A novel strategy involves combining antibody-drug conjugates (ADCs) with PARP inhibitors. This approach could potentially overcome the need for a germline BRCA mutation, significantly broadening the patient population that could benefit from PARP inhibitor therapy in triple-negative breast cancer.

A common barrier to PD-L1 testing in metastatic TNBC is insufficient tissue from the biopsy. Clinicians should remember that tissue from the primary tumor is a viable alternative for analysis. This simple workaround can prevent missed opportunities for patients to receive targeted immunotherapy.

The KEYNOTE-756 and Checkmate 7FL trials found high pathological complete response (pCR) rates with neoadjuvant immunotherapy in ER-low (1-10%) breast cancers. This suggests this unique subgroup, often excluded from triple-negative trials but behaving similarly, may benefit significantly from immunotherapy, though it is not yet standard of care.

It is crucial to re-biopsy metastatic breast cancer upon progression because the tumor's fundamental biology can change. A patient initially diagnosed with ER-positive disease can develop triple-negative, PD-L1 positive disease, which opens up entirely new treatment options like immunotherapy and different ADCs.

Contrary to the standard 'TKI-first' approach for driver mutations, a study in MET exon 14 skipping NSCLC suggests a different strategy. Patients with high PD-L1 expression appeared to have better outcomes with first-line chemoimmunotherapy, reserving the targeted therapy for later. This challenges the conventional wisdom of prioritizing the driver mutation over immunotherapy biomarkers in this specific subgroup.

For metastatic TNBC patients with both a germline BRCA mutation and PD-L1 positivity, experts favor initiating treatment with an ADC-immunotherapy combination. The rationale is that while PARP inhibitors are superior to chemo, there is no evidence they outperform a highly effective ADC, making the combo the preferred upfront choice.

For de novo metastatic, PD-L1 positive TNBC patients with a BRCA mutation, experts prefer an ADC with immunotherapy over a PARP inhibitor. This choice is driven by the potential for longer-lasting responses with the ADC/IO combination, even though PARP inhibitors directly target the underlying genetic mutation.

A significant portion of patients (30-50%) with metastatic triple-negative breast cancer do not survive to receive second-line treatment. This high attrition rate underscores the critical importance of administering the most effective therapy—offering the best PFS and response rate—in the first-line setting to maximize patient outcomes.

In high-risk, BRCA-positive patients eligible for both, clinicians favor giving a PARP inhibitor first. The rationale is based on established survival data, shorter one-year duration, and emerging biological evidence suggesting BRCA2-mutated tumors may be resistant to CDK4/6 inhibitors due to concurrent RB gene loss.