Cancer - breast
Description
Histology
- Invasive ductal (NST) 75-80%
- Invasive lobular 10-15% - arises from terminal duct lobular unit
- Lower grade, E-cadherin negative, diffuse infiltration
- Poorly seen on mammography; bilateral + multifocal more often; metastasises to peritoneum, GIT, ovary
- Special types: tubular, mucinous, medullary (better prognosis)
In situ
- DCIS - true precursor, treat as cancer (excision +/- RT +/- endocrine)
- LCIS - a risk marker, not a precursor; risk to both breasts
Molecular subtypes - the axis that drives everything
| Subtype | Receptors | Proliferation | Systemic therapy |
|---|---|---|---|
| Luminal A | ER/PR+++, HER2- | Low (Ki67 low) | Endocrine alone |
| Luminal B | ER/PR+, HER2- | High | Chemo + endocrine |
| HER2-positive | HER2 amplified | High | Chemo + anti-HER2 (+ endocrine if ER+) |
| Basal / TNBC | ER-, PR-, HER2- | High | Chemo (+ immunotherapy, PARPi) |
- HER2-low / HER2-ultralow now a distinct therapeutic category (IHC 1+ or 2+/ISH-, and faint incomplete staining)
- Not a biological subtype - a predictive category for trastuzumab deruxtecan
Special presentations
- Inflammatory - peau d'orange, erythema, no discrete lump; dermal lymphatic invasion; stage III minimum, poor prognosis
- Paget's of nipple - eczematous nipple, underlying DCIS/invasive in most
- Occult primary - axillary node adenocarcinoma, normal imaging -> breast MRI
Epidemiology
- Commonest cancer in Australian women; ~1 in 7 lifetime risk
- ~21,000 new cases/yr AU; ~3,300 deaths
- Median age ~62; incidence rises steeply with age
- Male 0.5-1% of cases - BRCA2 lifetime risk ~7% vs BRCA1 ~1%
- 5-yr survival ~92% overall (stage I ~100%, stage IV ~30%)
Aetiopathogenesis
Risk factors - descending magnitude
- BRCA1/2 germline mutation (RR 5-20)
- Chest RT before age 30 (Hodgkin mantle field)
- Dense breast tissue - high glandular:fatty ratio (also reduces mammographic sensitivity - two hits)
- Prior DCIS / LCIS / atypical hyperplasia
- Family history (esp. young, bilateral, male, ovarian)
- Hormonal - combined HRT, nulliparity, menarche <12, menopause >55, late first pregnancy
- Unifying theme: lifetime oestrogen exposure
- Lifestyle - obesity (postmenopausal), alcohol, sedentary, smoking
Hereditary breast cancer
- ~5% carry BRCA1/2; ~10% overall have a high-penetrance germline variant
- BRCA1/2 = double-strand break repair by homologous recombination
- Loss -> HR deficiency -> reliance on PARP-mediated single-strand repair
- -> synthetic lethality with PARP inhibitors
- Other genes: TP53 (Li-Fraumeni), PTEN (Cowden), CDH1 (lobular + diffuse gastric), STK11, PALB2, ATM, CHEK2 (moderate penetrance)
Phenotype by gene
| BRCA1 | BRCA2 | |
|---|---|---|
| Triple negative | ~69% | ~16% |
| ER-positive | minority | ~77% (like sporadic) |
| Grade 3 | ~75% | lower |
| Other cancers | ovarian (~40%) | ovarian (~15%), male breast, prostate, pancreas, melanoma |
Diagnosis
Triple assessment - all three, always
- Clinical - examination of breasts + axillae
- Imaging - mammogram (>=35-40) + US; MRI if dense breast, lobular, occult primary, extent unclear
- Pathology - core biopsy (not FNA - core gives grade, receptors, invasion)
Receptor testing on every invasive cancer
- ER, PR by IHC (>=1% = positive)
- HER2 IHC; ISH if 2+ equivocal
- Ki67 proliferation index
Staging
- TNM; anatomical stage now modified by biology (grade, ER/PR/HER2, genomic score) in AJCC prognostic staging
- Systemic staging only if node-positive/stage III, symptoms, or high-risk biology
- CT C/A/P + bone scan (or PET)
Genomic assays - who can safely skip chemotherapy
- Oncotype DX (21-gene RS) in ER+/HER2-/node-negative (and selected 1-3 node +ve)
- RS <26 postmenopausal -> chemo adds nothing (TAILORx)
