Abstract
Background: Although renal cell carcinoma (RCC) is believed to have a strong hereditary component, there is a paucity of published guidelines for genetic risk assessment. A panel of experts was convened to gauge current opinions. Methods: A North American multidisciplinary panel with expertise in hereditary RCC, including urologists, medical oncologists, clinical geneticists, genetic counselors, and patient advocates, was convened. Before the summit, a modified Delphi methodology was used to generate, review, and curate a set of consensus questions regarding RCC genetic risk assessment. Uniform consensus was defined as ≥85% agreement on particular questions. Results: Thirty-three panelists, including urologists (n = 13), medical oncologists (n = 12), genetic counselors and clinical geneticists (n = 6), and patient advocates (n = 2), reviewed 53 curated consensus questions. Uniform consensus was achieved on 30 statements in specific areas that addressed for whom, what, when, and how genetic testing should be performed. Topics of consensus included the family history criteria, which should trigger further assessment, the need for risk assessment in those with bilateral or multifocal disease and/or specific histology, the utility of multigene panel testing, and acceptance of clinician-based counseling and testing by those who have experience with hereditary RCC. Conclusions: In the first ever consensus panel on RCC genetic risk assessment, 30 consensus statements were reached. Areas that require further research and discussion were also identified, with a second future meeting planned. This consensus statement may provide further guidance for clinicians when considering RCC genetic risk assessment. Lay Summary: The contribution of germline genetics to the development of renal cell carcinoma (RCC) has long been recognized. However, there is a paucity of guidelines to define how and when genetic risk assessment should be performed for patients with known or suspected hereditary RCC. Without guidelines, clinicians struggle to define who requires further evaluation, when risk assessment or testing should be done, which genes should be considered, and how counseling and/or testing should be performed. To this end, a multidisciplinary panel of national experts was convened to gauge current opinion on genetic risk assessment in RCC and to enumerate a set of recommendations to guide clinicians when evaluating individuals with suspected hereditary kidney cancer.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3957-3966 |
| Number of pages | 10 |
| Journal | Cancer |
| Volume | 127 |
| Issue number | 21 |
| DOIs | |
| State | Published - Nov 1 2021 |
Keywords
- clinical consensus
- genetic risk assessment
- genetic testing
- germline mutations
- hereditary kidney cancer
- recommendations
- renal cell carcinoma
ASJC Scopus subject areas
- Oncology
- Cancer Research
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In: Cancer, Vol. 127, No. 21, 01.11.2021, p. 3957-3966.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Genetic risk assessment for hereditary renal cell carcinoma
T2 - Clinical consensus statement
AU - Bratslavsky, Gennady
AU - Mendhiratta, Neil
AU - Daneshvar, Michael
AU - Brugarolas, James
AU - Ball, Mark W.
AU - Metwalli, Adam
AU - Nathanson, Katherine L.
AU - Pierorazio, Phillip M.
AU - Boris, Ronald S.
AU - Singer, Eric A.
AU - Carlo, Maria I.
AU - Daly, Mary B.
AU - Henske, Elizabeth P.
AU - Hyatt, Colette
AU - Middleton, Lindsay
AU - Morris, Gloria
AU - Jeong, Anhyo
AU - Narayan, Vivek
AU - Rathmell, W. Kimryn
AU - Vaishampayan, Ulka
AU - Lee, Bruce H.
AU - Battle, Dena
AU - Hall, Michael J.
AU - Hafez, Khaled
AU - Jewett, Michael A.S.
AU - Karamboulas, Christina
AU - Pal, Sumanta K.
