No votes yet
Genetics & Genomics

Metastatic Prostate Cancer: Effects of Genetic Testing on Care

Laurie M. Connors
CJON 2019, 23(1), 32-35 DOI: 10.1188/19.CJON.32-35

The National Comprehensive Cancer Network now recommends BRCA1/2 genetic testing in men with metastatic prostate cancer. The purpose of this article is to provide a review of principles of genetic testing in prostate cancer and highlight the significance of clinical genetic testing of BRCA1/2 and other genes (CHEK2, HOXB13, PALB2), including Lynch syndrome genes (MLH1, MSH2, MSH6, and PMS2) in men with metastatic prostate cancer. The potential impact of genetic testing on systemic treatments and the significance of the pathogenic results for at-risk family members is discussed.


  • BRCA1/2 genetic testing is indicated for men with metastatic prostate cancer, regardless of age or family history.
  • Genetic testing results for BRCA1/2 and other cancer susceptibility genes affect treatment options and recommendations for cancer prevention and detection in men with metastatic prostate cancer.
  • Identification of a genetic mutation has implications for at-risk family members and provides opportunities for cancer screening and prevention.

Increased understanding of genetic predisposition to developing prostate cancer is directly influencing the treatment of prostate cancer. In late 2017, the National Comprehensive Cancer Network (NCCN) released updated guidelines that, for the first time, recommended BRCA1/2 genetic testing in men with metastatic prostate cancer (Daly et al., 2017). This article aims to highlight the significance of clinical genetic testing of BRCA1/2 and other genes in men with metastatic prostate cancer.

Prostate Cancer

Prostate cancer is the most common cancer in men in the United States, and about one in nine men will be diagnosed with prostate cancer during his lifetime. An estimated 164,690 men were diagnosed with the disease in 2018, and about 29,430 died from it that same year (American Cancer Society, 2018). Multiple local and systemic treatment options are available for prostate cancer. Local therapies include surgical resection and/or radiation therapy via external beam radiation therapy, brachytherapy, or radioactive seed implants. A wide variety of systemic treatment options are available and include hormone-based therapy, chemotherapy, immunotherapy, and personalized targeted treatments (NCCN, 2018c).

Screening for prostate cancer is controversial. Multiple screening modalities are available for prostate cancer, including digital rectal examination, serum testing of prostate-specific antigen (PSA), and imaging (e.g., ultrasound, magnetic resonance imaging) (NCCN, 2018d). In 2018, the U.S. Preventive Services Task Force ([USPSTF], 2018a) released updated guidelines recommending a personalized approach for prostate cancer screening after issuing a grade D recommendation (recommend against screening because the harms may be greater than the benefits) for PSA-based prostate cancer screening for men in the United States, regardless of age, in 2012 (Moyer, 2012; USPSTF, 2018b). Retrospective research has demonstrated that metastatic prostate cancer rates were steadily declining from 2004–2007 by 1.45% per year but began to increase by 0.58% per year after 2008 and further accelerated to 2.74% per year following the 2012 USPSTF recommendations not to screen for prostate cancer (Kelly, Anderson, Rosenberg, & Cook, 2018). It remains to be seen whether the USPSTF change in guidelines related to prostate cancer screening will affect rates of newly diagnosed and metastatic prostate cancer.

Metastatic Prostate Cancer

Among men who develop metastatic prostate cancer, a paradigm shift has occurred in terms of national guidelines recommending BRCA1/2 genetic testing (NCCN, 2018a). To qualify for a personalized hereditary cancer risk assessment and BRCA1/2 genetic testing, a man with metastatic prostate cancer must meet at least one of the following conditions: (a) have undergone biopsy proving metastatic disease; (b) have radiologic evidence of distant metastatic disease, such as bony metastases; or (c) have disease recurrence in the surgical bed or regional lymph nodes. Biochemical recurrence with an elevation of PSA with no clinical or radiologic evidence of disease is not considered metastatic disease in terms of criteria for BRCA1/2 genetic testing (NCCN, 2018a).

