What is the difference between Homologous Recombination Repair (HRR) and Homologous Recombination Deficiency (HRD) in guiding treatment decisions for cancer patients, particularly those with ovarian and breast cancers?

Differences Between Homologous Recombination Repair (HRR) and Homologous Recombination Deficiency (HRD) in Cancer Treatment

HRR refers to a functional DNA repair pathway, while HRD indicates a defect in this pathway that can be exploited therapeutically with PARP inhibitors, particularly in ovarian and breast cancers.

Understanding HRR and HRD

Homologous Recombination Repair (HRR)

• HRR is a conserved DNA repair mechanism that repairs double-strand breaks (DSBs) in DNA 1
• Functions primarily during S and G2 phases of the cell cycle, restoring the original DNA sequence at damage sites 1
• Process involves DNA sequence removal around the break (resection), revealing single-stranded DNA 1
• RAD51 protein binds to single-stranded DNA and uses the homologous sister chromatid as a template for new DNA synthesis 1
• Key proteins involved include BRCA1, BRCA2, RAD51, RAD51C, RAD51D, and PALB2 1

Homologous Recombination Deficiency (HRD)

• Represents a defect in DNA repair caused by hampered HRR function 1
• Most commonly caused by loss-of-function mutations in BRCA1/2 genes (found in 17-22% of high-grade serous ovarian cancers) 1
• Can also result from mutations in other HRR genes (RAD51C, RAD51D, PALB2), BRCA1 promoter hypermethylation, or other undefined mechanisms 1
• Forces cells to rely on error-prone DNA repair pathways like non-homologous end joining (NHEJ) 2
• Creates genomic instability that can be detected through various testing methods 1

Clinical Significance in Treatment Decisions

Impact on Treatment Selection

• HRD status predicts sensitivity to platinum-based chemotherapy and PARP inhibitors (PARPis) 1
• PARPis exploit synthetic lethality in HRD tumors by preventing repair of single-strand breaks, which convert to double-strand breaks during replication 1, 3
• In HRD tumors, these double-strand breaks cannot be repaired effectively, leading to cell death 1
• The European Society for Medical Oncology (ESMO) recognizes HRD testing as critical for optimizing clinical benefit from PARPis 1

HRD Testing Methods

• Three main categories of HRD tests exist 1:

  1. HRR pathway gene testing: Identifies specific genetic causes of HRD (mutations in BRCA1/2 and other HRR genes)
  2. Genomic scar assays: Measure patterns of somatic mutations that accumulate in HRD cancers regardless of underlying defect
  3. Functional assays: Provide real-time assessment of HRD/HRP status (e.g., RAD51 foci formation) 2

• Commercially available tests like myChoice CDx and FoundationOne CDx are FDA-approved companion diagnostics for identifying HRD-positive tumors 4

Clinical Application Challenges

Dynamic Nature of HRD Status

• HRD status can change over time and with treatment pressure 4
• Reversion mutations in BRCA genes can restore homologous recombination proficiency (HRP), affecting treatment response 1
• Current genomic scar assays may not reflect real-time HRD status, potentially leading to discordance with clinical response 4

Predictive Value Limitations

• Current HRD tests are better at predicting magnitude of PARPi benefit than identifying non-responders 1
• Tests lack strong negative predictive value - some patients without detected HRD may still benefit from PARPis 1
• ESMO notes that better biomarkers are urgently needed to identify current homologous recombination proficiency status 1

Practical Implications for Treatment

• BRCA mutation testing remains the gold standard for identifying patients most likely to benefit from PARPis 1
• Beyond BRCA mutations, genomic instability scores can help identify additional patients who may benefit 1
• HRD testing is particularly important in high-grade serous ovarian cancer, where approximately 50% of cases exhibit HRD 2
• Testing should be considered early in the treatment course to guide therapy selection and sequencing 5
• Accurate tumor typing by pathologists is crucial, as HRD is enriched in specific cancer types (ovarian, breast, pancreatic, prostate) 5

In summary, understanding the difference between HRR (the functional pathway) and HRD (deficiency in this pathway) is essential for optimizing treatment selection, particularly regarding PARP inhibitor therapy in ovarian and breast cancers. While current testing methods have limitations, they provide valuable information for predicting treatment benefit and improving patient outcomes.