A large phase III Unicancer ASTER 70s study showed that adding adjuvant chemotherapy to endocrine therapy does not result in a statistically significant overall survival (OS) benefit in patients older than 70 years with oestrogen receptor (ER)-positive, HER2-negative breast cancer with a high tumour genomic grade index. The study findings also point out to the need for greater measures to address limitations of predictive and prognostic tools in breast cancer. The final study results were presented by Dr. Etienne Brain of the Institut Curie in Saint-Cloud, France at ASCO 2022 Annual Meeting. Dr. Brain called for more representation of older patients in cancer research and was honoured with the 2022 B.J. Kennedy Geriatric Oncology Award at the 2022 ASCO Annual Meeting for his dedication to advancing research in breast cancer in older adult patients.
Dr. Brain explained in the background that benefit of adjuvant chemotherapy in addition to endocrine therapy is controversial for patients older than 70 years with ER-positive/HER2-negative breast cancer. In a large prospective study, the study team first assessed the tumour genomic grade index in all patients, and second in randomisd patients with a high tumour genomic grade index between chemotherapy plus endocrine therapy versus endocrine therapy alone. Eligible patients were women older than 70 years with ER-positive/HER2-negative primary breast cancer or isolated local relapse for whom adjuvant systemic treatment was considered.
The study team collected at baseline G8 score, Charlson comorbidity index and 4-year mortality Lee score. Tumour genomic grade index was centrally performed by RT-PCR on FFPE samples. Patients with low tumour genomic grade index were not recommended to receive adjuvant chemotherapy and were followed in an observational cohort. Patients with high tumour genomic grade index were randomised 1:1 to adjuvant chemotherapy plus endocrine therapy versus endocrine therapy alone, using G8, pN and centre for stratification.
The study investigators chose between 3 chemotherapy regimens: 4 cycles of doxorubicin/cyclophosphamide, non-pegylated liposomal doxorubicin/cyclophosphamide or docetaxel/cyclophosphamide, given every 3 weeks with G-CSF support. Standard endocrine therapy consisted of 5 years of aromatase inhibitor, tamoxifen or a sequence based on tolerance.
The study primary objective was to demonstrate an OS benefit for adjuvant chemotherapy with 4-year assumptions of 87.5% versus 80% (hazard ratio [HR] 0.60) in the intent-to-treat (ITT) population. With 171 events, the study had 90% power to demonstrate a difference with a bilateral test α=0.05. Secondary objectives included breast cancer specific survival, invasive disease-free survival (iDFS), event-free survival (EFS), competing events, cost-effectiveness and Q-TWiST analysis, geriatric dimensions, willingness and quality-of-life.
The study team enrolled 1,969 patients from 61 French and 12 Belgian centres and of those 1,089 (55%) were randomised between adjuvant chemotherapy plus endocrine therapy and endocrine therapy alone. Median follow-up was 5.94 years at the data cut-off with a total of 180 OS events occured. Median age was 75 years (range, 70 to 92), and G8 score, Charlson comorbidity index and Lee score were >14, ≤2, and ≤8 in 60%, 62% and 84% of patients, respectively. Tumours were ≥pT2, pN+, isolated local relapses, with histological grade III, in 56%, 46%, 11% and 39% of cases.
There was no statistically significant difference between treatment arms in terms of OS in the ITT analysis (HR 0.79, 95% confidence interval [CI] 0.60, 1.03; p = 0.08), but the per-protocol analysis did find a significantly greater OS with the addition of adjuvant chemotherapy to endocrine therapy versus endocrine therapy alone, 91.0% versus 89.3%, respectively (HR 0.73, 95% CI 0.55, 0.98; p = 0.03).
The forest plot could not identify any subgroup deriving significant benefit from adjuvant chemotherapy. The ITT and per protocol analysis of secondary objectives of breast cancer specific survival, iDFS, and EFS showed similar results.
Tumour genomic grade index did not predict a significant OS benefit from adjuvant chemotherapy plus endocrine therapy versus endocrine therapy alone in the ITT population. Despite this finding, Dr. Brain commented that the tumour genomic grade index was prognostic.
Dr. Nancy E. Davidson of the Fred Hutchinson Cancer Research Center, who discussed the study findings, said that the Unicancer ASTER 70s deserves praise for enrolment of older patients. The study use of the tumour genomic grade index, which is not a commonly used biomarker panel, may make it harder to contextualise the data. Despite this limitation, the study had ambitious primary endpoint of OS. She agreed that the tumour genomic grade index is prognostic, but it does not predict OS benefit with addition of chemotherapy. She also commented that currently there is little information about what the impact would be with the use of newer agents such as CDK4/6 inhibitors and bisphosphonates in this population.
Brain E, Viansone AA, Bourbouloux E, et al. 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. J Clin Oncol 2022; 40 (suppl 16; abstr 500). DOI: 10.1200/JCO.2022.40.16_suppl.500