Whole-genome sequencing based assessment of HER2 focal amplification for precision oncology of breast cancers.

person Ryul Kim Genome Insight Inc., San Diego, CA info_outline Ryul Kim, Joonoh Lim, Hansol Park, Seongyeol Park, Baek-Lok Oh, Sangmoon Lee, Ji-Yeon Kim, Seok Jin Nam, Seok Won Kim, Jeong Eon Lee, Jonghan Yu, Ji In Ryu, Jeong Seok Lee, Minsuk Kwon, Jeongmin Lee, Yeon Hee Park, Young Seok Ju

Authors person Ryul Kim Genome Insight Inc., San Diego, CA info_outline Ryul Kim, Joonoh Lim, Hansol Park, Seongyeol Park, Baek-Lok Oh, Sangmoon Lee, Ji-Yeon Kim, Seok Jin Nam, Seok Won Kim, Jeong Eon Lee, Jonghan Yu, Ji In Ryu, Jeong Seok Lee, Minsuk Kwon, Jeongmin Lee, Yeon Hee Park, Young Seok Ju Organizations Genome Insight Inc., San Diego, CA, Samsung Medical Center, Seoul, South Korea, Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, Seoul, South Korea, Samsung Medical Center, Gangnam-Gu, South Korea, Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, Ajou University, Suwon-Si, South Korea, The Catholic University of Korea Seoul St. Mary's Hospital, Seoul, South Korea Abstract Disclosures Research Funding No funding received None. Background: Focal oncogene amplification confers a growth advantage to tumor cells and drives cancer evolution. Herein, we aimed to explore focally amplified HER2 in breast carcinomas. Methods: We performed whole genome sequencing (WGS) and whole-transcriptome sequencing (WTS) in 787 breast cancer samples. HER2 focal amplification was defined as having a segment length less than 3Mbp and ≥4 higher copy number than the surrounding region. Results: Most of the patients were premenopausal women (n = 574, 72.9%) with a median age of 37 (range 21-76) years. We identified 57 (58.8%) and 27 (5.0%) samples with HER2 focal amplification in HER2-positive (n = 97) and even HER2-negative (n = 536) by immunohistochemistry (IHC) and in-situ hybridization (ISH) according to ASCO guideline for breast cancer, respectively. Regardless of HER2-positivity, HER2 focal amplification was significantly associated with higher HER2 RNA expression. Among 28 patients who received six cycles of docetaxel/carboplatin/trastuzumab/pertuzumab neoadjuvant therapy followed by curative surgery, 21 patients had HER2 focal amplification and 14 (66.7%) achieved pathologic complete remission (pCR). Intriguingly, all patients without HER2 focal amplification (n = 7) failed to achieve pCR. HER2 focal amplification showed enrichment of TP53 mutations (OR 0.245, q < 0.001), but was mutually exclusive with GATA3 mutations (OR 2.82, q = 0.055). The mutational spectrums suggested that the activity in APOBEC family of cytidine deaminases were responsible for the somatic single-nucleotide variants of breast cancer with HER2 focal amplification. Compared to samples without HER2 focal amplification, samples with HER2 focal amplification were less likely to have defective homologous recombination DNA repair pathway. HER focal amplifications were closely associated with various types of structural variations. Translocation partners of HER2 were widespread across the entire genome with notable exceptions on chromosome 2, and most of them were close to super-enhancers implying enhancer hijacking as one of mechanisms of HER2 overexpression. Breast cancers with or without HER2 focal amplification showed distinct RNA expression patterns. Notably, activity of genes involved in doxorubicin-resistance and AKT1 signaling were significantly associated with HER2 focal amplification. Conclusions: Our analysis demonstrates that WGS enables better classification of the HER2 amplification status in breast cancer than IHC with ISH, suggesting WGS as a sensitive tool for screening breast cancers for anti-HER2-targeted therapies.