POINT-Prostate Cancer Genomic Analysis: Routine or Research Only?

OncologyOncology Vol 32 No 12
Volume 32
Issue 12

In this side of the Point/Counterpoint, Drs. Bernard and Flaig state that genomic testing should be routine in the management of prostate cancer patients.

Oncology (Williston Park). 32(12):607-9.

Brandon Bernard, MD, MPH

Thomas W. Flaig, MD

Genomic Testing Should Be Routine in the Management of Prostate Cancer Patients

Advances in next-generation sequencing (NGS) are revolutionizing cancer research and care. Specifically, the accuracy, processing time, and cost of such tests have improved, and access to this technology has rapidly expanded. Its application to clinical care, however, is not new. Indeed, genomic analysis in melanoma, lung, and colorectal cancers is standard of care and predictive of response to numerous targeted drugs. Furthermore, genetic testing for hereditary cancer syndromes, including carriers of DNA damage repair (DDR) genes such as BRCA1/2, has been widely utilized for years, with breast cancer being an archetype for this approach. Until recently, the clinical value of NGS in prostate cancer was unclear, with DDR alteration frequency underappreciated. Notably, prostate cancer was shown to be highly heritable, with twin studies demonstrating a heritability estimate of 57% (95% CI, 51%–63%).[1] Of those, germline BRCA carriers display a more aggressive phenotype, with poorer outcomes.[2-5] Compellingly, the National Comprehensive Cancer Network (NCCN) guidelines now recommend consideration of germline testing for all patients with high-risk localized or metastatic prostate cancer.[6] Moreover, studies have demonstrated that DDR status may be a predictive biomarker in prostate cancer.[7,8] In light of these data, it has been argued that genomic testing should be offered to all patients with advanced disease.

The rationale for routine clinical use stems from emerging literature, including two large studies that sequenced primary tumors and metastases and found pathogenic DDR variants in approximately 20% of cases.[9,10] Surprisingly, 8% of mutations were identified in the germline. A subsequent study found that over 10% of metastatic prostate cancer patients had deleterious germline mutations in DDR genes.[11] Specifically, up to 12% of tumors may display microsatellite instability (MSI) as a consequence of deficient mismatch repair (dMMR) genes.[12] As mentioned, the prognostic implications of such findings are noteworthy. Additionally, a role for DDR as a predictive biomarker is rapidly emerging. Indeed, one phase II trial demonstrated a response rate of 88% in patients with somatic alterations in DDR treated with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib.[7] Furthermore, there are data suggesting that germline carriers may derive benefit from platinum-based chemotherapy.[8]

Other relevant genes in prostate cancer include HSD3B1, with studies demonstrating germline status as predictive of worse response to androgen deprivation therapy, yet improved response to abiraterone acetate,[13,14] and CDK12, where loss was shown to be associated with increased neoantigen burden and tumor T-cell infiltration, thus potentially identifying a tumor subset that may benefit from immunotherapy.[15] Ultimately, further work is needed to clarify the value of DDR status as both a prognostic and predictive biomarker in prostate cancer, and if that value differs when alterations are germline vs somatic.

Genomics aside, RNA expression for prostate cancer prognostication is being utilized clinically in some settings. Tests such as Prolaris and Oncotype DX Prostate may aid in risk stratifying men with low-risk or favorable intermediate-risk disease when deciding between active surveillance and treatment.[16-20] Similarly, the Decipher test may predict for risk of metastasis or death following local therapy.[21-24] Moreover, Decipher data have been used to develop predictive signatures for the potential benefit of adjuvant or salvage radiation following radical prostatectomy.[25] While not validated in large prospective clinical trials, these tools showcase the potential value of molecular analysis in localized prostate cancer.

Beyond the individual patient, assessment of germline status may have risk and prognostic implications for immediate and extended family members. Thus, from a public health perspective, the impact of cascade genetic testing is large and, if appropriate interventions are pursued, has the potential to dramatically affect those with familial syndromes, including those with BRCA findings. For example, female carriers of BRCA mutations may undergo earlier screening and potential prophylactic treatment to decrease the risk of breast and ovarian cancers; likewise, patients with dMMR may have Lynch syndrome and thus undergo specific colorectal and endometrial cancer screening. While not presently part of guidelines, knowledge of germline DDR status in prostate cancer patients may impact prostate-specific antigen and other screening modalities in the patient and in family members. Currently, the NCCN recommends consideration of germline testing for all men with metastatic and high-/very-high-risk clinically localized prostate cancer.[6] With an estimated 28,000 men diagnosed with metastatic disease at time of presentation in 2018,[26] this represents a large population in which screening may be of benefit. Such an approach has been adopted by breast cancer practitioners and has shown success with hereditary cancer clinics.

