Association of somatic driver alterations with prognosis in postmenopausal, hormone receptor-positive, HER2-negative early breast cancer - A secondary analysis of the BIG 1-98 randomized clinical trial

Importance: A range of somatic driver alterations have been described in estrogen receptor positive, HER2-negative (ER+/HER2-) early breast cancer (BC), however the clinical relevance is unknown. Objective: To investigate associations of driver alterations with prognosis and the role of PIK3CA mutations in prediction of benefit to endocrine therapy in postmenopausal patients with ER+/HER2- early BC treated with tamoxifen or letrozole. Design, setting, participants, and interventions: The BIG 1-98 trial randomized 8,010 post-menopausal patients with hormone receptor-positive operable invasive BC to monotherapy with letrozole or tamoxifen, or a sequential strategy for 5 years. Driver alterations were characterized using next generation sequencing in primary tumors from a subset of 764 patients from 7329 eligible ER+/HER2- patients, with 841 distant recurrences after 8.1 years median follow-up. To correct for the over-sampling of distant recurrences, weighted analysis methods were used. Main outcomes and measures: We analyzed the prevalence of driver alterations, associations with 5 clinicopathological factors, distant recurrence-free interval, and treatment interactions. Multivariable analyses were performed to adjust for clinicopathological factors