316P - Comprehensive characterization of the HER2-enriched intrinsic molecular subtype in ER-positive HER2-negative breast cancer

Background

Breast cancer that is estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) can be further stratified into intrinsic molecular subtypes by employing PAM50-based gene expression profiling. Despite its association with poor outcome, the HER2-enriched (HER2E) subtype currently holds no implications for clinical treatment decisions due to a lack of insight into its distinguishing features. Therefore, we aimed to evaluate the response of patients to conventionally administered therapies and identify molecular features to inform therapy optimization.

Methods

Two primary breast cancer cohorts provided clinical, transcriptomic, and genomic data on ER+/HER2- cases: SCAN-B 4413 (HER2E: 89, Luminal A (LumA): 3049, Luminal B (LumB): 1349) and METABRIC 1227 (HER2E: 58, LumA: 601, LumB: 340), including whole genome sequencing data for 32 HER2E cases. Focal points were analyses based on overall survival and invasive disease-free survival (IDFS), differential gene expression, pathway enrichment, mutational frequencies and signatures, and copy number alterations.

Results

Clinicopathological analyses highlighted HER2E breast cancer to be a small subgroup associated with worse prognoses than other luminal PAM50 subtypes, regardless of whether patients were treated with endocrine therapy (E) or both endocrine and chemotherapy (EC), independent of tumor size, grade, age, and lymph node status (IDFS; E: HR 4.0, CI95 2.0-7.8; EC: HR 2.8; CI95 1.16-6.9; LumA as reference). Furthermore, HER2E tumors were larger and higher graded than LumA tumors. Next to highly proliferative characteristics akin to LumB, HER2E tumors were distinguished by their low ESR1 expression, high FGFR4 expression, high immune response, and high frequency of TP53 mutations.

Conclusions

The HER2E subtype within ER+/HER2- disease is a small but clinically relevant patient subgroup that is not constituted by misclassified cases and is less ER dependent than other luminal subtypes. It does not represent a distinct biological entity, but it is nevertheless associated with potentially targetable molecular features, for instance in form of a high immune response and high FGFR4 expression.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Lund University.

Funding

Breast and Lung Cancer Research Group, Faculty of Medicine, Department of Clinical Sciences, Lund University.

Disclosure

All authors have declared no conflicts of interest.