Abstract PS4-01-22: The Utility of MT1-MMP in Predicting Treatment Efficacy with HER2-positive advanced or metastatic breast cancer: JBCRG-M06/EMERALD trial TR

Abstract Background: Malignant tumor cells grow invasively and form distant metastases after moving through multiple tissue barriers. Invasion requires cell locomotion, accompanied by the degradation of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs). MT1-MMP (Membrane Type 1 MMP) is an integral membrane protease that degrades a variety of protein components within the extracellular milieu. The substrates of MT1-MMP include a variety of components of the ECM membrane proteins, such as type 1 collagen. Type 1 Collagen is a physical varier not only affecting cancer cell invasion but also drug accessibility to cancer cells. It is reported that MT1-MMP regulates small compound drug resistances via activation of integrin signaling through type 1 collagen cleavage and higher expression of MT1-MMP was considered a marker of increased malignancy and poorer prognosis. However, it remains unclear whether larger drugs, such as antibodies, can be affected by MT1-MMP-related collagen remodeling. Here, we conducted a retrospective analysis of MT1-MMP on treatment effectiveness and survival using the JBCRG-M06/EMERALD clinical trial. The clinical trial is a Phase III study comparing two first-line chemotherapeutic treatments for HER2-positive local advanced or metastatic breast cancer: trastuzumab, pertuzumab, and taxane therapy versus trastuzumab, pertuzumab, and eribulin mesylate therapy. Method: In the EMERALD study, 231 specimens were collected from 231 patients who consented to biomarker research at the time of enrollment. Among these 182 specimens were collected from primary tumors, and 49 from metastatic sites. The tissue samples were immunostained with anti-MT1-MMP antibody and classified into low (score1), moderate (score2), and high (score3) expression based on staining proportion and intensity. We investigated the correlation between MT1-MMP expression and the therapeutic effects of trastuzumab and pertuzumab combination with eribulin mesylate or taxane, as well as Progression-Free Survival (PFS). Results: Of the 231 patients in this study, 123 were assigned to the eribulin group and 108 to the taxane group, with MT1-MMP scores 1/2/3 of 28/52/43 in the eribulin group and 26/43/39 in the taxane group, respectively. The median PFS in the eribulin group was 14.7 months and 13.4 months in the taxane group, and it was similar to the results for all patients in the EMERALD study. There was no difference between the eribulin and taxane groups. Whereas the median PFS for MT1-MMP scores 1/2/3 was 10.5/13.2/18.4 months, and it tended to be longer with higher MT1-MMP scores (p=0.0306). Although higher MT1-MMP scores tended to improve response rates overall, there was no significant difference between the two treatment groups. In this study of patients with HER2-positive local advanced or metastatic breast cancer patients, higher expression of MT1-MMP may be with better PFS and response rates. Conclusion: The MT1-MMP score is unable to distinguish the combined trastuzumab and pertuzumab with eribulin mesylate or trastuzumab and pertuzumab with taxane therapy. However, it may be a prognostic factor for HER2-positive local advanced or metastatic breast cancer patients treated with the trastuzumab and pertuzumab combination and eribulin mesylate or taxane. Citation Format: M. Yasukawa, S. Sato, N. Saito, S. Saji, N. Masuda, T. Yamanaka, S. Fujiwara, K. Goda, N. Mori, T. Takano, K. Watanabe, Y. Naito, H. Tada, M. Kitada, T. Iwasa, T. Morimoto, A. Takahashi, M. Isoda, T. Yamashita, D. Hoshino. The Utility of MT1-MMP in Predicting Treatment Efficacy with HER2-positive advanced or metastatic breast cancer: JBCRG-M06/EMERALD trial TR [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-01-22.