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PubMed2026

Outcomes of elacestrant in patients with ER-positive, HER2-negative, ESR1-mutated metastatic breast cancer who received prior endocrine therapy and cyclin-dependent kinase inhibitor in a real-world setting.

BACKGROUND: Real-world data analyses show durable benefits with elacestrant, with or without prior treatment with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). This cohort focused on patients with ER-positive/HER2-negative estrogen receptor 1 (ESR1)-mutated metastatic breast cancer (mBC) treated with elacestrant after at least one line of endocrine therapy (ET) combined with CDK4/6i (N = 281). PATIENTS AND METHODS: Claims data from the Komodo Research Dataset linked with Foundation Medicine clinical-genomics data were used. Primary outcome was median time-to-next-treatment (mTTNT). RESULTS: In patients with ER-positive/HER2-negative ESR1-mutated mBC who received one to two prior lines of ET + CDK4/6i (n = 108), mTTNT with elacestrant was 8.2 months [95% confidence interval (CI) 6.0-12.2]. In patients who received one to two prior lines of ET + CDK4/6i for ≥12 months (n = 85), mTTNT was 9.0 months (95% CI 7.7-13.7), including an mTTNT of 12.2 months (95% CI 9.0-not reached) in those who received one prior line of ET (n = 31). In patients with liver and/or lung metastasis (n = 169), mTTNT was 6.9 months (95% CI 5.8-8.3), whereas it was 7.4 months (95% CI 5.6-12.9) in patients with brain metastasis (n = 68). In patients with coexisting ESR1- and phosphoinositide 3-kinase-pathway-mutated tumors (n = 115), mTTNT was 6.1 months (95% CI 5.0-8.1). CONCLUSIONS: Elacestrant showed durable benefits in patients with ER-positive/HER2-negative ESR1-mutated mBC previously exposed to at least one line of ET + CDK4/6i, reinforcing the role of elacestrant as a potential first-choice option for patients with endocrine-sensitive tumors.

ESR1 mutation↗

PubMed2026

Activating mutations in ESR1 contribute to an immunosuppressive breast tumor microenvironment by dampening cytokine secretion.

Patients with estrogen receptor+ (ER+, ESR1+) breast cancer are most at risk of relapse, where activating mutations in ESR1 promote metastasis and therapeutic resistance. These patients are also disadvantaged in responding to immunotherapies, the mechanisms of which remain to be elucidated. Here, we engineered a transgenic mouse model carrying either Y541S or D542G mutation in ESR1, mirroring the 2 most common mutations seen in patients. ESR1mut tumors do not differ in the total number of immune cells yet display downregulation in immune pathways and decreased immune-modulatory cytokines, including IL-17a and IL-1β. T cells and macrophages have lower IFN-γ and antigen presentation, respectively. Mechanistically, ESR1mut negatively regulates immune modulator expression and upregulates Stat5 to dampen cytokine expression. In concordance, validation on ESR1mut patient tumors shows decreased IL-17a and IL-1β. Collectively, our findings reveal that ESR1 mutations contribute to an immunosuppressive tumor microenvironment by dampening cytokine secretion and immune cell activity.

Animals↗

PubMed2026

Genomic profiling by circulating tumor DNA in patients with hormone receptor-positive/HER2-negative advanced breast cancer: Prevalence of actionable mutations across treatment lines.

