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Assessing the Clinical Benefit of Systemic Adjuvant Therapies for Early Breast Cancer.

ABSTRACT: Oncologic therapy is currently undergoing significant changes. A number of innovative targeted medications currently in clinical development have raised high expectations. With that in mind, discussions about terms such as "clinical benefit" and "clinical relevance" are highly topical. This also applies to further developments in the field of adjuvant systemic therapies for early-stage breast cancer. As the treatment aim is curative, assessment of the clinical benefit of adjuvant therapies must be largely based on efficacy outcomes. The focus must be on improving disease-free survival rates and lowering the risk of recurrence. Because of the current low mortality rates, statements about overall survival rates are only possible after very long observation periods. Consequently, new drugs in adjuvant therapies should be considered as offering a clinical benefit, if they reduce the risk of recurrence below current low levels of risk. The evidence for established adjuvant therapy standards in early-stage breast cancer can be used as objective criteria for comparison. This review article considers the requirements for clinical benefit of new adjuvant therapies for early breast cancer, based on examples from adjuvant endocrine therapy, adjuvant polychemotherapy and adjuvant anti-HER2 therapy.

SUBMITTER: Mobus V

PROVIDER: S-EPMC5658231 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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Assessing the Clinical Benefit of Systemic Adjuvant Therapies for Early Breast Cancer.

Möbus Volker V Hell Susanne S Schmidt Marcus M

Geburtshilfe und Frauenheilkunde 20171026 10

Oncologic therapy is currently undergoing significant changes. A number of innovative targeted medications currently in clinical development have raised high expectations. With that in mind, discussions about terms such as "clinical benefit" and "clinical relevance" are highly topical. This also applies to further developments in the field of adjuvant systemic therapies for early-stage breast cancer. As the treatment aim is curative, assessment of the clinical benefit of adjuvant therapies must ...[more]

PMID: 29093601

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Project description:BackgroundThe absolute and relative benefits of adjuvant bisphosphonates on disease-free survival and overall survival in patients receiving contemporary systemic therapy for early breast cancer is uncertain.MethodsData from randomized trials of adjuvant bisphosphonates that recruited patients exclusively after 2000 and reported disease free survival and overall survival was utilized. Five-year disease-free survival and overall survival in bisphosphonates and control group along with associated hazard ratios were extracted. Absolute data were weighted by sample size and hazard ratios were pooled using inverse variance and random effects modelling. Meta-regression comprising linear regression weighted by sample size (mixed effects) was performed to explore association between disease and treatment related factors and absolute differences in benefit from bisphosphonates.ResultsEleven trials comprising 24023 patients were included in the analysis. For disease free survival, pooled hazard ratio was 0.89 (0.81-0.97, p = 0.008) with a 1.5 % weighted mean difference favoring bisphosphonates over control. There was no significant overall survival benefit (0.92, 0.82-1.03, p = 0.16). Among patients receiving anthracycline and taxane based chemotherapy, there were no differences in either disease free survival (0.95, 0.80-1.12) or overall survival (1.04, 0.81-1.32). Meta-regression showed lower benefits in higher risk patients (node-positive, larger tumor size, estrogen receptor-, grade 3 or those receiving chemotherapy). Overall, 1 % (95 % CI 0.75-1.15) of patients experienced osteonecrosis of jaw related to zoledronic acid.ConclusionsCompared to the Early Breast Cancer Trialist's Collaborative Group meta-analysis, benefit from adjuvant bisphosphonates is lower in recent trials especially in higher risk patients receiving contemporary chemotherapy. The balance between benefits and risks of adjuvant bisphosphonates should be considered in individual patients.

