This single-arm, phase Ib trial evaluated the antitumor activities and safety of afuresertib (a pan AKT inhibitor) plus fulvestrant for previously treated HR-positive, HER2-negative advanced breast cancer. Eligible patients received afuresertib at 125 mg/day and fulvestrant at 500 mg on days 1, 15, and 29, and every 28 days thereafter during safety run-in and, in the absence of serious toxicities, subsequent 4-week cycles. The trial enrolled 31 patients (median age 54 years; 30 women); 20 received prior CDK4/6 inhibitor therapy. The primary endpoint of investigators-assessed objective response rate was 25.8% (8/31; 90% CI 13.5-41.8). Nine patients (29.0%) had grade 3 or worse adverse events. No death due to adverse event occurred. In conclusion, afuresertib plus fulvestrant was well-tolerated and had promising antitumor activities against pretreated, advanced HR-positive, HER2-negative breast cancer, supporting further studies with randomized controlled trials. This trial is registered with ClinicalTrials.gov (NCT04851613).

Patients with HER2-negative advanced breast cancer (ABC) have limited chemotherapy options after progression on anthracyclines and taxanes. Mitoxantrone Hydrochloride Liposome (Lipo-MIT), a nanoparticle formulation with a 60-nm particle size, is designed to reduce toxicity and enhance tumor targeting. We investigated the safety and efficacy of Lipo-MIT combined with capecitabine in pretreated HER2-negative ABC. In this phase I dose-escalation study, eligible patients were sequentially enrolled to receive escalating doses of Lipo-MIT (ranging from 16 to 24 mg/m2) administered either every 3 weeks (Q3W) or every 4 weeks (Q4W), combined with standard capecitabine. Primary endpoints included dose-limiting toxicities (DLTs) and determination of the recommended phase 2 dose (RP2D). Secondary endpoints assessed safety and preliminary efficacy. Twenty-six patients were enrolled. Lipo-MIT 22 mg/m2 administered Q4W was identified as the RP2D. The combination demonstrated a manageable safety profile, with no reports of severe cardiac toxicity or hand-foot syndrome. Interstitial lung disease was observed in 19.2

3013 Background: B7-H4, a transmembrane glycoprotein, has limited expression in normal tissue, but is upregulated in a variety of solid tumors. BG-C9074 is an investigational topoisomerase I inhibitor antibody-drug conjugate (ADC) that targets B7-H4. We present results of monotherapy dose escalation and safety expansion from the ongoing phase 1 study. Methods: BG-C9074-101 (NCT06233942) is a first-in-human, multicenter study of BG-C9074 as monotherapy and in combination with other anticancer therapies in patients (pts) with advanced solid tumors. Pts with advanced solid tumors, irrespective of B7-H4 expression, received BG-C9074 IV every 3 weeks in escalating doses from 1 to 9 mg/kg. Endpoints included safety, preliminary antitumor activity (per RECIST v1.1) and pharmacokinetics. Results: As of Dec 29, 2025, 123 pts with advanced solid tumors received BG-C9074 monotherapy in phase 1a (ovarian [OC], n = 62; HR+/HER2- breast cancer, n = 28; triple negative breast cancer [TNBC], n = 18; cholangiocarcinoma, n = 11; endometrial, n = 3; squamous non-small cell lung cancer, n = 1). Median (range) prior lines were 4 (0-13). 8 pts experienced DLTs (thrombocytopenia [n = 2, 6.5 mg/kg; n = 1, 7 mg/kg], febrile neutropenia [n = 1, 6.5 mg/kg; n = 1, 7 mg/kg], neutropenic infection [n = 1, 7 mg/kg], fatigue [n = 1, 6 mg/kg], nausea [n = 1, 9 mg/kg], and unexplained death [n = 1, 9 mg/kg]). Treatment-related adverse events (TRAEs) occurred in 113 pts (91.9%); grade (gr) ≥3 in 30.1%. The most common TRAEs were nausea (53.7%; gr ≥3, 4.1%), neutrophil count decreased/neutropenia (44.7%; gr ≥3, 18.7%), and fatigue (37.4%; gr ≥3, 2.4%). Hematologic and gastrointestinal toxicities were manageable with dose modifications and/or supportive care. Among 114 efficacy-evaluable pts, confirmed ORR (cORR) was 28.1% (95% CI: 20.1-37.3), including 2 CRs (1 OC, 6.5 mg/kg, 1 TNBC, 5 mg/kg) and 30 PRs (Table); unconfirmed ORR was 33.3% (24.8-42.8; 3 CRs, 35 PRs). Responses were observed across doses and levels of B7-H4 expression, without consistent association of response with B7-H4 expression across tumor types. Median (range) study follow-up was 6.0 (0.3-17.7) months. ADC and free payload concentrations decreased in a biexponential manner with a half-life of ~7 days for ADC. Exposure for ADC and free payload increased approximately dose proportionally. Conclusions: BG-C9074 demonstrates a tolerable safety profile in pts with advanced solid tumors. Encouraging antitumor activity was observed in OC and TNBC. Dose expansion and optimization are ongoing. Clinical trial information: NCT06233942 . OC (n=55) TNBC (n=16) HR+/HER2- BC (n=28) Total (N=114) cORR, % (95% CI) 34.5(22.2-48.6) 31.3(11.0-58.7) 17.9(6.1-36.9) 28.1(20.1-37.3) CR, n (%) 1 (1.8) 1 (6.3) 0 (0.0) 2 (1.8) PR, n (%) 18 (32.7) 4 (25.0) 5 (17.9) 30 (26.3) SD, n (%) 32 (58.2) 5 (31.3) 16 (57.1) 60 (52.6) PD, n (%) 4 (7.3) 5 (31.3) 7 (25.0) 17 (14.9) Not evaluable, n (%) 0 (0.0) 1 (6.3) 0 (0.0) 5 (4.4)

