Abstract P3-11-17: A Randomized Phase II Trial of Neo-adjuvant Chemotherapy with Metformin or Placebo for HER-2 Positive Operable Breast Cancer (The HERMET Trial)

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Abstract Background: Human epidermal growth factor receptor 2 (HER-2) is overexpressed in 15-20% of breast cancer (BC). Pathologic complete response (pCR) after HER-2 directed chemotherapy is an important surrogate marker for survival in HER-2+ operable BC. Patients with diabetes who receive metformin have a lower risk of metastasis in HER-2+ breast cancer. Metformin’s inhibition of PI3K/AKT/mTOR pathway through IGF receptor inhibition has been proposed as a possible mechanism. However, its clinical benefit as an anticancer agent is not clear. We conducted a randomized, placebo-controlled study to assess the impact of adding metformin or placebo to neoadjuvant docetaxel, carboplatin, trastuzumab and pertuzumab (TCH-P) in HER2 positive breast cancer. Methods: Patients with HER-2+ operable breast cancer with at least 2 cm breast primary and/or axillary lymph node positive disease were eligible. HER-2 positivity was defined by the current ASCO-CAP guidelines. Patients were randomized 1:1 to receive neoadjuvant TCH-P every 3 weeks for 6 cycles, plus placebo (N=30) or metformin (N=31). Metformin dose was ramped up over the first 3 cycles to a target of 1500 mg twice daily on days 8-21 of each cycle. Breast surgery was performed 3-6 weeks after final chemotherapy cycle. The primary endpoint was pCR in breast and axilla. Subjects with unevaluable pCR were treated as non-responders for intent-to-treat analyses. Results: 61 patients were enrolled between 8/17/2017 and 03/21/2023. Median age was 51 years. 51% of the patients had node positive disease and 67% had estrogen receptor (ER) positive breast cancer. Among all patients pCR in both breast and axilla was 43.3% in TCH-P plus placebo group and 54.8% in the metformin group (p= 0.37). In patients with ER+ breast cancer pCR was 42.9% in placebo group and 40.0% in metformin group (p=0.85). Grade ≥3 adverse events occurred in 40% of placebo subjects and 48% of metformin subjects. Grade 3 diarrhea occurred in 29% of the patients in the metformin group compared to 17% in the placebo group. Conclusions: Metformin added to TCH-P neoadjuvant chemotherapy does not significantly improve pCR rate in HER-2+ breast cancer. Grade ≥3 diarrhea was greater in the metformin group. Citation Format: Maire Okoniewski, Cory Bivona, Colleen Bohnenkamp, Francisco Diaz, Junqiang Dai, Lauren Nye, Anne O'Dea, Kelsey Larson, Deepti Satelli, Jamie Wagner, Christa Balanoff, Lyndsey Kilgore, Stephanie Lafaver, Jamie Heldstab, Priyanka Sharma, Qamar Khan. A Randomized Phase II Trial of Neo-adjuvant Chemotherapy with Metformin or Placebo for HER-2 Positive Operable Breast Cancer (The HERMET Trial) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-11-17.

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