. “I have been surprised because we have had these trials out for 10 years, and we still are doing more axillary node dissections than we should be doing.”
At the global level, trends in use of ALND by country and region have varied depending on national practice patterns and acceptance of the trial data, according to Dr. Rutgers. “Taking a toy away from a surgeon is a difficult thing to do.”
Study details
The AMAROS trial was conducted by the European Organization for Research and Treatment of Cancer Breast Cancer Group and Radiation Oncology Group, in collaboration with the Dutch Breast Cancer Research Group and the ALMANAC Trialists’ Group.
The 1,425 patients randomized had breast cancer that was clinically node negative by either palpation or ultrasound (cT1-2,N0) and were scheduled for breast-conserving surgery or mastectomy.
The updated results showed that the 10-year cumulative incidence of axillary recurrence was 1.82% with axillary radiation and 0.93% with ALND, a nonsignificant difference (hazard ratio, 1.71; P = .365), Dr. Rutgers reported. The women also had statistically indistinguishable rates of disease-free survival (HR, 1.19; P = .105), as well as distant metastasis–free survival and overall survival.
The 10-year cumulative incidence of second primaries was higher with radiation than with ALND: 12.09% versus 8.33% (HR, 1.45; P = .035). “This is to some extent due to contralateral breast cancers,” Dr. Rutgers commented. “We cannot exclude an effect of the radiotherapy to the axilla, but we have to realize that 85% of these patients received radiotherapy anyway because of breast conservation. So for us, it is difficult to see whether the addition of the axillary radiation field would lead to more second primaries.”
The updated 5-year rate of lymphedema (data for this outcome were not collected at 10 years) showed persistence of a large difference in the occurrence of lymphedema as defined by clinical observation and/or treatment: 29.4% with ALND and 14.6% with radiation (P less than .0001).
Dr. Rutgers reported that he had no relevant conflicts of interest. The study was supported by the EORTC Charitable Trust.
SOURCE: Rutgers EJT et al. SABCS 2018, Abstract GS4-01.
SAN ANTONIO – For treatment of the axilla in women with early-stage breast cancer having a positive sentinel node, the risk-benefit calculus tilts toward radiation therapy over axillary lymph node dissection, finds an update of the phase 3, noninferiority, randomized AMAROS trial.
The trial’s previously reported 5-year results showed noninferiority of axillary radiation relative to axillary lymph node dissection (ALND) with respect to axillary recurrences, as well as less lymphedema (Lancet Oncol. 2014 Nov;15(12):1303-10). But the trial was criticized as being underpowered and having insufficient follow-up, according to principal investigator Emiel J. T. Rutgers, MD, PhD, of the Netherlands Cancer Institute in Amsterdam.
Now, at a median follow-up of 10 years, findings were basically the same, with few additional axillary recurrences having occurred in either group, he reported in a session and press conference at the San Antonio Breast Cancer Symposium. There was a nonsignificant difference in the very-low 10-year cumulative incidences of axillary recurrence, and no significant difference in other efficacy outcomes. Meanwhile, an update of the rate of lymphedema at 5 years continued to show that this treatment complication was about half as common with radiation.
The radiation therapy group did have a higher risk of second primaries, with an absolute difference of about 4%, mainly driven by more contralateral breast cancers. But it was unclear whether this difference was related to the radiation, according to Dr. Rutgers.
“Both axillary clearance and radiotherapy provide excellent, comparable locoregional control in patients who have a positive sentinel node in the axilla,” he summarized. “After 10 years [of follow-up], there is significantly less lymphedema after radiation therapy at 5 years, and therefore this can be considered a standard procedure.”
Putting data into practice
SABCS codirector and press conference moderator Virginia Kaklamani, MD, leader of the breast cancer program at University of Texas, San Antonio, wondered how Dr. Rutger’s institution has incorporated findings of the AMAROS trial and findings of the previously reported ACOSOG Z11 trial (JAMA. 2011;305:569-75).
They apply both, on a case-by-case basis, he replied. “If it’s limited node involvement in early breast cancer – and of course that’s subjective, we have some cutoffs for that – we do nothing if the sentinel node is positive. If it’s a larger tumor, high grade, lymphovascular invasion, and there are two positive sentinel nodes, then we irradiate the axilla according to the AMAROS trial. This is a discussion within our tumor board, of course, with the multidisciplinary team and together with the patient.”
Over the past 20 years, the percentage of women at his institute undergoing axillary clearance has fallen sharply, from about 75% to merely 3%, as a result of introduction of and growing evidence on sentinel node biopsy, advances in radiation therapy, and increased use of neoadjuvant chemotherapy, according to Dr. Rutgers. “At our institute, an axillary clearance in breast cancer is a rare operation for our residents. They have to go to the melanoma doctors to learn axillary clearance.” At the same time, the occurrence of lymph node metastases has remained unchanged at about 1% annually.
“This is really the beauty of this sort of deescalation in therapy, where you’re improving the morbidity of our patients – our patients have a better quality of life because they don’t have as much lymphedema – without compromising their outcomes. The chance of them having a local recurrence is very low,” Dr. Kaklamani commented. “So taking 20 and 30 and sometimes 40 lymph nodes out, like we used to do, isn’t needed anymore.”
Still, selecting the right patient for radiation is important, she cautioned, as the findings do not apply to those with a bulky lymph node, for example. “But the majority of patients we see with breast cancer have these small metastases to their axillas, if they do [have any], and in those cases, doing radiation, instead of doing more surgery or not doing anything, is very appropriate.”
Changing the standard in the United States has historically been slow. “It is the longer follow-ups from Z11, from AMAROS that are helping our surgeons cut back on the amount of surgery that they are doing,” Dr. Kaklamani maintained. “I have been surprised because we have had these trials out for 10 years, and we still are doing more axillary node dissections than we should be doing.”
At the global level, trends in use of ALND by country and region have varied depending on national practice patterns and acceptance of the trial data, according to Dr. Rutgers. “Taking a toy away from a surgeon is a difficult thing to do.”
Study details
The AMAROS trial was conducted by the European Organization for Research and Treatment of Cancer Breast Cancer Group and Radiation Oncology Group, in collaboration with the Dutch Breast Cancer Research Group and the ALMANAC Trialists’ Group.
The 1,425 patients randomized had breast cancer that was clinically node negative by either palpation or ultrasound (cT1-2,N0) and were scheduled for breast-conserving surgery or mastectomy.
The updated results showed that the 10-year cumulative incidence of axillary recurrence was 1.82% with axillary radiation and 0.93% with ALND, a nonsignificant difference (hazard ratio, 1.71; P = .365), Dr. Rutgers reported. The women also had statistically indistinguishable rates of disease-free survival (HR, 1.19; P = .105), as well as distant metastasis–free survival and overall survival.
The 10-year cumulative incidence of second primaries was higher with radiation than with ALND: 12.09% versus 8.33% (HR, 1.45; P = .035). “This is to some extent due to contralateral breast cancers,” Dr. Rutgers commented. “We cannot exclude an effect of the radiotherapy to the axilla, but we have to realize that 85% of these patients received radiotherapy anyway because of breast conservation. So for us, it is difficult to see whether the addition of the axillary radiation field would lead to more second primaries.”
