Pre-operative THP leads to a pCR in two-thirds of early-stage HER2+ ER- breast cancer patients

Patients with Stage II and III (early-stage) HER2+ breast cancer usually undergo pre-operative therapy with multi-agent 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, NCT04266249) by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN). While longer follow-up is needed to assess long-term outcomes, pathologic complete response (pCR) rates and predictors of pCR are being shared at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, 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 (pictured). “We also found that among ER-positive breast cancers, lower level of ER expression resulted in higher pCR rates.”

THP combines one chemotherapy drug (a taxane) with the HER2-targeting drugs trastuzumab and pertuzumab. THP is a standard treatment for patients with metastatic HER2+ breast cancer. 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, non-randomized trial is 12 weeks of pre-operative THP (4 cycles of trastuzumab and pertuzumab (HP)) with weekly paclitaxel (12 weeks) or docetaxel (q3w x 4), followed by surgery.

Despite the COVID-19 pandemic, patient enrollment in the trial was rapid, with 2175 participants joining between February 2020 and October 2023. Among them, 2141 started THP. Disease progression during THP 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 presented at ASCO (Abstract 501) are categorized by estrogen receptor (ER) status and other characteristics. A subset of 569 patients underwent biopsies for analysis using the HER2DX^® pCR-score (Reveal Genomics^®). 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+ breast cancer tumors, those that are ER-negative have a higher pCR rate compared to those that are ER-positive. This study reveals several other predictors of pCR in patients with Stage II and III HER2+ breast cancer. These include:

• ER-negative status
• Lower ER expression (≤70%) in ER+ tumors
• HER2 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+ breast cancer could be spared from the toxicity of more intensive chemotherapy," said Dr. Tung.

About CompassHER2
The CompassHER2 pCR trial (EA1181) is led by the ECOG-ACRIN Cancer Research Group, supported by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), and conducted within the NCI’s National Clinical Trials Network (NCTN). The Breast Cancer Research Foundation and Susan G. Komen^® provided additional support.

This trial is part of the CompassHER2 (Comprehensive Use of Pathologic Response Assessment to Optimize Therapy in HER2-Positive Breast Cancer) Trial Program. It is a collaboration between ECOG-ACRIN Cancer Research Group and the Alliance for Clinical Trials in Oncology, two cooperative research groups in the NCI’s National Clinical Trials Network.

About ECOG-ACRIN
The ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) is a membership-based scientific organization that includes approximately 1,400 cancer centers and community hospitals as members, with about 21,000 researchers and advocates. The group conducts studies spanning the cancer care spectrum, from early detection to management of advanced disease. To learn more, visit www.ecog-acrin.org and follow us on X@EAonc, Facebook, LinkedIn, YouTube, and Instagram.