Effect of Adjuvant Paclitaxel and Carboplatin on Survival in Women With Triple-Negative Breast Cancer

Abstract

The value of platinum-based adjuvant chemotherapy in patients with triple-negative breast cancer (TNBC) remains controversial, as does whether BRCA1 and BRCA2 (BRCA1/2) germline variants are associated with platinum treatment sensitivity. OBJECTIVE To compare 6 cycles of paclitaxel plus carboplatin (PCb) with a standard-dose regimen of 3 cycles of cyclophosphamide, epirubicin, and fluorouracil followed by 3 cycles of docetaxel (CEF-T). DESIGN, SETTING, AND PARTICIPANTS This phase 3 randomized clinical trial was conducted at 9 cancer centers and hospitals in China. Between July 1, 2011, and April 30, 2016, women aged 18 to 70 years with operable TNBC after definitive surgery (having pathologically confirmed regional node-positive disease or node-negative disease with tumor diameter >10 mm) were screened and enrolled. Exclusion criteria included having metastatic or locally advanced disease, having non-TNBC, or receiving preoperative anticancer therapy. Data were analyzed from December 1, 2019, to January 31, 2020, from the intent-to-treat population as prespecified in the protocol. INTERVENTIONS Participants were randomized to receive PCb (paclitaxel 80 mg/m 2 and carboplatin [area under the curve = 2] on days 1, 8, and 15 every 28 days for 6 cycles) or CEF-T (cyclophosphamide 500 mg/m 2 , epirubicin 100 mg/m 2 , and fluorouracil 500 mg/m 2 every 3 weeks for 3 cycles followed by docetaxel 100 mg/m 2 every 3 weeks for 3 cycles). MAIN OUTCOMES AND MEASURES The primary end point was disease-free survival (DFS). Secondary end points included overall survival, distant DFS, relapse-free survival, DFS in patients with germline variants in BRCA1/2 or homologous recombination repair (HRR)-related genes, and toxicity. RESULTS A total of 647 patients (mean [SD] age, 51 [44-57] years) with operable TNBC were randomized to receive CEF-T (n = 322) or PCb (n = 325). At a median follow-up of 62 months, DFS time was longer in those assigned to PCb compared with CEF-T (5-year DFS, 86.5% vs 80.3%, hazard ratio [HR] = 0.65; 95% CI, 0.44-0.96; P = .03). Similar outcomes were observed for distant DFS and relapse-free survival. There was no statistically significant difference in overall survival between the groups (HR = 0.71; 95% CI, 0.42-1.22, P = .22). In the exploratory and hypothesis-generating subgroup analyses of PCb vs CEF-T, the HR for DFS was 0.44 (95% CI, 0.15-1.31; P = .14) in patients with the BRCA1/2 variant and 0.39 (95% CI, 0.15-0.99; P = .04) in those with the HRR variant. Safety data were consistent with the known safety profiles of relevant drugs. CONCLUSIONS AND RELEVANCE These findings suggest that a paclitaxel-plus-carboplatin regimen is an effective alternative adjuvant chemotherapy choice for patients with operable TNBC. In the era of molecular classification, subsets of TNBC sensitive to PCb should be further investigated.

Breast cancer

“…148 One adjuvant therapy study, mainly in patients with pT1 and node-negative status, showed improved disease-free survival with a carboplatin anthracycline-free combination over epirubicin, fluoro uracil, and cyclophosphamide followed by docetaxel. 149 The carboplatin effect in early breast cancer seems to be independent of BRCA status. 150 To date, PARP inhibitors have not been shown to improve short-term or long-term outcomes in breast cancer.…”

The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers

“…Pending a tolerable dose, the combination treatment could be used for both inherent and acquired resistant TNBC with or without selection for basal biomarkers, such as expression of high molecular weight cytokeratins and EGFR1 overexpression. This combination could increase the fraction of patients achieving the benefits of responders to carboplatin in the neoadjuvant 5,6 , adjuvant 45 , and metastatic 46 settings. In conclusion, we show that low dose prexasertib can sensitize carboplatin-resistant TNBC to carboplatin.…”

AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2021

“…Thus, general use in TNBC cannot be recommended (LoE 1aa/A/AGO–) [56]. In TNBC, the question of adding carboplatin as a fourth substance has still not been finally clarified with regard to an OS advantage [57]. However, if an anthracycline-free therapy is chosen, a taxane/platinum combination should be used here (LoE 1b/B/AGO+) [58].…”