Non-clear cell renal carcinomas: Review of new molecular insights and recent clinical data

Abstract

Non-clear cell renal cell carcinomas (nccRCC) represent a highly heterogeneous group of kidney tumors, consisting of the following subtypes: papillary carcinomas, chromophobe renal cell carcinoma, so-called unclassified carcinomas or aggressive uncommon carcinomas such as Bellini carcinoma, renal cell carcinoma (RCC) with ALK rearrangement or fumarate hydratase-deficient RCC. Although non-clear cell cancers account for only 15 to 30% of renal tumors, they are often misclassified and accurate diagnosis continues to be an issue in clinical practice. Current therapeutic strategy of metastatic nccRCC is based primarily on guidelines established for clear cell tumors, the most common subtype, however this approach remains poorly defined. To date, published clinical trials for all histological nccRCC subtypes have been collectively characterized into one group, in contrast to clear-cell RCC, and given the small numbers of cases, the interpretation of study results continues to be challenging. This review summarizes the available literature for each nccRCC subtype and highlights the lack of supportive evidence from prospective clinical trials and retrospective studies. Future trials should evaluate treatment approaches which focus on a specific histological subtype and progress in treating nccRCC will be contingent on understanding the unique biology of their individual histologies.

Activity of ALK Inhibitors in Renal Cancer with ALK Alterations: A Systematic Review

“…Nevertheless, a considerable effort is still necessary to transform the evolving knowledge in identifying novel RCC entities into more personalized treatments. Indeed, a greater understanding of RCC underlying biological processes is essential to develop future therapeutic agents [ 60 ]. For example, the detection of novel fusion genes involved in the development, growth, and survival of cancer cells could lead to the identification of new potential druggable targets for “precision medicine” approaches [ 61 ].…”

“…In this direction, initial evidence suggests that ALK-RCC patients might benefit from the treatment with ALK-i [ 60 ]. Nevertheless, it will be essential to evaluate the activity of ALK-i firstly in large, multi-institutional clinical trials for pretreated ALK-RCC patients.…”

Immune Checkpoint Inhibition in Advanced Non-Clear Cell Renal Cell Carcinoma: Leveraging Success from Clear Cell Histology into New Opportunities

“…Until recently, trials have grouped all nccRCC tumors together in order to enable rapid conclusions. We now know that this is a failing strategy, as tumors are diverse entities with their own genetic underpinnings and natural history [39]. Some have called for the development and prioritization of multicenter and potentially international trials specific to each subtype to define the best therapeutic strategies [29,39].…”

“…We now know that this is a failing strategy, as tumors are diverse entities with their own genetic underpinnings and natural history [39]. Some have called for the development and prioritization of multicenter and potentially international trials specific to each subtype to define the best therapeutic strategies [29,39]. However, KEYNOTE-427 and COSMIC-021 both represent excellent examples in which an elegant trial design may maximize the enrollment of nccRCC patients into specific cohorts, without jeopardizing the study progress.…”

Start of a New Era: Management of Non-Clear Cell Renal Cell Carcinoma in 2022

“…PRCC is further subclassified histologically (and increasingly by molecular characteristics) into type 1 PRCC and type 2 PRCC [ 5 , 6 ]. Molecular alterations to MET are frequently found in type 1 including mutations and amplification with duplication of chromosome 7, the location of MET .…”