HR-positive / HER2-negative breast cancer: lines of therapy

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15 standard-of-care settings across 6 lines and 3 biomarker subgroups. Rows come from the cancer page's standard of care; the grid places each on its line and subgroup.

Line	All comers	HR-positive	Risk group
Screening, prevention and diagnosis	1	·	·
Early / localised	2	2	1
Advanced, first line	2	·	·
Second line	3	2	·
Third line and beyond	1	·	·
Special situations	1	·	·

Screening, prevention and diagnosis

Subgroup	Setting	Approach	Products and trials	Guideline	Evidence
All comers	Screening and diagnosis	Mammography ± tomosynthesis; supplemental MRI for dense breasts or high risk; core biopsy with ER/PR/HER2/Ki-67; AI-assisted reading being deployed.	Mammography & tomosynthesisAI in radiologyHistopathology & immunohistochemistry	NCCN · Breast Cancer Screening	40

Early / localised

Subgroup	Setting	Approach	Products and trials	Guideline	Evidence
All comers	Early stage, deciding on chemotherapy	Genomic assay (Oncotype DX RS ≤25 node-negative or postmenopausal 1-3 nodes; MammaPrint low risk) → endocrine therapy alone; premenopausal RS 16-25 or high clinical risk → chemotherapy or OFS-based escalation.	TAILORxRxPONDER (SWOG S1007)Oncotype DXMammaPrint (70-gene signature)	NCCN · 1	89
All comers	Early stage, extended and adjuvant SERD (emerging)	Extended AI to 10 years for higher-risk (MA.17R, NSABP B-42); adjuvant giredestrant positive in lidERA (2025, not yet approved); CAMBRIA (camizestrant) and EMBER-4 (imlunestrant) ongoing.	lidERACAMBRIA-1 & CAMBRIA-2Giredestrant		87
HR-positive	Early stage	Surgery, radiation, endocrine therapy 5-10 years; chemotherapy if genomic risk high; abemaciclib or ribociclib adjuvant for high-risk.	Oncotype DXAbemaciclibRibociclibmonarchENATALEE	NCCN · Category 1, preferred: adjuvant abemaciclib…ESMO-MCBS · A (monarchE); A (NATALEE)	93
HR-positive	Early stage, adjuvant endocrine therapy	Postmenopausal: aromatase inhibitor 5-10 years (or tamoxifen → AI switch). Premenopausal: tamoxifen 5-10 years; add OFS (+ AI or tamoxifen) for higher-risk or chemotherapy-treated women (SOFT/TEXT).	Letrozole (and other aromatase inhibitors)TamoxifenGoserelin / leuprolide (ovarian function suppression)SOFT & TEXT	NCCN · 1	93
Risk group	Early stage, high risk: adjuvant CDK4/6	Abemaciclib 2 years for node-positive high-risk (monarchE); ribociclib 3 years for stage II-III including node-negative high-risk (NATALEE). Palbociclib not effective (PALLAS/PENELOPE-B). Olaparib 1 year if gBRCA (OlympiA).	AbemaciclibRibociclibmonarchENATALEEPALLAS & PENELOPE-BOlaparib	NCCN · 1	93

Advanced, first line

Subgroup	Setting	Approach	Products and trials	Guideline	Evidence
All comers	Metastatic first line	CDK4/6 inhibitor + aromatase inhibitor or fulvestrant.	PalbociclibRibociclibAbemaciclib	ESMO-MCBS · 4-5 (MONALEESA-2, -3, -7); 2 (PALOMA-2); 2 …	85
All comers	Metastatic, first line	CDK4/6 inhibitor + aromatase inhibitor (or fulvestrant): ribociclib or abemaciclib preferred where OS data are valued; palbociclib acceptable. Premenopausal: add OFS. For relapse on/within 12 months of adjuvant ET with PIK3CA mutation: inavolisib + palbociclib + fulvestrant (INAVO120).	MONALEESA-2MONARCH 3PALOMA-2INAVO120RibociclibAbemaciclibPalbociclibInavolisib	NCCN · 1, preferredESMO-MCBS · 4 (ribociclib, OS)	88

