DNA Repair in Prostate Cancer

Prostate cancer is estimated to be the second most common male cancer globally, and the fifth most common cause of male deaths¹. In Europe, it is the third most common cause of male cancer-related deaths². Although most patients initially present with localised or locally advanced disease, approximately 20% will go on to develop metastatic disease that is currently incurable despite a shifting treatment paradigm^3,4.

Approximately 10–19% of primary prostate cancers and 23–27% of metastatic prostate cancers harbour DNA repair gene alterations^5–7.

DNA repair genes (for example, BRCA2, ATM, MSH2, MSH6 and PMS2) encode proteins that repair damaged DNA to maintain genome stability and prevent cancer onset and progression^8,9. There is increasing evidence that pathogenic germline DNA repair gene alterations may serve as biomarkers for prostate cancer risk, and risk of other cancers^10,11.

Dr Alexander Wyatt from the Vancouver Prostate Centre explains that molecular testing for DNA repair gene alterations in prostate cancer will become routine practice in the clinic.

The V2.2020 NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines^®) for Prostate Cancer recommends germline testing for DNA repair gene alterations in patients with high-risk, very-high-risk, regional or metastatic prostate cancer or those with a positive family history, Ashkenazi Jewish ancestry or intraductal/cribriform histology¹². These DNA repair genes include those involved in the homologous recombination repair (HRR) pathway, and the mismatch repair (MMR) pathway¹².

The ESMO Clinical Practice Guidelines for Prostate Cancer (2020) also recommends germline testing for BRCA2 and other DNA damage response (DDR) genes associated with predisposition syndromes in prostate cancer patients who have a family history of cancer¹³. It also suggests to consider germline testing for these genes in patients with metastatic prostate cancer¹³. The ESMO guidelines additionally suggest to consider tumour testing for homologous recombination repair genes and mismatch repair defects in patients with metastatic castration-resistant prostate cancer (mCRPC) ¹³.

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.
2. Ferlay J, Colombet M, Soerjomataram I, Dyba T, Randi G, Bettio M, et al. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018. European Journal of Cancer. 2018;103:356–387.
3. Chambers SK, Hyde MK, Laurie K, Legg M, Frydenberg M, Davis ID, et al. Experiences of Australian men diagnosed with advanced prostate cancer: A qualitative study. BMJ Open. 2018;8(2):e019917.
4. Albala DM. Imaging and treatment recommendations in patients with castrate-resistant prostate cancer. Rev Urol. 2017;19(3):200–202.
5. Cancer Genome Atlas Research Network. The Molecular Taxonomy of Primary Prostate Cancer. Cell. 2015;163(4):1011–25.
6. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215–1228.
7. Armenia J, Wankowicz SAM, Liu D, Gao J, Kundra R, Reznik E, et al. The long tail of oncogenic drivers in prostate cancer. Nat Genet. 2018;50(5):645–651.
8. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144(5):646–674.
9. Athie A, Arce-Gallego S, Gonzalez M, Morales-Barrera R, Suarez C, Casals Galobart T, et al. Targeting DNA Repair Defects for Precision Medicine in Prostate Cancer. Curr Oncol Rep. 2019;21(5):42.
10. Mersch J, Jackson MA, Park M, Nebgen D, Peterson SK, Singletary C, et al. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer. 2015;121(2):269–75.
11. Latham A, Srinivasan P, Kemel Y, Shia J, Bandlamudi C, Mandelker D, et al. Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer. J Clin Oncol. 2019;37(4):286–295.

12. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Prostate Cancer V.2.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed [31-05-2020]. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

13. Parker C, Castro E, Fizazi K, Heidenreich A, Ost P, Procopio G, et al. Journal Pre-proof Prostate Cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020. doi:10.1016/j.annonc.2020.06.011.