Low Recombination Proficiency Score (RPS) Predicts Heightened Sensitivity to DNA-Damaging Chemotherapy in Breast Cancer.
Purpose:Molecular-based cancer tests have been developed to augment the standard clinical and pathologic features used to tailor treatments to individual breast cancer patients. Homologous recombination (HR) repairs double-stranded DNA breaks and promotes tolerance to lesions that disrupt DNA replication. Recombination Proficiency Score (RPS) quantifies HR efficiency based on the expression of four genes involved in DNA damage repair. We hypothesized low RPS values can identify HR-deficient breast cancers most sensitive to DNA-damaging chemotherapy.Experimental Design:We collected pathologic tumor responses and tumor gene expression values for breast cancer patients that were prospectively enrolled on clinical trials involving preoperative chemotherapy followed by surgery (N= 513). We developed an algorithm to calculate breast cancer-specific RPS (RPSb) values on an individual sample basis.Results:Low RPSbtumors are approximately twice as likely to exhibit a complete pathologic response or minimal residual disease to preoperative anthracycline-based chemotherapy as compared with high RPSbtumors. Basal, HER2-enriched, and luminal B breast cancer subtypes exhibit low RPSbvalues. In addition, RPSbpredicts treatment responsiveness after controlling for clinical and pathologic features, as well as intrinsic breast subtype.Conclusions:Overall, our findings indicate that low RPS breast cancers exhibit aggressive features at baseline, but they have heightened sensitivity to DNA-damaging chemotherapy. Low RPSbvalues in basal, HER2-enriched, and luminal B subtypes provide a mechanistic explanation for their clinical behaviors and genomic instability. RPSbaugments standard clinical and pathologic features used to tailor treatments, thereby enabling more personalized treatment strategies for individual breast cancer patients.Clin Cancer Res; 23(15); 4493-500. ©2017 AACR.
Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois.|Ludwig Center for Metastasis Research, University of Chicago, Chicago, Illinois.
Sean P
SP
Pitroda
Center for Research Informatics, University of Chicago, Chicago, Illinois.
Riyue
R
Bao
Center for Research Informatics, University of Chicago, Chicago, Illinois.
Jorge
J
Andrade
Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois.|Ludwig Center for Metastasis Research, University of Chicago, Chicago, Illinois.
Ralph R
RR
Weichselbaum
Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois. pconnell@radonc.uchicago.edu.
Philip P
PP
Connell
D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D042822:Genomic Instability / Q000187:drug effects; D059765:Homologous Recombination / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D018365:Neoplasm, Residual / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D057234:Preoperative Period
D018943:Anthracyclines