mTOR Pathway Mutations and Response to Rapalogs in RCC—Letter

We have read with interest the article by Kwiatkowski and colleagues (1) reporting mTOR pathway activating mutations as possible predictors of mTOR inhibitor response in renal cell carcinoma (RCC). Recent evidence indicate inferior global efficacy of rapalogs compared with new agents; however, these drugs could be the best treatment for a subgroup of adequately selected patients. Kwiatkowski and colleagues (1) using 79 selected RCC cases treated with mTOR inhibitors found that 42% of patients with partial response (PR) had MTOR, TSC1, or TSC2 mutations compared with 11% of nonresponders (patients with disease progression during the first 3 months of therapy; P = 0.03). Interestingly, while TSC2 and MTOR mutation frequencies were similar to TCGA ccRCC (2), TSC1-inactivating mutations were detected in 13% of tumors (1), compared with 0.5% in TCGA (P < 0.0001; 1.5% for stage IV tumors). Differences may arise from patient selection (e.g., 50% TSC1 mutations occurred in poor prognosis patients), and this might influence the study results.

In our prospective cohort of 380 advanced RCC patients treated according to standard practice and accrued by the Spanish Oncology Genitourinary Group from 2007 to 2015, 57 patients received mTOR inhibitors: 81% everolimus, 19% temsirolimus, 86% had ccRCC histology, 62% had intermediate and 38% good prognosis (MSKCC). In 45 cases with FFPE sample successfully sequenced for MTOR, TSC1, and TSC2 coding region (TruSeq Custom Amplicon Kit; Illumina), we found 5 mutations activating mTOR pathway: 1 TSC1, 1 TSC2, and 3 MTOR mutations (2%, 2% and 7%, respectively, similarly to TCGA). The TSC1 mutation patient and one MTOR mutation patient had clear benefit from rapalogs (PR with 11 and 89 months PFS, respectively, both still receiving temsirolimus). Furthermore, in agreement with Voss and colleagues (3) this MTOR mutation was detected in all tumor regions with similar frequency to VHL mutation, suggesting an early event (4). In the remaining 2 patients with MTOR mutations, one had stable disease (SD) with 9 months PFS, the other achieved 3 months PFS. The TSC2 mutation patient had progressive disease (PD) as best response. Thus, 3 (60%) of 5 patients with mutations experienced significant clinical benefit from rapalogs. Among “wild-type” patients, 6 (17%) had PR, 14 (39%) SD, and 16 (44%) PD as best response.

Therefore, despite the differences with Kwiatkowski and colleagues, rapalog outcomes also seem better in patients with MTOR, TSC1, or TSC2 mutations. Still, additional efforts are needed to understand the incomplete correspondence between the genetic profile and mTOR inhibitors response, and to personalize RCC treatment.