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-TellezPatrick G. Johnston, Fergus J. Couch, D. Paul Harkin, Richard D. Kennedy

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54 Scopus citations

Abstract

BackgroundThere 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.MethodsDNA 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.ResultsIn 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.ConclusionsA 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.

Original languageEnglish (US)
Article numberdjt335
JournalJournal of the National Cancer Institute
Volume106
Issue number1
DOIs
StatePublished - Jan 24 2014

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Mulligan, J. M., Hill, L. A., Deharo, S., Irwin, G., Boyle, D., Keating, K. E., Raji, O. Y., McDyer, F. A., O'Brien, E., Bylesjo, M., Quinn, J. E., Lindor, N. M., Mullan, P. B., James, C. R., Walker, S. M., Kerr, P., James, J., Davison, T. S., Proutski, V., ... Kennedy, R. D. (2014). Identification and validation of an anthracycline/cyclophosphamide-based chemotherapy response assay in breast cancer. Journal of the National Cancer Institute, 106(1), [djt335]. https://doi.org/10.1093/jnci/djt335