AU - Hakimi, A. Ari
AU - Kutikov, Alexander
AU - Iliopoulos, Othon
AU - Linehan, W. Marston
AU - Jonasch, Eric
AU - Srinivasan, Ramaprasad
AU - Shuch, Brian
N1 - Funding Information: James Brugarolas reports grants from the National Institutes of Health/National Cancer Institute (P50 CA196516) during the conduct of the study. Eric A. Singer reports institutional clinical trial support from Astellas/Medivation outside the submitted work. Maria I. Carlo was supported by the Harold Amos Faculty Development Award and by grants from the Prostate Cancer Foundation during the conduct of the study. Colette Hyatt reports personal fees from GenomeSmart (which was bought by Ambry Genetics) and owned stock in GenomeSmart before it was sold; and honoraria from the Northern New England Oncology Society outside the submitted work. Vivek Narayan reports institutional research grants from Merck, Pfizer, Bristol-Myers Squibb, Tmunity Therapeutics, and Janssen; personal fees from Amgen, Myovant Sciences, Merck, Regeneron, and Janssen; and honoraria from Pfizer outside the submitted work. Ulka Vaishampayan reports personal fees and honoraria from Bristol-Myers Squibb, Exelixis, Merck, and Pfizer outside the submitted work. Michael A. S. Jewett is a member of the Genentech data safety monitoring or advisory board; is past chair of the Theralase Therapeutics data safety monitoring board and owns stock options in the company; is a member of the CEO Medial Advisory Board of Sesen Bio; and is a board member of the International Kidney Cancer Coalition outside the submitted work. Alexander Kutikov reports personal fees from OncoSec Immunotherapies Inc and UroToday Inc outside the submitted work. Ramaprasad Srinivasan reports participation without remuneration or compensation on the Peloton Inc and Calithera Biosciences advisory boards; and other support from Peloton/Merck and Calithera Biosciences outside the submitted work. The remaining authors made no disclosures. Twenty-four questions addressing who should undergo genetic risk assessment were reviewed (Table 2). Panelists reached uniform consensus for 18 (75%) questions. There was general agreement on the management of individuals with a personal or family history of classic syndromic manifestations associated with hereditary RCC, such as pheochromocytoma, melanoma, or spontaneous pneumothorax. This included assessment of those individuals with or without RCC who personally exhibited syndromic manifestations and those with or without RCC who had family members with syndromic manifestations. It was agreed that further genetic risk assessment should be performed for an individual who has a first-degree or second-degree relative (if no first-degree relative is available) with a documented germline mutation. Abbreviations: FH Fumarate hydratase; RCC, renal cell carcinoma; SDH, succinate dehydrogenase; SEER, Surveillance, Epidemiology, and End Results program of the National Cancer Institute. These statements represent those that reached a consensus. In discussing what constitutes a strong family history requiring further assessment, it was agreed that an individual with a renal tumor who has a first-degree relative or 2 second-degree (same lineage) relatives with RCC should undergo targeted genetic risk assessment. There was no consensus on testing unaffected individuals who have first-degree relatives with RCC; however, it was agreed that having 1 affected second-degree relative was not sufficient to recommend further genetic risk assessment. The panel also achieved uniform consensus that specific RCC histology should prompt further evaluation, including various nonclear cell RCC histologies suggestive of succinate dehydrogenase (SDH)-deficient tumors, fumarate hydratase (FH)-deficient tumors, or hybrid oncocytic renal tumors. There was uniform consensus that patients with bilateral or multifocal renal tumors should be offered genetic risk assessment, although there was a discussion that many of these patients, especially older individuals (aged >60 years), would likely not require further testing or would test negative. The discussion of a cutoff age for genetic risk assessment was highly contentious. Participants believed that the most pressing question was to broadly ask whether age alone was a sufficient criterion to recommend genetic risk assessment in a patient with a renal tumor. Although there was general consensus (70%) on this statement, there was no uniform consensus, as some argued that the overall prevalence of relevant genetic alterations is very low across age strata, whereas others expressed that age alone may reliably guide the need for testing. For those supporting further genetic risk assessment based on threshold age, most (67%) agreed on an age cutoff of ≤46 years. After invited questions were received and curated by the steering committee, in total, 53 questions were included for panel review. These questions were grouped into 5 categories: 1) who should undergo genetic risk assessment, 2) when should genetic risk assessment be performed, 3) what testing should be performed, 4) how should germline risk assessment be conducted, and 5) testing in cases of isolated extrarenal lesions associated with known syndromes. The results of the initial demographic and