New Framework for Genetic Testing in Prostate Cancer Takes Shape

Oncology Live®Vol. 21/No. 19
Volume 21
Issue 19

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In recent years, great progress has been made in understanding the genetics of metastatic prostate cancer which has translated into the development of new precision therapies.

Kerry R. Schaffer, MD

In recent years, great progress has been made in understanding the genetics of metastatic prostate cancer which has translated into the development of new precision therapies. The FDA has approved 2 PARP inhibitors—rucaparib (Rubraca) and olaparib (Lynparza)—for use in patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) defects.1,2 Pembrolizumab (Keytruda), a checkpoint inhibitor, is also approved for use in solid malignancies with mismatch repair deficiency (dMMR), microsatellite instability (MSI), or high tumor mutational burden (TMB).3 More than 20% of patients with mCRPC have HRR defects or dMMR on somatic tumor testing,4 and 12% reflect germline mutations.5

Given the high proportion of patients with actionable mutations, somatic testing is now an important standard of care for patients with metastatic prostate cancer.6 Additionally, national guidelines state that all men with metastatic prostate cancer and some men with localized prostate cancer qualify for germline testing.7,8 With increased genetic testing in metastatic prostate cancer, questions arise regarding the optimal biopsy site, timing, and type of testing to offer, and the interpretation of results. While no universal protocol has been established, data from recent studies can be used to create a framework for implementation of genetic testing.

Selecting Patients for Testing

National Comprehensive Cancer Network guidelines indicate that all men with metastatic prostate cancer qualify for somatic and germline testing,6 regardless of family history, age of cancer onset, indolent/aggressive nature of metastatic disease, or race. Initial prostate cancer genomic studies reflected data from predominantly Caucasian populations.4,5 However, recent studies demonstrate that the prevalence of germline and somatic mutations and genomic signatures that impact clinical decisions are not significantly different between racial groups. These include, but are not limited to, alterations in BRCA1/2, ATM, TMB, and MSI status.9,10 With higher prostate cancer incidence and mortality in African Americans compared to other racial groups, there is national recognition of the need to improve access to care for minorities,11 and genetic testing must be included in this strategy.

What to Look for in Somatic Testing Reports

Somatic features that qualify patients with metastatic prostate cancer for precision therapies include pathogenic mutations in HRR genes (eg, BRCA1/2, ATM), dMMR (eg, MSH2, MSH6, MLH1, PMS2), MSI-high status, or high TMB (≥ 10 mut/Mb). Treating providers should ensure that the test report specifically comments on these but also can review the report for other noteworthy findings such as variants of uncertain significance mutations in actionable genes that may be reclassified over time, genetic alterations suggestive of an incidental hereditary cancer syndrome,12 and mutations for which there is evolving knowledge regarding prognostication (eg, SPOP, WNT, MYC).13 It may be helpful to review these more nuanced findings at local or regional genitourinary or molecular tumor boards.

Somatic Testing Samples: Primary Versus Metastatic Site

HRR mutations, if present, are usually identified in prostate specimens in paired primary-metastatic studies, reflecting an early alteration.14 The PROfound trial (NCT02987543) identified a similar prevalence of actionable HRR mutations between different tissue types: archived primary (27.1%), archived metastatic (33.2%), new primary (28.9%), and new metastatic (29.5%).15 In this study, the majority of specimens (89.9%) were archived; rates of sequencing success were 63.9% for new versus 56.9% for archived specimens (Figure).16 This study also highlighted potential barriers to successful testing including decalcification technique of osseous biopsies, low tumor fraction, and older sample age. The proportion of samples on which somatic testing can successfully be performed declines over time, likely as tissue quality is compromised.

Figure. Tissue Testing Success Rates in the PROfound Trial16

Peripheral blood sampling for circulating tumor DNA (ctDNA) testing is convenient; however, if possible, a solid tumor biopsy is preferable to ctDNA, as ctDNA is not always entirely concordant with the tumor tissue genomics.17,18 If ctDNA is used, the highest yield would be at disease progression when considering precision therapies in patients with mCRPC and higher tumor burden.18

When to Send Somatic Testing

Ideally, all patients will be offered somatic testing prior to decline in function that prohibits further therapy. Each biopsy can subject patients to financial burden, possible discomfort, and additional medical appointments. Therefore, when possible, efforts should be made to use previously acquired tissue that may yield therapeutic information. Data from the PROfound trial demonstrate that both primary and metastatic sites can be used for testing. Thus, it is reasonable to offer testing on a prostate specimen or adequate site of metastatic biopsy at the time of metastatic prostate cancer diagnosis, increasing the likelihood that previously acquired tissue can be used, potentially avoiding subsequent biopsies.

For patients without an existing adequate biopsy at the time of hormone sensitive metastatic prostate cancer diagnosis, obtaining a biopsy at the time of mCRPC is warranted. Delaying somatic testing until mCRPC will maximize the potential of identifying actionable acquired mutations; most commonly these are ATM or dMMR.14

Finally, if actionable mutations are not identified on initial somatic testing, repeat biopsy for retesting should be considered for heavily treated patients. This may identify a mutation that had a false-negative or an acquired actionable mutation or genomic signature. While dMMR and MSI-high status are rare (approximately 3%),14 in select patients immunotherapy can provide tremendous benefit.19,20

Why is Genetic Testing Important?

