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Boost dose reduces recurrence in high-risk DCIS
Giving a tumor bed boost (TBB) reduced the risk of local recurrence and overall disease recurrence, but there were no significant differences in recurrence rates between conventional WBI and hypofractionated WBI.
Boon Hui Chua, MD, of the University of New South Wales, Sydney, presented these results at the 2020 San Antonio Breast Cancer Symposium.
Dr. Chua and colleagues studied 1,608 women with DCIS resected by conservative surgery. Patients were either younger than 50 years or age 50 and older with at least one of the following risk factors: symptomatic presentation, palpable tumor, multifocal disease, tumor size 1.5 cm or larger, intermediate or high nuclear grade, central necrosis, comedo histology, and/or surgical margins less than 10 mm.
The patients were randomized to treatment in three categories. In randomization A (n = 503), patients were randomized to one of the following treatments:
- WBI at 50 Gy in 25 fractions
- WBI at 42.5 Gy in 16 fractions
- WBI at 50 Gy in 25 fractions plus TBB at 16 Gy in 8 fractions
- WBI at 42.5 Gy in 16 fractions plus TBB at 16 Gy in 8 fractions.
In randomization B (n = 581), patients received WBI at 50 Gy in 25 fractions, with or without TBB at 16 Gy in 8 fractions. In randomization C (n = 524), patients received WBI at 42.5 Gy in 16 fractions, with or without TBB at 16 Gy in 8 fractions.
All patients underwent CT-based radiation planning. WBI was delivered with tangential MV photon beams, and TBB was performed with CT contouring of protocol-defined tumor bed target volumes, with electron or photon energy. The median follow-up was 6.6 years.
Giving a boost to better outcomes
The 5-year rate of freedom from local recurrence was 97% for patients who received TBB and 93% for patients who did not (hazard ratio, 0.47; P < .001). The benefit of TBB was consistent across subgroups.
There were no significant differences in 5-year rates of freedom from local recurrence by WBI fractionation, either in randomization A (P = .837) or among all randomized patients (P = .887).
The tests for interactions between TBB and WBI fractionation on local recurrence were not significant in randomization A (P = .89) or in all randomized patients (P = .89).
The risk of overall disease recurrence was lower among patients who had received TBB, with an HR of 0.63 (P = .004). The 5-year rate of freedom from disease recurrence was 97% with TBB and 91% with no boost (P = .002).
There were no significant differences in freedom from disease recurrence rates by WBI fractionation either in randomization A (P = .443) or among all randomized patients (P = .605).
Acute radiation dermatitis occurred in significantly more patients who received TBB (P = .006), as did late breast pain (P = .003), induration or fibrosis (P < .0001), and telangiectasia (P = .02). There were no significant differences by boost status for acute or late fatigue, pneumonitis, cardiac complications, or second malignancies.
Reduce the boost dose?
A radiation oncologist who was not involved in this study said that, while the results confirm a benefit of boost dose for patients with non–low-risk DCIS, the doses used in the BIG-3-07 study may be higher than needed to achieve a protective effect.
“Here in America, we usually give 10 Gy in five fractions, and, in many countries, actually, it’s 10 Gy in five fractions, although a few European centers give 16 Gy in eight fractions,” said Alphose Taghian, MD, of Massachusetts General Hospital in Boston.
“I personally only give 10 Gy in five fractions. I am not under the impression that 16 Gy in eight fractions will give better results. The local failure rate is so low, it’s likely that 10 Gy will do the job,” Dr. Taghian said in an interview.
Dr. Taghian noted that raising the dose to 16 Gy increases the risk of fibrosis, as seen in the BIG-3-07 trial.
Nonetheless, the trial demonstrates the benefit of radiation boost dose in patients with high-risk DCIS, he said, adding that the local recurrence-free benefit curves may separate further with longer follow-up.
The study was sponsored by the Trans Tasman Radiation Oncology Group. Dr. Chua and Dr. Taghian reported no conflicts of interest.
Giving a tumor bed boost (TBB) reduced the risk of local recurrence and overall disease recurrence, but there were no significant differences in recurrence rates between conventional WBI and hypofractionated WBI.
Boon Hui Chua, MD, of the University of New South Wales, Sydney, presented these results at the 2020 San Antonio Breast Cancer Symposium.
Dr. Chua and colleagues studied 1,608 women with DCIS resected by conservative surgery. Patients were either younger than 50 years or age 50 and older with at least one of the following risk factors: symptomatic presentation, palpable tumor, multifocal disease, tumor size 1.5 cm or larger, intermediate or high nuclear grade, central necrosis, comedo histology, and/or surgical margins less than 10 mm.
The patients were randomized to treatment in three categories. In randomization A (n = 503), patients were randomized to one of the following treatments:
- WBI at 50 Gy in 25 fractions
- WBI at 42.5 Gy in 16 fractions
- WBI at 50 Gy in 25 fractions plus TBB at 16 Gy in 8 fractions
- WBI at 42.5 Gy in 16 fractions plus TBB at 16 Gy in 8 fractions.
In randomization B (n = 581), patients received WBI at 50 Gy in 25 fractions, with or without TBB at 16 Gy in 8 fractions. In randomization C (n = 524), patients received WBI at 42.5 Gy in 16 fractions, with or without TBB at 16 Gy in 8 fractions.
All patients underwent CT-based radiation planning. WBI was delivered with tangential MV photon beams, and TBB was performed with CT contouring of protocol-defined tumor bed target volumes, with electron or photon energy. The median follow-up was 6.6 years.
Giving a boost to better outcomes
The 5-year rate of freedom from local recurrence was 97% for patients who received TBB and 93% for patients who did not (hazard ratio, 0.47; P < .001). The benefit of TBB was consistent across subgroups.
There were no significant differences in 5-year rates of freedom from local recurrence by WBI fractionation, either in randomization A (P = .837) or among all randomized patients (P = .887).
The tests for interactions between TBB and WBI fractionation on local recurrence were not significant in randomization A (P = .89) or in all randomized patients (P = .89).
The risk of overall disease recurrence was lower among patients who had received TBB, with an HR of 0.63 (P = .004). The 5-year rate of freedom from disease recurrence was 97% with TBB and 91% with no boost (P = .002).
There were no significant differences in freedom from disease recurrence rates by WBI fractionation either in randomization A (P = .443) or among all randomized patients (P = .605).
Acute radiation dermatitis occurred in significantly more patients who received TBB (P = .006), as did late breast pain (P = .003), induration or fibrosis (P < .0001), and telangiectasia (P = .02). There were no significant differences by boost status for acute or late fatigue, pneumonitis, cardiac complications, or second malignancies.
Reduce the boost dose?
A radiation oncologist who was not involved in this study said that, while the results confirm a benefit of boost dose for patients with non–low-risk DCIS, the doses used in the BIG-3-07 study may be higher than needed to achieve a protective effect.
“Here in America, we usually give 10 Gy in five fractions, and, in many countries, actually, it’s 10 Gy in five fractions, although a few European centers give 16 Gy in eight fractions,” said Alphose Taghian, MD, of Massachusetts General Hospital in Boston.
“I personally only give 10 Gy in five fractions. I am not under the impression that 16 Gy in eight fractions will give better results. The local failure rate is so low, it’s likely that 10 Gy will do the job,” Dr. Taghian said in an interview.
Dr. Taghian noted that raising the dose to 16 Gy increases the risk of fibrosis, as seen in the BIG-3-07 trial.
Nonetheless, the trial demonstrates the benefit of radiation boost dose in patients with high-risk DCIS, he said, adding that the local recurrence-free benefit curves may separate further with longer follow-up.
The study was sponsored by the Trans Tasman Radiation Oncology Group. Dr. Chua and Dr. Taghian reported no conflicts of interest.
Giving a tumor bed boost (TBB) reduced the risk of local recurrence and overall disease recurrence, but there were no significant differences in recurrence rates between conventional WBI and hypofractionated WBI.
Boon Hui Chua, MD, of the University of New South Wales, Sydney, presented these results at the 2020 San Antonio Breast Cancer Symposium.
Dr. Chua and colleagues studied 1,608 women with DCIS resected by conservative surgery. Patients were either younger than 50 years or age 50 and older with at least one of the following risk factors: symptomatic presentation, palpable tumor, multifocal disease, tumor size 1.5 cm or larger, intermediate or high nuclear grade, central necrosis, comedo histology, and/or surgical margins less than 10 mm.
The patients were randomized to treatment in three categories. In randomization A (n = 503), patients were randomized to one of the following treatments:
- WBI at 50 Gy in 25 fractions
- WBI at 42.5 Gy in 16 fractions
- WBI at 50 Gy in 25 fractions plus TBB at 16 Gy in 8 fractions
- WBI at 42.5 Gy in 16 fractions plus TBB at 16 Gy in 8 fractions.
In randomization B (n = 581), patients received WBI at 50 Gy in 25 fractions, with or without TBB at 16 Gy in 8 fractions. In randomization C (n = 524), patients received WBI at 42.5 Gy in 16 fractions, with or without TBB at 16 Gy in 8 fractions.
All patients underwent CT-based radiation planning. WBI was delivered with tangential MV photon beams, and TBB was performed with CT contouring of protocol-defined tumor bed target volumes, with electron or photon energy. The median follow-up was 6.6 years.
Giving a boost to better outcomes
The 5-year rate of freedom from local recurrence was 97% for patients who received TBB and 93% for patients who did not (hazard ratio, 0.47; P < .001). The benefit of TBB was consistent across subgroups.
There were no significant differences in 5-year rates of freedom from local recurrence by WBI fractionation, either in randomization A (P = .837) or among all randomized patients (P = .887).
The tests for interactions between TBB and WBI fractionation on local recurrence were not significant in randomization A (P = .89) or in all randomized patients (P = .89).
The risk of overall disease recurrence was lower among patients who had received TBB, with an HR of 0.63 (P = .004). The 5-year rate of freedom from disease recurrence was 97% with TBB and 91% with no boost (P = .002).
There were no significant differences in freedom from disease recurrence rates by WBI fractionation either in randomization A (P = .443) or among all randomized patients (P = .605).
Acute radiation dermatitis occurred in significantly more patients who received TBB (P = .006), as did late breast pain (P = .003), induration or fibrosis (P < .0001), and telangiectasia (P = .02). There were no significant differences by boost status for acute or late fatigue, pneumonitis, cardiac complications, or second malignancies.
Reduce the boost dose?
A radiation oncologist who was not involved in this study said that, while the results confirm a benefit of boost dose for patients with non–low-risk DCIS, the doses used in the BIG-3-07 study may be higher than needed to achieve a protective effect.
“Here in America, we usually give 10 Gy in five fractions, and, in many countries, actually, it’s 10 Gy in five fractions, although a few European centers give 16 Gy in eight fractions,” said Alphose Taghian, MD, of Massachusetts General Hospital in Boston.
“I personally only give 10 Gy in five fractions. I am not under the impression that 16 Gy in eight fractions will give better results. The local failure rate is so low, it’s likely that 10 Gy will do the job,” Dr. Taghian said in an interview.
Dr. Taghian noted that raising the dose to 16 Gy increases the risk of fibrosis, as seen in the BIG-3-07 trial.
Nonetheless, the trial demonstrates the benefit of radiation boost dose in patients with high-risk DCIS, he said, adding that the local recurrence-free benefit curves may separate further with longer follow-up.
The study was sponsored by the Trans Tasman Radiation Oncology Group. Dr. Chua and Dr. Taghian reported no conflicts of interest.
FROM SABCS 2020
RSClin: A new tool for ‘TAILOR-ing’ treatment in early breast cancer
When results of the TAILORx trial were presented at ASCO 2018, many oncologists thought it seemed too simple that a single number from a genomic assay could separate patients who would and would not benefit from adjuvant postoperative chemotherapy.
Those oncologists were right to be skeptical. Subsequent data indicated that better predictive tools were needed.
A new tool called “RSClin” may fit the bill. RSClin integrates the prognostic and predictive value of the 21-gene Oncotype DX recurrence score (RS) with the additional prognostic information conveyed by patient age, tumor grade, and tumor size.
RSClin provides individualized estimates of distant relapse risk for women with node-negative, endocrine sensitive, HER2/neu oncogene-negative early breast cancer – and a quantification of the additive freedom from distant relapse if that patient receives adjuvant chemotherapy. The tool is now available via a tab on the professional portal at https://online.genomichealth.com/.
Details on RSClin, including how the tool was developed and validated, were presented at the 2020 San Antonio Breast Cancer Symposium by Joseph A. Sparano, MD, of Albert Einstein College of Medicine in New York.
Beyond the initial publication of TAILORx
Results from the TAILORx trial published in The New England Journal of Medicine in 2018 offered the potential for genomic risk assessment to guide the choice of postoperative therapy for many women with the most common type of primary breast cancer. The relative risk reduction with chemotherapy increased with increasing RS result.
Subsequent analyses of the TAILORx dataset, published in The New England Journal of Medicine and JAMA Oncology in 2019, examined the added effect of parameters of clinical risk (tumor size and grade) and patient age for patients with known genomic risk.
In these analyses, clinical risk was prognostic for recurrence but did not predict the absolute magnitude of chemotherapy benefit, regardless of age. There was a trend toward chemotherapy benefit in women who were younger than 50 years of age who had RS 21-15, but it was irrespective of clinical risk.
The development of RSClin
RSClin was derived from a patient-specific meta-analysis of 10,004 women with hormone receptor–positive, HER2-negative, node-negative breast cancer, of whom 9,427 participated in the TAILORx trial.
In TAILORx, which ran from 2006 to 2015, women with RS 0-11 received contemporary hormone therapy alone. Women with RS 12-25 were randomized to receive hormone therapy alone or with conventional combination chemotherapy. Women with RS above 26 received chemotherapy plus endocrine therapy.
The other patients in the meta-analysis participated in NSABP studies B-14 (tamoxifen versus placebo) and B-20 (tamoxifen versus chemotherapy plus tamoxifen).
Cox regression models were fit separately to each study with covariates of the continuous variables of RS result, tumor size, and patient age and the discrete variable of histologic tumor grade (assessed centrally in B-14 and in local laboratories in TAILORx). The prespecified endpoint was time to first distant recurrence.
RSClin estimates of distant recurrence risk were generated using baseline risk with TAILORx event rates to reflect current medical practice.
Model estimates were calculated for specified endocrine therapy with tamoxifen or aromatase inhibitors utilizing the treatment effect hazard ratio from an Early Breast Cancer Trialists’ Collaborative Group meta-analysis.
Patient-specific absolute benefit of chemotherapy was estimated by combining patient-specific meta-analysis risk estimates for distant recurrence and for relative chemotherapy benefit using the B-20 and TAILORx trials.
RSClin results and external validation
Among all patients in the meta-analysis cohort, RSClin provided a significantly more accurate prediction of distant recurrence events, in comparison with RS alone or clinical-pathologic factors alone.
External validation was performed using data from real-world outcomes from the 1,098 evaluable node-negative patients in the Clalit Health Services registry, of whom 876 received endocrine therapy alone and 222 received endocrine therapy plus chemotherapy.
RSClin estimates of distant recurrence closely approximated the observed risk in the registry (standardized hazard ratio, 1.73; 95% confidence interval, 1.40-2.15; P < .001). Within each RSClin risk quintile, the average 10-year risk estimate approached the observed Kaplan-Meier estimates in the cohort (Lin concordance correlation = 0.962).
Shared decision-making
For many years, the dilemma of whether to recommend adjuvant chemotherapy to a patient with early breast cancer has prompted the generation of tools to quantify a patient’s risk of recurrence and the magnitude of benefit for endocrine therapy and/or chemotherapy.
When the original Adjuvant! Online program was developed, genomic risk profiling was in its infancy. Genomic tools such as the 21-gene RS have subsequently demonstrated that they can help optimize the adjuvant treatment we recommend.
The RSClin tool provides more precise, individualized information than does clinical-pathological or genomic data alone. It prognosticates the risk of distant recurrence of breast cancer, which patients and providers fervently wish to minimize.
RSClin estimates the incremental benefit of contemporary adjuvant chemotherapy over modern endocrine therapy alone, in absolute values, for individual patients. This transparent, discrete, easily explained information is vital for counseling patients.
However, as highlighted in an editorial published in the Journal of Clinical Oncology, RSClin is not without its potential drawbacks. These include:
- Tumor heterogeneity leading to misleading results.
- Variable patient adherence to endocrine therapy or chemotherapy.
- The influence of comorbid conditions on the risk/benefit ratio.
- The potential of ovarian function suppression in young women to approach the magnitude of benefit associated with chemotherapy.
Accordingly, RSClin may be the latest and best available tool, but it will not be the last.
For patients with RS above 26, for older women with intermediate RS, and for younger women with a low RS and low clinical-pathologic features, RSClin may not influence treatment recommendations.
However, for the common scenario of an intermediate-risk RS and a mix of pathologic features, the accurate prognostication for distant recurrence risk and estimate of absolute benefit from chemotherapy will be terrifically helpful to oncology caregivers.
Dr. Sparano disclosed funding from the National Cancer Institute and travel support from Rhenium.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
When results of the TAILORx trial were presented at ASCO 2018, many oncologists thought it seemed too simple that a single number from a genomic assay could separate patients who would and would not benefit from adjuvant postoperative chemotherapy.
Those oncologists were right to be skeptical. Subsequent data indicated that better predictive tools were needed.
A new tool called “RSClin” may fit the bill. RSClin integrates the prognostic and predictive value of the 21-gene Oncotype DX recurrence score (RS) with the additional prognostic information conveyed by patient age, tumor grade, and tumor size.
RSClin provides individualized estimates of distant relapse risk for women with node-negative, endocrine sensitive, HER2/neu oncogene-negative early breast cancer – and a quantification of the additive freedom from distant relapse if that patient receives adjuvant chemotherapy. The tool is now available via a tab on the professional portal at https://online.genomichealth.com/.
Details on RSClin, including how the tool was developed and validated, were presented at the 2020 San Antonio Breast Cancer Symposium by Joseph A. Sparano, MD, of Albert Einstein College of Medicine in New York.
Beyond the initial publication of TAILORx
Results from the TAILORx trial published in The New England Journal of Medicine in 2018 offered the potential for genomic risk assessment to guide the choice of postoperative therapy for many women with the most common type of primary breast cancer. The relative risk reduction with chemotherapy increased with increasing RS result.
