The K751Q polymorphism of XPD gene in lung cancer patients receiving platinum-based chemotherapy

Abstract

2500 Background: Cisplatin and derivatives represent the cornerstone drugs in lung cancer treatment. Nevertheless, treatment related toxicities are sometime relevant and survival is still limited. Platinum-based compounds act by forming DNA adducts and cross-links which are recognized and repaired through the NER repair pathway. The efficacy of platinum therapy may be affected by polymorphisms of the XPD protein, an essential participant in transcription-coupled repair. We have prospectively investigated the A>C Single Nucleotide Polymorphism (SNP) at exon 23, which results in a K751Q substitution, because of its high allele frequency and loss of functional activity. Methods: 196 consecutive lung cancer patients were prospectively enrolled: 82% males, 46% currently and 37% previous smokers, 82% non-small cell lung cancer. Among them, 128 out of 196 received cisplatin or derivatives, mainly in combination with gemcitabine. The control group was represented by 181 healthy medical students. As December 2003 median follow up period is 170 days. The SNP was characterized by digesting the amplified exon 23 with PstI using PCR-RFLP technique Results: Patients genotype frequencies (KK 42%, K/Q 46%, Q/Q 12%) were not significantly different from those observed in healthy volunteers (K/K 38.4%, K/Q 43.4%, Q/Q 18.2%). The XPD genotype was not associated with response to platinum-treatment and the smoking habit. In QQ homozygotes, relapses were more frequent, though not significantly (Odds Ratio= 2.7 p= 0,19), while deaths during follow up were significantly more frequent (35% vs 9% in KQ and 13% in KK, O.R of QQ vs KQ+KK= 4.5, 95% C.I. 1.4–14.4, p= 0.007). At the multivariate analysis the increased risk of death was confirmed after adjusting the XPD genotype for histological subtype. Conclusions: The XPD K751Q polymorphism may be an important marker associated with some aspects of the response to platinum chemotherapy, and may predict the non-responsiveness in a subgroup of patients who should be addressed to alternative non-platinum based treatments. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Italian Research Council