Historically, BRCA1/2 genes have been associated with a hereditary breast and ovarian cancer syndrome, and genetic testing has been focused on women (Bowling et al., 2016). Experts suggest renaming the syndrome associated with pathogenic mutations in the BRCA1/2 genes hereditary breast, ovarian, and prostate cancer syndrome because of the associated increased rates of prostate cancer in male mutation carriers, which are estimated to be as much as 16% for BRCA1 and as much as 20% for BRCA2 by age 70 years (Mersch et al., 2015). Women with BRCA1/2 mutations are at an elevated risk for developing breast and ovarian cancer, and men are at an increased risk for developing breast and prostate cancer; an increased risk for melanoma and pancreatic cancer also exists in some BRCA1/2 pathogenic mutation carriers (Mavaddat et al., 2013). Studies have demonstrated that men with BRCA1/2 mutations who are treated for prostate cancer with surgery or radiation therapy develop metastatic disease earlier than noncarriers and also die sooner (Castro et al., 2015).

Treatment Implications

The results of BRCA1/2 gene testing have direct clinical implications; men with a pathogenic mutation have additional systemic treatment options, with medications such as poly (ADP-ribose) polymerase (PARP) inhibitors (Martin, Chen, & Parikh, 2017). PARP inhibitors are a class of medications that take advantage of the BRCA mutation and DNA damage in a cell and cause apoptosis, or cell death, through a type of directed synthetic lethality, offering a targeted therapy option (Mateo et al., 2015). Studies have demonstrated that individuals with BRCA1/2 mutations are also more likely to respond to cisplatin-based chemotherapy (Mylavarapu, Das, & Roy, 2018).

Tumor Profiling

Genetic testing can also be done on the prostate cancer tumor to identify mutations that may be used to guide therapy and clinical research options (Mandelker et al., 2017). A genetic mutation in somatic tissue, or tumor tissue, does not necessarily signify an autosomal dominant inheritance, as has been observed with a positive germline pathogenic genetic mutation obtained from testing the DNA of cells from a blood or saliva sample.

Other Genetic Mutations Associated With Prostate Cancer Risk

Next-generation sequencing platforms allow for the testing of multiple genes simultaneously, as opposed to a single-gene testing approach. Clinically, there are other moderate- and high-penetrance genes associated with prostate cancer that can be tested concurrently at the time of BRCA1/2 gene testing (see Table 1). Pritchard et al. (2016) identified pathogenic germline mutations in 12% (n = 82) of 692 men with metastatic prostate cancer. Mutations were identified in 16 DNA repair genes; of these, the most frequent were BRCA2 (44%), ATM (13%), CHEK2 (12%), BRCA1 (7%), PALB2 (4%), and the Lynch Syndrome genes, PMS2 (2%), MSH2 (1%), and MSH6 (1%).

The PALB2 gene, which stands for partner and localizer of BRCA2, is involved in the Fanconi anemia/BRCA pathway and is a tumor suppressor gene (Southey, Winship, & Nguyen-Dumont, 2016). Pathogenic mutations in the PALB2 gene are associated with an increased risk for developing cancers similar to those linked to BRCA2, including melanoma and cancers of the breast, prostate, and pancreas (Southey et al., 2016).

ATM (ataxia telangiectasia mutated) mono-allelic genetic mutations can be identified in 1% of the general population (National Cancer Institute, 2018) and are associated with an elevated risk for prostate cancer, as well as breast and other cancers. ATM pathogenic mutations have been identified in 1.6% of men with metastatic prostate cancer (Pritchard et al., 2016).

CHEK2 is a tumor suppressor gene, and one of three pathogenic mutations of CHEK2 (1100delC, IVS2+1G>A, and I157T) have been identified in 5.5% of the population in Poland; all three variants are associated with an increased risk for prostate cancer. A pathogenic CHEK2 mutation carries an increased risk for the development of prostate cancer, as well as breast, colon, thyroid, and renal cancers (Cybulski et al., 2004; Siołek et al., 2015).

