Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017

Abstract

Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. MethodsAn expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. ResultsConsensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. ConclusionTo our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease. J Clin Oncol 36:414-424. © 2017 by American Society of Clinical Oncology INTRODUCTIONProstate cancer (PCA) is the third leading cause of cancer-related death in US men, accounting for 26,730 deaths in 2017. 1 There is increasing evidence that PCA has substantial inherited predisposition, 2,3 with higher risks conferred by BRCA2 and BRCA1 (associated with hereditary breast and ovarian cancer [HBOC] syndrome), and HOXB13 (associated with hereditary prostate cancer [HPC]). Furthermore, BRCA2 mutations have been associated with poor PCA-specific outcomes. [9][10][11][12][13] There is also emerging evidence of the link between PCA Author affiliations and support information (if applicable) appear at the end of this article.Published at jco.org on December 13, 2017. and DNA mismatch repair (MMR) gene mutations (accounting for Lynch syndrome [LS]). [25][26][27][28][29][30] Furthermore, inherited genetic mutations are being uncovered in up to 12% of men with metastatic PCA, primarily in DNA repair genes such as BRCA1, BRCA2, and ATM, 31,32 with improved clinical outcomes by specific targeted agents. 33,34 Identifying genetic mutations of inherited PCA, therefore, has implications for cancer...

Mutation HOXB13 c.853delT in Martinican prostate cancer patients

“…Other germline variants were detected in ethnic groups 9,10 . Recently, a consensus conference has recommended testing HOXB13 for suspected hereditary Pca 11 …”

Germline genetic testing for inherited prostate cancer in practice: Implications for genetic testing, precision therapy, and cascade testing

“…Germline genetic testing for men with PCA is rapidly rising with expansion of guidelines and expert opinion, along with increasing treatment and clinical trial options . Prior studies have reported germline pathogenic variants particularly in DNA repair genes among men selected for advanced/metastatic disease or based on strict family history criteria, leaving a gap regarding the germline spectrum and potential clinical impact from multigene testing among men unselected for metastatic disease.…”

“…Genetic testing for inherited prostate cancer (PCA) is increasing with expansion of genetic testing guidelines and increasing capability of clinical multigene testing . The NCCN Genetic/Familial High‐risk Assessment: Breast and Ovarian (Version 2.2019) recommends BRCA testing for men with metastatic PCA or men with Gleason score>= 7 who have any of the following: (1)>= 1 close blood relative with ovarian, pancreatic, metastatic PCA, or breast cancer at age <50, (2) > = 2 close blood relatives with breast or prostate cancer at any age, or (3) Ashkenazi Jewish ancestry .…”

“…For men with high risk to metastatic disease, the NCCN Prostate (Version 4.2018) guideline states to consider germline testing irrespective of family history . NCCN Prostate (Version 4.2018) guideline recommends testing several cancer predisposition genes primarily involved in DNA repair, including BRCA1, BRCA2, ATM, CHEK2, PALB2 , and FANCA due to increasing recognition of substantial rates of germline DNA repair pathogenic variants in men with metastatic PCA …”

“…This study was performed utilizing de‐identified genetic testing data from a commercial clinical genetic testing laboratory in the United States and represents a “real‐world” data analysis among men with PCA unselected for metastatic disease. The goal of the study was to estimate overall pathogenic variant rates among men with PCA, with a focus in pathogenic variants in DNA repair genes where there are significant clinical implications for treatment and screening for men with PCA and their families . Correlates of pathogenic variant rates were also assessed to optimize identification of men with PCA for genetic testing and inform implications for precision therapy, cancer screening, and cascade testing in families.…”