Hereditary diffuse gastric and lobular breast cancer syndrome associated with germline CDH1 variants: focus on lobular breast cancer

Abstract

Background: Hereditary lobular breast cancer (HLBC) is a distinct subset of hereditary breast cancer primarily associated with germline pathogenic variants in the CDH1 gene, which encodes E-cadherin, a crucial protein in cell adhesion. Loss of E-cadherin disrupts tissue architecture, contributing to the invasive growth pattern characteristic of lobular carcinoma. CDH1 mutations are also implicated in hereditary diffuse gastric cancer, predisposing some patients to both cancers. However, variable cancer risk is observed, as many HLBC patients with a family history of gastric cancer do not develop gastric malignancies, reflecting the complex interplay of E-cadherin's role in cell cohesion and tumorigenesis.

Main body: HLBC accounts for 4-5% of lobular breast cancer cases, even in the absence of a personal or family history of gastric cancer. These tumors typically present as hormone receptor-positive (estrogen receptor-positive and progesterone receptor-positive) and are often diagnosed at advanced stages due to their diffuse growth pattern and subtle imaging characteristics. Recent evidence underscores the importance of genetic screening for CDH1 mutations in women with early-onset bilateral lobular breast cancer or a strong family history of breast cancer. Despite the strong correlation between CDH1 mutations and HLBC, the absence of diffuse gastric cancer in many patients presents diagnostic challenges. Updated guidelines emphasize targeted surveillance and risk-reduction strategies, including prophylactic mastectomy for high-risk individuals, aiming to improve clinical outcomes.

Conclusion: This mini-review synthesizes recent advancements in understanding the genetics, diagnostic complexities, and clinical management of HLBC. The findings highlight the critical need for early identification and personalized approaches to optimize surveillance and therapeutic strategies for patients with this unique hereditary cancer.

Keywords: CDH1 gene; E-cadherin; Genetic screening; Hereditary lobular breast cancer; IGCLC guidelines.