HOXB13 is another gene associated with prostate cancer. The specific mutation in the HOXB13 gene is c.251G>A (p.Gly84Glu), which is also known as G84E. The lifetime risk for prostate cancer for men with a HOXB13 mutation is 33%–60% (Ewing et al., 2012). Prostate cancer is the only cancer definitively associated with the HOXB13 c.251G>A mutation (Xu et al., 2013).

In mid-2018, the NCCN (2018b) guidelines for Lynch syndrome were updated and included the recommendation that men with Lynch syndrome undergo prostate cancer screening, based on the existing prostate cancer early detection guidelines (NCCN, 2018d). Lynch syndrome is associated with increased risk for the development of colorectal cancer in men and women, as well as increased risk for endometrial and ovarian cancers in women; risks for other cancers (e.g., stomach, hepatobiliary, urinary tract, small bowel, brain, and pancreatic cancers; sebaceous neoplasms) are also elevated for men and women (NCCN, 2018b). Studies have shown that the Lynch syndrome genes may be associated with an increased risk for prostate cancer (Bauer et al., 2011; Grindedal et al., 2009).

Implications for Practice

Clinical genetic testing in men with metastatic prostate cancer should include consideration of the following genes: ATM, BRCA1/2, CHEK2, HOXB13, MLH1, MSH2, MSH6, PALB2, and PMS2. Oncology nurses should provide education to patients and families regarding the rationale for this genetic testing and what to expect during genetic counseling with a credentialed genetics professional.

The identification of a pathogenic gene mutation in a man with prostate cancer has implications for his at-risk family members because of the autosomal dominant inheritance pattern of these germline mutations. Genetic testing can confirm or rule out inheritance of the gene mutation; first-degree relatives have a 50% chance of inheritance, and second-degree relatives have a 25% chance of inheritance (National Foundation for Ectodermal Dysplasias, n.d.). Cascade testing (testing a proband’s biologic siblings, parents, and offspring after a pathogenic mutation is identified in the proband) of at-risk family members is recommended when a pathogenic gene mutation is identified. For at-risk relatives, such as siblings, parents, and offspring, it is usually sufficient to offer genetic testing specific to the pathogenic genetic mutation that was identified in the first person tested. Selection of the appropriate test and interpretation of results should be managed by a credentialed genetics professional. Genetic testing in relatives offers an opportunity for cancer prevention and early detection.


Evidence-based guidelines for genetic testing of men with metastatic prostate cancer that begin with germline and tumor tissue genetic testing are emerging. Genetic testing of men with metastatic prostate cancer can provide molecular stratification and direct therapeutic treatment options; consequently, nurses need to be aware that men with metastatic disease should be considered for clinical genetic testing regardless of age or family history. Nurses need to be aware of and understand the updated clinical guidelines so that men with metastatic prostate cancer can be appropriately referred for genetic counseling and testing that may affect their treatment options and family health. When a mutation is detected, other relatives should be offered the option of genetic testing to clarify risk and provide appropriate recommendations for cancer prevention and early detection.

About the Author(s)

Laurie M. Connors, DNP, APNG, FNP-BC, AGN-BC, AOCNP®, is an assistant professor in the School of Nursing at Vanderbilt University in Nashville, TN. The author takes full responsibility for this content. Connors has previously consulted for the American Association of Nurse Practitioners. Connors can be reached at laurie.m.connors@vanderbilt.edu, with copy to CJONEditor@ons.org.



American Cancer Society. (2018). Key statistics for prostate cancer. Retrieved from https://bit.ly/2krh8jL

Bauer, C.M., Ray, A.M., Halstead-Nussloch, B.A., Dekker, R.G., Raymond, V.M., Gruber, S.B., & Cooney, K.A. (2011). Hereditary prostate cancer as a feature of Lynch syndrome. Familial Cancer, 10, 37–42. https://doi.org/10.1007/s10689-010-9388-8

Bhalla, A., & Saif, M.W. (2014). PARP-inhibitors in BRCA-associated pancreatic cancer. Journal of the Pancreas, 15, 340–343.

