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• W2767581332 abstract "Background: Preclinically, KRAS mutation has been associated with enhanced dependency on the folate metabolism in non-small cell lung cancer (NSCLC). Whether this phenomenon is related to increased sensitivity to anti-metabolites and/or lower thymidylate synthase (TS) levels in KRAS mutant patients (pts) is unknown. Patients and Methods: Pts with EGFR WT nonsquamous advanced NSCLC were retrospectively evaluated at one Center. Only pts with a known KRAS mutation status who were treated with platinum-based chemotherapy as first-line were eligible. One-step RT-PCR was used to evaluate the expression of genes potentially associated with treatment outcome (including TS, ERCC1, RRM1 and BRCA1) in pts with available tissue. Results: KRAS-mutant pts who received platinum/pemetrexed (85/136, 62.5%) had shorter progression-free survival (PFS) (4 vs. 6 months, P = 0.05) and overall survival (OS) (8 vs. 20 months, P = 0.0019) compared to those who received platinum/gemcitabine (51/136, 37.5%). Similarly, a significantly lower overall response rate (28.2% vs 47%, P = 0.02) and disease control rate (50% vs. 72.5%, P = 0.01) was observed for platinum/pemetrexed compared with platinum/gemcitabine. No significant differences in PFS and OS were observed in the KRAS WT group according to the type of platinum-doublet received. When focusing only on pts treated with platinum/pemetrexed, a shorter PFS (4 vs. 6 months, P = 0.01) and OS (8 vs. 16 months, P = 0.0065) were noted for KRAS-mutant pts. On the other hand, among pts treated with platinum/gemcitabine no differences in terms of PFS and OS were observed according to KRAS mutation status. TS, ERCC1, RRM1 and BRCA1 levels were assessed in 93 KRAS-mutant and 93 KRAS WT pts. Pts with KRAS mutation had significantly lower mean expression levels of TS (P = 0.036) and higher mean expression levels of ERCC1 (P = 0.05) while no differences in terms of RRM1 and BRCA1 mean expression levels were observed. In unselected pts those with low TS and RRM1 levels, as assessed by ROC analysis, had a significantly higher probability to bear a KRAS mutation (P = 0.02 and 0.04, respectively). Conclusion: In EGFR WT nonsquamous advanced NSCLCs a poor outcome on platinum/pemetrexed was reported for KRAS-mutant pts, which could not be justified based on TS expression levels. Rather, activation of the KRAS pathway may drive resistance to platinum/pemetrexed regardless of TS levels. Whether platinum/gemcitabine represents the best option in KRAS-mutant pts should be assessed prospectively." @default.
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• W2767581332 date "2017-10-01" @default.
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• W2767581332 title "Efficacy of platinum-based chemotherapy in EGFR WT nonsquamous advanced non-small cell lung cancer (NSCLC) patients: association with KRAS mutation and thymidylate synthase (TS) levels" @default.
• W2767581332 doi "https://doi.org/10.1093/annonc/mdx426.013" @default.
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