Abstract
New therapeutic approaches are being developed based on the findings that several genetic abnormalities underlying non-small-cell lung cancer (NSCLC) could influence chemosensitivity. In this study, we assessed whether polymorphisms in genes of nucleotide excision repair (NER) pathway, including ERCC5, ERCC6, MMS19L, CCNH, XPC, RRM1, can affect the tolerability of platinum-based chemotherapy in NSCLC patients. We used AllGloTM probe to assess genotyping and polymorphisms in 388 stage IIIB and IV NSCLC patients treated with platinum-based chemotherapy. MMS19L might be associated with the adverse events of chemotherapy in NSCLC, especially for all grade leucopenia (P = 0.020), all grade jaundice (P = 0.037) and all grade creatinine increasing (P = 0.013). In terms of grade 3/4 adverse events, MMS19L was related with total grade 3/4 adverse events (P = 0.024) and grade 3/4 thrombocytopenia (P = 0.035), while RRM1 was related with total grade 3/4 adverse events (P = 0.047) and grade 3/4 vomiting (P = 0.046). ERCC5 was related with more infection (P = 0.017). We found that some SNPs in NER pathway genes were correlated with toxicity treated with double chemotherapy in advanced NSCLC patients, especially for SNPs of MMS19L, RRM1 and ERCC5.
Highlights
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer related deaths worldwide [1]
We have found some Single Nucleotide Polymorphisms (SNPs) of nucleotide excision repair (NER) genes may be related with severe toxicity in advanced NSCLC patients treated with platinum-based chemotherapy
No patient had received definitive thoracic radiotherapy, whereas 3.6% of the stage IIIB and 4.4% of the stage IV patients were radiated as palliative treatment to relieve symptoms caused by airway obstruction or pain by bone metastasis
Summary
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer related deaths worldwide [1]. Platinum based doublet chemotherapy with any third generation cytotoxic agent (vinorelbine, gemcitabine, paclitaxel, docetaxel, pemetrexed), has improved the survival of advanced NSCLC (stage IIIB or IV). A total of 1207 patients enrolled in the ECOG 1594 study, the results indicated that 85 to 93 percent of patients developed grade 3 to 5 toxicity, in the 1183 evaluable patients. The common adverse events of combination chemotherapy were myelosuppression, infection, febrile neutropenia, cardiac toxicity, renal dysfunction, nausea/vomiting, diarrhea, hypersensitivity, weakness, etc. A total of 1725 patients enrolled in the JMDB (pemetrexed plus cisplatin versus gemcitabine plus cisplatin) phase III study. 39.9 to 48 percent patients experienced grade 3/4 adverse events in TAX 326 study, which enrolled 1218 patients to compare docetaxel plus platinum versus vinorelbine plus cisplatin for advanced NSCLC as first line treatment [4] Hematological grade 3/4 drug-related toxicities (including neutropenia, anemia and thrombocytopenia) were 25 percent and 50 percent, respectively [3]. 39.9 to 48 percent patients experienced grade 3/4 adverse events in TAX 326 study, which enrolled 1218 patients to compare docetaxel plus platinum versus vinorelbine plus cisplatin for advanced NSCLC as first line treatment [4]
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