Bowling, L., Reineke, P., McFarland, R.E., Li, S., Dalton, E., & Dolinsky, J.S. (2016). Gender bias: Underdiagnosing hereditary cancer in men with prostate cancer. Journal of Clinical Oncology, 34(Suppl.), 1545. https://doi.org/10.1200/JCO.2016.34.15_suppl.1545

Castro, E., Goh, C., Leongamornlert, D., Saunders, E., Tymrakiewicz, M., Dadaev, T., . . . Eeles, R. (2015). Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. European Urology, 68, 186–193. https://doi.org/10.1016/j.eururo.2014.10.022

Cybulski, C., Górski, B., Huzarski, T., Masojć, B., Mierzejewski, M., Dębniak, T., . . . Lubiński, J. (2004). CHEK2 is a multiorgan cancer susceptibility gene. American Journal of Human Genetics, 75, 1131–1135. https://doi.org/10.1086/426403

Daly, M.B., Pilarski, R., Berry, M., Buys, S.S., Farmer, M., Friedman, S., . . . Darlow, S. (2017). NCCN guidelines insight: Genetic/familial high-risk assessment: Breast and ovarian, version 2.2017. Journal of the National Comprehensive Cancer Network, 15, 9–20. https://doi.org/10.6004/jnccn.2017.0003

Ewing, C.M., Ray, A.M., Lange, E.M, Zuhlke, K.A., Robbins, C.M., Tembe, W.D., . . . Cooney, K.A. (2012). Germline mutations in HOXB13 and prostate-cancer risk. New England Journal of Medicine, 366, 141–149. https://doi.org/10.1056/NEJMoa1110000

Gatti, R., & Perlman, S. (2016). Ataxia-telangiectasia. In M.P. Adam, H.H. Ardinger, R.A. Pagon, S.E. Wallace, A. Amemiya, L.J. Bean, . . . K. Stephens (Eds.), GeneReviews®. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK26468

Giri, V.N., Knudson, K.E., Kelly, W.K., Abida, W., Andriole, G.L., Bangma, C.H., . . . Gomella, L.G. (2018). Role of genetic testing for inherited prostate cancer risk: Philadelphia Prostate Cancer Consensus Conference 2017. Journal of Clinical Oncology, 36, 414–424.

Grindedal, E.M., Møller, P., Eeles, R., Stormorken, A.T., Bowitz-Lothe, I.M., Landrø, S.M., . . . Maehle, L. (2009). Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiology, Biomarkers and Prevention, 18, 2460–2467. https://doi.org/10.1158/1055-9965.EPI-09-0058

Kelly, S.P., Anderson, W.F., Rosenberg, P.S., & Cook, M.B. (2018). Past, current, and future incidence rates and burden of metastatic prostate cancer in the United States. European Urology Focus, 4, 121–127. https://doi.org/10.1016/j.euf.2017.10.014

Le, D.T., Durham, J.N., Smith, K.N., Wang, H., Bartlett, B.R., Aulakh, L.K., . . . Diaz, L.A., Jr. (2017). Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science, 357, 409–413. https://doi.org/10.1126/science.aan6733

Mandelker, D., Zhang, L., Kemel, Y., Stadler, Z.K., Joseph, V., Zehir, A., . . . Offit, K. (2017). Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing. JAMA, 318, 825–835. https://doi.org/10.1001/jama.2017.11137

Martin, G.A., Chen, A.H., & Parikh, K. (2017). A novel use of olaparib for the treatment of metastatic castration-recurrent prostate cancer. Pharmacotherapy, 37, 1406–1414. https://doi.org/10.1002/phar.2027

