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About prostate cancer and HRR mutations

  • Prostate cancer is:
    • the second most common cancer in men globally1
    • the third most deadly cancer in men in Canada2
  • Prostate cancer can be grouped based on where the cancer has spread3:
    • Localized prostate cancer is only in the prostate
    • Locally advanced prostate cancer has spread outside the prostate but not to distant parts of the body, such as the lymph nodes
    • Metastatic prostate cancer has spread beyond the prostate to distant parts of the body

  • Several clinical studies have indicated that 10% to 50% of prostate cancer cases progress to metastatic castration-resistant prostate cancer (mCRPC) within 3 years4

HRR mutations are more prevalent than you think

HRR mutations include BRCA1 and BRCA2 as the most common HRR gene mutations

  • Genetic aberrations, including those involving BRCA1/2, are significantly higher (19.3%) in patients with metastatic prostate cancer compared with those with advanced localized prostate cancer (5%)4

  • BRCA2 is the first (12% to 18%) most common altered gene involved in HRR1

  • BRCA1 is the fourth (<2%) most common altered gene involved in HRR1

Image - DNA - HRR mutations can be caused by alterations in over 20 genes(4*)

Homologous recombination repair gene mutations (HRR+) are a change in the nucleotide sequence of a gene involved in homologous recombination-type DNA 20 repair processes5

In a prospective cohort study, the presence of germline BRCA2 mutations reduced cause-specific survival by nearly half vs non-carriers (17.4 vs 33.2 months, 95% CI 1.07–4.10, p=0.27)1

Patients with HRR mutations have a genetically distinct disease driven by several mechanisms1:

  • Patients with deleterious HRR mutations in a cancer cell (called HRR+) have a genetically distinct disease that is driven by more than just androgen receptor (AR) signalling1

  • HRR positivity impairs prostate cancer cells’ ability to repair double-stranded DNA breaks via the normal HRR system1

  • DNA-damage response gene alteration induces a dependency on poly(adenosine diphosphate-ribose) polymerase (PARP), which binds to damaged DNA gaps1

Double-strand DNA break - DNA is repaired in normal cell via HRR therapy - Cell survival - DNA cannot be repaired in cell with HRR mutation - Genomic instability and carcinogenesis(6)

Adapted from Scott R J, et al. 2021.4

  • Two key oncogenic pathways (somatic and germline) may contribute to tumour progression in prostate cancer: defective HRR and the androgen signalling axis. AR signalling regulates a network of DNA repair genes7

Somatic HRR gene alterations have been reported in8:

  • 4.9%–22% of all prostate cancer patients

  • 10%–16.4% of metastatic prostate cancer patients

Germline HRR gene alterations have been reported in9:

  • 17.2%–19% of all prostate cancer patients

  • 11.4%–11.8% of metastatic prostate cancer patients

  • 7.5%–9.1% of metastatic castration-resistant prostate cancer patients

Somatic and germline mutations can be detected with multiple types of testing

MethodsSample Type

Somatic testing4

  • Provides information about translocations and amplification
  • Can detect germline and somatic mutations
Tumour/metastatic tissue

Germline testing4,9

  • Looks for inherited mutations that have been present since birth
  • Can detect germline mutations
  • A positive test can confirm HRR+ disease and does not require follow-up testing
Blood or saliva

Circulating tumour DNA testing4

  • Can detect germline and somatic mutations
Plasma

*

Mutations in HRR genes commonly investigated in mCRPC include BRCA1, BRCA2, ATM, ATR, BARD1, BRIP1, CHK1/2, DSS1, CHEK2, CDK12, FANCA, NBN, PALB2, HDAC2, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, and RPA1.4

BRCA1: Breast cancer gene 1

BRCA2: Breast cancer gene 2

HRR: Homologous recombination repair

mCRPC: Metastatic castration-resistant prostate cancer

PARP: Poly ADP-ribose polymerase

REFERENCES: 1. Teyssonneau D, Margot H, Cabart M, et al. J Hematol Oncol 2021;14(51):1–19.↵  2. Brenner D, Poirier A, Woods R, et al. CMAJ 2022;194(7):E601–607.↵  3. Canadian Cancer Society. 2021. Available: https://cancer.ca/en/cancer-information/cancer-types/prostate/staging.↵  4. Scott RJ, Mehta A, Macedo GS, et al. Oncotarget 2021;12(16):1600–1614.↵  5. National Cancer Institute Thesaurus. Available: https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&version=22.11d&ns=ncit&code=C133695&key=1827865363&b=1&n=null.↵  6. Minchom A, Aversa C, and Lopez J. Ther Adv Med Oncol 2018;10:1–18.↵  7. Polkinghorn WR, Parker JS, Lee MX, et al. Cancer Discovery 2013;3(11):1245–1253.↵  8. Lang S, Swift S, White H, et al. International Journal of Oncology 2019;55(3):597–616.↵  9. National Cancer Institute Thesaurus. Available: https://ncit.nci.nih.gov/ncitbrowser/pages/concept_details.jsf;jsessionid=F3512613504D1CDED992BA49CAB9C463.↵