The updated 5-year rate of lymphedema (data for this outcome were not collected at 10 years) showed persistence of a large difference in the occurrence of lymphedema as defined by clinical observation and/or treatment: 29.4% with ALND and 14.6% with radiation (P less than .0001).
Dr. Rutgers reported that he had no relevant conflicts of interest. The study was supported by the EORTC Charitable Trust.
SOURCE: Rutgers EJT et al. SABCS 2018, Abstract GS4-01.
SAN ANTONIO – For treatment of the axilla in women with early-stage breast cancer having a positive sentinel node, the risk-benefit calculus tilts toward radiation therapy over axillary lymph node dissection, finds an update of the phase 3, noninferiority, randomized AMAROS trial.
The trial’s previously reported 5-year results showed noninferiority of axillary radiation relative to axillary lymph node dissection (ALND) with respect to axillary recurrences, as well as less lymphedema (Lancet Oncol. 2014 Nov;15(12):1303-10). But the trial was criticized as being underpowered and having insufficient follow-up, according to principal investigator Emiel J. T. Rutgers, MD, PhD, of the Netherlands Cancer Institute in Amsterdam.
Now, at a median follow-up of 10 years, findings were basically the same, with few additional axillary recurrences having occurred in either group, he reported in a session and press conference at the San Antonio Breast Cancer Symposium. There was a nonsignificant difference in the very-low 10-year cumulative incidences of axillary recurrence, and no significant difference in other efficacy outcomes. Meanwhile, an update of the rate of lymphedema at 5 years continued to show that this treatment complication was about half as common with radiation.
The radiation therapy group did have a higher risk of second primaries, with an absolute difference of about 4%, mainly driven by more contralateral breast cancers. But it was unclear whether this difference was related to the radiation, according to Dr. Rutgers.
“Both axillary clearance and radiotherapy provide excellent, comparable locoregional control in patients who have a positive sentinel node in the axilla,” he summarized. “After 10 years [of follow-up], there is significantly less lymphedema after radiation therapy at 5 years, and therefore this can be considered a standard procedure.”
Putting data into practice
SABCS codirector and press conference moderator Virginia Kaklamani, MD, leader of the breast cancer program at University of Texas, San Antonio, wondered how Dr. Rutger’s institution has incorporated findings of the AMAROS trial and findings of the previously reported ACOSOG Z11 trial (JAMA. 2011;305:569-75).
They apply both, on a case-by-case basis, he replied. “If it’s limited node involvement in early breast cancer – and of course that’s subjective, we have some cutoffs for that – we do nothing if the sentinel node is positive. If it’s a larger tumor, high grade, lymphovascular invasion, and there are two positive sentinel nodes, then we irradiate the axilla according to the AMAROS trial. This is a discussion within our tumor board, of course, with the multidisciplinary team and together with the patient.”
Over the past 20 years, the percentage of women at his institute undergoing axillary clearance has fallen sharply, from about 75% to merely 3%, as a result of introduction of and growing evidence on sentinel node biopsy, advances in radiation therapy, and increased use of neoadjuvant chemotherapy, according to Dr. Rutgers. “At our institute, an axillary clearance in breast cancer is a rare operation for our residents. They have to go to the melanoma doctors to learn axillary clearance.” At the same time, the occurrence of lymph node metastases has remained unchanged at about 1% annually.
“This is really the beauty of this sort of deescalation in therapy, where you’re improving the morbidity of our patients – our patients have a better quality of life because they don’t have as much lymphedema – without compromising their outcomes. The chance of them having a local recurrence is very low,” Dr. Kaklamani commented. “So taking 20 and 30 and sometimes 40 lymph nodes out, like we used to do, isn’t needed anymore.”
Still, selecting the right patient for radiation is important, she cautioned, as the findings do not apply to those with a bulky lymph node, for example. “But the majority of patients we see with breast cancer have these small metastases to their axillas, if they do [have any], and in those cases, doing radiation, instead of doing more surgery or not doing anything, is very appropriate.”
Changing the standard in the United States has historically been slow. “It is the longer follow-ups from Z11, from AMAROS that are helping our surgeons cut back on the amount of surgery that they are doing,” Dr. Kaklamani maintained. “I have been surprised because we have had these trials out for 10 years, and we still are doing more axillary node dissections than we should be doing.”
At the global level, trends in use of ALND by country and region have varied depending on national practice patterns and acceptance of the trial data, according to Dr. Rutgers. “Taking a toy away from a surgeon is a difficult thing to do.”
Study details
The AMAROS trial was conducted by the European Organization for Research and Treatment of Cancer Breast Cancer Group and Radiation Oncology Group, in collaboration with the Dutch Breast Cancer Research Group and the ALMANAC Trialists’ Group.
The 1,425 patients randomized had breast cancer that was clinically node negative by either palpation or ultrasound (cT1-2,N0) and were scheduled for breast-conserving surgery or mastectomy.
The updated results showed that the 10-year cumulative incidence of axillary recurrence was 1.82% with axillary radiation and 0.93% with ALND, a nonsignificant difference (hazard ratio, 1.71; P = .365), Dr. Rutgers reported. The women also had statistically indistinguishable rates of disease-free survival (HR, 1.19; P = .105), as well as distant metastasis–free survival and overall survival.
The 10-year cumulative incidence of second primaries was higher with radiation than with ALND: 12.09% versus 8.33% (HR, 1.45; P = .035). “This is to some extent due to contralateral breast cancers,” Dr. Rutgers commented. “We cannot exclude an effect of the radiotherapy to the axilla, but we have to realize that 85% of these patients received radiotherapy anyway because of breast conservation. So for us, it is difficult to see whether the addition of the axillary radiation field would lead to more second primaries.”
The updated 5-year rate of lymphedema (data for this outcome were not collected at 10 years) showed persistence of a large difference in the occurrence of lymphedema as defined by clinical observation and/or treatment: 29.4% with ALND and 14.6% with radiation (P less than .0001).
Dr. Rutgers reported that he had no relevant conflicts of interest. The study was supported by the EORTC Charitable Trust.
SOURCE: Rutgers EJT et al. SABCS 2018, Abstract GS4-01.
REPORTING FROM SABCS 2018
Key clinical point: In patients with a positive sentinel node, axillary radiation has similar efficacy to axillary lymph node dissection and less morbidity.
Major finding: Compared with axillary lymph node dissection, axillary radiation therapy had a similar 10-year cumulative incidence of axillary recurrence (1.82% vs. 0.93%; P = .365) and half the 5-year rate of lymphedema (14.6% vs. 29.4%; P less than .0001).
Study details: A phase 3, noninferiority, randomized, controlled trial among 1,425 women with early-stage breast cancer and a positive sentinel node.
Disclosures: Dr. Rutgers reported that he had no relevant conflicts of interest. The study was supported by the European Organization for Research and Treatment of Cancer Charitable Trust.
Source: Rutgers EJT et al. SABCS 2018, Abstract GS4-01.
Dr. Ingrid A. Mayer on neoadjuvant endocrine therapy: The times are changing
SAN ANTONIO – Phase 2 neoadjuvant endocrine therapy breast cancer trials can and should serve as a testing platform to inform the design of phase 3 trials with the ability to change practice, according to Ingrid A. Mayer, MD.
