Abstract P4-07-05: PARP inhibition in breast and ovarian patient-derived tumor xenografts (PDX) harboring germline BRCA1/2 mutations unveils mechanisms of primary and acquired resistance that restore homologous recombination (HR)
Authors: C Cruz, Ld Bustos, A Gris, M Palafox, M Castroviejo, A Llop, B Morancho, O Diez, S Gutiérrez, G Caratú, L Prudkin, A Bruna, C Caldas, MJ O'Connor, IT Rubio, J Arribas, J Baselga, J Cortes, V Serra, J Balmaña
Journal: Cancer Research (2016)

Abstract Background: PARP1/2 inhibitors (PARPi) are active anti-cancer agents in BRCA1 or BRCA2 mutation carriers (BRCA) with advanced breast or ovarian cancer. However, not all BRCA-tumors respond to PARP blockade, and eventually all develop acquired resistance. Little is known about clinically relevant mechanisms of PARPi resistance in BRCA-breast cancer. Here, we sought to identify biomarkers correlating with primary and acquired resistance to PARPi using PDX derived from both the early disease and the metastatic setting. Methods: We have developed a panel of PDX from patients harboring germline BRCA1 or BRCA2 mutations, namely from 12 primary and advanced breast cancer and 1 high-grade serous metastatic ovarian cancer (HGSOC). The antitumor activity of the PARP1/2 inhibitor olaparib as single agent (50 mg/kg) was assessed in all models. To study the mechanisms of acquired resistance, the olaparib-sensitive PDXs were exposed to olaparib for &amp;gt;100 days, until individual tumors regrew. The tumor's capacity to repair DNA double strand breaks was estimated by quantification of the BRCA1 and RAD51 nuclear foci in the S-phase of the cell cycle. We investigated the correlation between the tumor's BRCA1/RAD51 foci formation and sensitivity to olaparib, and also identified potential genetic modifiers of PARPi sensitivity by targeted sequencing. Results: Four out of 13 PDX (31%) treated with single agent olaparib exhibited tumor regression or disease stabilization. Nuclear BRCA1/RAD51 foci formation correlated with PARPi resistance in six BRCA1 PDX models investigated, either with primary or acquired resistance. No reversions in BRCA1/2 mutations were identified as the mechanism of olaparib resistance. We identified four potential genetic modifiers of PARPi sensitivity and the corresponding validating studies will be presented. Conclusions: Among our BRCA PDX, reactivation of HR functionality is a frequent event that is associated with PARPi resistance and seems to occur through mechanisms other than secondary mutations in BRCA1/2 in contrast to what it has been reported for HGSOC. Citation Format: Cruz C, Bustos Ld, Gris A, Palafox M, Castroviejo M, Llop A, Morancho B, Diez O, Gutiérrez S, Caratú G, Prudkin L, Bruna A, Caldas C, O'Connor MJ, Rubio IT, Arribas J, Baselga J, Cortes J, Serra V, Balmaña J. PARP inhibition in breast and ovarian patient-derived tumor xenografts (PDX) harboring germline BRCA1/2 mutations unveils mechanisms of primary and acquired resistance that restore homologous recombination (HR). [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 P4-07-05.