Second line

Subgroup	Setting	Approach	Products and trials	Guideline	Evidence
All comers	Metastatic second line	Genotype-directed: capivasertib, inavolisib, alpelisib, everolimus; elacestrant/vepdegestrant if ESR1-mutant; gedatolisib.	CapivasertibInavolisibElacestrantVepdegestrantGedatolisib	ESMO-MCBS · 3 (CAPItello-291); 3 (INAVO120); 3 (EMERALD…	83
All comers	Metastatic, molecular progression on first line	Serial ctDNA; on emergent ESR1 mutation before radiographic progression, switch AI → camizestrant and continue the CDK4/6 inhibitor (SERENA-6; accelerated approval 4 Sep 2026).	SERENA-6Camizestrant	NCCN · Pending inclusion (approval Sep 2026)	76
All comers	Metastatic, second line by genotype	ESR1-mutant: elacestrant, imlunestrant (± abemaciclib), or vepdegestrant. PIK3CA/AKT1/PTEN: capivasertib + fulvestrant; alpelisib + fulvestrant. Any genotype after CDK4/6: gedatolisib + palbociclib + fulvestrant (PIK3CA-wild-type, 2026); everolimus + exemestane or giredestrant (filed); abemaciclib switch (postMONARCH, modest).	EMBER-3EMERALDVERITAC-2CAPItello-291SOLAR-1GedatolisibevERApostMONARCHElacestrantImlunestrantVepdegestrantCapivasertib	NCCN · 1 / 2A by agent	89
HR-positive	Endocrine-resistant	T-DXd (HER2-low/ultralow) before chemotherapy; sacituzumab govitecan or Dato-DXd after chemotherapy.	DESTINY-Breast06Trastuzumab deruxtecanSacituzumab govitecanDatopotamab deruxtecan	ESMO-MCBS · 4 (DESTINY-Breast04); 3 (DESTINY-Breast06);…	97
HR-positive	Metastatic, endocrine-resistant: ADC before chemotherapy	HER2-low or ultralow (~60%): T-DXd (DESTINY-Breast06 chemotherapy-naive; DESTINY-Breast04 after chemotherapy). HER2-zero: sacituzumab govitecan or Dato-DXd after chemotherapy (TROPiCS-02, TROPION-Breast01).	DESTINY-Breast06DESTINY-Breast04TROPiCS-02TROPION-Breast01Trastuzumab deruxtecanSacituzumab govitecanDatopotamab deruxtecan	NCCN · 1 (T-DXd HER2-low)ESMO-MCBS · 4 (DESTINY-Breast04)	97

Third line and beyond

Subgroup	Setting	Approach	Products and trials	Guideline	Evidence
All comers	Metastatic, chemotherapy and later lines	Sequential single-agent chemotherapy (capecitabine, taxanes, eribulin, vinorelbine); olaparib/talazoparib if gBRCA; clinical trials; supportive and palliative care integrated early.	Paclitaxel / nab-paclitaxelOlaparibTalazoparib		87

Special situations

Subgroup	Setting	Approach	Products and trials	Guideline	Evidence
All comers	Bone-predominant disease and survivorship	Bisphosphonate or denosumab for bone metastases and AI-induced bone loss; adjuvant bisphosphonates in postmenopausal women; exercise, cardio-oncology, and adherence support.	Exercise & lifestyle oncologyCardio-oncology		79

Sequence and caution pairings

SequenceApproved

Oral SERD + CDK4/6 inhibitor after ESR1 emergence

When an ESR1 mutation appears, swap the aromatase inhibitor for an oral SERD and keep the CDK4/6 inhibitor going.

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.

CautionApproved

Caution: TOP1 ADC immediately after TOP1 ADC

Giving a second ADC with the same kind of payload straight after the first often does not work well.

Regimens in the library

Everolimus Dose-dense AC → T TC (docetaxel + cyclophosphamide)Trastuzumab deruxtecan 5.4 mg/kg Sacituzumab govitecan Capecitabine (post-neoadjuvant)Olaparib (adjuvant, OlympiA)CDK4/6 inhibitor + aromatase inhibitor Eribulin Weekly paclitaxel

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.