Patients with stage II and III (early-stage) HER2-positive breast cancer usually undergo preoperative therapy with multiagent chemotherapy in combination with anti-HER2 antibodies, followed by surgery. A less intensive, reduced-chemotherapy treatment approach is currently being evaluated in the CompassHER2 pCR trial (EA1181; ClinicalTrials.gov idenitifer NCT04266249) by the ECOG-ACRIN Cancer Research Group. While longer follow-up is needed to assess long-term outcomes, pathologic complete response (pCR) rates and predictors of pCR were shared at the 2025 ASCO Annual Meeting (Abstract 501), detailing which patients may benefit most from the new approach.
“Neoadjuvant treatment with 12 weeks of THP led to a pCR rate of 64% in patients with early-stage, HER2-positive, ER-negative breast cancer at the time of surgery, compared to 33% for those with ER-positive tumors,” said lead investigator Nadine M. Tung, MD, a medical oncologist at Beth Israel Deaconess Medical Center in Boston. “We also found that among ER-positive breast cancers, lower level of ER expression resulted in higher pCR rates.”
THP, a standard treatment for patients with metastatic HER2-positive breast cancer, combines one chemotherapy drug (a taxane) with the HER2-targeting drugs trastuzumab and pertuzumab. Previous small studies have shown that patients with early-stage disease can also reach a pCR with less intensive therapies like THP.
CompassHER2 pCR (EA1181) is the first large-scale trial to evaluate this approach and its ultimate impact on survival. The regimen being assessed in this single-arm, nonrandomized trial is 12 weeks of preoperative THP (four cycles of trastuzumab and pertuzumab) with weekly paclitaxel (12 weeks) or docetaxel (every 3 weeks for four cycles), followed by surgery.
Patient enrollment in the trial was rapid, with 2,175 participants joining between February 2020 and October 2023. Among them, 2,141 started THP. Disease progression during THP receipt occurred in only 16 patients (0.7%).
“If patients achieved a pCR, they did not receive any more chemotherapy, only HER2-directed antibodies after surgery, as well as radiation and endocrine therapy if indicated,” said Dr. Tung. “Ultimately, this trial should establish if patients who have no residual cancer at surgery after THP can forgo further chemotherapy.”
The primary endpoint is 3-year recurrence-free survival, which requires longer follow-up.
The pCR rates are categorized by estrogen receptor (ER) status and other characteristics. A subset of 569 patients underwent biopsies for analysis using the HER2DX® pCR-score. This laboratory test assigns a low, medium, or high score based on tumor gene expression and clinical features.
It is already known that among HER2-positive breast cancer tumors, those that are ER-negative have a higher pCR rate compared with those that are ER-positive. The results presented at ASCO 2025 revealed several other predictors of pCR in patients with stage II and III HER2-positive breast cancer, including:
- ER-negative status
- Lower ER expression (≤ 70%) in ER-positive tumors
- HER2 immunohistochemistry (IHC) of 3+ (vs IHC 2+/ISH+)
- Use of weekly paclitaxel rather than every-3-week docetaxel
- Higher HER2DX pCR score regardless of ER status.
The analysis did not find an association with the baseline clinical stage of disease.
While THP can cause a range of side effects, it is less toxic than regimens that contain multiple chemotherapy drugs.
“The findings from this trial may ultimately help clinicians identify which patients with HER2-positive breast cancer could be spared from the toxicity of more intensive chemotherapy," said Dr. Tung.
Disclosure: This study was supported by the National Cancer Institute (NCI), part of the National Institutes of Health, and conducted within the NCI’s National Clinical Trials Network. The Breast Cancer Research Foundation and Susan G. Komen® provided additional support. For full disclosures of the study authors, visit coi.asco.org.
