Invasive Lobular Carcinoma of the Breast

Invasive lobular carcinoma is a breast cancer of discohesive, small uniform cells infiltrating the stroma in single files and concentric patterns, usually without a desmoplastic mass. It is the commonest special histological type of invasive breast cancer.

It accounts for 10% to 15% of invasive breast cancers. It occurs mainly in postmenopausal women (median age in the 60s), and incidence is higher with long term combined hormone replacement therapy.

Germline CDH1 loss-of-function variants cause hereditary diffuse gastric cancer, with a lifetime risk of lobular breast cancer of roughly 40% to 55% in women. Other associations are lobular carcinoma in situ, family history and pathogenic variants in BRCA2 and PALB2.

Pathophysiology. Loss of E-cadherin (through CDH1 mutation, loss of heterozygosity or promoter methylation) abolishes cell adhesion and explains the discohesive, single file growth. Most classic tumours are ER positive (over 90%), HER2 negative (over 90%), with low proliferation and grade 1 to 2.

Variants. Classic (about 70%), alveolar, solid, trabecular, tubulolobular and pleomorphic. Pleomorphic tumours are higher grade, more often HER2 positive or receptor negative, and behave aggressively.

Behaviour. Multifocal and bilateral disease are more frequent than in ductal cancer. The tumour is often large and underestimated by imaging. Chemotherapy sensitivity is low, and pathological complete response to neoadjuvant chemotherapy is uncommon (about 5% or less). Relapse continues beyond 10 years.

Metastatic pattern. Bone is commonest, but spread to the gastrointestinal tract (stomach, colon), peritoneum, retroperitoneum with ureteric obstruction, ovary, uterus, leptomeninges, orbit and skin is characteristic.

• Ill defined thickening, induration, or subtle architectural change rather than a discrete lump. Skin or nipple retraction without a mass is typical.
• Lesions are often larger at clinical examination than on imaging.
• Metastatic features: dysphagia, early satiety, vomiting, constipation or change in bowel habit (gastrointestinal infiltration), abdominal distension (ascites), flank pain or anuria (ureteric obstruction), abnormal vaginal bleeding, diplopia or proptosis (orbit), headache or cranial neuropathy (leptomeningeal).

• Mammography has lower sensitivity (distortion or asymmetry rather than a mass). Ultrasound shows an irregular hypoechoic shadowing area and underestimates size. MRI is useful before surgery to define extent and detect contralateral disease.
• Image targeted core biopsy. Immunohistochemistry shows loss of membranous E-cadherin with cytoplasmic p120 catenin. Report ER, PR, HER2 and proliferation.
• Systemic staging for stage III or symptoms uses CT of chest, abdomen and pelvis and bone scintigraphy. FDG-PET is less sensitive in lobular disease. Abdominal symptoms need endoscopy with biopsy, because gastric wall infiltration may look like linitis plastica.
• Distinguishing metastasis from a primary gastric signet ring cancer: lobular metastasis is GATA3 and ER positive, CK7 positive and CDX2 negative.
• 21-gene recurrence score to judge chemotherapy benefit (lobular tumours often score low).
• Germline testing for CDH1 in early onset or familial lobular cancer, and for BRCA1, BRCA2, PALB2.

Differential diagnosis.

• Invasive ductal carcinoma
• Lobular carcinoma in situ, including pleomorphic type
• Primary gastric or colonic signet ring adenocarcinoma
• Metastatic melanoma
• Lymphoma
• Granulomatous mastitis, sclerosing adenosis and radial scar

Local therapy follows the principles for invasive ductal cancer, with a higher mastectomy rate and more re-excisions for positive margins.

Surgery and radiotherapy.

• Breast conservation if clear margins are achievable, otherwise mastectomy. Sentinel node biopsy for clinically node negative disease.
• Radiotherapy after conservation: whole breast 40 Gy in 15 fractions, or 26 Gy in 5 fractions, with a boost of about 10 to 16 Gy for higher risk cases. Post-mastectomy radiotherapy for T3 to T4 disease or 4 or more positive nodes.

