Data from Breast Cancers with a <i>BRCA1</i>-like DNA Copy Number Profile Recur Less Often Than Expected after High-Dose Alkylating Chemotherapy

Abstract

<div>Abstract<p><b>Purpose:</b> Breast cancers in carriers of inactivating mutations of the <i>BRCA1</i> gene carry a specific DNA copy-number signature (“<i>BRCA1</i>-like”). This signature is shared with cancers that inactivate <i>BRCA1</i> through other mechanisms. Because BRCA1 is important in repair of DNA double-strand breaks through error-free homologous recombination, patients with a <i>BRCA1</i>-like tumor may benefit from high-dose alkylating (HD) chemotherapy, which induces DNA double-strand breaks.</p><p><b>Experimental Design:</b> We investigated a single institution cohort of high-risk patients that received tandem HD chemotherapy schedule comprising ifosfamide, epirubicin, and carboplatin or conventional chemotherapy. We classified copy-number profiles to be <i>BRCA1</i>-like or non–<i>BRCA1</i>-like and analyzed clinical associations and performed survival analysis with a treatment by biomarker interaction design.</p><p><b>Results:</b> <i>BRCA1</i>-like status associated with high-grade and triple-negative breast cancers. <i>BRCA1</i>-like cases benefitted from the HD compared with a conventional regimen on disease-free survival (DFS): [hazard ratio (HR), 0.05; 95% confidence interval (CI), 0.01–0.38; <i>P</i> = 0.003]; distant DFS (DDFS): (HR, 0.06; 95% CI, 0.01–0.43; <i>P</i> = 0.01); and overall survival (OS; HR, 0.15; 95% CI, 0.03–0.83; <i>P</i> = 0.03) after correction for prognostic factors. No such benefit was observed in the non–<i>BRCA1</i>-like cases on DFS (HR, 0.74; 95% CI, 0.38–1.46; <i>P</i> = 0.39), DDFS (HR, 0.79; 95% CI, 0.41–1.52; <i>P</i> = 0.47), and OS (HR, 0.93; 95% CI, 0.52–1.64; <i>P</i> = 0.79). The <i>P</i> values for interaction were 0.01 (DFS), 0.01 (DDFS), and 0.045 (OS).</p><p><b>Conclusions:</b> <i>BRCA1</i>-like tumors recurred significantly less often after HD than conventional chemotherapy. <i>BRCA1</i>-like copy-number profile classification may be a predictive marker for HD alkylating chemotherapy. <i>Clin Cancer Res; 21(4); 763–70. ©2014 AACR</i>.</p></div>