At present, because of the characteristic of TNBC, the clinical treatment for TNBC is still based on adjuvant and neoadjuvant chemotherapy (18). Although chemotherapy plays an important role in the treatment of TNBC, the 10-year risk of relapse of early TNBC remains up to 20–40%. Therefore, it is particularly important to further improve adjuvant and neoadjuvant chemotherapy regimens (12, 19, 20). Capecitabine is one of the most widely studied drugs in neoadjuvant and postoperative adjuvant therapy for TNBC. Several randomized clinical trials (RCTS) have evaluated the clinical value of capecitabine as a combination therapy for TNBC, but their results are still controversial (5, 7–9, 21, 22). In the two most recent studies, SYSUCC-001 suggested that capecitabine maintenance therapy using lower dosage and higher frequency after completing adjuvant chemotherapy could improve the DFS of early TNBC patients (9), whereas CIBOMA failed to show a statistically significant increase in DFS by adding extended capecitabine to standard chemotherapy in early TNBC patients (8).
Anthracycline-taxane combination chemotherapy have been recommended as the preferred choice for TNBC patients. BCIRG-001 trail compared standard adjuvant anthracycline chemotherapy with anthracycline-taxane combination chemotherapy, and the relapse-free survival and overall survival were improved by anthracycline-taxane combination (13). GEICAM 9906 trial also showed that patients with basal phenotypes benefited more from the addition of taxane than taxane-free chemotherapy (14). Furthermore, a meta-analysis showed that the addition of four separate cycles of taxane to a fixed anthracycline-based regimen reduced breast cancer mortality (12). Previous researches have showed that the dose is associated with the prognosis of breast cancer patients. The reduction of anthracycline dose was associated with higher mortality risk and significantly decreased 5-year absolute survival in all molecular subtypes (15). In addition, higher dose of taxanes was associated with a significant improvement in median time to progression (16). However, the CALGB 9344 trail showed that AC plus paclitaxel resulted in superior overall survival and DFS compared with escalating doxorubicin dose (17). An individual patient-level meta-analysis of 16,500 women with early-stage breast cancer which was reported in the 2021 SABCS showed that, comparing with the TC, anthracycline-taxane combination can reduce the breast cancer recurrence rate. According to above studies, we classified A/EC, TA/E, CMF, FA/EC, FA/EC-T, and TC to be medium regimen, while A/EC-T and TA/EC were classified to be strong regimen.
In the present study, we first retrospectively collected the specific information of chemotherapy dose and regimen in SYSUCC-001 study. Then, we found pre-adjuvant chemotherapy regimen in SYSUCC-001 study included a large number of regimens that were different from CIBOMA study, and significant differences in the pre-intervention adjuvant therapy intensity existed between the two studies. There were no single CMF or taxanes without anthracylines regimens permitted in CIBOMA trial. However, SYSUCC-001 trial included 3 and 42 patients receiving CMF and TC regimen separately. In addition, more than half of patients received lower dose of taxanes or anthracyclines according to the CIBOMA trial minimum acceptable regimens for chemotherapy. To analyze whether these differences would affect the survival results of SYSUCC-001 trial, we defined the adjuvant chemotherapy regimen for patients in SYSUCC-001 based on the CIBOMA study’s protocol intensity and dose intensity: standard dose regimen and nonstandard dose regimens. We found that patients who used strength chemotherapy regimen accounted for about 76.74%, and those who used medium regimen accounted for 23.26%. In addition, about 32.3% and 52.2% patients received standard dose of anthracyclines and taxanes separately according to the CIBOMA trial minimum acceptable regimens for chemotherapy.
To further clarify whether the enhanced benefit of capecitabine found in SYSUCC-001 was triggered by the fact that the regimen intensity or the dose intensity of prior adjuvant chemotherapy in enrolled patients were not strictly defined, we performed a correlation analysis for these subgroups. The results of multivariate analysis showed that, in the observation group, the strength of the regimen and the dose of anthracycline were not significantly correlated with DFS; in the capecitabine treatment group, the medium regimen might be an obstructive factor affecting DFS (HR, 0.28; 95% CI, 0.09–0.90), and the standard dose of taxanes might be a contributing factor to DFS (HR, 2.04; 95% CI, 1.02–4.06). Further interaction analysis results showed that the strength of the treatment plan and the dose of anthracyclines did not affect DFS. Subgroup analysis of standard doses of paclitaxel showed that capecitabine treatment was able to significantly improve the DFS of TNBC patients (P = 0.014).
Compared with the CIBOMA study, the SYSUCC-001 study has included patients with different pre-adjuvant chemotherapy regimens and dose intensities. In the present study, we determined the corresponding subgroups of patients in the SYSUCC-001 study based on the CIBOMA study’s pre-adjuvant chemotherapy regimen and dose intensity standards. Our result showed that when the standard dose of paclitaxel was used for pre-adjuvant chemotherapy, capecitabine can improve the DFS of TNBC patients, but this result is still inconsistent with the results of the CIBOMA study. The reason for this discrepancy may be due to differences in the racial/ethnic backgrounds of patients in different studies. Furthermore, CIBOMA study did not compare patients receiving paclitaxel or anthracycline individually, making its results somewhat controversial. In addition, a meta-analysis involving CIBOMA and SYSUCC-001 studies also showed that capecitabine supplementation significantly improved DFS (23).
As a retrospective study, there are many inevitable biases in the subgroups that are separated by the strength of chemotherapy regimen or dose. In addition, our study doesn’t include patients receiving the neo/adjuvant regimen with platinum or PD-1/PD-L1 inhibitor. We need further randomized controlled study or real-world data to validate and replenish results of our study in the future.
In summary, there are some differences between patients in capecitabine group and observation group based on the dose of anthracyclines and the strength of the adjuvant chemotherapy regimen, but there were no differences in age, menstrual status, tumor size, or axillary lymph node status between capecitabine group and observation group for the standard dose of paclitaxel. Although there existed insufficient strength of regimen and dose in SYSUCC-001, the benefit from capecitabine was not changed. Our results further support the addition of capecitabine in the standardized paclitaxel chemotherapy regimen for early TNBC patients. Moreover, the standard dose of chemotherapy especially taxanes might be a positive factor for the effect of capecitabine intensive treatment. This result may give us a suggestion, in the clinical practice, when the patients suitable for the capecitabine intensive treatment, however, she can’t endure the side effect of the anthracycline-taxane combination therapy, we’d better reduce the dose of anthracycline not the taxanes.