Typically, TNBC is characterized by lack of Her2, PR, and ER. Due to the lack of other effective treatment, cytotoxic chemotherapy is the main therapy for TNBC. TNBC responds well to cytotoxic chemotherapy and has a higher pCR rate after neoadjuvant chemotherapy. Patients who obtained a pCR could achieve prolonged EFS and OS1. However, the clinical progression of TNBC is dismal relative to non-TNBC11–15. Therefore, the direction of current research is aimed at improving the pCR rate of neoadjuvant chemotherapy to improve the prognosis.
Over time, taxane- and anthracycline-based neoadjuvant regimens have become a standard treatment for TNBC. Some phase 2 clinical trials have shown that adding platinum to taxane- and anthracycline-based neoadjuvant regimens can significantly improve the pCR rate. In a GeparSixto trial, more patients achieved a pCR rate of 53% in the group combining carboplatin with paclitaxel plus non-pegylated liposomal doxorubicin and bevacizumab relative to those treated without carboplatin4. In the CALGB 40603 trial, patients were randomly assigned to receive paclitaxel with or without carboplatin followed by doxorubicin plus cyclophosphamide. Similar to the GeparSixto trial results, the carboplatin-treated group achieved a higher pCR rate (54% vs 41%, p = 0.003)5. Sibylle Loibl et al. reported the results of the first randomized, double-blind, phase 3 trial, BrighTNess. The proportion of patients in the paclitaxel, carboplatin and veliparib group who achieved a pCR was higher than that in the paclitaxel only group (168 [53%] of 316 patients vs. 49 [31%] of 158 patients, p < 0.0001), but the pCR rate was similar to that of the paclitaxel plus carboplatin group (92 [58%] of 160 patients, p = 0.36)3. The results of the BrighTNess study further established the important role of carboplatin in neoadjuvant chemotherapy for TNBC.
However, adding carboplatin to anthracycline plus paclitaxel substantially increased acute toxicity, with only 64%-88% of patients completing all treatment cycles3, 4, 5. Due to the long-term cardiotoxicity caused by anthracycline, several studies have explored the efficacy of neoadjuvant taxanes plus carboplatin regimens in TNBC and have achieved satisfactory pCR rates6, 7. Previous results of our team showed that the pCR rate of 4 cycles of paclitaxel plus carboplatin in TNBC is 57.92%6. Priyanka Sharma et al. analyzed the efficacy of docetaxel plus carboplatin (DCb). Through combined analysis of two cohorts, they found that the total pCR rate and residual cancer burden (RCB) 0 / 1 rate of the DCb regimen were 55% and 68%, respectively7. The pCR rate of this DCb regimen seems to be numerically higher than that of the taxane- and anthracycline-based neoadjuvant regimens reported in several trials5, 16, 17. As a result, National Comprehensive Cancer Network (NCCN) guidelines have added weekly paclitaxel plus carboplatin or docetaxel plus carboplatin regimens for select patients with TNBC in the preoperative setting18. Recently published NeoSTOP study was confirmed that the pCR and RCB 0 + 1 rates of carboplatin plus docetaxel (CbD) were similar to carboplatin plus paclitaxel followed by doxorubicin plus cyclophosphamide19.
However, there is no study comparing the DCb regimen with the taxane- and anthracycline-based neoadjuvant regimens.
The NeoCART study is a multicenter prospective randomized controlled study to assess 6 cycles of DCb with epirubicin plus cyclophosphamide followed by docetaxel. Docetaxel combined with carboplatin showed a higher pCR rate (61.4%) with an absolute difference in the pCR rate of 22.8%. Our study supports the results of previous neoadjuvant chemotherapy studies on TNBC. In our study, the pCR rate was 38.6% in the control group, which is similar to the retes of 28%-46% reported in several trials of taxane- and anthracycline-based neoadjuvant regimens3, 5, 16, 17.
This multicenter, prospective, randomized controlled study showed that 6 cycles of DCb chemotherapy is tolerable and 88.6% of patients completed all 6 cycles of treatment. In the analysis of adverse reactions, the use of carboplatin resulted in increased thrombocytopenia, but most patients experienced grade 1/2 adverse events; patients in the EC-D group may need a longer treatment time and are more likely to experience neutropenia.
A previous meta-analysis confirmed that patients with TNBC who achieved a pCR after neoadjuvant treatment had prolonged EFS and OS compared those who did not achieve a pCR1. According to the results of previous studies, the survival benefit of carboplatin is not clear. Our study showed that 6 cycles of DCb can significantly improve the possibility of achieving a pCR in patients with early TNBC and that the toxicity is controllable, while the rate of EFS and OS were similar to the taxane- and anthracycline-based group.
In the BRCA status detection performed in our study, 5 patients (12.2%) had deleterious mutations, which was consistent with the results of previous studies3, 7, 20. In theory, the DNA repair defects associated with BRCA mutation indicate that TNBC with BRCA mutation should be sensitive to platinum, a DNA damage drug. In the TNT study on advanced breast cancer, a subgroup analysis demonstrated that carboplatin had a higher the objective response rate than that of docetaxel (68.0% vs. 33.3%, p = 0.03) in the BRCA mutation subgroup, and progression-free survival was significantly different in the two groups (6.8 m vs. 4.4 m, p = 0.002)21. However, the results of neoadjuvant studies are not the same. The secondary analysis of the GeparSixto study showed that carboplatin did not further increase the pCR rate in patients with BRCA mutations (66.7% vs. 65.4%), but it increased the pCR rate from 36.4–55% in patients with wild type BRCA20. A subgroup analysis of the phase III BrighTNess study showed that carboplatin did not significantly increase the pCR rate in the population with BRCA mutations3. Similarly, Priyanka Sharma et al. found that the deleterious BRCA mutation was not associated with a pCR and RCB 0 or 1, and similar pCR rates were found in patients with wild-type and mutant BRCA7. In addition, 40%-50% of BRCA wild-type TNBC had homologous recombination deficiency (HRD). Therefore, HRD may become a predictor of the benefits of platinum agents22, 23, 24. Further HRD detection and analysis in the NeoCART study is in progress.
Our study has some limitations. The control group of the NeoCART study, similar to the KEYNOTE-522 (NCT03036488) study and part of the BrighTNess study, used epirubicin plus cyclophosphamide followed by docetaxel every 3 weeks3. A recently published study from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) established the incremental benefit of 2-week regimens over 3-week regimens25. Additionally, the preferred recommended regimens in the NCCN guidelines were dose-dense doxorubicin/cyclophosphamide followed by weekly paclitaxel or every 2 weeks (ddAC-T). However, a head-to-head comparison is need between the EC-D and ddAC-T regimens for their effectiveness as neoadjuvant chemotherapy. The evidence for ddAC-T in the NCCN guidelines originates from the CALGB 9741 trial, which focuses on adjuvant chemotherapy26. In the EBCTCG meta-analysis, only 2583 (6.9%) cases were included from neoadjuvant chemotherapy studies25. In addition, according to the results of the ECOG 1199 study, the efficacy of docetaxel administration every 3 weeks was the same as that of weekly paclitaxel27.
In summary, as assessed with the regimen of taxane- and anthracycline-based neoadjuvant therapy, docetaxel combined with carboplatin showed a higher pCR rate, a low incidence of controllable treatment-related adverse events, and the similar survival rates. Docetaxel combined with carboplatin is an effective and promising neoadjuvant chemotherapy regimen for TNBC. The results need to be verified in a phase III study, and longer follow-up data are needed for the survival results.