INTRODUCTION: Plasma next-generation sequencing (NGS) is endorsed by ESMO as an alternative to tissue testing in advanced hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2- mBC), particularly after progression on endocrine therapy plus CDK4/6 inhibitors. However, prospective real-world data across distinct therapeutic contexts remain limited. PATIENTS AND METHODS: In this prospective observational study conducted within a nationwide cancer network in Brazil, centralized plasma NGS, and tissue NGS when available, was performed in two independent cohorts: prior to initiation of first-line endocrine therapy in the metastatic setting (Cohort 1) and at progression on endocrine therapy plus a CDK4/6 inhibitor (Cohort 2). The primary objective was to evaluate plasma-detected ESR1 mutation prevalence across these therapeutic contexts, and secondarily to assess other actionable drivers detected by plasma or tissue NGS. RESULTS: Among 86 collected plasma samples, 72 (84%) had evaluable NGS results (Cohort 1, n = 37; Cohort 2, n = 35). ESR1 mutations were identified in 18.9% of patients in Cohort 1 and 40.0% in Cohort 2, mostly at low variant allele fractions (<0.5%), corresponding to an absolute prevalence difference of 21.1 percentage points (95% CI, -0.2 to 40.3; P value=0.07). When considering any actionable alteration detected by plasma, including ESR1, PIK3CA, AKT1, PTEN, BRCA1, BRCA2, and ERBB2, prevalences were 43.2% and 68.6%, respectively (P value=0.04). Only four patients had ESR1 mutations identified in tissue, three in metastatic samples. Plasma-tissue concordance was higher for PIK3CA mutations (85.1%). CONCLUSION: Plasma NGS identified clinically meaningful ESR1 mutation rates across both contexts, supporting guideline-endorsed plasma-based genomic profiling in HR+/HER2- mBC.

CDK4/6 inhibitors↗

PubMed2026

Real-world estrogen receptor alpha 1 (ESR1) testing patterns and results for ER+/HER2- metastatic breast cancer in the United States, 2018-2024.

PURPOSE: To understand historical and recent ESR1 testing rates, and when ESR1 mutations emerge during first-line (1 L) treatment. METHODS: This retrospective, observational cohort study used the Flatiron Health Research Database (FHRD) and the Flatiron Health-Foundation Medicine metastatic breast cancer (mBC) Clinico-Genomic Database (CGDB). Adult patients with a confirmed diagnosis of hormone receptor-positive/human epidermal growth factor receptor 2-negative mBC from 1/1/2018 to 6/30/2024 were included. ESR1 testing patterns and test results were descriptively analyzed. RESULTS: Among 7772 patients with mBC in the FHRD who initiated 1 L therapy, tumor ESR1 mutation status was evaluated for 222 (3%) patients at baseline (≤ 90 days before 1 L) and 1355 (17%) during 1 L. The percentage of patients who had an ESR1 test result reported during 1 L increased over time (11% in 2018-19, 19% in 2020-21, 22% in 2022-24). Median time from 1 L start to first ESR1 test was 7.4 months (mos) among tested patients. A positive test result was reported for 29/222 (13%) patients tested at baseline and 240/1355 (18%) tested during 1 L. Most (60%) tests during 1 L used tissue specimens, while the remaining 40% were liquid biopsies, and the median time from specimen collection to result reporting in 1 L was 28 (IQR:10-84) days. Focusing on time periods wherein specimens were provided, ESR1 test positivity was 6.7% (76/1,127) for specimens provided at baseline, 23% (15/65) for specimens provided 9 to 12 months into 1L therapy, 38% (26/69) for those provided 15 to 18 months into 1L, and 40% (38/94) for those provided from 18 to 24 months into 1L. CONCLUSIONS: ESR1 mutations can be detected at any time interval during 1L. CLINICAL TRIAL NUMBER: Not applicable.

Adult↗

PubMed2019

Estrogen-independent molecular actions of mutant estrogen receptor 1 in endometrial cancer.

Estrogen receptor 1 (ESR1) mutations have been identified in hormone therapy-resistant breast cancer and primary endometrial cancer. Analyses in breast cancer suggest that mutant ESR1 exhibits estrogen-independent activity. In endometrial cancer, ESR1 mutations are associated with worse outcomes and less obesity, however, experimental investigation of these mutations has not been performed. Using a unique CRISPR/Cas9 strategy, we introduced the D538G mutation, a common endometrial cancer mutation that alters the ligand binding domain of ESR1, while epitope tagging the endogenous locus. We discovered estrogen-independent mutant ESR1 genomic binding that is significantly altered from wild-type ESR1. The D538G mutation impacted expression, including a large set of nonestrogen-regulated genes, and chromatin accessibility, with most affected loci bound by mutant ESR1. Mutant ESR1 is distinct from constitutive ESR1 activity because mutant-specific changes are not recapitulated with prolonged estrogen exposure. Overall, the D538G mutant ESR1 confers estrogen-independent activity while causing additional regulatory changes in endometrial cancer cells that are distinct from breast cancer cells.