Correlating outcomes such as the Preoperative Endocrine Prognostic Index and Ki67 blood levels from phase 2 trials to larger, similarly designed trials could reduce costs, time, and the need for large numbers of patients, thereby promoting more efficient development of effective breast cancer therapies, she said during a plenary lecture at the San Antonio Breast Cancer Symposium.
In this video interview, Dr. Mayer, director of breast medical oncology at Vanderbilt University, Nashville, Tenn., explained that while neoadjuvant endocrine therapy is suitable for down-staging tumors in women with stage I-III breast cancer, it is not commonly used, as those patients are also good surgery candidates.
However, neoadjuvant endocrine therapy can be “an incredible platform” to test novel combinations of endocrine therapy agents with or without targeted treatments, validate new biomarkers, discover mechanisms of resistance, and predict the best combinations for moving forward in phase 3 trials, she said, adding that “this is something that all academic institutions potentially should be doing.”
Although the direct clinical benefit for patients who participate in such trials is not tremendous, participation has the potential to ultimately improve outcomes for participants and for “their friends and families and daughters,” and to help propel the science forward, Dr. Meyer noted.
“I would argue that we really should be moving forward to designing trials in the neoadjuvant endocrine setting more and more, and really utilizing this platform for that end,” she said.
Dr. Mayer reported having no relevant disclosures.
SAN ANTONIO – Phase 2 neoadjuvant endocrine therapy breast cancer trials can and should serve as a testing platform to inform the design of phase 3 trials with the ability to change practice, according to Ingrid A. Mayer, MD.
Correlating outcomes such as the Preoperative Endocrine Prognostic Index and Ki67 blood levels from phase 2 trials to larger, similarly designed trials could reduce costs, time, and the need for large numbers of patients, thereby promoting more efficient development of effective breast cancer therapies, she said during a plenary lecture at the San Antonio Breast Cancer Symposium.
In this video interview, Dr. Mayer, director of breast medical oncology at Vanderbilt University, Nashville, Tenn., explained that while neoadjuvant endocrine therapy is suitable for down-staging tumors in women with stage I-III breast cancer, it is not commonly used, as those patients are also good surgery candidates.
However, neoadjuvant endocrine therapy can be “an incredible platform” to test novel combinations of endocrine therapy agents with or without targeted treatments, validate new biomarkers, discover mechanisms of resistance, and predict the best combinations for moving forward in phase 3 trials, she said, adding that “this is something that all academic institutions potentially should be doing.”
Although the direct clinical benefit for patients who participate in such trials is not tremendous, participation has the potential to ultimately improve outcomes for participants and for “their friends and families and daughters,” and to help propel the science forward, Dr. Meyer noted.
“I would argue that we really should be moving forward to designing trials in the neoadjuvant endocrine setting more and more, and really utilizing this platform for that end,” she said.
Dr. Mayer reported having no relevant disclosures.
SAN ANTONIO – Phase 2 neoadjuvant endocrine therapy breast cancer trials can and should serve as a testing platform to inform the design of phase 3 trials with the ability to change practice, according to Ingrid A. Mayer, MD.
Correlating outcomes such as the Preoperative Endocrine Prognostic Index and Ki67 blood levels from phase 2 trials to larger, similarly designed trials could reduce costs, time, and the need for large numbers of patients, thereby promoting more efficient development of effective breast cancer therapies, she said during a plenary lecture at the San Antonio Breast Cancer Symposium.
In this video interview, Dr. Mayer, director of breast medical oncology at Vanderbilt University, Nashville, Tenn., explained that while neoadjuvant endocrine therapy is suitable for down-staging tumors in women with stage I-III breast cancer, it is not commonly used, as those patients are also good surgery candidates.
However, neoadjuvant endocrine therapy can be “an incredible platform” to test novel combinations of endocrine therapy agents with or without targeted treatments, validate new biomarkers, discover mechanisms of resistance, and predict the best combinations for moving forward in phase 3 trials, she said, adding that “this is something that all academic institutions potentially should be doing.”
Although the direct clinical benefit for patients who participate in such trials is not tremendous, participation has the potential to ultimately improve outcomes for participants and for “their friends and families and daughters,” and to help propel the science forward, Dr. Meyer noted.
“I would argue that we really should be moving forward to designing trials in the neoadjuvant endocrine setting more and more, and really utilizing this platform for that end,” she said.
Dr. Mayer reported having no relevant disclosures.
REPORTING FROM SABCS 2018
DTCs in marrow herald worse outcomes for early breast cancer
SAN ANTONIO – When disseminated tumor cells – even a single cell – are detected in the bone marrow of patients with early breast cancer, it’s not a good sign, according to results of pooled international analysis.
The presence of disseminated tumor cells (DTCs) in marrow at the time of primary diagnosis was an independent prognostic factor for overall survival (OS), disease-free survival (DFS), and distant disease-free survival (DDFS), reported Andreas Daniel Hartkopf, MD, MSc, of the University of Tübingen, Germany, on behalf of colleagues in the PADDY study.
“The DTC detection was associated with higher local tumor burden and more aggressive biological subtype,” he said at the San Antonio Breast Cancer Symposium.
The PADDY (Pooled Analysis of DTC Detection in Early Breast Cancer) study is an international cooperative effort designed to evaluate the association between DTC detection in patients with early breast cancer and clinical outcomes.
The investigators collected individual data sets including information on bone marrow samples from 10,307 patients treated at 11 centers in the United States and Europe.
The patients had early invasive breast cancer (T1-4, NO-3, M0) and for inclusion in the study had to have had bone marrow aspiration performed at the time of diagnosis or during primary surgery, with no prior systemic therapy. DTCs were detected by cytokeratin staining.
Patients were defined as being DTC positive if one or more DTCs were detected.
A total of 2,814 of the 10,307 patients (27.3%) were DTC positive. DTC status was not significantly associated with menopausal status or tumor histology (invasive ductal, invasive lobular, or other), but was positively associated with tumor grade, with 21.1% of patients with grade 1 tumors being DTC positive, compared with 27.2% with grade 2 tumors, and 29.9% with grade 3 tumors (P less than .001).
At a median follow-up of 7.6 years from bone marrow sampling DTC positivity was significantly associated with, in addition to higher tumor grade, higher T stage, nodal positivity, estrogen and progesterone receptor negativity, and HER2 positivity (P less than .001 for all).
Univariate analysis showed that DTC-positive patients had significantly shorter OS, breast cancer–specific survival, and DDFS compared with DTC negative patients (P less than .001 for all).
In a multivariate model stratified by center and controlling for age, menopausal status, histology, tumor size, nodal status, and biological subtype, DTC was an independent prognostic marker for OS (hazard ratio 1.23, P = .006), DFS (HR 1.30, P less than .001) and DDFS (HR 1.30, P = .006), but not for locoregional relapse-free survival.
“These results confirm that DTC detection is an independent risk factor for metastatic relapse and poor overall survival in early breast cancer,” Dr. Hartkopf said.
There was a statistically significant interaction between DTCs and subtypes with regard to DDFS, with a HR of 2.34 for patients with luminal B disease (P = .014).
