Abstract 17P
Background
Clinically, breast cancer (BC) is divided into subgroups based on the assessment of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) status. HER2-/ER+ tumors constitute the luminal subgroup. By using the gene expression profiling assay PAM50, luminal tumors can be stratified into the intrinsic molecular subtypes Luminal A (LumA), Luminal B (LumB) and HER2-enriched (LumHER2). The study at hand aims to characterize the LumHER2 subtype based on clinicopathological and transcriptomic features to elucidate what cases constitute the subgroup and to identify drivers of disease that may be used to improve treatment decisions.
Methods
The analyses were based on mRNA-sequencing and clinical review data from 6660 cases of the Sweden Cancerome Analysis Network - Breast study, of which 4413 were clinically HER2-/ER+ (LumHER2: 79, LumA: 2856, LumB: 1249). Approaches included comparative statistics of clinicopathological variables, survival analyses based on recurrence-free intervals as well as differential gene expression, metagene, and single-gene expression analyses.
Results
The LumHER2 subtype is associated with larger and higher graded tumors than the LumA subtype. In patients that received endocrine therapy (E) or both endocrine and chemotherapy (EC), LumHER2 tumors were associated with a higher risk of relapse than LumA and LumB tumors, independent of age, tumor size, and lymph node status (E: LumA - HR 0.31, 95% CI 0.13-0.79; LumB - HR 0.41, 95% CI 0.17-0.98; EC: LumA - HR 0.39, 95% CI 0.16-0.99; LumB - HR 0.37, 95% CI 0.15-0.90). Metagene patterns indicated LumHER2 tumors to have a higher immune response and lower steroid response than the other luminal subtypes with similar proliferative characteristics to LumB tumors. ESR1 was less expressed in LumHER2 tumors, while ERBB2 expression was similar between all subtypes.
Conclusions
LumHER2 breast cancer is associated with a faster disease recurrence than other luminal subtypes, regardless of received treatment. The subgroup is not predominantly constituted by clinically misclassified cases and less ER-dependent than other luminal subtypes, providing a possible explanation for the comparatively poor response to endocrine therapy.
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.