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Background  The purpose of the present study was to retrospectively evaluate whether copy number changes of the genes encoding the ribonucleotide reductase subunit M1 ( RRM1 ) and/or subunit M2B ( RRM2B ) predict sensitivity to gemcitabine administered in combination with docetaxel compared to single agent docetaxel in advanced breast cancer patients.    Methods  Primary tumor samples from patients randomly assigned to gemcitabine plus docetaxel or docetaxel alone were analyzed for  RRM1  and  RRM2B  copy number changes using Fluorescence  In Situ  Hybridization (FISH) technology with probes covering respectively  RRM1  at 11p15.5 and a reference probe covering the centromere of chromosome 11 (CEN-11), and  RRM2B  at 8q22.3 and a reference probe covering the centromere of chromosome 8 (CEN-8). The assays were validated in a material of 60 normal breast samples. Time to progression (TTP) was the primary endpoint. Overall survival (OS) and response rate (RR) were secondary endpoints. Associations between  RRM1/ CEN-11 and/or  RRM2B /CEN-8 ratios and time-to-event endpoints were analyzed by unadjusted and adjusted Cox proportional hazards regression models. Heterogeneity of treatment effects on TTP and OS according to gene status were investigated by subgroup analyses, and the Wald test was applied. All statistical tests were two-sided.    Results  FISH analysis for both  RRM1  and  RRM2B  was successful in 251 patients.  RRM1  and  RRM2B  aberrations (deletions and amplifications) were observed in 15.9% and 13.6% of patients, respectively.  RRM1  aberrations were associated with a decreased OS in the time interval 1.5-7.4 years (hazard ratio = 1.72, 95% confidence interval = 1.05-2.79, P = 0.03).  RRM2B  aberrations alone or in combination with  RRM1  aberrations had no prognostic impact in terms of TTP or OS. RR was not different by gene status .  No significant differences were detected in TTP or OS within subgroups according to gene status and chemotherapy regimen.    Conclusions  This study demonstrated the presence of  RRM1  and  RRM2B  copy number changes in primary breast tumor specimens. Nevertheless, we found no support of the hypothesis that aberrations of  RRM1  or  RRM2B , neither individually nor in combination, are associated with an altered clinical outcome following chemotherapy with gemcitabine in combination with docetaxel compared to docetaxel alone in advanced breast cancer patients.

Gene aberrations of RRM1 and RRM2B and outcome of advanced breast cancer after treatment with docetaxel with or without gemcitabine