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14-04-2015 | Renal cell carcinoma | Article

Tumour and patient factors in renal cell carcinoma—towards personalized therapy

Authors: Ahmed Q. Haddad, Vitaly Margulis

Abstract

Renal cell carcinoma (RCC) comprises a heterogeneous group of histologically and molecularly distinct tumour subtypes. Current targeted therapies have improved survival in patients with advanced disease but complete response occurs rarely, if at all. The genomic characterization of RCC is central to the development of novel targeted therapies. Large-scale studies employing multiple 'omics' platforms have led to the identification of key driver genes and commonly altered pathways. Specific molecular alterations and signatures that correlate with tumour phenotype and clinical outcome have been identified and can be harnessed for patient management and counselling. RCC seems to be a remarkably diverse malignancy with significant intratumour and intertumour genetic heterogeneity. The tumour microenvironment is increasingly recognized as a vital regulator of RCC tumour biology. Patient factors, including immune response and drug metabolism, vary widely, which can lead to widely divergent responses to drug therapy. Intratumour heterogeneity poses a significant challenge to the development of personalized therapies in RCC as a single biopsy might not accurately represent the clonal population ultimately responsible for aggressive biologic behaviour. On the other hand, the diversity of genomic alterations in RCC could also afford opportunities for targeting unique pathways based on analysis of an individual tumour's molecular composition.

Nat Rev Urol 2015; 12: 253–262. doi:10.1038/nrurol.2015.71

Subject terms: Genetic variation • Genomics • Personalized medicine • Renal cancer

The past decade has witnessed a burgeoning in our understanding of the genetic and molecular pathogenesis of many cancers, made possible by the availability of increasingly precise and affordable 'omics' technologies. The knowledge garnered from large-scale genomic studies has facilitated the identification of potentially actionable genetic alterations on an unprecedented scale, setting the stage for the development of future targeted and personalized cancer therapies (Figure 1). The personalized approach to cancer therapy has already been realized for several malignancies, such as breast cancer, colon cancer and melanoma. The use of an anti-human epidermal growth factor receptor 2 (anti-HER2) antibody in HER2-amplified breast cancer,^1, 2 anti-epidermal growth factor receptor (anti-EGFR) therapies in KRAS wild-type colon cancer,³ and serine/threonine-protein kinase B-raf (BRAF) inhibitor in BRAF (V600E) mutant melanoma⁴ are a few examples of the potential of targeted individualized approaches to cancer treatment. Amongst urologic malignancies, renal cell carcinoma (RCC) has been at the forefront of advances in targeted molecular therapeutics. Comprehensive genomic studies have demonstrated the remarkable genetic diversity of RCC and identified several driver mutations and a large number of passenger alterations that could, in part, explain the heterogeneous outcomes for patients harbouring disease that is otherwise histologically similar.^{5, 6, 7, 8, 9, 10, 11, 12, 13}

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Medicine Matters Oncology

Abstract