“Future trials must evaluate the predictive value of DTC detection and/or their characterization on adjuvant therapy efficacy,” Dr. Hartkopf concluded.
Dr. Hartkopf did not disclose a study funding source or potential conflicts of interest.
SOURCE: Hartkopf AD et al. SABCS 2018. Abstract GS5-07.
SAN ANTONIO – When disseminated tumor cells – even a single cell – are detected in the bone marrow of patients with early breast cancer, it’s not a good sign, according to results of pooled international analysis.
The presence of disseminated tumor cells (DTCs) in marrow at the time of primary diagnosis was an independent prognostic factor for overall survival (OS), disease-free survival (DFS), and distant disease-free survival (DDFS), reported Andreas Daniel Hartkopf, MD, MSc, of the University of Tübingen, Germany, on behalf of colleagues in the PADDY study.
“The DTC detection was associated with higher local tumor burden and more aggressive biological subtype,” he said at the San Antonio Breast Cancer Symposium.
The PADDY (Pooled Analysis of DTC Detection in Early Breast Cancer) study is an international cooperative effort designed to evaluate the association between DTC detection in patients with early breast cancer and clinical outcomes.
The investigators collected individual data sets including information on bone marrow samples from 10,307 patients treated at 11 centers in the United States and Europe.
The patients had early invasive breast cancer (T1-4, NO-3, M0) and for inclusion in the study had to have had bone marrow aspiration performed at the time of diagnosis or during primary surgery, with no prior systemic therapy. DTCs were detected by cytokeratin staining.
Patients were defined as being DTC positive if one or more DTCs were detected.
A total of 2,814 of the 10,307 patients (27.3%) were DTC positive. DTC status was not significantly associated with menopausal status or tumor histology (invasive ductal, invasive lobular, or other), but was positively associated with tumor grade, with 21.1% of patients with grade 1 tumors being DTC positive, compared with 27.2% with grade 2 tumors, and 29.9% with grade 3 tumors (P less than .001).
At a median follow-up of 7.6 years from bone marrow sampling DTC positivity was significantly associated with, in addition to higher tumor grade, higher T stage, nodal positivity, estrogen and progesterone receptor negativity, and HER2 positivity (P less than .001 for all).
Univariate analysis showed that DTC-positive patients had significantly shorter OS, breast cancer–specific survival, and DDFS compared with DTC negative patients (P less than .001 for all).
In a multivariate model stratified by center and controlling for age, menopausal status, histology, tumor size, nodal status, and biological subtype, DTC was an independent prognostic marker for OS (hazard ratio 1.23, P = .006), DFS (HR 1.30, P less than .001) and DDFS (HR 1.30, P = .006), but not for locoregional relapse-free survival.
“These results confirm that DTC detection is an independent risk factor for metastatic relapse and poor overall survival in early breast cancer,” Dr. Hartkopf said.
There was a statistically significant interaction between DTCs and subtypes with regard to DDFS, with a HR of 2.34 for patients with luminal B disease (P = .014).
“Future trials must evaluate the predictive value of DTC detection and/or their characterization on adjuvant therapy efficacy,” Dr. Hartkopf concluded.
Dr. Hartkopf did not disclose a study funding source or potential conflicts of interest.
SOURCE: Hartkopf AD et al. SABCS 2018. Abstract GS5-07.
SAN ANTONIO – When disseminated tumor cells – even a single cell – are detected in the bone marrow of patients with early breast cancer, it’s not a good sign, according to results of pooled international analysis.
The presence of disseminated tumor cells (DTCs) in marrow at the time of primary diagnosis was an independent prognostic factor for overall survival (OS), disease-free survival (DFS), and distant disease-free survival (DDFS), reported Andreas Daniel Hartkopf, MD, MSc, of the University of Tübingen, Germany, on behalf of colleagues in the PADDY study.
“The DTC detection was associated with higher local tumor burden and more aggressive biological subtype,” he said at the San Antonio Breast Cancer Symposium.
The PADDY (Pooled Analysis of DTC Detection in Early Breast Cancer) study is an international cooperative effort designed to evaluate the association between DTC detection in patients with early breast cancer and clinical outcomes.
The investigators collected individual data sets including information on bone marrow samples from 10,307 patients treated at 11 centers in the United States and Europe.
The patients had early invasive breast cancer (T1-4, NO-3, M0) and for inclusion in the study had to have had bone marrow aspiration performed at the time of diagnosis or during primary surgery, with no prior systemic therapy. DTCs were detected by cytokeratin staining.
Patients were defined as being DTC positive if one or more DTCs were detected.
A total of 2,814 of the 10,307 patients (27.3%) were DTC positive. DTC status was not significantly associated with menopausal status or tumor histology (invasive ductal, invasive lobular, or other), but was positively associated with tumor grade, with 21.1% of patients with grade 1 tumors being DTC positive, compared with 27.2% with grade 2 tumors, and 29.9% with grade 3 tumors (P less than .001).
At a median follow-up of 7.6 years from bone marrow sampling DTC positivity was significantly associated with, in addition to higher tumor grade, higher T stage, nodal positivity, estrogen and progesterone receptor negativity, and HER2 positivity (P less than .001 for all).
Univariate analysis showed that DTC-positive patients had significantly shorter OS, breast cancer–specific survival, and DDFS compared with DTC negative patients (P less than .001 for all).
In a multivariate model stratified by center and controlling for age, menopausal status, histology, tumor size, nodal status, and biological subtype, DTC was an independent prognostic marker for OS (hazard ratio 1.23, P = .006), DFS (HR 1.30, P less than .001) and DDFS (HR 1.30, P = .006), but not for locoregional relapse-free survival.
“These results confirm that DTC detection is an independent risk factor for metastatic relapse and poor overall survival in early breast cancer,” Dr. Hartkopf said.
There was a statistically significant interaction between DTCs and subtypes with regard to DDFS, with a HR of 2.34 for patients with luminal B disease (P = .014).
“Future trials must evaluate the predictive value of DTC detection and/or their characterization on adjuvant therapy efficacy,” Dr. Hartkopf concluded.
Dr. Hartkopf did not disclose a study funding source or potential conflicts of interest.
SOURCE: Hartkopf AD et al. SABCS 2018. Abstract GS5-07.
REPORTING FROM SABCS 2018
Key clinical point: The presence of even a single DTC may be prognostic of metastases and poor survival.
Major finding: DTC was an independent prognostic marker for overall survival, disease-free survival, and distant disease-free survival.
Study details: Retrospective analysis of data on 10,030 patients, including 2,814 with detectable DTCs in bone marrow.
Disclosures: Dr. Hartkopf did not disclose a study funding source or potential conflicts of interest.
Source: Hartkopf AD et al. SABCS 2018. Abstract GS5-07.
Exercise during adjuvant breast cancer therapy improves CV outcomes
SAN ANTONIO – A tailored 12-month exercise program during adjuvant breast cancer treatment appears to protect cardiovascular function, particularly in patients receiving chemotherapy, according to findings from the randomized EBBA-II trial.
The overall change in VO2max at 12 months was +0.3% in 271 patients randomized to the intervention group, compared with –8.9% in 274 patients in the “usual care” control group, Inger Thune, MD, PhD, said at the San Antonio Breast Cancer Symposium.