Breast cancer remains a leading cause of cancer-related morbidity and mortality worldwide, driven by therapeutic resistance, recurrence, and metastasis. Patient-derived organoids (PDOs) have emerged as a robust platform that preserves histopathological, genetic, and functional features of parental tumors, enabling translational research and precision oncology. However, the lack of standardized procedures across laboratories limits reproducibility and clinical applicability. Here, we present a consensus-oriented standard for the establishment, characterization, quality control and application of human breast cancer organoids derived from diverse clinical sources, including surgical tissues, biopsies, pleural effusion, ascites, and circulating tumor cells (CTCs). This document defines key terminologies, outlines standardized workflows, and introduces quantitative validation criteria for successful organoid establishment. In addition, it provides structured guidance for advanced models, including immune–tumor, neuro–tumor, and microbiota−tumor organoid systems, with defined functional validation endpoints. Standardized protocols for drug sensitivity testing are also proposed, including seeding density, exposure duration, and response metrics such as IC50 and AUC. Representative validation strategies, including histological, molecular and functional concordance with parental tumors, are incorporated to enhance reproducibility and translational relevance. This standard aims to harmonize methodologies, improve cross−study comparability, and accelerate the clinical implementation of breast cancer organoid-based precision medicine.

This open-label phase III trial assessed a chemotherapy-free regimen for recurrent/metastatic triple-negative breast cancer (TNBC). Patients were 1:1 randomized to benmelstobart plus anlotinib or nab-paclitaxel monotherapy, stratified by prior taxane exposure, liver and brain metastases. Planned enrollment was 322, yet recruitment was prematurely stopped by COVID-19, leaving only 147 randomized participants (75 experimental, 72 control). All efficacy analyses are exploratory and require cautious interpretation. The primary endpoint, IRC-assessed progression-free survival (PFS), was not met. Investigator-assessed median PFS reached 7.85 months for the combination vs. 5.55 months for nab-paclitaxel (HR = 0.70, 95%CI 0.46–1.06, P = 0.1687). Median overall survival (OS) was 35.81 vs. 21.03 months (HR = 0.78, 95%CI 0.49–1.24, P = 0.2625). Grade ≥3 treatment-related adverse events affected 58.7% of combination patients and 36.6% of monotherapy patients. This regimen failed to deliver statistically superior clinical benefits over nab-paclitaxel, only showing a non-significant favorable trend. Further trials are warranted to validate this observation. Trial ID: NCT04405505, registered May 24, 2020 on ClinicalTrials.gov.