Although only a proportion of patients have actionable mutations, offering somatic testing to all patients with metastatic prostate cancer is imperative, as it can reveal precision therapy options. If a gene alteration is identified on somatic testing and a hereditary cancer syndrome is suspected, offering germline testing with formal genetic counseling is warranted.12 It is important to stress that a somatic testing result without pathogenic mutations in hereditary cancer genes is not equivalent to a negative formal germline test because depth of coverage and techniques of sequencing vary across the different platforms. In addition to somatic testing, all patients with metastatic prostate cancer should be informed of their eligibility for formal germline counseling and testing.6,8

Ultimately, patient-provider discussions regarding testing, tissue availability and quality, disease presentation, cost, and patient willingness to undergo biopsy all play into the implementation of somatic testing. When these factors come together effectively, the result is an improved, personalized approach to treatment. Although genetic testing in metastatic prostate cancer can be complex, the results benefit patients and, in some cases, their relatives as well. The use of genetic testing will likely continue to grow as knowledge of genetic vulnerabilities and drivers of prostate cancer continue to advance.


  1. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. FDA. Updated May 20, 2020. Accessed September 8, 2020.
  2. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. FDA. May 15, 2020. Accessed September 8, 2020.
  3. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA. Updated May 30, 2017. Accessed September 8, 2020.
  4. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-1228. doi:10.1016/j.cell.2015.05.001
  5. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453. doi:10.1056/NEJMoa1603144
  6. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer NCCN evidence blocks, version 2.2020. Accessed September 8, 2020.
  7. Giri VN, Knudsen K, Kelly WK, et al. Role of genetic testing for inherited prostate cancer risk: Philadelphia Prostate Cancer Consensus Conference 2017. J Clin Oncol. 2018;36(4):414-424. doi:10.1200/JCO.2017.74.1173
  8. NCCN. Clinical Practice Guidelines in Oncology. Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 1.2021. Accessed September 8, 2020.
  9. Koga Y, Song H, Chalmers ZR, et al. Genomic profiling of prostate cancers from men with African and European ancestry. Clin Cancer Res. 2020;26(17):4651-4660. doi:10.1158/1078-0432.CCR-19-4112
  10. Sartor O, Yang S, Ledet E, Moses M, Nicolosi P. Inherited DNA-repair gene mutations in African American men with prostate cancer. Oncotarget. 2020;11(4):440-442. doi:10.18632/oncotarget.27456
  11. Tackling cancer health disparities: small steps, big hopes. National Cancer Institute. Updated July 24, 2017. Accessed September 8, 2020.
  12. DeLeonardis K, Hogan L, Cannistra SA, Rangachari D, Tung N. When should tumor genomic profiling prompt consideration of germline testing? J Oncol Pract. 2019;15(9):465-473. doi:10.1200/JOP.19.00201
  13. Stopsack KH, Nandakumar S, Wibmer AG, et al. Oncogenic genomic alterations, clinical phenotypes, and outcomes in metastatic castration-sensitive prostate cancer. Clin Cancer Res. 2020;26(13):3230-3238. doi:10.1158/1078-0432.CCR-20-0168
  14. Abida W, Armenia J, Gopalan A, et al. Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making. JCO Precis Oncol. 2017;2017:10.1200/PO.17.00029. doi:10.1200/PO.17.00029
  15. Hussain M, Mateo J, Fizazi K, et al. PROfound: phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations. Ann Oncol. 2019;30(suppl 5):v881-v882. doi:10.1093/annonc/mdz394.039
  16. Hussain MHA, Mateo J, Sandhu SK, et al. Next-generation sequencing (NGS) of tumor tissue from >4000 men with metastatic castration-resistant prostate cancer (mCRPC): the PROfound phase III study experience. J Clin Oncol. 2020;38(suppl 6):195. doi:10.1200/JCO.2020.38.6_suppl.195
  17. Carreira S, Romanel A, Goodall J, et al. Tumor clone dynamics in lethal prostate cancer. Sci Transl Med. 2014;6(254):254ra125. doi:10.1126/scitranslmed.3009448
  18. González-Billalabeitia E, Conteduca V, Wetterskog D, Jayaram A, Attard G. Circulating tumor DNA in advanced prostate cancer: transitioning from discovery to a clinically implemented test. Prostate Cancer Prostatic Dis. 2019;22(2):195-205. doi:10.1038/s41391-018-0098-x
  19. Abida W, Cheng ML, Armenia J, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 2019;5(4):471-478. doi:10.1001/jamaoncol.2018.5801
  20. Tucker MD, Zhu J, Marin D, et al. Pembrolizumab in men with heavily treated metastatic castrate-resistant prostate cancer. Cancer Med. 2019;8(10):4644-4655. doi:10.1002/cam4.2375

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