Inflammatory Breast Cancer

Inflammatory breast cancer is an aggressive form of locally advanced breast carcinoma with a clinical diagnosis: rapid onset (under 6 months) of erythema over at least a third of the breast, oedema or peau d'orange, and warmth, with or without a palpable mass, plus biopsy proven invasive carcinoma. It is stage T4d and at least stage IIIB.

It accounts for 1% to 5% of breast cancers in high income countries and up to 10% in North Africa. It presents at a younger age, with higher BMI, and more often in Black women.

Dermal lymphatic tumour emboli support the diagnosis but are not required, and their absence does not exclude it.

Pathophysiology. Tumour emboli obstruct dermal lymphatics and cause oedema and erythema. Tumours are usually grade 3, 50% to 60% are ER negative, and about 40% overexpress HER2. Triple negative disease is common.

Behaviour. Presentation with distant metastases at diagnosis is seen in about 30%. Five year overall survival for non-metastatic disease is 40% to 50% with multimodal therapy, and median survival in metastatic disease is 2 to 3 years.

Treatment principle. Trimodality therapy (neoadjuvant systemic therapy, mastectomy with axillary clearance, and post-mastectomy radiotherapy) is mandatory. Breast conservation and sentinel node biopsy are contraindicated.

• Breast enlargement, firmness, warmth, tenderness or heaviness over days to weeks, with diffuse erythema (pink to red or purple) and peau d'orange. A discrete mass is present in under half of cases.
• Nipple retraction or flattening, enlarged axillary and supraclavicular nodes, arm swelling.
• Fever and leucocytosis are absent, which separates it from infection.

Red flags.

• Progression over days to weeks, with skin ulceration or satellite nodules.
• Bone pain, dyspnoea, jaundice or headache (early metastatic disease).
• Arm swelling or collateral veins (axillary vein or lymphatic obstruction).
• Back pain with limb weakness or sphincter change (cord compression).

• Clinical diagnosis with documented time course, extent of erythema and photographs.
• Two skin punch biopsies (erythematous area and unaffected skin) plus core biopsy of any mass for invasive carcinoma, ER, PR and HER2 status.
• Bilateral mammography, ultrasound of breast and nodes, and MRI. Imaging shows skin thickening, diffuse oedema, and often no mass.
• Staging for every patient: CT chest, abdomen and pelvis with bone scan, or whole body PET-CT, plus MRI brain if symptomatic.
• Baseline FBC, creatinine, liver tests, calcium, alkaline phosphatase, echocardiography, pregnancy test and germline testing.
• Antibiotics for suspected mastitis are given for no more than 7 to 14 days. Failure to improve mandates biopsy.

Differential diagnosis.

• Mastitis and breast abscess (lactational and non-lactational)
• Cellulitis
• Locally advanced non-inflammatory carcinoma with skin invasion
• Lymphoma or leukaemic infiltration
• Granulomatous mastitis
• Radiation dermatitis
• Axillary or subclavian vein thrombosis, and superior vena cava obstruction

Neoadjuvant systemic therapy for all patients, regardless of subtype.

• Doxorubicin: 60 mg/m2 IV on day 1 every 3 weeks for 4 cycles (every 2 weeks with pegfilgrastim 6 mg subcutaneously 24 to 72 hours after each cycle is an option); maximum cumulative working ceiling 450 mg/m2; monitoring: echocardiography at baseline and after completion, FBC before each cycle; adjustment: bilirubin 20 to 51 micromol/L reduce by 50%, 53 to 85 micromol/L reduce by 75%, over 85 micromol/L avoid; consider reduction when eGFR is under 30 mL/min/1.73 m2.
• Cyclophosphamide: 600 mg/m2 IV on day 1 with doxorubicin, on the same schedule, for 4 cycles; maximum 600 mg/m2 each cycle; monitoring: FBC, hydration, urinary symptoms (haemorrhagic cystitis); adjustment: reduce by about 25% to 50% when eGFR is under 30 mL/min/1.73 m2, reduce in severe hepatic impairment.
• Paclitaxel (12 weeks after the anthracycline): 80 mg/m2 IV weekly for 12 weeks; maximum 80 mg/m2 each week; monitoring: FBC, liver tests, neuropathy at each visit; premedication with dexamethasone, an antihistamine and an H2 blocker; adjustment: reduce by about 25% in moderate hepatic impairment, avoid when bilirubin is over 5 times the upper limit, no renal adjustment.
• HER2-positive disease: add trastuzumab (8 mg/kg IV loading then 6 mg/kg every 3 weeks) and pertuzumab (840 mg IV loading then 420 mg every 3 weeks) during the taxane phase and complete 12 months in total; maximum duration 12 months; monitoring: LVEF at baseline and every 3 months; adjustment: withhold if LVEF falls under 50% with a fall of 10 points or more, no renal adjustment.
• Triple negative disease: add carboplatin AUC 5 IV every 3 weeks and pembrolizumab 200 mg IV every 3 weeks to the taxane phase, with blood count, thyroid, liver and renal monitoring before each dose.
• Monitor response clinically every cycle. Progression or no response needs a change in regimen or early local therapy.

Surgery. Modified radical mastectomy with level I and II axillary dissection after response. No sentinel node biopsy, no skin sparing technique and no immediate reconstruction. Delayed reconstruction is possible after radiotherapy.

Radiotherapy. Chest wall and regional nodes (axillary, supraclavicular, internal mammary) 50 Gy in 25 fractions, with a chest wall boost of about 10 to 16 Gy. Accelerated hypofractionation is not established in this disease.

Adjuvant therapy.

• Hormone receptor positive: endocrine therapy for 5 to 10 years, selected by menopausal status, with ovarian suppression in premenopausal women.
• HER2-positive: complete 12 months of anti-HER2 therapy, with trastuzumab emtansine 3.6 mg/kg every 3 weeks for 14 cycles if residual disease remains.
• Triple negative: continue pembrolizumab for 9 cycles, and add capecitabine or olaparib for residual disease or a germline BRCA variant.

Metastatic disease. Systemic therapy by subtype with consideration of local therapy for control of skin disease.

Monitoring. Clinical review every 3 months for 2 years, then 6 monthly to year 5, then annually. Imaging by symptoms, with a lower threshold than for other breast cancers.

Referral and escalation.

• Urgent breast cancer unit review within days of suspicion. Delay worsens outcome.
• Same day oncology for cord compression, hypercalcaemia or febrile neutropenia.
• Radiation oncology to coordinate sequencing after surgery.

Special groups.

• Pregnancy and lactation: breast changes are commonly mistaken for mastitis. Biopsy early. Chemotherapy is possible from the second trimester.
• Older adults: consider reduced intensity chemotherapy, but local therapy still matters.
• Region specific: late presentation and limited radiotherapy access in sub-Saharan Africa. Prioritise neoadjuvant chemotherapy and mastectomy.