Abstract
Targeted drug decisions in metastatic renal cell carcinoma are exclusively made on the basis of clinical criteria. We investigated whether these biomarkers (HIF-1α, HIF-2α, CAIX, VEGF, VEGFR1, VEGFR2, VEGFR3, PDGFB, PDGFRA, PDGFRB, CD31, CD44, bcl-xL, KIT, p21, CXCR4, PTEN, (CSF)-1R, RET, and FLT-3) can predictive the different effects between sunitinib and sorafenib treatments and are available to guide targeted drug selection. We enrolled all patients who underwent nephrectomy with postoperative sunitinib- or sorafenib-treatment at our institution from 2007 to 2012. Immunohistochemical approach was applied to assess the potential differential effects of immunostainings between sunitinib- and sorafenib-treated groups. We found that patients with high HIF-2α, CD31 expression showed greater relative PFS and OS benefit and patients with high CAIX expression presented greater relative OS benefit from sunitinib than from sorafenib, patients with high VEGFR1 or PDGFRB expression levels exhibited worse relative PFS benefit from sunitinib than from sorafenib. Namely high HIF-2α, CD31, and CAIX expression levels along with low VEGFR1 and PDGFRB expression levels improved the benefit of sunitinib treatment compared with sorafenib treatment. These results can identify whether patients can benefit more from sunitinib or sorafenib for drug selection guidance, eventually with precision medicine.
Highlights
Metastatic renal cell carcinoma is a chemotherapy-resistant malignancy
We aimed to use the IHC approach to identify predictive markers of drug selection in patients with Metastatic renal cell carcinoma (mRCC)
E.g. 2014 National Comprehensive Cancer Network (NCCN ) Guideline Insights highlighted the important role of KIT or PDGFRA mutation status in treatment decisions of gastrointestinal stromal tumours with imatinib and/or sunitinib[24]; The antibody-drug conjugate trastuzumab emtansine has improved outcomes in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer compared with trastuzumab-based therapy, as demonstrated in phase III studies[25]; BRAF-positive non-small cell lung cancer (NSCLC) is sensitive to Dabrafenib
Summary
Metastatic renal cell carcinoma (mRCC) is a chemotherapy-resistant malignancy. Recent advances in molecular biology have led to the development of several novel agents to treat mRCC. The differential effects of patients treated with differential targeted drugs for mRCC do exist. A number of approaches such as blood-based biomarker, tissue-based biomarker, SNP biomarker, and cellular biomarkers are currently under investigation[2] These markers typically only provide clinicians with risk assessment for a patient based on multiple criteria and are prognostic (i.e. providing information about independent outcome of treatment). The differential effects indicated by these predictive markers are typically compared with placebo or cytokine treatment but not with other targeted drugs. Whether these biomarkers signify similar traits of distinguished therapeutic effects of other targeted drugs remains unclear. Sunitinib or sorafenib inhibition of these receptor tyrosine kinases has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays
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