Clinical Guidance

CDH1. Pathogenic variants located in the CDH1 linker regions between the extracellular domains have been associated with cleft lip/palate. A specific protein region responsible for calcium ion chelation displayed high intolerance to missense substitutions (between amino acids 253 and 260) .

Source: GeneReviews — "Diffuse Gastric and Lobular Breast Cancer Syndrome"

Penetrance

The penetrance of DGLBCS is reduced. CDH1. A study that included 75 families with germline CDH1 pathogenic variants found that by age 80 years, the cumulative incidence of gastric cancer including DGC was 70% (95% CI: 59%-80%) for males and 56% (95% CI: 44%-69%) for females, and the risk of breast cancer including LBC for females was 42% (95% CI: 23%-68%) . In a second study not exclusively selected based on strict DGLBC criteria, the cumulative incidence of gastric cancer including DGC by age 80 years was 42% (95% CI: 30%-56%) for males and 33% (95% CI: 21%-43%) for females with a CDH1 pathogenic variant. Additionally, the estimated cumulative incidence of female breast cancer in this cohort was 55% (95% CI: 39%-68%) .

Source: GeneReviews — "Diffuse Gastric and Lobular Breast Cancer Syndrome"

Diagnostic Criteria

Consensus genetic testing criteria for diffuse gastric and lobular breast cancer syndrome (DGLBCS), also known as hereditary diffuse gastric cancer (HDGC), have been published .

Suggestive Findings

DGLBCS should be suspected in a proband with ANY of the following clinical features or family history :

Clinical features

Source: GeneReviews — "Diffuse Gastric and Lobular Breast Cancer Syndrome"

Differential Diagnosis

An estimated 5%-10% of all gastric cancers are thought to present familial clustering ; only a small fraction of gastric cancers are believed to be hereditary and explained by a genetic cause. Identification of individuals at risk for diffuse gastric and lobular breast cancer syndrome (DGLBCS) is complicated by several factors: • DGLBCS is one of several hereditary cancer syndromes characterized by gastric and breast cancer and associated premalignant lesions. • Risk of a hereditary cancer syndrome with an overlapping tumor spectrum may not be apparent in an individual with an unknown/unreported family history presenting with isolated gastric or breast cancer detected at early age . Detailed histologic classification of gastric (diffuse vs non-diffuse) and breast (lobular vs non-lobular) cancers is necessary to identify individuals and families at risk for DGLBCS and to facilitate appropriate genetic testing. Cancer predisposition syndromes that include gastric and/or breast cancer as part of their disease spectrum (despite not being the primary associated cancers) are listed in . Table 4. Cancer Predisposition Syndromes in the Differential Diagnosis of Diffuse Gastric and Lobular Breast Cancer Syndrome

Management Guidelines

Clinical practice guidelines for diffuse gastric and lobular breast cancer syndrome (DGLBCS) have been published .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DGLBCS, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Diffuse Gastric and Lobular Breast Cancer Syndrome: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Diffuse gastric cancer (DGC)

| • Referral to a DGC center of expertise for screening

• Endoscopy w/multiple gastric biopsies to assess for macroscopic tumor microscopic pre-malignant or malignant lesions

• Eval for H pylori infection given its major role as risk factor in gastric carcinogenesis1

| • For those w/CDH1 pathogenic variant or CTNNA1 truncating pathogenic variant, beginning in early adulthood or 5-10 yrs prior to earliest gastric cancer diagnosis in family w/minimum age of 18 yrs

• For those w/suspected DGLBCS of unknown cause, beginning at age 40 yrs or 5-10 yrs prior to earliest gastric cancer case in family, w/minimum age of 18 yrs

Lobular breast cancer (LBC)

| In females:

• Referral to high-risk breast cancer clinic

• Clinical breast exam in those age ≥20 yrs

• Breast MRI in those age 30-40 yrs

• Breast MRI combined w/mammography in those age ≥40 yrs

| • Mammography alone is inadequate to identify LBC; if MRI is unavailable, consider incl breast ultrasound.

Source: GeneReviews — "Diffuse Gastric and Lobular Breast Cancer Syndrome"

Therapies Under Investigation

Clinical trials, targeted therapies, and predictive markers of therapy response directed to DGC or LBC are scarce. Ongoing studies are mainly investigating alternate medication doses and combining therapeutic agents that are approved for sporadic gastric cancer and other solid tumors (e.g., platinum compounds, fluropyrimidines, and topoisomerase I inhibitors). Immunotherapy for anti-HER2, anti-VEGDR2, and anti-PD1 have been approved for treatment of gastric adenocarcinoma; however, treatment data for DGC is weak. The MONO study (NCT01197885), a Phase II clinical trial, examined the outcome of zolbetuximab (monoclonal antibody against CLDN18.2: IMAB362) monotherapy in a series of individuals with recurrent or refractory, locally advanced or metastatic, CLDN18.

Source: GeneReviews — "Diffuse Gastric and Lobular Breast Cancer Syndrome"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized (individuals with CDH1- or CTNNA1-related DGLBCS) and 7b (individuals with DGLBCS of unknown genetic cause) are recommended.

Table 7a.

CDH1- or CTNNA1-Related Diffuse Gastric and Lobular Breast Cancer Syndrome: Recommended Surveillance

System/Concern | Evaluation | Frequency

Diffuse gastric cancer (DGC)

| Referral to high-risk gastric cancer screening program |

Upper endoscopy to incl:

• Thorough ≥30-minute exam

• Targeted biopsies of all suspicious lesions

• Followed by random biopsies from specific anatomic regions using IGCLC Cambridge1 or Bethesda method2,3

Note: Endoscopy permits direct inspection biopsy of suspicious areas; however, DGC tends to spread in submucosa, where lesions are difficult to identify. | • Every 6-12 mos beginning at age 40 yrs (or 5-10 yrs prior to earliest gastric cancer diagnosis in family), w/minimum age of 18 yrs

• Note: (1) For individuals w/unclear risk of DGC, the interval between endoscopies can be increased after 2 consecutive normal endoscopies at discretion of a DGC specialist based on endoscopy findings family history. (2) Choosing endoscopy surveillance vs prophylactic gastrectomy is challenging; it is difficult to determine if intramucosal lesions identified on endoscopy will remain indolent /or become aggressive.

Source: GeneReviews — "Diffuse Gastric and Lobular Breast Cancer Syndrome"