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Updated: Aug 5, 2025
Microarray-based Identification of Individual HERV Loci Expression: Application to Biomarker Discovery in Prostate Cancer
Published on: November 2, 2013
Molecular testing of DNA damage response pathways in prostate cancer patients
Lalit Patel1, Colin C Pritchard2,3
1Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Purpose Of Review:
Personalizing prostate cancer therapy requires germline and tumor molecular tests that predict who will respond to specific treatments and who may not. The review covers molecular testing of DNA damage response pathways, the first biomarker-driven precision target with clinical utility for treatment selection in patients with castration resistant prostate cancer (CRPC).
Recent Findings:
Recurrent somatic and germline variants cause deficiency of the mismatch repair (MMR) or homologous recombination (HR) pathways in about a quarter of CRPC patients. In prospective clinical trials, patients with deleterious variants in the MMR pathway more frequently experience a therapeutic response to immune checkpoint inhibitors (ICI). Similarly, somatic and germline events affecting HR predict response to poly(ADP) ribose polymerase inhibitor (PARPi) therapy. Molecular testing of these pathways currently involves assaying for loss of function variants in individual genes and for the genome-wide consequences of repair deficiency.
Summary:
DNA damage response pathways are the first major area of molecular genetic testing in CRPC settings and offer insights into this new paradigm. Our hope is that eventually an arsenal of molecularly-guided therapies will be developed across many pathways to enable precision medicine options for most men with prostate cancer.
Insights
Molecular testing of DNA damage response pathways helps personalize prostate cancer therapy. Identifying specific genetic variants predicts patient response to targeted treatments like immune checkpoint inhibitors and PARP inhibitors.
Area of Science:
- Oncology
- Genetics
- Precision Medicine
Background:
- Personalizing prostate cancer treatment necessitates molecular tests to predict therapeutic response.
- Castration-resistant prostate cancer (CRPC) management is evolving with biomarker-driven strategies.
Approach:
- The review examines molecular testing of DNA damage response (DDR) pathways.
- Focuses on mismatch repair (MMR) and homologous recombination (HR) pathways.
- Discusses assays for loss-of-function variants and genome-wide repair deficiency consequences.
Key Points:
- Deficiencies in MMR or HR pathways occur in approximately 25% of CRPC patients.
- MMR pathway variants predict response to immune checkpoint inhibitors (ICI).
- HR pathway alterations predict response to poly(ADP) ribose polymerase inhibitors (PARPi).
Conclusions:
- DDR pathway testing is a foundational step in precision oncology for CRPC.
- Future development aims for a broad range of molecularly-guided therapies for prostate cancer patients.
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