Contributors: Jia Wang, Jinze Yu (Second Affiliated Hospital of Dalian Medical University)Editor’s Note At the 2025 ASCO Annual Meeting, the West German Study Group (WSG) presented a pooled analysis (Abstract No. 502) of three trials—including the ADAPT TP study—exploring survival outcomes following chemotherapy de-escalation in HER2-positive early breast cancer (eBC). Oncology Frontier invited Prof. Jia Wang and Dr. Jinze Yu from the Second Affiliated Hospital of Dalian Medical University to interpret and comment on the findings for our readers.
Study Overview
Background Current de-escalation strategies in HER2-positive early breast cancer aim to reduce or eliminate systemic chemotherapy (CTx) in order to minimize both acute and long-term toxicities. In three randomized de-escalation trials, the WSG evaluated short-term (12-week), paclitaxel-free neoadjuvant therapy (NAT) and its impact on treatment outcomes and survival predictors in HER2-positive eBC.
Methods
The three WSG trials focused on comparing short-course neoadjuvant chemotherapy with standard-duration regimens. This pooled analysis included 713 patients from these trials. Patients were divided into a chemotherapy group (CTx) and a non-chemotherapy/ADC neoadjuvant chemotherapy group (CTx-free/ADC NCT), to compare outcomes between these two treatment strategies. Patients who achieved pathological complete response (pCR, defined as ypT0/is ypN0) were allowed to omit further systemic chemotherapy, while those who did not achieve pCR were required to undergo additional systemic treatment. pCR was the primary endpoint of each randomized controlled trial, while overall survival (OS) was a secondary endpoint. Survival analyses were performed using Kaplan-Meier curves and Cox regression models.
Baseline Characteristics
As shown in Figure 1 of the study, patient age was relatively evenly distributed. Most patients were diagnosed with stage I disease (76.2%), followed by stage II (19.8%), and stage III (4.1%). Clinically, the majority were staged as cT1 (44.6%) or cT2–3 (54.3%), with only 1.1% classified as cT4. In terms of nodal status, 68.7% were cN0, 28.3% were cN1, and 2.9% were cN2–3. The majority of patients were hormone receptor–positive (81.6%), with the remaining 18.4% hormone receptor–negative. Histologic grading showed that 70.4% of tumors were grade 3, while 28.9% were grade 1–2.
This pooled dataset provides a solid foundation for evaluating the potential of chemotherapy-sparing approaches in HER2-positive early breast cancer. The survival results and their clinical implications will be further discussed in the next sections.
Study Results
A total of 713 patients were included in the analysis, with 149 in the CTx group and 564 in the CTx-free/ADC NAT group. The median follow-up duration was 60.7 months. In terms of invasive disease-free survival (iDFS) events, there were 10 cases (7%) in the CTx group and 74 cases (13%) in the CTx-free/NAT group. Distant disease-free survival (dDFS) events occurred in 8 patients (5%) in the CTx group and 51 patients (9%) in the CTx-free group. A total of 6 patients (4%) in the CTx group and 34 patients (6%) in the CTx-free group died during follow-up.
The 5-year overall survival (OS) rates were 97.8% (95% CI: 93.3–99.3) in the CTx group and 96.8% (95% CI: 94.8–98.0) in the CTx-free/ADC NAT group (HR 0.88; 95% CI: 0.36–2.11; P=0.775). The 5-year iDFS rates were 96.4% (95% CI: 91.5–98.5) and 88.2% (95% CI: 85.1–90.7), respectively (HR 0.56; 95% CI: 0.29–1.08; P=0.083).
Pathologic complete response (pCR) was achieved by 95 patients (66%) in the CTx group and 171 patients (31%) in the CTx-free/ADC NAT group. Among pCR patients in the CTx group, 5 (5%) experienced iDFS events, while 5 non-pCR patients (10%) also had iDFS events. In the CTx-free/ADC NAT group, 14 pCR patients (8%) and 59 non-pCR patients (16%) experienced iDFS events. The 5-year iDFS rate among pCR patients was 97.8% (95% CI: 91.3–99.4) in the CTx group and 93.7% (95% CI: 88.6–96.6) in the CTx-free group (HR 0.76; 95% CI: 0.27–2.12; P=0.609).
Univariate analysis showed that in the CTx group, pCR was associated with iDFS (HR 0.18; 95% CI: 0.04–0.76). In the CTx-free NAT group, iDFS was associated with tumor size (cT3–4 vs. cT1: HR 2.54; 95% CI: 1.22–5.28), nodal stage (cN1+ vs. cN−: HR 2.40; 95% CI: 1.44–3.58), histologic grade (grade 3 vs. grade 1–2: HR 1.85; 95% CI: 0.97–3.52), and pCR status (HR 0.47; 95% CI: 0.26–0.84).
Using BC360 and GNE800 assays to generate a prognostic score (PS:pCR), patients were stratified by risk. In the CTx-free/ADC NAT group, 18.2% of pCR patients had a low prognostic score, and 60.7% had a high score. In the CTx group, 47.2% of pCR patients were classified as low PS, while 80.7% were classified as high PS.
