Abstract P4-07-04: PARP1/2 inhibition in a subset of triple negative breast cancer (TNBC) patient-derived tumor xenografts (PDX) identifies predictive biomarkers of response

Abstract

Abstract Background: BRCA1/2 mutation carriers (gBRCA) have a higher risk of breast or ovarian cancer, since BRCA1/2 mutation results in impaired high-fidelity DNA repair by homologous recombination (HR) and subsequently genetic instability. In non-gBRCA TNBC, HR deficiency occurs at the somatic level, by means of BRCA1 mutation, BRCA1 epigenetic loss or mutation in other HR-associated genes. Because PARP1/2 inhibitors (PARPi) are well-tolerated and active anti-cancer agents in the advanced setting of gBRCA tumors, we sought to expand their applicability by identifying response biomarkers in TNBC. Methods: We have assessed the antitumor response of the PARP1/2 inhibitor olaparib as single agent in a panel of 12 primary and advanced TNBC PDX models. On PDXs exhibiting primary sensitivity to olaparib, we have developed models of acquired resistance by continuous exposure to the drug and identifying progression on treatment. We have characterized the models through targeted sequencing and the analysis of the hypermethylation and expression levels of BRCA1 transcript to find potential correlates of drug-sensitivity. Results: Three out of 12 PDXs (25%) treated with single agent olaparib, exhibit tumor regression or disease stabilization. BRCA1 is hypermethylated in two of these PARPi-sensitive TNBC PDX models and is associated with loss of BRCA1 mRNA expression. The third PARPi-sensitive TNBC PDX harbors a frameshift, heterozygous PALB2 mutation, which is no longer detected in the acquired resistance PDX model. Acquired resistance in the hypermethylated PDXs is under study as well as the duration of response compared to gBRCA PDX models. Conclusions: Our study highlights that somatic HR-deficiency is frequent in TNBC and provides the basis of sensitivity to PARPi. Citation Format: Serra V, Cruz C, Bruna A, Ibrahim YH, Vivancos A, Vivancos A, Nuciforo P, Bellet M, Gómez P, Pérez JM, Saura C, Vidal M, Serres X, Rueda OM, Peg V, Caldas C, O'Connor MJ, Baselga J, Cortés J. PARP1/2 inhibition in a subset of triple negative breast cancer (TNBC) patient-derived tumor xenografts (PDX) identifies predictive biomarkers of response. [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 P4-07-04.