Among patients receiving chemotherapy, the VO2max change at 12 months was +1.6% in 120 patients in the intervention group, compared with –2.76% in 122 patients in the control group, said Dr. Thune of the Cancer Center at Oslo University Hospital.
Study participants were women aged 18-75 years (mean of 55 years at diagnosis) with stage I-II breast cancer, mean body mass index of 25 kg/m2, and a mean VO2max before surgery of 31.5 mL/kg per minute. The intervention group entered a 12-month individualized exercise program 2-3 weeks after surgery based on their own VO2max at baseline.
They met for training sessions in groups of 10-12 women for 60 minutes twice weekly over the 12-month study period, and were also told to perform at least 120 minutes of exercise at home for a total of 240 minutes of exercise weekly.
Of note, the adherence rate among participants was encouragingly high at about 90%, she said, adding that the findings strongly support tailored exercise during adjuvant breast cancer treatment, as such an intervention appears to counteract declines in cardiovascular function – particularly in those receiving chemotherapy.
In this video interview, Dr. Thune further discussed the study design, implications of the findings, and future directions.
“Cardiovascular morbidity is so important for our breast cancer patients that I think that it’s time to have physical activity [and] physical function as a main interest for all clinicians dealing with breast cancer patients,” she said.
Dr. Thune reported having no disclosures.
SAN ANTONIO – A tailored 12-month exercise program during adjuvant breast cancer treatment appears to protect cardiovascular function, particularly in patients receiving chemotherapy, according to findings from the randomized EBBA-II trial.
The overall change in VO2max at 12 months was +0.3% in 271 patients randomized to the intervention group, compared with –8.9% in 274 patients in the “usual care” control group, Inger Thune, MD, PhD, said at the San Antonio Breast Cancer Symposium.
Among patients receiving chemotherapy, the VO2max change at 12 months was +1.6% in 120 patients in the intervention group, compared with –2.76% in 122 patients in the control group, said Dr. Thune of the Cancer Center at Oslo University Hospital.
Study participants were women aged 18-75 years (mean of 55 years at diagnosis) with stage I-II breast cancer, mean body mass index of 25 kg/m2, and a mean VO2max before surgery of 31.5 mL/kg per minute. The intervention group entered a 12-month individualized exercise program 2-3 weeks after surgery based on their own VO2max at baseline.
They met for training sessions in groups of 10-12 women for 60 minutes twice weekly over the 12-month study period, and were also told to perform at least 120 minutes of exercise at home for a total of 240 minutes of exercise weekly.
Of note, the adherence rate among participants was encouragingly high at about 90%, she said, adding that the findings strongly support tailored exercise during adjuvant breast cancer treatment, as such an intervention appears to counteract declines in cardiovascular function – particularly in those receiving chemotherapy.
In this video interview, Dr. Thune further discussed the study design, implications of the findings, and future directions.
“Cardiovascular morbidity is so important for our breast cancer patients that I think that it’s time to have physical activity [and] physical function as a main interest for all clinicians dealing with breast cancer patients,” she said.
Dr. Thune reported having no disclosures.
SAN ANTONIO – A tailored 12-month exercise program during adjuvant breast cancer treatment appears to protect cardiovascular function, particularly in patients receiving chemotherapy, according to findings from the randomized EBBA-II trial.
The overall change in VO2max at 12 months was +0.3% in 271 patients randomized to the intervention group, compared with –8.9% in 274 patients in the “usual care” control group, Inger Thune, MD, PhD, said at the San Antonio Breast Cancer Symposium.
Among patients receiving chemotherapy, the VO2max change at 12 months was +1.6% in 120 patients in the intervention group, compared with –2.76% in 122 patients in the control group, said Dr. Thune of the Cancer Center at Oslo University Hospital.
Study participants were women aged 18-75 years (mean of 55 years at diagnosis) with stage I-II breast cancer, mean body mass index of 25 kg/m2, and a mean VO2max before surgery of 31.5 mL/kg per minute. The intervention group entered a 12-month individualized exercise program 2-3 weeks after surgery based on their own VO2max at baseline.
They met for training sessions in groups of 10-12 women for 60 minutes twice weekly over the 12-month study period, and were also told to perform at least 120 minutes of exercise at home for a total of 240 minutes of exercise weekly.
Of note, the adherence rate among participants was encouragingly high at about 90%, she said, adding that the findings strongly support tailored exercise during adjuvant breast cancer treatment, as such an intervention appears to counteract declines in cardiovascular function – particularly in those receiving chemotherapy.
In this video interview, Dr. Thune further discussed the study design, implications of the findings, and future directions.
“Cardiovascular morbidity is so important for our breast cancer patients that I think that it’s time to have physical activity [and] physical function as a main interest for all clinicians dealing with breast cancer patients,” she said.
Dr. Thune reported having no disclosures.
REPORTING FROM SABCS 2018
Key clinical point: An exercise program during adjuvant breast cancer treatment improves cardiovascular outcomes.
Major finding: The rate of VO2max change at 12 months was +0.3% in the exercise group versus –8.9% in the control group.
Study details: EBBA-II, a randomized trial of 546 women.
Disclosures: Dr. Thune reported having no disclosures.
Oxybutynin nets dramatic reduction in hot flashes
SAN ANTONIO – Oxybutynin (Ditropan), a drug approved to treat overactive bladder, is highly efficacious and well tolerated when used to alleviate hot flashes, according to results of a randomized, controlled trial of 150 women reported by lead author Roberto A. Leon-Ferre, MD.
The women, about two-thirds of whom were breast cancer survivors taking tamoxifen or aromatase inhibitors, were having at least 28 hot flashes weekly at baseline. Results of the trial showed that the 6-week reduction in a hot flash score capturing both frequency and severity was about 30% with placebo, 65% with oxybutynin 2.5 mg b.i.d., and 80% with oxybutynin 5 mg b.i.d. (P less than .01 across groups).
There also was a significant difference in quality of life in favor of the drug and, in the higher-dose group, significantly better scores for mood and life enjoyment. In a video interview, Dr. Leon-Ferre discussed how oxybutynin compares with other available treatment options, which women are good or poor candidates for this drug, and how the findings have influenced his own practice.
Dr. Leon-Ferre of the Mayo Clinic, Rochester, Minn., disclosed that he had no relevant conflicts of interest. The study was funded by the Breast Cancer Research Foundation.
SAN ANTONIO – Oxybutynin (Ditropan), a drug approved to treat overactive bladder, is highly efficacious and well tolerated when used to alleviate hot flashes, according to results of a randomized, controlled trial of 150 women reported by lead author Roberto A. Leon-Ferre, MD.
The women, about two-thirds of whom were breast cancer survivors taking tamoxifen or aromatase inhibitors, were having at least 28 hot flashes weekly at baseline. Results of the trial showed that the 6-week reduction in a hot flash score capturing both frequency and severity was about 30% with placebo, 65% with oxybutynin 2.5 mg b.i.d., and 80% with oxybutynin 5 mg b.i.d. (P less than .01 across groups).
There also was a significant difference in quality of life in favor of the drug and, in the higher-dose group, significantly better scores for mood and life enjoyment. In a video interview, Dr. Leon-Ferre discussed how oxybutynin compares with other available treatment options, which women are good or poor candidates for this drug, and how the findings have influenced his own practice.