Subsequent analyses of the TAILORx dataset, published in The New England Journal of Medicine and JAMA Oncology in 2019, examined the added effect of parameters of clinical risk (tumor size and grade) and patient age for patients with known genomic risk.
In these analyses, clinical risk was prognostic for recurrence but did not predict the absolute magnitude of chemotherapy benefit, regardless of age. There was a trend toward chemotherapy benefit in women who were younger than 50 years of age who had RS 21-15, but it was irrespective of clinical risk.
The development of RSClin
RSClin was derived from a patient-specific meta-analysis of 10,004 women with hormone receptor–positive, HER2-negative, node-negative breast cancer, of whom 9,427 participated in the TAILORx trial.
In TAILORx, which ran from 2006 to 2015, women with RS 0-11 received contemporary hormone therapy alone. Women with RS 12-25 were randomized to receive hormone therapy alone or with conventional combination chemotherapy. Women with RS above 26 received chemotherapy plus endocrine therapy.
The other patients in the meta-analysis participated in NSABP studies B-14 (tamoxifen versus placebo) and B-20 (tamoxifen versus chemotherapy plus tamoxifen).
Cox regression models were fit separately to each study with covariates of the continuous variables of RS result, tumor size, and patient age and the discrete variable of histologic tumor grade (assessed centrally in B-14 and in local laboratories in TAILORx). The prespecified endpoint was time to first distant recurrence.
RSClin estimates of distant recurrence risk were generated using baseline risk with TAILORx event rates to reflect current medical practice.
Model estimates were calculated for specified endocrine therapy with tamoxifen or aromatase inhibitors utilizing the treatment effect hazard ratio from an Early Breast Cancer Trialists’ Collaborative Group meta-analysis.
Patient-specific absolute benefit of chemotherapy was estimated by combining patient-specific meta-analysis risk estimates for distant recurrence and for relative chemotherapy benefit using the B-20 and TAILORx trials.
RSClin results and external validation
Among all patients in the meta-analysis cohort, RSClin provided a significantly more accurate prediction of distant recurrence events, in comparison with RS alone or clinical-pathologic factors alone.
External validation was performed using data from real-world outcomes from the 1,098 evaluable node-negative patients in the Clalit Health Services registry, of whom 876 received endocrine therapy alone and 222 received endocrine therapy plus chemotherapy.
RSClin estimates of distant recurrence closely approximated the observed risk in the registry (standardized hazard ratio, 1.73; 95% confidence interval, 1.40-2.15; P < .001). Within each RSClin risk quintile, the average 10-year risk estimate approached the observed Kaplan-Meier estimates in the cohort (Lin concordance correlation = 0.962).
Shared decision-making
For many years, the dilemma of whether to recommend adjuvant chemotherapy to a patient with early breast cancer has prompted the generation of tools to quantify a patient’s risk of recurrence and the magnitude of benefit for endocrine therapy and/or chemotherapy.
When the original Adjuvant! Online program was developed, genomic risk profiling was in its infancy. Genomic tools such as the 21-gene RS have subsequently demonstrated that they can help optimize the adjuvant treatment we recommend.
The RSClin tool provides more precise, individualized information than does clinical-pathological or genomic data alone. It prognosticates the risk of distant recurrence of breast cancer, which patients and providers fervently wish to minimize.
RSClin estimates the incremental benefit of contemporary adjuvant chemotherapy over modern endocrine therapy alone, in absolute values, for individual patients. This transparent, discrete, easily explained information is vital for counseling patients.
However, as highlighted in an editorial published in the Journal of Clinical Oncology, RSClin is not without its potential drawbacks. These include:
- Tumor heterogeneity leading to misleading results.
- Variable patient adherence to endocrine therapy or chemotherapy.
- The influence of comorbid conditions on the risk/benefit ratio.
- The potential of ovarian function suppression in young women to approach the magnitude of benefit associated with chemotherapy.
Accordingly, RSClin may be the latest and best available tool, but it will not be the last.
For patients with RS above 26, for older women with intermediate RS, and for younger women with a low RS and low clinical-pathologic features, RSClin may not influence treatment recommendations.
However, for the common scenario of an intermediate-risk RS and a mix of pathologic features, the accurate prognostication for distant recurrence risk and estimate of absolute benefit from chemotherapy will be terrifically helpful to oncology caregivers.
Dr. Sparano disclosed funding from the National Cancer Institute and travel support from Rhenium.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
When results of the TAILORx trial were presented at ASCO 2018, many oncologists thought it seemed too simple that a single number from a genomic assay could separate patients who would and would not benefit from adjuvant postoperative chemotherapy.
Those oncologists were right to be skeptical. Subsequent data indicated that better predictive tools were needed.
A new tool called “RSClin” may fit the bill. RSClin integrates the prognostic and predictive value of the 21-gene Oncotype DX recurrence score (RS) with the additional prognostic information conveyed by patient age, tumor grade, and tumor size.
RSClin provides individualized estimates of distant relapse risk for women with node-negative, endocrine sensitive, HER2/neu oncogene-negative early breast cancer – and a quantification of the additive freedom from distant relapse if that patient receives adjuvant chemotherapy. The tool is now available via a tab on the professional portal at https://online.genomichealth.com/.
Details on RSClin, including how the tool was developed and validated, were presented at the 2020 San Antonio Breast Cancer Symposium by Joseph A. Sparano, MD, of Albert Einstein College of Medicine in New York.
Beyond the initial publication of TAILORx
Results from the TAILORx trial published in The New England Journal of Medicine in 2018 offered the potential for genomic risk assessment to guide the choice of postoperative therapy for many women with the most common type of primary breast cancer. The relative risk reduction with chemotherapy increased with increasing RS result.
Subsequent analyses of the TAILORx dataset, published in The New England Journal of Medicine and JAMA Oncology in 2019, examined the added effect of parameters of clinical risk (tumor size and grade) and patient age for patients with known genomic risk.
In these analyses, clinical risk was prognostic for recurrence but did not predict the absolute magnitude of chemotherapy benefit, regardless of age. There was a trend toward chemotherapy benefit in women who were younger than 50 years of age who had RS 21-15, but it was irrespective of clinical risk.
The development of RSClin
RSClin was derived from a patient-specific meta-analysis of 10,004 women with hormone receptor–positive, HER2-negative, node-negative breast cancer, of whom 9,427 participated in the TAILORx trial.
In TAILORx, which ran from 2006 to 2015, women with RS 0-11 received contemporary hormone therapy alone. Women with RS 12-25 were randomized to receive hormone therapy alone or with conventional combination chemotherapy. Women with RS above 26 received chemotherapy plus endocrine therapy.
The other patients in the meta-analysis participated in NSABP studies B-14 (tamoxifen versus placebo) and B-20 (tamoxifen versus chemotherapy plus tamoxifen).
Cox regression models were fit separately to each study with covariates of the continuous variables of RS result, tumor size, and patient age and the discrete variable of histologic tumor grade (assessed centrally in B-14 and in local laboratories in TAILORx). The prespecified endpoint was time to first distant recurrence.
RSClin estimates of distant recurrence risk were generated using baseline risk with TAILORx event rates to reflect current medical practice.
Model estimates were calculated for specified endocrine therapy with tamoxifen or aromatase inhibitors utilizing the treatment effect hazard ratio from an Early Breast Cancer Trialists’ Collaborative Group meta-analysis.
Patient-specific absolute benefit of chemotherapy was estimated by combining patient-specific meta-analysis risk estimates for distant recurrence and for relative chemotherapy benefit using the B-20 and TAILORx trials.
RSClin results and external validation
Among all patients in the meta-analysis cohort, RSClin provided a significantly more accurate prediction of distant recurrence events, in comparison with RS alone or clinical-pathologic factors alone.
External validation was performed using data from real-world outcomes from the 1,098 evaluable node-negative patients in the Clalit Health Services registry, of whom 876 received endocrine therapy alone and 222 received endocrine therapy plus chemotherapy.
RSClin estimates of distant recurrence closely approximated the observed risk in the registry (standardized hazard ratio, 1.73; 95% confidence interval, 1.40-2.15; P < .001). Within each RSClin risk quintile, the average 10-year risk estimate approached the observed Kaplan-Meier estimates in the cohort (Lin concordance correlation = 0.962).
Shared decision-making
For many years, the dilemma of whether to recommend adjuvant chemotherapy to a patient with early breast cancer has prompted the generation of tools to quantify a patient’s risk of recurrence and the magnitude of benefit for endocrine therapy and/or chemotherapy.
When the original Adjuvant! Online program was developed, genomic risk profiling was in its infancy. Genomic tools such as the 21-gene RS have subsequently demonstrated that they can help optimize the adjuvant treatment we recommend.
The RSClin tool provides more precise, individualized information than does clinical-pathological or genomic data alone. It prognosticates the risk of distant recurrence of breast cancer, which patients and providers fervently wish to minimize.
RSClin estimates the incremental benefit of contemporary adjuvant chemotherapy over modern endocrine therapy alone, in absolute values, for individual patients. This transparent, discrete, easily explained information is vital for counseling patients.
However, as highlighted in an editorial published in the Journal of Clinical Oncology, RSClin is not without its potential drawbacks. These include:
- Tumor heterogeneity leading to misleading results.
- Variable patient adherence to endocrine therapy or chemotherapy.
- The influence of comorbid conditions on the risk/benefit ratio.
- The potential of ovarian function suppression in young women to approach the magnitude of benefit associated with chemotherapy.
Accordingly, RSClin may be the latest and best available tool, but it will not be the last.
For patients with RS above 26, for older women with intermediate RS, and for younger women with a low RS and low clinical-pathologic features, RSClin may not influence treatment recommendations.
However, for the common scenario of an intermediate-risk RS and a mix of pathologic features, the accurate prognostication for distant recurrence risk and estimate of absolute benefit from chemotherapy will be terrifically helpful to oncology caregivers.
Dr. Sparano disclosed funding from the National Cancer Institute and travel support from Rhenium.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
FROM SABCS 2020
Adaptive biomarker approach may spare some breast cancer patients chemo
The findings were reported at the 2020 San Antonio Breast Cancer Symposium.
“In early luminal breast cancer, optimal patient selection for omission of adjuvant chemotherapy, particularly in patients with one to three involved lymph nodes, is still unclear,” noted principal investigator Nadia Harbeck, MD, PhD, of the University of Munich.
Successive trials have used nodal status, genomic risk scores, and response to preoperative therapy to home in on subsets of women for whom this practice is safe.
The ADAPT HR+/HER2– trial is a phase 3 trial that enrolled 5,625 patients with luminal (hormone receptor–positive, HER2-negative) early breast cancer who were candidates for adjuvant chemotherapy based on conventional criteria.
The trial combined a static biomarker – Oncotype Dx recurrence score (RS) in the baseline core biopsy – and a dynamic biomarker – Ki-67 response to a 3-week course of preoperative endocrine therapy – to personalize adjuvant therapy.
At SABCS 2020, Dr. Harbeck reported results for 2,290 patients having zero to three involved lymph nodes: 868 patients with RS 0-11 and 1,422 patients with RS 12-25 who had a response to brief preoperative endocrine therapy (a Ki-67 fraction ≤10% at surgery). All were treated with endocrine therapy alone as adjuvant therapy.
Similar outcomes
The median follow-up was 60 months. The 5-year rate of invasive disease–free survival was 93.9% for the group with RS 0-11 and 92.6% for the group with RS 12-25 and a response to the preoperative endocrine therapy.
The study met its primary endpoint, as the lower limit of the 95% confidence interval for the difference between groups of –3.3% fell just within the predefined margin of –3.3% or less for noninferiority (P = .05).
The groups also had similarly “excellent” distant disease–free survival (96.3% for RS 0-11 and 95.6% for RS 12-25; P = .247) and overall survival (98.0% for RS 0-11 and 97.3% for RS 12-25; P = .160), Dr. Harbeck reported.
The similar distant disease–free survival was consistent regardless of whether women were younger or older than 50 years and regardless of whether women had involved nodes or not.
In multivariate analysis, women had greater risk of distant disease–free survival events if they had three positive lymph nodes versus zero to two (hazard ratio, 3.40) or a pathologic T stage of 2-4 versus 0-1 (HR, 2.24), whereas risk fell with increasing baseline progesterone receptor expression (HR, 0.92).
“Neither patient age nor study arm were prognostic factors for patient outcome,” Dr. Harbeck noted.
In stratified analysis, the negative impact of having three positive nodes was seen only in the group with RS 12-25 and response to preoperative endocrine therapy, suggesting this subgroup may not be good candidates for omission of chemotherapy, she said.
Applying results to practice
“In luminal early breast cancer, the following patients – irrespective of their age – can safely be treated by endocrine therapy alone: patients with zero to three involved lymph nodes and recurrence score 0-11, and those with limited nodal burden (zero to two lymph nodes), recurrence score 12-25, and endocrine response after short preoperative endocrine therapy,” Dr. Harbeck summarized.
“Oncotype Dx testing can spare chemotherapy for the majority of patients with up to three involved lymph nodes. Dynamic Ki-67 response testing is feasible in clinical routine and complements baseline risk assessment to define patient selection for therapy deescalation or escalation,” she added.
The investigators have used the trial’s data to develop an algorithm for predicting the probability of response to short-course preoperative endocrine therapy that is available free of charge online (www.enrep.info).
“This may support everyday clinical decision-making in luminal early breast cancer; for example, whether to start a short period of preoperative endocrine therapy at all, and whether to rely on adjuvant endocrine therapy alone, but also in times like these, whether it’s safe to delay surgery by putting patients on prolonged preoperative endocrine therapy if surgical resources are scarce,” Dr. Harbeck commented.
Her clinic is now recruiting patients for the ADAPT Cycle trial, which is testing an endocrine-based approach with a CDK4/6 inhibitor versus chemotherapy in patients who are not candidates for adjuvant endocrine therapy alone. Therefore, all eligible patients receive the short course of endocrine therapy up front as the standard.
“But if you don’t have a trial, what are you going to do on Monday morning? Please let your patient know whether her tumor is endocrine responsive by doing this 3-week preoperative endocrine therapy,” Dr. Harbeck recommended. “It’s easy to do, you can schedule your surgeries better, and in patients with up to three lymph nodes, it helps with your decision-making, not just in the postmenopausal patients but also in the premenopausal patients, regarding whether they can forgo chemotherapy.”
Findings in context
More than 75% of ADAPT patients with RS 12-25 had a response to short-course endocrine therapy, noted invited discussant Lajos Pusztai, MD, DPhil, of the Yale Cancer Center in New Haven, Conn.
“This implies that the endocrine challenge is not informative for most patients,” he said, adding that a related question is whether the 25% of patients who did not have a response and were therefore given chemotherapy benefited from that therapy.
Dr. Pusztai cautioned that, among patients in the group with RS 12-25 who had a response to preoperative endocrine therapy, certain subgroups were fairly or very small: those aged 50 years or younger (330 patients) and those with two or three positive nodes (75 and 22 patients, respectively).
And collective findings of the similar but much larger TAILORx trial and RxPONDER trial (also reported at SABCS 2020) do suggest a benefit of chemotherapy in younger women, regardless of the number of positive nodes.
“Selection of [estrogen receptor]–positive patients with zero to three lymph nodes for adjuvant chemotherapy currently should be based on age and baseline recurrence score or a similar validated molecular assay,” Dr. Pusztai recommended. “TAILORx results guide us in regard to the use of the recurrence score in node-negative patients with a recurrence score of less than 26, and the recently presented RxPONDER results provide evidence for the use of recurrence score in patients with one to three positive nodes with a recurrence score in the range of 0-26. Both of these trials showed benefit in younger women from adjuvant chemotherapy.”
The ADAPT trial was sponsored by Roche, Genomic Health/Exact Sciences, Celgene, Bayer, Teva, and Amgen. Dr. Harbeck disclosed relationships with Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Lilly, Merck, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche/Genentech, Samsung, Sandoz, and Seattle Genetics. Dr. Pusztai disclosed relationships with AstraZeneca, Athenex, Almac, Bristol-Myers Squibb, Biotheranostics, Clovis, Daiichi, Eisai, Genentech, H2Bio, H3 Biomedicine, Immunomedics, Merck, Novartis, Pfizer, Pieris, Radius Health, Syndax, and Seattle Genetics,.
The findings were reported at the 2020 San Antonio Breast Cancer Symposium.
“In early luminal breast cancer, optimal patient selection for omission of adjuvant chemotherapy, particularly in patients with one to three involved lymph nodes, is still unclear,” noted principal investigator Nadia Harbeck, MD, PhD, of the University of Munich.
Successive trials have used nodal status, genomic risk scores, and response to preoperative therapy to home in on subsets of women for whom this practice is safe.
The ADAPT HR+/HER2– trial is a phase 3 trial that enrolled 5,625 patients with luminal (hormone receptor–positive, HER2-negative) early breast cancer who were candidates for adjuvant chemotherapy based on conventional criteria.
The trial combined a static biomarker – Oncotype Dx recurrence score (RS) in the baseline core biopsy – and a dynamic biomarker – Ki-67 response to a 3-week course of preoperative endocrine therapy – to personalize adjuvant therapy.
At SABCS 2020, Dr. Harbeck reported results for 2,290 patients having zero to three involved lymph nodes: 868 patients with RS 0-11 and 1,422 patients with RS 12-25 who had a response to brief preoperative endocrine therapy (a Ki-67 fraction ≤10% at surgery). All were treated with endocrine therapy alone as adjuvant therapy.
Similar outcomes
The median follow-up was 60 months. The 5-year rate of invasive disease–free survival was 93.9% for the group with RS 0-11 and 92.6% for the group with RS 12-25 and a response to the preoperative endocrine therapy.
The study met its primary endpoint, as the lower limit of the 95% confidence interval for the difference between groups of –3.3% fell just within the predefined margin of –3.3% or less for noninferiority (P = .05).
The groups also had similarly “excellent” distant disease–free survival (96.3% for RS 0-11 and 95.6% for RS 12-25; P = .247) and overall survival (98.0% for RS 0-11 and 97.3% for RS 12-25; P = .160), Dr. Harbeck reported.
The similar distant disease–free survival was consistent regardless of whether women were younger or older than 50 years and regardless of whether women had involved nodes or not.
In multivariate analysis, women had greater risk of distant disease–free survival events if they had three positive lymph nodes versus zero to two (hazard ratio, 3.40) or a pathologic T stage of 2-4 versus 0-1 (HR, 2.24), whereas risk fell with increasing baseline progesterone receptor expression (HR, 0.92).