The addition of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to endocrine therapy has redefined the treatment paradigm for HR-positive, HER2-negative (HR+/HER2−) advanced breast cancer, with clear survival gains. However, resistance is almost inevitable and remains the central barrier to durable benefit. Selective estrogen receptor degraders (SERDs) have therefore moved from a later-line option to a core component of post-progression strategies aimed at targeting ESR1 mutations and estrogen receptor (ER) pathway reactivation. Notably, oral SERDs differ substantially in ER occupancy, degradation potency, and pharmacokinetic behavior, and these differences appear to translate into distinct efficacy and toxicity profiles across studies. This review summarizes recent progress in SERD-based therapeutic strategies, with a focus on post-CDK4/6 inhibitor sequencing and biomarker-driven combination approaches. Particular attention is given to rational combinations with PI3Kα and AKT inhibitors, HER2-directed tyrosine kinase inhibitors, and emerging targets such as FGFR, CDK2, and CDK7, as well as the growing role of liquid biopsy in guiding treatment adaptation. Together, these developments position SERD-centered strategies as a key framework for advancing mechanism-informed, precision treatment in HR+/HER2– advanced breast cancer.

BACKGROUND:Phase II and III trials have demonstrated progression-free survival (PFS) benefits of pyrotinib plus capecitabine over lapatinib plus capecitabine in HER2-positive metastatic breast cancer (MBC). However, long-term overall survival (OS) data from a single-center cohort remain limited. This pooled analysis compared OS between the two regimens and explored outcomes across prespecified subgroups. METHODS:We included patients with HER2-positive MBC from our center enrolled in a Phase Ic study, a Phase II study, or the Phase III PHOEBE trial. The primary endpoint was OS. OS was analyzed using Kaplan-Meier estimates, log-rank tests, and a multivariable Cox model adjusted for ECOG performance status, pathological grade, prior anti-HER2 therapy, trastuzumab exposure duration, trastuzumab resistance, and prior chemotherapy lines. The proportional hazards assumption was assessed using Schoenfeld residuals. Exploratory subgroup analyses used prespecified categories. RESULTS:At data cutoff, 82 patients were included; 53 received pyrotinib plus capecitabine and 29 received lapatinib plus capecitabine. Baseline characteristics were comparable between groups. Median OS was 74.61 months (95% CI 41.10-not reached) with pyrotinib plus capecitabine and 30.98 months (26.12-50.76) with lapatinib plus capecitabine (log-rank p = 0.0053). Cox models suggested a reduced risk of death with pyrotinib plus capecitabine. Subgroup analyses were exploratory and should be interpreted cautiously because several subgroup estimates were imprecise. CONCLUSION:In this single-center pooled analysis, pyrotinib plus capecitabine was associated with significantly longer OS than lapatinib plus capecitabine in patients with HER2-positive MBC. These exploratory results are consistent with prior Phase II/III trials and provide evidence supporting the OS benefit of pyrotinib.

BACKGROUND:Neratinib, an oral irreversible pan-HER tyrosine kinase inhibitor, was approved in China in 2020 for extended adjuvant treatment of early-stage HER2-positive breast cancer (BC) after completion of trastuzumab-based adjuvant therapy. With rising neoadjuvant therapy use, treatment landscape for HER2+ early breast cancer (EBC) is evolving. METHODS:This multicentre, real-world study included patients with HER2+ EBC who received ≥1 dose of neratinib as extended adjuvant treatment and completed treatment before 26 September 2024. The primary objective was to characterise patient demographics and clinical features at neratinib initiation. Secondary objectives included describing BC treatment patterns, neratinib use, and safety. RESULTS:A total of 508 patients from 11 centres were included. Median age was 48.0 years, and 64.8% had HER2+/HR+ tumours. At diagnosis, 52.8% had stage I-II disease and 46.1% had stage III disease. Most patients had clinical T1 (31.9%) or T2 (54.1%) tumours, and 86.7% were lymph node positive. Neoadjuvant therapy was administered in 141 patients (27.8%), of whom 49.6% did not achieve pathological complete response (pCR). Nearly all patients (99.6%) received adjuvant therapy, most commonly trastuzumab plus pertuzumab (88.7%). The median interval from prior adjuvant therapy completion to neratinib initiation was 52 days. Most patients (88.4%) started at 240 mg dose. Diarrhoea management strategies were used in 54.5% of patients; neratinib-related diarrhoea occurred in 19.3%, with 5.3% Grade 3 events. CONCLUSIONS:Patient characteristics reflect current Chinese practice. Increasing adoption of diarrhoea prophylaxis in real-world practice reflects growing clinical experience with neratinib and its recognised benefit in preventing diarrhoea.

