Invasive Ductal Carcinoma of the Breast

Invasive ductal carcinoma of no special type is the commonest invasive breast cancer, forming 70% to 80% of cases. It is the diagnosis when a tumour lacks the features of a special histological type, and it is managed by grade, receptor status and stage rather than histology alone.

Breast cancer is the commonest cancer in women worldwide, with about 2.3 million new cases and 670,000 deaths each year. Lifetime risk is about 1 in 8 in high income settings. In sub-Saharan Africa incidence is lower but outcomes are worse, because presentation is later, onset is younger (median 45 to 50 years) and triple negative disease is more frequent.

Risk factors are female sex, age, early menarche, late menopause, nulliparity, first birth after 30, no breastfeeding, combined hormone therapy, postmenopausal obesity, alcohol, physical inactivity, chest irradiation in youth, high breast density and atypical hyperplasia. Germline variants account for 5% to 10%. Lifetime risk is about 70% with BRCA1 or BRCA2, roughly 35% to 55% with PALB2 and very high with TP53.

Pathophysiology. Tumours arise from the terminal duct lobular unit through stepwise genomic change, with ER-driven (luminal) and ER-independent (basal, HER2-enriched) lineages.

Intrinsic subtypes and surrogates.

• Luminal A-like: ER positive, HER2 negative, low grade, low proliferation.
• Luminal B-like: ER positive, HER2 negative, higher grade or proliferation. A HER2-positive ER-positive variant also exists.
• HER2-positive: HER2 3+ by immunohistochemistry or gene amplification.
• Triple negative: ER, PR and HER2 negative, mostly basal like.

Receptor thresholds. ER and PR are positive at 1% or more of nuclei. ER 1% to 10% is "ER-low" and behaves clinically like triple negative disease. HER2-low (immunohistochemistry 1+, or 2+ with no amplification) is now clinically relevant for antibody drug conjugate therapy.

Grade. Scored 3 to 9 from tubule formation, nuclear pleomorphism and mitotic count. Grade 1 is 3 to 5, grade 2 is 6 to 7 and grade 3 is 8 to 9.

Spread. Lymphatic spread goes to axillary nodes, then infraclavicular, supraclavicular and internal mammary nodes. Haematogenous spread goes to bone (commonest), lung, liver, brain and pleura. Luminal tumours favour bone and late recurrence. Triple negative and HER2-positive tumours favour early visceral and brain relapse.

• Painless, hard, irregular, poorly mobile breast mass, found in most symptomatic patients.
• Skin dimpling or tethering, nipple retraction, bloodstained discharge, new axillary lump.
• Locally advanced disease: peau d'orange, skin ulceration or satellite nodules, fixation to the chest wall (not to pectoralis alone), matted or fixed axillary nodes, supraclavicular nodes.
• Metastatic disease: bone pain, cough or dyspnoea, hepatomegaly or jaundice, headache or focal deficit, weight loss.
• Examine both breasts, all nodal basins, spine tenderness, liver edge and chest.

• Triple assessment: clinical examination, bilateral mammography with ultrasound, and image targeted core biopsy (14 gauge, at least 3 cores).
• Pathology: grade, ER and PR (immunohistochemistry), HER2 (3+ positive, 2+ reflexed to in situ hybridisation), proliferation index and lymphovascular invasion.
• Axilla: ultrasound with sampling of suspicious nodes, and a clip in the biopsied node when neoadjuvant therapy is planned.
• MRI for discordant extent, dense breasts, young age or pathogenic variant carriers.
• Systemic staging with CT of chest, abdomen and pelvis plus bone scintigraphy (or whole body PET-CT) for clinical stage III, symptoms, bone pain, abnormal alkaline phosphatase, calcium or liver tests, or aggressive biology. It is not routine for asymptomatic stage I to IIA disease.
• Baseline FBC, creatinine, liver tests, calcium, alkaline phosphatase, pregnancy test in women of reproductive age, and echocardiography before anthracyclines or HER2-directed therapy.
• 21-gene recurrence score (0 to 100) for ER-positive, HER2-negative disease with 0 to 3 positive nodes.
  • Score 25 or under: women over 50 with node negative disease gain no chemotherapy benefit. Women aged 50 or under with scores of 16 to 25 gain a small benefit.
  • Score 26 or more: chemotherapy is advised.
  • One to three positive nodes in postmenopausal women with score 25 or under: no chemotherapy benefit.
• Germline testing for age 50 or under, triple negative disease at any age under 60, bilateral cancer, male sex or relevant family history.
• Fertility counselling before systemic therapy.

Differential diagnosis.

• Fibroadenoma and phyllodes tumour
• Fat necrosis and radial scar
• Breast abscess and granulomatous mastitis
• Invasive lobular, metaplastic and other special type carcinomas
• Lymphoma, sarcoma and metastasis to the breast
• Intraductal papilloma

Stages I to III are treated with curative intent. Systemic therapy is selected by subtype.

Surgery and axilla.

• Breast conservation with whole breast radiotherapy and mastectomy give equal survival. Mastectomy is chosen for large tumour-to-breast ratio, multicentric disease or patient preference.
• Sentinel node biopsy in clinically node negative disease. Axillary clearance is omitted for 1 to 2 positive sentinel nodes after breast conservation with whole breast radiotherapy. It is done for 3 or more positive nodes or clinically positive nodes, unless targeted axillary dissection after neoadjuvant therapy shows clearance.

