Abstract 962: Multiplexed mutational profiling of breast tumor as an efficient clinical tool for personalized breast cancer treatment
Authors: Bardia Aditya , Dias-Santagata Dora , Isakoff Steven J. , Borger Darrell R. , Juric Dejan , Higgins Michaela J. , Moy Beverly , Goss Paul E. , Baselga Jose , Iafrate A John , Ellisen Leif W. 
Published: August 2012

Introduction: Breast cancer is increasingly being recognized as a heterogeneous disease and previous studies have reported various oncogenic mutations in breast cancer specimens. However, a validated methodology for clinical assessment of mutation profiles is lacking. Applying such technologies will be increasingly important to accelerate development of targeted therapies toward tumor-specific oncogene pathways. Utilizing a high-throughput genotyping platform we evaluated the commonly described somatic mutations in tumor tissue among women diagnosed with metastatic breast cancer. Methods: We developed a CLIA (Clinical Laboratory Improvement Amendments) validated, highly sensitive multiplexed PCR-based assay (SNaPshot) to simultaneously identify 130 previously described mutations in 13 cancer genes using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. Data regarding demographics, tumor phenotype based on estrogen and progesterone receptor (ER, PR) status, HER-2 (Human Epidermal growth factor Receptor-2) status, BRCA carrier status, and clinical outcomes, was abstracted from clinical charts. Results: A total of 138 tumors from women with metastatic breast cancer, median age 69 (range 29-82), were analyzed. In this study, 34.7% of tumors had a detectable mutation, with PIK3CA mutation (70.8%) being the most common mutation detected followed by TP53 (27.1%), and Akt (4%). Unanticipated mutations in KRAS and BRAF were observed at lower frequencies. Detectable mutations were seen in all tumor sub-types although the frequency varied by tumor phenotype: ER+/PR+ (34.5%), ER+/PR- (52.6%), HER-2+ (44.4%), and triple negative (23.2%) tumors. Similarly, while the type of mutation varied somewhat by tumor phenotype, the common driver mutations were seen in all tumor subtypes. For PIK3CA mutations: ER+/PR+ (27.7%), ER+/PR- (42.8%), HER-2+ (29.6%), triple negative (6.7%) tumors, and for TP53 mutations: ER+/PR+ (3.6%), ER+/PR- (14.2%), HER-2+ (18.5%) and triple negative (10%) tumors. Correlation with clinical outcomes is ongoing. BRCA1/2 carriers were less likely to have a detectable somatic mutation in their tumor (15.3%) than patients with negative BRCA1/2 status (25.8%). Only 4 patients (2.8%) had more than one detectable somatic mutation. Conclusion: Oncogenic driver mutations can be detected by SNaPshot from routinely-collected FFPE tissue specimens obtained from women seen in the oncology clinic for metastatic breast cancer. While the type and frequency of mutation varies somewhat by tumor phenotype, the common oncogenic mutations are seen in all breast cancer subtypes and are often found in isolation. These findings highlight the necessity for broad tumor mutational analysis, independent of traditional breast cancer subtype, to efficiently tailor personalized therapies in the clinic based on individual tumor genetic profiles.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 962. doi:1538-7445.AM2012-962