We found an association between several proteins involved in hypoxia and sunitinib efficacy. In addition, low VEGFR3 expression was associated with worse outcome and with VEGFR3 rs307826 variant allele, reinforcing VEGFR3 as a marker of sunitinib resistance.
712 Background: Chromophobe renal cell carcinoma (chRCC) is a histologically and molecularly distinct class of rare renal cancer representing less than 5% of the kidney tumors. Molecular knowledge of this disease is limited, as well as prognostic factors for relapse if localized disease or response in the metastatic setting. Methods: From our database form different Spanish Hospitals, we identified a series of 89 chRCC with a localized stage and 3 patients stage IV at first diagnoses. We performed an in-depth characterization of mTOR pathway alterations, through targeted NGS and immunohistochemistry (IHC) of phospho-S6, tuberin and PTEN, and determined their impact on metastasis development and overall survival. Mutations in mitochondria and telomere maintenance genes were also assessed. TCGA kidney chromophobe project (KICH, n=64) was used for validation. Results: TP53, mTOR pathway ( MTOR, TSC2 or TSC1), telomere-related genes ( ATRX, TERT promoter or DAXX) and respiratory chain complex I, were mutated in 28%, 16%, 15% (26, 14, 12 of 87) and 15% (14 of 73) of primary tumors. PTEN and FLCN were mutated in four and three patients, respectively, two with bilateral tumors. IHC of phospho-S6 revealed positive staining in 37% of primary tumors (21 of 57), in association with MTOR, TSC2 and TSC1 mutations (P=0.009). Negative PTEN staining in 82% of cases (46 of 56) suggested PTEN loss as a chRCC characteristic, and was mutually exclusive with MTOR, TSC2 or TSC1 mutations (P=0.001). Weak or negative tuberin staining correlated with TSC2 mutations (P=0.02). Regarding metastasis development, TP53 mutations were enriched in malignant tumors (P=0.018), while telomere-related mutations showed a trend in the same direction. mTOR pathway mutations were associated with worse outcome. Overall survival in multivariable analysis adjusting for tumor stage gave a Hazard Ratio of 6.5 (P=0.009) This association was confirmed in TCGA-KICH (HR=11.9, P=0.05). Conclusions: Our study provides new genomic knowledge of chRCC and identifies novel markers of poor survival. Furthermore, we identified patients with mutations in mTOR pathway genes that showed high sensitivity to mTOR inhibitors.
10546 Background: Sunitinib (Sun) is a multitargeted tyrosine-kinase inhibitor approved for the treatment of renal cell carcinoma (RCC), GIST and pancreatic neuroendocrine tumors (pNETs). It is known that a polymorphism in Sun metabolizing gene CYP3A5, was associated with an increased risk of dose reductions due to toxicity (tox). Additionally, polymorphisms in VEGF-A and VEGFR2 were suggested to increase the risk of hypertension (HT) during treatment (García-Donas, et al. Lancet Oncol 2011). These data have not been validated so far. We aim to assess the value of these polymorphisms as markers of tox using a wide range of solid tumors treated with Sun. Methods: In this non-interventional and retrospective study, DNA was collected from 28 patients with different pathologies (16 pNETs, 5 medullary thyroid carcinomas, 2 NETs of the lung, 2 undifferentiated follicular carcinomas, 1 undifferentiated papillar carcinoma, 1 GIST, and 1 carcinoid of the rectum) treated with Sun in a daily practice setting. Genotyping for CYP3A5*1 allele (rs776746), VEGF-A -2578C>A (rs699947) and VEGFR2 Q472H (rs1870377) was performed. Associations between the genotypes and Sun dose reductions and HT were performed using univariable analyses. Results: In agreement with previous reports, we found that VEGF-A rs699947 conferred a statistically significant increased risk of developing HT during treatment (HR=9.8, 95%CI=1.2-82.0, P=0.034). CYP3A5*1 high metabolizing allele showed a trend towards the increase in the risk of Sun dose reductions due to tox (HR=2.4, 95%CI=0.8-6.8, P=0.11) with a median time to dose reduction of 7.0 months for wild type homozgygous patients and 4.6 months for heterozygous patients. A trend was also found on the relation between VEGF-A rs699947 A/A patients (HR=3.8, 95%CI=0.8-16.8, P=0.080) and dose reduction risk. No significant associations were found for VEGFR2 rs1870377. Conclusions: The present study suggests that VEGF-A rs699947 is a risk factor for Sun HT and has a role in other tox leading to dose reductions. Similarly, CYP3A5*1 shows a trend towards an increased risk of Sun dose reductions. If confirmed, these markers could be used to identify a subset of patients with an increased risk of Sun toxicity.
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