E-cadherin (encoded by the CDH1 gene) is a critical cell adhesion protein whose loss is a hallmark of invasive lobular breast cancer (ILC) and some triple-negative breast cancers (TNBC). E-cadherin-negative tumors exhibit distinct biological behaviors, including enhanced metastatic potential and resistance to conventional therapies. However, emerging evidence suggests that these tumors may be more susceptible to immunotherapy due to their unique molecular and immune microenvironment features. This article explores the current and experimental immunotherapy approaches for E-cadherin-negative breast cancer.
High Tumor Mutational Burden (TMB): CDH1-mutant tumors often have genomic instability, leading to increased neoantigens that can be recognized by the immune system.
Immune Microenvironment Alterations:
Loss of E-cadherin promotes epithelial-mesenchymal transition (EMT), which can increase PD-L1 expression.
Infiltration of tumor-infiltrating lymphocytes (TILs) has been observed in some E-cadherin-negative breast cancers.
Synthetic Lethality Opportunities:
CDH1 loss may create vulnerabilities exploitable by immune checkpoint inhibitors (ICIs).
Higher PD-L1 Expression: Some studies suggest E-cadherin-low tumors have elevated PD-L1 levels, making them potential candidates for anti-PD-1/PD-L1 therapy.
Response in Lobular Breast Cancer: Early-phase trials show durable responses to ICIs in metastatic ILC.
Pembrolizumab (Keytruda):
Approved for PD-L1+ TNBC, with potential applicability to E-cadherin-negative TNBC and ILC.
Clinical trials (e.g., KEYNOTE-119) exploring efficacy in metastatic breast cancer.
Atezolizumab (Tecentriq):
Previously used in TNBC; may benefit CDH1-mutant tumors with high TMB.
Less studied in breast cancer but may synergize with PD-1 inhibitors in immunologically "cold" tumors.
Early-phase trials show promise in metastatic breast cancer, particularly in patients with TIL-rich tumors.
E-cadherin loss may enhance tumor antigen presentation, improving TIL efficacy.
Mesothelin or HER2-targeted CAR-T cells are under investigation.
Challenges include tumor heterogeneity and immune escape mechanisms.
Neoantigen vaccines tailored to CDH1-mutant tumors are in preclinical development.
Dendritic cell vaccines may help overcome immune suppression.
Pembrolizumab + nab-paclitaxel has shown benefit in TNBC and may extend to E-cadherin-negative subtypes.
Gemcitabine + ICIs could enhance immune infiltration.
CDH1 loss induces DNA repair defects, increasing sensitivity to PARP inhibitors (e.g., olaparib).
Olaparib + durvalumab (anti-PD-L1) trials are ongoing.
AKT activation (common in E-cadherin-negative cancers) may suppress immune responses; combining AKT inhibitors (capivasertib) + ICIs is being explored.
Heterogeneity of E-Cadherin Loss
Not all E-cadherin-negative tumors respond equally to immunotherapy.
Immune Evasion Mechanisms
Upregulation of alternative checkpoints (e.g., LAG-3, TIM-3).
Biomarker Development
Better predictors (beyond PD-L1) are needed to identify responders.
Biomarker-Driven Trials
Using TMB, CD8+ T-cell infiltration, and PD-L1 status to select patients.
Novel Immunomodulators
Targeting TGF-β (often upregulated in E-cadherin-negative tumors).
Engineered Cellular Therapies
NK cell therapies and bispecific antibodies for enhanced tumor killing.
E-cadherin-negative breast cancers, particularly lobular and some TNBC subtypes, represent a unique subset that may benefit from immunotherapy. While immune checkpoint inhibitors show early promise, combination strategies (e.g., with PARP or AKT inhibitors) could further improve outcomes. Ongoing research into biomarkers and novel immunotherapies will be crucial for optimizing treatment in this challenging breast cancer subtype.
