Recent research on the genetic basis of renal cell carcinoma has expanded and improved treatment options; however, personalized medicine is still largely unavailable, so future efforts should aim to link genetic knowledge with prognosis and treatment selection, according to the authors of a recent review article.
The article, written by, of the Fox Chase Cancer Center in Philadelphia, and his colleagues provides an overview of renal cell carcinoma (RCC) mutations and associated therapies, with updates of ongoing trials and a look at future directions.
“The expansion of treatment options for patients with advanced RCC over the past 15 years is a testament to enhanced understanding of the genetics and genomics of RCC and the ability to apply this knowledge to drug development,” the authors wrote in. “However, much work remains to be done as there are still no validated biomarkers to select patient treatment, and in only rare cases, the knowledge of particular mutations in RCC can lead to rational treatment selection.”
RCC accounts for approximately 80%-85% of renal tumors. About three out of four RCC patients have clear cell disease, of which about 30% develop metastases and need systemic therapy. The authors pointed out that vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been standard first-line care for these patients since the mid-2000s, based on improved molecular understanding. Still, responses to TKIs are limited and patients eventually develop resistance. Several agents are in development to overcome this obstacle, including inhibitors of hypoxia inducible factor, which have recently shown promise. Among biomarkers for ccRCC, PBRM1 mutations may be associated with susceptibility to checkpoint inhibitors, and TSC1 could predict response to mTOR (mammalian target of rapamycin) inhibition.
Along with clear cell RCC, the review article addressed topics in papillary and sarcomatoid subtypes.
Patients with papillary RCC often have MET mutations, and ongoing research is focused on associated targeted therapies. For example, savolitinib is a highly selective MET inhibitor that has shown promise in this patient subgroup.
Sarcomatoid features remain characteristic of large and aggressive tumors. Unfortunately, treatment options are currently limited in this area. Recent studies suggest that TP53 and NF2 mutations are associated with sarcomatoid differentiation.
“Future studies should explore linking genetics to prognosis, resistance to targeted therapies, and the identification of future therapeutic targets,” the authors concluded.
SOURCE: D’Avella C et al. Urol Oncol. 2018 Nov 23.