Dr. Leon-Ferre of the Mayo Clinic, Rochester, Minn., disclosed that he had no relevant conflicts of interest. The study was funded by the Breast Cancer Research Foundation.
SAN ANTONIO – Oxybutynin (Ditropan), a drug approved to treat overactive bladder, is highly efficacious and well tolerated when used to alleviate hot flashes, according to results of a randomized, controlled trial of 150 women reported by lead author Roberto A. Leon-Ferre, MD.
The women, about two-thirds of whom were breast cancer survivors taking tamoxifen or aromatase inhibitors, were having at least 28 hot flashes weekly at baseline. Results of the trial showed that the 6-week reduction in a hot flash score capturing both frequency and severity was about 30% with placebo, 65% with oxybutynin 2.5 mg b.i.d., and 80% with oxybutynin 5 mg b.i.d. (P less than .01 across groups).
There also was a significant difference in quality of life in favor of the drug and, in the higher-dose group, significantly better scores for mood and life enjoyment. In a video interview, Dr. Leon-Ferre discussed how oxybutynin compares with other available treatment options, which women are good or poor candidates for this drug, and how the findings have influenced his own practice.
Dr. Leon-Ferre of the Mayo Clinic, Rochester, Minn., disclosed that he had no relevant conflicts of interest. The study was funded by the Breast Cancer Research Foundation.
REPORTING FROM SABCS 2018
Extent of breast surgery is tied to quality of life among young breast cancer survivors
SAN ANTONIO – Younger breast cancer patients who undergo unilateral or bilateral mastectomy report lower breast satisfaction and poorer psychosocial and sexual well-being than counterparts who undergo breast-conserving surgery, finds a cross-sectional cohort study presented by lead investigator Laura S. Dominici, MD, FACS, at the San Antonio Breast Cancer Symposium.
The 560 women studied had a mean age of 37 years and had completed the BREAST-Q questionnaire a median of 5.8 years after their breast cancer diagnosis. Results showed that the mean score for satisfaction with breasts was 65.5 with breast-conserving surgery, 59.3 with unilateral mastectomy, and 60.4 with bilateral mastectomy (P = .008). The mastectomy groups also had poorer scores for psychosocial well-being (P less than .001) and sexual well-being (P less than .001), but not physical well-being. Most of the differences remained significant in meta-analysis. In a video interview, Dr. Dominici, of Dana-Farber Cancer Institute, Boston, discussed worry and anxiety about recurrence and second cancers as drivers of choosing mastectomy, generalizability of the study’s findings, and strategies for incorporating this new information into counseling and shared decision making.
Dr. Dominici disclosed that she had no conflicts of interest. The study was funded by the Agency for Healthcare Research and Quality, Susan G. Komen, the Breast Cancer Research Foundation, and The Pink Agenda.
SAN ANTONIO – Younger breast cancer patients who undergo unilateral or bilateral mastectomy report lower breast satisfaction and poorer psychosocial and sexual well-being than counterparts who undergo breast-conserving surgery, finds a cross-sectional cohort study presented by lead investigator Laura S. Dominici, MD, FACS, at the San Antonio Breast Cancer Symposium.
The 560 women studied had a mean age of 37 years and had completed the BREAST-Q questionnaire a median of 5.8 years after their breast cancer diagnosis. Results showed that the mean score for satisfaction with breasts was 65.5 with breast-conserving surgery, 59.3 with unilateral mastectomy, and 60.4 with bilateral mastectomy (P = .008). The mastectomy groups also had poorer scores for psychosocial well-being (P less than .001) and sexual well-being (P less than .001), but not physical well-being. Most of the differences remained significant in meta-analysis. In a video interview, Dr. Dominici, of Dana-Farber Cancer Institute, Boston, discussed worry and anxiety about recurrence and second cancers as drivers of choosing mastectomy, generalizability of the study’s findings, and strategies for incorporating this new information into counseling and shared decision making.
Dr. Dominici disclosed that she had no conflicts of interest. The study was funded by the Agency for Healthcare Research and Quality, Susan G. Komen, the Breast Cancer Research Foundation, and The Pink Agenda.
SAN ANTONIO – Younger breast cancer patients who undergo unilateral or bilateral mastectomy report lower breast satisfaction and poorer psychosocial and sexual well-being than counterparts who undergo breast-conserving surgery, finds a cross-sectional cohort study presented by lead investigator Laura S. Dominici, MD, FACS, at the San Antonio Breast Cancer Symposium.
The 560 women studied had a mean age of 37 years and had completed the BREAST-Q questionnaire a median of 5.8 years after their breast cancer diagnosis. Results showed that the mean score for satisfaction with breasts was 65.5 with breast-conserving surgery, 59.3 with unilateral mastectomy, and 60.4 with bilateral mastectomy (P = .008). The mastectomy groups also had poorer scores for psychosocial well-being (P less than .001) and sexual well-being (P less than .001), but not physical well-being. Most of the differences remained significant in meta-analysis. In a video interview, Dr. Dominici, of Dana-Farber Cancer Institute, Boston, discussed worry and anxiety about recurrence and second cancers as drivers of choosing mastectomy, generalizability of the study’s findings, and strategies for incorporating this new information into counseling and shared decision making.
Dr. Dominici disclosed that she had no conflicts of interest. The study was funded by the Agency for Healthcare Research and Quality, Susan G. Komen, the Breast Cancer Research Foundation, and The Pink Agenda.
REPORTING FROM SABCS 2018
pCR may obviate need for adjuvant chemotherapy
SAN ANTONIO – Women with localized breast cancer who achieve a pathological complete response (pCR) after neoadjuvant chemotherapy may be able to safely skip adjuvant chemotherapy, suggest new data from a patient-level meta-analysis reported in a session and press conference at the San Antonio Breast Cancer Symposium.
“The focus of many breast cancer trials for several years has been on adding additional systemic therapies to reduce recurrence risk. However, adding therapies can result in additional toxicity and overtreatment for many patients,” noted lead investigator Laura M. Spring, MD, of Massachusetts General Hospital Cancer Center and Harvard Medical School, both in Boston. “The neoadjuvant chemotherapy model offers several additional clinical and research advantages over adjuvant chemotherapy, including the rapid evaluation of treatment response utilizing surrogate biomarkers, such as pathological complete response.”
The meta-analysis of 52 studies, which included a total of 27,895 women who were given neoadjuvant chemotherapy, confirmed a large positive prognostic effect of pCR on outcomes in the entire sample, with a 69% relative reduction in event-free survival (EFS) events and a 78% relative reduction in risk of death, a pattern that was consistent across clinical subtypes of breast cancer. More importantly, among those achieving a pCR, EFS did not differ significantly whether they went on to receive more chemotherapy after surgery or not.
“Achieving pCR following neoadjuvant chemotherapy is associated with significantly improved EFS and overall survival, particularly for triple-negative and HER2-positive breast cancer. The results are highly significant despite inclusion of a variety of neoadjuvant regimens, suggesting the path taken to attain a pCR may not be critical,” Dr. Spring proposed. “The similar outcomes with or without adjuvant chemotherapy in patients who attained pCR after neoadjuvant chemotherapy likely reflects tumor biology and suggests adjuvant chemotherapy could potentially be omitted in certain circumstances. Further research is needed to evaluate the clinical utility of escalation and de-escalation strategies in the adjuvant setting based on neoadjuvant response.”
