In what scenario might PARP inhibitors be considered despite a negative germline BRCA result?

• A. PARP inhibitors are never used if germline negative
• B. A somatic BRCA alteration can indicate suitability for PARP inhibitors
• C. PARP inhibitors used only if both germline and somatic BRCA are positive
• D. Somatic results do not affect PARP inhibitor use

Answer: (B)

The key idea is that PARP inhibitors can be effective when the tumor itself has BRCA-related repair defects, even if a patient’s germline BRCA test is negative. Tumors can acquire BRCA mutations somatically, meaning the cancer cells carry a BRCA alteration that is not present in the germline. When BRCA1/2 or other homologous recombination repair pathways are defective in the tumor, cancer cells become highly dependent on PARP-mediated DNA repair. Inhibiting PARP in this context leads to accumulation of DNA damage and cancer cell death, while normal cells with intact BRCA function are less affected. Therefore, a somatic BRCA alteration identified in tumor testing can indicate sensitivity to PARP inhibitors even if germline testing is negative. This is why tumor sequencing panels or other somatic HRD assessments can guide therapy. The other statements misstate how these drugs are used or ignore the role of tumor-specific alterations.