Abstract P1-05-18: Genomic copy number alterations (CNA) associated with pCR in HER2-positive (HER2+) early-stage breast cancer (BrCa) patients receiving neoadjuvant trastuzumab (T)

Abstract

Abstract Introduction: Genetic alterations such as amplifications and deletions frequently contribute to tumorigenesis. These alterations can change gene expression which alters the normal cell growth and survival regulatory mechanisms. Characterisation of DNA copy number alterations (CNA) is important to understand cancer progression and response to therapy. The aim of this study is to determine patterns of CNAs in HER2+ early-stage BrCa patients achieving pathological complete response (pCR) to neoadjuvant T therapy. Methods: Retrospective analysis of our database of 95 HER2+ BrCa (stages I-III) who received T neoadjuvantly revealed 46 % (44/95) achieved pCR compared with 53 % (51/95) who did not respond (NR). DNA from pre-treatment tumour biopsy specimens from neoadjuvant T therapy patients was extracted, and array-based comparative genomic hybridization (aCGH, n = 8; 6 pCR:2 NR) was used to identify CNAs, which correlated with pCR. Pathway analysis was then used to identify functionally relevant genes in aberrant regions. Results: aCGH analysis of DNA from pCR and NR identified distinct patterns of CNAs. HER2 amplicon was confirmed by IHC and aCGH in all samples. Although there was no significant difference in the average CNAs between groups (20±17 vs 17±2), there was greater variation in the range of CNAs in pCR (8-56 CNA) compared to NR (15-19 CNA). More gains and amplifications were observed in pCR patients with more deletions in the NR group. The most common chromosomal amplification region included chr8q12.1-q24 with 87.5% of all cases displaying gains. Of the 6 patients who achieved pCR, 50% displayed a deletion in chr9 spanning p24.3-p21.3, consistent with a deletion of tumour suppressor CDKN2A. No aberrations in chr9 were observed in NR cohort. The deleted genomic region contained 65 common protein-coding genes, with the interferon biological pathway as the most significant (p=1.03E-36). Conclusions: Distinct genomic CNAs were observed between patients achieving pCR compared to NR. However, of the 8 pts characterised here, none have relapsed. Follow-up data revealed a relapse rate of 6.8 % (3/44) vs 11.8 % (6/51) in the pCR and NR groups, respectively. To further elucidate the immunological response, we will present CNA data patterns on relapse and response and compare the impact of CNAs, immune-related proteins and pCR as surrogate predictors for outcome. Citation Format: Walsh N, Gullo G, Maguire A, O'Donovan N, Quinn C, Crown J. Genomic copy number alterations (CNA) associated with pCR in HER2-positive (HER2+) early-stage breast cancer (BrCa) patients receiving neoadjuvant trastuzumab (T) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-05-18.