Neoadjuvant endocrine therapy downstages large ER-positive tumours.

• Letrozole: 2.5 mg orally once daily for 4 to 6 months (up to 12 months while responding); maximum 2.5 mg daily; monitoring: clinical and ultrasound response every 2 months, bone density; adjustment: 2.5 mg every other day in severe hepatic impairment, none for renal impairment; postmenopausal or with ovarian suppression only.

Adjuvant endocrine therapy is the mainstay.

• Tamoxifen (premenopausal women): 20 mg orally once daily for 5 years (up to 10 years in selected higher risk women); maximum 20 mg daily; monitoring: ask about abnormal vaginal bleeding at each visit, thromboembolic symptoms, annual gynaecological review; adjustment: no renal adjustment, avoid strong CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion), avoid in severe hepatic impairment and pregnancy, caution with prior venous thromboembolism.
• Anastrozole (postmenopausal women): 1 mg orally once daily for 5 years, extended to 7 to 10 years in higher risk women because late recurrence is common; maximum 1 mg daily; monitoring: bone mineral density at baseline then every 1 to 2 years, calcium and vitamin D, lipids; adjustment: none in mild to moderate renal or hepatic impairment.
• Add ovarian suppression for premenopausal women at higher risk. Chemotherapy is reserved for pleomorphic, grade 3, HER2-positive or high recurrence score tumours, because the benefit is smaller than in ductal disease.

Metastatic disease. Endocrine therapy with a CDK4/6 inhibitor is first line.

• Ribociclib: 600 mg orally once daily on days 1 to 21 of each 28-day cycle with an aromatase inhibitor or fulvestrant, until progression; maximum 600 mg daily; monitoring: FBC and liver tests every 2 weeks for 2 cycles then at the start of the next 4 cycles; ECG for QTc before starting, on day 14 of cycle 1 and at the start of cycle 2; adjustment: reduce stepwise to 400 mg then 200 mg for toxicity, 400 mg in moderate to severe hepatic impairment, 200 mg in severe renal impairment, no use with QTcF over 450 ms or strong CYP3A inhibitors.
• Fulvestrant: 500 mg IM on days 1, 15 and 29, then every 28 days, until progression; maximum 500 mg each dose; monitoring: liver tests, injection site reactions, bleeding risk with anticoagulants; adjustment: 250 mg in moderate hepatic impairment, caution when creatinine clearance is under 30 mL/min.
• Capecitabine (after endocrine resistance): 1250 mg/m2 orally twice daily on days 1 to 14 of each 21-day cycle until progression; maximum 2500 mg/m2 daily; monitoring: FBC, creatinine and liver tests each cycle, hand foot syndrome, diarrhoea; adjustment: reduce to 75% when creatinine clearance is 30 to 50 mL/min, contraindicated under 30 mL/min, test for DPYD variants before starting, avoid with warfarin.
• Later line options include oral targeted agents directed at PIK3CA or ESR1 alterations, selected by molecular testing.
• Disease is often non-measurable. Response is judged by symptoms, examination, serial MRI or CT, and FDG-PET or oestrogen receptor PET where available.

Monitoring. Clinical review every 3 to 6 months for 3 years then 6 to 12 monthly. Annual mammography, and MRI where breast density limits mammography. Maintain surveillance beyond 10 years.

Referral and escalation.

• Urgent urology for ureteric obstruction or anuria (stent or nephrostomy).
• Urgent surgery or gastroenterology for obstruction or bleeding from gastrointestinal metastases.
• Urgent neuro oncology for new cranial neuropathy or headache with suspected leptomeningeal disease.

Special groups.

• CDH1 carriers: risk reducing total gastrectomy is advised in adulthood. Discuss bilateral mastectomy and annual breast MRI. Lobular cancer in a carrier needs gastric surveillance until surgery.
• Postmenopausal women on hormone replacement therapy: stop it at diagnosis.
• Older adults: endocrine therapy alone is often sufficient.