Abstract PD8-04: Evolutionary history and genomic landscape of metastatic breast cancer

Background: The majority of deaths from breast cancer are due to distant metastatic disease. Despite this, few systematic genomic analyses have been performed on metastatic tumors. This results from the relative difficulty of performing biopsies on metastatic tumors, as well as the uncertainty regarding genomic determinism, according to which the majority of actionable mutations present in metastases can be discovered in the primary tumor. Methods: “METAMORPH” is an ongoing prospective cohort study of women with suspected or confirmed recurrent breast cancer enrolled prior to starting a new therapy for recurrent metastatic disease. Biopsies of metastatic lesions were performed under radiologic guidance, and archival primary tumors were subsequently obtained. WES and sWGS were performed to determine coding mutations and aberrant copy-number in metastatic tumors from 67 patients, 33 of which were assayed with corresponding matched primary tumors. Results: Using Bayesian approaches, we find that cancers fit one of two patterns: canonical linear evolution (whereby the metastatic tumor arises from one or more advanced primary tumor subclones) vs. branched evolution (whereby both primary and metastatic tumors develop mutations that go on to become clonal within their respective tumors after the time of dissemination). In cases where tumors show evidence of branched evolution or small subclone dissemination, we expect that a large proportion of mutations may not be represented in both the primary and corresponding metastatic tumors. Indeed, primary-metastatic tumor pairs show substantial discordance at the genomic level, sharing only ˜30% of mutations and ˜28% of copy-number alterations on average. Furthermore, we find that metastatic tumors have decreased clonal heterogeneity, suggesting a history of selection. Indeed, we find clinically relevant mutations that are present exclusively in the primary or the corresponding recurrent metastatic tumor, as well as genes that are recurrently altered in metastatic tumors, such as amplification of SRC-1, loss of genes encoding CDK inhibitors, and alterations in JAK1/2/3.Finally, compared to the primary tumors from which they arose, metastatic tumors exhibit increased frequencies of alterations in several discrete pathways, including those involving the extracellular matrix as well as PI3K/AKT/mTOR, estrogen, and HER2 signaling. Conclusions: The low degree of genomic concordance between primary and metastatic tumors due to evolutionary distance, as well as the presence of activating and targetable mutations specifically in metastatic tumors, suggests that there is value in comprehensively characterizing metastatic tumors to inform patient treatment and identify novel targets underlying breast cancer progression. Citation Format: Paul MR, Pan T-C, Pant D, Belka GK, Chen Y, Shih N, Lieberman D, Morrissette JJD, Soucier-Ernst D, Clark C, Stavropoulos W, Maxwell K, Feldman M, DeMichele A, Chodosh LA. Evolutionary history and genomic landscape of metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD8-04.