“Neither patient age nor study arm were prognostic factors for patient outcome,” Dr. Harbeck noted.
In stratified analysis, the negative impact of having three positive nodes was seen only in the group with RS 12-25 and response to preoperative endocrine therapy, suggesting this subgroup may not be good candidates for omission of chemotherapy, she said.
Applying results to practice
“In luminal early breast cancer, the following patients – irrespective of their age – can safely be treated by endocrine therapy alone: patients with zero to three involved lymph nodes and recurrence score 0-11, and those with limited nodal burden (zero to two lymph nodes), recurrence score 12-25, and endocrine response after short preoperative endocrine therapy,” Dr. Harbeck summarized.
“Oncotype Dx testing can spare chemotherapy for the majority of patients with up to three involved lymph nodes. Dynamic Ki-67 response testing is feasible in clinical routine and complements baseline risk assessment to define patient selection for therapy deescalation or escalation,” she added.
The investigators have used the trial’s data to develop an algorithm for predicting the probability of response to short-course preoperative endocrine therapy that is available free of charge online (www.enrep.info).
“This may support everyday clinical decision-making in luminal early breast cancer; for example, whether to start a short period of preoperative endocrine therapy at all, and whether to rely on adjuvant endocrine therapy alone, but also in times like these, whether it’s safe to delay surgery by putting patients on prolonged preoperative endocrine therapy if surgical resources are scarce,” Dr. Harbeck commented.
Her clinic is now recruiting patients for the ADAPT Cycle trial, which is testing an endocrine-based approach with a CDK4/6 inhibitor versus chemotherapy in patients who are not candidates for adjuvant endocrine therapy alone. Therefore, all eligible patients receive the short course of endocrine therapy up front as the standard.
“But if you don’t have a trial, what are you going to do on Monday morning? Please let your patient know whether her tumor is endocrine responsive by doing this 3-week preoperative endocrine therapy,” Dr. Harbeck recommended. “It’s easy to do, you can schedule your surgeries better, and in patients with up to three lymph nodes, it helps with your decision-making, not just in the postmenopausal patients but also in the premenopausal patients, regarding whether they can forgo chemotherapy.”
Findings in context
More than 75% of ADAPT patients with RS 12-25 had a response to short-course endocrine therapy, noted invited discussant Lajos Pusztai, MD, DPhil, of the Yale Cancer Center in New Haven, Conn.
“This implies that the endocrine challenge is not informative for most patients,” he said, adding that a related question is whether the 25% of patients who did not have a response and were therefore given chemotherapy benefited from that therapy.
Dr. Pusztai cautioned that, among patients in the group with RS 12-25 who had a response to preoperative endocrine therapy, certain subgroups were fairly or very small: those aged 50 years or younger (330 patients) and those with two or three positive nodes (75 and 22 patients, respectively).
And collective findings of the similar but much larger TAILORx trial and RxPONDER trial (also reported at SABCS 2020) do suggest a benefit of chemotherapy in younger women, regardless of the number of positive nodes.
“Selection of [estrogen receptor]–positive patients with zero to three lymph nodes for adjuvant chemotherapy currently should be based on age and baseline recurrence score or a similar validated molecular assay,” Dr. Pusztai recommended. “TAILORx results guide us in regard to the use of the recurrence score in node-negative patients with a recurrence score of less than 26, and the recently presented RxPONDER results provide evidence for the use of recurrence score in patients with one to three positive nodes with a recurrence score in the range of 0-26. Both of these trials showed benefit in younger women from adjuvant chemotherapy.”
The ADAPT trial was sponsored by Roche, Genomic Health/Exact Sciences, Celgene, Bayer, Teva, and Amgen. Dr. Harbeck disclosed relationships with Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Lilly, Merck, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche/Genentech, Samsung, Sandoz, and Seattle Genetics. Dr. Pusztai disclosed relationships with AstraZeneca, Athenex, Almac, Bristol-Myers Squibb, Biotheranostics, Clovis, Daiichi, Eisai, Genentech, H2Bio, H3 Biomedicine, Immunomedics, Merck, Novartis, Pfizer, Pieris, Radius Health, Syndax, and Seattle Genetics,.
The findings were reported at the 2020 San Antonio Breast Cancer Symposium.
“In early luminal breast cancer, optimal patient selection for omission of adjuvant chemotherapy, particularly in patients with one to three involved lymph nodes, is still unclear,” noted principal investigator Nadia Harbeck, MD, PhD, of the University of Munich.
Successive trials have used nodal status, genomic risk scores, and response to preoperative therapy to home in on subsets of women for whom this practice is safe.
The ADAPT HR+/HER2– trial is a phase 3 trial that enrolled 5,625 patients with luminal (hormone receptor–positive, HER2-negative) early breast cancer who were candidates for adjuvant chemotherapy based on conventional criteria.
The trial combined a static biomarker – Oncotype Dx recurrence score (RS) in the baseline core biopsy – and a dynamic biomarker – Ki-67 response to a 3-week course of preoperative endocrine therapy – to personalize adjuvant therapy.
At SABCS 2020, Dr. Harbeck reported results for 2,290 patients having zero to three involved lymph nodes: 868 patients with RS 0-11 and 1,422 patients with RS 12-25 who had a response to brief preoperative endocrine therapy (a Ki-67 fraction ≤10% at surgery). All were treated with endocrine therapy alone as adjuvant therapy.
Similar outcomes
The median follow-up was 60 months. The 5-year rate of invasive disease–free survival was 93.9% for the group with RS 0-11 and 92.6% for the group with RS 12-25 and a response to the preoperative endocrine therapy.
The study met its primary endpoint, as the lower limit of the 95% confidence interval for the difference between groups of –3.3% fell just within the predefined margin of –3.3% or less for noninferiority (P = .05).
The groups also had similarly “excellent” distant disease–free survival (96.3% for RS 0-11 and 95.6% for RS 12-25; P = .247) and overall survival (98.0% for RS 0-11 and 97.3% for RS 12-25; P = .160), Dr. Harbeck reported.
The similar distant disease–free survival was consistent regardless of whether women were younger or older than 50 years and regardless of whether women had involved nodes or not.
In multivariate analysis, women had greater risk of distant disease–free survival events if they had three positive lymph nodes versus zero to two (hazard ratio, 3.40) or a pathologic T stage of 2-4 versus 0-1 (HR, 2.24), whereas risk fell with increasing baseline progesterone receptor expression (HR, 0.92).
“Neither patient age nor study arm were prognostic factors for patient outcome,” Dr. Harbeck noted.
In stratified analysis, the negative impact of having three positive nodes was seen only in the group with RS 12-25 and response to preoperative endocrine therapy, suggesting this subgroup may not be good candidates for omission of chemotherapy, she said.
Applying results to practice
“In luminal early breast cancer, the following patients – irrespective of their age – can safely be treated by endocrine therapy alone: patients with zero to three involved lymph nodes and recurrence score 0-11, and those with limited nodal burden (zero to two lymph nodes), recurrence score 12-25, and endocrine response after short preoperative endocrine therapy,” Dr. Harbeck summarized.
“Oncotype Dx testing can spare chemotherapy for the majority of patients with up to three involved lymph nodes. Dynamic Ki-67 response testing is feasible in clinical routine and complements baseline risk assessment to define patient selection for therapy deescalation or escalation,” she added.
The investigators have used the trial’s data to develop an algorithm for predicting the probability of response to short-course preoperative endocrine therapy that is available free of charge online (www.enrep.info).
“This may support everyday clinical decision-making in luminal early breast cancer; for example, whether to start a short period of preoperative endocrine therapy at all, and whether to rely on adjuvant endocrine therapy alone, but also in times like these, whether it’s safe to delay surgery by putting patients on prolonged preoperative endocrine therapy if surgical resources are scarce,” Dr. Harbeck commented.
Her clinic is now recruiting patients for the ADAPT Cycle trial, which is testing an endocrine-based approach with a CDK4/6 inhibitor versus chemotherapy in patients who are not candidates for adjuvant endocrine therapy alone. Therefore, all eligible patients receive the short course of endocrine therapy up front as the standard.
“But if you don’t have a trial, what are you going to do on Monday morning? Please let your patient know whether her tumor is endocrine responsive by doing this 3-week preoperative endocrine therapy,” Dr. Harbeck recommended. “It’s easy to do, you can schedule your surgeries better, and in patients with up to three lymph nodes, it helps with your decision-making, not just in the postmenopausal patients but also in the premenopausal patients, regarding whether they can forgo chemotherapy.”
Findings in context
More than 75% of ADAPT patients with RS 12-25 had a response to short-course endocrine therapy, noted invited discussant Lajos Pusztai, MD, DPhil, of the Yale Cancer Center in New Haven, Conn.
“This implies that the endocrine challenge is not informative for most patients,” he said, adding that a related question is whether the 25% of patients who did not have a response and were therefore given chemotherapy benefited from that therapy.
Dr. Pusztai cautioned that, among patients in the group with RS 12-25 who had a response to preoperative endocrine therapy, certain subgroups were fairly or very small: those aged 50 years or younger (330 patients) and those with two or three positive nodes (75 and 22 patients, respectively).
And collective findings of the similar but much larger TAILORx trial and RxPONDER trial (also reported at SABCS 2020) do suggest a benefit of chemotherapy in younger women, regardless of the number of positive nodes.
“Selection of [estrogen receptor]–positive patients with zero to three lymph nodes for adjuvant chemotherapy currently should be based on age and baseline recurrence score or a similar validated molecular assay,” Dr. Pusztai recommended. “TAILORx results guide us in regard to the use of the recurrence score in node-negative patients with a recurrence score of less than 26, and the recently presented RxPONDER results provide evidence for the use of recurrence score in patients with one to three positive nodes with a recurrence score in the range of 0-26. Both of these trials showed benefit in younger women from adjuvant chemotherapy.”
The ADAPT trial was sponsored by Roche, Genomic Health/Exact Sciences, Celgene, Bayer, Teva, and Amgen. Dr. Harbeck disclosed relationships with Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Lilly, Merck, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche/Genentech, Samsung, Sandoz, and Seattle Genetics. Dr. Pusztai disclosed relationships with AstraZeneca, Athenex, Almac, Bristol-Myers Squibb, Biotheranostics, Clovis, Daiichi, Eisai, Genentech, H2Bio, H3 Biomedicine, Immunomedics, Merck, Novartis, Pfizer, Pieris, Radius Health, Syndax, and Seattle Genetics,.
FROM SABCS 2020
Entinostat doesn’t overcome endocrine resistance in advanced breast cancer
The study showed no difference in response, progression-free survival, or overall survival whether entinostat was added to exemestane or exemestane was given with placebo.
These results were reported at the 2020 San Antonio Breast Cancer Symposium.
“Clearly, we were very disappointed with these results after so many years of work,” said study investigator Roisin M. Connolly, MD, of University College Cork (Ireland) and Cork University Hospital in Wilton, Ireland.
“I think we’ve realized again the importance of phase 3 confirmation of promising phase 2 data,” she said, referring to results of the phase 2 ENCORE 301 trial.
“I think that the results speak for themselves. In this population of endocrine-resistant patients, the HDAC inhibitors clearly do not have a role unless we find something further on additional review of the correlative analyses,” Dr. Connolly said.
Why HDAC inhibitors in advanced breast cancer?
“Despite many advances in breast cancer in recent decades, resistance to endocrine therapy remains a significant clinical problem,” Dr. Connolly said.
One suggested approach to overcoming this resistance is to block the overacetylation of histones using HDAC inhibitors. This has been shown in preclinical studies with entinostat to inhibit growth factor signaling pathways and normalize the expression of the estrogen receptor, helping to overcome resistance to aromatase inhibitors in letrozole-resistant mouse models.
Results from the phase 2 ENCORE 301 trial, published in the Journal of Clinical Oncology, also suggested this approach could be effective. There was a 2-month improvement in progression-free survival and an 8.3-month improvement in overall survival when entinostat was added to exemestane.
Phase 3 trial details and results
The E2112 study enrolled 608 women with hormone receptor–positive, HER2-negative advanced breast cancer, 85% of whom had experienced progression after taking a nonsteroidal aromatase inhibitor in the metastatic setting.
The type of endocrine resistance, such as if ESR1 mutations were present, was not determined. Tissue samples and blood samples have been archived, so this might be a question that is investigated later on.
A quarter of patients had received one prior chemotherapy regimen for metastatic disease, around 30% had been treated with fulvestrant, and about a third of patients had received a CDK4/6 inhibitor.
“I think we had representation from both patients who did receive and did not receive a prior CDK4/6 inhibitor within E2112,” Dr. Connolly said, observing that the study started in 2014 before the use of these drugs was really established.
Patients were randomized to receive entinostat (5 mg daily) plus exemestane (25 mg daily) or exemestane plus placebo (at the same dose).
The median progression-free survival was 3.3 months in the entinostat arm and 3.1 months in the placebo arm (hazard ratio, 0.87; P = .30).
The median overall survival was 23.4 months with entinostat and 21.7 months with placebo (HR, 0.99; P = .94). The overall response rates were a respective 4.6% and 4.3%.
Grade 3/4 adverse events were more frequent in the entinostat arm. The most common were neutropenia (20% with entinostat vs. <1% with placebo), hypophosphatemia (14% vs. 1%), and anemia (8% vs. 2%).
There were three treatment-related deaths (heart failure, pneumonitis, and hepatic failure) in the entinostat arm and one (MI) in the placebo arm.
Implications and next steps
“The study is completely negative, with no benefit in progression-free or overall survival,” commented Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the study.
“It is unclear that this is a good clinical approach for further trials in advanced breast cancer, as correlative studies suggest the drug did hit the target,” he added.
Dr. Burstein’s takeaway was that “HDAC inhibition is stuck in a cul-de-sac, if not a complete dead end, for breast cancer.”
When asked if using a different aromatase inhibitor than exemestane might have affected the results, Dr. Connolly said that “it’s possible, but I think it’s unlikely.”
Exemestane was used in the phase 3 trial because it had been used in the ENCORE 301 study. Preclinical work had shown that both letrozole- and exemestane-resistant models benefited from the addition of an HDAC inhibitor.
“There is ongoing investigation of HDAC inhibitors in various combinations,” Dr. Connolly said. “HDAC inhibitors have been used with chemotherapies and other targeted therapies over the years but unfortunately have not broken into the solid tumor space. I think that ongoing work will be required to see where these may fit in the future.”
The E2122 study was coordinated by the ECOG-ACRIN Cancer Research Group with funding from the National Institutes of Health. Dr. Connolly disclosed relationships with Genentech, Merck, Novartis, Puma Biotechnology, Marcogenics, and Pfizer. Dr. Burstein had no relevant disclosures.
The study showed no difference in response, progression-free survival, or overall survival whether entinostat was added to exemestane or exemestane was given with placebo.
These results were reported at the 2020 San Antonio Breast Cancer Symposium.
“Clearly, we were very disappointed with these results after so many years of work,” said study investigator Roisin M. Connolly, MD, of University College Cork (Ireland) and Cork University Hospital in Wilton, Ireland.
“I think we’ve realized again the importance of phase 3 confirmation of promising phase 2 data,” she said, referring to results of the phase 2 ENCORE 301 trial.
“I think that the results speak for themselves. In this population of endocrine-resistant patients, the HDAC inhibitors clearly do not have a role unless we find something further on additional review of the correlative analyses,” Dr. Connolly said.
Why HDAC inhibitors in advanced breast cancer?
“Despite many advances in breast cancer in recent decades, resistance to endocrine therapy remains a significant clinical problem,” Dr. Connolly said.
One suggested approach to overcoming this resistance is to block the overacetylation of histones using HDAC inhibitors. This has been shown in preclinical studies with entinostat to inhibit growth factor signaling pathways and normalize the expression of the estrogen receptor, helping to overcome resistance to aromatase inhibitors in letrozole-resistant mouse models.
Results from the phase 2 ENCORE 301 trial, published in the Journal of Clinical Oncology, also suggested this approach could be effective. There was a 2-month improvement in progression-free survival and an 8.3-month improvement in overall survival when entinostat was added to exemestane.
Phase 3 trial details and results
The E2112 study enrolled 608 women with hormone receptor–positive, HER2-negative advanced breast cancer, 85% of whom had experienced progression after taking a nonsteroidal aromatase inhibitor in the metastatic setting.
The type of endocrine resistance, such as if ESR1 mutations were present, was not determined. Tissue samples and blood samples have been archived, so this might be a question that is investigated later on.
A quarter of patients had received one prior chemotherapy regimen for metastatic disease, around 30% had been treated with fulvestrant, and about a third of patients had received a CDK4/6 inhibitor.
“I think we had representation from both patients who did receive and did not receive a prior CDK4/6 inhibitor within E2112,” Dr. Connolly said, observing that the study started in 2014 before the use of these drugs was really established.
Patients were randomized to receive entinostat (5 mg daily) plus exemestane (25 mg daily) or exemestane plus placebo (at the same dose).
The median progression-free survival was 3.3 months in the entinostat arm and 3.1 months in the placebo arm (hazard ratio, 0.87; P = .30).
The median overall survival was 23.4 months with entinostat and 21.7 months with placebo (HR, 0.99; P = .94). The overall response rates were a respective 4.6% and 4.3%.
Grade 3/4 adverse events were more frequent in the entinostat arm. The most common were neutropenia (20% with entinostat vs. <1% with placebo), hypophosphatemia (14% vs. 1%), and anemia (8% vs. 2%).
There were three treatment-related deaths (heart failure, pneumonitis, and hepatic failure) in the entinostat arm and one (MI) in the placebo arm.
Implications and next steps
“The study is completely negative, with no benefit in progression-free or overall survival,” commented Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the study.
“It is unclear that this is a good clinical approach for further trials in advanced breast cancer, as correlative studies suggest the drug did hit the target,” he added.
Dr. Burstein’s takeaway was that “HDAC inhibition is stuck in a cul-de-sac, if not a complete dead end, for breast cancer.”
When asked if using a different aromatase inhibitor than exemestane might have affected the results, Dr. Connolly said that “it’s possible, but I think it’s unlikely.”
Exemestane was used in the phase 3 trial because it had been used in the ENCORE 301 study. Preclinical work had shown that both letrozole- and exemestane-resistant models benefited from the addition of an HDAC inhibitor.
