Breast Invasive Lobular Carcinoma (ILC)

Overview

Breast Invasive Lobular Carcinoma (ILC) is the second most common histologic subtype of invasive breast cancer (~10–15% of cases), defined by loss of E-cadherin (CDH1) function and characteristic single-file infiltration of the stroma. It sits at OncoTree level 3 under BRCA. ILC is predominantly Luminal A (83% of ILC vs 41% of IDC), ER-positive (94%), and has the highest pAKT activity of any breast cancer subtype. Its diffuse metastatic pattern (GI tract, peritoneum) and poor detection on PET distinguish it clinically from IDC.

Cohorts in the corpus

  • brca_tcga_pub2015 — 127 ILC samples profiled by whole-exome sequencing, RNA-seq, miRNA-seq, copy number (SNP6), DNA methylation, and RPPA (633 samples); the primary ILC discovery cohort PMID:26451490.
  • brca_metabric — validation cohort (median follow-up 7.2 years) used for ILC transcriptional subtype survival analyses PMID:26451490.

Recurrent alterations

  • CDH1 mutation: 63% of ILC vs 2% of IDC (q=3.94E-53); 83% truncating; biallelic loss (mutation + 16q heterozygous loss) in 95% of ILC; no promoter hypermethylation detected PMID:26451490.
  • PIK3CA mutation: 48% of ILC vs 33% of IDC (q=0.02); not associated with pAKT levels in this dataset PMID:26451490.
  • PTEN inactivation (homozygous deletion + mutation): 14% in Luminal A ILC vs 3% in Luminal A IDC (p=9E-4); mutually exclusive with PIK3CA PMID:26451490.
  • FOXA1 mutation: 7% of ILC (vs 2% IDC, q=0.08); all ILC mutations cluster in the fork-head W2 wing loop (I176, D226 hotspot residues); associated with increased FOXA1 mRNA, suggesting gain-of-function PMID:26451490.
  • TBX3 mutation: 9% of ILC vs 2% of IDC (q=0.003) PMID:26451490.
  • RUNX1 mutation: 10% of ILC vs 3% of IDC (q=0.008) PMID:26451490.
  • TP53 mutation: ILC-depleted (8% ILC vs 44% IDC, q=1.9E-14), consistent with predominantly Luminal A biology PMID:26451490.
  • ERBB2 amplification and mutations identified among upstream drivers of AKT activation in ILC PMID:26451490.
  • pAKT-S473 and pAKT-T308 levels are highest in ILC among all breast cancer subtypes, matching levels seen in HER2+ and Basal-like IDC, despite predominantly Luminal A classification PMID:26451490.
  • WES of 216 metastatic breast carcinomas (SAFIR01/SAFIR02/SHIVA/MOSCATO trials) included ILC tumors within the HR+/HER2- subgroup; CDH1 identified as a significantly mutated driver in both metastatic and early breast cancer PMID:28027327

Subtypes

  • Three ILC transcriptional subtypes defined by consensus hierarchical clustering of 106 Luminal A ILC (TCGA; validated in METABRIC):
    • Reactive-like: high stromal/epithelial signaling (keratins, kallikreins, EGFR, MET, PDGFRA, KIT); low tumor purity; better disease-specific survival (HR=0.47, p=0.038) PMID:26451490.
    • Immune-related: high ILs, chemokines, MHC, TNFs, IDO1, IFNG; macrophage-dominated microenvironment PMID:26451490.
    • Proliferative: high cell-cycle and DNA-repair proteins (Cyclin E1, FoxM1, PCNA, pChk1-S345, BRCA2); worse disease-specific survival (HR=2.0, p=0.025) PMID:26451490.
  • Mixed IDC/ILC tumors (n=88) resolve into ILC-like (24/88) or IDC-like (64/88) classes; CDH1 status is the dominant discriminating feature; no third hybrid entity is supported PMID:26451490.
  • ILC is predominantly Luminal A (83%) and ER-positive (94%, 113/120 by IHC) PMID:26451490.

Therapeutic landscape

  • PI3K/AKT/mTOR inhibition is proposed as a priority strategy for ILC given the highest average pAKT levels of any breast cancer subtype and frequent PTEN inactivation; 40% of ILC samples carry upstream AKT pathway alterations by MEMo analysis PMID:26451490.
  • Lower GATA3 and reduced total/phospho-ER in Luminal A ILC are consistent with prior reports of improved aromatase inhibitor (letrozole) vs tamoxifen response PMID:26451490.
  • Prognostic stratification by mRNA subtype (reactive-like vs proliferative) carries survival differences (p=0.023–0.038 in METABRIC), suggesting potential for trial stratification PMID:26451490.

Sources

  • PMID:26451490 — Ciriello et al., Comprehensive molecular portraits of invasive lobular breast cancer, Cell 2015.

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