Background

Most patients with estrogen receptor-positive (ER+) metastatic breast cancer develop resistance to hormone therapy after long-term treatment. In first-line treatment, the standard approach has been combining aromatase inhibitors (AI) or selective estrogen receptor degraders (SERDs) such as fulvestrant with CDK4/6 inhibitors. The problem is that acquired mutations in the ESR1 gene, which encodes the estrogen receptor, occur in up to 40% of patients.

Mutations in the ligand-binding domain of the ESR1 gene cause the receptor to remain continuously active even without hormone binding. This is why existing endocrine therapies lose effectiveness and cancer cells proliferate rapidly. Until now, there was a lack of precise diagnostic tools to identify these resistant patients, and since there were no suitable oral treatment options to selectively degrade the mutated receptor proteins, patients were frequently switched to cytotoxic chemotherapy.

Key Findings

Recently, academia and industry have combined a companion diagnostic method that rapidly tracks ESR1 mutations using circulating tumor DNA (ctDNA) in the blood with a next-generation oral targeted therapy. Instead of invasive tissue biopsies, the presence of ESR1 mutations in patient ctDNA is precisely determined through digital droplet polymerase chain reaction (ddPCR) or next-generation sequencing (NGS)-based tests using simple blood draws.

In a Phase 3 clinical study, a significant prolongation of progression-free survival (PFS) was observed in the subgroup with ESR1 mutations identified via ctDNA testing among patients whose disease progressed after CDK4/6 inhibitor treatment. It showed superior efficacy, with a reduction in the risk of disease progression or death by more than 45% compared to the standard therapy group. As an orally administrable small molecule, it acts by binding strongly to the mutant estrogen receptor to promote protein degradation. This overcomes the limitations of existing first-generation injectable degraders, which suffered from low administration convenience due to the requirement for intramuscular injection and reduced binding affinity against resistance mutations.

Significance and Outlook

The combination of liquid biopsy-based companion diagnostics and next-generation receptor degraders changes the paradigm of metastatic breast cancer treatment guidelines. It has become possible to immediately capture resistance mutations via blood tests and switch to customized second-line therapies without the need for re-biopsying tissue at the time of disease progression. This moves away from the existing practice of randomly changing drugs after treatment failure toward selective treatment based on molecular genetic evidence.

Challenges remain. As treatment progresses, mutations in other cell signaling pathways, such as PIK3CA, AKT1, and PTEN, may accumulate alongside ESR1, potentially inducing new resistance. Since there are limits to the duration of disease suppression with degrader monotherapy alone, additional clinical trials to verify combination strategies with other targeted therapies or antibody-drug conjugates (ADCs) must follow.