Abstract PL-1: Genome-Directed Therapeutics for Endocrine Therapy Resistant ER+ Breast Cancer

Abstract As a result of improvements in DNA and RNA sequencing techniques the genomic structure of estrogen receptor positive breast cancer is increasingly well documented, but extracting clinically actionable information from these complex data sets has proved fraught with difficulties. Barriers to progress include the lack of pharmacological hypotheses for novel luminal breast cancer tumor suppressor genes (e.g. MAP3K1, MLL3, SF3B1); 2) a lack of a full understanding of interactions between mutation status, the prognosis of ER+ breast cancer, and the effectiveness of endocrine therapy; 3) an inadequate collection of patient-derived xenograft (PDX) models for luminal breast cancer that fully encompass the heterogeneity of the disease; 4) the logistical barriers of developing adjuvant strategies to exploit rare drivers present in less than 5% of tumor samples; 5) insufficient genomic discovery efforts directed towards samples accrued from patients suffering from endocrine therapy resistant disease progression and 6) an incomplete understanding of how complex somatic genotypes drive the biochemical events responsible for the “hallmarks” of luminal cancer. To better address these issues, five areas of investigation will be discussed: 1) somatic mutation diagnosis in DNA from primary breast cancer samples from patients treated with adjuvant tamoxifen and followed for over 20 years; 2) DNA and RNA sequencing of samples accrued from patients treated with neoadjuvant endocrine therapy to define the molecular origins of intrinsic aromatase inhibitor resistance and to identify pharmacological hypothesis; 3) efforts to expand and catalog patient-derived xenografts from ER+ breast cancers, including the use of mass spectrometry-based analysis of their proteomes and phosphoproteomes to expand our knowledge of the biochemistry of individual tumors; 4) a functional and pharmacological investigation of mutations in ESR1, including resistance-activating chromosomal translocations, and 5) the development of a neoadjuvant endocrine therapy strategy that identifies patients with intrinsic endocrine therapy resistance within a month of starting treatment so that they can be triaged to mutation-matched investigational treatment. Citation Format: Matthew J. Ellis. Genome-Directed Therapeutics for Endocrine Therapy Resistant ER+ Breast Cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PL-1.