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Editorial Comment to Effect of improved systemic therapy on patient survival in metastatic non‐clear‐cell renal cell carcinoma

A greater understanding of molecular biology has led to major breakthroughs in medical treatment for patients with metastatic renal cell cancer (mRCC). Various agents, including inhibitors of vascular endothelial growth factor and mammalian target of rapamycin, are available as a result of the first breakthrough in mRCC therapy. In addition, as the second breakthrough, immune checkpoint inhibitors and their combination therapies are being rapidly introduced in mRCC clinical practice in Japan, dramatically changing the therapeutic strategy for mRCC. As a urologist, I have observed that treatment outcomes are improving. However, the fact that RCC is a heterogeneous disease must be kept in mind. Treatment strategy is fundamentally constructed on the basis of the results of various randomized phase III clinical trials carried out in patients with clear cell RCC (ccRCC). As such, there remains a paucity of information relating to whether or not the therapeutic outcomes of patients with metastatic non-ccRCC have truly been improved. In this issue of the International Journal of Urology, Ishihara et al. clarified the therapeutic outcome of metastatic nonccRCC patients and also investigated whether it was improved by recent advancements in systemic therapy. Among all 38 patients, papillary RCC was the most frequent diagnosis (n = 25, 66%), followed by mucinous tubular and spindle cell carcinoma (n = 3, 8%), and Xp11 translocation RCC (n = 3, 8%). The median overall survival period after the initiation of first-line therapy and the objective response rate was 15.4 months and 13%, respectively. When patients were divided into two groups based on the date of therapy initiation, namely, early (2008–2011, n = 12) and late (2012–2018, n = 26) groups, the median overall survival period was significantly longer in patients in the late group (25.0 months) than in the early group (12.1 months, P = 0.0009). VHL is the gene known to be associated with ccRCC. Due to advances in our understanding of molecular pathology, a significant alteration in the RCC classification has been shown. In non-ccRCC, MET, fumarate hydratase and Birt–Hogg–Dub e genes have been identified as the genes responsible for type 1 and 2 papillary and chromophobe RCCs, respectively. Against this background, ccRCC and non-ccRCC can essentially be considered different diseases. Nevertheless, when tumor types are ordered by their somatic mutation frequency, ccRCC and papillary RCC are located adjoining each other among the various malignancies. In addition, in terms of the deletion and insertion mutation, ccRCC was found to have the highest proportion, followed by papillary and chromophobe RCCs across all tumor types. Therefore, although ccRCC and non-ccRCC are different diseases, they have similar genetic characteristics. To date, the therapeutic strategy for non-ccRCC has fundamentally followed that for ccRCC. Ishihara et al. reported improvements in the survival of metastatic non-ccRCC patients as a result of recent advancements in systemic therapy. Nevertheless, to pursue further improvements in therapeutic efficacy for these patients, prospective studies focusing on the non-ccRCC cohort are necessary.