| Setting | Treatment |
|---|---|
| HR+/HER2− early / locally advanced | Backbone at EVERY stage: surgery → radiotherapy → adjuvant endocrine therapy 5–10 yr
lumpectomy or mastectomy + axillary staging · whole-breast RT after lumpectomy (may be omitted in older women with small node-negative tumours), post-mastectomy / nodal RT if node-positive or high-risk · endocrine = tamoxifen (premenopausal) or an aromatase inhibitor ± ovarian suppression (postmenopausal). This is the least chemo-sensitive subtype — endocrine therapy is the main event; chemo is selective. Stage I (T1 N0) → surgery first, and chemo is usually NOT needed
a genomic assay makes the chemo call — Oncotype RS ≥26 → chemo; most small node-negative tumours skip it (TAILORx) Stage II / node-positive (operable) → surgery first → then adjuvant therapy
neoadjuvant rarely earns its place here (HR+ downstages poorly) — operate, then treat · chemo decided by assay in 1–3-node disease (RxPONDER), and when given chemo = dose-dense AC→T (doxorubicin + cyclophosphamide → a taxane; lower-risk alternative TC = docetaxel + cyclophosphamide) · node-positive high-risk → add adjuvant CDK4/6 inhibitor (abemaciclib 2 yr (monarchE) · ribociclib 3 yr (NATALEE)) · germline BRCA + high-risk → add adjuvant olaparib ×1 yr (OlympiA) (the HR+ bar is high: ≥4 nodes, or CPS+EG ≥3 residual) Stage III (locally advanced, T3–4 / N2–3) → neoadjuvant AC→T FIRST → surgery → RT → adjuvant endocrine + the escalations above
a pathological complete response is uncommon in HR+, but neoadjuvant still downstages the breast and axilla and exposes residual disease to guide the CDK4/6 and olaparib decisions |
| HR+/HER2− metastatic | 1st line → endocrine therapy (an AI or fulvestrant) + a CDK4/6 inhibitor
almost everyone · palbociclib / ribociclib / abemaciclib · biomarker-driven throughout — test ctDNA (circulating tumour DNA) / tissue, and the mutation picks the drug Exception → inavolisib + palbociclib + fulvestrant (INAVO120)
PIK3CA-mutant AND relapsed ≤12 mo on adjuvant endocrine therapy — already endocrine-resistant, PI3K driving it On progression → re-test ctDNA and match the mutation ESR1-mutant → elacestrant (EMERALD)
an oral SERD · ESR1 emerges under the AI's pressure PIK3CA / AKT1 / PTEN altered → capivasertib (CAPItello-291) or alpelisib (SOLAR-1)
capivasertib targets AKT — covers all three · alpelisib is PIK3CA-only Germline BRCA → a PARP inhibitor Later → single-agent chemotherapy, or an ADC
chemo = capecitabine, a taxane, eribulin, or vinorelbine · ADC = T-DXd if HER2-low, or sacituzumab govitecan (a Trop-2 ADC) |
| HER2+ early / locally advanced | Stage I, small (T1a–b N0, ≤~2 cm node-negative) → surgery → adjuvant paclitaxel + trastuzumab
the de-escalated APT regimen — weekly paclitaxel ×12 + trastuzumab to 1 yr; no anthracycline, no pertuzumab Stage II–III (≥T2 or node-positive) → neoadjuvant TCHP → surgery → locoregional RT → adjuvant trastuzumab ± pertuzumab to 1 yr
TCHP = docetaxel + carboplatin + trastuzumab + pertuzumab · surgery = lumpectomy/mastectomy + axillary staging · keep pertuzumab adjuvantly if node-positive (APHINITY) Residual disease at surgery → switch adjuvant to T-DXd
trastuzumab deruxtecan — beat T-DM1 (DESTINY-Breast05), which had itself beaten trastuzumab for residual disease (KATHERINE) · recent change — confirm your NCCN version reflects it HR+/HER2+ high-risk → extended adjuvant neratinib (ExteNET) ⚠ Anti-HER2 needs adequate LVEF
left-ventricular ejection fraction — significant cardiac dysfunction → cardio-oncology co-management rather than automatic exclusion |
| HER2+ metastatic | 1st line → T-DXd + pertuzumab (DESTINY-Breast09)
new benchmark, replacing taxane + trastuzumab + pertuzumab (THP) where available · very recent approval — confirm local/formulary adoption before treating on this basis If THP used 1st line → 2nd line T-DXd 3rd line → tucatinib + trastuzumab + capecitabine
brain-active |
| TNBC early / locally advanced | Stage I, small (cT1a–b N0) → surgery → adjuvant chemo
an anthracycline + taxane; the very small node-negative tumours do not need the full neoadjuvant immunotherapy regimen Stage II–III (cT2+ or node-positive — NCCN prefers neoadjuvant from cT1c N+) → neoadjuvant pembrolizumab + chemo → surgery → locoregional RT → adjuvant pembrolizumab
the KEYNOTE-522 regimen = carboplatin + paclitaxel → then AC, all with pembrolizumab (a PD-1 checkpoint inhibitor), then pembrolizumab alone after surgery (KEYNOTE-522) Residual disease after neoadjuvant → adjuvant capecitabine Germline BRCA → adjuvant olaparib (OlympiA)
a PARP (poly-ADP-ribose polymerase) inhibitor · ≥pT2 or ≥pN1 after adjuvant chemo, or any residual disease after neoadjuvant chemo |
| TNBC metastatic | PD-L1-positive → pembrolizumab + chemo
programmed death-ligand 1, CPS-based Germline BRCA → a PARP inhibitor Later → sacituzumab govitecan (ASCENT)
a Trop-2 ADC (antibody-drug conjugate) |
| HER2-low / ultralow metastatic only | T-DXd after ≥1 line of endocrine therapy
HER2-low = IHC 1+, or 2+/ISH− (DESTINY-Breast04) extended to HER2-ultralow = IHC 0 with faint incomplete staining (DESTINY-Breast06) |