For up to 1 in 3 men diagnosed with advanced prostate cancer,
Can the mechanism of HRR mutations help inform their prognosis?
HRR genes such as BRCA1/2, ATM, and CDK12 are part of a family of genes involved in DNA damage repair.1,2,5
Mutations to HRR genes can increase the risk of developing prostate cancer that is more aggressive—leading to a poorer prognosis.1-3
HRR gene mutations can compromise the ability of tumor cells to correct damage to the genome through the loss of HRR—which may increase reliance on PARP-mediated DNA repair pathways for survival.6
Tumor cells that lose the ability to repair damage through HRR must fix double-strand breaks (DSBs) through an error-prone pathway called nonhomologous end joining (NHEJ).6 Due to their impaired HRR capabilities, HRRm tumor cells may rely on the PARP enzyme’s corrective response to repair single-strand breaks (SSBs) before they result in DSBs that require NHEJ.6 HRRm tumor cells may be particularly vulnerable to disruption of the PARP repair mechanism, which can lead to accelerated cell death in vitro.9,10
Knowing the HRRm status of your patients’ prostate cancer may help inform their prognosis.3,11
Patients with certain HRRm mCRPC are at risk for more aggressive disease and poorer outcomes.3,11
Within a retrospective study of patients with prostate cancer,* a subgroup analysis of patients diagnosed with metastatic prostate cancer (n=122) assessed the median survival time for patients with and without BRCA1/2 or ATM mutations3:
*Results were not adjusted for effects of differing treatments among the different sets of patients and how these treatments may affect outcome.
Uncover hidden risks—Test for HRR mutations.
Testing men with advanced prostate cancer for tumor HRR mutations may help as you develop a treatment plan.4
Molecular testing, either by tumor or liquid biopsy, can identify HRR mutations.12,13
NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) recommend germline testing and consideration of tumor molecular testing for all patients diagnosed with regional or metastatic prostate cancer to look for mutations to the following HRR genes: ATM, CHEK2, BRCA1, PALB2, BRCA2, RAD51D.4†
†RAD51D testing is for tumor testing, not germline testing.
View the latest testing recommendations for prostate cancer in the NCCN Guidelines® for Prostate Cancer4View Recommendations
Test all patients with advanced prostate cancer for HRR mutations.
Discovering if your patient has HRRm advanced prostate cancer is an important step to:
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53BP1=p53-binding protein 1; ATM=ataxia-telangiectasia mutated; ATMm=ATM mutation; BRCA1/2m=BRCA1/2 mutation; CDK=cyclin-dependent kinase; G1=gap 1; G2=gap 2; HRRm=HRR-mutated; LIG3=DNA ligase 3; mCRPC=metastatic castration-resistant prostate cancer; MRE11=MRE11 homolog A; NBS1=nibrin; NCCN=National Comprehensive Cancer Network® (NCCN®); P=phosphate; PALB2=partner and localizer of BRCA2; PARP=poly (ADP-ribose) polymerase; PARP1=poly (ADP-ribose) polymerase 1; PNKP=polynucleotide kinase 3'-phosphatase; POLβ=DNA polymerase beta; RAD50=RAD50 double-strand break repair protein; RAD51D=RAD51 paralog D; RPA=replication protein-A; S=synthesis; SSBR=single-strand break repair; XRCC1=x-ray repair cross-complementing 1.
REFERENCES: 1. 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 [published online May 31, 2017]. JCO Precis Oncol. 2017. doi:10.1200/PO.17.00029. 2. Pezaro CJ, Marciscano AE, Madan RA. The winds of change: emerging therapeutics in prostate cancer. Am Soc Clin Oncol Educ Book. 2018;38:382-390. 3. Na R, Zheng SL, Han M, et al. Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death. Eur Urol. 2017;71(5):740-747. 4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.4.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed August 26, 2019. 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. 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. 6. Minchom A, Aversa C, Lopez J. Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies. Ther Adv Med Oncol. 2018;10:1758835918786658. 7. Caldecott KW. DNA single-strand break repair. Exp Cell Res. 2014;329(1):2-8. 8. O'Kane GM, Connor AA, Gallinger S. Characterization, detection, and treatment approaches for homologous recombination deficiency in cancer. Trends Mol Med. 2017;23(12):1121-1137. 9. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913-917. 10. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-921. 11. 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(14):1748-1757. 12. Raymond VM, Gray SW, Roychowdhury S, et al; Clinical Sequencing Exploratory Research Consortium Tumor Working Group. Germline findings in tumor-only sequencing: points to consider for clinicians and laboratories. J Natl Cancer Inst. 2015;108(4). doi:10.1093/jnci/djv351. 13. Clark TA, Chung JH, Kennedy M, et al. Analytical validation of a hybrid capture-based next-generation sequencing clinical assay for genomic profiling of cell-free circulating tumor DNA. J Mol Diagn. 2018;20(5):686-702. https://doi.org/10.1016/j.jmoldx.2018.05.004.