Transcriptomic insights into lobular breast cancer biology and patient outcomes: analysis of the MINDACT clinical trial

BACKGROUND: Invasive lobular carcinoma (ILC) is the second most common subtype of breast cancer after invasive breast cancer of no special type (IBC-NST). This retrospective analysis of the MINDACT trial investigated transcriptomic differences between estrogen receptor-positive/HER2-negative (ER+/HER2-) ILC versus ER+/HER2- IBC-NST, classic and non-classic ER+/HER2- ILC, and, recurring and non-recurring ER+/HER2- ILC in patients with a low genomic risk and either a low (cL/gL) or high clinical risk (cH/gL). PATIENTS AND METHODS: We analyzed 4261 ER+/HER2- tumors (63.7%, 464 ILC, 3798 IBC-NST) with central pathology review. Differential gene expression analysis was adjusted for age and grade, followed by gene set enrichment analysis. Adjusted regression models evaluated associations of transcriptomic profiles with disease-free (DFS) and distant recurrence-free survival (DRFS). RESULTS: An increased expression of CDH1 (E-cadherin) in IBC-NST compared to ILC was observed. ILC showed more uptake of extracellular lipid sources (LPL, CD36, LEP, LEPR), while IBC-NST favored lipid synthesis (FASN). Decreased ER-signaling, increased PI3K/Akt-signaling, and differences related to the extracellular matrix was also observed in ILC. Classic and non-classic ILC differed subtly, notably in cell cycle regulation. In ER+/HER2- ILC patients with a cL/gL risk, enrichment of apoptosis, inflammatory response, hypoxia and oncogenic signaling (PI3K/Akt, Ras, c-Myc) was associated with worse survival. In contrast, in the cH/gL group, associations between ILC transcriptomic features and survival were more subtle. CONCLUSIONS: This represents the largest transcriptomic dataset for ILC from a clinical trial with central histology review. Findings may provide insights to refine treatment and relapse risk assessment for ILC patients.