The review emphasizes that resistance is not a single event but a heterogeneous, evolving process. Clinically, it is classified as primary—relapse within the first two years of adjuvant endocrine therapy or progression within six months of first-line treatment for advanced disease—or secondary, which encompasses later relapses and progression on subsequent lines. According to the updated ABC6/7 consensus definitions, the presence of a known ESR1 mutation also falls under secondary resistance. In practice, the authors argue, endocrine sensitivity and resistance are better understood as a continuum, interpreted alongside prior treatment exposure, disease tempo, and molecular biomarkers rather than rigid categories.

At the molecular level, the most direct route to resistance runs through the estrogen receptor gene itself, ESR1. Mutations in this gene are exceedingly rare in untreated primary tumors but climb to approximately 20 to 40 percent in metastatic disease after aromatase inhibitor therapy. The most common alterations, Y537S and D538G, cluster in the ligand-binding domain of the receptor. These missense mutations change the receptor’s three-dimensional conformation so that it recruits coactivators and drives transcription continuously, even without estrogen. This ligand-independent activation renders aromatase inhibitors—which work by depleting estrogen—ineffective, and it also weakens the binding of fulvestrant, the first-generation selective estrogen receptor degrader, producing partial cross-resistance.

Whole-transcriptome sequencing has uncovered a second structural mechanism: ESR1 gene fusions. In endocrine-resistant metastatic lesions, researchers have identified fusions such as ESR1–YAP1 and ESR1–CCDC170. When ESR1–YAP1 forms, the potent transcriptional activation domain of YAP1 replaces the receptor’s ligand-binding domain, allowing estrogen-independent growth. ESR1–CCDC170 takes a different route, forming a complex with HER2, HER3, and SRC that activates the SRC–PI3K–AKT pathway; knocking down this fusion reduces HER2/HER3 expression and restores endocrine sensitivity. Beyond these structural changes, resistant cells undergo broader transcriptional reprogramming, in which epigenetic modifications enhance ER binding at specific chromatin sites and sustain the transcriptional programs tumors need to survive—a phenomenon the authors call transcriptional dependency, which complicates any single-target strategy.

When the ER pathway is pharmacologically blocked, tumor cells frequently reroute their signaling through growth factor pathways, a process known as crosstalk. The PI3K/AKT/mTOR pathway has attracted the most attention: roughly 40 percent of HR+/HER2− patients harbor activating PIK3CA mutations, which drive proliferation and can induce ligand-independent phosphorylation of ER through downstream kinases such as S6K1. Conversely, when endocrine therapy suppresses ER signaling, the negative feedback ER normally exerts is released, AKT phosphorylation rises, and receptor tyrosine kinase signaling through HER3 and IGF1R intensifies. Even without HER2 amplification, ligand-driven HER2/HER3 heterodimerization can activate SRC/PI3K/AKT signaling and, through the HER2/HER3–HDAC2–FOXA1 axis, reshape ER transcription by redirecting the receptor toward resistance, invasion, and metastasis loci. The authors caution that HER2-low or HER2-ultralow classifications are treatment-selection descriptors for antibody–drug conjugates, not mechanisms of resistance in themselves.

Resistance to CDK4/6 inhibitors follows its own logic. These drugs work by arresting the cell cycle at the G1-to-S transition, an effect that depends on an intact retinoblastoma (Rb) protein. When the RB1 gene is lost or mutated, E2F transcription factors escape suppression, the cell cycle proceeds, and cells become less dependent on the CDK4/6–Cyclin D1 complex. Although RB1 inactivation is not highly frequent in metastatic HR+/HER2− disease, its impact is well defined: among patients treated with palbociclib plus fulvestrant, those with RB1 loss show markedly shorter progression-free survival. Additional escape routes include amplification of Cyclin E1 or overexpression of CDK2, which allow cells to rely on the Cyclin E–CDK2 complex, and loss of FAT1, which inactivates the Hippo pathway. Single-cell studies also implicate the tumor microenvironment, where immunosuppressive cell populations expand under the selective pressure of CDK4/6 inhibition.

These mechanistic insights are now being translated into drugs. Next-generation oral selective estrogen receptor degraders, or SERDs, offer better bioavailability than injectable fulvestrant. Elacestrant, the first approved oral SERD, significantly prolonged progression-free survival versus standard endocrine therapy in ESR1-mutated patients previously treated with a CDK4/6 inhibitor in the phase III EMERALD trial. Camizestrant outperformed fulvestrant regardless of ESR1 status in SERENA-2, and imlunestrant, another oral SERD, extended median progression-free survival to 5.5 versus 3.8 months in ESR1-mutated patients in EMBER-3; when combined with abemaciclib, imlunestrant achieved 10.9 versus 5.5 months, and the FDA approved imlunestrant on September 25, 2025 for ESR1-mutated advanced disease after at least one prior endocrine line. A parallel approach uses PROTACs—proteolysis-targeting chimeras such as vepdegestrant (ARV-471)—which hijack the cell’s ubiquitin–proteasome machinery to degrade ER directly, with preclinical degradation exceeding 90 percent. In the phase III VERITAC-2 trial, vepdegestrant doubled median progression-free survival to 5.0 versus 2.1 months in the ESR1-mutated cohort, though the overall population showed no significant benefit, underscoring the importance of biomarker selection. Complete estrogen receptor antagonists, or CERANs such as OP-1250, block both ER transcriptional activation domains while promoting receptor degradation, and preclinical data suggest possible blood–brain barrier penetration.

