Abstract 4820: A clinical test for BRCAness: Using array comparative genomic hybridization to predict benefit of high-dose, platinum-containing chemotherapy in ER-low/HER2-negative breast cancer patients
Authors: Vollebergh Marieke A. , Nederlof Petra M. , Wessels Lodewyk F. , Schmidt Marjanka K. , van Beers Erik , Holtkamp Marjo , Froklage Femke E. , de Vries Elisabeth G.E. , Schrama Jolanda G. , Wesseling Jelle , van de Vijver Marc J. , van Tinteren Harm , de Bruin Michiel , Hauptmann Michael , Rodenhuis Sjoerd , Linn Sabine C. 
Published: February 2011

BACKGROUND: Homologous recombination deficient (HRD) cancer cells are hypersensitive to agents inducing double strand DNA breaks (DSB), such as bifunctional alkylators. BRCA1-mutated breast cancers, which are considered HRD, can be detected with a Comparative Genomic Hybridization classifier. We hypothesized that the BRCA1-classifier could also detect HRD in sporadic tumors (BRCAness) and therefore would predict sensitivity to DSB-inducing agents.

METHODS: We modified a previously developed BRCA1-classifier to identify tumors of metastatic breast cancer (MBC) patients (n=39) with a long progression-free survival after treatment with high dose carboplatin-thiotepa-cyclophosphamide (HD-chemotherapy). We validated this classifier in estrogen-receptor low, HER2-negative tumors of stage-III breast cancer patients (n=77), who had been randomized between adjuvant HD-chemotherapy and conventional chemotherapy. Additionally, we assessed the concordance between the BRCA1-classifier and BRCA1-mutations in the MBC tumors.

RESULTS: The new classifier scored 16/39 tumors as BRCA1-like in the MBC-series (2 of which harbored a BRCA1-mutation). In the adjuvant validation series, patients with BRCA1-like tumors (39/77=51%) benefited more from carboplatin-thiotepa-cyclophosphamide HD-chemotherapy than those with non-BRCA1-like tumors (38/77=49%) (test for interaction p=0.026). HD-chemotherapy strongly decreased the risk of recurrence in patients with BRCA1-like tumors (HR=0.15, p=0.001; 5-year recurrence free survival (RFS) 78% versus 29%), while RFS in the non-BRCA1-like group was not improved by HD-chemotherapy.

CONCLUSION: The BRCA1-classifier is an effective test to identify patients benefiting from intensive therapy with bifunctional alkylators and may therefore recognize BRCAness. In the presence of BRCAness and subsequently in the absence of error-free double strand break repair, alkylating chemotherapy may have targeted the Achilles heel of these tumors resulting in a high recurrence free survival. Although we evaluated only one specific chemotherapy regimen, we speculate that this classifier may also be predictive for other agents/regimens that target HRD, e.g. poly(ADP-ribose)polymerase(PARP)-inhibitors. This exploratory study warrants further investigation and validation, preferably in a prospective randomized controlled trial. Additionally, this study represents a proof-of-concept that may be applicable to other tumor types, including ovarian and prostate cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4820.