Final results from a phase III randomized clinical trial of adjuvant endocrine therapy ± chemotherapy in women ≥ 70 years old with ER+ HER2- breast cancer and a high genomic grade index: The Unicancer ASTER 70s trial.
Background: Benefit of adjuvant chemotherapy (CT) in addition to endocrine therapy (ET) remains controversial for patients (pts) aged ≥ 70 years with oestrogen receptors-positive (ER+) HER2-negative (HER2-) breast cancer (BC). In a large prospective trial, we first assessed the tumour genomic grade index (GGI) in all pts, and second, randomized pts with a high GGI between CT + ET vs. ET alone.
Methods: Eligible pts were women ≥ 70 years with ER+ HER2- primary BC or isolated local relapse, irrespective of other characteristics, for whom adjuvant systemic treatment was considered. G8 score, Charlson comorbidity index (CCI) and 4-year mortality Lee score were collected at baseline. GGI was centrally performed by RT-PCR on FFPE samples. Pts with low GGI were not recommended to receive CT and were followed in an observational cohort. Pts with high (+ equivocal) GGI were randomized 1:1 to CT + ET vs. ET alone, using G8, pN and centre for stratification. Investigators chose between 3 CT regimens: 4 cycles of doxorubicin/cyclophosphamide, non-pegylated liposomal doxorubicin/cyclophosphamide or docetaxel/cyclophosphamide, given q3w with G-CSF. Standard ET consisted of 5 years of aromatase inhibitor, tamoxifen or a sequence based on tolerance. Based on CALGB 49907 results, the primary objective was to demonstrate an overall survival (OS) benefit for CT (4-year assumptions 87.5 vs 80%, HR=0.60) in the intent to treat (ITT) population. With 171 events, the trial had 90% power to demonstrate a difference with a bilateral test α=0.05. Secondary objectives included BC specific survival (BCSS), invasive disease-free survival (iDFS), event-free survival (EFS), competing events, cost-effectiveness and Q-TWiST analysis, geriatric dimensions, willingness and quality of life.
Results: Between 04/2012 and 05/2016, 1,969 pts from 61 French and 12 Belgian centres were enrolled. Of them, 1,089 (55%) were randomized between CT + ET and ET alone. Median follow-up was 5.8 years at the data cut-off (17/12/2021) with 180 OS events observed. Median age was 75 (70-92), G8 score, CCI and Lee score being >14, ≤ 2, and ≤ 8 in 60%, 62% and 84% of pts, respectively. Tumours were ≥ pT2, pN+, isolated local relapses, with histological grade III, in 56%, 46%, 11% and 39% of cases, respectively. No significant OS difference was observed between arms (HR 0.85 [0.64-1.13], p=0.2538); 4-year OS was 90.5% in the CT + ET arm and 89.7% in the ET alone arm. The forest plot could not identify any subgroup deriving significant benefit from CT. ITT and per protocol analysis of secondary objectives (BCSS, iDFS, EFS) showed similar results.
Conclusions: In this large phase III trial, we did not find a statistically significant OS benefit with the addition of CT to ET after surgery for ER+ HER2- BC with a high GGI. Analysis of the other outcome measures will be presented.
Research Sponsor:PHRC 2011Pharmaceutical/Biotech Company
LIGUE CONTRE LE CANCER, ARCS (AIDE A LA RECHERCHE CANCEROLOGIQUE DE SAINT-CLOUD).