Single nucleotide polymorphisms (SNPs) of the platinum pharmacogenetic and VEGF pathways: Association with survival of platinum-treated stage IV non-small cell lung cancer (NSCLC) patients
| Autor: | Ronald Feld, Devalben Patel, Kevin Boyd, Nicole Perera, Sevtap Savas, Dangxiao Cheng, Natasha B. Leighl, Xin Qiu, Zhuo Chen, Wei Xu, Sharon Marsh, Prakruthi R. Palepu, Frances A. Shepherd, Geoffrey Liu, Qin Kuang, Xiaoping Qiu, Marjan Emami, Sinead Cuffe, Ming-Sound Tsao, Abul Kalam Azad |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
biology business.industry DNA repair VEGF receptors chemistry.chemical_element Single-nucleotide polymorphism Bioinformatics medicine.disease Stage IV non-small cell lung cancer Multiple drug resistance Oncology chemistry biology.protein Cancer research Medicine Platinum business Lung cancer Pharmacogenetics |
| Zdroj: | Journal of Clinical Oncology. 30:7586-7586 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2012.30.15_suppl.7586 |
| Popis: | 7586 Background: Two potentially important host pathways in lung cancer systemic therapy are: (i) the pharmacogenetic pathway of platinum agents (DNA repair, metabolism, and multidrug resistance genes); and (ii) the vascular endothelial growth factor (VEGF) pathway. We investigated the relationship between SNPs in these two pathways and clinical outcome in platinum-treated NSCLC patients. Methods: 188 platinum-treated Stage IV NSCLC patients underwent SNP genotyping for the platinum-related (48 SNPs in 7 genes) and VEGF (64 SNPs in 3 genes) pathways. SNPs were selected from the literature and through tagging. Association of SNPs and overall (OS) and progression free survival (PFS) were assessed using multivariate Cox proportional hazards models. Results: 72% were Caucasian; 73%, adenocarcinoma; 92%, ECOG PS 0-1; median age, 60 years; 54% received > one line of systemic therapy; 10% received anti-VEGF therapy/placebo; Median OS, 1.3 yrs; median follow up, 2.2 yrs. The top significant SNPs in the platinum-related pathway were in ABCC2 (rs8187710 and rs2756109, r2=0.68). The G variants of the top SNP, ABCC2 rs8187710 (4554G>A), were associated with worse OS (adjusted hazard ratio [aHR], 2.62; 95%CI: 1.5-4.5; p=0.0005) and PFS (aHR, 1.97; 95%CI: 1.2-3.4; p=0.01). Functionally, 4554G>A impairs ATP-ase activity and is associated with higher cellular accumulation of ABCC2 substrates [PMID: 22027652]; furthermore, ABCC2 expression is associated with cisplatin resistance and clinical outcome in other cancers [PMID: 17145840]. Within the VEGF pathway, the top significant SNPs were in the same haplotype block of VEGFR1/FLT1 (rs1324057, rs7324547, r2=1.0): for rs1324057, the aHR for OS was 1.59 (95%CI 1.2-2.1); p=0.001; and the aHR for PFS, 1.48 (95%CI 1.1-1.9); p=0.004. VEGFR1/FLT1 rs7324547 has been associated with esophageal cancer risk [PMID: 21751195], but has not been assessed in lung cancer. Conclusions: SNPS of the VEGFR1 and ABCC2 genes are strongly associated with OS and PFS in this cohort of platinum-treated advanced NSCLC patients. Future studies should assess whether these are predictive or prognostic markers. |
| Databáze: | OpenAIRE |
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