Clinical Pearls & Morning Reports

Published January 25, 2017

Clear-cell renal-cell carcinoma is associated with mutations in what gene?

Although more than 14,000 patients die from kidney cancer each year, we have seen considerable progress in the systemic treatment of metastatic renal-cell carcinoma in the past 20 years. Researchers have achieved a better understanding of the pathogenesis of the most common type of renal-cell carcinoma, clear-cell renal-cell carcinoma. This understanding has led to new agents, expanded treatment options, and increased rates of survival. A new Review Article explains.

Clinical Pearls

Q: Who gets renal-cell carcinoma?

A: Kidney cancer is a disease of the middle-aged and elderly: 91% of patients receive a diagnosis at 45 years of age or older, and 48% receive a diagnosis at 65 years of age or older. Renal-cell carcinoma, the most common form of kidney cancer, occurs in 90% of cases and is nearly twice as common in men as in women. One third of patients with kidney cancer present with regional or distant metastases, and of patients with localized renal-cell carcinoma treated with nephrectomy with curative intent, approximately one quarter have relapses in distant sites.

Q: Why has metastatic renal-cell carcinoma historically been difficult to treat?

A: Hormonal therapy and cytotoxic chemotherapy have little to no activity in metastatic renal-cell carcinoma. Interferon alfa was the mainstay of treatment until 10 years ago, but it had a low response rate of 12% and a high level of toxicity. High-dose interleukin-2 was reported to achieve a complete response in 5% of patients with advanced renal-cell carcinoma; many of these responses were durable. However, high-dose interleukin-2 is associated with severe cardiovascular toxicity, and it is used only in hospitals that can provide sufficient supportive care measures to manage the acute toxic effects.

Morning Report Questions

Q: Clear-cell renal-cell carcinoma is associated with mutations in what gene?

A: Clear-cell renal-cell carcinoma is associated with mutations in VHL, an essential component of the cellular oxygen-sensing pathway. VHL is located on chromosome 3p and is inactivated by mutation in 52% of clear-cell renal-cell carcinomas. In normal cells, the VHL-containing complex targets hypoxia-inducible factor for degradation. However, in clear-cell renal-cell carcinoma, this complex is dysfunctional and hypoxia-inducible factor accumulates in the cell and activates many downstream hypoxia-driven genes, including vascular endothelial growth factor (VEGF) and other genes involved in angiogenesis, cell growth, and survival. The treatment of renal-cell carcinoma has been transformed by achievement of a basic understanding of these events. This understanding has led to the development of new antiangiogenic drugs that target VEGF or its receptors.

Figure 2. (10.1056/NEJMra1601333/F2) Proposed Decision-Making Strategy for the Treatment of Advanced Clear-Cell Renal-Cell Carcinoma.

Q: Are there any clinically validated biomarkers to guide systemic therapy for patients with metastatic renal-cell carcinoma?

A: Multiple candidates for predictive biomarkers from plasma, tumor, and host tissues have been explored in patients with metastatic renal-cell carcinoma who are receiving various systemic therapies, but none have been validated for clinical use. Two retrospective studies have shown that mutations in elements of the mTOR pathway (TSC1, TSC2, and MTOR) are associated with an objective response to everolimus and temsirolimus; this finding has also been noted in other cancer types. In pretreatment samples, higher levels of tumor PD-L1 expression were associated with a reduced rate of survival among patients with renal-cell carcinoma who were receiving the PD-1 inhibitor nivolumab (as well as VEGF-targeted agents), but these data do not provide support for the use of PD-L1 as a predictive marker of a treatment benefit associated with nivolumab. Tumor heterogeneity is a challenge that needs to be addressed before such markers can be identified and validated. Intratumor heterogeneity can lead to an underestimation of the frequency of mutated genes; in one study, up to 69% of all somatic mutations varied according to biopsy site.

Browse more Clinical Pearls & Morning Reports »