Homologous recombination deficiency (HRD) is a key molecular feature in a subset of triple-negative breast cancer (TNBC). The optimal treatment strategy for metastatic TNBC with HRD remains unclear despite multiple therapeutic options. A systematic search was performed in PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov, including conference proceedings, up to November 27, 2024. Eligible studies included randomized controlled trials and retrospective studies reporting efficacy outcomes for metastatic TNBC with HRD biomarkers. Pairwise meta-analysis using random-effects models and Bayesian network meta-analysis were conducted. Hazard ratios (HRs) or odds ratios (ORs) with 95

Importance:The BRIGHT-2 interim analysis demonstrated the efficacy of bireociclib plus fulvestrant in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (ERBB2; previously HER2)-negative advanced breast cancer (ABC) after endocrine therapy progression. This final analysis includes an additional 11-month follow-up. Objective:To evaluate the efficacy and safety of bireociclib plus fulvestrant in HR-positive, ERBB2-negative ABC. Design, Setting, and Participants:This double-blind, placebo-controlled phase 3 randomized clinical trial was conducted at 64 hospitals in China between December 8, 2021, and October 24, 2022. Patients were enrolled and randomly assigned in a 2:1 to receive bireociclib plus fulvestrant or placebo plus fulvestrant. Data were analyzed from April 2024 to December 2025. Interventions:Patients received bireociclib, 360 mg, or placebo orally every 12 hours in combination with fulvestrant, 500 mg, intramuscularly (days 1 and 15 of cycle 1, then day 1 of each 28-day cycle). Main Outcomes and Measures:The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival, objective response rate, duration of response, and safety. Results:Of 305 included patients, the mean (SD) age was 54.1 (10.2) years, and the median (IQR) follow-up at data cutoff was 19 (18.5-19.6) months. Patients were randomized to bireociclib plus fulvestrant (n = 204) or placebo plus fulvestrant (n = 101); 275 (90.2%) had measurable disease and 268 (87.9%) had received prior systemic chemotherapy. Bireociclib plus fulvestrant significantly prolonged PFS vs placebo (median PFS, 14.7 months [95% CI, 11.1-20.2] vs 7.3 months [95% CI, 5.5-11.0]; hazard ratio, 0.54; 95% CI, 0.40-0.74; P < .001). The objective response rate was higher (45.6% [95% CI, 38.6-52.7] vs 14.9% [95% CI, 8.6-23.3]) in the bireociclib group, with a prolonged median duration compared with placebo (not reached [95% CI, 11.1 to not reached] vs 13.1 months [95% CI, 10.2 to not reached]). Safety was consistent with the interim findings and the profiles of known cyclin-dependent kinase 4/6 inhibitors. Subgroup analyses across multiple patient characteristics (menopausal status, metastatic sites, prior treatment, disease-free interval, ESR1/PIK3CA/TP53 alterations and others) showed consistent PFS improvements with bireociclib vs placebo. Patients with early-onset diarrhea appeared to derive more benefit from bireociclib (hazard ratio, 0.49; 95% CI, 0.36-0.68). Conclusions and Relevance:The final analysis of the BRIGHT-2 randomized clinical trial confirms improved PFS with the addition of bireociclib to fulvestrant, with manageable safety as a treatment option for patients with HR-positive, ERBB2-negative ABC with progression after prior endocrine therapy. Trial Registration:ClinicalTrials.gov Identifier: NCT05077449.

