2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:T657,Radiation therapy (RT) remains a cornerstone of management for metastatic breast cancer (mBC), though systemic therapy drives overall disease control. Administering RT concomitantly with systemic treatment may raise concerns regarding toxicity. This multicentre retrospective study evaluated the safety of trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate, when delivered alongside RT. Data from six European centres were analysed. Concomitancy was defined as RT administered during T-DXd or within 10 days of a treatment cycle. The primary endpoint was the incidence of grade ≥3 adverse events (AEs). Exploratory endpoints included progression-free survival (PFS) and overall survival (OS). A total of 147 patients were included; 67 received concomitant RT (71 courses) and 80 received T-DXd alone. Median age was 49 years (range 25-85). The central nervous system was the most frequent RT site (54.9 %). Grade ≥3 AEs occurred in 24 patients (16.3 %), with no significant difference between RT and no-RT cohorts (11.9 % vs 20.0 %; p = 0.30). Permanent T-DXd discontinuation due to toxicity occurred in 19 patients (12.9 %), with similar rates in the RT and no-RT groups (11.9 % vs 13.8 %). One case of symptomatic radionecrosis was observed after intracranial RT. Exploratory analyses showed no adverse effect of concomitant RT on PFS or OS. Concomitant administration of T-DXd and RT appears feasible and well tolerated, without increased risk of severe or treatment-limiting toxicity. These real-world findings support the safety of this combination and warrant confirmation in prospective studies.31:T798,The EMERALD trial led to the approval of elacestrant for estrogen receptor (ER)-positive, HER2-negative, estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer (mBC) with disease progression following at least one line of endocrine therapy (ET). Subgroup analyses provided evidence suggesting that elacestrant enables ET sequencing in the second line before other targeted combinations, which could delay chemotherapy-based regimens. This study used claims data from the Komodo Research Dataset linked with Foundation Medicine Inc. clinical genomic data from patients with estrogen receptor+/HER2- mBC harboring an ESR1 mutation treated with elacestrant. The primary outcome measure was time to next treatment (TTNT). Among 306 patients, 93.8% had prior ET ± cyclin-dependent kinase 4/6 inhibitor for ≥12 months, 50.0% had prior chemotherapy, and 72.2% had prior fulvestrant. Median TTNT (mTTNT) was 8.2 months [95% confidence interval (CI), 6.3-13.0] in patients with 1 to 2 prior lines and 7.5 months (95% CI, 7.1-9.9) in those with ≥3 prior lines of ET. In patients with coexisting ESR1- and PI3K-pathway-mutated tumors, mTTNT was 6.3 months (95% CI, 4.8-7.9). mTTNT was 7.9 months (95% CI, 7.1-9.8) in all patients and was also sustained in patients with no prior fulvestrant [12.9 months (95% CI, 7.2-not reached)], no prior chemotherapy [8.4 months (95% CI, 7.1-13.3)], visceral metastasis [7.9 months (95% CI, 7.0-9.9)], and liver metastases [7.2 months (95% CI, 6.3-9.0)]. Elacestrant demonstrated a durable benefit in real-world clinical practice, particularly in earlier lines and in patients with prolonged prior ET exposure. Despite coexisting ESR1 and PI3K pathway mutations, TTNT remained clinically meaningful, reinforcing the role of elacestrant in personalized ET sequencing strategies prior to chemotherapy, antibody-drug conjugates, or targeted combinations. See related article by Lloyd et al., p. 169.32:Ta60,Abstract Purpose: The EMERALD trial led to the approval of elacestrant for estrogen receptor (ER)–positive, HER2-negative, estrogen receptor 1 (ESR1)–mutated advanced or metastatic breast cancer (mBC) with disease progression following at least one line of endocrine therapy (ET). Subgroup analyses provided evidence suggesting that elacestrant enables ET sequencing in the second line before other targeted combinations, which could delay chemotherapy-based regimens. Experimental Design: This study used claims data from the Komodo Research Dataset linked with Foundation Medicine Inc. clinical genomic data from patients with estrogen receptor+/HER2− mBC harboring an ESR1 mutation treated with elacestrant. The primary outcome measure was time to next treatment (TTNT). Results: Among 306 patients, 93.8% had prior ET ± cyclin-dependent kinase 4/6 inhibitor for ≥12 months, 50.0% had prior chemotherapy, and 72.2% had prior fulvestrant. Median TTNT (mTTNT) was 8.2 months [95% confidence interval (CI), 6.3–13.0] in patients with 1 to 2 prior lines and 7.5 months (95% CI, 7.1–9.9) in those with ≥3 prior lines of ET. In patients with coexisting ESR1- and PI3K-pathway–mutated tumors, mTTNT was 6.3 months (95% CI, 4.8–7.9). mTTNT was 7.9 months (95% CI, 7.1–9.8) in all patients and was also sustained in patients with no prior fulvestrant [12.9 months (95% CI, 7.2–not reached)], no prior chemotherapy [8.4 months (95% CI, 7.1–13.3)], visceral metastasis [7.9 months (95% CI, 7.0–9.9)], and liver metastases [7.2 months (95% CI, 6.3–9.0)]. Conclusions: Elacestrant demonstrated a durable benefit in real-world clinical practice, particularly in earlier lines and in patients with prolonged prior ET exposure. Despite coexisting ESR1 and PI3K pathway mutations, TTNT remained clinically meaningful, reinforcing the role of elacestrant in personalized ET sequencing strategies prior to chemotherapy, antibody–drug conjugates, or targeted combinations. See related article by Lloyd et al., p. 169 33:T699,Abstract Trastuzumab Deruxtecan (T-DXd) is clinically beneficial in HER2-positive and HER2-low metastatic breast cancer. However, therapeutic resistance emerges over time in most patients, with poorly defined resistance mechanisms. Through a molecular characterization of paired patient specimens before and after T-DXd treatment, we found that 49% cases had major decreases in HER2 expression at progression, and among them, 52% exhibited complete HER2 loss. Using isogenic model systems, we demonstrated that decreases in HER2 expression corresponded to reductions in T-DXd internalization and major increases in drug IC50 value for tumor growth inhibition. We further identified and validated ERBB2 mutations in the trastuzumab binding interface (V597M and P593R) that promoted T-DXd resistance. As a strategy to overcome impaired T-DXd binding and internalization, we tested low-dose combinations of T-DXd with TROP2-directed antibody–drug conjugates (ADC) and found that these could more uniformly deliver DXd payloads and thereby overcome resistance mediated by HER2 loss. Significance: The mechanisms underlying clinical T-DXd resistance have not been established. We now report on two mechanisms of resistance that converge on loss of target binding and propose combinations of distinct ADCs with shared payloads as a strategy to overcome resistance by enhancing intratumor delivery. 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"Metastatic Breast Cancer: condition Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on Metastatic Breast Cancer (condition). Clinician-written summaries and actionable practice insights. 