Radiotherapy.

• Whole breast 40 Gy in 15 fractions over 3 weeks, or 26 Gy in 5 fractions over 1 week. A boost of about 10 to 16 Gy is added for higher recurrence risk.
• Regional nodal radiotherapy for node positive disease.
• Post-mastectomy chest wall radiotherapy for T3 to T4 disease or 4 or more positive nodes, and discussed for 1 to 3 positive nodes.

Neoadjuvant systemic therapy. Used for triple negative and HER2-positive tumours over 2 cm or node positive, and for luminal disease when downstaging is needed.

Luminal (ER-positive, HER2-negative) disease: endocrine therapy.

• Tamoxifen: 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 (letrozole 2.5 mg or exemestane 25 mg once daily are equivalent options); maximum 1 mg, 2.5 mg and 25 mg daily respectively; monitoring: bone mineral density at baseline then every 1 to 2 years, calcium and vitamin D, lipids, arthralgia; adjustment: none in mild to moderate renal or hepatic impairment, letrozole 2.5 mg every other day in severe hepatic impairment. Extension to 7 to 10 years is considered in selected higher risk women.
• Goserelin (premenopausal women at higher risk, with an aromatase inhibitor or tamoxifen): 3.6 mg subcutaneously every 28 days (or 10.8 mg every 12 weeks) for 2 to 5 years; maximum 3.6 mg every 28 days or 10.8 mg every 12 weeks; monitoring: oestradiol by sensitive assay when combined with an aromatase inhibitor, bone density, vasomotor symptoms, mood; adjustment: none for renal or hepatic impairment; exclude pregnancy first because it is not contraception.

Adjuvant CDK4/6 inhibitors (added to endocrine therapy for higher risk node positive or larger tumours):

• Ribociclib: 400 mg orally once daily on days 1 to 21 of each 28-day cycle for 3 years, with an aromatase inhibitor; maximum 400 mg daily in this setting; monitoring: FBC and liver tests every 2 weeks for 2 cycles, at the start of the next 4 cycles, then as needed; ECG for QTc before starting, on day 14 of cycle 1 and at the start of cycle 2; adjustment: reduce stepwise to 200 mg for toxicity, do not start with QTcF over 450 ms, avoid strong CYP3A inhibitors and tamoxifen, reduce starting dose in moderate to severe hepatic impairment and severe renal impairment.
• Abemaciclib: 150 mg orally twice daily for 2 years, with endocrine therapy, for 4 or more positive nodes, or 1 to 3 positive nodes with grade 3 disease or tumour 5 cm or more; maximum 300 mg daily; monitoring: FBC and liver tests every 2 weeks for 2 months, monthly for 2 months, then as needed; diarrhoea (start loperamide at the first loose stool), venous thromboembolism, interstitial lung disease; adjustment: reduce stepwise to 100 mg then 50 mg twice daily for toxicity, once daily dosing in severe hepatic impairment, reduce to 100 mg twice daily with strong CYP3A inhibitors.

Chemotherapy. Selected by the recurrence score, nodal status and grade. Sequential anthracycline and taxane is the usual regimen when chemotherapy is given.

• 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 and triple negative tumours need subtype specific regimens with an anti-HER2 antibody or a checkpoint inhibitor and carboplatin respectively.

Metastatic luminal disease. Endocrine therapy plus a CDK4/6 inhibitor is first line, including in visceral disease without crisis. Chemotherapy is reserved for visceral crisis or endocrine resistance.

• 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.
• Zoledronic acid: 4 mg IV over at least 15 minutes every 3 to 4 weeks (every 12 weeks after the first year is an option) for 2 years or longer while benefit continues; maximum 4 mg each dose; monitoring: creatinine before each dose, calcium, phosphate, magnesium, dental review before starting; adjustment by creatinine clearance: over 60 mL/min 4 mg, 50 to 60 3.5 mg, 40 to 49 3.3 mg, 30 to 39 3.0 mg, under 30 avoid; give calcium 500 mg and vitamin D 400 to 800 IU daily.

Monitoring. Clinical review every 3 to 6 months for 3 years, then 6 to 12 monthly; annual mammography. Bone density with aromatase inhibitors. Echocardiography every 3 months on HER2-directed therapy.

Referral and escalation.

• Febrile neutropenia (temperature 38.0 C or more during chemotherapy) needs same day admission and an intravenous antipseudomonal beta lactam within 1 hour.
• Same day oncology and imaging for back pain with limb weakness or sphincter change (cord compression), corrected calcium over 3.0 mmol/L, or new neurological deficit.
• Multidisciplinary review for oligometastatic disease amenable to local therapy.

Special groups.

• Pregnancy: surgery in any trimester, chemotherapy from the second trimester, no endocrine therapy, radiotherapy or HER2-directed therapy until after delivery.
• Pathogenic variants: consider bilateral mastectomy. Add a PARP inhibitor for germline BRCA disease at high risk.
• Older adults: use geriatric assessment. Endocrine therapy alone is reasonable in frail older adults with luminal disease.
• Men: tamoxifen 20 mg daily for 5 to 10 years.
• Africa and low resource settings: late presentation is common. Early surgery, tamoxifen or anastrozole when receptor testing is unavailable, and access to radiotherapy are the priorities.