HER2-positive breast cancer: lines of therapy

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12 standard-of-care settings across 5 lines and 2 biomarker subgroups. Rows come from the cancer page's standard of care; the grid places each on its line and subgroup.

Line	All comers	HER2
Early / localised	6	·
Advanced, first line	2	·
Second line	1	·
Third line and beyond	1	·
Special situations	1	1

Early / localised

Subgroup	Setting	Approach	Products and trials	Guideline	Evidence
All comers	Early stage	Neoadjuvant THP or T-DXd → surgery → trastuzumab/pertuzumab (pCR) or T-DXd/T-DM1 (residual).	TrastuzumabTrastuzumab deruxtecanTrastuzumab emtansineDESTINY-Breast11	NCCN · Category 1, preferred: neoadjuvant pertuzum…ESMO-MCBS · A (KATHERINE); A (HERA); C (NeoSphere, APHI…	97
All comers	Stage I (≤2-3 cm, node-negative)	Surgery then weekly paclitaxel × 12 + trastuzumab × 1 year (APT); T-DM1 × 17 cycles is an alternative (ATEMPT). Endocrine therapy if HR+.	APT (adjuvant paclitaxel-trastuzumab)Paclitaxel / nab-paclitaxelTrastuzumabTrastuzumab emtansine	NCCN · 2A	89
All comers	Stage II-III, neoadjuvant	TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab) or anthracycline-taxane + HP; from 2026, T-DXd × 4 → THP (DESTINY-Breast11, pCR 67%). PET-adapted chemotherapy omission (PHERGain) in trials.	DESTINY-Breast11Trastuzumab deruxtecanPertuzumabPHERGain	NCCN · 1	97
All comers	Post-neoadjuvant, pathologic complete response	Complete 1 year of trastuzumab (± pertuzumab if node-positive at diagnosis); endocrine therapy if HR+; radiation per stage.	TrastuzumabPertuzumabAPHINITYHERA, NSABP B-31 & NCCTG N9831 (adjuvant trastuzumab)	NCCN · 1	94
All comers	Post-neoadjuvant, residual invasive disease	T-DXd (DESTINY-Breast05, iDFS HR 0.47 vs T-DM1; approved 2026) replacing T-DM1 (KATHERINE); consider extended adjuvant neratinib for HR+ high-risk.	DESTINY-Breast05KATHERINETrastuzumab deruxtecanTrastuzumab emtansineNeratinib	NCCN · 1 (T-DM1); T-DXd pending update	97
All comers	Adjuvant (upfront surgery), node-positive	Chemotherapy + trastuzumab + pertuzumab for 1 year (APHINITY); trastuzumab alone for lower risk; 6 months acceptable where resources are limited (PERSEPHONE).	APHINITYPERSEPHONEPertuzumabTrastuzumab	NCCN · 1	92

Advanced, first line

Subgroup	Setting	Approach	Products and trials	Guideline	Evidence
All comers	Metastatic	T-DXd + pertuzumab first line (DESTINY-Breast09); tucatinib + trastuzumab + capecitabine for brain metastases; palbociclib maintenance if HR+.	DESTINY-Breast09TucatinibPalbociclib	ESMO-MCBS · 4 (DESTINY-Breast03); 4 (CLEOPATRA); 4 (HER…	83
All comers	Metastatic, first line	T-DXd + pertuzumab (DESTINY-Breast09, PFS 40.7 months; approved 2025) or taxane + trastuzumab + pertuzumab (CLEOPATRA) followed by maintenance: HP ± tucatinib (HER2CLIMB-05) and, if HR+, endocrine therapy + palbociclib (PATINA, approved 2026).	DESTINY-Breast09CLEOPATRAHER2CLIMB-05Trastuzumab deruxtecanPertuzumabTucatinibPalbociclib	NCCN · 1, preferred (T-DXd + pertuzumab)ESMO-MCBS · 4 (CLEOPATRA)	97

Second line

Subgroup	Setting	Approach	Products and trials	Guideline	Evidence
All comers	Metastatic, second line	T-DXd if not used first line (DESTINY-Breast03, PFS HR 0.33 vs T-DM1); tucatinib + trastuzumab + capecitabine, especially with brain metastases (HER2CLIMB).	DESTINY-Breast03HER2CLIMBTrastuzumab deruxtecanTucatinib	NCCN · 1ESMO-MCBS · 4 (DESTINY-Breast03)	97

Third line and beyond

Subgroup	Setting	Approach	Products and trials	Guideline	Evidence
All comers	Metastatic, later lines	T-DM1; neratinib or lapatinib + capecitabine; margetuximab + chemotherapy; trastuzumab + chemotherapy (continued HER2 blockade); zanidatamab and Chinese ADCs (trastuzumab rezetecan, disitamab vedotin) where available; trials.	Trastuzumab emtansineNeratinibLapatinibMargetuximabZanidatamabTrastuzumab rezetecanDisitamab vedotin	NCCN · 2A	84

Special situations

Subgroup	Setting	Approach	Products and trials	Guideline	Evidence
All comers	Brain metastases	Systemic: tucatinib triplet or T-DXd (DESTINY-Breast12, intracranial ORR 72%); local: stereotactic radiosurgery or surgery for symptomatic or large lesions; whole-brain RT reserved.	HER2CLIMBDESTINY-Breast12TucatinibTrastuzumab deruxtecanSBRT / SABR (stereotactic radiotherapy)	NCCN · 1 (tucatinib triplet)	97
HER2	Cardiac monitoring and survivorship	LVEF every 3 months during anti-HER2 therapy; hold and cardioprotect for declines; anthracycline-free regimens preferred; long-term surveillance for late recurrence in HR+/HER2+.	Cardio-oncologyPERSEPHONE		92

Sequence and caution pairings

CautionApproved

Caution: DXd ADC + agents with pneumonitis risk

Enhertu and its DXd cousins can inflame the lungs; combining them with immunotherapy, radiation, or mTOR inhibitors stacks that risk.

Regimens in the library

Dose-dense AC → T TCHP APT (weekly paclitaxel + trastuzumab)THP (docetaxel + trastuzumab + pertuzumab)Trastuzumab deruxtecan 5.4 mg/kg

Lines and subgroups are parsed from the setting text of each standard-of-care row and can misclassify an unusual phrasing; the row’s own setting is always shown. Guideline chips reflect the NCCN category and ESMO-MCBS grade recorded on the cancer page, checked on its stated date. Not medical advice.