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OS data were immature (medians not reached; HR 0.62, 95% CI 0.38–1.03). Grade ≥3 TEAEs occurred in 69.8% vs. 63.7%; ocular adverse events were notably more frequent with trastuzumab botidotin but generally resolved with a protocol-defined management algorithm.","limitations":"- OS data were immature at data cutoff, limiting conclusions on survival benefit.\n- Trial conducted exclusively in China, which may limit generalizability to other populations.\n- Open-label design introduces potential for performance and assessment bias.","practice_takeaway":"In HER2-positive metastatic breast cancer after trastuzumab and taxane exposure, trastuzumab botidotin nearly tripled median PFS compared to T-DM1 — clinicians should be aware of its higher rate of ocular toxicity and follow a structured monitoring and management algorithm."}},{"doi":"10.1016/j.breast.2026.104911","pmid":"42715877","title":"Which quality of life issues are important to patients with metastatic breast cancer: Phase 1 and 2 development of European Organisation for Research and Treatment of Cancer metastatic breast cancer module (EORTC QLQ-MBR)","journal_title":"The Breast","journal_issn":"0960-9776","published_at":"2026-09-05T00:00:00.000Z","url":"https://doi.org/10.1016/j.breast.2026.104911","source_score":1,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-09-11T06:20:03.046Z","updated_at":"2026-09-11T06:20:03.046Z","tags":[{"paper_doi":"10.1016/j.breast.2026.104911","tag_type":"age_group","value":"mixed","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104911","tag_type":"category","value":"Obstetrics & Gynecology","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104911","tag_type":"condition","value":"Metastatic Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104911","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104911","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104911","tag_type":"modality","value":"Patient-Reported Outcome Measure","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104911","tag_type":"sample_size","value":"n=228","value_numeric":228},{"paper_doi":"10.1016/j.breast.2026.104911","tag_type":"sex","value":"female","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104911","tag_type":"study_design","value":"Questionnaire/Instrument Development Study","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104911","tag_type":"warning","value":"Phase 3 psychometric validation is still underway as of the publication date; the QLQ-MBR44 is provisional and not yet validated for clinical use.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104911","tag_type":"warning","value":"Study_design is classified as a questionnaire development study, which does not map cleanly to standard trial design hierarchies; the level of evidence rating should be interpreted cautiously.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104911","tag_type":"warning","value":"The sample size tag (n=228) reflects the combined total of 187 patients and 41 HCPs interviewed; these are not all patients in a clinical outcome study, but interview participants in an instrument development process. The level of evidence (3) reflects a well-structured mixed-methods development study with no comparator intervention or clinical outcomes.","value_numeric":null}],"summaries":{"what_studied":"This study describes phases 1 and 2 of developing the EORTC QLQ-MBR44, the first quality-of-life (QoL) module specific to metastatic breast cancer (MBC), involving systematic literature review, investigator brochure review, and semi-structured interviews with 187 female MBC patients and 41 healthcare professionals (HCPs) across 8 countries.","key_result":"From 185 candidate QoL issues, 44 were rated relevant and important enough to form a 44-item provisional module (QLQ-MBR44) covering 10 domains: physical symptoms/side-effects (10 items), fear-uncertainty (9), family impact (5), musculoskeletal pain (4), sexual issues (4), treatment/disease impact (3), independence (3), fatigue (2), body image (2), and anxiety-depression (2). Psychosocial issues dominated patient priorities; 8 of patients' top 10 issues were psychological, with fatigue as the top physical concern for both patients and HCPs.","limitations":"- Systematic review was conducted in 2019; rapidly emerging MBC treatments (e.g., trastuzumab deruxtecan, tucatinib) were only captured via investigator brochure review, not a full updated search.\n- Only female patients were included, excluding the rare but distinct male MBC population.\n- Psychometric validation (phases 3–4) is still ongoing; reliability, validity, and cross-cultural applicability are not yet established.","practice_takeaway":"No validated MBC-specific QoL tool currently exists; clinicians running MBC trials or clinics should be aware the QLQ-MBR44 is in active development and, once validated, will be used alongside the EORTC QLQ-C30. Psychosocial concerns—especially fear, uncertainty, and family impact—ranked as highly important to patients and should be routinely addressed in MBC care."}},{"doi":"10.1016/j.breast.2026.104902","pmid":"42612559","title":"Beyond safety: rethinking concomitant radiotherapy and trastuzumab deruxtecan in metastatic breast cancer — from feasibility to precision practice","journal_title":"The Breast","journal_issn":"0960-9776","published_at":"2026-08-12T00:00:00.000Z","url":"https://doi.org/10.1016/j.breast.2026.104902","source_score":1,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-08-22T06:53:24.722Z","updated_at":"2026-08-22T06:53:24.722Z","tags":[{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"brand","value":"Enhertu","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"category","value":"Obstetrics & Gynecology","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"condition","value":"HER2-Low Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"condition","value":"Metastatic Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"generic","value":"trastuzumab deruxtecan","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"generic","value":"trastuzumab emtansine","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"level_of_evidence","value":"7","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"modality","value":"Antibody-Drug Conjugate","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"modality","value":"Radiotherapy","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"study_design","value":"Expert Opinion / Viewpoint","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"warning","value":"HER2-low metastatic breast cancer is discussed as a subgroup of interest but no outcome data specific to this population are presented.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"warning","value":"No sample size is applicable — the 'largest real-world evidence' cited belongs to the Visani et al. study being critiqued, not this paper.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"warning","value":"Study design classification as 'Expert Opinion / Viewpoint' is inferred from abstract language; the journal section label is not explicitly stated.