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KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy.

ABSTRACT: Bevacizumab, combined with platinum-based chemotherapy, has been widely used in the treatment of advanced-stage lung adenocarcinoma (LADC). Although KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation is the most common genetic alteration in human LADC and its role in promoting angiogenesis has been well established, its prognostic and predictive role in the above setting remains unclear. The association between KRAS exon 2 mutational status and clinicopathological variables including progression-free survival and overall survival (PFS and OS, respectively) was retrospectively analyzed in 501 Caucasian stage IIIB-IV LADC patients receiving first-line platinum-based chemotherapy (CHT) with or without bevacizumab (BEV). EGFR (epidermal growth factor receptor)-mutant cases were excluded. Of 247 BEV/CHT and 254 CHT patients, 95 (38.5%) and 75 (29.5%) had mutations in KRAS, respectively. KRAS mutation was associated with smoking (p = 0.008) and female gender (p = 0.002) in the BEV/CHT group. We found no difference in OS between patients with KRAS-mutant versus KRAS wild-type tumors in the CHT-alone group (p = 0.6771). Notably, patients with KRAS-mutant tumors demonstrated significantly shorter PFS (p = 0.0255) and OS (p = 0.0186) in response to BEV/CHT compared to KRAS wild-type patients. KRAS mutation was an independent predictor of shorter PFS (hazard ratio, 0.597; p = 0.011) and OS (hazard ratio, 0.645; p = 0.012) in the BEV/CHT group. G12D KRAS-mutant patients receiving BEV/CHT showed significantly shorter PFS (3.7 months versus 8.27 months in the G12/13x group; p = 0.0032) and OS (7.2 months versus 16.1 months in the G12/13x group; p = 0.0144). In this single-center, retrospective study, KRAS-mutant LADC patients receiving BEV/CHT treatment exhibited inferior PFS and OS compared to those with KRAS wild-type advanced LADC. G12D mutations may define a subset of KRAS-mutant LADC patients unsuitable for antiangiogenic therapy with BEV.

SUBMITTER: Ghimessy AK

PROVIDER: S-EPMC6827133 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy.

Ghimessy Aron Kristof AK Gellert Aron A Schlegl Erzsebet E Hegedus Balazs B Raso Erzsebet E Barbai Tamas T Timar Jozsef J Ostoros Gyula G Megyesfalvi Zsolt Z Gieszer Balazs B Moldvay Judit J Renyi-Vamos Ferenc F Lohinai Zoltan Z Hoda Mir Alireza MA Klikovits Thomas T Klepetko Walter W Laszlo Viktoria V Dome Balazs B

Cancers 20191009 10

Bevacizumab, combined with platinum-based chemotherapy, has been widely used in the treatment of advanced-stage lung adenocarcinoma (LADC). Although KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation is the most common genetic alteration in human LADC and its role in promoting angiogenesis has been well established, its prognostic and predictive role in the above setting remains unclear. The association between KRAS exon 2 mutational status and clinicopathological variables inc ...[more]

PMID: 31600989

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Project description:BackgroundAlthough the platinum regimen is adopted widely nowadays in spite of the excessive side effects, there is still no international standard for palliative chemotherapy of advanced gastric cancer. This meta-analysis assessed the efficacy and tolerability of platinum versus non-platinum chemotherapy as first-line palliative treatment in patients with inoperable, advanced gastric cancer.MethodsRandomized phase II and III clinical trials on first-line palliative chemotherapy in inoperable, advanced gastric cancer were identified by electronic searches of PubMed, Embase, and the Cochrane Controlled Trial Register, and hand searches of relevant abstract books and reference lists. Response rates, overall survival, and toxicity were analyzed. Depending on whether new-generation agents (S-1, taxanes and irinotecan) were utilized, the non-platinum regimens were divided into two subgroup.ResultsCompared to non-platinum regimens containing new-generation agents, the use of platinum-based regimens was associated with better response (risk ratio (RR) = 1.94, 95%CI[1.48, 2.55], p<0.001), an increase of overall survival (hazard ratio (HR) = 0.85, 95%CI[0.78, 0.92], p<0.001), a higher risk of hematological and non-hematological toxicity. No statistically significant increase in response (RR = 1.03, 95%CI [0.85, 1.24], p = 0.76) or overall survival (HR = 1.07, 95%CI [0.88, 1.30], p = 0.49) was found when platinum therapies were compared to new-generation agent based combination regimens. The toxicity of platinum-based regimens was significantly higher for hematologic toxicity, nausea and vomiting, and neurotoxicity, but not for diarrhea and toxic death rate.ConclusionNew-generation agent based combination regimens achieved similar response rate and overall survival as platinum-based therapy that had generally higher side effects. S-1, taxanes and irinotecan seemed to be valid options for patients with inoperable, advanced gastric cancer as first-line chemotherapy.

Project description:ObjectiveAngiogenesis plays an important role in the growth and metastasis of non-small cell lung cancer (NSCLC). Bevacizumab is a humanized monoclonal antibody that mainly acts on vascular endothelial growth factor A (VEGFA). Kinase insert domain receptor (KDR) is the most important target of VEGFA. The aim of present study was to investigate the influence of KDR genetic variation on the efficacy and safety of patients with advanced NSCLC receiving first-line bevacizumab plus chemotherapy regimen.MethodsA total of 169 patients with advanced NSCLC who received bevacizumab combined with chemotherapy were recruited in this study. Clinical outcome of the regimens was evaluated in the hospital. Peripheral blood and biopsy tissue specimens of patients were collected for the genotyping of KDR genetic variation and KDR mRNA expression, respectively. The association between KDR genotype status and other variables were analyzed. Univariate analysis of genotype status and prognosis was implemented using the Kaplan-Meier survival analysis method. Multivariate Cox regression analysis was performed to adjust the confounding factors.ResultsOf the polymorphisms analyzed, only V297 L was of clinical significance. The prevalence of V297 L among the study population were as follows: CC genotype 123 cases (72.8%), CT genotype 41 cases (24.3%), TT genotype 5 cases (2.9%). The minimum allele frequency is 0.15. The distribution frequencies of the 3 genotypes corresponded with Hardy-Weinberg equilibrium (P = 0.489). Patients with TT and CT genotypes were merged in the subsequent comparison of clinical outcomes. The analysis of efficacy exhibited that the objective response rates (ORR) of patients with CC genotype and CT/TT genotypes were 52.8% and 47.8% (P = 0.561), respectively. Prognosis indicated that the median progression free survival (PFS) of patients with CC genotype and CT/TT genotype were 8.9 and 5.5 months, respectively (P = 0.006). The median OS of the 2 genotypes were 20.0 and 14.9 months, respectively (P = 0.021). Adjusted in multivariate Cox regression analysis of PFS, CT/TT genotypes were an independent factor for PFS [hazard ratio (HR) = 1.59, P = 0.011). Safety profile according to genotype status of V297 L failed to find significant difference. Interestingly, the expression of KDR mRNA of patients with CT/TT genotype was significantly higher than that of patients with CC genotype in the 58 cancer tissue specimens (P < 0.001).ConclusionThe clinical comes of patients with advanced NSCLC receiving first-line bevacizumab plus chemotherapy regimens might be impacted by polymorphism V297 L through mediating the mRNA expression of KDR.

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KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy.

Publications

KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy.

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