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Understanding
HRRm Testing Methods

HRR testing approaches

Testing methods

Somatic vs Germline
Upon progression to metastatic prostate cancer, guidelines recommend testing for both germline and somatic gene alterations to inform treatment decision-making.1
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Test-methods

GERMLINE

Germline mutations

(or inherited mutations) are passed from parent to child and are found in every cell in the body, including those in the tumor2,3

SOMATIC

Somatic tumor mutations

(or acquired mutations) develop during the life of the patient and are typically found in tumor cells3

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mutations
  • Both germline and somatic tumor HRR alterations can exist within prostate cancer tumors4
  • If a patient has only been tested for germline mutations in earlier stages of disease, somatic tumor testing upon progression to metastatic prostate cancer may identify additional HRR gene alterations4
  • Tumor molecular profiles may change with subsequent treatments, so consider retesting for somatic tumor mutations at time of cancer progression1
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mutation-comp

Types of tests

Expand all

Tissue Tests4-8

  • Sample types
    1. Biopsies
    2. Surgical specimens
    3. Metastatic deposits
  • Sample prep
    1. Formalin-fixed, paraffin-embedded (FFPE) slides
  • Alteration types detected
    1. Somatic
    2. Germline
  • Sample quality
    1. DNA quantity: medium
    2. DNA quality: low
  • Potential advantages
    1. Considered the “gold” standard
    2. Can use archival tissue
  • Potential limitations
    1. Bone biopsies difficult to collect
    2. Bone may not have enough quality DNA for sequencing
    3. May not show tumor heterogeneity
  • TAT
    1. 2-4 weeks

ctDNA Tests4-6,9

  • Sample types
    1. Blood (whole)
  • Sample prep
    1. Ethylenediamine-tetraacetic Ethylenediaminetetraacetic acid (EDTA) tubes or cfDNA-stabilizing tubes
  • Alteration types detected
    1. Somatic
    2. Germline
  • Sample quality
    1. DNA quantity: low
    2. DNA quality: variable
  • Potential advantages
    1. Surrogate for tissue when it is not available
    2. High-quality DNA alternative to bone biopsy
    3. Represents tumor heterogeneity
    4. Prognostic insights on outcomes
    5. Minimally invasive, easily repeatable monitoring for clonal evolution and treatment resistance
  • Potential limitations
    1. Early-stage disease may have low concentrations of ctDNA
    2. Potential for false-positive if HRR genes affected by CHIP
    3. Some platforms may have limited ability to detect copy number
  • TAT
    1. ~ 1-2 weeks

Germline Tests4-6,8

  • Sample types
    1. Saliva
    2. Blood
  • Sample prep
    1. DNA extracted from peripheral blood leukocytes in liquid biopsy
  • Alteration types detected
    1. Germline
  • Sample quality
    1. DNA quality extracted with liquid biopsy: high
  • Potential advantages
    1. Reliably detects germline mutations
    2. Large panels of tests can detect mutations
  • Potential limitations
    1. Cannot detect relevant somatic mutations
  • TAT
    1. ~ 2-4 weeks
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Test-types

Some considerations

CHIP interpretation with ctDNA

According to the NCCN Guidelines®, HRRm testing can be performed using ctDNA when tissue testing is unsafe or unfeasible.1

An issue associated with ctDNA is CHIP (clonal hematopoiesis of indeterminate potential), an age-related acquisition of somatic mutations that leads to clonal expansion in regenerating hematopoietic stem cell populations.10

CHIP is detected by collecting and analyzing leukocytes in the cell pellet or leukocyte coating. The simultaneous discovery of plasma DNA and leukocyte DNA is recommended to bypass false-positive results from CHIP mutation.10

Genetic counseling for germline testing

Genetic counseling is strongly recommended for germline testing.1

Post-test genetic counseling is strongly recommended if a germline mutation (pathogenic/likely pathogenic variant) is identified. It’s vital to test all relatives of the patient to identify the risk of cancer to family members.

Credentialing organizations, such as the National Society of Genetic Counselors, American Board of Genetic Counseling, and American College of Medical Genetics and Genomics, provide searchable online directories that may help you identify genetic counseling providers.11

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Test-consideration

cfDNA, circulating free DNA; ctDNA, circulating tumor DNA; HRR, homologous recombination repair; HRRm, homologous recombination repair gene-mutated; NCCN, National Comprehensive Cancer Network; TAT, turnaround time.

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V4.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed August 29, 2024. 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.
Cheng HH, Sokolova AO, Schaeffer EM, Small EJ, Higano CS. Germline and somatic mutations in prostate cancer for the clinician. J Natl Compr Canc Netw 2019;17(5):515-21.
Cleveland Clinic. Somatic & germline mutations. Cleveland Clinic. Accessed August 9, 2024. https://my.clevelandclinic.org/health/body/23067-somatic--germline-mutations
Scott RJ, Mehta A, Macedo GS, Borisov PS, Kanesvaran R, El Metnawy W. Genetic testing for homologous recombination repair (HRR) in metastatic castration-resistant prostate cancer (mCRPC): challenges and solutions. Oncotarget 2021;12(16):1600-14.
Vandekerkhove G, Giri VN, Halabi S, et al. Toward informed selection and interpretation of clinical genomic tests in prostate cancer. JCO Precis Oncol 2024;8:e2300654.
Cimadamore A, Cheng L, Massari F, et al. Circulating tumor DNA testing for homology recombination repair genes in prostate cancer: from the lab to the clinic. Int J Mol Sci 2021;22(11):5522.
Catalano M, Generali D, Gatti M, et al. DNA repair deficiency as circulating biomarker in prostate cancer. Front Oncol 2023;13:1115241.
Selvarajah S, Schrader KA, Kolinsky MP, et al. Recommendations for the implementation of genetic testing for metastatic prostate cancer patients in Canada. Can Urol Assoc J 2022;16(10):321-32.
Kostos L, Fettke H, Kwan EM, Azad AA. Utility and clinical application of circulating tumor DNA (ctDNA) in advanced prostate cancer. SIUJ 2023;4(4):273-86.
He W, Xiao Y, Yan S, Zhu Y, Ren S. Cell-free DNA in the management of prostate cancer: current status and future prospective. Asian J Urol 2023;10(3):298-316.
NIH MedlinePlus. Help Me Understand Genetics, Genetic Consultation. Updated May 12, 2021. https://medlineplus.gov/genetics/understanding/consult/
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