Highlight
- Neoadjuvant combination of paclitaxel, trastuzumab, and pertuzumab (THP) induced excellent 5-year survival outcomes in stage II–III ERBB2-positive breast cancer patients in the DAPHNe trial.
- High baseline detection rate of circulating tumor DNA (ctDNA) was observed pre-treatment, with near-complete clearance after 12 weeks of neoadjuvant THP therapy.
- Ultrasensitive, tumor-informed ctDNA monitoring showed potential as a biomarker for treatment response and minimal residual disease in ERBB2-positive breast cancer.
- Study supports further exploration of ctDNA-guided therapy de-escalation strategies to minimize toxicity while maintaining excellent oncologic control.
Study Background
ERBB2-positive (formerly HER2-positive) breast cancer, characterized by amplification or overexpression of the ERBB2 gene, represents approximately 15-20% of breast cancer patients and historically confers a poorer prognosis. The introduction of targeted therapies, notably trastuzumab and pertuzumab, has transformed management, particularly in neoadjuvant settings for early-stage disease. Neoadjuvant therapy aims to reduce tumor burden before surgery, increase breast conservation rates, and provide prognostic information based on pathologic response. However, long-term clinical outcomes of short-course THP regimens and the utility of ultrasensitive circulating tumor DNA (ctDNA) assays to monitor minimal residual disease have been inadequately explored.
The DAPHNe trial addresses these gaps by assessing the efficacy of an abbreviated neoadjuvant paclitaxel, trastuzumab, and pertuzumab (THP) protocol over 12 weeks in stage II–III ERBB2-positive breast cancer, coupled with sophisticated ctDNA monitoring to assess tumor dynamics and treatment response.
Study Design
The DAPHNe trial was a prospective, single-arm, phase 2, nonrandomized clinical study conducted between November 2018 and January 2020 at a multicenter academic cancer center and affiliated community practices. The trial enrolled 98 patients with stage II to III ERBB2-positive breast cancer. The majority were female (99%) with a median age of 49.5 years, predominantly stage II disease (92.9%), and two-thirds had hormone receptor-positive tumors.
Intervention consisted of neoadjuvant administration of paclitaxel, trastuzumab, and pertuzumab (THP) over 12 weeks, followed by surgery and adjuvant therapy contingent upon pathologic response.
Ultrasensitive ctDNA analyses were performed in 57 patients with available tumor tissue and serial plasma samples, utilizing a whole-genome-based, tumor-informed assay at four predefined time points: baseline (pre-treatment), preoperative (post-neoadjuvant therapy), postoperative, and late adjuvant follow-up.
Primary outcomes included 5-year event-free survival (EFS), recurrence-free interval (RFI), distant RFI, and overall survival (OS). ctDNA detection and clearance dynamics were exploratory but informative measures.
Key Findings
With a median follow-up of 5.2 years, patients in the DAPHNe trial exhibited remarkable long-term outcomes. The 5-year EFS was 99% (95% CI, 97%-100%), 5-year RFI was 98% (95% CI, 93%-100%), 5-year distant RFI was 100% (95% CI, 100%-100%), and 5-year OS was 99% (95% CI, 97%-100%). These outcomes indicate that the abbreviated 12-week THP regimen is highly effective in this patient population.
Regarding ctDNA dynamics, baseline ctDNA was detected in 89.5% (51/57) of patients, reflecting high assay sensitivity and tumor DNA shedding pre-treatment. Following neoadjuvant therapy, ctDNA clearance occurred in 96.1% (49/51) of these patients. Only two individuals remained ctDNA-positive preoperatively, indicating residual disease at a molecular level. During postoperative follow-up, ctDNA detectability remained low (<10%), aligning with the excellent clinical outcomes observed.
Notably, a single patient developed local recurrence. CtDNA was detected at the time of recurrence and subsequently cleared following surgical resection, underscoring the potential role of ctDNA as an early marker of relapse and its responsiveness to therapeutic intervention.
Expert Commentary
The DAPHNe trial results support that an abbreviated 12-week neoadjuvant THP regimen provides excellent disease control in early-stage ERBB2-positive breast cancer, potentially simplifying treatment without compromising efficacy. This shorter duration regimen could reduce treatment-related toxicity, costs, and patient burden compared with longer, more intense protocols.
The utilization of ultrasensitive, tumor-informed ctDNA assays to monitor minimal residual disease represents a clinically transformative strategy. The high baseline detection rate and near-universal clearance post-therapy observed suggest that ctDNA monitoring can serve as a real-time surrogate of treatment response and enable early detection of residual disease or relapse.
Limitations include the single-arm design without a randomized comparator, which restricts definitive conclusions about comparative efficacy versus standard regimens. The study population mainly had stage II disease and hormone receptor-positive tumors, potentially limiting applicability to more advanced or ERBB2-positive/hormone receptor-negative subgroups. Further large-scale, randomized trials are warranted to validate the predictive and prognostic utility of ctDNA-guided treatment decisions.
Conclusion
In summary, the DAPHNe trial demonstrates that an abbreviated neoadjuvant regimen consisting of paclitaxel, trastuzumab, and pertuzumab achieves outstanding long-term clinical outcomes in patients with stage II to III ERBB2-positive breast cancer. Ultrasensitive tumor-informed ctDNA monitoring exhibits promising capacity to track treatment response and minimal residual disease, paving the way for ctDNA-guided de-escalation strategies that could minimize toxicity while maintaining efficacy. These findings strengthen the evolving paradigm of personalized medicine and molecular surveillance in breast oncology.
Funding and Registration
The DAPHNe trial is a nonrandomized investigator-initiated phase 2 study funded by relevant academic and institutional sources (details not specified in the abstract). This study is registered with ClinicalTrials.gov under identifier NCT03716180.
References
- Tarantino P, Li T, Ogayo ER, et al. Neoadjuvant Paclitaxel, Trastuzumab, and Pertuzumab for Stage II to III, ERBB2-Positive Breast Cancer: A Secondary Analysis of the DAPHNe Trial. JAMA Oncol. 2026 Jun 25. PMID: 42348190.
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