In the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer, the choice of chemotherapy regimen, timing of administration (neoadjuvant vs. adjuvant), and optimization of dose density remain focal points of clinical debate for biologically high-risk patients. In a recent academic conference, Professor Oleg Gluz from the West German Study Group (WSG) shared pooled analysis data from the WSG ADAPT-HR+/HER2- and PlanB studies. This analysis focused on a high-risk population with a Recurrence Score (RS) >25 or lymph node positivity (>4), aiming to explore the impact of different chemotherapy strategies on long-term patient survival.01 Research Background: Clinical Dilemmas in Chemotherapy for High-Risk HR+/HER2- Breast Cancer
HR+/HER2- breast cancer exhibits high heterogeneity. With the widespread application of multigene assays (such as Oncotype DX), clinicians can more precisely identify biologically high-risk patients with a high risk of recurrence. For this population, uncertainties remain regarding the application of anthracyclines, the choice of taxanes, and the value of dose-dense regimens. Traditional dose-dense anthracycline-taxane regimens are considered the standard of care for high-risk patients, but the benefit of anthracyclines has been challenged in certain subgroups. Meanwhile, there is a lack of large-scale head-to-head pooled data regarding survival differences between neoadjuvant chemotherapy (NACT) and adjuvant chemotherapy (ACT) in this specific subgroup, as well as the impact of different taxanes (docetaxel vs. paclitaxel) and their administration frequencies. Therefore, WSG pooled two landmark studies, ADAPT and PlanB, in an attempt to provide higher-level evidence for clinical decision-making.
02 Pooled Study Design: Screening and Allocation Based on Biological High-Risk Definitions
This pooled analysis included a total of 1,910 patients with biologically high-risk HR+/HER2- breast cancer. High risk was defined as: a 21-gene Recurrence Score (RS) >25, or the presence of 4 or more positive lymph nodes (LN+). • PlanB Study Design: Patients were randomly assigned to either 6 cycles of docetaxel + cyclophosphamide (TC6) or 4 cycles of epirubicin + cyclophosphamide (EC) followed by 4 cycles of docetaxel (T). All patients with 0-3 positive lymph nodes also had their chemotherapy necessity determined based on genomic testing results. • ADAPT Study Design: For patients with an RS between 12-25, short-term (2-3 weeks) induction endocrine therapy (ET) was administered. For patients with clear indications for chemotherapy (RS >25 or >4 LN+), neoadjuvant or adjuvant chemotherapy was chosen based on the investigator’s decision. Chemotherapy regimens included weekly paclitaxel or nab-paclitaxel for 8 weeks, followed by 4 cycles of dose-dense EC. In this study, 83% of patients had an RS >25, and approximately 30% had 4 or more positive lymph nodes confirmed by clinical or pathological assessment. In the ADAPT study, 62% of patients received preoperative induction endocrine therapy, providing a unique perspective for evaluating the relationship between endocrine response and chemotherapy benefit.
03 Timing of Administration and Endocrine Induction: “Equivalence” of Neoadjuvant and Adjuvant Chemotherapy
A core finding was that the timing of chemotherapy administration (neoadjuvant vs. adjuvant) did not significantly impact patient survival outcomes. In both univariate and multivariate analyses of the ADAPT study, neoadjuvant and adjuvant chemotherapy showed high consistency in terms of invasive disease-free survival (iDFS). This means that for high-risk HR+/HER2- patients, the choice of neoadjuvant chemotherapy should be based more on the need for surgical downstaging or assessing chemotherapy sensitivity, rather than considerations of survival benefit. Furthermore, the study explored the impact of short-term induction endocrine therapy. Data showed that in these biologically high-risk patients, even a short-term (2-3 weeks) induction ET before chemotherapy did not negatively affect long-term survival. This result provides a safety guarantee for clinical IIT (investigator-initiated trials) and for assessing tumor biological behavior through short-term endocrine response.
04 The Role of Anthracyclines: Nodal Burden is a Key Consideration
The use of anthracyclines in HR+/HER2- breast cancer has become more cautious in recent years. The PlanB study previously confirmed that in the overall population, the TC6 regimen is non-inferior to anthracycline-containing regimens (EC-T). In this pooled analysis, Professor Oleg Gluz pointed out that regardless of RS levels, no additional survival dividend from adding anthracyclines was observed in the overall high-risk population. However, subgroup analysis showed that for patients with 4 or more positive lymph nodes (>4 LN+), anthracycline-containing regimens showed a trend toward benefit. This finding emphasizes the importance of nodal burden in chemotherapy regimen design: for patients with very high nodal burden, the sequential combination of anthracycline-taxane remains a robust choice; while for patients whose only high-risk factor is a high RS but have low nodal burden, de-anthracycline regimens (such as TC6) may be preferred to reduce the risk of potential cardiotoxicity and secondary hematologic malignancies.
05 Regimen Design and Dose Density: Potential Advantages of Docetaxel Combination Regimens
One of the most notable findings of the study was the comparison between taxane-based regimens and their durations. The pooled analysis showed that compared to the shorter (8-week) dose-dense paclitaxel monotherapy followed by the EC regimen, the longer (18-24 weeks) docetaxel-based combination regimen showed superior outcomes in iDFS. Specific data observed that the docetaxel-based regimens used in the PlanB study (such as TC6 or EC-T, with a total duration of approximately 18-24 weeks) provided better survival benefits compared to the weekly paclitaxel monotherapy (8 weeks) followed by dose-dense EC used in ADAPT. This difference was particularly prominent in subgroups with lower RS and extremely high nodal burden. Professor Oleg Gluz explained that although meta-analyses usually support the benefit of dose-dense therapy, those studies were mostly based on paclitaxel regimens. This study suggests that in this specific HR+/HER2- subgroup, the treatment intensity or longer duration of combination therapy with docetaxel may be more effective at suppressing the recurrence of high-risk clones than simply shortening the administration interval (dose density). This conclusion suggests that we cannot simply apply the logic of dose-density benefits from triple-negative breast cancer directly to high-risk HR+/HER2- patients.
06 Conclusion and Clinical Outlook: Toward More Precise Chemotherapy Decisions
This pooled analysis based on the WSG ADAPT and PlanB studies provides the following key guidance for the chemotherapy management of high-risk HR+/HER2- breast cancer:
- Timing of administration does not affect survival: The choice between neoadjuvant and adjuvant chemotherapy should be based on clinical downstaging needs and personalized management; both are equivalent in terms of long-term survival (iDFS).
- Endocrine induction is safe: Short-term endocrine screening does not impair the prognosis of high-risk patients and can serve as a means to evaluate biological behavior.
- Regimen optimization is more important than density: In this study population, long-duration docetaxel combination regimens performed better than short-duration weekly paclitaxel. The value of dose-dense regimens in this population needs to be re-evaluated in conjunction with the type of drug (docetaxel vs. paclitaxel).
- Stratify for de-anthracycline: De-anthracycline can be considered for the overall population, but anthracyclines still have their place for patients with a high nodal burden (>4 LN+). Professor Oleg Gluz concluded: “Although retrospective pooled analyses have certain limitations, this large sample size and clearly defined RS-screened population provide valuable data for our understanding of chemotherapy benefit patterns in HR+/HER2- breast cancer. Future research should further explore how to optimally combine chemotherapy with new targeted drugs (such as CDK4/6 inhibitors) in the era of adjuvant therapy to achieve true precision benefit.”