“There is ongoing investigation of HDAC inhibitors in various combinations,” Dr. Connolly said. “HDAC inhibitors have been used with chemotherapies and other targeted therapies over the years but unfortunately have not broken into the solid tumor space. I think that ongoing work will be required to see where these may fit in the future.”
The E2122 study was coordinated by the ECOG-ACRIN Cancer Research Group with funding from the National Institutes of Health. Dr. Connolly disclosed relationships with Genentech, Merck, Novartis, Puma Biotechnology, Marcogenics, and Pfizer. Dr. Burstein had no relevant disclosures.
The study showed no difference in response, progression-free survival, or overall survival whether entinostat was added to exemestane or exemestane was given with placebo.
These results were reported at the 2020 San Antonio Breast Cancer Symposium.
“Clearly, we were very disappointed with these results after so many years of work,” said study investigator Roisin M. Connolly, MD, of University College Cork (Ireland) and Cork University Hospital in Wilton, Ireland.
“I think we’ve realized again the importance of phase 3 confirmation of promising phase 2 data,” she said, referring to results of the phase 2 ENCORE 301 trial.
“I think that the results speak for themselves. In this population of endocrine-resistant patients, the HDAC inhibitors clearly do not have a role unless we find something further on additional review of the correlative analyses,” Dr. Connolly said.
Why HDAC inhibitors in advanced breast cancer?
“Despite many advances in breast cancer in recent decades, resistance to endocrine therapy remains a significant clinical problem,” Dr. Connolly said.
One suggested approach to overcoming this resistance is to block the overacetylation of histones using HDAC inhibitors. This has been shown in preclinical studies with entinostat to inhibit growth factor signaling pathways and normalize the expression of the estrogen receptor, helping to overcome resistance to aromatase inhibitors in letrozole-resistant mouse models.
Results from the phase 2 ENCORE 301 trial, published in the Journal of Clinical Oncology, also suggested this approach could be effective. There was a 2-month improvement in progression-free survival and an 8.3-month improvement in overall survival when entinostat was added to exemestane.
Phase 3 trial details and results
The E2112 study enrolled 608 women with hormone receptor–positive, HER2-negative advanced breast cancer, 85% of whom had experienced progression after taking a nonsteroidal aromatase inhibitor in the metastatic setting.
The type of endocrine resistance, such as if ESR1 mutations were present, was not determined. Tissue samples and blood samples have been archived, so this might be a question that is investigated later on.
A quarter of patients had received one prior chemotherapy regimen for metastatic disease, around 30% had been treated with fulvestrant, and about a third of patients had received a CDK4/6 inhibitor.
“I think we had representation from both patients who did receive and did not receive a prior CDK4/6 inhibitor within E2112,” Dr. Connolly said, observing that the study started in 2014 before the use of these drugs was really established.
Patients were randomized to receive entinostat (5 mg daily) plus exemestane (25 mg daily) or exemestane plus placebo (at the same dose).
The median progression-free survival was 3.3 months in the entinostat arm and 3.1 months in the placebo arm (hazard ratio, 0.87; P = .30).
The median overall survival was 23.4 months with entinostat and 21.7 months with placebo (HR, 0.99; P = .94). The overall response rates were a respective 4.6% and 4.3%.
Grade 3/4 adverse events were more frequent in the entinostat arm. The most common were neutropenia (20% with entinostat vs. <1% with placebo), hypophosphatemia (14% vs. 1%), and anemia (8% vs. 2%).
There were three treatment-related deaths (heart failure, pneumonitis, and hepatic failure) in the entinostat arm and one (MI) in the placebo arm.
Implications and next steps
“The study is completely negative, with no benefit in progression-free or overall survival,” commented Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the study.
“It is unclear that this is a good clinical approach for further trials in advanced breast cancer, as correlative studies suggest the drug did hit the target,” he added.
Dr. Burstein’s takeaway was that “HDAC inhibition is stuck in a cul-de-sac, if not a complete dead end, for breast cancer.”
When asked if using a different aromatase inhibitor than exemestane might have affected the results, Dr. Connolly said that “it’s possible, but I think it’s unlikely.”
Exemestane was used in the phase 3 trial because it had been used in the ENCORE 301 study. Preclinical work had shown that both letrozole- and exemestane-resistant models benefited from the addition of an HDAC inhibitor.
“There is ongoing investigation of HDAC inhibitors in various combinations,” Dr. Connolly said. “HDAC inhibitors have been used with chemotherapies and other targeted therapies over the years but unfortunately have not broken into the solid tumor space. I think that ongoing work will be required to see where these may fit in the future.”
The E2122 study was coordinated by the ECOG-ACRIN Cancer Research Group with funding from the National Institutes of Health. Dr. Connolly disclosed relationships with Genentech, Merck, Novartis, Puma Biotechnology, Marcogenics, and Pfizer. Dr. Burstein had no relevant disclosures.
FROM SABCS 2020
After 48 years, NCI aims to track breast cancer recurrences
Change to SEER eventually planned.
Patients with breast cancer want accurate information on the risk of their cancer recurring once they have completed treatment.
“I would like to know the true stats of how many breast cancers come back no matter what the hell we do for treatment,” comments a typical post on a breast cancer patient bulletin board.
But those statistics have not been available from a robust population-based source.
Now, there is hope that they will – at last – be collected.
A new pilot project at the National Cancer Institute is setting out to collect that information, although the researchers say it is a “long-term goal” that will take a few years.
But it has already been a long time coming. The mother lode of all U.S. cancer data, the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program, started collecting cancer data in 1973.
“When they began to capture cancer data, the focus was primarily on the incidence of cancer, the different types of cancer, and survival,” explained Esmeralda Ramirez-Pena, PhD, MPH, cancer prevention fellow at the NCI.
“Later, SEER expanded to include subgroups of various cancers and different stages at diagnosis,” she added.
But this database has never included information on cancer recurrence.
In a 2017 press statement, the NCI commented: “Collecting recurrence data has been challenging for cancer registries because recurrence can be diagnosed through diverse methods and in a variety of locations.”
New project
The NCI now has a “long-term goal” to implement additional “data elements” into SEER that will allow calculation of breast cancer recurrences, said Dr. Ramirez-Pena.
The Breast Cancer Recurrence Project, a pilot program funded via an NCI–Department of Energy collaboration, “will take a couple of years,” she said.
She presented some details of the new project as a poster at the recent San Antonio Breast Cancer Symposium 2020.
“SEER has added data elements over time,” she said, and this latest move will – at last – include information on breast cancer recurrence.
Why the change now?
“There’s been so much interest [in breast cancer recurrence]. It’s a top cause of cancer death in the United States and globally. The urgent need is evident,” she explained.
Breast cancer advocates have long been calling for SEER to count recurrence, including metastatic recurrence.
Katherine O’Brien, a breast cancer “metser” from Chicago, is credited with especially turning the heat up on the NCI.
In 2015, Ms. O’Brien spearheaded the creation of an online petition on the website change.org, calling on the NCI’s SEER, the Centers for Disease Control and Prevention, and all state cancer registries to start counting all people living with metastatic breast cancer, including those whose early-stage disease progressed. The petition, which is now closed, collected nearly 12,000 signatures.
Tracking recurrences
In the new project, cancer recurrence is defined as a cancer that was treated, reduced to undetectable levels, and later returned either locally, regionally, or distantly.
Tracking recurrence is not a simple matter because posttreatment surveillance to detect it includes clinical exams, biomarker testing, pathologic studies, molecular testing, imaging, and patient-reported symptoms and because recurrence frequency varies by subtype of breast cancer and TNM classification. Additionally, recurrence may depend on age at diagnosis, a variety of risk factors, treatment type, and access to quality of care.
“It’s likely there are many elements that influence recurrence,” said Dr. Ramirez-Pena.
To get a handle on the complexity, the NCI needs to first identify which data are needed to tally recurrence and the frequency at which they are collected, explained Dr. Ramirez-Pena. To do so, she and her coinvestigators conducted a systematic review of phase 3 clinical trials of early-stage breast cancer.
On their own, such trials are not sufficient to provide recurrence estimates at the population level because they lack diversity, represent fewer than 5% of all cancer patients, and the study period may not be long enough to capture recurrences for long-latency breast cancers, such as estrogen receptor–positive malignancies.
Nonetheless, these clinical trials provide a starting place.
The investigators identified 444 early-stage clinical trials. They stratified participants by subtype and tumor characteristics, which will enable analysis of risk-group and treatment-dependent differences in recurrence.
The changing science of breast cancer makes this work a challenge, the investigators said. For example, in clinical trials from the early 1990s through the early 2000s, receptor status and subtyping was not commonly reported, and some treatment endpoints were added during the past few years.
“Our next step will be to extract recurrence rates from these trials so we can eventually provide individualized information about recurrence risk to survivors,” Dr. Ramirez-Pena said, describing the big-picture aims.
The Breast Cancer Recurrence Project is collaborating with external agencies, such as the International Agency for Research on Cancer and Public Health England, in fine-tuning data elements, because “recurrence is not captured well globally either,” said Dr. Ramirez-Pena.
The study was supported by NCI.
A version of this article first appeared on Medscape.com.
Change to SEER eventually planned.
Change to SEER eventually planned.
Patients with breast cancer want accurate information on the risk of their cancer recurring once they have completed treatment.
“I would like to know the true stats of how many breast cancers come back no matter what the hell we do for treatment,” comments a typical post on a breast cancer patient bulletin board.
But those statistics have not been available from a robust population-based source.
Now, there is hope that they will – at last – be collected.
A new pilot project at the National Cancer Institute is setting out to collect that information, although the researchers say it is a “long-term goal” that will take a few years.
But it has already been a long time coming. The mother lode of all U.S. cancer data, the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program, started collecting cancer data in 1973.
“When they began to capture cancer data, the focus was primarily on the incidence of cancer, the different types of cancer, and survival,” explained Esmeralda Ramirez-Pena, PhD, MPH, cancer prevention fellow at the NCI.
“Later, SEER expanded to include subgroups of various cancers and different stages at diagnosis,” she added.
But this database has never included information on cancer recurrence.
In a 2017 press statement, the NCI commented: “Collecting recurrence data has been challenging for cancer registries because recurrence can be diagnosed through diverse methods and in a variety of locations.”
New project
The NCI now has a “long-term goal” to implement additional “data elements” into SEER that will allow calculation of breast cancer recurrences, said Dr. Ramirez-Pena.
The Breast Cancer Recurrence Project, a pilot program funded via an NCI–Department of Energy collaboration, “will take a couple of years,” she said.
She presented some details of the new project as a poster at the recent San Antonio Breast Cancer Symposium 2020.
“SEER has added data elements over time,” she said, and this latest move will – at last – include information on breast cancer recurrence.
Why the change now?
“There’s been so much interest [in breast cancer recurrence]. It’s a top cause of cancer death in the United States and globally. The urgent need is evident,” she explained.
Breast cancer advocates have long been calling for SEER to count recurrence, including metastatic recurrence.
Katherine O’Brien, a breast cancer “metser” from Chicago, is credited with especially turning the heat up on the NCI.
In 2015, Ms. O’Brien spearheaded the creation of an online petition on the website change.org, calling on the NCI’s SEER, the Centers for Disease Control and Prevention, and all state cancer registries to start counting all people living with metastatic breast cancer, including those whose early-stage disease progressed. The petition, which is now closed, collected nearly 12,000 signatures.
Tracking recurrences
In the new project, cancer recurrence is defined as a cancer that was treated, reduced to undetectable levels, and later returned either locally, regionally, or distantly.
Tracking recurrence is not a simple matter because posttreatment surveillance to detect it includes clinical exams, biomarker testing, pathologic studies, molecular testing, imaging, and patient-reported symptoms and because recurrence frequency varies by subtype of breast cancer and TNM classification. Additionally, recurrence may depend on age at diagnosis, a variety of risk factors, treatment type, and access to quality of care.
“It’s likely there are many elements that influence recurrence,” said Dr. Ramirez-Pena.
To get a handle on the complexity, the NCI needs to first identify which data are needed to tally recurrence and the frequency at which they are collected, explained Dr. Ramirez-Pena. To do so, she and her coinvestigators conducted a systematic review of phase 3 clinical trials of early-stage breast cancer.
On their own, such trials are not sufficient to provide recurrence estimates at the population level because they lack diversity, represent fewer than 5% of all cancer patients, and the study period may not be long enough to capture recurrences for long-latency breast cancers, such as estrogen receptor–positive malignancies.
Nonetheless, these clinical trials provide a starting place.
The investigators identified 444 early-stage clinical trials. They stratified participants by subtype and tumor characteristics, which will enable analysis of risk-group and treatment-dependent differences in recurrence.
The changing science of breast cancer makes this work a challenge, the investigators said. For example, in clinical trials from the early 1990s through the early 2000s, receptor status and subtyping was not commonly reported, and some treatment endpoints were added during the past few years.
“Our next step will be to extract recurrence rates from these trials so we can eventually provide individualized information about recurrence risk to survivors,” Dr. Ramirez-Pena said, describing the big-picture aims.
The Breast Cancer Recurrence Project is collaborating with external agencies, such as the International Agency for Research on Cancer and Public Health England, in fine-tuning data elements, because “recurrence is not captured well globally either,” said Dr. Ramirez-Pena.
The study was supported by NCI.
A version of this article first appeared on Medscape.com.
Patients with breast cancer want accurate information on the risk of their cancer recurring once they have completed treatment.
“I would like to know the true stats of how many breast cancers come back no matter what the hell we do for treatment,” comments a typical post on a breast cancer patient bulletin board.
But those statistics have not been available from a robust population-based source.
Now, there is hope that they will – at last – be collected.
A new pilot project at the National Cancer Institute is setting out to collect that information, although the researchers say it is a “long-term goal” that will take a few years.
But it has already been a long time coming. The mother lode of all U.S. cancer data, the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program, started collecting cancer data in 1973.
“When they began to capture cancer data, the focus was primarily on the incidence of cancer, the different types of cancer, and survival,” explained Esmeralda Ramirez-Pena, PhD, MPH, cancer prevention fellow at the NCI.
“Later, SEER expanded to include subgroups of various cancers and different stages at diagnosis,” she added.
But this database has never included information on cancer recurrence.
In a 2017 press statement, the NCI commented: “Collecting recurrence data has been challenging for cancer registries because recurrence can be diagnosed through diverse methods and in a variety of locations.”
New project
The NCI now has a “long-term goal” to implement additional “data elements” into SEER that will allow calculation of breast cancer recurrences, said Dr. Ramirez-Pena.
The Breast Cancer Recurrence Project, a pilot program funded via an NCI–Department of Energy collaboration, “will take a couple of years,” she said.
She presented some details of the new project as a poster at the recent San Antonio Breast Cancer Symposium 2020.
“SEER has added data elements over time,” she said, and this latest move will – at last – include information on breast cancer recurrence.
Why the change now?
“There’s been so much interest [in breast cancer recurrence]. It’s a top cause of cancer death in the United States and globally. The urgent need is evident,” she explained.
Breast cancer advocates have long been calling for SEER to count recurrence, including metastatic recurrence.
Katherine O’Brien, a breast cancer “metser” from Chicago, is credited with especially turning the heat up on the NCI.
In 2015, Ms. O’Brien spearheaded the creation of an online petition on the website change.org, calling on the NCI’s SEER, the Centers for Disease Control and Prevention, and all state cancer registries to start counting all people living with metastatic breast cancer, including those whose early-stage disease progressed. The petition, which is now closed, collected nearly 12,000 signatures.
Tracking recurrences
In the new project, cancer recurrence is defined as a cancer that was treated, reduced to undetectable levels, and later returned either locally, regionally, or distantly.
Tracking recurrence is not a simple matter because posttreatment surveillance to detect it includes clinical exams, biomarker testing, pathologic studies, molecular testing, imaging, and patient-reported symptoms and because recurrence frequency varies by subtype of breast cancer and TNM classification. Additionally, recurrence may depend on age at diagnosis, a variety of risk factors, treatment type, and access to quality of care.
“It’s likely there are many elements that influence recurrence,” said Dr. Ramirez-Pena.
To get a handle on the complexity, the NCI needs to first identify which data are needed to tally recurrence and the frequency at which they are collected, explained Dr. Ramirez-Pena. To do so, she and her coinvestigators conducted a systematic review of phase 3 clinical trials of early-stage breast cancer.
On their own, such trials are not sufficient to provide recurrence estimates at the population level because they lack diversity, represent fewer than 5% of all cancer patients, and the study period may not be long enough to capture recurrences for long-latency breast cancers, such as estrogen receptor–positive malignancies.
Nonetheless, these clinical trials provide a starting place.
The investigators identified 444 early-stage clinical trials. They stratified participants by subtype and tumor characteristics, which will enable analysis of risk-group and treatment-dependent differences in recurrence.
The changing science of breast cancer makes this work a challenge, the investigators said. For example, in clinical trials from the early 1990s through the early 2000s, receptor status and subtyping was not commonly reported, and some treatment endpoints were added during the past few years.
“Our next step will be to extract recurrence rates from these trials so we can eventually provide individualized information about recurrence risk to survivors,” Dr. Ramirez-Pena said, describing the big-picture aims.
The Breast Cancer Recurrence Project is collaborating with external agencies, such as the International Agency for Research on Cancer and Public Health England, in fine-tuning data elements, because “recurrence is not captured well globally either,” said Dr. Ramirez-Pena.
The study was supported by NCI.
A version of this article first appeared on Medscape.com.
Study: Doctors underreport side effects of breast irradiation
There is a substantial mismatch between patient and physician reports of toxicity during radiotherapy for breast cancer, according to an analysis of nearly 10,000 U.S. patients.
Researchers assessed physician underrecognition of four key symptoms – pain, pruritus, edema, and fatigue – during radiotherapy. Physicians underrecognized one of these four symptoms at least once in 53.2% of patients who reported having at least one substantial symptom.
“Understanding whether physicians detect when their patients are experiencing substantial toxicity is important, not only because recognition of symptoms is necessary for appropriate supportive care, but also because it influences what techniques and treatments we adopt,” said Reshma Jagsi, MD, DPhil, of the University of Michigan, Ann Arbor.
Dr. Jagsi presented the study results at the 2020 San Antonio Breast Cancer Symposium.
The underrecognition of symptoms during radiotherapy may reflect differences in physician or patient behaviors, according to Dr. Jagsi. “It’s absolutely something we need to understand better.”