Mateo, J., Carreira, S., Sandhu, S., Miranda, S., Mossop, H., Perez-Lopez, R., . . . de Bono, J.S. (2015). DNA-repair defects and olaparib in metastatic prostate cancer. New England Journal of Medicine, 373, 1697–1708. https://doi.org/10.1056/NEJMoa1506859

Mavaddat, N, Peock, S., Frost, D., Ellis, S., Platte, R., Fineberg, E., . . . Easton, D.F. (2013). Cancer risks for BRCA1 and BRCA2 mutation carriers: Results from prospective analysis of EMBRACE. Journal of the National Cancer Institute, 105, 812–822. https://doi.org/10.1093/jnci/djt095

Mersch, J., Jackson, M.A., Park, M., Nebgen, D., Peterson, S.K., Singletary, C., . . . Litton, J.K. (2015). Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer, 121, 269–275. https://doi.org/10.1002/cncr.29041

Moyer, V.A. (2012). Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Annals of Internal Medicine, 157, 120–134. https://doi.org/10.7326/0003-4819-157-2-201207170-00459

Mylavarapu, S., Das, A., & Roy, M. (2018). Role of BRCA mutations in the modulation of response to platinum therapy. Frontiers in Oncology, 8, 16. https://doi.org/10.3389/fonc.2018.00016

National Cancer Institute. (2018). Ataxia telangiectasia. Retrieved from https://www.cancer.gov/about-cancer/causes-prevention/genetics/ataxia-fa...

National Comprehensive Cancer Network. (2018a). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Genetic/familial high-risk assessment: Breast and ovarian [v.2.2019]. Retrieved from https://www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf

National Comprehensive Cancer Network. (2018b). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Genetic/familial high-risk assessment: Colorectal [v.1.2018]. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf

National Comprehensive Cancer Network. (2018c). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Genetic/familial high-risk assessment: Prostate cancer [v.4.2018]. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

National Comprehensive Cancer Network. (2018d). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Genetic/familial high-risk assessment: Prostate cancer early detection [v.2.2018]. Retrieved from https://www.nccn.org/professionals/physician_gls/PDF/prostate_detection.pdf

National Foundation for Ectodermal Dysplasias. (2006). Genetics and inheritance. Retrieved from https://www.nfed.org/learn/genetics-inheritance/

Pritchard, C.C., Mateo, J., Walsh, M.F., De Sarkar, N., Abida, W., Beltran, H., . . . Nelson, P.S (2016). Inherited DNA-repair gene mutations in men with metastatic prostate cancer. New England Journal of Medicine, 375, 443–453. https://doi.org/10.1056/NEJMoa1603144

Siołek, M., Cybulski, C., Gąsior-Perczak, D., Kowalik, A., Kozak-Klonowska, B., Kowalska, A., . . . Góźdż, S. (2015). CHEK2 mutations and the risk of papillary thyroid cancer. International Journal of Cancer, 137, 548–552. https://doi.org/10.1002/ijc.29426

Southey, M.C., Winship, I., & Nguyen-Dumont, T. (2016). PALB2: Research reaching to clinical outcomes for women with breast cancer. Hereditary Cancer in Clinical Practice, 14, 9. https://doi.org/10.1186/s13053-016-0049-2

U.S. Preventive Services Task Force. (2018a). Final recommendation statement: Prostate cancer: Screening. Retrieved from https://www.uspreventiveservicestaskforce.org/Page/Document/Recommendati...

U.S. Preventive Services Task Force. (2018b). Grade definitions. Retrieved from https://www.uspreventiveservicestaskforce.org/Page/Name/grade-definitions

Xu, J., Lange, E.M., Lu, L., Zheng, S.L., Wang, Z., Thibodeau, S.N., . . . Isaacs, W.B. (2013). HOXB13 is a susceptibility gene for prostate cancer: Results from the International Consortium for Prostate Cancer Genetics (ICPCG). Human Genetics, 132, 5–14. https://doi.org/10.1007/s00439-012-1229-4