The clinical relevance of apocrine morphology in breast cancer depends on the estrogen receptor status

Apocrine morphology is a distinctive histopathological feature of breast cancer associated with unique clinical behavior, particularly in estrogen receptor (ER)-negative tumors. However, its molecular basis remains unclear and its relevance in ER-positive breast cancer has not been systematically examined. We performed an integrative analysis of breast cancer patients from the SEER database ( n = 226,584) and The Cancer Genome Atlas (TCGA; n = 1017), incorporating clinicopathological, transcriptomic, and genomic data. Apocrine carcinoma was associated with favorable prognosis in ER-negative but worse survival in ER-positive breast cancer. Molecular and AR-related classifications did not fully recapitulate apocrine morphology. In ER-negative tumors, apocrine morphology correlated with lower proliferation and reduced predicted chemotherapy sensitivity. Conversely, in ER-positive tumors, apocrine morphology was associated with increased proliferation, enhanced immune-related signaling, and greater genomic instability. In conclusion, apocrine morphology represents an ER-dependent biological state with distinct prognostic and molecular implications.