What is the recommended treatment approach for CDH1 (Cadh1 gene) positive lobular breast cancer?

Treatment of CDH1-Positive Lobular Breast Cancer

CDH1-positive lobular breast cancer should be treated according to standard invasive lobular carcinoma protocols based on tumor stage, hormone receptor status, and HER2 status, with the critical addition of genetic counseling and consideration of bilateral risk-reducing mastectomy due to the hereditary nature and high contralateral breast cancer risk. 1

Initial Management of Diagnosed Cancer

Surgical Approach

• Breast-conserving surgery with radiation is acceptable for early-stage disease if clear margins can be achieved and the tumor-to-breast size ratio is favorable 1
• Mastectomy is indicated when:
  • Tumor size is large relative to breast size 1
  • Multicentricity is present 1
  • Patient preference, particularly given hereditary risk 1
• Bilateral mastectomy should be strongly considered given the 30-56% lifetime risk of contralateral lobular breast cancer in CDH1 carriers 1
• Skin and nipple-sparing mastectomy with immediate reconstruction is acceptable provided adequate surgical margins are achievable 1

Axillary Management

• Sentinel lymph node biopsy is the standard of care for clinically node-negative disease 1
• Patients with isolated tumor cells (<0.2 mm) or micrometastases (0.2-2 mm) in sentinel nodes who receive tangential breast irradiation may not require further axillary procedures 1

Radiation Therapy

• Postoperative radiation is strongly recommended after breast-conserving surgery 1
• Post-mastectomy radiation is indicated for T3-T4 tumors or four or more positive nodes, and should be considered for one to three positive nodes 1
• Shorter fractionation schemes (15-16 fractions) are validated and recommended 1

Systemic Therapy

Endocrine Therapy

• All patients with ER expression ≥1% should receive endocrine therapy 1
• Premenopausal patients: tamoxifen is standard 1
• Postmenopausal patients: aromatase inhibitors or tamoxifen are valid options 1

Chemotherapy Decisions

• For luminal HER2-negative cancers (most CDH1-related lobular cancers), chemotherapy indications depend on individual relapse risk and presumed endocrine responsiveness 1
• Sequential anthracycline and taxane regimens (4-8 cycles) are recommended when chemotherapy is indicated 1

HER2-Targeted Therapy

• CDH1-altered lobular breast cancer with ERBB2 mutation has significantly worse prognosis and should receive trastuzumab with chemotherapy 2
• Standard trastuzumab is indicated for HER2-positive disease 1

Hereditary Cancer Management

Genetic Counseling and Testing

• All patients with lobular breast cancer and CDH1 mutations require comprehensive genetic counseling regarding gastric cancer risk 1
• The lifetime risk of diffuse gastric cancer is 42-70% in men and 33-56% in women with CDH1 mutations 1

Prophylactic Gastrectomy

• Prophylactic total gastrectomy should be discussed with all CDH1 carriers, ideally performed between ages 20-30 years 1
• This is the only effective strategy to prevent gastric cancer in hereditary diffuse gastric cancer 1
• Not generally recommended after age 70 1

Contralateral Breast Management

• Bilateral risk-reducing mastectomy reduces breast cancer risk by 90-95% and should be offered given the high contralateral risk 1, 3
• If surveillance is chosen over prophylactic mastectomy, annual breast MRI starting at age 30 is recommended, with annual mammography from age 35 1
• MRI demonstrates 88% sensitivity for detecting invasive lobular carcinoma in CDH1 carriers 4

Special Considerations

Histopathologic Confirmation

• Confirm lobular phenotype using β-catenin and p120-catenin immunohistochemistry 1
• p120-catenin shows cytoplasmic staining in lobular neoplasia (membranous in ductal carcinoma) 1
• β-catenin is negative in lobular neoplasia 1
• This is critical because CDH1 carriers can occasionally develop invasive carcinoma of no special type (ductal), which are likely coincidental sporadic cancers 1

LCIS Management

• Finding of lobular carcinoma in situ does not mandate risk-reducing mastectomy but this option should be discussed alongside surveillance and chemoprevention 1
• Background LCIS is present in 88% of hereditary lobular breast cancers versus only 1% of sporadic cases 4

Tumor Characteristics

• CDH1-related lobular breast cancers are typically diagnosed at younger ages (median 40-49 years) compared to sporadic cases 4, 5
• These tumors are usually smaller at diagnosis (median 1.4 cm) when detected through surveillance 4
• 95% are progesterone receptor-positive 4

Common Pitfalls to Avoid

• Do not treat CDH1-positive lobular breast cancer differently from sporadic lobular cancer in terms of oncologic management - the same staging, surgical margins, and systemic therapy principles apply 1
• Do not fail to address gastric cancer risk - this is the primary mortality driver in CDH1 carriers and prophylactic gastrectomy discussion is mandatory 1
• Do not offer unilateral mastectomy without discussing bilateral procedure given the 30-56% lifetime contralateral breast cancer risk 1
• Do not assume all breast cancers in CDH1 carriers are hereditary - review pathology to confirm lobular phenotype, as occasional ductal cancers are likely sporadic 1