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104902","tag_type":"warning","value":"This is a viewpoint/commentary with no original patient data; findings are opinion-based and reference a single real-world study (Visani et al.) not reproduced here.","value_numeric":null}],"summaries":{"what_studied":"This viewpoint critiques and extends real-world evidence on the safety of concomitant trastuzumab deruxtecan (T-DXd) and radiotherapy (RT) in metastatic breast cancer, arguing for stratified decision-making beyond binary safety assessments across RT intent, site, fractionation, and tumor biology.","key_result":"The authors contend that 'concomitant' is not a sufficient biological concept; radiosensitization risk varies by RT site, fractionation, and payload (distinguishing T-DM1 vs. T-DXd radionecrosis profiles), and three high-priority gaps remain: thoracic irradiation safety, HER2-low metastatic breast cancer, and cardiac vulnerability during combined therapy.","limitations":"This is an expert viewpoint/commentary — no original patient data, no comparator arm, and no quantitative outcomes are reported. Conclusions are largely opinion-based and derive from critique of a single referenced real-world study.","practice_takeaway":"Do not treat all concomitant T-DXd + RT combinations as equivalent; stratify decisions by anatomical site, fractionation schedule, and HER2 status. Treat thoracic irradiation and cardiac exposure during combined therapy as priority areas requiring extra caution until prospective data are available."}},{"doi":"10.1001/jamaoncol.2026.2661","pmid":"42560727","title":"Electronic Patient-Reported Outcome Monitoring With Alert-Based Interventions in Metastatic Breast Cancer","journal_title":"JAMA Oncology","journal_issn":"2374-2437","published_at":"2026-08-06T00:00:00.000Z","url":"https://doi.org/10.1001/jamaoncol.2026.2661","source_score":39,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-08-12T13:26:07.214Z","updated_at":"2026-08-12T13:26:07.214Z","tags":[{"paper_doi":"10.1001/jamaoncol.2026.2661","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1001/jamaoncol.2026.2661","tag_type":"category","value":"Oncology","value_numeric":null},{"paper_doi":"10.1001/jamaoncol.2026.2661","tag_type":"condition","value":"Metastatic Breast Cancer","value_numeric":null},{"paper_doi":"10.1001/jamaoncol.2026.2661","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1001/jamaoncol.2026.2661","tag_type":"level_of_evidence","value":"1","value_numeric":null},{"paper_doi":"10.1001/jamaoncol.2026.2661","tag_type":"modality","value":"Digital Health / Electronic Patient-Reported Outcome Monitoring","value_numeric":null},{"paper_doi":"10.1001/jamaoncol.2026.2661","tag_type":"sample_size","value":"n=909","value_numeric":909},{"paper_doi":"10.1001/jamaoncol.2026.2661","tag_type":"sex","value":"female","value_numeric":null},{"paper_doi":"10.1001/jamaoncol.2026.2661","tag_type":"study_design","value":"Randomized Controlled Trial","value_numeric":null},{"paper_doi":"10.1001/jamaoncol.2026.2661","tag_type":"warning","value":"Baseline fatigue scores were significantly higher in the control group (60.2 vs 57.6; P<0.001) despite randomization, raising concern about residual confounding even after ANCOVA adjustment — the reported treatment effect magnitude should be interpreted with caution.","value_numeric":null},{"paper_doi":"10.1001/jamaoncol.2026.2661","tag_type":"warning","value":"The full text provided is primarily the study protocol and statistical analysis plan, not the final results manuscript; the key numerical results are drawn from the abstract only.","value_numeric":null},{"paper_doi":"10.1001/jamaoncol.2026.2661","tag_type":"warning","value":"The specific nature of alert-triggered interventions was left to each center's discretion, making the 'active ingredient' of the intervention heterogeneous and difficult to replicate precisely.","value_numeric":null},{"paper_doi":"10.1001/jamaoncol.2026.2661","tag_type":"warning","value":"The trial enrolled only women insured by three specific German statutory health insurers, which may limit generalizability to other healthcare systems or uninsured/privately insured populations.","value_numeric":null}],"summaries":{"what_studied":"This multicenter RCT (PRO-B, n=909, Germany, 52 centers, May 2021–February 2024) tested weekly smartphone-based PRO monitoring with automated alerts to nurses/physicians (contacted within 48 hours) versus quarterly PRO monitoring without alerts in women with metastatic breast cancer (mBC) on systemic therapy, over 12 months of follow-up.","key_result":"At 6 months, the intervention group had significantly lower adjusted mean fatigue T-scores (54.5 vs 59.9; mean difference −5.4 points, 95% CI −6.6 to −4.1; P<0.001), exceeding the MCID of 3.3 points. Physical functioning also improved beyond its MCID (mean difference +4.0, 95% CI 2.6–5.4). The between-group quality-of-life difference was 0.8 points, below the MCID of 2.9.","limitations":"- Baseline fatigue scores differed between groups (57.6 vs 60.2; P<0.001), suggesting randomization imbalance that could inflate the intervention effect despite ANCOVA adjustment.\n- Trial was conducted in Germany with specific health-insurer enrollment requirements, limiting generalizability.\n- No blinding was possible; alert-triggered nursing/physician contact was not standardized, introducing variability in the actual intervention delivered.","practice_takeaway":"Weekly digital PRO monitoring with alert-based nurse or physician callbacks produces clinically meaningful reductions in fatigue and improved physical function in women with mBC on systemic therapy. Oncology teams should consider integrating structured PRO alert systems into routine mBC care, using existing digital infrastructure."}},{"doi":"10.1016/j.breast.2026.104891","pmid":"42575049","title":"Central nervous system metastases in metastatic breast cancer: Incidence, subtype-specific patterns, and outcomes from the Austrian AGMT_MBC registry","journal_title":"The Breast","journal_issn":"0960-9776","published_at":"2026-08-03T00:00:00.000Z","url":"https://doi.org/10.1016/j.breast.2026.104891","source_score":1,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-08-12T13:26:21.131Z","updated_at":"2026-08-12T13:26:21.131Z","tags":[{"paper_doi":"10.1016/j.breast.2026.104891","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104891","tag_type":"category","value":"Obstetrics & Gynecology","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104891","tag_type":"condition","value":"Brain Metastases","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104891","tag_type":"condition","value":"Metastatic Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104891","tag_type":"condition","value":"Triple-Negative Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104891","tag_type":"impact_flag","value":"confirms_prior","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104891","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104891","tag_type":"modality","value":"Focal Radiotherapy","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104891","tag_type":"modality","value":"Neurosurgery","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104891","tag_type":"modality","value":"Whole Brain Radiotherapy","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104891","tag_type":"sample_size","value":"n=2775","value_numeric":2775},{"paper_doi":"10.1016/j.breast.2026.104891","tag_type":"sex","value":"female","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104891","tag_type":"study_design","value":"Registry-Based Cohort Study","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104891","tag_type":"warning","value":"Publication date (2026-08-03) is recent; findings have not yet been subject to extensive independent replication.