With widespread genomic profiling of prostate cancer patients, there are a number of practical considerations worth mentioning. First, there is the option of tumor genomic profiling vs germline genetic testing, individually, sequentially, or in parallel. For the latter, the NCCN gives some guidance, and a referral to a genetic counselor may be made if the criteria are met. Somatic testing, however, is less clear, given the uncertainty regarding prognostication and actionability should a deleterious DDR alteration be identified. However, if a somatic DDR mutation is identified that suggests a hereditary syndrome, a referral to a genetic counselor and germline testing should be considered.

Secondly, there are the technical aspects of testing to consider. For example, the Centers for Medicare and Medicaid Services have recently finalized a National Coverage Determination approving NGS tests as a companion diagnostic for patients with advanced cancer for which a US Food and Drug Administration (FDA)-approved drug exists. This announcement coincided with the FDA approval of a commercial NGS-based in vitro diagnostic.

Despite the described benefit of routine genomic sequencing for men with prostate cancer, certain pitfalls remain. As mentioned, the identification of germline changes may have far-reaching and unintended negative consequences for family members, including heightened anxiety, uncertainty regarding how and when to screen positive individuals, and adverse impact on certain insurance coverage. In terms of management, there is no clear guidance on how to incorporate genomic data into therapeutic recommendations when clinical trial data may be lacking and when proven standard therapies exist. Notably, there is at best level IIB evidence for therapy based on somatic alterations in prostate cancer[27]; as such, obtaining insurance reimbursement presents a challenge. The exception, of course, is identifying patients who may be eligible for biomarker-based clinical trials.

Next, there is the question of which assay is used and the interpretability of the results; currently, physicians may opt to sequence archival tissue, obtain a fresh biopsy, or utilize a liquid biopsy to analyze circulating tumor DNA. Each of these carries its own limitations, including nucleic acid breakdown, temporal changes from the time of biopsy, and tumor heterogeneity. Moreover, without clear instruction, it can be difficult to determine if an alteration is a pathogenic driver, a passenger, or a variant of unknown significance. Also, with rapidly changing technology, being aware of the validity of specific assays is critical. For example, studies leading to the approval of the checkpoint inhibitor pembrolizumab for solid tumors with MSI/dMMR used investigator-developed polymerase chain reaction (PCR) to determine MSI status and immunohistochemistry for MMR. Commercial NGS assays routinely use targeted exome sequencing; thus, interpreting and applying MSI/MMR results from such tests presents a challenge. That said, recent studies have demonstrated that NGS performs well and has high sensitivity and concordance with PCR at identifying tumors with MSI, including prostate cancer.[28,29] Such studies do well to allay concerns among oncologists regarding use of these assays.

Lastly, one must be cognizant of cost and the uncertainty of insurance coverage for the growing number of available tests. Given the FDA approval of pembrolizumab for MSI-high/dMMR solid tumors, it is reasonable to assume that men with prostate cancer would be included and thus covered for diagnostic testing. For those with commercial insurance, reimbursement is likely variable; therefore, an open discussion with patients about potential direct costs is necessary.

In conclusion, the benefits of genomic testing for patients with advanced prostate cancer are clear. Patients may derive meaningful benefit if their tumor or germline contains a predictive alteration for a targeted treatment, platinum-based chemotherapy, or clinical trial enrollment. Moreover, those found to have MSI may be eligible for immunotherapy with pembrolizumab. Overall, comprehensive genomic sequencing carries both clinical and research implications, as the lines between these are blurred. In terms of cost, it may be argued that overall healthcare expenditures are less if the right drug is chosen for the right patient based on a genomic profile and the application of precision medicine. Patients with other cancer types have a long history of access to novel technology and treatments; the time is now for men with prostate cancer to attain what’s right, what’s necessary, and what the evidence shows with routine genomic testing to improve their lives and those of their families.

Financial Disclosure:Dr. Flaig receives clinical trial support from AstraZeneca, Merck, and Pfizer. Dr. Bernard has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.


