Gene aberrations of RRM1 and RRM2B and outcome of advanced breast cancer after treatment with docetaxel with or without gemcitabine.
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.
Department of Pathology, Herlev University Hospital, Copenhagen, Denmark. charlotte.levin.tykjaer.joergensen@regionh.dk.
Charlotte L T
CL
Jørgensen
Bent
B
Ejlertsen
Karsten D
KD
Bjerre
Eva
E
Balslev
Dorte L
DL
Nielsen
Kirsten V
KV
Nielsen
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D056915:DNA Copy Number Variations; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018450:Disease Progression; D000077143:Docetaxel; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009367:Neoplasm Staging; D012262:Ribonucleoside Diphosphate Reductase; D012264:Ribonucleotide Reductases / Q000235:genetics* / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D000093542:Gemcitabine
D018797:Cell Cycle Proteins; D043823:Taxoids; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; D000077143:Docetaxel; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D000093542:Gemcitabine