Abstract ES5-1: Predictive gene expression profiles in breast cancer, where are we?

Abstract

Abstract Successful sequencing of the entire human genome offered an enormous potential for improving human health, especially in oncology. Nearly 20 years after successful completion of the human genome project, the Cancer Genome Atlas (TCGA) has catalogued the most common mutations in most cancers, including breast. Further, the technical advances that facilitate the ability to fully analyze both germline and somatic DNA and RNA has resulted in rapid (<4 weeks) and relatively inexpensive (<$3000) assays to emerge. Indeed, the NCI-sponsored Lung MAP and Cancer MATCH, and the ASCO-sponsored TAPUR, trials are now opening in the U.S., testing whether knowledge of somatic genetic changes improves patient outcomes. However, arguably, the most clinically useful product of the Human Genome Project to date has been the emergence of multiparameter gene expression assays that can be used to direct cancer care, particularly in breast cancer. The 21-gene assay was the first of these to be shown to have sufficiently high analytical validity and clinical utility to be used to identify patients with node negative, ER positive early stage breast cancer who, assuming adequate adjuvant endocrine therapy, could be spared the toxicity of adjuvant chemotherapy based on prognosis alone. Subsequently, several other assays have now been reported to be equally satisfactory for this same use context. The Oxford Overview has suggested that adjuvant chemotherapy reduces the odds of distant recurrence and death by approximately 1/3, regardless of initial prognosis. However, many retrospective correlative studies over the last 4 decades have suggested that chemotherapy may have differing relative activities within distinct biological, or more recently designated “intrinsic,” subtypes, based mostly on expression of estrogen receptor and proliferation genes. Preliminary, prospective retrospective studies by the NSABP in B20 and SWOG in S8814 have, indeed, suggested that patients with ER positive breast cancer with low recurrence scores, as determined by the 21-gene assay, not only have better prognosis than those with intermediate or higher RS, but that chemotherapy may simply not work in this category. However, these studies were both confounded by a number of biases. Therefore, before potentially life-saving chemotherapy is with-held from node positive breast cancer patients based on prediction alone, a prospective clinical trial, SWOG S1007 (the RxPonder Trial), was initiated. The primary objective of the RxPonder trial is to determine if women with node positive, ER positive breast cancer with RS <25 may not benefit from adjuvant chemotherapy even if their prognosis is worse than those with node negative disease. This trial, which is now fully accrued, will not only tell us if we can spare yet another group of women from receiving unnecessary or inactive chemotherapy, it also offers the promise of identification of targets that could be further interrogated with newer biological treatments in the future. Citation Format: Hayes DF. Predictive gene expression profiles in breast cancer, where are we?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES5-1.