EAU 2018: Results from the TRACERx Renal Study: Deterministic Routes to Tumor Progression in Clear Cell Renal Cell Carcinoma

Copenhagen, Denmark (UroToday.com) Dr. Samra Turajlic from the Francis Crick Institute in London provided initial results from the TRACERx Renal study. Dr. Turajlic opened by noting that there are a wide range of clinical phenotypes/outcomes among patients with advanced renal cell carcinoma, including (i) indolent disease – oligo metastatic progression among which patients may benefit from cytoreductive nephrectomy and oligo-metastasectomy, and (ii) aggressive disease – disseminated metastases and early death among which patients do not benefit from cytoreductive nephrectomy and have a poor response to therapy. There are three important clinical dilemmas according to Dr. Turajlic: (i) treatment of metastatic disease, which may include surgery to defer systemic therapy, (ii) adjuvant therapy for high-risk disease, (iii) active surveillance of small renal masses.

The TRACERx (Tracking Renal Cell Carcinoma Evolution Through Therapy Rx) study is an ongoing prospective study at four centers in the UK with six main aims:

To examine the association of intratumor heterogeneity with disease stage and clinical outcomes through multiregion genomic profiling of primary tumours
To investigate genotype–phenotype relationships through multiregion phenotypic profiling of primary tumours
To examine how subclonal drivers contribute to metastasis and treatment resistance by genomic profiling of tumour tissues over the disease course
To examine the patterns of evolution and natural selection over space and time
To investigate the effect of the genomic landscape on the tumour immune landscape and response to checkpoint inhibition
To establish whether analysis of cell-free tumour DNA (cfDNA) enables detection of changes in clonal dynamics.

At the first reporting of results of the TRACERx study, the population included 100 patients of which 1,201 primary biopsies and 169 metastatic biopsies were obtained. What Dr. Turajlic and her colleagues found was that high intratumor heterogeneity (ie. diversity) and high chromosomal complexity was associated with poor outcomes, which was also validated in a TCGA cohort of patients. Furthermore, high chromosomal complexity and low intratumor heterogeneity was associated with disseminated disease, early progression and death. Patients with two “high-risk” somatic copy number alterations were significantly associated with metastases.

Dr. Turajlic concluded with several important take home points:

Clear cell RCC evolutionary subtypes correlate with clinical phenotypes
Early fixation of multiple driver events leads to rapid growth and metastases
Subclonal diversification is linked with slower growth and attenuated metastases

This study is in press in Cell and will be published forthcoming.

Presented by: Samra Turajlic, The Francis Crick Institute, London, United Kingdom

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, twitter: @zklaassen_md at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark

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