Comprehensive Review of Molecular Mechanisms and Clinical Features of Invasive Lobular Cancer

Abstract

Invasive lobular carcinoma (ILC) accounts for 10% to 15% of breast cancers in the United States, 80% of which are estrogen receptor (ER)-positive, with an unusual metastatic pattern of spread to sites such as the serosa, meninges, and ovaries, among others. Lobular cancer presents significant challenges in detection and clinical management given its multifocality and multicentricity at presentation. Despite the unique features of ILC, it is often lumped with hormone receptor-positive invasive ductal cancers (IDC); consequently, ILC screening, treatment, and follow-up strategies are largely based on data from IDC. Despite both being treated as ER-positive breast cancer, querying the Cancer Genome Atlas database shows distinctive molecular aberrations in ILC compared with IDC, such as E-cadherin loss (66% vs. 3%), FOXA1 mutations (7% vs. 2%), and GATA3 mutations (5% vs. 20%). Moreover, compared with patients with IDC, patients with ILC are less likely to undergo breast-conserving surgery, with lower rates of complete response following therapy as these tumors are less chemosensitive. Taken together, this suggests that ILC is biologically distinct, which may influence tumorigenesis and therapeutic strategies. Long-term survival and clinical outcomes in patients with ILC are worse than in stage- and grade-matched patients with IDC; therefore, nuanced criteria are needed to better define treatment goals and protocols tailored to ILC's unique biology. This comprehensive review highlights the histologic and clinicopathologic features that distinguish ILC from IDC, with an in-depth discussion of ILC's molecular alterations and biomarkers, clinical trials and treatment strategies, and future targets for therapy. IMPLICATIONS FOR PRACTICE: The majority of invasive lobular breast cancers (ILCs) are hormone receptor (HR)-positive and low grade. Clinically, ILC is treated similar to HR-positive invasive ductal cancer (IDC). However, ILC differs distinctly from IDC in its clinicopathologic characteristics and molecular alterations. ILC also differs in response to systemic therapy, with studies showing ILC as less sensitive to chemotherapy. Patients with ILC have worse clinical outcomes with late recurrences. Despite these differences, clinical trials treat HR-positive breast cancers as a single disease, and there is an unmet need for studies addressing the unique challenges faced by patients diagnosed with ILC.

Keywords: Dormancy; E-cadherin; ERBB2; Late recurrence; Lobular cancer.

Figure 1

Analysis using TCGA data set. (A): CDH1 alteration frequency in different breast cancer subtypes (TCGA dataset). (B): CDH1 mutations in invasive lobular cancer primarily lead to shallow deletions. Plot shows CDH1 mRNA expression versus copy number alteration due to different mutation resulting in deep deletion, shallow deletion, or gain of function. Each dot represents a sample, color coded for nature of mutation.Abbreviations: GISTIC, genomic identification of significant targets in cancer; NOS, not otherwise specified; RSEM, RNA‐seq by expectation–maximization; TCGA, The Cancer Genome Atlas; VUS, variant of uncertain significance.

Figure 2

Histological subtypes of ILC. Hematoxylin and eosin stained sections of classical (A), pleomorphic (B), qlveolar (C), histiocytoid (D), lobular invasive carcinoma‐classical (E), and lobular invasive carcinoma‐pleomorphic (F).

Figure 3

Schematic representation of different molecular pathways involved in progression of invasive lobular breast cancer. (A): Mechanism by which a functional E‐cadherin maintains cell–cell adhesion. Juxtamembranous binding of p120, β‐catenin, and α‐catenin facilitates binding to actin cytoskeleton. The catenins are sequestered by E‐cadherin, facilitating the suppression of WNT11 via Kaiso. (B): Loss of E‐cadherin in ILC results in the translocation of p120 into the cytoplasm and nucleus. In the cytoplasm it sequesters MRIP and relieves Rho/Rock repression. In the nucleus, it binds Kaiso and initiates transcriptional expression of WNT11, which then activates Rho/Rock signaling, both leading to anoikis resistance. (C): Amplifications of FGFR in ILC results in increased receptor dimerization and transphosphorylation at several tyrosine residues, leading to the activation of Ras‐dependent MAPK signaling, PI3K/AKT signaling, and PLC‐γ signaling, contributing to endocrine resistance. (D): ILC can harbor activating HER2 mutations, initiating PI3K/AKT and Ras/MAPK signaling cascades, which contributes to cell survival, proliferation, and uncontrolled cell growth. (E): FOXA1 mutations in ILC result in increased expression, contributing to endocrine therapy resistance by facilitating the binding of ERα/E2 complexes to non‐ERE sites and expression of target genes.Abbreviations: AKT, protein kinase B; ERα/E2, estrogen receptor alpha/estradiol; ERE, estrogen response element; GPCR, G‐Protein coupled receptor; ILC, invasive lobular cancer; MAPK, mitogen‐activated protein kinase; MRIP, myosin phosphatase Rho‐interacting protein; PKC, Protein Kinase C; PI3K, phosphoinositide 3‐kinase; PLC, pleomorphic lobular cancer.