1014 Background: SG demonstrated significant and clinically meaningful progression-free survival (PFS) improvement vs chemo in pts with previously untreated, locally advanced unresectable or metastatic TNBC who were not candidates for PD-(L)1i in ASCENT-03 (NCT05382299). We report preplanned exploratory efficacy analyses in ASCENT-03 by Trop-2 expression, BRCA status, and HER2 expression. Methods: 588 pts randomized 1:1 to SG or chemo (taxane or gemcitabine + carboplatin). Trop-2 expression was measured by immunohistochemistry (IHC), tumor BRCA (tBRCA) status by whole exome sequencing, and HER2 expression by in situ hybridization (ISH) and IHC, all in centrally tested tumor samples (fresh or archival; 43% from metastatic sites). Pts were subgrouped by Trop-2 expression quartile, tBRCA wild-type (WT) or mutant (mut; mut in BRCA1, BRCA2, or both) status, and HER2 status (IHC 0 vs Low [IHC 1+ or IHC 2+/ISH-]). Biomarker status was analyzed to determine association with PFS by blinded independent central review (BICR). Other efficacy outcomes by biomarker status will be presented. Results: Median Trop-2 H-score: 240; H-scores by quartile (Q): Q1 0-184, Q2 185-239, Q3 240-283, Q4 284-300. Trop-2 expression was available in 499 pts. PFS by BICR was longer with SG vs chemo in all Trop-2 expression quartiles (Table). Hazard ratio (HR; 95% confidence interval [CI]) was 0.54 (0.35-0.84) in Q1, 0.62 (0.40-0.97) in Q2, 0.84 (0.54-1.31) in Q3, and 0.60 (0.38-0.95) in Q4. tBRCA status was available in 423 pts; proportion of pts with tBRCA mutations was comparable between treatment groups (~18%). PFS was longer with SG vs chemo in tBRCA WT and mut subgroups, with HR (95% CI) 0.70 (0.54-0.92) in tBRCA WT and 0.59 (0.32-1.09) in tBRCA mut. HER2 status was available in 551 pts; PFS was longer with SG vs chemo in both HER2 subgroups. HR was 0.63 (0.46-0.85) in the IHC 0 subgroup and 0.74 (0.55-1.01) in the HER2 Low subgroup. Conclusions: PFS was longer with SG vs chemo across all Trop-2 categories, tBRCA genotypes, and HER2 subgroups. These results reinforce the significant, clinically meaningful benefit of SG as first-line treatment for pts in this population across multiple biomarker subgroups. Clinical trial information: NCT05382299 . Efficacy, BICR N Median PFS (95% CI), months Biomarker Subgroup SG Chemo SG Chemo HR (95% CI) Trop-2(n = 499) Q1 68 55 8.5(5.6-12.7) 5.5(4.2-8.1) 0.54(0.35-0.84) Q2 60 62 8.3(5.6-12.4) 6.8(4.2-9.0) 0.62(0.40-0.97) Q3 50 74 9.7(7.6-11.3) 7.0(5.3-8.5) 0.84(0.54-1.31) Q4 74 56 9.9(6.9-NR) 8.1(4.4-8.5) 0.60(0.38-0.95) tBRCA(n = 423) WT 177 169 8.8(7.2-9.9) 6.9(5.4-8.3) 0.70(0.54-0.92) Mut 40 37 12.7(7.2-18.7) 8.3(5.6-11.2) 0.59(0.32-1.09) HER2(n = 551) IHC 0 115 138 8.3(6.9-10.3) 5.6(4.3-7.0) 0.63(0.46-0.85) Low 159 139 9.8(8.3-12.4) 8.3(5.7-9.7) 0.74(0.55-1.01)

Importance The BRIGHT-2 interim analysis demonstrated the efficacy of bireociclib plus fulvestrant in hormone receptor (HR)–positive, human epidermal growth factor receptor 2 ( ERBB2 ; previously HER2 )–negative advanced breast cancer (ABC) after endocrine therapy progression. This final analysis includes an additional 11-month follow-up. Objective To evaluate the efficacy and safety of bireociclib plus fulvestrant in HR-positive, ERBB2 -negative ABC. Design, Setting, and Participants This double-blind, placebo-controlled phase 3 randomized clinical trial was conducted at 64 hospitals in China between December 8, 2021, and October 24, 2022. Patients were enrolled and randomly assigned in a 2:1 to receive bireociclib plus fulvestrant or placebo plus fulvestrant. Data were analyzed from April 2024 to December 2025. Interventions Patients received bireociclib, 360 mg, or placebo orally every 12 hours in combination with fulvestrant, 500 mg, intramuscularly (days 1 and 15 of cycle 1, then day 1 of each 28-day cycle). Main Outcomes and Measures The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival, objective response rate, duration of response, and safety. Results Of 305 included patients, the mean (SD) age was 54.1 (10.2) years, and the median (IQR) follow-up at data cutoff was 19 (18.5-19.6) months. Patients were randomized to bireociclib plus fulvestrant (n = 204) or placebo plus fulvestrant (n = 101); 275 (90.2%) had measurable disease and 268 (87.9%) had received prior systemic chemotherapy. Bireociclib plus fulvestrant significantly prolonged PFS vs placebo (median PFS, 14.7 months [95% CI, 11.1-20.2] vs 7.3 months [95% CI, 5.5-11.0]; hazard ratio, 0.54; 95% CI, 0.40-0.74; P < .001). The objective response rate was higher (45.6% [95% CI, 38.6-52.7] vs 14.9% [95% CI, 8.6-23.3]) in the bireociclib group, with a prolonged median duration compared with placebo (not reached [95% CI, 11.1 to not reached] vs 13.1 months [95% CI, 10.2 to not reached]). Safety was consistent with the interim findings and the profiles of known cyclin-dependent kinase 4/6 inhibitors. Subgroup analyses across multiple patient characteristics (menopausal status, metastatic sites, prior treatment, disease-free interval, ESR1 / PIK3CA / TP53 alterations and others) showed consistent PFS improvements with bireociclib vs placebo. Patients with early-onset diarrhea appeared to derive more benefit from bireociclib (hazard ratio, 0.49; 95% CI, 0.36-0.68). Conclusions and Relevance The final analysis of the BRIGHT-2 randomized clinical trial confirms improved PFS with the addition of bireociclib to fulvestrant, with manageable safety as a treatment option for patients with HR-positive, ERBB2 -negative ABC with progression after prior endocrine therapy. Trial Registration ClinicalTrials.gov Identifier: NCT05077449

