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Estrogen-receptor positive (ER+) and human epidermal growth factor receptor positive (HER2+) subtypes of breast cancers feature distinct histopathologies and prognoses. Their molecular profiles inform subtype-specific treatment combinations and possible therapeutic targets. However, the evolutionary trajectory of somatic mutations within each subtype has not been characterized, despite its utility in prioritizing drug development and therapeutic approaches. Quantifying the selective effects of somatic mutations on cancer conveys the likely efficacy of extant targeted therapies between subtypes. Furthermore, knowledge of epistatic interactions involving targetable mutations enables precision therapy at any stage of tumorigenesis. The strength of these interactions differ between receptor subtypes, mediated by differences in the adaptive landscape of each subtype. To investigate differences in subtype etiologies, we quantified selection on single-nucleotide mutations within ER and HER2 receptor subtypes using an aggregated multi-institutional cohort of tumor samples. We observed differential selection acting on mutations: PIK3CA H1047R is a strongly selected variant for which selection varied significantly based on the receptor subtype, experiencing maximal selection in ER+ HER2﹣ breast cancer. On a stage-specific basis, we show that adaptive landscapes change, altering optimal timings for treatment. We then infer epistasis by 1) stage-specific analysis that suggests likely orderings of mutations, 2) calculation of pairwise selective epistasis amongst mutations, which lends mechanistic explanations to these orderings, and 3) phylogenetic reconstruction of the evolution of ten breast cancers, revealing common orderings that further support inferred selective epistatic interactions. Our estimates of differential and stage-specific selection and epistasis between subtypes suggest distinct adaptive landscapes for breast cancer subtypes. These estimates should inform the development of targeted therapeutics and guide treatment schedules based on molecular profiling of the cancer. Citation Format: Krishna Dasari, J. Nick Fisk, Jeffrey Townsend. Somatic mutations of ER and HER2 subtypes exhibit divergent evolutionary trajectories determined by selective epistasis revealed in phylogenetic reconstruction and stage-specific analyses [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-14-07. |