CRISPR-Cas Systems↗

PubMed2026

The genomic landscape of HER2 negative metastatic breast cancer with loss of estrogen and progesterone receptors.

INTRODUCTION: Loss of estrogen receptor (ER) and/or progesterone receptor (PR) might occur during the metastatic progression of ER positive and HER2 negative (ER+/HER2-) breast cancer (BC), but the underpinning molecular alterations remain elusive. We explored the genomic context of HER2- tumors with ER and/or PR loss to investigate potential drivers and actionable alterations that might help personalize treatment of ER+/HER2- BC. METHODS: We accessed data from metastatic HER2- BC included in the MSK-2018 dataset to compare outcome, tumor characteristics and genomic alterations of BC with loss of ER (ER+/-, n = 66) to those maintaining ER positivity (ER+/+, n = 364) or ER negativity (ER-/-, n = 50). We also compared metastatic ER+/+ BC with loss of PR (PR+/-, n = 111) to those maintaining PR positivity (PR+/+, n = 192) or PR negativity (PR-/-, n = 41). RESULTS: In line with previous reports, ER+/- BC was associated with aggressive clinico-pathological characteristics and poor outcome. ER+/- BC showed significantly higher frequency of TP53 and RB1 mutations and lower frequency of PIK3CA and GATA3 mutations compared to ER+/+. ER+/- or PR+/- status was mutually exclusive with ESR1 mutations and was associated with a significantly higher tumor mutational burden. Moreover, ER+/- BC were enriched in driver alterations in the genes of the Notch and Retinoblastoma pathways and showed a significantly lower frequency of level 1 actionable alterations according to OncoKB. CONCLUSIONS: Loss of ER and/or PR may identify a distinct evolutionary trajectory of ER+/HER2- metastatic progression, largely non-overlapping with ESR1-mutant endocrine resistance. Further studies on matched primary and metastatic samples are warranted.

Humans↗

PubMed2026

Clinically actionable genomic alterations in breast cancer brain metastases.

BACKGROUND: Breast cancer brain metastases (BCBMs) represent a critical unmet clinical need in metastatic breast cancer (MBC) and the identification of novel therapeutic targets is urgently needed in this context. In this study, we describe clinically actionable targets in BCBMs using comprehensive genomic profiling. PATIENTS AND METHODS: Genomic DNA was extracted from formalin-fixed paraffin-embedded archival BCBM samples and analyzed using the commercially available Agilent SureSelect V6 whole exome sequencing (WES) kit and an Illumina NovaSeq 6000 platform. Pathogenic alterations were classified as actionable alterations (AAs) if they met the updated MBC or tumor-agnostic ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) I or II criteria of the ESCAT scale. RESULTS: WES data from 56 BCBM samples were available [33.9% hormone receptor (HR)-negative/human epidermal growth factor receptor (HER)2-negative; 25.0% HR-positive/HER2-negative; and 38% HER2-positive]. ESCAT I/II AAs were detected in 76.8% (n = 43) of all BCBMs and the most frequently detected AAs were in genes involved in the homologous recombination repair pathway (BRCA1/BRCA2/PALB2; 53.6% overall). Biallelic inactivation of BRCA1, BRCA2, or PALB2 was observed in 19.6% of samples, with higher rates in HER2-negative BCBMs (26% in HR-negative /HER2-negative and 21% in HR-positive/HER2-negative). ESCAT I/II PIK3CA/AKT1/PTEN pathway alterations were present in 48.2% of samples and, in particular, in 50% of HR-positive/HER2-negative BCBMs. No ESR1 mutation was detected in HR-positive/HER2-negative BCBMs. The prognostic impact of previously described AAs was evaluated overall and according to breast cancer subtype. Twenty-three BCBMs (41%) were classified as HER2-positive; among these, 3 (13%) presented a hotspot PIK3CA mutation and 7 (30%) presented a PTEN deletion. Among patients with HER2-positive BCBMs, the identification of a hotspot PIK3CA mutation was significantly associated with worse prognosis. CONCLUSIONS: ESCAT I/II actionable genomic alterations are frequent in BCBMs, highlighting the potential for genomically targeted treatments in this setting.

