Abstract
PURPOSE: Breast cancer molecular subtypes significantly influence metastatic behavior and survival outcomes. However, data on subtype-specific patterns of distant metastasis and prognosis in Middle Eastern populations remain scarce. This study addresses this gap by analyzing a large cohort from southern Iran to better characterize these differences and aid personalized treatment. METHODS: In this study, 8,491 women with breast cancer from the Shiraz Breast Cancer Registry were analyzed. Patients had known molecular subtypes based on estrogen receptor, progesterone receptor, and HER2 status, and no distant metastases at diagnosis. Patients were followed up until December 30, 2024. Kaplan-Meier, restricted mean survival time and Cox proportional hazards models assessed overall survival (OS) and distant metastasis-free survival (DMFS). (SPSSv27.0 & R package RMST2) RESULTS: Luminal A (58.7%) was the most common subtype, followed by Luminal B (18.0%), Triple-Negative (12.7%), and HER2-enriched (10.6%). Among 1,304 patients who developed metastases, Luminal subtypes predominantly showed bone metastasis, whereas Triple-Negative and HER2-enriched tumors favored lung metastasis. Five-year OS differed significantly (p = 0.002), highest in Luminal A (85.1%) and lowest in HER2-enriched (74.2%). Cox regression revealed increased mortality risks for HER2-enriched (HR = 1.83), Triple-Negative (HR = 1.78), and Luminal B (HR = 1.24) compared to Luminal A. DMFS also favored Luminal A. CONCLUSION: This study fills an important regional research gap by demonstrating distinct distant metastasis patterns and survival outcomes across breast cancer molecular subtypes in southern Iran. Luminal A patients have the best prognosis, while HER2-enriched and Triple-Negative subtypes are more aggressive. These findings reinforce the prognostic and therapeutic value of subtype classification in guiding personalized breast cancer management.