Overcoming Resistance in Triple-Negative Breast Cancer: A Translational Perspective on Next-Generation DNA Damage...

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to its heterogeneity and resistance mechanisms.
• Specific vulnerabilities in DNA repair pathways, such as those associated with BRCA1/2 alterations or homologous recombination deficiency (HRD), are key therapeutic targets.

Purpose of the Study:

• To review the current landscape of DNA damage response (DDR)-targeted and synthetic lethality strategies for TNBC.
• To synthesize evidence on emerging DDR targets and resistance mechanisms.

Main Methods:

• A narrative review of mechanistic, preclinical, clinical, and translational evidence.
• Summary of TNBC heterogeneity, biomarker-guided treatments, PARP inhibition, and novel DDR targets.

Main Results:

• Poly(ADP-ribose) polymerase (PARP) inhibitors and platinum agents are clinically validated for HRD-positive TNBC.
• Most novel DDR inhibitors are in early-stage development, facing challenges from resistance mechanisms like BRCA reversion.
• Safety, selectivity, and biomarker standardization hinder clinical translation.

Conclusions:

• Exploiting HRD in TNBC with PARP inhibitors and platinum agents is effective in selected patients.
• Future progress depends on validating biomarkers, assessing HRD dynamically, and optimizing combination strategies for improved therapeutic index.