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104891","tag_type":"warning","value":"Sex not explicitly stated in the abstract but assumed female given the breast cancer population; confirm if male breast cancer patients were included.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104891","tag_type":"warning","value":"Study design is labeled as a registry cohort; causal conclusions about treatment modalities (e.g., focal RT vs. WBRT) should be interpreted cautiously due to potential selection bias.","value_numeric":null}],"summaries":{"what_studied":"Real-world incidence, subtype-specific risk, and outcomes of brain metastases (BM) in 2,775 metastatic breast cancer (MBC) patients from the Austrian AGMT_MBC registry, with a median follow-up of 77 months.","key_result":"17.2% of patients developed BM during the metastatic course. BM risk was highest in HR+/HER2+ (OR 4.43) and HR−/HER2+ (OR 3.57) subtypes vs. luminal MBC; TNBC had OR 2.91. BM were associated with markedly shorter OS (HR 4.23; p<0.001). TNBC had the worst OS after BM diagnosis (4.7 months). Brain-only disease conferred better OS than concurrent extracranial disease (HR 0.58; p=0.001). Focal radiotherapy or neurosurgery outperformed whole brain radiotherapy, which declined over time.","limitations":"Registry-based design limits causal inference and may have incomplete treatment data. Receptor discordance data (HR loss 14.5%, HER2 gain 9.8%) may reflect biopsy sampling bias. The Austrian single-country cohort may limit generalizability to other healthcare settings.","practice_takeaway":"HER2+ and TNBC patients face the highest BM risk and shortest survival after BM—prioritize active CNS surveillance and enroll these patients in BM-specific trials. When BM are detected, focal radiotherapy or neurosurgery is associated with longer OS than whole brain radiotherapy."}},{"doi":"10.1093/jnci/djag256","pmid":"42530873","title":"A multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab, and pertuzumab in hormone receptor (HR)-positive, HER2-positive metastatic breast cancer (ASPIRE)","journal_title":"JNCI: Journal of the National Cancer Institute","journal_issn":"0027-8874","published_at":"2026-07-30T00:00:00.000Z","url":"https://doi.org/10.1093/jnci/djag256","source_score":14,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-08-11T13:26:21.632Z","updated_at":"2026-08-11T13:26:21.632Z","tags":[{"paper_doi":"10.1093/jnci/djag256","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"brand","value":"Arimidex","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"brand","value":"Herceptin","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"brand","value":"Ibrance","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"brand","value":"Perjeta","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"category","value":"Oncology","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"condition","value":"HR-Positive HER2-Positive Breast Cancer","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"condition","value":"Metastatic Breast Cancer","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"generic","value":"anastrozole","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"generic","value":"palbociclib","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"generic","value":"pertuzumab","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"generic","value":"trastuzumab","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"modality","value":"Aromatase Inhibitor","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"modality","value":"CDK4/6 Inhibitor","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"modality","value":"HER2-Targeted Therapy","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"sample_size","value":"n=29","value_numeric":29},{"paper_doi":"10.1093/jnci/djag256","tag_type":"sex","value":"female","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"study_design","value":"Phase I/II Trial","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"warning","value":"Median OS was not reached, so OS benefit cannot be fully assessed from available follow-up data.","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"warning","value":"Phase I/II single-arm design (no randomized comparator); level of evidence assigned as 3 reflects non-randomized controlled trial status.","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"warning","value":"Sample size is very small (n=29 response-evaluable); efficacy estimates should be interpreted with caution.","value_numeric":null},{"paper_doi":"10.1093/jnci/djag256","tag_type":"warning","value":"Sex not explicitly reported in the abstract, but assumed female given the breast cancer population — clinicians should verify in the full paper.","value_numeric":null}],"summaries":{"what_studied":"The ASPIRE trial evaluated frontline anastrozole + palbociclib + trastuzumab + pertuzumab in previously untreated HR-positive, HER2-positive metastatic breast cancer (MBC) in a multicenter Phase I/II design; Phase I used 3+3 dose escalation and Phase II used an optimal Simon two-stage design.","key_result":"Palbociclib MTD was 125 mg (no dose-limiting toxicities at 100 mg or 125 mg). In 29 response-evaluable patients, 6-month clinical benefit rate was 97% (n=28; 95% CI: 82–99%), median PFS was 24.9 months (95% CI: 17.2–44.8), and median OS was not reached at 39.4 months follow-up. Grade 3–4 treatment-related adverse events occurred in 62% of patients (n=18), mostly hematologic.","limitations":"Single-arm trial without a randomized comparator limits causal inference. Very small sample size (n=29 response-evaluable) reduces precision of efficacy estimates. Hormone receptor and HER2 subgroup results cannot be generalized without confirmatory randomized data.","practice_takeaway":"This chemotherapy-free regimen of anastrozole + palbociclib + trastuzumab + pertuzumab showed high clinical benefit (97%) and durable PFS (~25 months) in HR+/HER2+ MBC, but remains investigational pending randomized trial confirmation. Monitor closely for hematologic toxicity, which drove most grade 3–4 adverse events."