Background Diarrhea is the most common adverse event of pyrotinib. This study analyzed the association between diarrhea and survival in patients with HER2-positive advanced breast cancer treated with pyrotinib-based therapy. Methods A secondary analysis was performed using the individual patient data from the nationwide, prospective real-world PRETTY study. Baseline and treatment characteristics were summarized in groups by severity of diarrhea. Multivariable Cox regression analysis was used to analyze the association of diarrhea with real-world progression-free survival (rwPFS) and overall survival (OS), respectively. Immortal-time bias was adjusted using the landmark analysis and time-dependent Cox model. Multiple imputation was performed for missing data, and pooling ln(hazard ratio [HR]) estimations on the association between diarrhea and survival were reported. Results Of 1129 patients, 826 (73.2%) had any-grade treatment-related diarrhea (including 174 [15.4%] with grade ≥3 diarrhea). After multiple imputation, the multivariable Cox regression analysis showed that diarrhea was independently associated with longer OS (grade 1-2 diarrhea vs. none: HR=0.57 [95% CI, 0.38-0.86], P=0.007; grade ≥3 diarrhea vs. none: HR=0.56 [95% CI, 0.31-0.99], P=0.047) but was not associated with rwPFS. Significant association between diarrhea and OS was also observed in the 1-month landmark analysis (grade 1-2 diarrhea vs. none: HR=0.59 [95% CI, 0.39-0.89], P=0.012; grade ≥3 diarrhea vs. none: HR=0.54 [95% CI, 0.30-0.98], P=0.043). Time-dependent Cox model indicated the trend on better OS when diarrhea occurred, but without statistical significance. Conclusion For patients with HER2-positive advanced breast cancer, diarrhea that occurs during pyrotinib-based therapy maybe a prognostic marker of longer OS.

Abstract Background Although the novel cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor bireociclib demonstrated potent efficacy for hormone receptor -positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in the BRIGHT-2 study (NCT05077449), patient exhibited substantial heterogeneity in therapeutic efficacy—some demonstrated high sensitivity, while others rapidly developed resistance. Consequently, a critical research aim is to ascertain sensitivity before treatment initiation and define biomarkers that can dynamically detect therapeutic outcomes earlier than imaging. Methods Based on the BRIGHT-2 study, longitudinal circulating tumor DNA (ctDNA) analysis was performed using a 1021-gene panel at baseline, on-treatment, and end-of-treatment timepoints. Somatic mutations were identified and molecular tumor burden index (mTBI) was calculated. Survival analyses employed Kaplan-Meier curves with log-rank tests and Cox proportional hazards models, while the interaction analysis between treatment and gene alternations were conducted using False Discovery Rate (FDR) method. All the analyses were performed using R software, with statistical significance set at p<0.05. Results The bireociclib group collected 197, 139, and 86 ctDNA samples from three timepoints, compared with 79, 46, and 49 from placebo group. The most frequently mutated genes were PIK3CA (48%), TP53 (37%), and ESR1 (23%). Patients with ctDNA-positive or high mTBI had conspicuously shorter progression-free survival (PFS) and overall survival (OS) than those with ctDNA-negative or low mTBI. The gene alterations in CCND1 and FGF19 were associated with a greater PFS benefit with bireociclib versus placebo (FDR-adjusted P values of 0.030 and 0.002, respectively). The gBRCA and homologous recombination repair genes mutation indicated poorer prognosis compared to wild-type in bireociclib group. Dynamic clearance of ctDNA or specific gene mutations was correlated with improved efficacy and survival outcomes for CDK4/6 inhibitor. Conclusions Both baseline and dynamic monitoring of ctDNA demonstrated salient predictive value for treatment response and survival outcomes in hormone receptor-positive, HER2-negative breast cancer patients receiving bireociclib plus fulvestrant. These potential biomarkers warrant further validation through larger clinical trials and basic researches. Citation Format: Yan Wang, Hangcheng Xu, Yiran Zhou, Liang Cui, Qiang Sa, Hong Cheng, Renchi Gao, Qingyuan Zhang, HHiping Li, Zhongsheng Tong, Quchang Ouyang, Xinxin Tan, Jing Bai, Li Wang, Xianghui Duan, Fan Yang, Jiayu Wang, Binghe Xu. Dynamic monitoring and identification of reliable biomarkers to predict efficacy of bireociclib and fulvestrant: An exploratory ctDNA analysis of the BRIGHT-2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7633.

