Abstract LB-179: Molecular biomarker profiling of archival primary breast cancers from a Phase 3 adjuvant study of capecitabine in early stage breast cancer patients
Authors: O'Brien Carol Lynn , Wilson Tim R. , Spoerke Jill M. , Xiao Yuanyuan , Savage Heidi , Tam Rachel , Schleifman Erica , Patel Rajesh , Huw Ling , Koeppen Hartmut , Fu Ling , Sumiyoshi Teiko , O'Shaughnessy Joyce , Lackner Mark 
Published: May 2015

Current clinical practice stratifies patients for treatment and enrollment in clinical breast cancer studies based on ER, PR and HER2 status. Emerging data suggest that these three biomarkers do not fully capture the heterogeneity that exists within breast cancer. In addition, understanding the genetic landscape of breast cancer is critical for defining clinically actionable patient subsets that may derive benefit from targeted therapies. PIK3CA and TP53 mutations have previously been reported to be the most common mutations within breast cancer; however the prognostic significance of these alterations, as well as their overlap/exclusivity with other important biomarkers is poorly understood.

USON 01062 (O’Shaughnessy J, et al. Proc SABCS, 2010, abstract S4-2) is a phase III study that evaluated the addition of capecitabine to standard adjuvant chemotherapy. The study did not meet its primary endpoint of 5-year disease-free survival (HR 0.84, p=0.125), but showed improvement in overall survival (HR 0.68, p=0.011). FFPE primary breast cancers were obtained from approximately 2000 of the 2610 patients (pts) enrolled, and here we report results from our comprehensive biomarker analyses on 817 of these pts. Samples were profiled using a multiplexed PCR-based platform to determine somatic mutations in 6 key oncogenes, as well as assayed for 800 breast cancer-related genes encompassing a variety of signaling pathways and published breast cancer signatures. IHC for the proliferation marker Ki67 and the tumor suppressor PTEN was also performed.

Intrinsic subtyping analysis determined that 296 pts’ cancers were basal, 69 were HER2-enriched, 327 were luminal A, 124 were luminal B and 1 was normal-like. Approximately 80% of the triple negative breast cancers (TNBCs) were of the basal subtype, and 80% of the ER+ cancers were of the luminal A and B subtypes. The most heterogeneous group was the HER2-enriched group that was comprised of 60% HER2+ and 30% TN cancers. PIK3CA mutations were found at a frequency of 44% in luminal A, 24% in luminal B, 33% in HER2-enriched and 3% in the basal subtypes. Within the TNBC subset, 42% were basal like 1/2, 21% were immunomodulatory, 15% were mesenchymal stem-like, 13% were mesenchymal-like and 9% were luminal AR.

In conclusion, luminal A breast cancers were the most common subtype treated with chemotherapy on this adjuvant trial that evaluated the effectiveness of the anti-proliferative agent, capecitabine. Intrinsic subtyping and molecular profiling of pts’ primary breast cancer reveals the substantial heterogeneity of early breast cancers, highlighting the challenges in identifying patients who may benefit from adjuvant capecitabine based on standard clinical-pathologic features. Analysis of intrinsic subtyping, Ki67 levels and genomic alterations of these early breast cancer pts will be presented.

Citation Format: Carol Lynn O'Brien, Tim R. Wilson, Jill M. Spoerke, Yuanyuan Xiao, Heidi Savage, Rachel Tam, Erica Schleifman, Rajesh Patel, Ling Huw, Hartmut Koeppen, Ling Fu, Teiko Sumiyoshi, Joyce O'Shaughnessy, Mark Lackner. Molecular biomarker profiling of archival primary breast cancers from a Phase 3 adjuvant study of capecitabine in early stage breast cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-179. doi:10.1158/1538-7445.AM2014-LB-179