Different Subtypes of Kidney cancer – Exploring treatment landscape with Precision Oncology

Avishek Roy

Scientific Liaison Manager
4baseCare

Kidney cancer: In the era of precision oncology
Kidney cancer is a heterogeneous group of cancers with different histologic subtypes. Before the advent of precision oncology, it was treated with chemotherapy, radiotherapy, nephrectomy and cryotherapy. The tools of genomic characterization like CGP by NGS have quicken the investigation and provide novel approaches toward improving early detection, intervention and monitoring of common and rare kidney cancers.

Types of kidney cancer
Kidney cancer is mainly of two type i.e., Renal cell carcinoma (RCC) and Renal pelvis carcinoma. RCC is the most common subtype of adult kidney cancer which accounts for 85% of all cases. It is heterogenic in nature and develops in the proximal renal tubules. Renal Pelvis carcinoma also called as urothelial or transitional cell carcinoma, accounts for 6%–7% of all kidney cancers. This cancer usually begins in the area of renal pelvis. Other rare types are Wilms tumor (≤5%) and renal sarcoma (≤1%). Young children are more likely to develop Wilms’ tumor kidney cancer. This is the most common type kidney cancer in children.

Renal cell carcinoma: Subtypes
Each subtype of RCC has unique genetic alterations, cell biology changes and clinical findings. CGP provides a molecular characterization of heterogeneity of RCC. Among all, clear cell RCC (ccRCC), papillary RCC (PRCC) and chromophobe RCC (chRCC) subtypes are the most common (≥5% of total incidence) and other subtypes are rare (renal sarcoma, renal medullary carcinoma and collecting duct RCC with ≤ 1% of total incidences). Unclassified RCC are 4% of total incidences.
1. Clear cell renal cell carcinoma
It is the most common subtype of RCC that accounts for approximately 60% of all RCC and 75%-80% of metastatic RCC. Large scale genome analysis depicts that ccRCC is characterized by dysregulation of the VHL/HIF pathway. Recently, other prevalent somatic mutations in ccRCC such as PBRM1 and TCEB1 gene mutations were identified which may act as a molecular biomarker.
2. Papillary renal cell carcinoma
It is the second most common form of RCC after ccRCC and accounts for approximately 15%-20% of all kidney cancers. PRCC is again classified into type 1 and type 2. At the molecular level, The Cancer Genome Atlas (TCGA) further characterize the heterogeneity of PRCC tumors into 4 subgroups (C1, C2a, C2b and C2c). Mutations in MET gene is the main cause of PRCC; signifying MET pathway as an attractive target for clinical assessment.
3. Chromophobe RCC
It is an uncommon subtype that is rarely spread but is aggressive. Clinical trials are underway to find its treatment.

Treatment strategies
The main cause of mortality in kidney cancer is ccRCC, especially metastatic ccRCC (mccRCC). The recent implementation of NGS in precision oncology, targeted therapies and immunotherapies have been developed for the treatment of kidney cancer subtypes. CGP analysis showed mutations in BAP1, PBRM1 or KDM5C20 genes, which offer the potential for individualized therapeutic approaches. 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 in RCC. RECORD 3 trial also demonstrated that PBRM1 and VHL genes can be used as predictive biomarkers for the development of precision medicines for kidney cancer.

Another phase III COMPARZ trial showed that PBRM1 mutant tumor treated with Sunitinib in advance or mRCC cases significantly improved overall survival (OS) and PFS compared with PBRM1 non mutant group. These findings were supported by phase II IMmotion 150 trial where sunitinib treated group showed improved PFS but not atezolizumab single or combination with bevacizumab patients. It concluded that PBRM1 mutations can be used as a predictive biomarker for vascular endothelial growth factor (VEGF) targeted therapy for mRCC.

Tyrosine kinase inhibitors (TKIs) targeting VEGF receptor and mTOR inhibitors (temsirolimus and everolimus) target rapamycin (mTOR) pathways have been used for the treatment of ccRCC. TKIs like sorafenib, sunitinib, pazopanib, axitinib, lenvatinib and cabozantinib are approved as the first-line and second-line treatment of mRCC in the US and the EU. All TKIs are approved for the use as single agents. However, the combination of lenvatinib with everolimus and the anti-VEGF monoclonal antibody bevacizumab with interferon-α is also approved for treatment. The mTOR inhibitors everolimus and temsirolimus are approved as single agents in the second-line and in the first-line in patients with with mRCC. Other targeted novel agents is Belzutifan that selectively inhibit HIF2α to provide clinically effective treatments of RCC.

In the era of precision oncology, novel immune checkpoint inhibitors (ICIs) are developed. Combinations of ICIs with anti-VEGF therapy are effective in advance RCC. ICIs like avelumab and atezolizumab are used to target programmed cell death protein 1 ligand 1 (PDL1) and nivolumab and pembrolizumab are against programmed cell death protein 1 (PD1) to treat kidney cancer. Combination of nivolumab with ipilimumab which is also a targeted drug.