Purpose:The study aims to explore the predictive value of the Ki67 index for everolimus efficacy in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). Materials and Methods:We collected data on 2,518 cancer patients who received everolimus treatment from three cancer centers in China. Their clinicopathologic characteristics were retrospectively collected. A training cohort and a validation cohort were developed. Results:A total of 300 patients with HR+/HER2- ABC were included in the study, with 200 patients in the training cohort and 100 patients in the validation cohort. When analyzing the Ki67 index from 14% to 50%, only the Ki67 cut-off of 40% was found to be significantly correlated with progression-free survival (PFS) for patients in the training cohort. Multivariate Cox analyses further showed that Ki67 index of 40% (p=0.03) was significantly associated with PFS in patients treated with everolimus. Patients with Ki67 less than 40% had an improved PFS of 7.0 months, significantly better than 4.6 months for patients with Ki67 more than 40% (p=0.03, HR=0.67, 95CI%=0.46-0.97). In the validation cohort, patients with a Ki67 index of less than 40% had a significantly longer PFS of 4.3 months (2.1 months versus 4.3 months, p<0.001, HR=0.29, 95CI%=0.17-0.51). Conclusion:The Ki67 cut-off value of 40% was identified as an optimal index for predicting the efficacy of everolimus, which may help with the management of everolimus in Chinese patients with HR+/HER2- ABC.

Importance Approximately 70% of patients with breast cancer (BC) have hormone receptor–positive, human epidermal growth factor receptor 2 ( ERBB2 ; formerly HER2 )–negative disease. Objective To evaluate the efficacy and safety of fovinaciclib plus an aromatase inhibitor as first-line treatment for hormone receptor–positive, ERBB2 -negative advanced BC. Design, Setting, and Participants This double-blind, phase 3 randomized clinical trial enrolled patients from March 2, 2022, to June 28, 2023, from 63 centers in China. Eligible patients were adult women with hormone receptor–positive, ERBB2 -negative advanced BC and no history of systemic therapy for advanced disease. The data cutoff date was June 25, 2024. Data were analyzed from September to October 2024. Intervention Patients were randomized (1:1) to receive fovinaciclib, 200 mg (orally once daily on days 1 to 21), or placebo plus letrozole, 2.5 mg, or anastrozole, 1 mg (orally once daily on days 1 to 28), in 28-day cycles. Premenopausal or perimenopausal patients also received goserelin, 3.6 mg (subcutaneously on day 1). Main Outcomes and Measures The primary end point was progression-free survival (PFS) per blinded independent central review (BICR). Secondary end points included other efficacy end points and safety. Exploratory end points included overall survival (OS) and quality of life. Results Of 417 randomized female patients, the median (range) age was 57.0 (32-84) years. A total of 208 were randomized to the fovinaciclib arm and 209 to the placebo arm. At prespecified interim analysis (median [range] follow-up, 16.6 [0.3-27.8] months), a significantly prolonged median PFS was observed with fovinaciclib compared with placebo (not reached vs 20.2 months [95% CI, 16.4 months to not evaluable]; hazard ratio, 0.55; 95% CI, 0.38-0.77; 1-sided P < .001) per BICR assessments. Consistent PFS benefit was observed in most patient subgroups. Fovinaciclib was also favored across secondary efficacy end points. OS data were immature, with only 40 events (9.6%). The most common treatment-emergent adverse events were hematologic toxic effects, none of which led to serious adverse events or study drug discontinuation. Incidence of discontinuation due to treatment-emergent adverse events was only 1.4% in both arms (3 of 208 receiving fovinaciclib and 3 of 209 receiving placebo). Longitudinal changes in global health status, function domains, and symptom domains of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 were similar between the 2 arms. Conclusions and Relevance In this randomized clinical trial, adding fovinaciclib to first-line aromatase inhibitor conferred significant and clinically meaningful PFS benefit and consistent improvements in other efficacy outcomes, along with manageable safety and unaffected quality of life. Trial Registration ClinicalTrials.gov Identifier: NCT05439499