}},{"doi":"10.1016/j.breast.2026.104853","pmid":"42398129","title":"Antibody–drug conjugates beyond HER2: Translating evidence into practice for HR+ HER2-negative and triple-negative metastatic breast cancer","journal_title":"The Breast","journal_issn":"0960-9776","published_at":"2026-06-30T00:00:00.000Z","url":"https://doi.org/10.1016/j.breast.2026.104853","source_score":11,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-07-11T13:32:58.677Z","updated_at":"2026-07-11T13:32:58.677Z","tags":[{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"brand","value":"Enhertu","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"brand","value":"Trodelvy","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"category","value":"Obstetrics & Gynecology","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"condition","value":"HR-Positive HER2-Negative Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"condition","value":"Metastatic Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"condition","value":"Triple-Negative Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"generic","value":"datopotamab deruxtecan","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"generic","value":"pembrolizumab","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"generic","value":"sacituzumab govitecan","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"generic","value":"sacituzumab tirumotecan","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"generic","value":"trastuzumab deruxtecan","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"modality","value":"Antibody-Drug Conjugate","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"modality","value":"HER2-Targeted ADC","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"modality","value":"Immune Checkpoint Inhibitor","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"modality","value":"TROP2-Targeted ADC","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"sex","value":"female","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"warning","value":"No brand name tags added for Dato-DXd or sac-TMT as they lack widely established proprietary names in Western markets at time of publication.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"warning","value":"Sac-TMT (sacituzumab tirumotecan) is approved only in China as of the publication date; its safety data derive exclusively from East Asian populations and may not generalize to Western patients.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"warning","value":"Sample size tag omitted: this is a review article aggregating multiple trials with no single overall N.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"warning","value":"The paper is published June 2026; some trial data cited (e.g., ASCENT-03, ASCENT-04, TROPION-Breast02 OS) were recently presented and may have been updated since publication.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104853","tag_type":"warning","value":"This is a narrative review with multiple authors disclosing financial relationships with manufacturers of the reviewed agents (AstraZeneca/Daiichi Sankyo, Gilead, MSD, Pfizer, Novartis, among others); potential influence on recommendations should be considered.","value_numeric":null}],"summaries":{"what_studied":"This narrative review synthesizes clinical trial evidence for four ADCs—trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), datopotamab deruxtecan (Dato-DXd), and sacituzumab tirumotecan (sac-TMT)—in HR+/HER2-negative and triple-negative metastatic breast cancer, covering mechanisms, efficacy, toxicity management, biomarkers, and sequencing strategies.","key_result":"All four ADCs improved PFS vs chemotherapy in their pivotal phase 3 trials. Key highlights include: T-DXd vs chemo in chemotherapy-naïve HR+/HER2-low mBC (PFS 13.2 vs 8.1 months; HR 0.62); SG vs chemo in pretreated HR+ mBC (OS 14.4 vs 11.2 months; HR 0.79); Dato-DXd vs chemo in first-line TNBC (OS 23.7 vs 18.7 months; HR 0.79); sac-TMT vs chemo in pretreated HR+ mBC (PFS 8.3 vs 4.1 months; HR 0.35). SG plus pembrolizumab improved PFS over chemo plus pembrolizumab in first-line PD-L1–positive TNBC (11.2 vs 7.8 months; HR 0.65).","limitations":"- All cross-ADC comparisons are indirect; no head-to-head randomized trials exist between ADCs.\n- Sac-TMT data derive exclusively from East Asian populations, limiting generalizability to Western patients.\n- Most sequencing and biomarker data (including post-ADC outcomes) come from retrospective analyses with small samples and selection bias.","practice_takeaway":"For HR+/HER2-low or ultralow mBC after CDK4/6 inhibitor progression, T-DXd is preferred when ADC therapy is indicated, especially with symptomatic or rapidly progressing disease; SG or Dato-DXd are alternatives for HER2-null tumors. In first-line TNBC, SG plus pembrolizumab is the preferred option for PD-L1–positive disease, while Dato-DXd monotherapy is an emerging option for PD-L1–negative or immunotherapy-ineligible patients—clinicians should individualize ADC choice based on HER2 status, toxicity profile (ILD risk with T-DXd, neutropenia/diarrhea with SG, stomatitis with Dato-DXd/sac-TMT), and infusion logistics."}},{"doi":"10.1016/j.breast.2026.104786","pmid":"41999684","title":"Integrating PIK3CA Testing into Clinical Practice for Advanced HR+/HER2- Breast Cancer: An Expert Consensus","journal_title":"The Breast","journal_issn":"0960-9776","published_at":"2026-04-10T00:00:00.000Z","url":"https://doi.org/10.1016/j.breast.2026.104786","source_score":23,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-07T22:49:45.686Z","updated_at":"2026-05-07T22:49:45.686Z","tags":[{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"brand","value":"Faslodex","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"brand","value":"Ibrance","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"brand","value":"Itovebi","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"brand","value":"Kisqali","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"category","value":"Obstetrics & Gynecology","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"condition","value":"Hormone Receptor-Positive HER2-Negative Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"condition","value":"Metastatic Breast Cancer","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"generic","value":"alpelisib","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"generic","value":"capivasertib","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"generic","value":"fulvestrant","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"generic","value":"inavolisib","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"generic","value":"palbociclib","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"modality","value":"CDK4/6 Inhibitor","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"modality","value":"Liquid Biopsy","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"modality","value":"Next-Generation Sequencing","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"modality","value":"PI3K Inhibitor","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"sex","value":"female","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"study_design","value":"Expert Consensus / Delphi Study","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"warning","value":"Brand name 'Itovebi' is the FDA-approved trade name for inavolisib; European trade name may differ. Verify local formulary.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"warning","value":"Sample size tag is not applicable here as this is a consensus document with no patient cohort enrolled.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"warning","value":"Some referenced regulatory approvals (e.g., European Commission July 2025 for inavolisib) are stated as forthcoming relative to the paper's April 2026 publication date — these have not been independently verified.