“Basically, it appears that the impact of chemotherapy is going to be early, or if you use it early, you really don’t lose the impact [that it has] if you wait until after surgery,” commented SABCS codirector and press conference moderator Carlos Arteaga, MD, director of the Harold C. Simmons Comprehensive Cancer Center and associate dean of Oncology Programs at UT Southwestern Medical Center, Dallas, Texas. “So if it was me, I would have it done before the operation, frankly, because at a minimum, it’s not worse than delaying it until after surgery – at a minimum. And you get the benefit of potential breast conservation, a lesser surgery.”
Study details
For the meta-analysis, Dr. Spring and her coinvestigators searched for published studies of localized breast cancer that had 25 patients or more, featured neoadjuvant chemotherapy, and reported pCR using definitions allowed by the FDA (ypT0 ypN0 or ypT0/is ypN0), as well as recurrence and/or survival based on pathologic outcome. They excluded studies reporting only local recurrence and those using neoadjuvant endocrine therapy or neoadjuvant radiation.
Results showed that the pCR rate averaged 21.1% for the entire study population, according to Dr. Spring. But there was wide variation by tumor subtype, as expected, with a rate of less than 10% for hormone receptor–positive/HER2-negative breast cancer, to rates in the mid-30% range for triple-negative breast cancer and HER2-positive breast cancer.
Women who had pCR after neoadjuvant chemotherapy had a significantly lower risk of EFS events than peers who had residual disease (hazard ratio, 0.31; 95% probability interval, 0.24-0.39). The corresponding 5-year EFS rates were 88% and 67%.
Similarly, women who had pCR had a significantly lower risk of death (HR, 0.22; 95% probability interval, 0.15-0.30). The corresponding 5-year overall survival rates were 94% and 75%.
The EFS benefit of pCR versus residual disease was consistently seen across subgroups with triple-negative breast cancer (90% vs. 57%), HER2-positive breast cancer (86% vs. 63%), and hormone receptor–positive/HER2-negative breast cancer (97% vs. 88%). Findings were essentially the same for overall survival, according to Dr. Spring.
Among patients attaining pCR, the 5-year EFS rate was 86% for those who went on to receive adjuvant chemotherapy (HR, 0.36; 95% probability interval, 0.19-0.67) and 88% for those who did not (HR, 0.36; 95% probability interval, 0.27-0.54). The difference in hazard ratios between groups was not significant (P = .60).
Finally, the investigators conducted modeling to assess how the change in pCR rate corresponded with the change in EFS benefit. “This approach could be helpful in the design of neoadjuvant studies,” Dr. Spring explained.
“Assuming pCR is a valid surrogate endpoint, this is, it mediates all treatment effects, and that the average pCR is 50%, the magnitude of pCR change is predictive of treatment effects on EFS within a certain amount of uncertainty, based on the model,” she reported. For example, a change in pCR of 0.3 had a corresponding HR of 0.72, with a 95% probability interval of 0.68-0.77.
Dr. Spring disclosed that she has a consulting or advisory role with Novartis and that she receives institutional research funding from Tesaro. The study was supported by grants from the National Cancer Institute and Susan G. Komen.
SOURCE: Spring LM et al. SABCS 2018, Abstract GS2-03.
SAN ANTONIO – Women with localized breast cancer who achieve a pathological complete response (pCR) after neoadjuvant chemotherapy may be able to safely skip adjuvant chemotherapy, suggest new data from a patient-level meta-analysis reported in a session and press conference at the San Antonio Breast Cancer Symposium.
“The focus of many breast cancer trials for several years has been on adding additional systemic therapies to reduce recurrence risk. However, adding therapies can result in additional toxicity and overtreatment for many patients,” noted lead investigator Laura M. Spring, MD, of Massachusetts General Hospital Cancer Center and Harvard Medical School, both in Boston. “The neoadjuvant chemotherapy model offers several additional clinical and research advantages over adjuvant chemotherapy, including the rapid evaluation of treatment response utilizing surrogate biomarkers, such as pathological complete response.”
The meta-analysis of 52 studies, which included a total of 27,895 women who were given neoadjuvant chemotherapy, confirmed a large positive prognostic effect of pCR on outcomes in the entire sample, with a 69% relative reduction in event-free survival (EFS) events and a 78% relative reduction in risk of death, a pattern that was consistent across clinical subtypes of breast cancer. More importantly, among those achieving a pCR, EFS did not differ significantly whether they went on to receive more chemotherapy after surgery or not.
“Achieving pCR following neoadjuvant chemotherapy is associated with significantly improved EFS and overall survival, particularly for triple-negative and HER2-positive breast cancer. The results are highly significant despite inclusion of a variety of neoadjuvant regimens, suggesting the path taken to attain a pCR may not be critical,” Dr. Spring proposed. “The similar outcomes with or without adjuvant chemotherapy in patients who attained pCR after neoadjuvant chemotherapy likely reflects tumor biology and suggests adjuvant chemotherapy could potentially be omitted in certain circumstances. Further research is needed to evaluate the clinical utility of escalation and de-escalation strategies in the adjuvant setting based on neoadjuvant response.”
“Basically, it appears that the impact of chemotherapy is going to be early, or if you use it early, you really don’t lose the impact [that it has] if you wait until after surgery,” commented SABCS codirector and press conference moderator Carlos Arteaga, MD, director of the Harold C. Simmons Comprehensive Cancer Center and associate dean of Oncology Programs at UT Southwestern Medical Center, Dallas, Texas. “So if it was me, I would have it done before the operation, frankly, because at a minimum, it’s not worse than delaying it until after surgery – at a minimum. And you get the benefit of potential breast conservation, a lesser surgery.”
Study details
For the meta-analysis, Dr. Spring and her coinvestigators searched for published studies of localized breast cancer that had 25 patients or more, featured neoadjuvant chemotherapy, and reported pCR using definitions allowed by the FDA (ypT0 ypN0 or ypT0/is ypN0), as well as recurrence and/or survival based on pathologic outcome. They excluded studies reporting only local recurrence and those using neoadjuvant endocrine therapy or neoadjuvant radiation.
Results showed that the pCR rate averaged 21.1% for the entire study population, according to Dr. Spring. But there was wide variation by tumor subtype, as expected, with a rate of less than 10% for hormone receptor–positive/HER2-negative breast cancer, to rates in the mid-30% range for triple-negative breast cancer and HER2-positive breast cancer.
Women who had pCR after neoadjuvant chemotherapy had a significantly lower risk of EFS events than peers who had residual disease (hazard ratio, 0.31; 95% probability interval, 0.24-0.39). The corresponding 5-year EFS rates were 88% and 67%.
Similarly, women who had pCR had a significantly lower risk of death (HR, 0.22; 95% probability interval, 0.15-0.30). The corresponding 5-year overall survival rates were 94% and 75%.
