Combining TMEM Doorway Score and Mena^Calc Score Improves the Prediction of Distant Recurrence Risk in HR+/HER2− Breast Cancer Patients

Purpose: to develop several digital pathology‐based machine vision algorithms for combining TMEM and Mena^Calc scores and determine if a combination of these biomarkers improves the ability to predict development of distant metastasis over and above that of either biomarker alone. Methods: This retrospective study included a subset of 130 patients (65 patients with no recurrence and 65 patients with a recurrence at 5 years) from the Calgary Tamoxifen cohort of breast cancer patients. Patients had confirmed invasive breast cancer and received adjuvant tamoxifen therapy. Of the 130 patients, 86 cases were suitable for analysis in this study. Sequential sections of formalin‐fixed paraffin‐embedded patient samples were stained for TMEM doorways (immunohistochemistry triple staining) and Mena^Calc (immunofluorescence staining). Stained sections were imaged, aligned, and then scored for TMEM doorways and Mena^Calc. Different ways of combining TMEM doorway and Mena^Calc scores were evaluated and compared to identify the best performing combined marker by using the restricted mean survival time (RMST) difference method. Results: the best performing combined marker gave an RMST difference of 5.27 years (95% CI: 1.71–8.37), compared to 3.56 years (95% CI: 0.95–6.1) for the associated standalone TMEM doorway analysis and 2.94 years (95% CI: 0.25–5.87) for the associated standalone Mena^Calc analysis. Conclusions: combining TMEM doorway and Mena^Calc scores as a new biomarker improves prognostication over that observed with TMEM doorway or Mena^Calc Score alone in this cohort of 86 patients.