practice pattern questionnaire are detailed in Table 1. Attendance included 33 panelists with significant clinical expertise in the field of hereditary RCC and RCC patient advocates. The panel included representation from urologists (n = 13), medical oncologists (n = 12), genetic counselors and clinical geneticists (n = 6), and patient advocates (n = 2) (see Supporting Table 2). Twenty-four questions addressing who should undergo genetic risk assessment were reviewed (Table 2). Panelists reached uniform consensus for 18 (75%) questions. There was general agreement on the management of individuals with a personal or family history of classic syndromic manifestations associated with hereditary RCC, such as pheochromocytoma, melanoma, or spontaneous pneumothorax. This included assessment of those individuals with or without RCC who personally exhibited syndromic manifestations and those with or without RCC who had family members with syndromic manifestations. It was agreed that further genetic risk assessment should be performed for an individual who has a first-degree or second-degree relative (if no first-degree relative is available) with a documented germline mutation. Abbreviations: FH Fumarate hydratase; RCC, renal cell carcinoma; SDH, succinate dehydrogenase; SEER, Surveillance, Epidemiology, and End Results program of the National Cancer Institute. These statements represent those that reached a consensus. In discussing what constitutes a strong family history requiring further assessment, it was agreed that an individual with a renal tumor who has a first-degree relative or 2 second-degree (same lineage) relatives with RCC should undergo targeted genetic risk assessment. There was no consensus on testing unaffected individuals who have first-degree relatives with RCC; however, it was agreed that having 1 affected second-degree relative was not sufficient to recommend further genetic risk assessment. The panel also achieved uniform consensus that specific RCC histology should prompt further evaluation, including various nonclear cell RCC histologies suggestive of succinate dehydrogenase (SDH)-deficient tumors, fumarate hydratase (FH)-deficient tumors, or hybrid oncocytic renal tumors. There was uniform consensus that patients with bilateral or multifocal renal tumors should be offered genetic risk assessment, although there was a discussion that many of these patients, especially older individuals (aged >60 years), would likely not require further testing or would test negative. The discussion of a cutoff age for genetic risk assessment was highly contentious. Participants believed that the most pressing question was to broadly ask whether age alone was a sufficient criterion to recommend genetic risk assessment in a patient with a renal tumor. Although there was general consensus (70%) on this statement, there was no uniform consensus, as some argued that the overall prevalence of relevant genetic alterations is very low across age strata, whereas others expressed that age alone may reliably guide the need for testing. For those supporting further genetic risk assessment based on threshold age, most (67%) agreed on an age cutoff of ≤46 years. Seven questions on when genetic risk assessment should be initiated were reviewed (Table 3). Panelists reached uniform consensus on only 2 (28.4%) questions. The panel agreed (93%) that, for individuals with a localized renal lesion <3 cm and a strong suspicion for a hereditary RCC syndrome, genetic risk assessment should be performed before management. In addition, for those with a renal tumor and a suspicious associated skin lesion, there was consensus that a skin biopsy would not be required before genetic risk assessment (86%). There was agreement among most participants (79%) that patients with bilateral or multifocal tumors (without syndromic manifestations) should have genetic risk assessment performed before management, but there was only limited agreement (57%) about the role of histologic diagnosis before initiating genetic risk assessment. Similarly, for individuals with a solitary renal tumor who had ≥1 hereditary risk factor(s), defined as a first-degree relative with RCC, a documented mutation, multifocal disease, or other syndromic manifestations, there was general consensus regarding the need for histologic diagnosis (59%) and providing risk assessment before surgical management (59%). Abbreviation: RCC, renal cell carcinoma. These statements represent those that reached a consensus. Five questions addressed what specific testing should be performed when genetic risk assessment was indicated (Table 4). Panelists reached uniform consensus on only 2 (40%) questions. There was uniform consensus (90%) that an individual without suspicion of a particular syndrome but with risk factors for hereditary kidney cancer should undergo multigene panel testing, rather than single-gene testing. There was general consensus (83%) that individuals suspected of having a particular syndrome (with a defined gene) be considered for single-gene, rather than multigene, panel testing. Abbreviations: RCC, renal cell carcinoma; VHL, von Hippel-Lindau disease. These statements represent those that reached a consensus. Seventy-nine percent voted that the response to this