When stratified by PS:pCR, the estimated 5-year iDFS rate in the low PS:pCR group was 96.1% (95% CI: 85.2–99.0) in the CTx group and 85.7% (95% CI: 80.0–89.9) in the CTx-free/ADC NAT group. In the high PS:pCR group, the 5-year estimated iDFS was 95.0% (95% CI: 85.4–98.4) for the CTx group and 94.3% (95% CI: 89.6–96.9) for the CTx-free group.
Study Conclusion
This pooled analysis supports the feasibility and safety of neoadjuvant de-escalation therapy in patients with HER2-positive early breast cancer (eBC). A 12-week neoadjuvant regimen combining paclitaxel with anti-HER2 agents demonstrated both efficacy and good tolerability, achieving high 5-year survival rates.
For patients with prognostic stage I–II disease, a CTx-free/ADC NAT approach may be a reasonable option. Treatment decisions should be guided by baseline clinical and molecular factors. Notably, patients who achieve pCR after receiving CTx-free/ADC NAT appear to derive no significant additional benefit from standard adjuvant systemic chemotherapy.
Expert Commentary by Prof. Jia Wang
An increasing body of evidence supports the feasibility and safety of de-escalation strategies in HER2-positive early breast cancer (eBC). From a therapeutic perspective, current approaches to de-escalation can be categorized as follows. First, omitting certain chemotherapeutic agents—such as anthracyclines or platinum compounds—while maintaining a taxane (docetaxel or paclitaxel) plus trastuzumab and pertuzumab backbone. Representative trials include BCIRG 006, APT, TRAIN-2, TRYPHAENA, NeoSphere, and Keyriched-1 for anthracycline-free regimens, and BCIRG-007, neoCARHP, and HELEN-006 for platinum-free strategies. Second, replacing taxanes with novel antibody-drug conjugates (ADCs), either as monotherapy or in combination with pertuzumab or tyrosine kinase inhibitors (TKIs). Relevant studies include KRISTINE, PAMELA, TBCRC006/023, PerELISA, PHERGain, FASCINATE-N, and DB-11. While these studies often focus on pCR as the primary endpoint, long-term survival—typically a secondary endpoint—provides more meaningful evidence for the viability of de-escalation.
Although six cycles of TCbHP as neoadjuvant therapy is now widely accepted as the standard for early-stage HER2-positive breast cancer, questions remain as to whether this regimen is universally optimal across hormone receptor subtypes and anatomical stages. Many challenges lie ahead. First, we need reliable biomarkers to guide the selection of patients for chemotherapy omission or de-escalation strategies right from baseline. Second, radiomics could assist in evaluating early neoadjuvant response, helping adjust treatment before surgery to improve the chance of achieving pCR. Third, rather than debating whether ADCs should still be classified as chemotherapy, we should focus on identifying which patients benefit from complete chemotherapy-free regimens—such as dual-targeted therapy with trastuzumab and pertuzumab or ADC monotherapy—particularly in HR-negative and stage I–II patients. Fourth, surrogate survival endpoints for neoadjuvant endocrine therapy combined with targeted agents also deserve exploration.
The WSG’s ADAPT HER2+/HR−, ADAPT TP, and ADAPT TP-II studies have each reported five-year survival outcomes—in 2021, 2023, and 2024, respectively. These trials demonstrated that for patients who achieve pCR after neoadjuvant targeted therapy or targeted therapy combined with endocrine therapy, the omission of adjuvant chemotherapy does not compromise long-term survival. Although the pooled analysis included a heterogeneous population with both HR-positive and HR-negative tumors, and treatment regimens ranged from dual HER2-targeting with trastuzumab and pertuzumab to T-DM1-based therapies, the overall sample size exceeded 700 patients with five-year follow-up. This makes it one of the largest and most valuable studies on de-escalation to date.
Several key takeaways emerge from this pooled analysis. First, patients who achieve pCR after de-intensified neoadjuvant therapy do not benefit from additional adjuvant chemotherapy. The previously held belief that supplementing “missing” chemotherapy might further improve long-term outcomes now seems redundant—akin to drawing legs on a snake. Second, although treatment escalation is easy and de-escalation is difficult, a subset of HER2-positive patients can indeed achieve excellent long-term disease control without any chemotherapy. Though the path is challenging, it is certainly achievable. Third, future de-escalation strategies for HER2-positive eBC should be tailored according to the initial tumor burden. In other words, de-escalation should not be applied uniformly to all patients. Based on the ADAPT data, patients with stage I–II HER2-positive breast cancer appear to be ideal candidates, and at least 12 weeks of paclitaxel plus trastuzumab and pertuzumab represents a reliable and well-tolerated de-intensified option. Fourth, it is essential to continue following and even initiating de-escalation trials targeting different subgroups (HR-positive/negative, stage I–II versus stage III and above) with long-term survival as the primary endpoint.
Prof. Jia Wang Chief Physician, Professor, Master’s Supervisor Second Affiliated Hospital of Dalian Medical University