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104786","tag_type":"warning","value":"This is an Italian expert panel consensus, not a systematic review or RCT; recommendations reflect expert opinion and may not fully apply outside Italian/European practice contexts.","value_numeric":null}],"summaries":{"what_studied":"A multidisciplinary Italian expert panel used a modified Delphi method (2 rounds, June–October 2025) to build consensus on PIK3CA molecular testing in advanced HR+/HER2- breast cancer, covering sample selection, analytical methods, sensitivity thresholds, reporting standards, and clinical integration.","key_result":"23 of 29 statements reached 100% agreement. Key recommendations include: NGS preferred over PCR (full exon 1–20 coverage); liquid biopsy valid but tissue is reference matrix; LOD ≤0.5% VAF required for plasma assays; any activating PIK3CA mutation (canonical or non-canonical) in either tissue or plasma is sufficient for PI3K inhibitor eligibility; inavolisib + palbociclib + fulvestrant is the preferred first-line regimen for PIK3CA-mutated patients progressing during or within 12 months of adjuvant endocrine therapy (INAVO120: PFS HR 0.42, OS HR 0.67, ORR 62.7% vs 28%).","limitations":"Consensus was confined to Italian experts, limiting geographic generalizability. The Delphi format reflects expert opinion rather than primary data; no new clinical trial data were generated. Concordance thresholds and LOD recommendations rely on existing (often industry-sponsored) trial data.","practice_takeaway":"Test all advanced HR+/HER2- breast cancer patients for PIK3CA using NGS panels covering the full coding sequence; a positive result in tissue or plasma at any VAF is actionable. For patients progressing on or within 12 months of adjuvant endocrine therapy with a confirmed PIK3CA mutation, offer inavolisib + palbociclib + fulvestrant as first-line metastatic treatment."}},{"doi":"10.1016/j.breast.2026.104691","pmid":"41496431","title":"Concomitant radiation therapy and trastuzumab deruxtecan in metastatic breast cancer: feasibility, safety, and outcomes from a real-life multicentre international cohort","journal_title":"The Breast","journal_issn":"0960-9776","published_at":"2026-01-07T00:00:00.000Z","url":"https://doi.org/10.1016/j.breast.2026.104691","source_score":40,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2026-01-08","doi":"10.1016/j.breast.2026.104691","days":"14","issn":"0960-9776","rank":"1","field":"Clinical Medicine","score":"40","category":"Obstetrics & Gynecology","categories":["Obstetrics & Gynecology"],"_categories":["Obstetrics & Gynecology"]},"pubmed":{"doi":"10.1016/j.breast.2026.104691","title":"Concomitant radiation therapy and trastuzumab deruxtecan in metastatic breast cancer: feasibility, safety, and outcomes from a real-life multicentre international cohort.","journal":"Breast (Edinburgh, Scotland)","methods":"","results":"A total of 147 patients were included; 67 received concomitant RT (71 courses) and 80 received T-DXd alone. Median age was 49 years (range 25-85). The central nervous system was the most frequent RT site (54.9 %). Grade ≥3 AEs occurred in 24 patients (16.3 %), with no significant difference between RT and no-RT cohorts (11.9 % vs 20.0 %; p = 0.30). Permanent T-DXd discontinuation due to toxicity occurred in 19 patients (12.9 %), with similar rates in the RT and no-RT groups (11.9 % vs 13.8 %). One case of symptomatic radionecrosis was observed after intracranial RT. Exploratory analyses showed no adverse effect of concomitant RT on PFS or OS.","abstract":"$30","keywords":["Adverse events","Brain metastases","Concomitant therapy","Metastatic breast cancer","Radiotherapy","Trastuzumab deruxtecan"],"pubmed_id":"41496431","conclusions":"Concomitant administration of T-DXd and RT appears feasible and well tolerated, without increased risk of severe or treatment-limiting toxicity. 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full protocol details are not available here.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104691","tag_type":"warning","value":"Exploratory PFS/OS analyses are described without effect sizes or hazard ratios in the abstract.","value_numeric":null},{"paper_doi":"10.1016/j.breast.2026.104691","tag_type":"warning","value":"RT dose, technique, and fractionation are not reported in the abstract, which may affect toxicity risk.","value_numeric":null}],"summaries":{"what_studied":"A multicentre retrospective cohort across six European centres evaluated the safety of giving radiation therapy (RT) concomitantly with trastuzumab deruxtecan (T-DXd) in metastatic breast cancer, versus T-DXd alone. Concomitancy was defined as RT during T-DXd or within 10 days of a cycle; the primary endpoint was grade ≥3 adverse events, with exploratory progression-free and overall survival.","key_result":"Grade ≥3 adverse events occurred in 24/147 patients (16.3%), with no significant difference between concomitant RT and no-RT groups (11.9% vs 20.0%; p=0.30); permanent T-DXd discontinuation for toxicity occurred in 19/147 (12.9%) with similar rates (11.9% vs 13.8%). One symptomatic radionecrosis was reported after intracranial RT, and exploratory analyses showed no adverse effect of concomitant RT on progression-free or overall survival.","limitations":"Retrospective, non-randomized, multicentre design may introduce selection and treatment heterogeneity. The abstract does not report RT dosing/fractionation or effect estimates for PFS/OS, limiting interpretation of efficacy signals.","practice_takeaway":"In real-world practice, concomitant RT with T-DXd for metastatic breast cancer appears feasible without excess severe AEs or treatment-limiting toxicity compared with T-DXd alone. Monitor for rare intracranial radionecrosis; confirmation in prospective studies is needed."}},{"doi":"10.1158/1078-0432.ccr-25-3040","pmid":"41235919","title":"Real-World Outcomes of Elacestrant in ER+, HER2−,\n ESR1\n -Mutant Metastatic Breast Cancer","journal_title":"Clinical Cancer Research","journal_issn":"1078-0432","published_at":"2025-11-14T00:00:00.000Z","url":"https://doi.org/10.1158/1078-0432.ccr-25-3040","source_score":208,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2025-12-23","doi":"10.1158/1078-0432.ccr-25-3040","days":"30","issn":"1078-0432","rank":"4","field":"Clinical Medicine","score":"208","category":"Oncology","categories":["Oncology"],"_categories":["Oncology"]},"pubmed":{"doi":"10.1158/1078-0432.CCR-25-3040","title":"Real-World Outcomes of Elacestrant in ER+, HER2-, ESR1-Mutant Metastatic Breast Cancer.","journal":"Clinical cancer research : an official journal of the American Association for Cancer Research","methods":"","results":"Among 306 patients, 93.8% had prior ET ± cyclin-dependent kinase 4/6 inhibitor for ≥12 months, 50.0% had prior chemotherapy, and 72.2% had prior fulvestrant. 