question depends on the specific gene in question. When somatic tumor testing had been previously performed and an alteration in a gene associated with a hereditary cancer syndrome was identified, the majority of the panel believed that further genetic evaluation would depend on the particular gene. However, if performed, there was uniform consensus that only a single-gene test should be conducted in the absence of other risk factors. There was general consensus (61%) that, if somatic-only tumor profiling is performed and does not identify an alteration in genes associated with hereditary RCC, this information should not influence germline genetic risk assessment. Six questions addressed how genetic risk assessment should be performed (Table 5), of which 4 (66.7%) had uniform consensus. The panel agreed with uniform consensus that no germline testing should be done without pretest counseling (100%) and that physicians, such as urologists and oncologists with expertise in hereditary kidney cancer syndromes, may themselves offer counseling before genetic testing (92%). Because access to qualified providers may be a barrier to care, there was uniform consensus (93%) that a telehealth visit with a licensed counselor would be sufficient for evaluation. Some (59%) believed that a standardized video covering essential elements of pretest counseling may be sufficient before testing. However, there was significant concern that this may not be sufficient without an opportunity for discussion with a qualified provider and further refinement of individualized risk. If a nonstandardized approach was taken, there was consensus that a kidney-specific panel (92%) should be pursued to avoid testing too broadly. These statements represent those that reached a consensus. A long discussion was held on the topic of variants of unknown significance (VUS) in genes that could explain a hereditary kidney cancer phenotype and their implications for screening and surgical management. Whereas most members (56%) agreed that the presence of hereditary syndromic manifestations with a VUS in the relevant gene raises suspicion for a pathogenic variant, there was strong sentiment that a VUS should be noted but not acted upon and that patients should be managed based on standard clinical criteria. Eight questions addressed pursuing testing for an isolated extrarenal manifestation associated with known RCC syndromes in the absence of family history (Table 6). Panelists reached uniform consensus for 4 (50%) questions. The panel reached uniform consensus that patients with a pheochromocytoma/paraganglioma (100%), an endolymphatic sac tumor (100%), uveal melanoma (88%), and FH-deficient uterine fibroids (93%) should undergo genetic risk assessment and consideration of genetic testing. Other isolated extrarenal manifestations that did not reach consensus regarding necessitation of genetic testing included an isolated hemangioblastoma (brain, spinal cord, or retina), cutaneous or uterine leiomyomas with unknown FH status, spontaneous pneumothorax, and fibrofolliculoma. Abbreviations: CNS, central nervous system; FH, fumarate hydratase. These statements represent those that reached a consensus. Funding Information: James Brugarolas reports grants from the National Institutes of Health/National Cancer Institute (P50 CA196516) during the conduct of the study. Eric A. Singer reports institutional clinical trial support from Astellas/Medivation outside the submitted work. Maria I. Carlo was supported by the Harold Amos Faculty Development Award and by grants from the Prostate Cancer Foundation during the conduct of the study. Colette Hyatt reports personal fees from GenomeSmart (which was bought by Ambry Genetics) and owned stock in GenomeSmart before it was sold; and honoraria from the Northern New England Oncology Society outside the submitted work. Vivek Narayan reports institutional research grants from Merck, Pfizer, Bristol‐Myers Squibb, Tmunity Therapeutics, and Janssen; personal fees from Amgen, Myovant Sciences, Merck, Regeneron, and Janssen; and honoraria from Pfizer outside the submitted work. Ulka Vaishampayan reports personal fees and honoraria from Bristol‐Myers Squibb, Exelixis, Merck, and Pfizer outside the submitted work. Michael A. S. Jewett is a member of the Genentech data safety monitoring or advisory board; is past chair of the Theralase Therapeutics data safety monitoring board and owns stock options in the company; is a member of the CEO Medial Advisory Board of Sesen Bio; and is a board member of the International Kidney Cancer Coalition outside the submitted work. Alexander Kutikov reports personal fees from OncoSec Immunotherapies Inc and UroToday Inc outside the submitted work. Ramaprasad Srinivasan reports participation without remuneration or compensation on the Peloton Inc and Calithera Biosciences advisory boards; and other support from Peloton/Merck and Calithera Biosciences outside the submitted work. The remaining authors made no disclosures. Publisher Copyright: © 2021 American Cancer Society
PY - 2021/11/1
Y1 - 2021/11/1
