A Paradigm shift in Kidney Cancer Management

Avishek Roy

Scientific Liaison Manager
4baseCare

Kidney cancer is a heterogeneous group of cancers as it involves different cell types. Most of kidney cancers develop in renal tubules. Owing to the several challenges in managing kidney cancer including severe adverse events, unresponsiveness, and poor prognosis of the metastatic or advanced form of cancer with available treatments, there is a paradigm shift toward personalized treatment. The main cause of mortality is advanced or metastatic renal cell carcinoma (mRCC) which requires effective precision medicines.

Personalized medicine and hurdles
In recent years, personalized therapies have transformed the management of many advanced malignancies. It is becoming important to develop a more tailored approach for the selection of personalized medicines which increases life expectancy, identify individual at risk for disease and reduce adverse events. Personalized medicine in kidney cancer is the concept of managing treatment of a patient which is based on the individual patient’s specific characteristics. The main hurdle in the development of personalized treatment for kidney cancer is its heterogeneity and drug toxicity. The subpopulation of different cancer cells affects the development of precision medicines for individual patients. Apart from this, there is a lack of coordination between genetic findings and clinical applications which is a necessary step towards the development of personalized treatment or precision medicines.

Role of NGS and CGP in the development of personalized treatments
There is a need to improve and renovate genomic studies to overcome the difficulties of heterogeneity of kidney cancer. In the era of precision oncology, gene-expression profiling including CGP and NGS has led to the introduction of new approaches that enable to efficiently diagnose of kidney cancer subtypes, drug development and individualized therapy. The use of a personalized treatment may tailor the doses of drug therapy that is most appropriate for a patient, with potential efficacy and safety.

Genome-wide association study (GWAS) identified RCC genetic variants along with its etiology and provided enough data for the development of novel therapeutics for advance RCC patients according to their specific genotype. NGS has systematic cataloging of RCC genomes which could be utilized in the clinical practices to achieve the goal of development of personalized medicines. Genomics studies really serve as the first step toward personalized treatment in RCC.

Step towards personalized treatment
The recent implementation in precision oncology is the development of targeted therapies and immune checkpoint inhibitors (ICIs) for the treatment of advance or metastatic kidney cancer. The improved understanding of kidney cancer with CGP, has led to the development of more effective therapies, provides molecular biomarkers and set the background for the personalized treatments. CGP analysis showed mutations in BAP1, PBRM1 or KDM5C20 genes which may offer the potential for individualized therapeutic approaches for kidney cancer. Genomic biomarker analysis of patients enrolled in RECORD ­3 and other trials showed that BAP1 and KDM5C mutations were associated with more progression-free survival (PFS) with sunitinib. RECORD 3 trial also demonstrated that PBRM1 and VHL genes can be used as predictive biomarkers for the development of precision medicines in kidney cancer by improving PFS with sunitinib. Another trial phase III COMPARZ showed that PBRM1 mutant tumor treated with sunitinib in advance or mRCC cases significantly improved overall survival (OS) and PFS compared with PBRM1 nonmutant group. It concluded that PBRM1 mutations can be used as a predictive biomarker for vascular endothelial growth factor (VEGF) targeted therapy and may help in the development of personalized medicines. In the recent phase III CheckMate 214 trial comparing nivolumab plus ipilimumab with sunitinib, longer PFS was observed with nivolumab plus ipilimumab among patients with positive TC PD-L1 expression but not among those with negative TC PD-L1 expression. This findings shown that TC PD-L1 expression are associated with PFS in nivolumab plus ipilimumab group and further provide base for the personalized treatment approach for kidney cancer with ICIs. The Journal of Immunotherapy of Cancer suggests that TERT gene mutations present in a patient may not be receptive to ICIs.

Whole exome sequencing of metastatic ccRCC from 35 patients treated with nivolumab, shown that loss-of-function mutations in PBRM1 gene associated with increased clinical benefit to ICIs. PBRM1 loss patients had significantly prolonged OS and PFS compared with patients without PBRM1 loss. This study provide benefited outcomes by associating PBRM1 mutations with nivolumab. Gene expression profiling detect four robust ccRCC subtypes (ccRCC1-ccRCC4). These four molecular subtypes were associated with different responses to sunitinib. ccRCC1/ ccRCC4 tumors had a shorter PFS and OS rate compared with the ccRCC2/ccRCC3 subtypes. The ccRCC4 subtype was associated with the poorest sunitinib response. These findings support to the development of personalized treatment benefits for ccRCC2/ccRCC3 subtype kidney cancer patients with sunitinib.

For the development of personalized medicine in kidney cancer, the identification of specific molecular markers for subtypes of kidney cancer is also a necessary step. Genetic information must be incorporated into clinical applications. All the findings of studies require further prospective validation before application in clinical practice.