ESCAT↗

PubMed2025

Detection of heterogeneous resistance mechanisms to tyrosine kinase inhibitors from cell-free DNA.

Though there has been substantial progress in the development of anti-human epidermal growth factor receptor 2 (HER2) therapies to treat HER2-positive metastatic breast cancer (MBC) within the past two decades, most patients still experience disease progression and cancer-related death. HER2-directed tyrosine kinase inhibitors can be highly effective therapies for patients with HER2-positive MBC; however, an understanding of resistance mechanisms is needed to better inform treatment approaches. We performed whole-exome sequencing on 111 patients with 73 tumor biopsies and 120 cell-free DNA samples to assess mechanisms of resistance. In 11 of 26 patients with acquired resistance, we identified alterations in previously characterized genes, such as PIK3CA and ERBB2, that could explain treatment resistance. Mutations in growing subclones identified potential mechanisms of resistance in 5 of 26 patients and included alterations in ESR1, FGFR2, and FGFR4. Additional studies are needed to assess the functional role and clinical utility of these alterations in driving resistance.

Humans↗

PubMed2026

Tumor Mutational Landscape and Its Correlation With Histopathological Characteristics in Breast Cancer.

BACKGROUND/AIM: In breast cancer, knowledge of the associations between clinicopathologic characteristics, genetic changes, and subtype-specific patterns is expanding. This study investigated how pathological and clinical variables affect the actionability of Next Generation Sequencing (NGS)-based tumor molecular data. MATERIALS AND METHODS: 227 breast cancer patients referred to Genekor's laboratory for tumor molecular profile analysis were included in the study. Pathology records were used to assess critical clinicopathological features, including HER2, ER, PR, Ki67, grade, metastatic site, and age. A 1021-gene NGS-based multigene panel was utilized to assess tumor biology alongside tumor mutational burden (TMB) and microsatellite instability (MSI). RESULTS: Comprehensive genomic profiling revealed that 95.6% of the patients harbored at least one oncogenic or likely oncogenic alteration, highlighting the high diagnostic yield of NGS-based testing. Distinct subtype-specific patterns were observed: HR+/HER2- tumors were enriched for PIK3CA and ESR1 gene alterations, whereas triple-negative breast cancer (TNBC) was dominated by TP53 alterations. Clinically actionable alterations were most common in HR+/HER2- tumors (~60% on-label), whereas TNBC more often harbored off-label or trial-associated targets. The inclusion of tumor-agnostic biomarkers (TMB/MSI) increased on-label actionability up to 64.5% in HR+/HER2- tumors, primarily driven by TMB-high cases. Median TMB values were low, and age was the only independent predictor. Furthermore, the presence of actionable alterations was significantly higher in metastatic tumors, and TP53 alterations were associated with aggressive tumor characteristics. CONCLUSION: Comprehensive NGS-based genomic profiling identifies clinically actionable alterations in over half of breast cancer patients, with substantial variability across molecular subtypes. The HR+/HER2- subtype demonstrates the highest prevalence of on-label actionable biomarkers. These findings support the routine implementation of comprehensive genomic profiling, especially in metastatic HER2-negative breast cancer, to guide precision oncology strategies and enable enrollment in biomarker-driven clinical trials.

Humans↗