What is the role of neoadjuvant Poly (ADP-ribose) polymerase (PARP) inhibitors with or without chemotherapy in patients with Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer?

Neoadjuvant PARP Inhibitors in HER2-Negative Breast Cancer: Role and Efficacy

For patients with HER2-negative breast cancer, neoadjuvant PARP inhibitors should be considered primarily for those with germline BRCA1/2 mutations, with talazoparib monotherapy showing the most promising pathological complete response rates of approximately 50% in this population.

Patient Selection for Neoadjuvant PARP Inhibitors

The role of PARP inhibitors in the neoadjuvant setting for HER2-negative breast cancer is primarily defined by:

Germline BRCA Status

• PARP inhibitors are most effective in patients with germline BRCA1/2 mutations
• These mutations create defects in homologous recombination repair that can be exploited by PARP inhibitors

Disease Characteristics

• Triple-negative breast cancer (TNBC) patients with BRCA mutations show higher response rates
• Hormone receptor-positive patients with BRCA mutations may also benefit, particularly those with high-risk features

Evidence for Neoadjuvant PARP Inhibitor Use

Single-Agent PARP Inhibition

• Talazoparib as monotherapy has demonstrated impressive pathological complete response (pCR) rates of nearly 50% in HER2-negative breast cancer patients with germline BRCA1/2 mutations 1
• Single-agent therapy may offer advantages in terms of reduced toxicity compared to combination approaches

Combination Approaches

• Recent network meta-analysis suggests that chemotherapy plus olaparib may achieve higher pCR rates (82.5%) in hormone receptor-positive, HER2-negative breast cancer 2
• However, this must be balanced against potentially increased toxicity with combination regimens

Comparative Efficacy of Different Approaches

When comparing different neoadjuvant approaches:

1. PARP inhibitor monotherapy: Offers significant efficacy in BRCA-mutated patients with potentially fewer adverse events
2. PARP inhibitor + chemotherapy: May provide higher pCR rates but with increased toxicity
3. Chemotherapy alone: Remains standard of care for patients without BRCA mutations

Considerations for Clinical Implementation

Toxicity Management

• Myelosuppression is a common adverse effect of PARP inhibitors
• Monitoring for anemia, neutropenia, and thrombocytopenia is essential
• Dose interruptions or reductions may be necessary to manage toxicities 3

Long-Term Safety Concerns

• Risk of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) with PARP inhibitors
• Careful monitoring for hematological toxicity is required
• Discontinue treatment if MDS/AML is confirmed 3

Special Considerations

Triple-Negative vs. Hormone Receptor-Positive Disease

• PARP inhibitors may be more effective in TNBC with BRCA mutations
• For hormone receptor-positive disease, higher risk features (e.g., multiple positive lymph nodes) may identify patients most likely to benefit 4

Future Directions

• Ongoing trials are investigating PARP inhibitors in combination with immune checkpoint inhibitors for TNBC
• Expanding beyond germline BRCA mutations to include somatic BRCA mutations and other homologous recombination defects 5

Practical Algorithm for Decision-Making

1. Test all HER2-negative breast cancer patients for germline BRCA1/2 mutations
2. For patients with confirmed germline BRCA1/2 mutations:
   • Consider neoadjuvant talazoparib monotherapy (particularly for TNBC)
   • Alternative: Consider combination of chemotherapy plus PARP inhibitor
3. For patients without BRCA mutations:
   • Standard neoadjuvant chemotherapy remains the treatment of choice
   • Consider clinical trials investigating PARP inhibitors in homologous recombination deficient tumors

Pitfalls to Avoid

• Do not use PARP inhibitors in patients without confirmed BRCA mutations outside of clinical trials
• Avoid combining PARP inhibitors with platinum agents without careful monitoring due to overlapping toxicities
• Do not neglect genetic counseling for patients found to have germline BRCA mutations

While the evidence for neoadjuvant PARP inhibitors is still evolving, their role in HER2-negative breast cancer with germline BRCA mutations is promising, particularly as monotherapy or in carefully selected combination approaches.