HR+ / HER2− Advanced Breast Cancer: Systemic Therapy

HR+ / HER2− Advanced Breast Cancer: overview

This algorithm sequences systemic therapy for HR-positive, HER2-negative advanced breast cancer, branching on endocrine sensitivity and then on tumor or germline biomarkers.

For endocrine-sensitive disease, frontline therapy is a CDK4/6 inhibitor plus endocrine therapy (MONALEESA, PALOMA). In the second line, treatment is biomarker driven: elacestrant for ESR1 mutation (EMERALD); capivasertib plus fulvestrant for PIK3CA, AKT or PTEN alterations (CAPItello-291); alpelisib plus fulvestrant for PIK3CA mutation (SOLAR-1); and olaparib or talazoparib for germline BRCA1/2 mutation (OlympiAD). For endocrine-resistant disease, PIK3CA-mutated tumors are treated with palbociclib plus fulvestrant plus inavolisib (INAVO120), and tumors without a driver with everolimus plus an aromatase inhibitor or fulvestrant (BOLERO-2). In later lines, antibody-drug conjugates are selected by HER2 status and target: trastuzumab deruxtecan for HER2-low disease (DESTINY-Breast04), and the TROP2-directed agents datopotamab deruxtecan (TROPION-Breast01) and sacituzumab govitecan (TROPiCS-02), the latter improving overall survival versus chemotherapy.

Trials behind this algorithm

MONALEESA-2 Hortobagyi GN et al, Ann Oncol, 2022; PMID: 35085735
EMERALD Bidard FC et al, JCO, 2022; PMID: 35584336
CAPItello-291 Turner NC et al, NEJM, 2023; PMID: 37256976
SOLAR-1 André F et al, NEJM, 2019; PMID: 31091374
OlympiAD Robson M et al, NEJM, 2017; PMID: 28578601
INAVO120 Turner NC et al, NEJM, 2024; PMID: 39476340
BOLERO-2 Baselga J et al, NEJM, 2012; PMID: 22149876
DESTINY-Breast04 Modi S et al, NEJM, 2022; PMID: 35665782
TROPION-Breast01 Bardia A et al, J Clin Oncol, 2024; PMID: 39265124
TROPiCS-02 Rugo HS et al, JCO, 2022; PMID: 36027558

Background reading: Breast Cancer (Part 2): DCIS, Early-Stage and Metastatic Treatment board review notes.

HR+ / HER2− Advanced Breast Cancer: the algorithm in words

Starting point: HR+ / HER2− advanced breast cancer. Full background: Breast Cancer (Part 2): DCIS, Early-Stage and Metastatic Treatment notes.

Endocrine-sensitive (first-line): Frontline: CDK4/6 inhibitor + ET (MONALEESA / PALOMA).
ESR1 mutation (second-line): Oral SERD: Elacestrant (EMERALD).
PIK3CA / AKT / PTEN (second-line): AKT pathway: Capivasertib + fulvestrant (CAPItello-291).
PIK3CA mutation (second-line): PI3K: Alpelisib + fulvestrant (SOLAR-1).
gBRCA1/2 (second-line): PARP: Olaparib / talazoparib (OlympiAD).
Endocrine-resistant (second-line): PIK3CA: Palbo + fulvestrant + inavolisib (INAVO120); No driver: Everolimus + AI / fulvestrant (BOLERO-2).
ADC by HER2 status (later-line): HER2-low: Trastuzumab deruxtecan (DESTINY-Breast04); TROP2: Datopotamab deruxtecan (TROPION-Breast01); TROP2: Sacituzumab govitecan (TROPiCS-02).