What is the recommended second-line treatment for a patient with triple negative breast cancer (TNBC) that has metastasized to the bone diffusely and has a programmed death-ligand 1 (PD-L1) score of 1?

Second-Line Treatment for Metastatic Triple-Negative Breast Cancer with PD-L1 Score = 1

For second-line treatment of metastatic TNBC with diffuse bone involvement and PD-L1 score of 1, sacituzumab govitecan is the preferred option, demonstrating dramatic superiority with an objective response rate of 35% versus 5% with standard chemotherapy and median progression-free survival of 5.6 versus 1.7 months (HR 0.41, P < 0.001). 1, 2

Primary Second-Line Recommendation

Sacituzumab govitecan should be strongly considered as the preferred second-line agent after progression on first-line therapy, as it is specifically recommended by NCCN for patients who have received ≥2 prior therapies for metastatic disease, though emerging evidence supports its use earlier in the treatment sequence. 3, 1 This antibody-drug conjugate has transformed the second-line landscape for metastatic TNBC regardless of PD-L1 status. 1

Alternative Second-Line Options Based on Specific Clinical Scenarios

If BRCA1/2 Mutation Testing is Positive

• PARP inhibitors (olaparib or talazoparib) are category 1 preferred over chemotherapy for patients with germline BRCA1/2 mutations who have received prior chemotherapy, demonstrating 40-60% improvement in progression-free survival (median PFS 7.0-8.6 months versus 4.2-5.6 months with chemotherapy). 3, 2, 1

• This represents a critical decision point: all patients with TNBC must undergo germline BRCA1/2 mutation testing to identify candidates for PARP inhibitors, as this fundamentally changes the treatment algorithm. 3, 2

If Sacituzumab Govitecan is Unavailable or Contraindicated

Single-agent chemotherapy remains the backbone of second-line treatment, with the following hierarchy based on prior exposures: 4

• Anthracyclines (if taxanes were used first-line and anthracyclines were not used in the neoadjuvant/adjuvant setting within 12 months) 4, 5

• Taxanes (paclitaxel or docetaxel if anthracyclines were used first-line) 5, 6

• Platinum agents (carboplatin or cisplatin), particularly if BRCA mutation is present, showing response rates of 68.0% versus 33.3% for docetaxel in BRCA-mutated disease 3, 5

• Other single agents including capecitabine, eribulin, gemcitabine, or vinorelbine, though these demonstrate diminished returns in second-line and beyond 4, 5, 1

Critical Pitfall Regarding PD-L1 Score of 1

A PD-L1 score of 1 creates a significant clinical dilemma because the definition of "PD-L1 positive" varies by assay and clinical trial: 4

• For atezolizumab: PD-L1 positivity requires ≥1% tumor-infiltrating immune cells using the SP142 antibody 4

• For pembrolizumab: The KEYNOTE-355 trial showed benefit primarily in patients with Combined Positive Score (CPS) ≥10 using the 22C3 antibody, with marginal benefit at CPS ≥1 4

Therefore, a PD-L1 score of 1 likely does NOT qualify this patient for immunotherapy rechallenge in the second-line setting, as the threshold for meaningful benefit appears to be CPS ≥10 for pembrolizumab, and the patient has presumably already progressed on first-line immunotherapy if they received it. 4

Why Combination Chemotherapy is Generally NOT Recommended

Single-agent sequential chemotherapy is strongly preferred over combination regimens in the second-line setting because: 4

• Combination therapy demonstrates higher response rates but no improvement in overall survival 4

• Combination regimens are reserved for visceral crisis or immediately life-threatening disease requiring rapid response 4

• Resistance to chemotherapy develops quickly, and lines of treatment past the second have demonstrated diminished returns 4

Bone-Specific Considerations

For diffuse bone metastases, ensure appropriate supportive care including:

• Bone-modifying agents (denosumab or zoledronic acid) should be administered concurrently with systemic therapy to reduce skeletal-related events, though this is supportive rather than disease-modifying treatment 5

Treatment Sequencing Algorithm

1. First, verify BRCA1/2 mutation status - if positive and not previously treated with PARP inhibitors, use olaparib or talazoparib 3, 1

2. If BRCA wild-type, prioritize sacituzumab govitecan as the preferred second-line option 1, 2

3. If sacituzumab govitecan unavailable, select single-agent chemotherapy based on prior exposures (anthracycline if taxane was used first-line, or vice versa) 4, 5

4. Avoid immunotherapy rechallenge in second-line with PD-L1 score of 1, as this falls below the threshold for demonstrated benefit 4

5. Reserve combination chemotherapy only for symptomatic visceral crisis requiring immediate response 4