Ian E. Krop, MD, PhD, of the Dana-Farber Cancer Institute in Boston, moderated the session where this research was presented and called the work “striking,” noting that it “clearly identifies an important area that needs improvement.”
“We need to do a better job. We as physicians need to listen more to our patients,” said Virginia Kaklamani, MD, of the University of Texas Health Science Center, San Antonio, and codirector of the SABCS 2020 meeting.
Comparing patient and physician reports
Dr. Jagsi and colleagues analyzed data on patients who had received radiotherapy after lumpectomy for breast cancer and had completed patient-reported outcome measures (PROs) as part of the Michigan Radiation Oncology Quality Consortium (MROQC). The MROQC registry collects data on patients receiving radiation for breast, lung, and prostate cancers, as well as for bone metastases.
Results of the PROs were compared with physician reports of toxicity as assessed using the Common Terminology Criteria for Adverse Events (CTCAE) system.
The researchers evaluated underrecognition of toxicity in 9,868 patients by comparing 37,593 independent paired observations from patients and their doctors. Patient and physician reports were made on the same day (n = 35,797) or within 3 days of each other (n = 1,796).
The comparison showed underrecognition of all four symptoms assessed – pain, pruritus, edema, and fatigue.
Underrecognition of pain was defined as patients reporting moderate pain while physicians graded pain as absent or as patients reporting severe pain while physicians rated pain as grade 1 or lower. Underrecognition of fatigue, bother from pruritus, or bother from edema were defined as physicians grading these symptoms as absent when patients reported fatigue or bother from pruritus/edema often or all of the time.
The percentage of observations with underrecognized symptoms was 30.9% for moderate to severe pain, 36.7% for frequent bother from pruritus, 51.4% for frequent bother from edema, and 18.8% for severe fatigue.
Factors independently associated with symptom underrecognition were younger age (odds ratio, 1.4 for <50 years and 1.2 for 50-59 years), Black or other non-White race (OR, 1.9 and 1.8, respectively), conventional fractionation (OR, 1.2), not having a supraclavicular field (OR, 1.3), and being treated at an academic center (OR, 1.1).
Underreporting worse in the time of COVID?
Data collection for this study ended before the start of the COVID-19 pandemic, but Dr. Jagsi expressed concern that the pandemic could lead to underrecognition of toxicity as well.
“We are doing more virtual visits, and I think the relationships between physicians and patients are a bit more strained,” Dr. Jagsi said. While virtual visits mean that patients can be seen safely, they are “not the same as being in the same room as one another.”
On the other hand, in-person visits during the pandemic may pose challenges as well. The need to wear masks during in-person consultations could lead to a lot of nonverbal communication being missed.
“I wouldn’t be surprised at all if underrecognition were worse in this context,” Dr. Jagsi said.
Encourage patients to speak up, use PROs
“I think we need to encourage patients that when we’ve told them that certain side effects are expected, it doesn’t mean that they shouldn’t tell us if they’re bothered by those side effects,” Dr. Jagsi said. “They’re not bothering us. They’re not troubling us to bring those symptoms to our attention, because there actually are things that we can do to help support them through the experience.”
Dr. Jagsi also said PROs should be included in clinical trials. Trials tend to rely on physician assessment of possible toxicity using the CTCAE system, but this can miss important symptoms that patients experience during radiotherapy.
The current study and MROQC were sponsored by Blue Cross Blue Shield of Michigan and the Blue Care Network as part of the BCBSM Value Partnership program. Dr. Jagsi disclosed financial relationships with Amgen, Equity Quotient, Genentech, Vizient, law firms, various foundations, the National Institutes of Health, and BCBSM for the MROQC. Dr. Kaklamani and Dr. Krop disclosed relationships with many pharmaceutical companies.
SOURCE: Jagsi R J et al. SABCS 2020, Abstract GS3-07.
There is a substantial mismatch between patient and physician reports of toxicity during radiotherapy for breast cancer, according to an analysis of nearly 10,000 U.S. patients.
Researchers assessed physician underrecognition of four key symptoms – pain, pruritus, edema, and fatigue – during radiotherapy. Physicians underrecognized one of these four symptoms at least once in 53.2% of patients who reported having at least one substantial symptom.
“Understanding whether physicians detect when their patients are experiencing substantial toxicity is important, not only because recognition of symptoms is necessary for appropriate supportive care, but also because it influences what techniques and treatments we adopt,” said Reshma Jagsi, MD, DPhil, of the University of Michigan, Ann Arbor.
Dr. Jagsi presented the study results at the 2020 San Antonio Breast Cancer Symposium.
The underrecognition of symptoms during radiotherapy may reflect differences in physician or patient behaviors, according to Dr. Jagsi. “It’s absolutely something we need to understand better.”
Ian E. Krop, MD, PhD, of the Dana-Farber Cancer Institute in Boston, moderated the session where this research was presented and called the work “striking,” noting that it “clearly identifies an important area that needs improvement.”
“We need to do a better job. We as physicians need to listen more to our patients,” said Virginia Kaklamani, MD, of the University of Texas Health Science Center, San Antonio, and codirector of the SABCS 2020 meeting.
Comparing patient and physician reports
Dr. Jagsi and colleagues analyzed data on patients who had received radiotherapy after lumpectomy for breast cancer and had completed patient-reported outcome measures (PROs) as part of the Michigan Radiation Oncology Quality Consortium (MROQC). The MROQC registry collects data on patients receiving radiation for breast, lung, and prostate cancers, as well as for bone metastases.
Results of the PROs were compared with physician reports of toxicity as assessed using the Common Terminology Criteria for Adverse Events (CTCAE) system.
The researchers evaluated underrecognition of toxicity in 9,868 patients by comparing 37,593 independent paired observations from patients and their doctors. Patient and physician reports were made on the same day (n = 35,797) or within 3 days of each other (n = 1,796).
The comparison showed underrecognition of all four symptoms assessed – pain, pruritus, edema, and fatigue.
Underrecognition of pain was defined as patients reporting moderate pain while physicians graded pain as absent or as patients reporting severe pain while physicians rated pain as grade 1 or lower. Underrecognition of fatigue, bother from pruritus, or bother from edema were defined as physicians grading these symptoms as absent when patients reported fatigue or bother from pruritus/edema often or all of the time.
The percentage of observations with underrecognized symptoms was 30.9% for moderate to severe pain, 36.7% for frequent bother from pruritus, 51.4% for frequent bother from edema, and 18.8% for severe fatigue.
Factors independently associated with symptom underrecognition were younger age (odds ratio, 1.4 for <50 years and 1.2 for 50-59 years), Black or other non-White race (OR, 1.9 and 1.8, respectively), conventional fractionation (OR, 1.2), not having a supraclavicular field (OR, 1.3), and being treated at an academic center (OR, 1.1).
Underreporting worse in the time of COVID?
Data collection for this study ended before the start of the COVID-19 pandemic, but Dr. Jagsi expressed concern that the pandemic could lead to underrecognition of toxicity as well.
“We are doing more virtual visits, and I think the relationships between physicians and patients are a bit more strained,” Dr. Jagsi said. While virtual visits mean that patients can be seen safely, they are “not the same as being in the same room as one another.”
On the other hand, in-person visits during the pandemic may pose challenges as well. The need to wear masks during in-person consultations could lead to a lot of nonverbal communication being missed.
“I wouldn’t be surprised at all if underrecognition were worse in this context,” Dr. Jagsi said.
Encourage patients to speak up, use PROs
“I think we need to encourage patients that when we’ve told them that certain side effects are expected, it doesn’t mean that they shouldn’t tell us if they’re bothered by those side effects,” Dr. Jagsi said. “They’re not bothering us. They’re not troubling us to bring those symptoms to our attention, because there actually are things that we can do to help support them through the experience.”
Dr. Jagsi also said PROs should be included in clinical trials. Trials tend to rely on physician assessment of possible toxicity using the CTCAE system, but this can miss important symptoms that patients experience during radiotherapy.
The current study and MROQC were sponsored by Blue Cross Blue Shield of Michigan and the Blue Care Network as part of the BCBSM Value Partnership program. Dr. Jagsi disclosed financial relationships with Amgen, Equity Quotient, Genentech, Vizient, law firms, various foundations, the National Institutes of Health, and BCBSM for the MROQC. Dr. Kaklamani and Dr. Krop disclosed relationships with many pharmaceutical companies.
SOURCE: Jagsi R J et al. SABCS 2020, Abstract GS3-07.
There is a substantial mismatch between patient and physician reports of toxicity during radiotherapy for breast cancer, according to an analysis of nearly 10,000 U.S. patients.
Researchers assessed physician underrecognition of four key symptoms – pain, pruritus, edema, and fatigue – during radiotherapy. Physicians underrecognized one of these four symptoms at least once in 53.2% of patients who reported having at least one substantial symptom.
“Understanding whether physicians detect when their patients are experiencing substantial toxicity is important, not only because recognition of symptoms is necessary for appropriate supportive care, but also because it influences what techniques and treatments we adopt,” said Reshma Jagsi, MD, DPhil, of the University of Michigan, Ann Arbor.
Dr. Jagsi presented the study results at the 2020 San Antonio Breast Cancer Symposium.
The underrecognition of symptoms during radiotherapy may reflect differences in physician or patient behaviors, according to Dr. Jagsi. “It’s absolutely something we need to understand better.”
Ian E. Krop, MD, PhD, of the Dana-Farber Cancer Institute in Boston, moderated the session where this research was presented and called the work “striking,” noting that it “clearly identifies an important area that needs improvement.”
“We need to do a better job. We as physicians need to listen more to our patients,” said Virginia Kaklamani, MD, of the University of Texas Health Science Center, San Antonio, and codirector of the SABCS 2020 meeting.
Comparing patient and physician reports
Dr. Jagsi and colleagues analyzed data on patients who had received radiotherapy after lumpectomy for breast cancer and had completed patient-reported outcome measures (PROs) as part of the Michigan Radiation Oncology Quality Consortium (MROQC). The MROQC registry collects data on patients receiving radiation for breast, lung, and prostate cancers, as well as for bone metastases.
Results of the PROs were compared with physician reports of toxicity as assessed using the Common Terminology Criteria for Adverse Events (CTCAE) system.
The researchers evaluated underrecognition of toxicity in 9,868 patients by comparing 37,593 independent paired observations from patients and their doctors. Patient and physician reports were made on the same day (n = 35,797) or within 3 days of each other (n = 1,796).
The comparison showed underrecognition of all four symptoms assessed – pain, pruritus, edema, and fatigue.
Underrecognition of pain was defined as patients reporting moderate pain while physicians graded pain as absent or as patients reporting severe pain while physicians rated pain as grade 1 or lower. Underrecognition of fatigue, bother from pruritus, or bother from edema were defined as physicians grading these symptoms as absent when patients reported fatigue or bother from pruritus/edema often or all of the time.
The percentage of observations with underrecognized symptoms was 30.9% for moderate to severe pain, 36.7% for frequent bother from pruritus, 51.4% for frequent bother from edema, and 18.8% for severe fatigue.
Factors independently associated with symptom underrecognition were younger age (odds ratio, 1.4 for <50 years and 1.2 for 50-59 years), Black or other non-White race (OR, 1.9 and 1.8, respectively), conventional fractionation (OR, 1.2), not having a supraclavicular field (OR, 1.3), and being treated at an academic center (OR, 1.1).
Underreporting worse in the time of COVID?
Data collection for this study ended before the start of the COVID-19 pandemic, but Dr. Jagsi expressed concern that the pandemic could lead to underrecognition of toxicity as well.
“We are doing more virtual visits, and I think the relationships between physicians and patients are a bit more strained,” Dr. Jagsi said. While virtual visits mean that patients can be seen safely, they are “not the same as being in the same room as one another.”
On the other hand, in-person visits during the pandemic may pose challenges as well. The need to wear masks during in-person consultations could lead to a lot of nonverbal communication being missed.
“I wouldn’t be surprised at all if underrecognition were worse in this context,” Dr. Jagsi said.
Encourage patients to speak up, use PROs
“I think we need to encourage patients that when we’ve told them that certain side effects are expected, it doesn’t mean that they shouldn’t tell us if they’re bothered by those side effects,” Dr. Jagsi said. “They’re not bothering us. They’re not troubling us to bring those symptoms to our attention, because there actually are things that we can do to help support them through the experience.”
Dr. Jagsi also said PROs should be included in clinical trials. Trials tend to rely on physician assessment of possible toxicity using the CTCAE system, but this can miss important symptoms that patients experience during radiotherapy.
The current study and MROQC were sponsored by Blue Cross Blue Shield of Michigan and the Blue Care Network as part of the BCBSM Value Partnership program. Dr. Jagsi disclosed financial relationships with Amgen, Equity Quotient, Genentech, Vizient, law firms, various foundations, the National Institutes of Health, and BCBSM for the MROQC. Dr. Kaklamani and Dr. Krop disclosed relationships with many pharmaceutical companies.
SOURCE: Jagsi R J et al. SABCS 2020, Abstract GS3-07.
FROM SABCS 2020
No edge for anastrozole over tamoxifen in DCIS
“Our analysis shows that there was really no significant difference in recurrences,” said investigator Ivana Sestak, PhD, of Queen Mary University of London.
Similarly, there were no significant differences in overall deaths or breast cancer deaths. On the other hand, there were “clear differences” in adverse events with the two treatments, Dr. Sestak said.
“[W]e observed an excess of endometrial cancer and ovarian cancers in women who were randomized to tamoxifen and an excess of fractures, strokes, and transient ischemic attacks for women who were randomized to anastrozole,” Dr. Sestak said.
She presented these results at the 2020 San Antonio Breast Cancer Symposium.
Comparing IBIS-II DCIS with prior results
“The long-term results of the IBIS-II [DCIS] trial are consistent with previous results,” said Halle Moore, MD, of the Cleveland Clinic, who was not involved in this study.
However, the results do contrast with the findings of the NSABP-B35 study, “which demonstrated a very modest advantage to anastrozole that was mostly limited to younger postmenopausal women,” she said.
Indeed, a significant 27% reduction in recurrence was seen with anastrozole, compared with tamoxifen at a median of 9 years of follow-up in the NSABP-B35 study. But, as Dr. Sestak pointed out, that reduction “was mainly observed during the posttreatment follow-up period and not during the active treatment period.”
In the IBIS-II DCIS study, there was a nonsignificant 11% reduction in breast cancer recurrence with anastrozole.
The investigators did examine the potential effect of age on the rate of breast cancer recurrence, but no significant differences were found. They also looked at the active and post–endocrine therapy treatment periods, all showing no benefit of one drug over the other.
“So we clearly cannot replicate the findings of the NSABP-B35 study,” Dr. Sestak acknowledged.
IBIS-II DCIS details and results
Aromatase inhibitors such as anastrozole have been shown to be more effective than tamoxifen for preventing recurrence in postmenopausal HR+ women with invasive breast cancer, but it wasn’t previously known if this included women with HR-positive DCIS.
The IBIS-II DCIS study was therefore designed to determine if there was any advantage of anastrazole over tamoxifen. The phase 3 trial enrolled 2,980 postmenopausal women with HR-positive DCIS. They were randomized to 5 years of anastrozole or 5 years of tamoxifen.
“Women were followed up during this active period of treatment by clinic visits,” explained Dr. Sestak. “Thereafter, we collected data via questionnaire, registry data sets, and clinic visits.”
Baseline characteristics were similar between the treatment arms. The median age was about 60 years in both arms. Similar proportions of patients had received hormone replacement therapy (44.2% in the tamoxifen arm and 46.8% in the anastrozole arm) or undergone radiotherapy (71.5% and 70.9%, respectively).
Results showed little difference in breast cancer recurrence rates. At a median follow-up of 11.6 years, the rate of recurrence was 9.7% with tamoxifen and 8.5% with anastrozole (hazard ratio, 0.89; P = .401).
Trends were seen favoring anastrozole in estrogen receptor–positive and HER2-negative women, but this was only while women were being actively treated.
Death rates were similar – 4.2% with anastrozole and 4.5% with tamoxifen (odds ratio, 0.93). There were three breast cancer deaths in each treatment arm.
Adverse events could be the deciding factor
“The main take-away from this presentation is that choice of adjuvant endocrine therapy for DCIS should be individualized based primarily on the different side effect profiles of the two medications,” Dr. Moore said.
During the trial, “a significant 34% increase in fractures was observed in women who received anastrozole, compared to tamoxifen [HR, 1.34; P = .013],” Dr. Sestak said.
“We also observed a threefold increase in strokes and transient ischemic attacks with anastrozole, compared to tamoxifen [HR, 3.10; P = .021 for both strokes and transient ischemic attacks],” Dr. Sestak added.
She acknowledged that this finding is inconsistent with what is known about aromatase inhibitors in general. It could be that, rather than anastrozole raising the risk of strokes and transient ischemic attacks, tamoxifen was having a beneficial effect. This could be a result of tamoxifen improving endothelial function by increasing vasodilation, “but it is really not clear what the mechanism is,” Dr. Sestak said.
Also contrary to what is known about tamoxifen was an excess of deaths because of endometrial cancer or ovarian cancers. Wherever possible, the pathology reports had been requested to confirm the cause of death, “so we are pretty sure that they are true ovarian cancers and not some other abdominal tumors,” Dr. Sestak said.
“We did observe very clear differences in terms of adverse events,” she said, adding that “improved understanding of adverse event profiles will help patients with HR-positive DCIS to make an informed decision regarding their treatment.”
The IBIS-II DCIS trial was funded by Cancer Research UK, the National Health and Medical Research Council Australia, Breast Cancer Research Foundation, AstraZeneca, and Sanofi Aventis. Two investigators disclosed relationships with AstraZeneca, and one disclosed a relationship with Cancer Research UK. Dr. Sestak and Dr. Moore had no relevant disclosures.
SOURCE: Sestak I et al. SABCS 2020, Abstract GS2-02.
“Our analysis shows that there was really no significant difference in recurrences,” said investigator Ivana Sestak, PhD, of Queen Mary University of London.
Similarly, there were no significant differences in overall deaths or breast cancer deaths. On the other hand, there were “clear differences” in adverse events with the two treatments, Dr. Sestak said.
“[W]e observed an excess of endometrial cancer and ovarian cancers in women who were randomized to tamoxifen and an excess of fractures, strokes, and transient ischemic attacks for women who were randomized to anastrozole,” Dr. Sestak said.
She presented these results at the 2020 San Antonio Breast Cancer Symposium.
