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RESEARCH PRODUCT

Abstract PD3-6: ConvertHER: Evolution of genomic alterations from primary to metastatic breast cancer

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Abstract Background: Changes in breast cancer receptor status over disease progression and treatment have been described to a point that could alter response to therapy. There is growing interest in delivering biomarker/genomically-based targeted therapies. We aimed to determine the concordance of genomic alterations between primary (P) and metastatic (M) breast cancer in a prospective collection study. Methods: Targeted capture and next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 202 cancer relevant genes in 61 pairs (primary and corresponding recurrence/metastasis). Tumors were classified at baseline as [hormone receptor (HR)+/HER2-, HR+/HER2+, HER-/HER2+, and triple negative breast cancer (TNBC)]. We aligned data to human reference assembly hg19 using Burrows-Wheeler Aligner's (BWA) and removed duplicated reads. We identified somatic mutations variants and called copy number alterations (CNA) using an algorithm which reports gain or loss status of each exon. Alterations potentially targetable with established or investigational therapeutics were considered "actionable." Results: Of the 61 cases, 15% changed breast cancer subtype. Of 747 mutations detected in 156 genes, 309 (41%) were discordant. Median number of mutations were 10 (range 6-11) in P and 8 (range 6-10) in M. Most common mutations occurred at NOTCH2, PCLO, MAP3K1, MLL3, NOTCH4, CRIPAK, TP53, PIK3CACSMD1, and FLG. Mutations were less common in HR-/HER2+ tumors in both P and M. Mutation discordance was not different in cases of changed breast cancer subtype (P=.31). Of 986 CNA detected in 173 genes, 758 (77%) were discordant. There was an increased frequency of EGFR1, ERBB2, FGFR3, CRIPAK, MEN1 and WT1 amplifications in M. CNA were less common in HR-/HER2+ tumors in both P and M. CNA discordances were more common in cases of changed breast cancer subtype (P<.0001) and driven by HER2- tumors. Fifty-eight (95%) patients had actionable alterations that could inform targeted treatment options. Conclusion: Deep targeted exome sequencing of cancer-related genes revealed potentially targeted alterations. We found 41% and 77% mutation and CNA discordance between P and M. CNA were more common when breast cancer subtype changed. Citation Format: Ana Maria Gonzalez-Angulo, Ana Lluch, Agda K Eterovic, Angel Guerrero, Xiaofeng Zheng, Ramon Perez, Shuying Liu, José I Chacón, Ken Chen, Silvia Antolin, Gordon B Mills, Jaime Ferrer, Octavio Burgues, Begona Bermejo, Elia Munoz, Rosalia Caballero, Eva Carrasco, Eduardo Martinez, Funda Meric-Bernstam. ConvertHER: Evolution of genomic alterations from primary to metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD3-6.