Polymorphisms of DNA-repair genes associated with clinical outcome in metastatic breast cancer (MBC) patients treated with gemcitabine/cisplatin (GC) (California Cancer Consortium)

Abstract

675 Background: DNA repair enzymes may play an important role in determining efficacy of chemotherapy in MBC. In particular, GC combination therapy may be dependent on activity of DNA repair enzymes in host cells, since cisplatin acts by inducing DNA damage. Cancer cells with increased DNA repair capacity may be resistant to GC, and specific genes may be responsible for this increased repair capacity. We examined whether polymorphisms in genes related to DNA repair were associated with clinical outcome in MBC patients treated with GC, enrolled in a parent phase II clinical trial (Ph II-14 A & B). Methods: Fifty-five patients with MBC were evaluated. Patients received the following regimen: 25 mg/m2 cisplatin on days 1–4; 1000 mg/m2 gemcitabine on days 2 and 8 of 21-day cycle. Thirteen polymorphisms in 10 cancer-related genes were tested for association with overall survival, time to tumor progression, and tumor response using a PCR RFLP based assay. Results: Of 55 patients evaluated, there were 17 responders (31%) and 33 non-responders (60%). Five patients (9%) inevaluable for response. Of 33 non-responders, 15 had stable disease, 18 had progressive disease. Median survival: 11.7 months with median follow-up 32.4 months for 4 patients alive at time of analysis. Median progression-free survival: 4.2 months. XPD Lys751Gln polymorphism was associated with overall survival and time to tumor progression (p=0.0003, p=0.006, respectively, log-rank test). Thirty-five patients carried Lys/Lys genotype, of which 29% resopnded. Fourteen patients carried Lys/Gln genotype, of which 54% resopnded. Five patients carried Gln/Gln genotype, with no responders. XRCC3 Thr241Met polymorphism was associated with time to tumor progression and tumor response (p=0.03, p=0.002, respectively). Eighteen patients had Met/Met genotype, of which 47% responded. Twenty-six patients had heterozygous genotype, of which 17% responded. Five patients had homozygous Thr/Thr, of which 100% responded. Conclusions: Our results suggest that polymorphisms in DNA repair genes XPD and XRCC3 may be important markers in predicting clinical outcome in MBC patients treated with GC. Supported by the following NCI grant: N01 CM1701. [Table: see text]