Comparing IBIS-II DCIS with prior results
“The long-term results of the IBIS-II [DCIS] trial are consistent with previous results,” said Halle Moore, MD, of the Cleveland Clinic, who was not involved in this study.
However, the results do contrast with the findings of the NSABP-B35 study, “which demonstrated a very modest advantage to anastrozole that was mostly limited to younger postmenopausal women,” she said.
Indeed, a significant 27% reduction in recurrence was seen with anastrozole, compared with tamoxifen at a median of 9 years of follow-up in the NSABP-B35 study. But, as Dr. Sestak pointed out, that reduction “was mainly observed during the posttreatment follow-up period and not during the active treatment period.”
In the IBIS-II DCIS study, there was a nonsignificant 11% reduction in breast cancer recurrence with anastrozole.
The investigators did examine the potential effect of age on the rate of breast cancer recurrence, but no significant differences were found. They also looked at the active and post–endocrine therapy treatment periods, all showing no benefit of one drug over the other.
“So we clearly cannot replicate the findings of the NSABP-B35 study,” Dr. Sestak acknowledged.
IBIS-II DCIS details and results
Aromatase inhibitors such as anastrozole have been shown to be more effective than tamoxifen for preventing recurrence in postmenopausal HR+ women with invasive breast cancer, but it wasn’t previously known if this included women with HR-positive DCIS.
The IBIS-II DCIS study was therefore designed to determine if there was any advantage of anastrazole over tamoxifen. The phase 3 trial enrolled 2,980 postmenopausal women with HR-positive DCIS. They were randomized to 5 years of anastrozole or 5 years of tamoxifen.
“Women were followed up during this active period of treatment by clinic visits,” explained Dr. Sestak. “Thereafter, we collected data via questionnaire, registry data sets, and clinic visits.”
Baseline characteristics were similar between the treatment arms. The median age was about 60 years in both arms. Similar proportions of patients had received hormone replacement therapy (44.2% in the tamoxifen arm and 46.8% in the anastrozole arm) or undergone radiotherapy (71.5% and 70.9%, respectively).
Results showed little difference in breast cancer recurrence rates. At a median follow-up of 11.6 years, the rate of recurrence was 9.7% with tamoxifen and 8.5% with anastrozole (hazard ratio, 0.89; P = .401).
Trends were seen favoring anastrozole in estrogen receptor–positive and HER2-negative women, but this was only while women were being actively treated.
Death rates were similar – 4.2% with anastrozole and 4.5% with tamoxifen (odds ratio, 0.93). There were three breast cancer deaths in each treatment arm.
Adverse events could be the deciding factor
“The main take-away from this presentation is that choice of adjuvant endocrine therapy for DCIS should be individualized based primarily on the different side effect profiles of the two medications,” Dr. Moore said.
During the trial, “a significant 34% increase in fractures was observed in women who received anastrozole, compared to tamoxifen [HR, 1.34; P = .013],” Dr. Sestak said.
“We also observed a threefold increase in strokes and transient ischemic attacks with anastrozole, compared to tamoxifen [HR, 3.10; P = .021 for both strokes and transient ischemic attacks],” Dr. Sestak added.
She acknowledged that this finding is inconsistent with what is known about aromatase inhibitors in general. It could be that, rather than anastrozole raising the risk of strokes and transient ischemic attacks, tamoxifen was having a beneficial effect. This could be a result of tamoxifen improving endothelial function by increasing vasodilation, “but it is really not clear what the mechanism is,” Dr. Sestak said.
Also contrary to what is known about tamoxifen was an excess of deaths because of endometrial cancer or ovarian cancers. Wherever possible, the pathology reports had been requested to confirm the cause of death, “so we are pretty sure that they are true ovarian cancers and not some other abdominal tumors,” Dr. Sestak said.
“We did observe very clear differences in terms of adverse events,” she said, adding that “improved understanding of adverse event profiles will help patients with HR-positive DCIS to make an informed decision regarding their treatment.”
The IBIS-II DCIS trial was funded by Cancer Research UK, the National Health and Medical Research Council Australia, Breast Cancer Research Foundation, AstraZeneca, and Sanofi Aventis. Two investigators disclosed relationships with AstraZeneca, and one disclosed a relationship with Cancer Research UK. Dr. Sestak and Dr. Moore had no relevant disclosures.
SOURCE: Sestak I et al. SABCS 2020, Abstract GS2-02.
“Our analysis shows that there was really no significant difference in recurrences,” said investigator Ivana Sestak, PhD, of Queen Mary University of London.
Similarly, there were no significant differences in overall deaths or breast cancer deaths. On the other hand, there were “clear differences” in adverse events with the two treatments, Dr. Sestak said.
“[W]e observed an excess of endometrial cancer and ovarian cancers in women who were randomized to tamoxifen and an excess of fractures, strokes, and transient ischemic attacks for women who were randomized to anastrozole,” Dr. Sestak said.
She presented these results at the 2020 San Antonio Breast Cancer Symposium.
Comparing IBIS-II DCIS with prior results
“The long-term results of the IBIS-II [DCIS] trial are consistent with previous results,” said Halle Moore, MD, of the Cleveland Clinic, who was not involved in this study.
However, the results do contrast with the findings of the NSABP-B35 study, “which demonstrated a very modest advantage to anastrozole that was mostly limited to younger postmenopausal women,” she said.
Indeed, a significant 27% reduction in recurrence was seen with anastrozole, compared with tamoxifen at a median of 9 years of follow-up in the NSABP-B35 study. But, as Dr. Sestak pointed out, that reduction “was mainly observed during the posttreatment follow-up period and not during the active treatment period.”
In the IBIS-II DCIS study, there was a nonsignificant 11% reduction in breast cancer recurrence with anastrozole.
The investigators did examine the potential effect of age on the rate of breast cancer recurrence, but no significant differences were found. They also looked at the active and post–endocrine therapy treatment periods, all showing no benefit of one drug over the other.
“So we clearly cannot replicate the findings of the NSABP-B35 study,” Dr. Sestak acknowledged.
IBIS-II DCIS details and results
Aromatase inhibitors such as anastrozole have been shown to be more effective than tamoxifen for preventing recurrence in postmenopausal HR+ women with invasive breast cancer, but it wasn’t previously known if this included women with HR-positive DCIS.
The IBIS-II DCIS study was therefore designed to determine if there was any advantage of anastrazole over tamoxifen. The phase 3 trial enrolled 2,980 postmenopausal women with HR-positive DCIS. They were randomized to 5 years of anastrozole or 5 years of tamoxifen.
“Women were followed up during this active period of treatment by clinic visits,” explained Dr. Sestak. “Thereafter, we collected data via questionnaire, registry data sets, and clinic visits.”
Baseline characteristics were similar between the treatment arms. The median age was about 60 years in both arms. Similar proportions of patients had received hormone replacement therapy (44.2% in the tamoxifen arm and 46.8% in the anastrozole arm) or undergone radiotherapy (71.5% and 70.9%, respectively).
Results showed little difference in breast cancer recurrence rates. At a median follow-up of 11.6 years, the rate of recurrence was 9.7% with tamoxifen and 8.5% with anastrozole (hazard ratio, 0.89; P = .401).
Trends were seen favoring anastrozole in estrogen receptor–positive and HER2-negative women, but this was only while women were being actively treated.
Death rates were similar – 4.2% with anastrozole and 4.5% with tamoxifen (odds ratio, 0.93). There were three breast cancer deaths in each treatment arm.
Adverse events could be the deciding factor
“The main take-away from this presentation is that choice of adjuvant endocrine therapy for DCIS should be individualized based primarily on the different side effect profiles of the two medications,” Dr. Moore said.
During the trial, “a significant 34% increase in fractures was observed in women who received anastrozole, compared to tamoxifen [HR, 1.34; P = .013],” Dr. Sestak said.
“We also observed a threefold increase in strokes and transient ischemic attacks with anastrozole, compared to tamoxifen [HR, 3.10; P = .021 for both strokes and transient ischemic attacks],” Dr. Sestak added.
She acknowledged that this finding is inconsistent with what is known about aromatase inhibitors in general. It could be that, rather than anastrozole raising the risk of strokes and transient ischemic attacks, tamoxifen was having a beneficial effect. This could be a result of tamoxifen improving endothelial function by increasing vasodilation, “but it is really not clear what the mechanism is,” Dr. Sestak said.
Also contrary to what is known about tamoxifen was an excess of deaths because of endometrial cancer or ovarian cancers. Wherever possible, the pathology reports had been requested to confirm the cause of death, “so we are pretty sure that they are true ovarian cancers and not some other abdominal tumors,” Dr. Sestak said.
“We did observe very clear differences in terms of adverse events,” she said, adding that “improved understanding of adverse event profiles will help patients with HR-positive DCIS to make an informed decision regarding their treatment.”
The IBIS-II DCIS trial was funded by Cancer Research UK, the National Health and Medical Research Council Australia, Breast Cancer Research Foundation, AstraZeneca, and Sanofi Aventis. Two investigators disclosed relationships with AstraZeneca, and one disclosed a relationship with Cancer Research UK. Dr. Sestak and Dr. Moore had no relevant disclosures.
SOURCE: Sestak I et al. SABCS 2020, Abstract GS2-02.
FROM SABCS 2020
Omitting postop radiotherapy doesn’t affect survival in older breast cancer patients
Skipping whole-breast adjuvant radiotherapy does not appear to affect long-term survival in women age 65 and older who have had surgery for early-stage, hormone receptor–positive (HR+) breast cancer, according to 10-year follow-up of the phase 3 PRIME-2 study.
Although the risk for local recurrence was higher among patients who did not receive radiotherapy, the absolute risk for recurrence was still low, said study investigator Ian Kunkler, MRCPUK, FRCR, of Western General Hospital, University of Edinburgh in Scotland.
Dr. Kunkler presented results from PRIME-2 at the 2020 San Antonio Breast Cancer Symposium.
“In older patients, we have to carefully balance benefits [of radiotherapy] in terms of local control and survival against toxicities,” Dr. Kunkler said in an interview.
Omitting radiotherapy could help women avoid complications such as fatigue, changes to lung function, and an increased risk of cardiovascular damage.
“We think that these results should provide some reassurance that the omission of radiotherapy could be an option,” Dr. Kunkler said.
PRIME-2 results
The PRIME-2 study was a randomized trial that recruited 1,326 women with histologically confirmed, unilateral invasive breast cancer who were all 65 years or older.
For inclusion, the women had to have a tumor measuring 3 cm or less, have no nodal involvement, and be about to undergo breast-conserving surgery. Women also needed to be HR+ and be treated with adjuvant endocrine therapy.
The women were randomized 1:1 to receive adjuvant whole-breast irradiation at a dosing schedule of 40-50 Gy in 15-25 fractions or no radiotherapy in addition to adjuvant endocrine therapy.
The primary endpoint was the recurrence of breast cancer in the same breast at 10 years. There was a significantly lower rate of ipsilateral recurrence with radiotherapy than without it, at 0.9% and 9.8%, respectively (P = .00008).
Similarly, the 10-year rate of regional recurrence was significantly lower in the radiotherapy arm than in the no-radiotherapy arm (0.5% vs. 2.3%, P = .014).
However, there was no significant difference in the radiotherapy and nonradiotherapy arms when it came to distant recurrence (3.6% vs. 1.9%, P = .07), contralateral recurrence (2.2% vs. 1.2%, P = .20), or new, non–breast cancer (8.7% vs. 10.2%, P = .41).
The overall survival estimate at 10 years was 80.4% in women who did not receive radiotherapy and 81.0% in those who did (P = .68). Rates of metastasis-free survival were also similar (98.1% vs. 96.4%, P = .28).
“Most of these women are dying from non–breast cancer causes, reflecting the impact of competitive causes of non–breast cancer mortality,” Dr. Kunkler said.
Implications for practice
The current findings build on prior findings from the PRIME-2 study 5 years ago, which showed a small benefit of postoperative radiotherapy over no radiotherapy in reducing the rate of local recurrence. This led to the recommendation that postoperative radiotherapy might be safely omitted in some older women and influenced U.K. practice.
Indeed, Dr. Kunkler observed that U.K. guidelines have pretty much adopted the entry criteria for the PRIME-2 study (HR+, axillary node-negative [N0], T1–T2 up to 3 cm at the longest dimension, and clear margins) for the omission of radiotherapy.
“It’s had much less impact in the United States, where the usage of radiotherapy after breast-conserving surgery still remains very high,” Dr. Kunkler said.
He acknowledged that the current U.S. guidelines include the omission of radiotherapy in older women, but only those with much smaller (T1, N0) tumors, based on the findings of the Cancer and Leukemia Group B (CALGB) 9343 study.
“The findings from PRIME-2 so far seem consistent with long-term findings from CALGB 9343,” Matthew Katz, MD, of Lowell (Mass.) General Hospital Cancer Center, said in an interview.
However, “the median follow-up of the study was only 7 years, so it’s a little early to analyze 10-year data,” he added.
As to why leaving out radiotherapy in older women may be less common in the United States than in the U.K., Dr. Katz said it was probably due to a “tendency on the part of U.S. oncologists and cancer patients to lean more toward treatment to lower the risk of recurrence.
“When I discuss omitting radiation to women 70 or older with an early-stage, low risk breast cancer, the majority of people I see choose treatment,” he said. “The key is that a cancer patient can make informed choices about treatment based upon her or his values, looking at both the risks of cancer recurrence and the side effects of cancer treatments.”
“The decision as to whether radiotherapy is omitted or not has become a bit more nuanced,” since the PRIME-2 study started in 2003, Dr. Kunkler acknowledged.
He said there’s now evidence to suggest that shorter radiotherapy regimens may be beneficial. For example, the FAST-Forward trial showed that a regimen of 26 Gy in five fractions over 1 week was noninferior to a regimen of 40 Gy in 15 fractions over 3 weeks.
“There are really only two studies – the PRIME-2 study and the CALGB 9343 study – which are specific to an older age group,” Dr. Kunkler noted. “Most of the previous studies of breast-conserving surgery with or without radiotherapy receiving endocrine therapy have been predominantly in women under the age of 70. And indeed, 70 was often considered an exclusion criterion for randomized trials.”
PRIME-2 was funded by the Chief Scientist Office (Scottish Government) and the Breast Cancer Institute at the Western General Hospital in Edinburgh, Scotland. Neither Dr. Kunkler nor Dr. Katz had relevant disclosures.
SOURCE: Kunkler IH J et al. SABCS 2020, Abstract GS2-03.
Skipping whole-breast adjuvant radiotherapy does not appear to affect long-term survival in women age 65 and older who have had surgery for early-stage, hormone receptor–positive (HR+) breast cancer, according to 10-year follow-up of the phase 3 PRIME-2 study.
Although the risk for local recurrence was higher among patients who did not receive radiotherapy, the absolute risk for recurrence was still low, said study investigator Ian Kunkler, MRCPUK, FRCR, of Western General Hospital, University of Edinburgh in Scotland.
Dr. Kunkler presented results from PRIME-2 at the 2020 San Antonio Breast Cancer Symposium.
“In older patients, we have to carefully balance benefits [of radiotherapy] in terms of local control and survival against toxicities,” Dr. Kunkler said in an interview.
Omitting radiotherapy could help women avoid complications such as fatigue, changes to lung function, and an increased risk of cardiovascular damage.
“We think that these results should provide some reassurance that the omission of radiotherapy could be an option,” Dr. Kunkler said.
PRIME-2 results
The PRIME-2 study was a randomized trial that recruited 1,326 women with histologically confirmed, unilateral invasive breast cancer who were all 65 years or older.
For inclusion, the women had to have a tumor measuring 3 cm or less, have no nodal involvement, and be about to undergo breast-conserving surgery. Women also needed to be HR+ and be treated with adjuvant endocrine therapy.
The women were randomized 1:1 to receive adjuvant whole-breast irradiation at a dosing schedule of 40-50 Gy in 15-25 fractions or no radiotherapy in addition to adjuvant endocrine therapy.
The primary endpoint was the recurrence of breast cancer in the same breast at 10 years. There was a significantly lower rate of ipsilateral recurrence with radiotherapy than without it, at 0.9% and 9.8%, respectively (P = .00008).
Similarly, the 10-year rate of regional recurrence was significantly lower in the radiotherapy arm than in the no-radiotherapy arm (0.5% vs. 2.3%, P = .014).
However, there was no significant difference in the radiotherapy and nonradiotherapy arms when it came to distant recurrence (3.6% vs. 1.9%, P = .07), contralateral recurrence (2.2% vs. 1.2%, P = .20), or new, non–breast cancer (8.7% vs. 10.2%, P = .41).
The overall survival estimate at 10 years was 80.4% in women who did not receive radiotherapy and 81.0% in those who did (P = .68). Rates of metastasis-free survival were also similar (98.1% vs. 96.4%, P = .28).
“Most of these women are dying from non–breast cancer causes, reflecting the impact of competitive causes of non–breast cancer mortality,” Dr. Kunkler said.
Implications for practice
The current findings build on prior findings from the PRIME-2 study 5 years ago, which showed a small benefit of postoperative radiotherapy over no radiotherapy in reducing the rate of local recurrence. This led to the recommendation that postoperative radiotherapy might be safely omitted in some older women and influenced U.K. practice.
Indeed, Dr. Kunkler observed that U.K. guidelines have pretty much adopted the entry criteria for the PRIME-2 study (HR+, axillary node-negative [N0], T1–T2 up to 3 cm at the longest dimension, and clear margins) for the omission of radiotherapy.
“It’s had much less impact in the United States, where the usage of radiotherapy after breast-conserving surgery still remains very high,” Dr. Kunkler said.
He acknowledged that the current U.S. guidelines include the omission of radiotherapy in older women, but only those with much smaller (T1, N0) tumors, based on the findings of the Cancer and Leukemia Group B (CALGB) 9343 study.
“The findings from PRIME-2 so far seem consistent with long-term findings from CALGB 9343,” Matthew Katz, MD, of Lowell (Mass.) General Hospital Cancer Center, said in an interview.
However, “the median follow-up of the study was only 7 years, so it’s a little early to analyze 10-year data,” he added.
As to why leaving out radiotherapy in older women may be less common in the United States than in the U.K., Dr. Katz said it was probably due to a “tendency on the part of U.S. oncologists and cancer patients to lean more toward treatment to lower the risk of recurrence.
