(UroToday.com) The tenth session of the 2022 International Kidney Cancer Symposium (IKCS): North America meeting focused on the genetics of renal cell carcinoma (RCC). In this context, Dr. Brian Shuch discussed the importance of germline genetics in kidney cancer and the role of a consensus statement to guide testing in these patients.
He began by noting that an understanding of the hereditary linkage with cancer was first recognized five to six centuries ago, starting with the recognition of neurofibromatosis. The first description of a “cancer gene” was in the 1870s, however, it wasn’t until 1990 that we had the first characterization of a cancer gene. Dr. Linehan then provided key next steps in our understanding of kidney cancer, with characterization of the VHL gene.
Dr. Such emphasized that 5 to 20% of cancers may be related to a hereditary predisposition. To date, there are 80 or more known cancer syndromes linked to single gene alterations. In the context of renal cell carcinoma, 2 to 8% of tumors are cited to be due to hereditary causes though this is not based on evidence. There are more than 15 different gene mutations associated with RCC syndromes. However, many of these may “hide in plain sight” and, as such, we may not identify these if we don’t look for them.
Dr. Shuch noted that the 2022 WHO Renal Tumor categorization designates a large number of tumor types, though only 2 are conclusively linked to germline alterations. However, highlighting work from Dr. Linehan, he emphasized that many “sporadic appearing” renal cancer may have a potential hereditary background.
Dr. Shuch noted that there is a clear benefit to having guidelines for community practitioners. This allows identification of hereditary cancer patients with appropriate provision of care for the patient as well as cascade testing for their family members. Further, appropriate provision of testing may protect limited resources in the context of a genetic counselor shortage. Currently, referral guidelines in this context are generally vague or unclear with a lack of uniformity between various guideline bodies. Additionally, while most guidelines discuss who should have genetic testing, there is little guidance on when or how to perform this testing.
More recently, in the last two years, both the NCCN and AUA have updated guidance in this space. However, these have been developed by relatively small groups of experts and, as much, Dr. Shuch noted that the methodology is less robust with interpretation differing between centres.
In terms of developing hereditary kidney cancer guidelines, Dr. Shuch noted that there are numerous challenges that derive from the many subtypes of kidney cancer, each with unique biology and specific driver alterations. Importantly, many hereditary forms of kidney cancer resemble sporadic forms of kidney cancer. Further, several RCC syndromes have low penetrance and limited extra-renal manifestations and a significant rate of de novo occurrence.
Considering approaches for genetic testing, Dr. Shuch provided potential lessons from other tumor sites. In the context of pancreatic cancer, there is a “test all” approach in part driven by a sizeable cohort of patients (~10%) with germline alterations, as well as the principle that early detection is believed to save lives. As a result, there are uniform reimbursement policies, and streamlined patient counseling. Alternatively, in the context of prostate cancer, a “test some” approach has been adopted. Thus, guidelines for prostate cancer specify particular subsets of patients for testing. In the context of kidney cancer, Dr. Shuch noted that similar principles apply: there is a sizeable cohort of patients with germline alterations, cascade testing may allow screening, the early detection of disease is believed to save lives, and germline testing may have important therapeutic implications.
To inform germline testing approaches, he emphasized that expert consensus provides a living document that can be improved upon. This approach has been used in HNPCC in colon cancer, among others. In the context of kidney cancer, the Renal Cancer Hereditary Risk Assessment Consensus Conference brought together a group of experts to assess questions relating to who, what, where, when, and how to perform genetic testing in kidney cancer patients. In a paper published in 2019, a clinical consensus statement based on a modified Delphi methodology addressed key questions in this space. The authors first addressed the question of who should get genetic testing. First among the characteristics here is a positive family history. Many prior guidelines have noted a “strong” family history without really clarifying what that means. The group suggested that genetic risk assessment should be offered to those with:
- Renal tumors and a first-degree relative with “syndromic manifestations” associated with hereditary RCC
- A first-degree relative with a documented germline mutation in an RCC gene
- Renal tumor and one first-degree or more than one second-degree relative with RCC
They further noted that testing may be indicated in patients with bilateral or multifocal renal tumors, regardless of histology or the presence of syndromic manifestations. Additionally, specific histologies including SDH renal tumors, an FH-deficient renal tumor, a hybrid oncocytic renal tumor, or a FH-deficient fibroid should prompt genetic risk assessment. An area of controversy surrounds the importance of age of onset: early onset is recognized as increasing suspicion for hereditary RCC. However, it is unclear whether age alone should be sufficient and what cut-point should be used to determine eligibility.
Among those deemed appropriate for testing, the next question is when and how to perform testing. First, the group emphasized that germline testing should not be performed in the absence of pre-test counseling. In many genetically defined syndromes, there are clear management strategies. Thus, for patients with localized disease and a strong suspicion of a hereditary syndrome, genetic testing should be performed prior to treatment. However, there was no consensus for those with metastatic disease. In testing, Dr. Shuch considered options including single gene testing, the use of a renal panel, and expanded panels.
Despite these useful advances, there was an ongoing need to provide further development including addressing prior conflicts. In 2022, a second Delphi consensus meeting was held. In this meeting, there was considerable consensus reached, including 34 of 46 topics. Moving forward, these results will be presented in a manuscript that is currently in the works.
Concluding, Dr. Shuch noted that hereditary kidney cancer can have variable presentation. However, in the absence of testing, we will not identify patients with hereditary syndromes. Currently available guidelines may not be sufficient to identify all patients with hereditary syndrome linked tumors.
Presented by: Brian Shuch, MD, UCL Health, Los Angeles, CA