N2 - Background: Although renal cell carcinoma (RCC) is believed to have a strong hereditary component, there is a paucity of published guidelines for genetic risk assessment. A panel of experts was convened to gauge current opinions. Methods: A North American multidisciplinary panel with expertise in hereditary RCC, including urologists, medical oncologists, clinical geneticists, genetic counselors, and patient advocates, was convened. Before the summit, a modified Delphi methodology was used to generate, review, and curate a set of consensus questions regarding RCC genetic risk assessment. Uniform consensus was defined as ≥85% agreement on particular questions. Results: Thirty-three panelists, including urologists (n = 13), medical oncologists (n = 12), genetic counselors and clinical geneticists (n = 6), and patient advocates (n = 2), reviewed 53 curated consensus questions. Uniform consensus was achieved on 30 statements in specific areas that addressed for whom, what, when, and how genetic testing should be performed. Topics of consensus included the family history criteria, which should trigger further assessment, the need for risk assessment in those with bilateral or multifocal disease and/or specific histology, the utility of multigene panel testing, and acceptance of clinician-based counseling and testing by those who have experience with hereditary RCC. Conclusions: In the first ever consensus panel on RCC genetic risk assessment, 30 consensus statements were reached. Areas that require further research and discussion were also identified, with a second future meeting planned. This consensus statement may provide further guidance for clinicians when considering RCC genetic risk assessment. Lay Summary: The contribution of germline genetics to the development of renal cell carcinoma (RCC) has long been recognized. However, there is a paucity of guidelines to define how and when genetic risk assessment should be performed for patients with known or suspected hereditary RCC. Without guidelines, clinicians struggle to define who requires further evaluation, when risk assessment or testing should be done, which genes should be considered, and how counseling and/or testing should be performed. To this end, a multidisciplinary panel of national experts was convened to gauge current opinion on genetic risk assessment in RCC and to enumerate a set of recommendations to guide clinicians when evaluating individuals with suspected hereditary kidney cancer.
AB - Background: Although renal cell carcinoma (RCC) is believed to have a strong hereditary component, there is a paucity of published guidelines for genetic risk assessment. A panel of experts was convened to gauge current opinions. Methods: A North American multidisciplinary panel with expertise in hereditary RCC, including urologists, medical oncologists, clinical geneticists, genetic counselors, and patient advocates, was convened. Before the summit, a modified Delphi methodology was used to generate, review, and curate a set of consensus questions regarding RCC genetic risk assessment. Uniform consensus was defined as ≥85% agreement on particular questions. Results: Thirty-three panelists, including urologists (n = 13), medical oncologists (n = 12), genetic counselors and clinical geneticists (n = 6), and patient advocates (n = 2), reviewed 53 curated consensus questions. Uniform consensus was achieved on 30 statements in specific areas that addressed for whom, what, when, and how genetic testing should be performed. Topics of consensus included the family history criteria, which should trigger further assessment, the need for risk assessment in those with bilateral or multifocal disease and/or specific histology, the utility of multigene panel testing, and acceptance of clinician-based counseling and testing by those who have experience with hereditary RCC. Conclusions: In the first ever consensus panel on RCC genetic risk assessment, 30 consensus statements were reached. Areas that require further research and discussion were also identified, with a second future meeting planned. This consensus statement may provide further guidance for clinicians when considering RCC genetic risk assessment. Lay Summary: The contribution of germline genetics to the development of renal cell carcinoma (RCC) has long been recognized. However, there is a paucity of guidelines to define how and when genetic risk assessment should be performed for patients with known or suspected hereditary RCC. Without guidelines, clinicians struggle to define who requires further evaluation, when risk assessment or testing should be done, which genes should be considered, and how counseling and/or testing should be performed. To this end, a multidisciplinary panel of national experts was convened to gauge current opinion on genetic risk assessment in RCC and to enumerate a set of recommendations to guide clinicians when evaluating individuals with suspected hereditary kidney cancer.
KW - clinical consensus
KW - genetic risk assessment
KW - genetic testing
KW - germline mutations
KW - hereditary kidney cancer
KW - recommendations
KW - renal cell carcinoma
UR - http://www.scopus.com/inward/record.url?scp=85111799949&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85111799949&partnerID=8YFLogxK
U2 - 10.1002/cncr.33679
DO - 10.1002/cncr.33679
M3 - Article
C2 - 34343338
AN - SCOPUS:85111799949
SN - 0008-543X
VL - 127
SP - 3957
EP - 3966
JO - Cancer
JF - Cancer
IS - 21
ER -