Abstract C042: TMEM doorway score as a predictive biomarker for therapy selection in ER+/HER2- breast cancer

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Abstract Background: Endocrine therapy is the standard of care for ER+/HER- breast cancer; but some patients need additional adjuvant chemotherapy to counter the risk of metastasis. While chemotherapy can reduce metastasis, some patients still relapse. Tumor cells metastasize through TMEM (Tumor Microenvironment of Metastasis) Doorways, consisting of a Mena-expressing tumor cell, a macrophage, and a vascular endothelial cell, all in direct contact. High TMEM doorway scores correlate with increased dissemination in mice and metastatic outcomes in ER+/HER2- breast cancer patients. Recent studies show that adjuvant chemotherapy may activate growth in disseminated tumor cells (DTCs). Thus, we hypothesized that patients with high TMEM doorway scores who receive endocrine plus chemotherapy will have worse distant recurrence-free survival (DRFS) than those with lower TMEM Doorway scores, or those who receive endocrine therapy alone. Methods: We conducted a retrospective study on 119 patients with stage I-III, ER+/HER2- unilateral invasive ductal breast carcinoma (age≥18) from 2005- 2018. All underwent surgery and received adjuvant endocrine treatment alone or with chemotherapy. We excluded patients who had metastatic disease at diagnosis, received neoadjuvant chemotherapy, or lacked treatment data. Formalin-fixed paraffin-embedded primary tumor tissues were stained for TMEM doorways. A pathologist categorized the TMEM doorway scores as low, intermediate, or high. Kaplan-Meier curves and Cox-proportional hazard models compared DRFS based on treatment type and TMEM doorway scores. Multivariate logistic regression analyzed the association between macrophage density or TMEM Doorway Score and metastatic outcomes, adjusting for tumor size, grade, and node positivity. Results: Of all patients, 72 received endocrine plus chemotherapy and 47 endocrine therapy alone. In the chemotherapy group, 34 (47.2%) developed metastases, while 38 (52.8%) remained disease-free. In the endocrine alone group, 37 (78.7%) remained disease-free and 9 (19.1%) developed metastases. There was no significant difference in TMEM Doorway Scores between groups (p=0.07). In patients who received endocrine plus chemotherapy, a high TMEM Doorway Score was associated with greater odds of metastasis (OR 6.8; 95% CI 1.35–33.76; p=0.02), controlling for tumor size, grade, and node positivity but not when endocrine therapy was used alone (p=0.817). Patients with high TMEM Doorway Scores had worse DRFS in the endocrine plus chemotherapy group (HR 2.61; 95% CI 1.08–6.27; p=0.03), but not in the endocrine therapy alone group (p=0.77) adjusted similarly. Conclusions: This study highlights potential clinical utility of TMEM Doorway Scores as a predictive biomarker for chemotherapy selection in ER+/HER2- breast cancer patients. Larger trials are needed to confirm these findings and with confirmation, physicians considering giving chemotherapy to ER+/HER2- breast cancer patients might consider pre-treatment stratification using TMEM Doorway Scores to mitigate the risk of chemotherapy-induced metastasis. Citation Format: Priyanka Parmar, Andrew Miller, Burcu Karadal-Ferrena, Suryansh Shukla, Cien Huang, Mindy Ginsberg, Chedva Rosenbaum, Malka Felder, Chenxin Zhang, John S. Condeelis, Xiaonan Xue, Thomas E. Rohan, Joseph A. Sparano, Jesus D. Anampa, David Entenberg, Maja H. Oktay. TMEM doorway score as a predictive biomarker for therapy selection in ER+/HER2- breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C042.