Mixed molecular subtypes coexist in estrogen receptor heterogenous primary breast cancers
Breast cancers show intratumor heterogeneity in estrogen receptor (ER) expression, but it is unclear whether cancer cells of different molecular subtypes (i.e. Luminal A, Luminal B, HER2-enriched, or Normal) can coexist in the same tumor. We performed spatial transcriptomic profiling of ER-negative, ER-low, and ER-high tumor cell regions of breast cancers that were 10-60% ER positive on routine immunohistochemistry using the GeoMxTM platform targeting 18,676 genes. We found that Luminal A and B molecular subtypes were intermixed in these tumors but there were no Basal-like cell populations. The ER-negative tumor regions were Luminal B-like and showed significantly lower expression of ESR1 and endocrine therapy sensitivity gene signatures but higher expression of inflammation and immune related genes, and also had higher recurrence scores indicating an endocrine-resistant but more chemotherapy sensitive phenotype. We also found that ESR1 strongly positive cells were enriched after preoperative chemotherapy in clinical trial tissues. These findings explain the worse clinical outcome of ER heterogenous breast cancers and suggest benefit from combined endocrine and chemotherapy strategies.