Abstract P2-06-03: Clinicopathologic characteristics and genomic essence analyses revealed estrogen receptor positive, progesterone receptor negative and human epidermal growth factor receptor 2 negative breast cancer to be more basal-like and endocrine resistant
Authors: Liu X , Ma D , Jiang Y-Z , Liu Y-R , Yu K-D , Shao Z-M 
Published: February 2018

Background: Estrogen receptor positive/ progesterone receptor negative/ human epidermal growth factor receptor 2 negative (ER+/PR-/HER2-) tumors define a distinct subtype of ER+ breast cancer, characterized by poor response to endocrine therapy and poor prognosis. The genomic landscape of ER+/PR-/HER2- tumor has yet to be systematically studied,and driver events for tumor progression and endocrine resistance with loss of PR expression are yet to be identified. Methods: We assessed 13,410 ER+/PR-/HER2- patients from Surveillance, Epidemiology, and End Results (SEER), the Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) for clinicopathologic characteristics, survival and genomic analyses. Patients were divided into endocrine-resistant and endocrine-sensitive groups using an endocrine therapy sensitivity score [(0.8*ER+1.2*PGR+BCL2+SCUBE2)/4], and we further explored genomic events enriched in the endocrine-resistant group. Results: Clinicopathologic features and survival outcomes of ER+/PR-/HER2- patients were worse than ER+/PR+/HER2- in SEER and METABRIC cohort. The genomic landscape of ER+/PR-/HER2- tumors revealed them to have more aggressive properties, like a higher percentage of luminal B (29-35%) and basal-like (4-16%) subtypes; more intClust subtypes with high genomic instability (intClust1, 6); more TP53 mutation and less PIK3CA mutation; and more copy number variation events. ER+/PR-/HER2- tumors have more focal amplification events, including 8p11.23 (ZNF703) and 17q23.1 (RPS6KB1) and more focal deletion events, such as 17q21.31 (BRCA1) and 14q24.3 (MLH3). Pathifier pathway analyses showed that up-regulated pathways in ER+/PR-/HER2-tumors included those associated with biosynthesis, metabolism, drug resistance and DNA replications (FDR&lt;0.1). Endocrine sensitivity score for ER+/PR-/HER2- group was significantly lower than ER+/PR+/HER2- group. When split by 1st quartile of endocrine sensitivity score, up to 72.7% of ER+/PR-/HER2- tumors were grouped into the endocrine-resistant group. Mutant-allele tumor heterogeneity (MATH) score is significantly lower in the endocrine-resistant group. Several focal SCNA events were more common in the endocrine-resistant group (P&lt;0.05), including 8q24.21 amplification with only the MYC gene in the “peak” region. Pathways unregulated in the endocrine-resistant group of ER+/PR-/HER2- tumor included MYC pathway and mTORC1 signaling (FDR&lt;0.25). Conclusion: ER+/PR-/HER2- breast cancer was a heterogeneous tumor group and featured more basal-like and luminal B characteristics. The ER+/PR-/HER2- tumors are relatively resistant to endocrine therapy, and MYC pathway enrichment and corresponding 8q24.21 amplification might be one of the drug-resistance mechanisms. Our study provides an overall understanding of the distinct genomic landscape of ER+/PR-/HER2- breast cancer. Further investigations into the pathways activated with the loss of PR expression may provide clues for novel changes in the therapeutic regimens of ER+/PR-/HER2- breast cancer.

Citation Format: Liu X, Ma D, Jiang Y-Z, Liu Y-R, Yu K-D, Shao Z-M. Clinicopathologic characteristics and genomic essence analyses revealed estrogen receptor positive, progesterone receptor negative and human epidermal growth factor receptor 2 negative breast cancer to be more basal-like and endocrine resistant [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 P2-06-03.