Background and importance Platinum-based doublet-chemotherapy is the standard treatment for non-small cell lung cancer (NSCLC) for epidermal growth factor receptor (EGFR) wild-type patients, which presents high percentages of severe adverse events, such nephrotoxicity (20%–30%).
Nephrotoxicity is characterised by high morbidity and mortality. Cisplatin is one of the major causes of nephrotoxicity. Several studies have shown that vitamin D activation through CYP27B1 and CYP2R1 enzymes is protective against chronic kidney disease among other pathological pathways. However, few studies have focused on the role of vitamin D pathway genetic polymorphisms in nephrotoxicity.
Aim and objectives The aim of this study was to evaluate the influence of CYP27B1 and CYP2R1 gene polymorphisms on nephrotoxicity due to platinum-based chemotherapy in NSCLC.
Material and methods Prospective cohort study. 165 patients diagnosed with NSCLC between 2003 and 2019, followed up until December 2020. CYP27B1 (rs4646536, rs3782130, rs703842, rs10877012) and CYP2R1 (rs10741657) polymorphisms were analysed by real-time polymerase chain reaction (PCR) using TaqMan probes. Nephrotoxicity was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0.
Results Patients’ median age at NSCLC diagnosis was 62 (53–67) years; 73.3% (121/165) men; 69.09% (114/165) stage IIIB-V; 59.39% (98/165) adenocarcinoma; 58.18% (96/165) family history of cancer; 24.24% (40/165) previous lung disease; EGFR status: 10.91% (18/165) mutated. Chemotherapy agents: 18.29% (30/164) gemcitabine; 21.34% (35/164) paclitaxel; 24.39% (40/164); 35.98% (59/164). Nephrotoxicity: 17.58% (29/165).
Patients carrying the CYP27B1-rs4646536 (p=0.0312; OR 0.32; CI95%0.10 to 0.84; AG vs AA); CYP27B1-rs3782130 (p=0.0247; OR 0.22; CI95%0.05 to 0.85; CC vs G); CYP27B1-rs703842 (p=0.0121; OR 0.15; CI95%0.03 to 0.67; CT vs CC) and CYP27B1-rs10877012 (p=0.0239; OR 4.50; CI95%1.17 to 17.2; TT vs G), were associated with nephrotoxicity. However, for CYP2R1-rs10741657 we did not find a statistically significant association.
Conclusion and relevance Our results suggest that rs4646536, rs3782130, rs703842 and rs10877012 influence nephrotoxicity in platinum-based chemotherapy. CYP27B1 is the only enzyme capable of activating vitamin D. Therefore, genetic study of these polymorphisms could be used as a toxicity prediction biomarker in NSCLC patients undergoing platinum-based chemotherapy.
Conflict of interest No conflict of interest
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