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In patients with coexisting ESR1- and PI3K-pathway-mutated tumors, mTTNT was 6.3 months (95% CI, 4.8-7.9). mTTNT was 7.9 months (95% CI, 7.1-9.8) in all patients and was also sustained in patients with no prior fulvestrant [12.9 months (95% CI, 7.2-not reached)], no prior chemotherapy [8.4 months (95% CI, 7.1-13.3)], visceral metastasis [7.9 months (95% CI, 7.0-9.9)], and liver metastases [7.2 months (95% CI, 6.3-9.0)].","abstract":"$31","keywords":[],"pubmed_id":"41235919","conclusions":"","publication_date":"2025-11-14T00:00:00"},"crossref":{"DOI":"10.1158/1078-0432.ccr-25-3040","URL":"https://doi.org/10.1158/1078-0432.ccr-25-3040","ISSN":["1078-0432","1557-3265"],"link":[{"URL":"https://aacrjournals.org/clincancerres/article-pdf/doi/10.1158/1078-0432.CCR-25-3040/3670623/ccr-25-3040.pdf","content-type":"application/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https://aacrjournals.org/clincancerres/article-pdf/doi/10.1158/1078-0432.CCR-25-3040/3684733/ccr-25-3040.pdf","content-type":"application/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https://aacrjournals.org/clincancerres/article-pdf/32/1/179/3721774/ccr-25-3040.pdf","content-type":"application/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https://aacrjournals.org/clincancerres/article-pdf/32/1/179/3721774/ccr-25-3040.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":"179-187","type":"journal-article","issue":"1","score":1,"title":["Real-World Outcomes of Elacestrant in ER+, HER2−,\n ESR1\n -Mutant Metastatic Breast Cancer"],"author":[{"given":"Hope S.","family":"Rugo","sequence":"first","affiliation":[{"name":"1City of Hope Comprehensive Cancer Center, Duarte, California."}]},{"given":"Virginia","family":"Kaklamani","sequence":"additional","affiliation":[{"name":"2University of Texas Health Sciences Center, San Antonio, Texas."}]},{"given":"Heather","family":"McArthur","sequence":"additional","affiliation":[{"name":"3UT Southwestern Medical Center, Dallas, Texas."}]},{"given":"Seth A.","family":"Wander","sequence":"additional","affiliation":[{"name":"4Massachusetts General Hospital Cancer Center, Boston, Massachusetts."}]},{"given":"William","family":"Gradishar","sequence":"additional","affiliation":[{"name":"5Robert H. 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HER2-negative, ESR1-mutant metastatic breast cancer treated in routine practice (n=306).","key_result":"Median TTNT was 7.9 months (95% CI, 7.1–9.8) overall; 8.2 months (6.3–13.0) after 1–2 prior lines vs 7.5 months (7.1–9.9) after ≥3 lines; 6.3 months (4.8–7.9) with coexisting PI3K-pathway mutations; 12.9 months (7.2–not reached) with no prior fulvestrant; 8.4 months (7.1–13.3) with no prior chemotherapy; 7.9 months (7.0–9.9) with visceral metastases; and 7.2 months (6.3–9.0) with liver metastases.","limitations":"Observational claims–genomics study without a comparator arm, using TTNT (not PFS/OS) as the primary endpoint; details on adjustment for confounding are not provided in the abstract.","practice_takeaway":"In ESR1-mutant ER+/HER2− metastatic breast cancer progressing after endocrine therapy, elacestrant achieved a median TTNT of about 8 months in routine care, with longer durability in earlier lines and in those without prior fulvestrant—supporting its role in endocrine sequencing before chemotherapy or targeted combinations."}},{"doi":"10.1158/2159-8290.cd-25-0647","pmid":"41212147","title":"Trastuzumab Deruxtecan Resistance via Loss of HER2 Expression and Binding","journal_title":"Cancer Discovery","journal_issn":"2159-8274","published_at":"2025-11-10T00:00:00.000Z","url":"https://doi.org/10.1158/2159-8290.cd-25-0647","source_score":94,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2025-12-30","doi":"10.1158/2159-8290.cd-25-0647","days":"14","issn":"2159-8274","rank":"4","field":"Clinical Medicine","score":"94","category":"Oncology","categories":["Oncology"],"_categories":["Oncology"]},"pubmed":{"doi":"10.1158/2159-8290.CD-25-0647","title":"Trastuzumab Deruxtecan (T-DXd) Resistance via Loss of HER2 Expression and Binding.","journal":"Cancer discovery","methods":"","results":"","abstract":"T-DXd is clinically beneficial in HER2 positive and HER2 low metastatic breast cancer. However, therapeutic resistance emerges over time in most patients, with poorly defined resistance mechanisms. Through a molecular characterization of paired pre- and post-T-DXd treatment patient specimens, we found that 49% cases had major decreases in HER2 expression at progression, among them, 52% exhibited complete HER2 loss. Using isogenic model systems, we demonstrated that decreases in HER2 expression corresponded to reductions in T-DXd internalization and major increases in drug IC50 for tumor growth inhibition. We further identified and validated HER2 mutations in the trastuzumab binding interface (V597M and P593R) that promoted T-DXd resistance. As a strategy to overcome impaired T-DXd binding and internalization, we tested low dose combinations of T-DXd with TROP2-directed ADCs and found these could more uniformly deliver DXd payloads and thereby overcome resistance mediated by HER2 loss.","keywords":[],"pubmed_id":"41212147","conclusions":"","publication_date":"2025-11-10T00:00:00"},"crossref":{"DOI":"10.1158/2159-8290.cd-25-0647","URL":"https://doi.org/10.1158/2159-8290.cd-25-0647","ISSN":["2159-8274","2159-8290"],"link":[{"URL":"https://aacrjournals.org/cancerdiscovery/article-pdf/doi/10.1158/2159-8290.CD-25-0647/3669759/cd-25-0647.pdf","content-type":"application/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https://aacrjournals.org/cancerdiscovery/article-pdf/doi/10.1158/2159-8290.CD-25-0647/3719943/cd-25-0647.pdf","content-type":"application/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https://aacrjournals.org/cancerdiscovery/article-pdf/doi/10.1158/2159-8290.CD-25-0647/3719943/cd-25-0647.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":"OF1-OF15","type":"journal-article","issue":null,"score":1,"title":["Trastuzumab Deruxtecan Resistance via Loss of HER2 Expression and Binding"],"author":[{"given":"Wanyi","family":"Chen","sequence":"first","affiliation":[{"name":"1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"2Weill Cornell Graduate School, Weill Cornell Medicine, New York, New York."}]},{"given":"Avantika","family":"Gupta","sequence":"additional","affiliation":[{"name":"1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Nicholas","family":"Mai","sequence":"additional","affiliation":[{"name":"3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Sharanya","family":"Nag","sequence":"additional","affiliation":[{"name":"1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Joshua S.","family":"Lau","sequence":"additional","affiliation":[{"name":"4Gerstner Sloan Kettering Graduate School, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Sukrit","family":"Singh","sequence":"additional","affiliation":[{"name":"5Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"John D.","family":"Chodera","sequence":"additional","affiliation":[{"name":"2Weill Cornell Graduate School, Weill Cornell Medicine, New York, New York."},{"name":"5Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Bo","family":"Liu","sequence":"additional","affiliation":[{"name":"1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Elisa","family":"de Stanchina","sequence":"additional","affiliation":[{"name":"6Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Fresia","family":"Pareja","sequence":"additional","affiliation":[{"name":"7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Atif Ali","family":"Hashmi","sequence":"additional","affiliation":[{"name":"7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Miriam M.","family":"Lieberman","sequence":"additional","affiliation":[{"name":"3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."