EAU 2018: Precision Medicine in Renal Cell Cancer, Can We Select The Treatment?

Copenhagen, Denmark (UroToday.com) Dr. Alessandro Volpe provided a discussion on precision medicine for patients with renal cell cancer. Precision medicine is a medical model that proposes the customization of healthcare with medical decisions, treatment and practices tailored to the individual patient. Precision medicine, specifically in patients with high risk/advanced/metastatic RCC, includes (i) selection of the optimal targeted/immunotherapy, (ii) indications for adjuvant therapy after radical nephrectomy, and (iii) indications for cytoreductive nephrectomy in the setting of metastatic RCC. Precision medicine, specifically in patients with localized RCC, includes (i) indications for nephron-sparing surgery in larger tumors (T1b-T2), (ii) indications for lymph node dissection in high-risk disease, and (iii) indications for non-surgical management in select patients. 

For patients with small renal masses, active surveillance is a viable option. Data from Canada assessing progression patterns among 209 incidental small renal masses (<4 cm) showed that over a median follow-up of 28 months (range 1-60) the mean growth rate was 0.13 cm/year [1]. There were 27 patients that experienced progression (34 lesions), including local progression for 25 patients and metastasis for 2 patients. For the patients experiencing local progression, nine patients were treated (7 nephrectomy, 2 probe ablation), 15 continued surveillance and 1 patients was lost to follow-up. This lead Dr. Volpe to quote the age-old Whitmore Aphorism for prostate cancer, but to insert renal cancer “Is it possible to cure renal cancer when it is necessary, and is it necessary to cure renal cancer when it is possible?”

So how do we select patients for active surveillance? Patient features and tumor features. Unfortunately, imaging has no significant ability to assess tumor aggressiveness, and as such we need to better characterize lesions by percutaneous needle biopsy in order to obtain further information regarding malignancy, histotype, grade, and genetic and molecular characteristics. A systematic review assessed the accuracy of percutaneous renal tumor biopsy found that the pooled estimate for sensitivity was 99.1% and 99.7% for specificity [2]. Furthermore, median concordance rates between percutaneous biopsy and final pathology is more than 90% and nearly 96% for small renal masses. When assessing concordance rates for grade between biopsy and final pathology, using a 4-tiered grading system the rate is 62.5%, and 87% when using a 2-tiered grading system. 

Dr. Volpe then outlined the proposed European Active Surveillance of Renal Cell Carcinoma (EASE) study, which is a multi-center prospective study of active surveillance of small, histologically confirmed RCC. This trial will have standardized indications, follow-up, criteria for progression and to indicated delayed intervention. Biopsy tissue and blood/urine specimens will be collected at baseline and at different time points in order to allow the identification of predictors of fast growth/progression of small renal masses. 

Dr. Volpe then commenced a discussion of adjuvant therapy for high-risk patients after radical nephrectomy. The current status of clinical trials of adjuvant therapy is as follows: 

Precision Medicine in Renal Cell Cancer

The currently used prognostic tools for selecting patients for adjuvant therapy do not capture well the biology of the tumor and do not adequately discriminate recurrence risk. Grade, necrosis and performance status are subject to substantial interobserver variability, and the addition of prognostic molecular and genetic biomarkers may improve the identification of the very high-risk population. When looking specifically at the S-TRAC study analysis by immunohistochemistry, among 191 of the 615 patients analyzed 101 received sunitinib and 90 received placebo [3]. There was no DFS difference between PD-L1 positive and negative subgroups in both arms, and no statistically significant association between tumor infiltrating CD4 or CD68 levels and DFS or OS in either group. However, increased density of CD8+ T-cells in tumor tissue was associated with longer DFS/OS in sunitinib treated patients, but not placebo patients, suggesting a potential predictive role. 

Many studies have suggested that poor risk mRCC patients have no survival benefit with cytoreductive nephrectomy. The ongoing SURTIME study is an EORTC-GU 30073 phase III study investigating the sequence of nephrectomy and sunitinib. Patients with mRCC and primary tumor in suite are being randomized (expected n=458) to nephrectomy or sunitinib followed by crossover. The primary endpoint is PFS and secondary endpoints include OS and association with prognostic gene and protein expression profiles. The CARMENA phase III study is assessing sunitinib only vs nephrectomy followed by sunitinib; the primary objective is whether sunitinib alone is non-inferior to nephrectomy plus sunitinib in terms of OS. 

Dr. Volpe concluded with several key messages:

  • RCC has heterogeneous histologic, molecular and genetic features
  • Research of genetic and molecular biomarkers is a clinical priority to assist clinical decision making in several clinical settings of localized and advanced disease, and to predict responses to systematic targeted therapy/immunotherapy in the adjuvant/metastatic setting
  • Percutaneous biopsy should be increasingly used to support clinical decision making in the precision medicine era
  • Clinicians must consider RCC heterogeneity when they use information from renal tumor biopsy to guide treatment decisions
  • Further studies are needed to define the ideal pattern of biopsy and to optimize the accuracy of biopsies by better sampling potentially heterogeneous renal tumors
References:
1. Jewett MAS, Mattar K, Basiuk J, et al. Active surveillance of small renal masses: Progression patterns of early stage kidney cancer. Eur Urol 2011;60(1):39-44. 
2. Marconi L, Dabestani S, Lam TB, et al. Systematic review and meta-analysis of diagnostic accuracy of percuteanous renal tumor biopsy. Eur Urol 2016;69(4):660-673.
3. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med 2016;375(23):2246-2254.


Presented by: Alessandro Volpe, Universita’ Del Piemonte Orientale Ospedale Maggiore Della Carita, Novara, Italy

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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