Contribution of genetic factors to platinum-based chemotherapy sensitivity and prognosis of non-small cell lung cancer.
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.
UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, Spain; Department of Biochemistry, Faculty of Pharmacy, University of Granada Campus Universitario de Cartuja, s/n, 18071 Granada, Spain. Electronic address: cperezramirez87@gmail.com.
Cristina
C
Pérez-Ramírez
UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, Spain. Electronic address: marisacgarre@gmail.com.
Marisa
M
Cañadas-Garre
Pangaea Biotech, S.L., Hospital Universitario Quirón Dexeus, C/ Sabino Arana, 5-19, 8028 Barcelona, Spain. Electronic address: mamolina@pangaeabiotech.com.
Miguel Ángel
MÁ
Molina
National Cancer Institute, 37 Convent Dr, 37/3060D, Bethesda, United States. Electronic address: Ana_Robles@nih.gov.
Ana I
AI
Robles
Department of Biochemistry, Faculty of Pharmacy, University of Granada Campus Universitario de Cartuja, s/n, 18071 Granada, Spain. Electronic address: mfaus@ugr.es.
María José
MJ
Faus-Dáder
UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, Spain; Department of Pharmacology, Faculty of Pharmacy, University of Granada, Campus Universitario de Cartuja, s/n, 18071 Granada, Spain. Electronic address: mangel.calleja.sspa@juntadeandalucia.es.
Miguel Ángel
MÁ
Calleja-Hernández
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D011379:Prognosis
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds
Non-small cell lung cancer; Platinum based chemotherapy; Polymorphisms; Response; Survival; Toxicity