The HELEN-001 trial compared the efficacy of docetaxel plus cisplatin with that of docetaxel plus doxorubicin and cyclophosphamide as the neoadjuvant treatment for TNBC. The results indicated the docetaxel plus cisplatin regimen achieved higher pCR rates significantly than docetaxel plus doxorubicin and cyclophosphamide, with a manageable toxicity profile. To the best of our knowledge, this is the first trial to directly compare these two regimens in patients with TNBC.
The literature suggests that adding platinum to anthracycline- and taxane-based regimens enhances the pCR rate in patients with TNBC, although it was linked with high toxicity risk5–7. In contrast, neoadjuvant platinum-taxane regimens without anthracycline have demonstrated efficacy with a manageable toxicity profile in TNBC. For instance, the NeoSTOP trial indicated a pCR rate of 54% with the 6-cycle docetaxel plus carboplatin regimen but with a more favorable toxicity profile16. However, evidence comparing neoadjuvant platinum-taxane regimens with standard anthracycline-taxane regimens is few. The NeoCART trial reported a markedly increased pCR rate in patients treated with docetaxel plus carboplatin compared to those treated with epirubicin plus cyclophosphamide followed by docetaxel (61.4% vs. 38.6%, P = 0.044), with a pCR increase of 22.8%17. The data of this investigation are consistent with the NeoCART trial, although the absolute increase in pCR in this trial (16.1%) was smaller, likely due to the higher tumor burden of participants, with 63% of patients having node-positive tumors, including those with N3 involvement. The strength of this trial is its original design, adequate sample size, and sufficient statistical power to detect pCR differences.
In our study, the pCR of the 6-cycle docetaxel plus cisplatin regimen was 51.9%, comparable to that of carboplatin, anthracycline, and taxane-based regimens in the Geparsixto, CALGB40603, and BrighTNess trials (53.2–57%)5–7. However, only 64–88% of patients in these trials completed all treatment cycles. In this trial, only 13 (12%) patients who received docetaxel plus cisplatin discontinued the treatment, and 2 discontinuations were due to severe toxicity.
Furthermore, cisplatin was used, partly due to the positive evidence from a few studies indicating its efficacy as a neoadjuvant treatment against TNBC18–21. Additionally, in another study involving 144 patients with TNBC,adding cisplatin to anthracycline- and taxane-based neoadjuvant chemotherapy increased pCR (36% vs. 21%, P = 0.076), improved progression-free (HR = 0.49, P = 0.007), and overall (HR = 0.40, P = 0.002) survival compared to adding carboplatin10. It is important to note that cisplatin and carboplatin have distinct spectrums of adverse reactions22,23. Therefore, it was postulated that combining docetaxel plus cisplatin could offer advantages over combining it with carboplatin regarding efficacy and hematological toxicity. Although the comparison of efficacy and safety of neoadjuvant regimens comprising cisplatin versus carboplatin was not assessed in this trial, the neoadjuvant regimen comprising cisplatin revealed a pCR rate similar to that of a carboplatin-containing regimen without increasing the occurrence of grade 3 or 4 adverse events compared to the anthracycline-taxane-based therapy. However, to compare the safety and efficacy of docetaxel plus cisplatin to that of docetaxel plus carboplatin, further prospective randomized trials are needed.
The dysregulated BRCA pathway is associated with TNBC24,25. In this study, 25 patients (11.8%) had gBRCA1/2 mutations, consistent with the literature26,27. Platinum-based regimens have been shown to be effective in gBRCA1/2 mutation carriers by a meta-analysis comparing between gBRCA1/2 mutation individuals who received platinum-based treatment versus those who did not28. However, the exploratory analyses in this trial contradicted this. This might be because 1), the small sample size of gBRCA1/2 mutation carriers which restricted sufficient statistical measurement and differences analyses, and 2), non-BRCA1/2 homologous recombination deficiency(HRD) carriers might have diluted and therefore, affected the results27,29–31. To confirm this, HRD detection for HELEN-001 study analysis is in progress.
The follow-up period of this trial was not long enough to depict prolonged EFS in the docetaxel plus cisplatin group than in the docetaxel plus doxorubicin and cyclophosphamide group. However, other investigations have indicated a sustained clinical benefit in TNBC patients who achieved pCR after neoadjuvant chemotherapy3,6.
This trial had the following limitations: (I) the definition of TNBC might differ from the guidelines set by the College of American Pathologists, as the cutoff value of < 10% was applied for hormone receptor negativity32. However, estrogen receptor 1–9% stained was considered equivocal, and low estrogen receptor-positive and -negative individuals had similar survival rates and may not be benefited from endocrine therapy33. (II) Docetaxel plus doxorubicin and cyclophosphamide was no longer a primary National Comprehensive Cancer Network guideline recommendation. According to the ECOG 1199 study findings, doxorubicin plus cyclophosphamide followed by a weekly paclitaxel regimen (AC-wP) may be better for TNBC patients. However, it was noteworthy that this trial was specifically focused on evaluating adjuvant therapy, and a direct comparison was required between the docetaxel plus doxorubicin and cyclophosphamide and AC-wP therapies to assess their effectiveness as neoadjuvant chemotherapy. (III) According to the KEYNOTE-522 study, adding pembrolizumab to neoadjuvant carboplatin plus weekly paclitaxel followed by anthracycline plus cyclophosphamide can improve pCR and EFS in TNBC34–36, making it the optimal neoadjuvant treatment option for TNBC. However, at the time of this trial, pembrolizumab was not available in China. Based on the above preliminary results, another study HELEN-011 study (NCT05475678) has been designed to explore the efficacy of adding a programmed cell death protein 1 (PD-1) inhibitor to neoadjuvant docetaxel plus platinum chemotherapy in TNBC, which is currently underway. (IV) This trial was conducted in China, which may limit the generalizability of the results to other populations.
In summary, the HELEN-001 trial revealed that docetaxel plus cisplatin had a substantially increased pCR rate than docetaxel plus doxorubicin and cyclophosphamide against TNBC. Furthermore, the docetaxel plus cisplatin regimen also indicated a manageable incidence of treatment-related adverse events. Therefore, the taxane plus platinum regimen may serve as an alternative or even preferred neoadjuvant chemotherapy strategy for TNBC patients.