- Premenopausal women benefit from chemo at intermediate RS 16-25 - partly an ovarian suppression effect
- EndoPredict, MammaPrint, Prosigna alternatives
- Not PBS-funded in Australia - patient-funded
Prognostic factors
- Nodal status (strongest), tumour size, grade, LVI
- ER/PR (better), HER2 (worse untreated, now favourable with therapy), TNBC (worst early, but plateaus)
When to think hereditary
- Breast Ca <30; HER2+ <35; TNBC <60
- >=2 breast primaries, first <50
- Ovarian/primary peritoneal at any age
- Male breast cancer
- Ashkenazi Jewish ancestry
- 1st/2nd degree relative with breast or ovarian cancer <50
Management
A. Screening and risk reduction
- BreastScreen Australia - free biennial mammography, actively invites 50-74; available 40-49 and 75+ on request
- ~20-25% breast cancer mortality reduction in the invited age range
- Annual MRI + mammogram from age 25-30: BRCA1/2, TP53, prior chest RT <30
- dec stage 2+ diagnoses ~70%; mortality benefit proven only in the Hodgkin-RT cohort
- Risk-reducing surgery in BRCA carriers
- Bilateral mastectomy: dec breast cancer risk ~90%
- Bilateral salpingo-oophorectomy once childbearing complete, before 40 (BRCA1) / 45 (BRCA2): dec ovarian risk ~80%
- Must remove tubes - most high-grade serous "ovarian" cancer arises in fimbrial epithelium
- Chemoprevention: tamoxifen or anastrozole for 5 yr in high-risk women (~50% risk reduction)
B. Local therapy
- BCS + whole-breast RT = mastectomy for survival
- RT after BCS is near-mandatory; omission considered only in >=65-70, small, ER+, node-negative on endocrine therapy
- Sentinel node biopsy if clinically node-negative
- Axillary dissection now avoided for 1-2 positive sentinel nodes if BCS + RT (Z0011)
- Post-mastectomy RT if T3/T4, positive margins, or >=4 nodes (and considered for 1-3 nodes)
C. Systemic therapy - ER+/HER2- (the commonest)
Endocrine therapy: minimum 5 years
- Premenopausal
- Tamoxifen alone (low risk), OR
- Ovarian suppression (goserelin) + AI (exemestane) for higher risk - better DFS than tamoxifen, more toxicity (SOFT/TEXT)
- Postmenopausal
- AI > tamoxifen - lower 10-yr mortality
- Extended therapy to 7-10 yr if high risk: ATLAS showed 10 vs 5 yr tamoxifen dec breast cancer mortality ~29% relative (~2.8% absolute)
- Adjuvant CDK4/6 inhibitor added for high-risk node-positive disease
- Abemaciclib 2 yr (monarchE) - >=4 nodes, or 1-3 nodes with G3 or T>=5cm; now with OS benefit
- Ribociclib 3 yr (NATALEE) - broader, includes selected node-negative
- Chemotherapy added when genomic score high, node-positive, or Luminal B biology
- Regimens: AC-T (doxorubicin/cyclophosphamide -> paclitaxel; superior to AC alone), TC x4 if anthracycline-sparing
- Dose-dense scheduling improves outcome, more toxicity + needs G-CSF
D. Systemic therapy - HER2-positive
- Trastuzumab 12 months with chemotherapy (+ endocrine if ER+)
- 12 mo > 6 mo; 24 mo adds nothing, more cardiotoxicity
- Neoadjuvant chemo + trastuzumab + pertuzumab for T>=2cm or node-positive
- If residual invasive disease at surgery -> switch to T-DM1 x14 (KATHERINE) - the single highest-yield adjuvant decision point
- If pCR -> complete trastuzumab
- Neratinib x1 yr after trastuzumab in high-risk ER+/HER2+ (severe diarrhoea - loperamide prophylaxis)
- Echo/MUGA baseline and 3-monthly - hold if EF falls >10% to <50%
E. Systemic therapy - triple negative
- Neoadjuvant pembrolizumab + carboplatin/taxane -> anthracycline for stage II-III (KEYNOTE-522), continued adjuvantly
- Residual disease after neoadjuvant chemo -> adjuvant capecitabine
- Adjuvant olaparib 1 yr if germline BRCA1/2 and high risk (OlympiA) - OS benefit
F. Metastatic disease
Goal is duration + quality, not cure. Biopsy a metastasis - receptors discordant in ~15%.
