Dang, Chau T.

PurposeBevacizumab improves progression-free survival but not overall survival in patients with metastatic breast cancer. E5103 tested the effect of bevacizumab in the adjuvant setting in patients with human epidermal growth factor receptor 2–negative disease.Patients and MethodsPatients were assigned 1:2:2 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A), bevacizumab only during AC and paclitaxel (arm B), or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C). Random assignment was stratified and bevacizumab dose adjusted for choice of AC schedule. Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C. The primary end point was invasive disease–free survival (IDFS).ResultsFour thousand nine hundred ninety-four patients were enrolled. Median age was 52 years; 64% of patients were estrogen receptor positive, 27% were lymph node negative, and 78% received dose-dense AC. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across all arms. Grade ≥ 3 hypertension was more common in bevacizumab-treated patients, but thrombosis, proteinuria, and hemorrhage were not. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0% in arms A, B, and C, respectively. Bevacizumab exposure was less than anticipated, with approximately 24% of patients in arm B and approximately 55% of patients in arm C discontinuing bevacizumab before completing planned therapy. Five-year IDFS was 77% (95% CI, 71% to 81%) in arm A, 76% (95% CI, 72% to 80%) in arm B, and 80% (95% CI, 77% to 83%) in arm C.ConclusionIncorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2–negative breast cancer. Longer duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation.

Abstract Background: Late recurrence 5 or more years after diagnosis accounts for least one-half of all breast cancer recurrences, especially in hormone receptor (HR)+ disease. Biomarkers prognostic for late recurrence offer potential to more accurately identify subjects who might benefit from extended adjuvant endocrine therapy, or novel strategies to reduce late recurrence risk. Methods: CTCs were assessed at a single time point using the CELL SEARCH® assay in patients without clinical evidence of recurrence between 4.5-7.5 years after an initial diagnosis of HER2- stage II-III breast cancer and enrolled in trial E5103; all patients received surgery plus adjuvant chemotherapy and endocrine therapy for at least 5 years if HR+ disease. Patients were followed for evidence of clinical recurrence in accordance with standard care, and the association between CTCs and clinical recurrence was evaluated. Results: 546 patients without clinical evidence of recurrence enrolled between 2/25/13-7/29/16 and provided a blood sample that yielded a CTC result; 16 (2.9%) subsequently had a recurrence, of whom 15 had HR-positive disease. The median time between enrollment on E5103 and CTC assay was 5.2 years, and median/mean followup after the CTC assay was 1.6 years (range 0-3.9 years). The CTC assay was positive in 27 (4.9%) (median CTC count 1/7.5 ml blood, range 1-15). There were no significant differences in patient characteristics in the CTC+ vs. CTC- cases, including age < 50 years at initial diagnosis (52% vs. 44%), tumor size > 2 cm (63% vs. 59%), >/= 1 positive axillary node (81% vs. 72%), ER and/or PR+ (70% vs. 64%) or poor histologic grade (44% vs 55%). The recurrence rate per person-year in the CTC+ vs. CTC- groups was 19.6% vs. 1.1%, respectively (P<0.01). The median/mean time to recurrence after a positive CTC assay was 2.8 years. In multivariate analysis adjusted for clinical covariates (see table), a positive CTC assay was associated with an 18.3-fold increased risk of recurrence. Univariate and Multivariate Analysis - Association Between CTC Status and RecurrenceCovariateHazard Ratio for Recurrence - Univariate Analysis (95% CI)Hazard Ratio for Recurrence - Multivariate Analysis (95% CI)Age < 50 years3.4 (0.95-11.8)3.0 (0.8-10.9)Tumor size > 2 cm4.2 (0.98-19.2)2.9 (0.6-13.2)>/= 1+ node2.6 (0.59-11.5)0.7 (0.1-3.8)ER and/or PR+8.3 (1.1-63.5)7.7 (0.7-79.9)Poor grade0.43 (0.14-1.2)1.2 (0.4-3.8)CTC -pos vs CTC-neg20.9 (7.5-58.3)18.3 (5.7-58.2) Conclusions: A single positive CTC assay in patients without clinical evidence of recurrence 5 years after diagnosis of stage II-III HR+, HER2- breast cancer provides independent prognostic information for late recurrence, providing proof of concept for using liquid-based biomarkers for late relapse risk assessment. These findings provide a foundation for further evaluation of this new risk assessment paradigm using CTC and other blood-based assays in this setting, and designing clinical trials to tailor therapeutic risk interventions. Supported by Breast Cancer Research Foundation (J. Sparano; R. Comis) and Susan G. Komen Foundation (J. Sparano), and by the National Cancer Institute (CA180820, CA180794, CA180790, CA180791, CA180795, CA180802, CA180816, CA180821, CA189859). Citation Format: Sparano JA, O'Neill A, Alpaugh K, Wolff AC, Northfelt DW, Dang C, Sledge, Jr. GW, Miller KD. Circulating tumor cells (CTCs) five years after diagnosis are prognostic for late recurrence in operable stage II-III breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS6-03.

BACKGROUNDPublished studies have suggested that most patients with early stage breast cancer are willing, for modest survival benefits, to receive 6 months of adjuvant cyclophosphamide, methotrexate, and 5‐fluorouracil, an older regimen that is used infrequently today. We examined preferences regarding the survival benefit needed to justify 6 months of a contemporary chemotherapy regimen.METHODSThe Eastern Cooperative Oncology Group Protocol 5103 was a phase 3 trial that randomized breast cancer patients to receive standard adjuvant doxorubicin, cyclophosphamide, and paclitaxel with either bevacizumab or placebo. Serial surveys to assess quality of life were administered to patients enrolled between January 1, 2010, and June 8, 2010. Survival benefit needed to justify 6 months of chemotherapy by patients was collected at the 18‐month assessment. A parallel survey was sent to physicians who had enrolled patients in the study.RESULTSOf 519 patients who had not withdrawn at a time point earlier than 18 months, 87.8% responded to this survey. A total of 175 physicians participated. We found considerable variation in patient preferences, particularly for modest survival benefits: for 2 months of benefit, 57% would consider 6 months of chemotherapy, whereas 96% of patients would consider 6 months of chemotherapy for 24 months. Race and education were associated with the choices. Physicians who responded were less likely to accept chemotherapy for modest benefit.CONCLUSIONSAmong patients who received contemporary adjuvant chemotherapy in a randomized controlled trial, we found substantial variation in preferences regarding benefits that justified undergoing chemotherapy. Differences between patients' and physicians' choices were also apparent. Eliciting preferences regarding risks and benefits of adjuvant chemotherapy is critical. Cancer 2017;123:2821–28. © 2017 American Cancer Society.