Chromophobe renal cell carcinoma (chRCC) is the third most frequent kidney cancer histologic subtype, accounting for approximately 5% of all RCC cases. At diagnosis, chRCC is generally confined to the kidney but can metastasize. At advanced stages, clinical options are limited, and the median overall survival for patients with chRCC treated with targeted drugs ranges between 25 and 32 months.1–3 The rapamycin analogs everolimus and temsirolimus are effective anticancer drugs that inhibit mTOR complex 1 (TORC1) signaling.4–6 The mTOR pathway is frequently activated in cancer through activating mutations in the MTOR gene or inactivation of the mTOR-negative regulators TSC1 and TSC2.7,8 In RCC, approximately 10% of clear cell and 5% of papillary and chromophobe subtypes have mutations in MTOR, TSC1, or TSC2.9–11 In addition, inactivation of PTEN is frequent in chRCC. Altogether, genomic targeting of the mTOR pathway occurs in 23% of chRCC cases,11,12 suggesting sensitivity of this RCC subtype to mTOR inhibitors. A recent phase II randomized trial in patients with non–clear cell RCC found that everolimus was associated with a longer median progression-free survival (PFS) than sunitinib for chRCC13; however, the number of cases included was low, stressing the need for additional studies.
Extraordinary responses to mTOR inhibitors have rarely been described in patients with cancer. These responses include a patient with metastatic bladder cancer who experienced a complete response to everolimus for >2 years,14 a patient with platinum- and taxane-refractory urothelial carcinoma treated with pazopanib/everolimus who experienced a complete radiologic response for >14 months,15 and a patient with metastatic anaplastic thyroid cancer with a sustained 18-month response to everolimus.16 In all of these patients, either TSC1/TSC2-inactivating or MTOR-activating mutations were identified. In metastatic chRCC, cases with partial response (PR) to mTOR inhibitors have been described,2,17–22 and in clear cell RCC an overrepresentation of MTOR, TSC1, and TSC2 mutations in patients with a PR to rapalogs was found.23,24 Further studies determining the impact of mutational events on the response to mTOR inhibitors are required.
In this study, we performed a genomic and functional characterization of a metastatic chRCC with an extraordinary response to temsirolimus. Complete remission of the metastatic lesions and an >80% reduction in the size of the primary tumor occurred on temsirolimus treatment, and the patient remained disease-free for >8 years. The mechanism underlying the extraordinary response to temsirolimus was identified by whole-exome sequencing (WES), in vitro functional assessment, and immunohistochemistry.
This study was supported by the Spanish Ministry of Economy and Competitiveness (grant number SAF2015-70820-ERC), by “A 4 EL KILOMETRE,” and by the Michelle Foundation (The Netherlands), TS Association (United Kingdom), and TS Alliance (United States). Juan M. Roldán and María Apellániz-Ruiz are predoctoral fellows of “la Caixa”/CNIO international PhD programme. The authors wish to thank the Centro de Análisis Genómico personnel, and especially Sergi Beltran and Sophia Derdak, for their excellent support in WES, and to the “club a 4 el KM; club de atletismo de les Franqueses del Valles” for support to the work.
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