JNCI Journal of the National Cancer Institute 2014-01-01

Identification and validation of an anthracycline/cyclophosphamide-based chemotherapy response assay in breast cancer.

Jude M Mulligan, Laura A Hill, Steve Deharo, Gareth Irwin, David Boyle, Katherine E Keating, Olaide Y Raji, Fionnuala A McDyer, Eamonn O'Brien, Max Bylesjo, Jennifer E Quinn, Noralane M Lindor, Paul B Mullan, Colin R James, Steven M Walker, Peter Kerr, Jacqueline James, Timothy S Davison, Vitali Proutski, Manuel Salto-Tellez, Patrick G Johnston, Fergus J Couch, D Paul Harkin, Richard D Kennedy

Index: J. Natl. Cancer Inst. 106(1) , djt335, (2014)

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Abstract

There is no method routinely used to predict response to anthracycline and cyclophosphamide-based chemotherapy in the clinic; therefore patients often receive treatment for breast cancer with no benefit. Loss of the Fanconi anemia/BRCA (FA/BRCA) DNA damage response (DDR) pathway occurs in approximately 25% of breast cancer patients through several mechanisms and results in sensitization to DNA-damaging agents. The aim of this study was to develop an assay to detect DDR-deficient tumors associated with loss of the FA/BRCA pathway, for the purpose of treatment selection.DNA microarray data from 21 FA patients and 11 control subjects were analyzed to identify genetic processes associated with a deficiency in DDR. Unsupervised hierarchical clustering was then performed using 60 BRCA1/2 mutant and 47 sporadic tumor samples, and a molecular subgroup was identified that was defined by the molecular processes represented within FA patients. A 44-gene microarray-based assay (the DDR deficiency assay) was developed to prospectively identify this subgroup from formalin-fixed, paraffin-embedded samples. All statistical tests were two-sided.In a publicly available independent cohort of 203 patients, the assay predicted complete pathologic response vs residual disease after neoadjuvant DNA-damaging chemotherapy (5-fluorouracil, anthracycline, and cyclophosphamide) with an odds ratio of 3.96 (95% confidence interval [Cl] =1.67 to 9.41; P = .002). In a new independent cohort of 191 breast cancer patients treated with adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, a positive assay result predicted 5-year relapse-free survival with a hazard ratio of 0.37 (95% Cl = 0.15 to 0.88; P = .03) compared with the assay negative population.A formalin-fixed, paraffin-embedded tissue-based assay has been developed and independently validated as a predictor of response and prognosis after anthracycline/cyclophosphamide-based chemotherapy in the neoadjuvant and adjuvant settings. These findings warrant further validation in a prospective clinical study.