What is the recommended adjuvant chemotherapy regimen for a patient with stage 3C triple-negative breast cancer?

Recommended Adjuvant Chemotherapy for Stage 3C Triple-Negative Breast Cancer

For stage 3C triple-negative breast cancer in the adjuvant setting, you should use dose-dense AC (doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m²) every 2 weeks for 4 cycles with G-CSF support, followed by paclitaxel 80 mg/m² weekly for 12 weeks, with strong consideration for adding carboplatin and pembrolizumab based on the neoadjuvant KEYNOTE-522 protocol adapted to the adjuvant setting. 1, 2

Standard Adjuvant Chemotherapy Backbone

The foundation of adjuvant treatment for stage 3C TNBC consists of:

• Anthracycline-taxane sequential regimens are the evidence-based standard for triple-negative breast cancer, with chemotherapy recommended for the vast majority of these patients 3

• Dose-dense AC followed by weekly paclitaxel is the preferred regimen (Category 1), demonstrating superior disease-free survival compared to every-3-week paclitaxel (HR 1.27,95% CI 1.03-1.57, P=0.006) 1

• The specific protocol: doxorubicin 60 mg/m² IV + cyclophosphamide 600 mg/m² IV every 2 weeks for 4 cycles with G-CSF support, followed by paclitaxel 80 mg/m² IV weekly for 12 consecutive weeks 1

Carboplatin Addition: The Evidence and Controversy

The role of carboplatin in the adjuvant setting specifically is controversial and differs from the neoadjuvant setting:

• In the neoadjuvant setting, platinum-based chemotherapy using carboplatin improves disease-free survival (HR 0.63,95% CI 0.53 to 0.75) and overall survival (HR 0.69,95% CI 0.55 to 0.86) with high-certainty evidence 4

• However, a retrospective single-center study in the adjuvant setting showed no benefit from adding carboplatin to standard anthracycline/taxane therapy, with median time to distant relapse of 29.5 months without carboplatin versus 25.0 months with carboplatin (p=0.606) 5

• The ESMO guidelines note that evidence for adding carboplatin to neoadjuvant regimens is mixed and does not consistently translate to improved survival outcomes 6

• Despite this, carboplatin is routinely indicated for node-positive disease (which includes stage 3C), particularly when used with pembrolizumab-based regimens 1

Pembrolizumab Integration

For stage 3C disease, pembrolizumab should be strongly considered as part of the regimen:

• The KEYNOTE-522 protocol (adapted from neoadjuvant to adjuvant use) includes pembrolizumab with chemotherapy, achieving a hazard ratio of 0.63 (95% CI 0.48-0.82, P<0.001) for event-free survival 1

• Pembrolizumab benefit is independent of PD-L1 status, so PD-L1 testing is not required to determine eligibility 1

• The regimen would consist of pembrolizumab combined with paclitaxel-carboplatin, followed by pembrolizumab with anthracycline-cyclophosphamide, then continued as adjuvant pembrolizumab for up to one year regardless of pathologic response 2

Essential Pre-Treatment Testing

Before initiating therapy, you must:

• Test all TNBC patients for germline BRCA1/2 mutations to guide potential adjuvant therapy decisions, particularly for PARP inhibitor eligibility 2

• Obtain baseline cardiac assessment with LVEF measurement if anthracyclines are planned, as doxorubicin cumulative dose should not exceed 240 mg/m² 1, 2

Post-Chemotherapy Adjuvant Considerations

If residual disease is present after surgery (or if this is purely adjuvant without neoadjuvant therapy):

• For germline BRCA1/2 wild-type patients, add capecitabine 1,250 mg/m² PO twice daily on days 1-14 of 21-day cycles for 6-8 cycles, which improves recurrence-free survival (HR 0.53, P=0.02) and overall survival (HR 0.55, P=0.03) in triple-negative disease 2

• For patients with germline BRCA1/2 mutations and high-risk features (≥pT2 or ≥pN1 disease), adjuvant olaparib may be added for 1 year after completing adjuvant chemotherapy 2

Critical Implementation Points and Pitfalls

Toxicity management is essential given the aggressive regimen:

• Carboplatin addition increases haematological toxicity, with grade III/IV neutropenia (RR 1.53), anaemia (RR 8.20), and thrombocytopenia (RR 7.59) more common 4

• Chemotherapy delays (RR 2.23) and dose reductions (RR 1.77) are more likely with platinum-containing regimens 4

• However, serious adverse events including febrile neutropenia (RR 1.16, not statistically significant), renal impairment (0.4%), and treatment-related death (0.2%) are not significantly increased 4

• Avoid delaying treatment start—initiate therapy within 2-4 weeks of diagnosis completion to avoid compromising outcomes 2

• Administer G-CSF (filgrastim or pegfilgrastim) starting 24-72 hours after each AC cycle 1

Alternative Considerations

If anthracyclines are contraindicated (cardiac dysfunction, prior anthracycline exposure approaching cumulative dose limits):

• Anthracycline-free regimens (carboplatin-taxane) should only be used when anthracyclines are specifically contraindicated 2

• Non-anthracycline, taxane-based regimens such as four cycles of docetaxel and cyclophosphamide may be used as an alternative in selected patients at risk of cardiac complications 3