De-Escalated Neoadjuvant HER2-Targeted Therapy Shows Durable 5-Year Survival

Five-year follow-up data from the phase 2 WSG TP-II trial (NCT03272477) show that both a chemotherapy-free regimen and a single-agent chemotherapy regimen—each paired with dual HER2 blockade—produced excellent survival outcomes in patients with hormone receptor–positive, HER2-positive early breast cancer, according to results published in the Journal of Clinical Oncology.¹

The multicenter, open-label trial randomly assigned 207 patients 1:1 to receive 12 weeks of neoadjuvant trastuzumab (Herceptin) plus pertuzumab (Perjeta) combined with either endocrine therapy or weekly paclitaxel. All patients subsequently received adjuvant dual HER2-targeted therapy plus endocrine therapy; further chemotherapy was mandatory for patients without a pathologic complete response (pCR) and optional for those who achieved pCR. Trastuzumab emtansine (T-DM1; Kadcyla) was not used in either arm.

The trial's primary end point, reported previously, showed a significantly higher pCR rate with paclitaxel than with endocrine therapy (56.4% vs 23.7%; P <.001).¹ The present analysis reports the prespecified secondary survival end points after a median follow-up of approximately 60 months in both arms.

Survival Outcomes

The 5-year overall survival rate was 100% (95% CI, 100.0%-100.0%) in the endocrine therapy arm vs 97.9% (95% CI, 95.0%-100.0%) in the paclitaxel arm. Five-year event-free survival–ductal carcinoma in situ rates, which incorporate noninvasive events, were 92.1% (95% CI, 86.6%-97.9%) and 94.8% (95% CI, 90.5%-99.3%) in the endocrine therapy and paclitaxel arms, respectively. In an exploratory analysis using the more recently standardized invasive disease-free survival definition that begins at the surgery landmark, rates were 97.7% (95% CI, 94.5%-100.0%) in the endocrine therapy arm and 79.8% (95% CI, 55.6%-100.0%) in the paclitaxel arm; the authors noted this estimate is based on a small number of at-risk patients late in follow-up and should be interpreted cautiously.

Achievement of pCR was not associated with invasive disease-free survival overall or within either treatment arm. Among the 82 patients who achieved pCR, only 1 invasive breast cancer event and 1 nonmetastatic death occurred, compared with 5 invasive events and 1 nonmetastatic death among the 118 patients without pCR. Most patients with pCR—76.3%—received no further chemotherapy, and outcomes in this group were comparable to those who received poststudy chemotherapy, though the authors cautioned that adjuvant chemotherapy use was not randomly assigned and residual confounding cannot be excluded.

Grade 3 to 4 treatment-emergent adverse events during the neoadjuvant phase were more frequent with paclitaxel than with endocrine therapy (35.6% vs 14.1%), and neoadjuvant polyneuropathy was substantially more common with paclitaxel (28.9% vs 6.1%). Adverse event rates during the adjuvant phase were somewhat higher in the endocrine therapy arm, which the authors attributed to greater subsequent chemotherapy use in that group.

The authors concluded that both de-escalated approaches—omitting chemotherapy entirely in favor of endocrine therapy or limiting chemotherapy to 12 weeks of single-agent paclitaxel—can be paired safely with a pCR-guided adjuvant strategy using dual HER2 blockade. They noted that robust predictive biomarkers, such as circulating tumor DNA or the HER2DX assay, are still needed to optimize patient selection for de-escalated regimens. The findings add to a growing body of evidence, including the CompassHER2-pCR trial (NCT04266249),² supporting reduced-intensity neoadjuvant regimens in appropriately selected patients with HER2-positive early breast cancer. Ongoing trials, including ADEPT (NCT04569747)³ and PHERGAIN-II (NCT04733118),⁴ are expected to further refine de-escalation strategies in this population.

REFERENCES

1. Gluz O, Nitz UA, Christgen M, et al. Survival analysis of the WSG TP-II trial: neoadjuvant trastuzumab and pertuzumab plus endocrine therapy versus chemotherapy in hormone receptor–positive/human epidermal growth factor receptor 2–positive early breast cancer. J Clin Oncol. 2026;44(21):1974-1980. doi:10.1200/JCO-25-01047

2. CompassHER2-pCR: Decreasing Chemotherapy for Breast Cancer Patients After Pre-surgery Chemo and Targeted Therapy. ClinicalTrials.gov. Updated July 10, 2026. Accessed July 17, 2026. https://clinicaltrials.gov/study/NCT04266249

3. A Single Arm Phase II Study of ADjuvant Endocrine Therapy, Pertuzumab, and Trastuzumab for Patients With Anatomic Stage I Hormone Receptor-positive, HER2-positive Breast Cancer (ADEPT). ClinicalTrials.gov. Updated April 2, 2026. Accessed July 17, 2026. https://clinicaltrials.gov/study/NCT04569747

4. Chemotherapy-Free pCR-Guided Strategy With Trastuzumab-pertuzumab and T-DM1 in HER2-positive Early Breast Cancer (PHERGAIN-2). ClinicalTrials.gov. Updated April 29, 2026. Accessed July 17, 2026. https://clinicaltrials.gov/study/NCT04733118