The EFS benefit of pCR versus residual disease was consistently seen across subgroups with triple-negative breast cancer (90% vs. 57%), HER2-positive breast cancer (86% vs. 63%), and hormone receptor–positive/HER2-negative breast cancer (97% vs. 88%). Findings were essentially the same for overall survival, according to Dr. Spring.
Among patients attaining pCR, the 5-year EFS rate was 86% for those who went on to receive adjuvant chemotherapy (HR, 0.36; 95% probability interval, 0.19-0.67) and 88% for those who did not (HR, 0.36; 95% probability interval, 0.27-0.54). The difference in hazard ratios between groups was not significant (P = .60).
Finally, the investigators conducted modeling to assess how the change in pCR rate corresponded with the change in EFS benefit. “This approach could be helpful in the design of neoadjuvant studies,” Dr. Spring explained.
“Assuming pCR is a valid surrogate endpoint, this is, it mediates all treatment effects, and that the average pCR is 50%, the magnitude of pCR change is predictive of treatment effects on EFS within a certain amount of uncertainty, based on the model,” she reported. For example, a change in pCR of 0.3 had a corresponding HR of 0.72, with a 95% probability interval of 0.68-0.77.
Dr. Spring disclosed that she has a consulting or advisory role with Novartis and that she receives institutional research funding from Tesaro. The study was supported by grants from the National Cancer Institute and Susan G. Komen.
SOURCE: Spring LM et al. SABCS 2018, Abstract GS2-03.
SAN ANTONIO – Women with localized breast cancer who achieve a pathological complete response (pCR) after neoadjuvant chemotherapy may be able to safely skip adjuvant chemotherapy, suggest new data from a patient-level meta-analysis reported in a session and press conference at the San Antonio Breast Cancer Symposium.
“The focus of many breast cancer trials for several years has been on adding additional systemic therapies to reduce recurrence risk. However, adding therapies can result in additional toxicity and overtreatment for many patients,” noted lead investigator Laura M. Spring, MD, of Massachusetts General Hospital Cancer Center and Harvard Medical School, both in Boston. “The neoadjuvant chemotherapy model offers several additional clinical and research advantages over adjuvant chemotherapy, including the rapid evaluation of treatment response utilizing surrogate biomarkers, such as pathological complete response.”
The meta-analysis of 52 studies, which included a total of 27,895 women who were given neoadjuvant chemotherapy, confirmed a large positive prognostic effect of pCR on outcomes in the entire sample, with a 69% relative reduction in event-free survival (EFS) events and a 78% relative reduction in risk of death, a pattern that was consistent across clinical subtypes of breast cancer. More importantly, among those achieving a pCR, EFS did not differ significantly whether they went on to receive more chemotherapy after surgery or not.
“Achieving pCR following neoadjuvant chemotherapy is associated with significantly improved EFS and overall survival, particularly for triple-negative and HER2-positive breast cancer. The results are highly significant despite inclusion of a variety of neoadjuvant regimens, suggesting the path taken to attain a pCR may not be critical,” Dr. Spring proposed. “The similar outcomes with or without adjuvant chemotherapy in patients who attained pCR after neoadjuvant chemotherapy likely reflects tumor biology and suggests adjuvant chemotherapy could potentially be omitted in certain circumstances. Further research is needed to evaluate the clinical utility of escalation and de-escalation strategies in the adjuvant setting based on neoadjuvant response.”
“Basically, it appears that the impact of chemotherapy is going to be early, or if you use it early, you really don’t lose the impact [that it has] if you wait until after surgery,” commented SABCS codirector and press conference moderator Carlos Arteaga, MD, director of the Harold C. Simmons Comprehensive Cancer Center and associate dean of Oncology Programs at UT Southwestern Medical Center, Dallas, Texas. “So if it was me, I would have it done before the operation, frankly, because at a minimum, it’s not worse than delaying it until after surgery – at a minimum. And you get the benefit of potential breast conservation, a lesser surgery.”
Study details
For the meta-analysis, Dr. Spring and her coinvestigators searched for published studies of localized breast cancer that had 25 patients or more, featured neoadjuvant chemotherapy, and reported pCR using definitions allowed by the FDA (ypT0 ypN0 or ypT0/is ypN0), as well as recurrence and/or survival based on pathologic outcome. They excluded studies reporting only local recurrence and those using neoadjuvant endocrine therapy or neoadjuvant radiation.
Results showed that the pCR rate averaged 21.1% for the entire study population, according to Dr. Spring. But there was wide variation by tumor subtype, as expected, with a rate of less than 10% for hormone receptor–positive/HER2-negative breast cancer, to rates in the mid-30% range for triple-negative breast cancer and HER2-positive breast cancer.
Women who had pCR after neoadjuvant chemotherapy had a significantly lower risk of EFS events than peers who had residual disease (hazard ratio, 0.31; 95% probability interval, 0.24-0.39). The corresponding 5-year EFS rates were 88% and 67%.
Similarly, women who had pCR had a significantly lower risk of death (HR, 0.22; 95% probability interval, 0.15-0.30). The corresponding 5-year overall survival rates were 94% and 75%.
The EFS benefit of pCR versus residual disease was consistently seen across subgroups with triple-negative breast cancer (90% vs. 57%), HER2-positive breast cancer (86% vs. 63%), and hormone receptor–positive/HER2-negative breast cancer (97% vs. 88%). Findings were essentially the same for overall survival, according to Dr. Spring.
Among patients attaining pCR, the 5-year EFS rate was 86% for those who went on to receive adjuvant chemotherapy (HR, 0.36; 95% probability interval, 0.19-0.67) and 88% for those who did not (HR, 0.36; 95% probability interval, 0.27-0.54). The difference in hazard ratios between groups was not significant (P = .60).
Finally, the investigators conducted modeling to assess how the change in pCR rate corresponded with the change in EFS benefit. “This approach could be helpful in the design of neoadjuvant studies,” Dr. Spring explained.
“Assuming pCR is a valid surrogate endpoint, this is, it mediates all treatment effects, and that the average pCR is 50%, the magnitude of pCR change is predictive of treatment effects on EFS within a certain amount of uncertainty, based on the model,” she reported. For example, a change in pCR of 0.3 had a corresponding HR of 0.72, with a 95% probability interval of 0.68-0.77.
Dr. Spring disclosed that she has a consulting or advisory role with Novartis and that she receives institutional research funding from Tesaro. The study was supported by grants from the National Cancer Institute and Susan G. Komen.
SOURCE: Spring LM et al. SABCS 2018, Abstract GS2-03.
REPORTING FROM SABCS 2018
Key clinical point: Adjuvant chemotherapy does not further improve outcome after a pathological complete response to neoadjuvant chemotherapy.
Major finding: Patients achieving pCR had a similar reduction in risk of EFS events whether they went on to receive adjuvant chemotherapy (hazard ratio, 0.36) or not (hazard ratio, 0.36; P = .60 for difference between groups).
Study details: Individual-level meta-analysis of 27,895 patients who received neoadjuvant chemotherapy for localized breast cancer.
Disclosures: Dr. Spring disclosed that she has a consulting or advisory role with Novartis and that she receives institutional research funding from Tesaro. The study was supported by grants from the National Cancer Institute and Susan G. Komen.
Source: Spring LM et al. SABCS 2018, Abstract GS2-03.