Transcriptomic Insights into Lobular Breast Cancer Biology and Patient Outcomes: Analysis of the MINDACT Clinical Trial

PURPOSE: 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 (ER)-positive/HER2-negative ILC and ER+/HER2- IBC-NST; classic and nonclassic ER+/HER2- ILC; and recurring and nonrecurring ER+/HER2- ILC in patients with a low genomic risk and either a low clinical/low genomic (cL/gL) or high clinical/low genomic (cH/gL) risk. EXPERIMENTAL DESIGN: We analyzed 4,262 ER+/HER2- tumors (63.7%; 464 ILC and 3,798 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 survival and distant recurrence-free survival. RESULTS: An increased expression of CDH1 (E-cadherin) in IBC-NST compared with ILC was observed. ILC showed more uptake of extracellular lipid sources (LPL, CD36, LEP, and LEPR), whereas IBC-NST favored lipid synthesis (FASN). Decreased ER signaling, increased PI3K/Akt signaling, and differences related to the extracellular matrix were also observed in ILC. Classic and nonclassic ILC differed subtly, notably in cell-cycle regulation. In patients with ER+/HER2- ILC with a cL/gL risk, enrichment of apoptosis, inflammatory response, hypoxia, and oncogenic signaling (PI3K/Akt, Ras, and c-Myc) were 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. These findings may provide insights to refine treatment strategies and relapse risk assessment for patients with ILC.