Precision medicine in prostate cancer, HRR testing

Precision medicine: Advancing cancer patient care

Precision Medicine customizes cancer healthcare. It enables physicians to identify patients who are more likely to benefit from the specific treatment based on biomarker testing.

Hereditary Risk¹

Familial risk of cancer: Family members with HRR gene mutations may be at higher risk of developing cancer. Positive test can result in genetic counselling and preventive measures.

Prognostic Value²

Identify prostate cancer patients with HRR gene mutations that are at higher risk of disease progression and worse prognosis, and could be potentially enrolled in ongoing clinical trials

Targeted Drug Therapy³

Treating physician can make informed treatment decision and ensures that the patients are getting the right treatment and appropriate medical care

HRR = Homologous Recombination Repair

  1. Nicolosi, P. et al. (2019) 'Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines', JAMA Oncology.
  2. Olmos, D. et al. (2023) 'Presence of somatic/germline homologous recombination repair (HRR) mutations and outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) receiving first-line (1L) treatment stratified by BRCA status', Abstract 5003 presented at ASCO.
  3. Fallah, J. et al. (2024) 'Efficacy of Poly(ADP-ribose) Polymerase Inhibitors by Individual Genes in Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer: A US Food and Drug Administration Pooled Analysis', Journal of Clinical Oncology.

Why test for HRR gene mutations?

Understanding HRR status can help inform clinical and treatment decisions

Metastatic prostate cancer patients often carry somatic mutations in BRCA and other relevant HRR genes, as well as germline HRR mutations linked to hereditary risk

Homologous recombination repair (HRR) is critical mechanism for repairing DNA double-stranded breaks. A cascade of well orchestrated events involving molecules such as MRN complex, ATM, BRCA1/2, PALB2, RAD51 etc. is essential for correct DNA repair, genome stability and cell survival. Mutations in HRR genes lead to accumulation of DNA damage and error-prone DNA repair, and this HRR deficiency plays an important role in cancer development. 1,2

  1. Akhoundova, D. et al. (2024) 'DNA Damage Response and Mismatch Repair Gene Defects in Advanced and Metastatic Prostate Cancer', Advances in Anatomic Pathology.
  2. O'Connor, M. et al. (2015) 'Targeting the DNA Damage Response in Cancer', Molecular Cell.
  3. Pritchard, C.C. et al. (2016) 'Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer', New England Journal of Medicine.
  4. Robinson, D. et al. (2015) 'Integrative clinical genomics of advanced prostate cancer', Cell.
  5. Mateo, J. et al. (2017) 'DNA Repair in Prostate Cancer: Biology and Clinical Implications', European Urology.
  6. De Bono, J. et al. (2020) 'Olaparib for Metastatic Castration-Resistant Prostate Cancer', New England Journal of Medicine.

Prognostic value: HRR alterations are associated with more aggressive disease and worse outcomes

Retrospective analysis of association between HRR mutation status and treatment outcomes revealed that  BRCA1/2 alterations were associated with worst mCRPC outcomes (rPFS, PFS2, and OS), followed by patients with other HRR mutations, compared to patients with no HRR mutations that had the best outcomes. No significant differences in prognosis were observed between somatic and germline BRCA patients.1

HRR = Homologous Recombination Repair; mCRPC = Metastatic Castration Resistant Prostate Cancer; rPFS = Radiographic Progression Free Survival; OS = Overall Survival; PFS2 = Progression Free Survival 2

  1. Olmos, D. et al. (2023) 'Presence of somatic/germline homologous recombination repair (HRR) mutations and outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) receiving first-line (1L) treatment stratified by BRCA status', Abstract 5003 presented at ASCO.
  2. Olmos, D., Lorente, D., Alameda, D., Cattrini, C., Romero-Laorden, N., Lozano, R., Lopez-Casas, P.P., Jambrina, A., Capone, C., Vanden Broecke, A.M., Trevisan, M., Van Sanden, S., Jürgens, A., Herrera-Imbroda, B. and Castro, E. (2024). Treatment patterns and outcomes in metastatic castration-resistant prostate cancer patients with and without somatic or germline alterations in homologous recombination repair genes. Annals of Oncology, [online] 35(5), pp.458–472. doi:https://doi.org/10.1016/j.annonc.2024.01.011.

PARP inhibitors: Mode of Action

DNA repair mechanisms maintain integrity of our genome. PARP is a critical enzyme involved in base excision repair of single strand DNA breaks, while the homologous recombination repair (HRR) mechanism repairs double strand DNA breaks. If both of these mechanisms are impaired, first one through PARP inhibition, and later through mutations in HRR genes, cancer cells will not be able to cope with DNA damage and will likely undergo cell death.1,2

  1. Akhoundova, D. et al. (2024) 'DNA Damage Response and Mismatch Repair Gene Defects in Advanced and Metastatic Prostate Cancer', Advances in Anatomic Pathology.
  2. O'Connor, M. et al. (2015) 'Targeting the DNA Damage Response in Cancer', Molecular Cell.

Predictive value: HRR status can potentially inform treatment decisions and enable selection of patients who could benefit from treatment with PARP inhibitors1,2

  1. Fallah J et al. (2024) 'Efficacy of Poly(ADP-ribose) Polymerase Inhibitors by Individual Genes in Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer: A US Food and Drug Administration Pooled Analysis', J Clin Onc.
  2. Taylor et al. (2023) 'PARP inhibitors in metastatic prostate cancer', Front On. 

Due to the prognostic and predictive value of HRR genes in prostate cancer, there is currently a shift in diagnostic practice from BRCA1/2 testing towards broader HRR gene panels

The requirement to test a larger number of HRR genes requires consideration on appropriate testing methodologies

HRR = Homologous Recombination Repair; PC = Prostate Cancer

  1. De Bono et al. (2019) 'Central, prospective detection of homologous recombination repair gene mutations (HRRm) in tumour tissue from >4000 men with metastatic castration-resistant prostate cancer (mCRPC) screened for the PROfound study', Abstract 847PD presented at ESMO.
  2. De Bono et al. (2020) 'Olaparib for Metastatic Castration-Resistant Prostate Cancer', NEJM.

Up Next

Sample Testing

Different sample types can be used for HRR testing in prostate cancer, depending on sample availability and if the testing is performed for somatic or germline mutations, and each approach comes with some advantages and limitations.

Learn More