Metastatic Breast Cancer — HR+/HER2-

Sequencing for hormone receptor-positive, HER2-negative metastatic breast cancer: first-line CDK4/6 inhibitor plus endocrine therapy, then a biomarker-guided second line (alpelisib for PIK3CA, elacestrant for ESR1, capivasertib for AKT-pathway alterations, everolimus otherwise), followed by antibody-drug conjugates and sequential chemotherapy.

ECOG performance status and candidacy for combination therapy?

• ECOG 0-1 → CDK4/6 inhibitor + aromatase inhibitor
• ECOG 2 → CDK4/6 inhibitor + aromatase inhibitor
• ECOG 3-4 → Endocrine monotherapy (aromatase inhibitor or fulvestrant)

1L: CDK4/6 inhibitor + aromatase inhibitor

Preferred first line for endocrine-sensitive disease. Ribociclib carries the strongest overall-survival evidence; monitor QTc and LFTs. Fulvestrant may replace the aromatase inhibitor in prior-endocrine-exposed patients.

Evidence: MONALEESA-2 · PALOMA-2 · MONARCH 3

• Progression → Actionable alteration at endocrine progression? (repeat NGS / ctDNA)

1L: Endocrine monotherapy (aromatase inhibitor or fulvestrant)

For frail patients (ECOG 3-4) or when CDK4/6-inhibitor toxicity is unacceptable. Consider best supportive care if performance status precludes systemic therapy.

• Progression → Actionable alteration at endocrine progression? (repeat NGS / ctDNA)

Actionable alteration at endocrine progression? (repeat NGS / ctDNA)

• PIK3CA-mutant → Alpelisib + fulvestrant
• ESR1-mutant → Elacestrant
• AKT-pathway altered (PIK3CA/AKT1/PTEN) → Capivasertib + fulvestrant
• No actionable alteration → Everolimus + exemestane

2L: Alpelisib + fulvestrant

PIK3CA-activating mutation. Monitor and manage hyperglycemia and rash; prophylactic antihistamines reduce rash.

• Progression → Antibody-drug conjugate (sacituzumab govitecan; trastuzumab deruxtecan if HER2-low)

2L: Elacestrant

ESR1 mutation after progression on prior endocrine therapy plus a CDK4/6 inhibitor. Oral SERD; monitor GI tolerability and lipids.

• Progression → Antibody-drug conjugate (sacituzumab govitecan; trastuzumab deruxtecan if HER2-low)

2L: Capivasertib + fulvestrant

PIK3CA, AKT1, or PTEN alteration. Monitor for diarrhea, hyperglycemia, and rash.

• Progression → Antibody-drug conjugate (sacituzumab govitecan; trastuzumab deruxtecan if HER2-low)

2L: Everolimus + exemestane

Biomarker-unselected option when no PIK3CA/ESR1/AKT-pathway target is present. Monitor for stomatitis (prophylactic steroid mouthwash), pneumonitis, and hyperglycemia.

• Progression → Antibody-drug conjugate (sacituzumab govitecan; trastuzumab deruxtecan if HER2-low)

3L+: Antibody-drug conjugate (sacituzumab govitecan; trastuzumab deruxtecan if HER2-low)

After endocrine-based therapy exhaustion. Trastuzumab deruxtecan is preferred for HER2-low (IHC 1+ or 2+/ISH-) disease; sacituzumab govitecan otherwise. Monitor for neutropenia, diarrhea, and (T-DXd) interstitial lung disease.

Evidence: TROPiCS-02 · DESTINY-Breast04

• Progression → Sequential single-agent chemotherapy

3L+: Sequential single-agent chemotherapy

Sequential single agents (capecitabine, taxane, eribulin, vinorelbine) once endocrine-based and ADC options are exhausted; prioritize a biomarker-matched clinical trial where available.