Project description:Brachytherapy after lumpectomy is an increasingly popular breast cancer treatment, but data concerning its effectiveness are conflicting. Recently proposed "suitability" criteria guiding patient selection for brachytherapy have never been empirically validated.Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we compared women aged 66 years or older with invasive breast cancer (n=28,718) or ductal carcinoma in situ (n=7229) diagnosed from 2002 to 2007, treated with lumpectomy alone, brachytherapy, or external beam radiation therapy (EBRT). The likelihood of breast preservation, measured by subsequent mastectomy risk, was compared by use of multivariate proportional hazards, further stratified by American Society for Radiation Oncology (ASTRO) brachytherapy suitability groups. We compared 1-year postoperative complications using the ?(2) test and 5-year local toxicities using the log-rank test.For patients with invasive cancer, the 5-year subsequent mastectomy risk was 4.7% after lumpectomy alone (95% confidence interval [CI], 4.1%-5.4%), 2.8% after brachytherapy (95% CI, 1.8%-4.3%), and 1.3% after EBRT (95% CI, 1.1%-1.5%) (P<.001). Compared with lumpectomy alone, brachytherapy achieved a more modest reduction in adjusted risk (hazard ratio [HR], 0.61; 95% CI, 0.40-0.94) than achieved with EBRT (HR, 0.22; 95% CI, 0.18-0.28). Relative risks did not differ when stratified by ASTRO suitability group (P=.84 for interaction), although ASTRO "suitable" patients did show a low absolute subsequent mastectomy risk, with a minimal absolute difference in risk after brachytherapy (1.6%; 95% CI, 0.7%-3.5%) versus EBRT (0.8%; 95% CI, 0.6%-1.1%). For patients with ductal carcinoma in situ, EBRT maintained a reduced risk of subsequent mastectomy (HR, 0.40; 95% CI, 0.28-0.55; P<.001), whereas the small number of patients treated with brachytherapy (n=179) precluded definitive comparison with lumpectomy alone. In all patients, brachytherapy showed a higher postoperative infection risk (16.5% vs 9.9% after lumpectomy alone vs 11.4% after EBRT, P<.001); higher incidence of breast pain (22.9% vs 11.2% vs 16.7%, P<.001); and higher incidence of fat necrosis (15.3% vs 5.3% vs 7.7%, P<.001).In this study era, brachytherapy showed lesser breast preservation benefit compared with EBRT. Suitability criteria predicted differential absolute, but not relative, benefit in patients with invasive cancer.

Project description:PurposeRisk of recurrence is the primary consideration in breast cancer adjuvant therapy recommendations. The TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive breast cancer, testing exemestane plus ovarian function suppression (OFS), tamoxifen plus OFS, and tamoxifen alone. We examined absolute treatment effect across a continuum of recurrence risk to individualize endocrine therapy decision making for premenopausal women with human epidermal growth factor receptor 2 (HER2) -negative disease.Patients and methodsThe TEXT and SOFT hormone receptor-positive, HER2-negative analysis population included 4,891 women. The end point was breast cancer-free interval (BCFI), defined as time from random assignment to first occurrence of invasive locoregional, distant, or contralateral breast cancer. A continuous, composite measure of recurrence risk for each patient was determined from a Cox model incorporating age, nodal status, tumor size and grade, and estrogen receptor, progesterone receptor, and Ki-67 expression levels. Subpopulation treatment effect pattern plot methodology revealed differential treatment effects on 5-year BCFI according to composite risk.ResultsSOFT patients who remained premenopausal after chemotherapy experienced absolute improvement of 5% or more in 5-year BCFI with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone, reaching 10% to 15% at intermediate to high composite risk; the benefit of tamoxifen plus OFS versus tamoxifen alone was apparent at the highest composite risk. The SOFT no-chemotherapy cohort-for whom composite risk was lowest on average-did well with all endocrine therapies. For TEXT patients, the benefit of exemestane plus OFS versus tamoxifen plus OFS in 5-year BCFI ranged from 5% to 15%; patients not receiving chemotherapy and with lowest composite risk did well with both treatments.ConclusionPremenopausal women with hormone receptor-positive, HER2-negative disease and high recurrence risk, as defined by clinicopathologic characteristics, may experience improvement of 10% to 15% in 5-year BCFI with exemestane plus OFS versus tamoxifen alone. An improvement of at least 5% may be achieved for women at intermediate risk, and improvement is minimal for those at lowest risk.

Dataset Information

Assessing the Clinical Benefit of Systemic Adjuvant Therapies for Early Breast Cancer.

Publications

Assessing the Clinical Benefit of Systemic Adjuvant Therapies for Early Breast Cancer.

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