DNA repair gene expression and risk of locoregional relapse in breast cancer patients.
OBJECTIVE
Radiation therapy appears to kill cells mainly by inducing DNA double-strand breaks. We investigated whether the DNA repair gene expression status might influence the risk of locoregional recurrence (LRR) in breast cancer patients.


METHODS
We used a quantitative reverse transcriptase PCR-based approach to measure messenger RNA levels of 20 selected DNA repair genes in tumor samples from 97 breast cancer patients enrolled in a phase III trial (Centre René Huguenin cohort). Normalized mRNA levels were tested for an association with LRR-free survival (LRR-FS) and overall survival (OS). The findings were validated in comparison with those of an independent cohort (Netherlands Cancer Institute (NKI) cohort). Multivariate analysis encompassing known prognostic factors was used to assess the association between DNA repair gene expression and patient outcome.


RESULTS
RAD51 was the only gene associated with LRR in both cohorts. With a median follow-up of 126 months in the CRH cohort, the 5-year LRR-FS and OS rates were 100% and 95% in the 61 patients with low RAD51 expression, compared with 70% and 69% in the 36 patients with high RAD51 expression, respectively (p < 0.001). RAD51 overexpression was associated with a higher risk of LRR (hazard ratio [HR], 12.83; 95% confidence interval [CI], 3.6-45.6) and death (HR, 4.10; 95% CI, 1.7-9.7). RAD51 overexpression was also significantly associated with shorter LRR-FS and OS in the NKI cohort.


CONCLUSIONS
Overexpression of RAD51, a key component of the homologous DNA repair pathway, is associated with poor breast cancer outcome. This finding warrants prospective studies of RAD51 as a prognosticator and therapeutic target.
Le Scodan
Romuald
R
Department of Radiation Oncology, Centre René Huguenin, Saint Cloud, France. lescodan@crh1.org
Cizeron-Clairac
Géraldine
G
Fourme
Emmanuelle
E
Meseure
Didier
D
Vacher
Sophie
S
Spyratos
Frédérique
F
de la Lande
Brigitte
B
Cvitkovic
Frédérique
F
Lidereau
Rosette
R
Bieche
Ivan
I
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy*; D017326:Clinical Trials, Phase III as Topic; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality; D012333:RNA, Messenger / Q000032:analysis*; D051135:Rad51 Recombinase / Q000235:genetics*; D018714:Radiotherapy, Adjuvant; D016032:Randomized Controlled Trials as Topic; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018709:Statistics, Nonparametric
D012333:RNA, Messenger; C495153:RAD51 protein, human; D051135:Rad51 Recombinase