Genomic Profiling Comparison of Germline BRCA and Non-BRCA Carriers Reveals CCNE1 Amplification as a Risk Factor for Non-BRCA Carriers in Patients With Triple-Negative Breast Cancer

Abstract

Background: Differences in genomic profiling and immunity-associated parameters between germline BRCA and non-BRCA carriers in TNBC with high tumor burden remain unexplored. This study aimed to compare the differences and explore potential prognostic predictors and therapeutic targets. Methods:The study cohort included 21 consecutive TNBC cases with germline BRCA1/2 mutations and 54 non-BRCA carriers with a tumor size ≥ 2 cm and/or ≥1 affected lymph nodes. Differences in clinicopathological characteristics and genomic profiles were analyzed through next-generation sequencing. Univariate Kaplan-Meier analysis and Cox regression model were applied to survival analysis. Immunohistochemistry was used to confirm the consistency between CCNE1 amplification and cyclin E1 protein overexpression.Results: The cohort included 16 and five patients with germline BRCA1 and BRCA2 mutations, respectively. Patients with germline BRCA1/2 mutations were diagnosed at a significantly younger age and were more likely to have a family history of breast and/or ovarian cancer. Six non-BRCA carriers (11.11%) carried germline mutations in other cancer susceptibility genes, including five mutations in five homologous recombination repair (HRR) pathway genes (9.26%) and one mutation in MSH3 (1.85%). Somatic mutations in HRR pathway genes were found in 22.22 and 14.29% of the non-BRCA and BRCA carriers, respectively. PIK3CA missense mutation (p = 0.046) and CCNE1 amplification (p = 0.2) were found only in the non-BRCA carriers. The median tumor mutation burden (TMB) was 4.1 Muts/Mb, whereas none of the cases had high microsatellite instability (MSI). BRCA status did not affect disease-free survival (DFS, p = 0.15) or overall survival (OS, p = 0.52). CCNE1 amplification was an independent risk factor for DFS in non-BRCA carriers with TNBC (HR 13.07, 95% CI 2.47-69.24, Huang et al.BRCA and Non-BRCA Carrier Genomic Profiling p = 0.003). Consistency between CCNE1 amplification and cyclin E1 protein overexpression was confirmed with an AUC of 0.967 for cyclin E1 signal intensity.Conclusions: We found differences in genetic alterations between germline BRCA and non-BRCA carriers with TNBC and a high tumor burden. TMB and MSI may not be suitable predictors of TNBC for immune checkpoint inhibitors. Notably, CCNE1 amplification is a novel potential prognostic marker and therapeutic target for non-BRCA carriers with TNBC. Cyclin E1 may be used instead of CCNE1 to improve clinical applicability.

High cyclin E1 protein, but not gene amplification, is prognostic for basal‐like breast cancer

“…CCNE1 amplification was associated with poor progression‐free survival in a small cohort of trastuzumab‐treated HER2+ breast cancers ( n = 34) [25], but not in a similar study of 185 patients [42]. In a cohort of 54 triple‐negative breast cancers (TNBC) without BRCA1/BRCA2 mutations, CCNE1 amplification detected by targeted exome sequencing was associated with poor disease‐free survival, although not poor overall survival [26]. In the study of Zhao et al on chemotherapy‐treated TNBC disease ( n = 59), which includes some BLBC cases, CCNE1 amplification was associated with poor overall survival [27].…”

“…Meta-analysis identifies that CCNE1 amplification and cyclin E1 protein expression are both prognostic for HGSOC, but only cyclin E1 protein expression is prognostic for BLBC Cyclin E1 protein and CCNE1 amplification have been reported as prognostic markers in subtypes of breast cancer [25][26][27] and in HGSOC, which has many similarities to BLBC. The kConFab, TCGA, and Metabric BLBC cohorts are small and hence underpowered for survival analyses, and the kConFab cohort also has inherent bias as it is highly enriched for mutation carriers for BRCA1 and BRCA2.…”

Genomic copy number alterations as biomarkers for triple negative pregnancy-associated breast cancer

“…Cyclin E1 (CCNE1) plays a critical role in cell cycle regulation, DNA replication, chromosome segregation, and G1 to S-phase transition [50]. CCNE1 overexpression and gene amplification have both been associated with poor prognosis in triple negative breast cancer [51][52][53] as well as epithelial ovarian cancer [54]. In ovarian cancer, the near mutual exclusivity of homologous recombination pathway mutations and CCNE1 amplification generally results in resistance to platinum-based cytotoxic chemotherapies and ineffective Poly (Adenosine Diphosphate (ADP)-Ribose Polymerase (PARP) inhibition [54].…”

Liquid Biopsy as a Diagnostic and Prognostic Tool for Women and Female Dogs with Breast Cancer

“…CCNE gene amplification is highly associated with the development of BC, especially TNBC [35]. According to Huang et al [7], CCNE1 amplification represents an independent risk factor in non-BRCA carriers with TNBC. Moreover, Zhao et al [35] reported that CCNE1 amplification may confer resistance to chemotherapy and is associated with poor overall survival in patients with TNBC.…”

“…BC is a complex disease encompassing several distinct entities at the molecular and clinical presentation. Hereditary BC is represented mainly by mutations in the BRCA1 and BRCA2 genes [6,7] and accounts for only a small percentage of cases; otherwise, most BCs are sporadic and result from the accumulation of somatic changes [8]. Recent advances in sequencing-based technologies have provided understanding of genetic changes and deregulation of oncogenic signaling pathways, involving growth signaling, stress-related response, metabolism, and cell-cell communication, which affect the growth and progression of cancer.…”