}]},{"given":"Shanu","family":"Modi","sequence":"additional","affiliation":[{"name":"3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"8Weill Cornell Medical College, Weill Cornell Medicine, New York, New York."}]},{"given":"Jacqueline","family":"Bromberg","sequence":"additional","affiliation":[{"name":"3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"8Weill Cornell Medical College, Weill Cornell Medicine, New York, New York."}]},{"given":"Pedram","family":"Razavi","sequence":"additional","affiliation":[{"name":"3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"8Weill Cornell Medical College, Weill Cornell Medicine, New York, New York."}]},{"given":"Joshua Z.","family":"Drago","sequence":"additional","affiliation":[{"name":"3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"8Weill Cornell Medical College, Weill Cornell Medicine, New York, New York."}]},{"given":"Sarat","family":"Chandarlapaty","sequence":"additional","affiliation":[{"name":"1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"2Weill Cornell Graduate School, Weill Cornell Medicine, New York, New York."},{"name":"3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"4Gerstner Sloan Kettering Graduate School, Memorial Sloan Kettering Cancer Center, New York, New York."}]}],"funder":[{"name":"Sussman Family Fund","award":["Sussman Family Fund"],"award-info":[{"award-number":["Sussman Family Fund"]}]},{"id":[{"id":"10.13039/100001006","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/100001006","name":"Breast Cancer Research Foundation","award":["BCRF-24-185"],"award-info":[{"award-number":["BCRF-24-185"]}],"doi-asserted-by":"publisher"},{"id":[{"id":"10.13039/100031022","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/100031022","name":"Center for Cancer Research","award":["P30 CA008748"],"award-info":[{"award-number":["P30 CA008748"]}],"doi-asserted-by":"publisher"},{"id":[{"id":"10.13039/100000025","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/100000025","name":"National Institute of Mental Health","award":["P50 CA247749-01"],"award-info":[{"award-number":["P50 CA247749-01"]}],"doi-asserted-by":"publisher"},{"id":[{"id":"10.13039/100000002","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/100000002","name":"National Institutes of Health","award":["1R01CA249666-01A"],"award-info":[{"award-number":["1R01CA249666-01A"]}],"doi-asserted-by":"publisher"},{"id":[{"id":"10.13039/100000002","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/100000002","name":"National Institutes of Health","award":["P30 CA008748 S5"],"award-info":[{"award-number":["P30 CA008748 S5"]}],"doi-asserted-by":"publisher"},{"id":[{"id":"10.13039/100000038","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/100000038","name":"U.S. Food and Drug Administration","award":["1U01FD007909-01A1"],"award-info":[{"award-number":["1U01FD007909-01A1"]}],"doi-asserted-by":"publisher"}],"issued":{"date-parts":[[2025,12,30]]},"member":"1086","prefix":"10.1158","source":"Crossref","volume":null,"created":{"date-time":"2025-11-10T15:26:53Z","timestamp":1762788413000,"date-parts":[[2025,11,10]]},"indexed":{"date-time":"2026-01-10T08:00:05Z","timestamp":1768032005773,"date-parts":[[2026,1,10]]},"license":[{"URL":"https://creativecommons.org/licenses/by-nc-nd/4.0/","start":{"date-time":"2025-12-30T00:00:00Z","timestamp":1767052800000,"date-parts":[[2025,12,30]]},"delay-in-days":0,"content-version":"unspecified"}],"subject":[],"abstract":"$33","language":"en","relation":{},"resource":{"primary":{"URL":"https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-25-0647/771250/Trastuzumab-Deruxtecan-Resistance-via-Loss-of-HER2"}},"subtitle":[],"deposited":{"date-time":"2025-12-30T18:22:12Z","timestamp":1767118932000,"date-parts":[[2025,12,30]]},"issn-type":[{"type":"print","value":"2159-8274"},{"type":"electronic","value":"2159-8290"}],"published":{"date-parts":[[2025,12,30]]},"publisher":"American Association for Cancer Research (AACR)","reference":null,"short-title":[],"update-policy":"https://doi.org/10.1158/crossmark_policy","content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"original-title":[],"container-title":["Cancer Discovery"],"reference-count":0,"published-online":{"date-time":null,"timestamp":null,"date-parts":[[2025,12,30]]},"references-count":0,"short-container-title":[],"is-referenced-by-count":2},"unpaywall":{"doi":"10.1158/2159-8290.cd-25-0647","is_oa":true,"title":"Trastuzumab Deruxtecan Resistance via Loss of HER2 Expression and 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deruxtecan","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-0647","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-0647","tag_type":"modality","value":"Antibody-Drug Conjugate","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-0647","tag_type":"study_design","value":"Case Series","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-0647","tag_type":"warning","value":"Design classification is approximate; this is a translational study using paired patient specimens and preclinical models.","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-0647","tag_type":"warning","value":"The T-DXd plus TROP2-directed ADC combination was tested in models only; no clinical outcomes were reported.","value_numeric":null},{"paper_doi":"10.1158/2159-8290.cd-25-0647","tag_type":"warning","value":"Total sample size and patient characteristics are not provided in the abstract.","value_numeric":null}],"summaries":{"what_studied":"Paired pre- and post–trastuzumab deruxtecan (T-DXd) specimens from metastatic HER2-positive and HER2-low breast cancer were profiled to define resistance mechanisms, with validation in isogenic models and testing of low-dose T-DXd plus TROP2-directed ADC combinations.","key_result":"At progression, 49% of cases showed major decreases in HER2 expression; among these, 52% had complete HER2 loss. Lower HER2 reduced T-DXd internalization and increased IC50 in isogenic models; HER2 binding-site mutations (V597M, P593R) promoted resistance; low-dose T-DXd plus TROP2-directed ADCs improved DXd delivery and overcame HER2-loss–mediated resistance in models.","limitations":"The abstract does not report total sample size or patient characteristics. Combination strategy and mechanistic validation are preclinical with no clinical outcomes reported.","practice_takeaway":"HER2 expression can fall or be lost at progression on T-DXd, and binding-site HER2 mutations may drive resistance; rechecking HER2 at progression may be informative. Combining T-DXd with a TROP2-directed ADC is investigational and supported only by preclinical data here."}}],"initialOffset":12,"fetchConfig":{"kind":"tags","tags":[{"tag_type":"condition","value":"Metastatic Breast Cancer"}]},"breadcrumbItems":[{"name":"Home","href":"/"},{"name":"Research Hub","href":"/hub"},{"name":"Conditions","href":"/hub/tag/condition"},{"name":"Metastatic Breast Cancer"}],"hrefConfig":{"basePath":"/hub/papers","webViewQueryParams":{"hub_ctx":"tag","hub_tag_type":"condition","hub_tag_value":"Metastatic Breast Cancer"}}}]]

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