Sorafenib, the first oral anti-angiogenic multikinase inhibitor, is primarily used in the treatment of advanced renal cell carcinoma (RCC), hepatocellular carcinoma, and thyroid cancer. Common toxicities experienced by patients treated with sorafenib limit its use and affect adherence to treatment, reducing sorafenib efficacy. No biomarkers are currently available to identify patients at risk of toxicity.
Metastatic RCC (mRCC) patients (n = 153) treated with sorafenib, as part of the TARGET study (Escudier B, N Engl J Med. 2007), were genotyped for common germline DNA variants in 56 candidate genes. Associations between 5846 variants and grade 2-4 toxicities were analyzed. Patients treated for ≤28 days were excluded. Toxicities included diarrhea, hypertension, hand-foot skin reaction, and/or rash or desquamation. For each toxicity, the worst grade event for each patient was used. After linkage disequilibrium-based pruning, 685 variants were utilized for analysis via a chi-squared test.
Out of 153 patients, 28 (18%) experienced grade ≥2 diarrhea. The A allele of rs917881 (G > A) in the epidermal growth factor receptor (EGFR) gene was associated with an increased risk of grade ≥2 diarrhea (p = 0.00006, p = 0.04 after Bonferroni's correction, odds ratio 3.6). The frequency of grade ≥2 diarrhea was 50% (3/6) in AA, 33% (15/45) in GA, and 10% (10/102) in GG patients. The frequency of grade 3 diarrhea was 8% (4/51) in patients with the A allele (AA + GA) versus 2% (2/102) in patients with the GG genotype. No other variants were significantly associated with sorafenib toxicity after Bonferroni correction.
To our knowledge, this is the first reported study of a genetic basis of sorafenib toxicity. rs917881 is a common intronic variant (17% allele frequency) in EGFR. RAF kinase, a critical component of the EGFR signaling pathway, is a known target of sorafenib. Patients with the rs917881 A allele treated with sorafenib may be at an increased risk for diarrhea as a result of decreased EGFR expression potentiated by sorafenib-induced inhibition of the RAF/MEK/Erk pathway, which regulates chloride secretion (Keely SJ, J Biol Chem. 1998). Replication analyses in additional patient cohorts and functional studies are ongoing.
Clinical trial identification
Legal entity responsible for the study
University of North Carolina at Chapel Hill
National Institutes of Health
C. Pena: Employee of and owns stock in Bayer Healthcare Pharmaceuticals. All other authors have declared no conflicts of interest.