Contribution of genetic factors to platinum-based chemotherapy sensitivity and prognosis of non-small cell lung cancer

Abstract

Although platinum-based chemotherapy remains the standard treatment for advanced NSCLC patients, clinical outcomes are poor and most patients develop high-grade toxicities. Genetic factors, such as single nucleotide polymorphisms (SNPs) involved in platinum pharmacodynamics, metabolism and mechanism of action, may account for inter-individual differences shown in effectiveness and toxicity. Polymorphisms in genes involved in DNA repair and others such as PI3K/PTEN/AKT and TGF-β pathways have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with platinum-based chemotherapy. Other cellular processes, like DNA methylation and proliferation have been connected with clinical outcome for platinum-based chemotherapy regimens through folate metabolism and cytokine signaling. The influence of gene polymorphisms in the NER pathway on clinical outcome has been extensively investigated in advanced NSCLC patients treated with platinum-based chemotherapy but contradictory results have been reported. The most recent and thorough meta-analyses have failed to show an association between ERCC1 C118T/C8092A and ERCC5 rs1047768 polymorphisms and response to platinum based chemotherapy. However, other polymorphisms in ERCC2 (Lys751Gln and Asp312Asn) and ERCC5 (rs2094258 and rs2296147) and have been related with overall survival (OS) and progression-free survival (PFS), respectively. The Arg194Trp and Gln399Arg polymorphisms in XRCC1, have also been extensively investigated. Their effects seem to be dependent on ethnicity, and recent meta-analyses have confirmed an association with response in Asian but not in Caucasian patients. The influence on overall response rate (ORR) of the rs861539 polymorphism in XRCC3, part of (DSB) repair pathway, has also been confirmed in a meta-analysis. Finally, SNPs in genes coding proteins of the p53, PI3K, TGF-β, membrane transporters, gluthatione metabolism enzymes and cytokine pathways have been less extensively investigated. Some polymorphisms have been reported to be associated with toxicity or clinical outcome, but data generally come from a limited number of studies and need to be confirmed.

Genetic Polymorphisms and Platinum-Based Chemotherapy-Induced Toxicities in Patients With Lung Cancer: A Systematic Review and Meta-Analysis

“…Findings on genetic polymorphisms that affect platinuminduced toxicities were inconclusive in most studies, and the sample size of most studies was generally small. Polymorphisms in genes encoding the nucleotide excision repair (NER) pathway are among the most clinically relevant genetic determinants with susceptibility to platinum-based toxicities (42). The NER pathway is responsible for repairing DNA intrastrand crosslinks induced by platinum-based chemotherapy, and the most commonly reported candidate gene associated with platinumbased toxicities include ERCC1, XRCC1, and XPD (43).…”

Effect of <i>TOP2A</i> and <i>ERCC1</i> gene polymorphisms on the efficacy and toxicity of cisplatin and etoposide-based chemotherapy in small cell lung cancer patients

“…Small cell lung cancer (SCLC), which is diagnosed in 15-20% of lung cancer patients, progresses rapidly and in many cases distant metastases are detected at the time of disease diagnosis [1][2][3]. The aggressive course of SCLC and its association with smoking limit the possibilities of molecularly targeted treatment, which influences the poor prognosis.…”

“…Lack of genetic predictive factors in SCLC limits the possibilities of personalized treatment. However, there are some promising genetic alterations that may predict efficiency and toxicity of chemotherapy [1,2,4].…”

“…Single nucleotide polymorphisms (SNPs) in DNA repair genes were previously reported as a predictive factors for platinum-based chemotherapy in non-small cell lung cancer (NSCLC) [2]. Moreover, polymorphic variants in DNA repair genes may interact with smoking status as risk factors of lung cancer in non-smokers but protective factors in heavy smokers who have smoked more than 15 pack years during their life [5].…”

Interleukins as new prognostic genetic biomarkers in non-small cell lung cancer

“…Pathologic staging is an essential prognostic factor for NSCLC, but a significantly variability in progression and survival among patients with the same stage of disease have been reported, suggesting other factors may influence NSCLC prognosis [4,25]. Remarkably, genetic alterations, such as single nucleotide polymorphisms (SNPs), have showed to be related with inter-individual differences in recurrence and survival in NSCLC patients [26][27][28][29].…”