Chemotherapy-related amenorrhea (CRA) after adjuvant ado-trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT Trial).

PURPOSE: Chemotherapy-related amenorrhea (CRA) is a surrogate for ovarian toxicity and associated risk of infertility and premature menopause. Here, we compare CRA rate with paclitaxel (T)-trastuzumab (H) to that with ado-trastuzumab emtansine (T-DM1). METHODS: Patients with T1N0 HER2 + early-stage breast cancer (eBC) enrolled on the ATEMPT trial and were randomized 3:1 to T-DM1 3.6 mg/kg IV every (q) 3 weeks (w) × 17 vs. T 80 mg/m2 with H IV qw × 12 (4 mg/kg load → 2 mg/kg), followed by H (6 mg/kg IV q3w × 13). Enrollees who self-reported as premenopausal were asked to complete menstrual surveys at baseline and every 6-12 months for 60 months. 18-month CRA (no periods reported during prior 6 months on 18-month survey) was the primary endpoint of this analysis. RESULTS: Of 512 ATEMPT enrollees, 123 who began protocol therapy and answered baseline and at least one follow-up menstrual survey were premenopausal at enrollment. 76 had menstrual data available at 18 months without having received a gonadotropin-releasing hormone agonist or undergone hysterectomy and/or oophorectomy. Median age was 45 (range 23-53) among 18 who had received TH and 46 (range 34-54) among 58 who had received T-DM1. The 18-month rate of CRA was 50% after TH and 24% after T-DM1 (p = 0.045). CONCLUSION: Amenorrhea at 18 months was less likely in recipients of adjuvant T-DM1 than TH. Future studies are needed to understand how T-DM1 impacts risk of infertility and permanent menopause, and to assess amenorrhea rates when T-DM1 is administered after standard HER2-directed chemotherapy regimens.

'ADVANCE' (a pilot trial) ADjuVANt chemotherapy in the elderly: Developing and evaluating lower-toxicity chemotherapy options for older patients with breast cancer.

INTRODUCTION: Older adults with breast cancer receiving neo/adjuvant chemotherapy are at high risk for poor outcomes and are underrepresented in clinical trials. The ADVANCE (ADjuVANt Chemotherapy in the Elderly) trial evaluated the feasibility of two neo/adjuvant chemotherapy regimens in parallel-enrolling cohorts of older patients with human epidermal growth factor receptor 2-negative breast cancer: cohort 1-triple-negative; cohort 2-hormone receptor-positive. MATERIALS AND METHODS: Adults age ≥ 70 years with stage I-III breast cancer warranting neo/adjuvant chemotherapy were enrolled. Cohort 1 received weekly carboplatin (area under the curve 2) and weekly paclitaxel 80 mg/m2 for twelve weeks; cohort 2 received weekly paclitaxel 80 mg/m2 plus every-three-weekly cyclophosphamide 600 mg/m2 over twelve weeks. The primary study endpoint was feasibility, defined as ≥80% of patients receiving ≥80% of intended weeks/doses of therapy. All dose modifications were applied per clinician discretion. RESULTS: Forty women (n = 20 per cohort) were enrolled from March 25, 2019 through August 3, 2020 from three centers; 45% and 35% of patients in cohorts 1 and 2 were age > 75, respectively. Neither cohort achieved targeted thresholds for feasibility. In cohort 1, eight (40.0%) met feasibility (95% confidence interval [CI] = 19.1-63.9%), while ten (50.0%) met feasibility in cohort 2 (95% CI = 27.2-72.8). Neutropenia was the most common grade 3-4 toxicity (cohort 1-65%, cohort 2-55%). In cohort 1, 80% and 85% required ≥1 dose holds of carboplatin and/or paclitaxel, respectively. In cohort 2, 10% required dose hold(s) for cyclophosphamide and/or 65% for paclitaxel. DISCUSSION: In this pragmatic pilot examining chemotherapy regimens in older adults with breast cancer, neither regimen met target goals for feasibility. Developing efficacious and tolerable regimens for older patients with breast cancer who need chemotherapy remains an important goal. CLINICALTRIALS: gov Identifier: NCT03858322.

Clonal hematopoiesis in older patients with breast cancer receiving chemotherapy.

BACKGROUND: The expansion of hematopoietic stem cells carrying recurrent somatic mutations, termed clonal hematopoiesis (CH), is common in elderly individuals and is associated with increased risk of myeloid malignancy and all-cause mortality. Though chemotherapy is a known risk factor for developing CH, how myelosuppressive therapies affect the short-term dynamics of CH remains incompletely understood. Most studies have been limited by retrospective design, heterogeneous patient populations, varied techniques to identifying CH, and analysis of single timepoints. METHODS: We examined serial samples from 40 older women with triple-negative or hormone receptor-positive breast cancer treated on the prospective ADjuVANt Chemotherapy in the Elderly trial to evaluate the prevalence and dynamics of CH at baseline and throughout chemotherapy (6 and 12 weeks). RESULTS: CH was detected in 44% of patients at baseline and in 53% at any timepoint. Baseline patient characteristics were not associated with CH. Over the course of treatment, mutations exhibited a variety of dynamics, including emergence, expansion, contraction, and disappearance. All mutations in TP53 (n = 3) and PPM1D (n = 4), genes that regulate the DNA damage response, either became detectable or expanded over the course of treatment. Neutropenia was more common in patients with CH, particularly when the mutations became detectable during treatment, and CH was significantly associated with cyclophosphamide dose reductions and holds (P = .02). CONCLUSIONS: Our study shows that CH is common, dynamic, and of potential clinical significance in this population. Our results should stimulate larger efforts to understand the biological and clinical importance of CH in solid tumor malignancies. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03858322). Clinical trial registration number: NCT03858322.