1. Mucci LA, Hjelmborg JB, Harris JR, et al. Familial risk and heritability of cancer among twins in Nordic countries. JAMA. 2016;315:68-76.

2. Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31:1748-57.

3. Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68:186-93.

4. Mitra A, Fisher C, Foster CS, et al. Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype. Br J Cancer. 2008;98:502-7.

5. Annala M, Struss WJ, Warner EW, et al. Treatment outcomes and tumor loss of heterozygosity in germline DNA repair-deficient prostate cancer. Eur Urol. 2017;72:34-42.

6. National Comprehensive Cancer Network. NCCN guidelines on prostate cancer. Version 4.2018. https://www.nccn.org/store/login/login.aspx.

7. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697-708.

8. Pomerantz MM, Spisak S, Jia L, et al. The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer. 2017;123:3532-9.

9. Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011-25.

10. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215-28.

11. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375:443-53.

12. Pritchard CC, Morrissey C, Kumar A, et al. Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer. Nat Commun. 2014;5:4988.

13. Hearn JWD, Xie W, Nakabayashi M, et al. Association of HSD3B1 genotype with response to androgen-deprivation therapy for biochemical recurrence after radiotherapy for localized prostate cancer. JAMA Oncol. 2018;4:558-62.

14. Almassi N, Reichard C, Li J, et al. HSD3B1 and response to a nonsteroidal CYP17A1 inhibitor in castration-resistant prostate cancer. JAMA Oncol. 2018;4:554-7.

15. Wu YM, Cieslik M, Lonigro RJ, et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. Cell. 2018;173:1770-82.

16. Cooperberg MR, Simko JP, Cowan JE, et al. Validation of a cell-cycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort. J Clin Oncol. 2013;31:1428-34.

17. Freedland SJ, Gerber L, Reid J, et al. Prognostic utility of cell cycle progression score in men with prostate cancer after primary external beam radiation therapy. Int J Radiat Oncol Biol Phys. 2013;86:848-53.

18. Bishoff JT, Freedland SJ, Gerber L, et al. Prognostic utility of the cell cycle progression score generated from biopsy in men treated with prostatectomy. J Urol. 2014;192:409-14.

19. Cuzick J, Stone S, Fisher G, et al. Validation of an RNA cell cycle progression score for predicting death from prostate cancer in a conservatively managed needle biopsy cohort. Br J Cancer. 2015;113:382-9.

20. Brand TC, Zhang N, Crager MR, et al. Patient-specific meta-analysis of 2 clinical validation studies to predict pathologic outcomes in prostate cancer using the 17-gene genomic prostate score. Urology. 2016;89:69-75.

21. Klein EA, Haddad Z, Yousefi K, et al. Decipher genomic classifier measured on prostate biopsy predicts metastasis risk. Urology. 2016;90:148-52.

22. Karnes RJ, Choeurng V, Ross AE, et al. Validation of a genomic risk classifier to predict prostate cancer-specific mortality in men with adverse pathologic features. Eur Urol. 2018;73:168-75.

23. Spratt DE, Yousefi K, Deheshi S, et al. Individual patient-level meta-analysis of the performance of the Decipher genomic classifier in high-risk men after prostatectomy to predict development of metastatic disease. J Clin Oncol. 2017;35:1991-8.

24. Nguyen PL, Martin NE, Choeurng V, et al. Utilization of biopsy-based genomic classifier to predict distant metastasis after definitive radiation and short-course ADT for intermediate and high-risk prostate cancer. Prostate Cancer Prostatic Dis. 2017;20:186-92.

25. Zhao SG, Chang SL, Spratt DE, et al. Development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched, retrospective analysis. Lancet Oncol. 2016;17:1612-20.

26. National Cancer Institute. SEER cancer stat facts: prostate cancer. https://seer.cancer.gov/statfacts/html/prost.html. Accessed November 15, 2018.

27. Zehir A, Benayed R, Shah RH, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23:703-13.

28. Middha S, Zhang L, Nafa K, et al. Reliable pan-cancer microsatellite instability assessment by using targeted next-generation sequencing data. JCO Precis Oncol. Epub 2017 Oct 3.

29. Hempelmann JA, Lockwood CM, Konnick EQ, et al. Microsatellite instability in prostate cancer by PCR or next-generation sequencing. J Immunother Cancer. 2018;6:29.

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