Key Clinical Summary: Personalizing Therapy in ER⁺/HER2⁻ Metastatic Breast Cancer via Biomarkers and Evidence-Based Decision-Making

This is a micro-learning module summary of Prof Seth Wander's session which you can find here. Before participating please read our CME and disclosure information which can be found here.

Acknowledgment: This activity is supported by an educational grant from Pfizer Inc. and Arvinas. This online education program has been designed for healthcare professionals globally.

Introduction

Recent advances in molecular profiling and targeted therapy have transformed the management of estrogen receptor-positive (ER⁺), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (mBC). This summary synthesizes key insights from current clinical trials, focusing on resistance mechanisms, biomarker-driven treatment strategies, and emerging therapeutic options across endocrine, targeted, and antibody-drug conjugate (ADC) classes.

Resistance to Anti-Estrogens and CDK4/6 Inhibitors

Resistance to endocrine therapy and CDK4/6 inhibitors is multifactorial. Estrogen-receptor 1 (ESR1) mutations, typically acquired under aromatase inhibitor (AI) pressure, occur in up to 40% of patients in later-line settings and result in ligand-independent estrogen receptor activation. In contrast, PIK3CA mutations are truncal events present at diagnosis in ~40% of ER⁺ tumors.

CDK4/6 resistance mechanisms include Rb loss, cyclin E amplification, and CDK2 and CDK6 upregulation. Activation of oncogenic signaling pathways such as RAS/MAPK, PI3K/AKT/mTOR and FGFR are also frequently implicated.

These alterations not only confer resistance to CDK4/6 inhibitors but may also compromise the efficacy of concurrent endocrine therapy.
To address these challenges, multiple next-generation agents are under clinical development for CDK4/6-refractory ER+ mBC, including inhibitors of CDK2, RAS, AKT, and FGFR.
Many of these alterations also contribute to resistance against the anti-estrogen component of therapy, underscoring the need for integrated approaches that target both endocrine and cell-cycle escape mechanisms.

Novel antiestrogen agents: Oral SERDs and PROTACs

Novel antiestrogen agents include next-generation oral selective estrogen receptor degraders (SERDs) and proteolysis-targeting chimeras (PROTACs). Evidence for their use includes:

SERDs

EMERALD Trial (elacestrant): In heavily pretreated patients with ER+/HER2- mBC, elacestrant significantly improved progression-free survival (PFS) versus standard of care (SOC) therapy (hazard ratio [HR] 0.70; p=0.0018). Benefit was greatest in patients with ≥12 months’ prior CDK4/6 inhibitor response.
EMBER-3 Trial (imlunestrant): In a less pretreated ER+/HER2- mBC population, imlunestrant showed significant PFS improvement versus SOC therapy in ESR1-mutated patients (p<0.001). Combination with the CDK4/6 inhibitor abemaciclib extended the PFS benefit by up to 9 months.
SERENA-6 Trial (camizestrant): This adaptive trial demonstrated that early switch to camizestrant upon ESR1-mutation emergence (via ctDNA) significantly prolonged PFS versus AI therapy (p<0.0001) and improved time to deterioration in quality of life.

PROTACs

VERITAC-2 Trial (vepdegestrant): In patients with ER+/HER2- advanced breast cancer with prior CDK4/6 exposure, vepdegestrant significantly improved PFS versus fulvestrant in patients with ESR1-mutant tumors (HR 0.58, p<0.001).

PI3K/AKT/mTOR Pathway Targeting

PIK3CA mutations are actionable in both first- and second-line settings:

SOLAR-1 Trial (alpelisib): In PIK3CA-mutant, AI pretreated patients with HR+/HER2- advanced breast cancer, alpelisib plus fulvestrant significantly improved PFS versus placebo (HR 0.65, p<0.001).
INAVO120 Trial (inavolisib): In high-risk, endocrine-refractory patients with PIK3CA-mutant, HR+/HER2- advanced breast cancer and no prior therapy for advanced disease, triplet therapy with inavolisib, palbociclib, and fulvestrant significantly improved PFS versus placebo (HR 0.43, p<0.001) and showed OS benefit.
CAPItello-291 Trial (capivasertib): Capivasertib plus fulvestrant significantly improved PFS versus placebo (HR 0.60, p<0.001) in pretreated (including CDK4/6 inhibitors) patients with HR+/HER2- advanced breast cancer. Greater benefit was seen in patients harboring PIK3CA, AKT, or PTEN mutations.

Antibody-Drug Conjugates (ADCs)

ADCs offer chemotherapy-like efficacy with improved tolerability:

DESTINY-Breast06 (trastuzumab deruxtecan [T-DXd)): In HER2-low and ultra-low ER⁺ mBC, T-DXd significantly improved PFS versus chemotherapy (HR 0.64, p<0.001), with OS trending favorably.
TROPiCS-02 (sacituzumab govitecan): In heavily pretreated patients with HR+/HER2- mBC, sacituzumab significantly improved PFS (HR 0.66, p=0.003) and OS (HR 0.79, p=0.020) versus chemotherapy.
TROPION-Breast01 (datopotamab deruxtecan [Dato-DXD]): This ADC significantly improved PFS versus chemotherapy (HR 0.63, p<0.0001) in patients with previously treated HR+/HER2- breast cancer.

Defining Relevant Patient Populations for Precision Therapeutics

Further to these data, three patient populations can be identified based on PFS probability, which may help to guide precision therapy selection:

Rapid Progressor: Complete ER-Independence → ADC or chemotherapy
Intermediate/Transient Responders: Partial ER-Dependence → Personalized next-generation antiestrogen and targeted therapy combinations
Extraordinary Responders: High ER-Dependence → Next-generation antiestrogen monotherapy

Conclusion

Therapeutic sequencing in ER⁺/HER2⁻ mBC is increasingly guided by molecular biomarkers. CDK4/6 inhibitors remain foundational in the first-line setting. For endocrine-refractory disease, options include oral SERDs, PI3K/AKT inhibitors, and ADCs, selected based on ESR1, PIK3CA, AKT, and PTEN status. Emerging data support dynamic treatment adaptation using ctDNA monitoring, and combination regimens are reshaping second- and third-line strategies. Continued integration of biomarker-driven approaches will be essential to optimize outcomes in this evolving landscape.