Mixed Molecular Subtypes Coexist in Estrogen Receptor Heterogeneous Primary Breast Cancers

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Intratumor heterogeneity in estrogen receptor (ER) expression is a key feature of breast cancer.
• Understanding the coexistence of different molecular subtypes within a single tumor is crucial for treatment strategies.

Purpose of the Study:

• To investigate intratumor heterogeneity in ER expression in ER-intermediate breast cancers.
• To determine if different molecular subtypes (Luminal A, Luminal B, HER2-enriched, Basal-like) coexist within the same tumor.
• To analyze the molecular characteristics of ER-negative regions in ER-heterogeneous tumors.

Main Methods:

• Digital spatial profiling using the NanoString GeoMx platform and Human Whole Transcriptome Atlas probe set.
• Analysis of 10 ER-heterogeneous (10%-60% ER+) and 10 ER-high (>60% ER+) primary breast cancers.

Main Results:

• Luminal A and Luminal B subtypes were intermixed in ER-heterogeneous tumors; no Basal-like populations were detected.
• ER-negative regions displayed Luminal B-like features, with lower ESR1 and endocrine therapy sensitivity gene expression.
• ER-negative regions showed higher immune-related gene expression and recurrence scores, indicating endocrine resistance and chemotherapy sensitivity.

Conclusions:

• ER-intermediate breast cancers exhibit mixed Luminal A and Luminal B subtypes.
• ER-negative tumor cell populations demonstrate endocrine resistance but chemotherapy sensitivity.
• These findings may explain poorer outcomes in ER-heterogeneous breast cancer and suggest combined endocrine and chemotherapy benefits.