(UroToday.com) The 2024 GU ASCO annual meeting featured a session on the management of renal cell carcinoma with sarcomatoid features or variant histologies and a presentation by Dr. Ramaprasad Srinivasan discussing who, when, and how to perform genetic testing. Dr. Srinivasan started his presentation by emphasizing that genetic testing in kidney cancer is starting to come of age. This is likely secondary to a heightened understanding of the genetic basis of various kidney cancer subtypes and that there are now 20 known genes to be associated with kidney cancer. However, based on the known drivers of kidney cancer, it is critical to develop individualized treatment strategies and to utilize the easy access to genetic testing.
Dr. Srinivasan then discussed the differences between somatic and germline genetic alterations. For somatic testing, there is widespread availability of NGS-based cancer susceptibility gene panels that are often performed in search of targetable genetic alterations. Somatic testing also aids in the diagnosis (for instance, MiTF associated translocation RCC), and the incidental identification of alterations in genes associated with inherited forms of RCC may prompt germline testing. Furthermore, somatic testing is allowing us to understand the genomic landscape of RCC, aiding in the identification of alterations with prognostic significance. With regards to germline testing, this is aimed at those patients who are suspected of having an inherited form of kidney cancer, which is critical for establishing or confirming a diagnosis. This may also lead to cascade testing to screen asymptomatic relatives of individuals with known inherited kidney cancer. It is important to identify appropriate patients for testing and address appropriate pre-test counseling.
The exact prevalence of hereditary kidney cancer is unknown, although it is estimated that 5-8% of all kidney cancers are inherited, with known entities likely undiagnosed and new identities being evaluated. To date, there are over 15 genes associated with inherited kidney cancer, with the identification of the VHL gene dating back to the NCI Dr. W. Marston Linehan and Dr. Berton Zbar. The hereditary predisposition to kidney cancer and summary of the known hereditary kidney cancer syndromes is as follows:
The main reason to do germline testing is ultimately to establish a diagnosis, given that clinicopathologic features and the clinical context are helpful but often insufficient. Moreover, recognition of a genetically defined inherited cancer is key to appropriate management of the individual and family members:
- Appropriate screening is aimed at limiting morbidity/mortality related to kidney cancer and other manifestations
- Guide surgical management (ie. different surgical principles guide management of FH- deficient and VHL associated renal tumors)
- Guide systemic therapy choices (ie. Belzutifan in VHL, Bevacizumab + erlotinib in HLRCC)
- Early identification of family members (cascade testing)
With regards to who we should test, arguably the most comprehensive and contemporary guidance comes from the NCCN guidelines:
From a practical standpoint, common triggers for genetic risk assessment include:
- A ‘strong’ family history of kidney cancer or family history of inherited RCC
- Young age of onset (<46 years)
- Bilateral or multifocal renal tumors
- Personal or family history of ‘syndromic features’
- Histologic features: non-variants, variants consistent with hereditary kidney cancer
Work from Shuch et al.1 assessed more than 600 patients with inherited forms of kidney cancer with a median age of onset of 37 years. They found that that the sensitivity and specificity was highest in patients with age of onset <46 years of age for germline testing. A retrospective analysis from Truong et al.2 assessed 231 patients with early onset kidney cancer who had germline testing and found that alterations in known RCC genes were present in 9% of cases. Bilateral multifocal disease, presence of extra-renal tumors, and histology correlated with higher probabilities of alterations. In 2021, a genetic risk assessment for hereditary renal cell carcinoma consensus conference was held, leading to a clinical consensus statement published in Cancer.3 There were 33 participants made up of medical oncologists, urologists, genetic counselors, geneticists, and patient advocates. There were 53 questions posed to the panel and a uniform consensus was achieved on 30/53 questions. The highest level of consensus supported testing for:
- Patients with a strong family history, including those with RCC in an individual with 1 or more affected first degree relatives or 2 or more affected second degree relatives
- Presence of bilateral or multifocal tumors
- Presence of syndromic features
- Suggestive histology
Age as the sole risk factor was contentious, with a general consensus in favor of germline testing (70% of respondents).
Dr. Srinivasan notes that the timing of testing depends on the clinical context: in patients with localized tumors, testing usually precedes and often aids in management decisions, whereas in patients with metastatic disease, testing can usually be done before the initiation of systemic therapy. For unaffected at-risk individuals, testing should typically be done before the usual age of onset of clinical manifestations. This is important because patients with early manifestations, such as those with VHL (<5 years) and HLRCC (<8 years), require testing in childhood.
Finally, Dr. Srinivasan addressed how we should test. First, pre-test counseling is important and should address risks and benefits of undergoing testing, performed by staff experienced in managing patients with hereditary kidney cancer. Single gene testing is appropriate in those patients undergoing cascade testing and those in whom a specific entity is strongly suspected. Renal multigene panels are appropriate when risk factors dictate germline evaluation but there isn’t strong evidence to support a specific diagnosis. Broader cancer susceptibility gene panels can be used but are rarely necessary.
Dr. Srinivasan concluded his presentation by discussing who, when, and how to perform genetic testing with the following take-home points:
- It is important to identify individuals at risk
- There should be a low threshold for initiating an evaluation/referral given that an inability to make a timely diagnosis can be catastrophic for the individual and family
- Guidelines are available that are based on expert opinion
- Further evaluation should ideally be undertaken at a center with experience in managing familial kidney cancer
- Timing of testing
- Dependent on the clinical context
- Age of testing is tailored to the underlying/suspected diagnosis and individual patient circumstances
- Some entities merit screening in early childhood
- Both targeted single gene testing and panel testing is available and appropriate under specific circumstances
Presented by: Ramaprasad Srinivasan, MD, PhD, National Cancer Institute, Bethesda, MD
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25th – January 27th, 2024
References:
- Shuch B, Vourganti S, Ricketts CJ, et al. Defining Early-Onset Kidney Cancer: Implications for Germline and Somatic Mutation Testing and Clinical Management. J Clin Oncol. 2014;32(5):993-1000.
- Truong H, Sheikh R, Kotecha R, et al. Germline variants identified in patients with early-onset renal cell carcinoma referred for Germline Genetic Testing. Eur Urol Oncol. 2021;4:993-1000.
- Bratslavsky G, Mendhiratta N, Daneshvar M, et al. Genetic Risk Assessment for Hereditary Renal Cell Carcinoma: Clinical Consensus Statement. Cancer. 2021 Nov 1;127(21):3957-3966.