- ER+/HER2-: endocrine backbone first if minimally symptomatic, low-volume visceral, long DFI
- AI or fulvestrant + CDK4/6 inhibitor = first line (ribociclib and abemaciclib have OS benefit)
- On progression, test ESR1 (elacestrant), PIK3CA/AKT1/PTEN (capivasertib, alpelisib, inavolisib), BRCA (olaparib/talazoparib)
- Everolimus + exemestane after endocrine resistance (BOLERO-2)
- HER2+: 1st line taxane + trastuzumab + pertuzumab; 2nd line trastuzumab deruxtecan; then T-DM1, tucatinib+capecitabine+trastuzumab (CNS activity)
- T-DXd also active in HER2-low and HER2-ultralow after endocrine therapy - interstitial lung disease is the toxicity to know
- TNBC: pembrolizumab + chemo if PD-L1 CPS>=10; sacituzumab govitecan after >=2 lines; PARPi if gBRCA
- Bone metastases: denosumab or zoledronic acid + calcium/vitD (dental review first - MRONJ)
Endocrine therapy toxicity - the exam comparison
| Tamoxifen | Aromatase inhibitor | |
|---|---|---|
| Use | Pre- or post-menopausal | Postmenopausal only (or with OS) |
| Hot flushes | Yes | Yes |
| Bone | inc BMD (agonist) | Osteopenia/fracture - DEXA + bone protection |
| Lipids | dec LDL | Neutral/worse |
| VTE | 2-3x inc | No inc |
| Endometrial Ca | 2-3x inc | No inc |
| Musculoskeletal | - | Arthralgia - commonest cause of non-adherence |
- CYP2D6 converts tamoxifen to endoxifen - avoid strong inhibitors (paroxetine, fluoxetine); use venlafaxine for flushes
Chemotherapy toxicity
- Anthracyclines - nausea, alopecia, myelosuppression; late cardiomyopathy (dose-dependent) and secondary AML/MDS
- Taxanes - hypersensitivity (premedicate), myalgia, fluid retention (docetaxel), nail changes; peripheral neuropathy may be permanent
- Fertility: goserelin during chemotherapy dec permanent ovarian failure (~8% vs ~22%) - discuss oocyte/embryo cryopreservation before starting
Associations
- Ovarian, fallopian tube and primary peritoneal cancer (BRCA)
- Prostate, pancreatic cancer, melanoma (BRCA2)
- Diffuse gastric cancer (CDH1)
- Sarcoma, brain, adrenocortical Ca (TP53 / Li-Fraumeni)
- Thyroid and endometrial cancer, macrocephaly (PTEN / Cowden)
- Hodgkin lymphoma treated with mantle RT
- Klinefelter syndrome (male breast cancer)
- Lymphoedema post axillary clearance +/- RT
- Anaplastic large cell lymphoma associated with textured breast implants (rare, ALK-negative)
Natural history & complications
- Curable when localised; metastatic disease is treatable, not curable
- Node status is the dominant anatomical prognostic factor
Recurrence patterns by subtype
- ER+ - low but relentless annual hazard, recurs out to 20+ years (hence extended endocrine therapy)
- TNBC / HER2+ - early peak at 2-3 yr, then hazard falls; late recurrence uncommon
- Bone-only ER+ disease can run for many years
Metastatic sites
- Bone (commonest), liver, lung, brain
- HER2+ and TNBC -> brain; screen if neurological symptoms
- Lobular -> peritoneum, retroperitoneum, GIT, ovary (may present as bowel obstruction)
Survivorship - what to monitor
- Annual mammography of remaining breast tissue; clinical review
- No role for routine tumour markers or surveillance imaging in asymptomatic patients
- Bone density on AI or ovarian suppression
- Cardiac function after anthracycline/trastuzumab
- Lymphoedema, arthralgia, cognitive change, menopausal symptoms, fear of recurrence
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