“When I discuss omitting radiation to women 70 or older with an early-stage, low risk breast cancer, the majority of people I see choose treatment,” he said. “The key is that a cancer patient can make informed choices about treatment based upon her or his values, looking at both the risks of cancer recurrence and the side effects of cancer treatments.”
“The decision as to whether radiotherapy is omitted or not has become a bit more nuanced,” since the PRIME-2 study started in 2003, Dr. Kunkler acknowledged.
He said there’s now evidence to suggest that shorter radiotherapy regimens may be beneficial. For example, the FAST-Forward trial showed that a regimen of 26 Gy in five fractions over 1 week was noninferior to a regimen of 40 Gy in 15 fractions over 3 weeks.
“There are really only two studies – the PRIME-2 study and the CALGB 9343 study – which are specific to an older age group,” Dr. Kunkler noted. “Most of the previous studies of breast-conserving surgery with or without radiotherapy receiving endocrine therapy have been predominantly in women under the age of 70. And indeed, 70 was often considered an exclusion criterion for randomized trials.”
PRIME-2 was funded by the Chief Scientist Office (Scottish Government) and the Breast Cancer Institute at the Western General Hospital in Edinburgh, Scotland. Neither Dr. Kunkler nor Dr. Katz had relevant disclosures.
SOURCE: Kunkler IH J et al. SABCS 2020, Abstract GS2-03.
Skipping whole-breast adjuvant radiotherapy does not appear to affect long-term survival in women age 65 and older who have had surgery for early-stage, hormone receptor–positive (HR+) breast cancer, according to 10-year follow-up of the phase 3 PRIME-2 study.
Although the risk for local recurrence was higher among patients who did not receive radiotherapy, the absolute risk for recurrence was still low, said study investigator Ian Kunkler, MRCPUK, FRCR, of Western General Hospital, University of Edinburgh in Scotland.
Dr. Kunkler presented results from PRIME-2 at the 2020 San Antonio Breast Cancer Symposium.
“In older patients, we have to carefully balance benefits [of radiotherapy] in terms of local control and survival against toxicities,” Dr. Kunkler said in an interview.
Omitting radiotherapy could help women avoid complications such as fatigue, changes to lung function, and an increased risk of cardiovascular damage.
“We think that these results should provide some reassurance that the omission of radiotherapy could be an option,” Dr. Kunkler said.
PRIME-2 results
The PRIME-2 study was a randomized trial that recruited 1,326 women with histologically confirmed, unilateral invasive breast cancer who were all 65 years or older.
For inclusion, the women had to have a tumor measuring 3 cm or less, have no nodal involvement, and be about to undergo breast-conserving surgery. Women also needed to be HR+ and be treated with adjuvant endocrine therapy.
The women were randomized 1:1 to receive adjuvant whole-breast irradiation at a dosing schedule of 40-50 Gy in 15-25 fractions or no radiotherapy in addition to adjuvant endocrine therapy.
The primary endpoint was the recurrence of breast cancer in the same breast at 10 years. There was a significantly lower rate of ipsilateral recurrence with radiotherapy than without it, at 0.9% and 9.8%, respectively (P = .00008).
Similarly, the 10-year rate of regional recurrence was significantly lower in the radiotherapy arm than in the no-radiotherapy arm (0.5% vs. 2.3%, P = .014).
However, there was no significant difference in the radiotherapy and nonradiotherapy arms when it came to distant recurrence (3.6% vs. 1.9%, P = .07), contralateral recurrence (2.2% vs. 1.2%, P = .20), or new, non–breast cancer (8.7% vs. 10.2%, P = .41).
The overall survival estimate at 10 years was 80.4% in women who did not receive radiotherapy and 81.0% in those who did (P = .68). Rates of metastasis-free survival were also similar (98.1% vs. 96.4%, P = .28).
“Most of these women are dying from non–breast cancer causes, reflecting the impact of competitive causes of non–breast cancer mortality,” Dr. Kunkler said.
Implications for practice
The current findings build on prior findings from the PRIME-2 study 5 years ago, which showed a small benefit of postoperative radiotherapy over no radiotherapy in reducing the rate of local recurrence. This led to the recommendation that postoperative radiotherapy might be safely omitted in some older women and influenced U.K. practice.
Indeed, Dr. Kunkler observed that U.K. guidelines have pretty much adopted the entry criteria for the PRIME-2 study (HR+, axillary node-negative [N0], T1–T2 up to 3 cm at the longest dimension, and clear margins) for the omission of radiotherapy.
“It’s had much less impact in the United States, where the usage of radiotherapy after breast-conserving surgery still remains very high,” Dr. Kunkler said.
He acknowledged that the current U.S. guidelines include the omission of radiotherapy in older women, but only those with much smaller (T1, N0) tumors, based on the findings of the Cancer and Leukemia Group B (CALGB) 9343 study.
“The findings from PRIME-2 so far seem consistent with long-term findings from CALGB 9343,” Matthew Katz, MD, of Lowell (Mass.) General Hospital Cancer Center, said in an interview.
However, “the median follow-up of the study was only 7 years, so it’s a little early to analyze 10-year data,” he added.
As to why leaving out radiotherapy in older women may be less common in the United States than in the U.K., Dr. Katz said it was probably due to a “tendency on the part of U.S. oncologists and cancer patients to lean more toward treatment to lower the risk of recurrence.
“When I discuss omitting radiation to women 70 or older with an early-stage, low risk breast cancer, the majority of people I see choose treatment,” he said. “The key is that a cancer patient can make informed choices about treatment based upon her or his values, looking at both the risks of cancer recurrence and the side effects of cancer treatments.”
“The decision as to whether radiotherapy is omitted or not has become a bit more nuanced,” since the PRIME-2 study started in 2003, Dr. Kunkler acknowledged.
He said there’s now evidence to suggest that shorter radiotherapy regimens may be beneficial. For example, the FAST-Forward trial showed that a regimen of 26 Gy in five fractions over 1 week was noninferior to a regimen of 40 Gy in 15 fractions over 3 weeks.
“There are really only two studies – the PRIME-2 study and the CALGB 9343 study – which are specific to an older age group,” Dr. Kunkler noted. “Most of the previous studies of breast-conserving surgery with or without radiotherapy receiving endocrine therapy have been predominantly in women under the age of 70. And indeed, 70 was often considered an exclusion criterion for randomized trials.”
PRIME-2 was funded by the Chief Scientist Office (Scottish Government) and the Breast Cancer Institute at the Western General Hospital in Edinburgh, Scotland. Neither Dr. Kunkler nor Dr. Katz had relevant disclosures.
SOURCE: Kunkler IH J et al. SABCS 2020, Abstract GS2-03.
FROM SABCS 2020
An all-oral option for advanced HR+, HER2– breast cancer?
These results suggest tesetaxel plus capecitabine is “a potential new treatment option” for this patient population, said study investigator Joyce O’Shaughnessy, MD, of Baylor University Medical Center and Texas Oncology, both in Dallas.
“This should launch an oral taxane into the clinical space, which will be a nice addition to the toolbox for treating advanced breast cancer, with real upsides for patients,” said Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the trial but commented on the results in an interview.
Another commenter was more critical of CONTESSA’s results, which were presented at the 2020 San Antonio Breast Cancer Symposium.
“Three months’ difference in PFS in this setting is meaningless without overall survival [OS] results,” Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, said in a question submitted through the virtual meeting’s chat system.
At this point, the OS data are immature, and mature data won’t be available for another couple of years at least, according to the study’s protocol.
Dr. O’Shaughnessy defended the PFS result as being significant, however, saying it was comparable with outcomes seen previously with docetaxel-capecitabine and paclitaxel-gemcitabine combinations.
Other meeting attendees questioned why the waters had been muddied by testing the effects of tesetaxel in combination with capecitabine, albeit at a reduced dose, versus the approved full dose of capecitabine as monotherapy, particularly as a phase 2 trial had shown that tesetaxel demonstrated “significant activity” as monotherapy.
“The reason for the combination versus a monotherapy is because it was designed as a registration trial,” Dr. O’Shaughnessy explained. The trial was designed to be very similar to early taxane studies where docetaxel was assessed with or without capecitabine, or paclitaxel with or without gemcitabine.
“Probably we’re going to be using a doublet for patients who have virulent disease who really need a response,” Dr. O’Shaughnessy explained. She noted that the objective response rate was much higher with the tesetaxel-capecitabine combination than with capecitabine alone, and that result alone is “probably enough that we would utilize a doublet.”
The key thing is that it now gives patients an all-oral option, Dr. O’Shaughnessy said.
“The data are exciting because it would be terrific to have an orally available taxane chemotherapy,” agreed Dr. Burstein. “It is far more convenient for patients and opens access globally in places that do not have adequate resources for administration of IV therapeutics. Also, the data suggest that tesetaxel has a different side effect profile than IV taxane, with less neuropathy and less alopecia.”
Trial design
CONTESSA is an ongoing randomized, controlled trial that started in 2017 and is projected to end in early 2023. It is investigating the use of tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone in 685 women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer who had previously been treated with a taxane.
Being intrinsically orally bioavailable and more soluble than the other taxanes means that tesetaxel has a much longer half-life that allows for a “more convenient treatment experience for patients,” Dr. O’Shaughnessy observed.
Indeed, because tesetaxel only needs to be dosed once every 3 weeks, patients in the trial received tesetaxel at 27 mg/m2 only on the first day of a 21-day treatment cycle. This was combined with a reduced, 825-mg/m2 dose of capecitabine, given orally twice-daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
The combination regimen was compared with the recommended full dose of capecitabine alone, 1,250 mg/m2 given orally twice daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
Efficacy and safety
PFS was 9.8 months with tesetaxel plus capecitabine and 6.9 months with capecitabine alone, representing a 2.9-month improvement with the combination (hazard ratio, 0.716; P = .003).
A similar PFS benefit was seen regardless of multiple predefined subgroups, such as age, baseline performance status, duration of disease-free interval before study entry, and the use of CDK4/6 inhibitors.
The objective response rate was 57% with tesetaxel plus capecitabine and 41% with capecitabine alone (P = .0002). The 24-week disease control rate was 67% and 50%, respectively (P < .0001).
The most frequent treatment-emergent adverse event seen with the tesetaxel-capecitabine combination was neutropenia, occurring in 76.9% of patients, compared with 22.6% of patients in the monotherapy arm. Rates of grade 3-4 neutropenia were much higher in the combination arm (32.6% and 38.3%, respectively) than in the monotherapy arm (7.4% and 0.9%, respectively).
The neutropenia seen was “generally manageable,” Dr. O’Shaughnessy said, primarily with dose reductions and granulocyte colony–stimulating factor as needed.
She pointed out that rates of grade 3 or higher neuropathy and grade 2 alopecia were low, a respective 5.9% and 8%, with the combination.
The dose of capecitabine used in the control arm was noted to be higher than that used in usual practice.
“This was because of the global nature of the study and the regulatory requirements globally,” Dr. O’Shaughnessy said.
“The dose-modification scheme was that patients could have a dose reduction at the first sign of grade 2 toxicity,” she added, giving investigators the flexibility to reduce the dose as soon as possible.
This study was sponsored by Odonate Therapeutics. Dr. O’Shaughnessy disclosed consulting fees from AbbVie, Agendia, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, Genentech/Roche, Genomic Health, GRAIL, Heron, Immunomedics, Ipsen, Jounce, Lilly, Novartis, Odonate, Pfizer, Puma, and Seagen. Dr. Burstein and Dr. Cardoso had no relevant disclosures.
SOURCE: O’Shaughnessy J et al. SABCS 2020, Abstract GS4-01.
These results suggest tesetaxel plus capecitabine is “a potential new treatment option” for this patient population, said study investigator Joyce O’Shaughnessy, MD, of Baylor University Medical Center and Texas Oncology, both in Dallas.
“This should launch an oral taxane into the clinical space, which will be a nice addition to the toolbox for treating advanced breast cancer, with real upsides for patients,” said Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the trial but commented on the results in an interview.
Another commenter was more critical of CONTESSA’s results, which were presented at the 2020 San Antonio Breast Cancer Symposium.
“Three months’ difference in PFS in this setting is meaningless without overall survival [OS] results,” Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, said in a question submitted through the virtual meeting’s chat system.
At this point, the OS data are immature, and mature data won’t be available for another couple of years at least, according to the study’s protocol.
Dr. O’Shaughnessy defended the PFS result as being significant, however, saying it was comparable with outcomes seen previously with docetaxel-capecitabine and paclitaxel-gemcitabine combinations.
Other meeting attendees questioned why the waters had been muddied by testing the effects of tesetaxel in combination with capecitabine, albeit at a reduced dose, versus the approved full dose of capecitabine as monotherapy, particularly as a phase 2 trial had shown that tesetaxel demonstrated “significant activity” as monotherapy.
“The reason for the combination versus a monotherapy is because it was designed as a registration trial,” Dr. O’Shaughnessy explained. The trial was designed to be very similar to early taxane studies where docetaxel was assessed with or without capecitabine, or paclitaxel with or without gemcitabine.
“Probably we’re going to be using a doublet for patients who have virulent disease who really need a response,” Dr. O’Shaughnessy explained. She noted that the objective response rate was much higher with the tesetaxel-capecitabine combination than with capecitabine alone, and that result alone is “probably enough that we would utilize a doublet.”
The key thing is that it now gives patients an all-oral option, Dr. O’Shaughnessy said.
“The data are exciting because it would be terrific to have an orally available taxane chemotherapy,” agreed Dr. Burstein. “It is far more convenient for patients and opens access globally in places that do not have adequate resources for administration of IV therapeutics. Also, the data suggest that tesetaxel has a different side effect profile than IV taxane, with less neuropathy and less alopecia.”
Trial design
CONTESSA is an ongoing randomized, controlled trial that started in 2017 and is projected to end in early 2023. It is investigating the use of tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone in 685 women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer who had previously been treated with a taxane.
Being intrinsically orally bioavailable and more soluble than the other taxanes means that tesetaxel has a much longer half-life that allows for a “more convenient treatment experience for patients,” Dr. O’Shaughnessy observed.
Indeed, because tesetaxel only needs to be dosed once every 3 weeks, patients in the trial received tesetaxel at 27 mg/m2 only on the first day of a 21-day treatment cycle. This was combined with a reduced, 825-mg/m2 dose of capecitabine, given orally twice-daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
The combination regimen was compared with the recommended full dose of capecitabine alone, 1,250 mg/m2 given orally twice daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
Efficacy and safety
PFS was 9.8 months with tesetaxel plus capecitabine and 6.9 months with capecitabine alone, representing a 2.9-month improvement with the combination (hazard ratio, 0.716; P = .003).
A similar PFS benefit was seen regardless of multiple predefined subgroups, such as age, baseline performance status, duration of disease-free interval before study entry, and the use of CDK4/6 inhibitors.
The objective response rate was 57% with tesetaxel plus capecitabine and 41% with capecitabine alone (P = .0002). The 24-week disease control rate was 67% and 50%, respectively (P < .0001).
The most frequent treatment-emergent adverse event seen with the tesetaxel-capecitabine combination was neutropenia, occurring in 76.9% of patients, compared with 22.6% of patients in the monotherapy arm. Rates of grade 3-4 neutropenia were much higher in the combination arm (32.6% and 38.3%, respectively) than in the monotherapy arm (7.4% and 0.9%, respectively).
The neutropenia seen was “generally manageable,” Dr. O’Shaughnessy said, primarily with dose reductions and granulocyte colony–stimulating factor as needed.
She pointed out that rates of grade 3 or higher neuropathy and grade 2 alopecia were low, a respective 5.9% and 8%, with the combination.
The dose of capecitabine used in the control arm was noted to be higher than that used in usual practice.
“This was because of the global nature of the study and the regulatory requirements globally,” Dr. O’Shaughnessy said.
“The dose-modification scheme was that patients could have a dose reduction at the first sign of grade 2 toxicity,” she added, giving investigators the flexibility to reduce the dose as soon as possible.
This study was sponsored by Odonate Therapeutics. Dr. O’Shaughnessy disclosed consulting fees from AbbVie, Agendia, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, Genentech/Roche, Genomic Health, GRAIL, Heron, Immunomedics, Ipsen, Jounce, Lilly, Novartis, Odonate, Pfizer, Puma, and Seagen. Dr. Burstein and Dr. Cardoso had no relevant disclosures.
SOURCE: O’Shaughnessy J et al. SABCS 2020, Abstract GS4-01.
These results suggest tesetaxel plus capecitabine is “a potential new treatment option” for this patient population, said study investigator Joyce O’Shaughnessy, MD, of Baylor University Medical Center and Texas Oncology, both in Dallas.
“This should launch an oral taxane into the clinical space, which will be a nice addition to the toolbox for treating advanced breast cancer, with real upsides for patients,” said Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the trial but commented on the results in an interview.
Another commenter was more critical of CONTESSA’s results, which were presented at the 2020 San Antonio Breast Cancer Symposium.
“Three months’ difference in PFS in this setting is meaningless without overall survival [OS] results,” Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, said in a question submitted through the virtual meeting’s chat system.
At this point, the OS data are immature, and mature data won’t be available for another couple of years at least, according to the study’s protocol.
Dr. O’Shaughnessy defended the PFS result as being significant, however, saying it was comparable with outcomes seen previously with docetaxel-capecitabine and paclitaxel-gemcitabine combinations.
Other meeting attendees questioned why the waters had been muddied by testing the effects of tesetaxel in combination with capecitabine, albeit at a reduced dose, versus the approved full dose of capecitabine as monotherapy, particularly as a phase 2 trial had shown that tesetaxel demonstrated “significant activity” as monotherapy.
“The reason for the combination versus a monotherapy is because it was designed as a registration trial,” Dr. O’Shaughnessy explained. The trial was designed to be very similar to early taxane studies where docetaxel was assessed with or without capecitabine, or paclitaxel with or without gemcitabine.
“Probably we’re going to be using a doublet for patients who have virulent disease who really need a response,” Dr. O’Shaughnessy explained. She noted that the objective response rate was much higher with the tesetaxel-capecitabine combination than with capecitabine alone, and that result alone is “probably enough that we would utilize a doublet.”
The key thing is that it now gives patients an all-oral option, Dr. O’Shaughnessy said.
“The data are exciting because it would be terrific to have an orally available taxane chemotherapy,” agreed Dr. Burstein. “It is far more convenient for patients and opens access globally in places that do not have adequate resources for administration of IV therapeutics. Also, the data suggest that tesetaxel has a different side effect profile than IV taxane, with less neuropathy and less alopecia.”