Bypass signaling has yielded its own arsenal. Inavolisib, a selective PI3Kα inhibitor that also promotes degradation of the mutant p110α protein, extended median progression-free survival to 15.0 versus 7.3 months and median overall survival to 34 versus 27 months in the phase III INAVO120 trial when added to palbociclib and fulvestrant in first-line PIK3CA-mutated disease. The pan-AKT inhibitor capivasertib, tested with fulvestrant in CAPItello-291, improved median progression-free survival to 7.2 versus 3.6 months overall and 7.3 versus 3.1 months in tumors with PIK3CA, AKT1, or PTEN alterations, with some benefit even in pathway-wild-type tumors. On the mTOR front, everolimus plus exemestane raised median progression-free survival from 4.1 to 10.6 months by central assessment in BOLERO-2, though at the cost of grade 3–4 stomatitis, infections, rash, and hyperglycemia. The multitargeted inhibitor gedatolisib, which blocks multiple PI3K isoforms and mTORC1/2 simultaneously, achieved 9.3 versus 2.0 months in PIK3CA wild-type disease after CDK4/6 progression in VIKTORIA-1, with relatively low rates of hyperglycemia and stomatitis, and received FDA approval in combination with fulvestrant, with or without palbociclib, on July 14, 2026.

Perhaps the most striking shift is toward acting before tumors visibly progress. Liquid biopsy studies show that circulating tumor DNA can detect ESR1 mutations in 20 to 50 percent of previously treated metastatic cases, often predicting poorer aromatase inhibitor responses. In the randomized PADA-1 trial, switching from an aromatase inhibitor to fulvestrant—both with palbociclib—as soon as rising ESR1 mutation levels were detected in ctDNA significantly prolonged median progression-free survival. The phase III SERENA-6 trial went further: patients on first-line aromatase inhibitor plus CDK4/6 therapy whose ctDNA revealed emergent ESR1 mutations, but who had no radiographic progression, were switched to camizestrant while continuing the same CDK4/6 inhibitor. The extended analysis showed median progression-free survival of 16.8 versus 9.2 months and second progression-free survival of 25.7 versus 19.1 months—compelling evidence that molecular progression can be intercepted before clinical relapse. The authors note that assay performance is platform-specific: droplet digital PCR excels at tracking predefined ESR1 hotspots with detection limits of 0.07 to 0.19 percent mutant allele fraction, while targeted next-generation sequencing offers broader coverage but platform-dependent sensitivity, and negative plasma results should prompt repeat or tissue-based testing when suspicion is high.

The review also maps the frontier beyond established targets. Epigenetic therapies, including EZH2 inhibitors such as tazemetostat and HDAC inhibitors, aim to reverse the chromatin states that sustain resistant transcriptional programs. Metabolic reprogramming offers another angle: resistant cells increasingly depend on fatty acid oxidation and oxidative phosphorylation, with CPT1A-mediated transport of long-chain fatty acids into mitochondria sustaining ATP production in slow-cycling persister cells; the CPT1 inhibitor etomoxir showed greater activity in resistant than sensitive cells in preclinical models, though such approaches remain investigational. After endocrine resistance is established, antibody–drug conjugates provide antigen-directed options: sacituzumab govitecan improved survival in heavily pretreated patients in TROPiCS-02, and datopotamab deruxtecan was FDA-approved in January 2025 for previously treated metastatic HR+/HER2− disease. The authors conclude that no single biomarker captures the full resistance landscape, and that integrating multi-omics analysis, single-cell sequencing, and dynamic ctDNA monitoring will be essential to move clinical management from empiric treatment switching toward truly individualized, mechanism-guided, whole-course care.

Subject of Research: Molecular mechanisms of endocrine resistance and emerging targeted therapies in HR-positive/HER2-negative breast cancer

Article Title: Endocrine resistance in HR+/HER2− breast cancer: molecular mechanisms and emerging therapeutic strategies

Article References: Shen, T., Li, H., Zhang, X., & Zhou, Q. (2026). Endocrine resistance in HR+/HER2− breast cancer: molecular mechanisms and emerging therapeutic strategies. Frontiers in Oncology, 16, Article 1983430. https://doi.org/10.3389/fonc.2026.1983430

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1983430

Keywords: endocrine resistance, HR-positive HER2-negative breast cancer, ESR1 mutations, oral SERDs, PROTAC, PI3K/AKT/mTOR pathway, CDK4/6 inhibitors, circulating tumor DNA, liquid biopsy, antibody-drug conjugates, epigenetic therapy, precision oncology