Trial design
CONTESSA is an ongoing randomized, controlled trial that started in 2017 and is projected to end in early 2023. It is investigating the use of tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone in 685 women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer who had previously been treated with a taxane.
Being intrinsically orally bioavailable and more soluble than the other taxanes means that tesetaxel has a much longer half-life that allows for a “more convenient treatment experience for patients,” Dr. O’Shaughnessy observed.
Indeed, because tesetaxel only needs to be dosed once every 3 weeks, patients in the trial received tesetaxel at 27 mg/m2 only on the first day of a 21-day treatment cycle. This was combined with a reduced, 825-mg/m2 dose of capecitabine, given orally twice-daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
The combination regimen was compared with the recommended full dose of capecitabine alone, 1,250 mg/m2 given orally twice daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
Efficacy and safety
PFS was 9.8 months with tesetaxel plus capecitabine and 6.9 months with capecitabine alone, representing a 2.9-month improvement with the combination (hazard ratio, 0.716; P = .003).
A similar PFS benefit was seen regardless of multiple predefined subgroups, such as age, baseline performance status, duration of disease-free interval before study entry, and the use of CDK4/6 inhibitors.
The objective response rate was 57% with tesetaxel plus capecitabine and 41% with capecitabine alone (P = .0002). The 24-week disease control rate was 67% and 50%, respectively (P < .0001).
The most frequent treatment-emergent adverse event seen with the tesetaxel-capecitabine combination was neutropenia, occurring in 76.9% of patients, compared with 22.6% of patients in the monotherapy arm. Rates of grade 3-4 neutropenia were much higher in the combination arm (32.6% and 38.3%, respectively) than in the monotherapy arm (7.4% and 0.9%, respectively).
The neutropenia seen was “generally manageable,” Dr. O’Shaughnessy said, primarily with dose reductions and granulocyte colony–stimulating factor as needed.
She pointed out that rates of grade 3 or higher neuropathy and grade 2 alopecia were low, a respective 5.9% and 8%, with the combination.
The dose of capecitabine used in the control arm was noted to be higher than that used in usual practice.
“This was because of the global nature of the study and the regulatory requirements globally,” Dr. O’Shaughnessy said.
“The dose-modification scheme was that patients could have a dose reduction at the first sign of grade 2 toxicity,” she added, giving investigators the flexibility to reduce the dose as soon as possible.
This study was sponsored by Odonate Therapeutics. Dr. O’Shaughnessy disclosed consulting fees from AbbVie, Agendia, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, Genentech/Roche, Genomic Health, GRAIL, Heron, Immunomedics, Ipsen, Jounce, Lilly, Novartis, Odonate, Pfizer, Puma, and Seagen. Dr. Burstein and Dr. Cardoso had no relevant disclosures.
SOURCE: O’Shaughnessy J et al. SABCS 2020, Abstract GS4-01.
FROM SABCS 2020
Pembro benefits in mTNBC regardless of chemo type
Adding pembrolizumab to chemotherapy substantially increases progression-free survival (PFS) in treatment-naive advanced or metastatic triple-negative breast cancer (TNBC) regardless of chemotherapy type, suggests an analysis of the clinical trial KEYNOTE-355.
There was also a trend for improved outcomes with increasing programmed death–ligand 1 (PD-L1) expression in the tumor, as measured by combined positive score (CPS).
“These data further support a role for the addition of pembro to standard chemo for the first-line treatment of metastatic TNBC,” said study presenter Hope S. Rugo, MD, from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.
The research was presented at the 2020 San Antonio Breast Cancer Symposium on Dec. 10.
Last month, pembrolizumab was granted accelerated approval by the Food and Drug Administration in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).
The approval was based on data from KEYNOTE-355, which involved almost 850 women with previously untreated locally recurrent inoperable or metastatic TNBC randomized 2:1 to pembrolizumab plus investigator’s choice of chemotherapy who were followed for 2 years.
For the current analysis, patients were stratified by PD-L1 CPS in the tumor, including over 320 patients with CPS ≥10, and by accompanying chemotherapy regimen.
In the overall intention-to-treat (ITT) population (n = 847), median PFS was longer with pembrolizumab plus chemotherapy versus placebo plus chemotherapy, at 9.7 months versus 5.6 months (hazard ratio, 0.82).
PFS improved step-wise with increased PD-L1 expression. In patients with PD-L1 CPS ≥1, the HR was 0.74, and in those with PD-L1 CPS ≥10, it was 0.65.
A similar incremental improvement by PD-L1 expression was seen in the overall response rate, with the rate topping out at 53.2% in the pembrolizumab plus chemotherapy arm, among the PD-L1 CPS ≥10 group.
Duration of response told a similar story, with the pembro-chemo combination providing superior results and the treatment effect increasing with PD-L1 enrichment.
Study discussant Sylvia Adams, MD, New York University Perlmutter Cancer Center, New York, said the “consistency of treatment effect” with different chemotherapy backbones seen in the study is “very important, as it is currently unknown what the optimal backbone is.”
She also noted that the chemotherapy analysis presented by Dr. Rugo was “exploratory” and “not powered to show the winner of the chemotherapy backbone.”
Nevertheless, in the postpresentation debate, Ian Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, said that there are “several questions over the chemotherapy partner,” including whether there were differences in the populations who received each type of regimen.
Dr. Rugo replied that “because the trial wasn’t powered to look at the separate chemotherapy groups with any statistical significance ... it’s really impossible to draw any specific conclusions because it’s the overall population that’s evaluated.”
Asked about when overall survival results will be presented, Dr. Rugo said that “everybody is very interested” in that, “and we expect these results to be available next year.”
Study details
For KEYNOTE-355, researchers recruited women with previously untreated metastatic TNBC who had completed treatment with curative intent ≥6 months prior to their first disease recurrence.
They were randomized 2:1 to pembrolizumab or placebo plus investigator’s choice of chemotherapy from nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin for up to 35 administrations of pembrolizumab or placebo or until progression, intolerable toxicity, or cessation of treatment.
Crossover was not allowed. Patients were stratified by type of chemotherapy, PD-L1 expression in the tumor, and prior treatment in the neoadjuvant or adjuvant setting with the same class of chemotherapy.
Response was assessed with imaging every 8 weeks until week 24, then every 9 weeks during the first year of follow-up, and then every 12 weeks.
Of 847 randomized patients, 566 received pembrolizumab plus chemotherapy and 281 were assigned to the placebo group. The median age was 53 years in both groups.
The majority (75.1%) of patients in both groups were PD-L1 positive with a centrally assessed CPS ≥1, while 38.9% of patients in the pembrolizumab arm and 36.7% of those given placebo had a CPS ≥10.
After a median follow-up of 25.9 months, 16 patients given pembrolizumab had completed the study and 33 were still ongoing.
This compares with five patients having completed the placebo arm, and 12 still ongoing, after a median follow-up of 26.3 months.
The overall response rate was higher with pembrolizumab plus chemotherapy in the ITT population, at 41.0% versus 35.9%, rising to 45.2% versus 37.9% in patients with PD-L1 CPS ≥1 and 53.2% versus 39.8% in the PD-L1 CPS ≥10 group.
Again, when the groups were stratified by on-study chemotherapy, the overall response rate was higher with pembrolizumab versus placebo regardless of the chemotherapy partner.
Finally, the duration of response with pembrolizumab plus chemotherapy was longer than that seen with placebo, at a median of 10.1 months versus 6.4 months in the ITT population.
In the PD-L1 CPS ≥1 group, the duration of response was 10.1 months versus 6.5 months, rising to 19.3 months versus 7.3 months in the PD-L1 CPS ≥10 group.
Dr. Adams nevertheless said that PD-L1 remains an “imperfect” biomarker in metastatic TNBC, although it is “the best to date.” Furthermore, the IMpassion130 trial, featuring atezolizumab, showed that there is “very poor” analytic and clinical concordance between assays, which “complicates clinical decision-making.”
This study was sponsored by Merck. Dr. Rugo, Dr. Adams, and Dr. Krop have disclosed financial ties to multiple pharmaceutical companies, including Merck.
A version of this article first appeared on Medscape.com.
Adding pembrolizumab to chemotherapy substantially increases progression-free survival (PFS) in treatment-naive advanced or metastatic triple-negative breast cancer (TNBC) regardless of chemotherapy type, suggests an analysis of the clinical trial KEYNOTE-355.
There was also a trend for improved outcomes with increasing programmed death–ligand 1 (PD-L1) expression in the tumor, as measured by combined positive score (CPS).
“These data further support a role for the addition of pembro to standard chemo for the first-line treatment of metastatic TNBC,” said study presenter Hope S. Rugo, MD, from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.
The research was presented at the 2020 San Antonio Breast Cancer Symposium on Dec. 10.
Last month, pembrolizumab was granted accelerated approval by the Food and Drug Administration in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).
The approval was based on data from KEYNOTE-355, which involved almost 850 women with previously untreated locally recurrent inoperable or metastatic TNBC randomized 2:1 to pembrolizumab plus investigator’s choice of chemotherapy who were followed for 2 years.
For the current analysis, patients were stratified by PD-L1 CPS in the tumor, including over 320 patients with CPS ≥10, and by accompanying chemotherapy regimen.
In the overall intention-to-treat (ITT) population (n = 847), median PFS was longer with pembrolizumab plus chemotherapy versus placebo plus chemotherapy, at 9.7 months versus 5.6 months (hazard ratio, 0.82).
PFS improved step-wise with increased PD-L1 expression. In patients with PD-L1 CPS ≥1, the HR was 0.74, and in those with PD-L1 CPS ≥10, it was 0.65.
A similar incremental improvement by PD-L1 expression was seen in the overall response rate, with the rate topping out at 53.2% in the pembrolizumab plus chemotherapy arm, among the PD-L1 CPS ≥10 group.
Duration of response told a similar story, with the pembro-chemo combination providing superior results and the treatment effect increasing with PD-L1 enrichment.
Study discussant Sylvia Adams, MD, New York University Perlmutter Cancer Center, New York, said the “consistency of treatment effect” with different chemotherapy backbones seen in the study is “very important, as it is currently unknown what the optimal backbone is.”
She also noted that the chemotherapy analysis presented by Dr. Rugo was “exploratory” and “not powered to show the winner of the chemotherapy backbone.”
Nevertheless, in the postpresentation debate, Ian Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, said that there are “several questions over the chemotherapy partner,” including whether there were differences in the populations who received each type of regimen.
Dr. Rugo replied that “because the trial wasn’t powered to look at the separate chemotherapy groups with any statistical significance ... it’s really impossible to draw any specific conclusions because it’s the overall population that’s evaluated.”
Asked about when overall survival results will be presented, Dr. Rugo said that “everybody is very interested” in that, “and we expect these results to be available next year.”
Study details
For KEYNOTE-355, researchers recruited women with previously untreated metastatic TNBC who had completed treatment with curative intent ≥6 months prior to their first disease recurrence.
They were randomized 2:1 to pembrolizumab or placebo plus investigator’s choice of chemotherapy from nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin for up to 35 administrations of pembrolizumab or placebo or until progression, intolerable toxicity, or cessation of treatment.
Crossover was not allowed. Patients were stratified by type of chemotherapy, PD-L1 expression in the tumor, and prior treatment in the neoadjuvant or adjuvant setting with the same class of chemotherapy.
Response was assessed with imaging every 8 weeks until week 24, then every 9 weeks during the first year of follow-up, and then every 12 weeks.
Of 847 randomized patients, 566 received pembrolizumab plus chemotherapy and 281 were assigned to the placebo group. The median age was 53 years in both groups.
The majority (75.1%) of patients in both groups were PD-L1 positive with a centrally assessed CPS ≥1, while 38.9% of patients in the pembrolizumab arm and 36.7% of those given placebo had a CPS ≥10.
After a median follow-up of 25.9 months, 16 patients given pembrolizumab had completed the study and 33 were still ongoing.
This compares with five patients having completed the placebo arm, and 12 still ongoing, after a median follow-up of 26.3 months.
The overall response rate was higher with pembrolizumab plus chemotherapy in the ITT population, at 41.0% versus 35.9%, rising to 45.2% versus 37.9% in patients with PD-L1 CPS ≥1 and 53.2% versus 39.8% in the PD-L1 CPS ≥10 group.
Again, when the groups were stratified by on-study chemotherapy, the overall response rate was higher with pembrolizumab versus placebo regardless of the chemotherapy partner.
Finally, the duration of response with pembrolizumab plus chemotherapy was longer than that seen with placebo, at a median of 10.1 months versus 6.4 months in the ITT population.
In the PD-L1 CPS ≥1 group, the duration of response was 10.1 months versus 6.5 months, rising to 19.3 months versus 7.3 months in the PD-L1 CPS ≥10 group.
Dr. Adams nevertheless said that PD-L1 remains an “imperfect” biomarker in metastatic TNBC, although it is “the best to date.” Furthermore, the IMpassion130 trial, featuring atezolizumab, showed that there is “very poor” analytic and clinical concordance between assays, which “complicates clinical decision-making.”
This study was sponsored by Merck. Dr. Rugo, Dr. Adams, and Dr. Krop have disclosed financial ties to multiple pharmaceutical companies, including Merck.
A version of this article first appeared on Medscape.com.
Adding pembrolizumab to chemotherapy substantially increases progression-free survival (PFS) in treatment-naive advanced or metastatic triple-negative breast cancer (TNBC) regardless of chemotherapy type, suggests an analysis of the clinical trial KEYNOTE-355.
There was also a trend for improved outcomes with increasing programmed death–ligand 1 (PD-L1) expression in the tumor, as measured by combined positive score (CPS).
“These data further support a role for the addition of pembro to standard chemo for the first-line treatment of metastatic TNBC,” said study presenter Hope S. Rugo, MD, from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.
The research was presented at the 2020 San Antonio Breast Cancer Symposium on Dec. 10.
Last month, pembrolizumab was granted accelerated approval by the Food and Drug Administration in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).
The approval was based on data from KEYNOTE-355, which involved almost 850 women with previously untreated locally recurrent inoperable or metastatic TNBC randomized 2:1 to pembrolizumab plus investigator’s choice of chemotherapy who were followed for 2 years.
For the current analysis, patients were stratified by PD-L1 CPS in the tumor, including over 320 patients with CPS ≥10, and by accompanying chemotherapy regimen.
In the overall intention-to-treat (ITT) population (n = 847), median PFS was longer with pembrolizumab plus chemotherapy versus placebo plus chemotherapy, at 9.7 months versus 5.6 months (hazard ratio, 0.82).
PFS improved step-wise with increased PD-L1 expression. In patients with PD-L1 CPS ≥1, the HR was 0.74, and in those with PD-L1 CPS ≥10, it was 0.65.
A similar incremental improvement by PD-L1 expression was seen in the overall response rate, with the rate topping out at 53.2% in the pembrolizumab plus chemotherapy arm, among the PD-L1 CPS ≥10 group.
Duration of response told a similar story, with the pembro-chemo combination providing superior results and the treatment effect increasing with PD-L1 enrichment.
Study discussant Sylvia Adams, MD, New York University Perlmutter Cancer Center, New York, said the “consistency of treatment effect” with different chemotherapy backbones seen in the study is “very important, as it is currently unknown what the optimal backbone is.”
She also noted that the chemotherapy analysis presented by Dr. Rugo was “exploratory” and “not powered to show the winner of the chemotherapy backbone.”
Nevertheless, in the postpresentation debate, Ian Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, said that there are “several questions over the chemotherapy partner,” including whether there were differences in the populations who received each type of regimen.
Dr. Rugo replied that “because the trial wasn’t powered to look at the separate chemotherapy groups with any statistical significance ... it’s really impossible to draw any specific conclusions because it’s the overall population that’s evaluated.”
Asked about when overall survival results will be presented, Dr. Rugo said that “everybody is very interested” in that, “and we expect these results to be available next year.”
Study details
For KEYNOTE-355, researchers recruited women with previously untreated metastatic TNBC who had completed treatment with curative intent ≥6 months prior to their first disease recurrence.
They were randomized 2:1 to pembrolizumab or placebo plus investigator’s choice of chemotherapy from nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin for up to 35 administrations of pembrolizumab or placebo or until progression, intolerable toxicity, or cessation of treatment.
Crossover was not allowed. Patients were stratified by type of chemotherapy, PD-L1 expression in the tumor, and prior treatment in the neoadjuvant or adjuvant setting with the same class of chemotherapy.
Response was assessed with imaging every 8 weeks until week 24, then every 9 weeks during the first year of follow-up, and then every 12 weeks.
Of 847 randomized patients, 566 received pembrolizumab plus chemotherapy and 281 were assigned to the placebo group. The median age was 53 years in both groups.
The majority (75.1%) of patients in both groups were PD-L1 positive with a centrally assessed CPS ≥1, while 38.9% of patients in the pembrolizumab arm and 36.7% of those given placebo had a CPS ≥10.
After a median follow-up of 25.9 months, 16 patients given pembrolizumab had completed the study and 33 were still ongoing.
This compares with five patients having completed the placebo arm, and 12 still ongoing, after a median follow-up of 26.3 months.
The overall response rate was higher with pembrolizumab plus chemotherapy in the ITT population, at 41.0% versus 35.9%, rising to 45.2% versus 37.9% in patients with PD-L1 CPS ≥1 and 53.2% versus 39.8% in the PD-L1 CPS ≥10 group.
Again, when the groups were stratified by on-study chemotherapy, the overall response rate was higher with pembrolizumab versus placebo regardless of the chemotherapy partner.
Finally, the duration of response with pembrolizumab plus chemotherapy was longer than that seen with placebo, at a median of 10.1 months versus 6.4 months in the ITT population.
In the PD-L1 CPS ≥1 group, the duration of response was 10.1 months versus 6.5 months, rising to 19.3 months versus 7.3 months in the PD-L1 CPS ≥10 group.
Dr. Adams nevertheless said that PD-L1 remains an “imperfect” biomarker in metastatic TNBC, although it is “the best to date.” Furthermore, the IMpassion130 trial, featuring atezolizumab, showed that there is “very poor” analytic and clinical concordance between assays, which “complicates clinical decision-making.”
This study was sponsored by Merck. Dr. Rugo, Dr. Adams, and Dr. Krop have disclosed financial ties to multiple pharmaceutical companies, including Merck.
A version of this article first appeared on Medscape.com.