Vepdegestrant is an investigational, orally administered PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader being evaluated for the treatment of ER+/HER2- advanced breast cancer, with promising results in prior studies of Western and Japanese patients. Vepdegestrant had not been previously evaluated in Chinese patients. This phase 1 study (NCT05732428) assessed pharmacokinetics (PK) of vepdegestrant and its epimer (ARV-473), and safety and preliminary efficacy of vepdegestrant monotherapy (200 mg once daily [QD] in 28-day cycles) in Chinese adults with ER+/HER2- advanced breast cancer who had received ≥ 1 prior line of endocrine therapy. Nine female Chinese patients were treated (median age, 56.0 [range: 42.0–69.0] years; six received ≥ 3 prior anticancer therapies in the advanced setting). Geometric mean area under the plasma concentration–time curve over the dosing interval was 9575 ng*h/mL following a single dose and 18,340 ng*h/mL following multiple daily doses on day 15; maximum observed concentration of vepdegestrant was 633.2 ng/mL and 1035 ng/mL after single and multiple doses, respectively. Vepdegestrant was well tolerated. Most treatment-related adverse events (TRAEs) were grade 1 or 2. Two patients experienced grade 3 TRAEs; no patients discontinued due to AEs. Objective response and clinical benefit rates were 33.3

1090 Background: Endocrine therapy combined with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor is the standard first-line therapy for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Fovinaciclib is a novel CDK4/6 inhibitor that showed survival benefit when added to fulvestrant in the later-line setting. This randomized, double-blind, placebo-controlled phase 3 trial evaluated the efficacy and safety of fovinaciclib plus an aromatase inhibitor (AI) as initial therapy. Methods: Adult women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting were enrolled across 63 centers. Eligible patients were randomized in a 1:1 ratio to receive oral fovinaciclib (200 mg, once daily, days 1–21) or placebo plus an AI (letrozole 2.5 mg or anastrozole 1 mg, orally, once daily, days 1–28) in 28-day cycles. Pre- or perimenopausal patients also received goserelin (3.6 mg, subcutaneous, day 1). The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR). Secondary endpoints included other efficacy endpoints and safety. Results: A total of 417 patients were assigned to the fovinaciclib ( n = 208) or placebo arm ( n = 209) with balanced baseline characteristics. At the protocol-specified interim analysis (median follow-up 16.6 months, data cutoff date June 25, 2024), adding fovinaciclib significantly improved PFS (hazard ratio 0.55, 95% CI 0.38–0.77; p = 0.0003): median PFS was not reached in the fovinaciclib arm and 20.2 months (95% CI 16.4 months–not evaluable) in the placebo arm. The 2-year PFS rates were 65.5% (95% CI 55.3%–73.9%) and 38.9% (95% CI 27.5%–50.2%), respectively. Consistent PFS benefit was observed in investigator assessments (hazard ratio 0.49 [95% CI 0.36–0.68], p < 0.0001) and across most subgroups. Fovinaciclib also showed favorable results across secondary efficacy endpoints. OS data remain immature. Treatment-emergent adverse events (TEAEs) occurred in 207 (99.5%) and 199 (95.2%) patients in the fovinaciclib and placebo arms, respectively, with serious adverse events (SAEs) reported in 30 (14.4%) and 24 (11.5%). Discontinuation due to TEAEs was only 1.4% in both arms. The most common TEAEs were hematologic toxicities, which did not lead to SAEs or study drug discontinuation. Grade ≥3 gastrointestinal toxicities (2.4% versus 0) or renal toxicities (0 versus 0.5%) were rare. Conclusions: Adding fovinaciclib to first-line AI therapy provided a significant and clinically meaningful PFS benefit, along with consistent improvements in other survival outcomes and a manageable safety profile. These findings support fovinaciclib as a first-line treatment option for patients with HR-positive, HER2-negative advanced breast cancer. Clinical trial information: NCT05439499 .

Multidimensional breakthroughs reshaping treatment paradigm In 2025-2026,the most striking advances in breast cancer treatment center on the synergistic interplay between antibody-drug conjugates (ADCs) and refined molecular stratification. In the human epidermal growth factor receptor 2-positive (HER2+) arena,trastuzumab deruxtecan (T-DXd) continues to cement its cornerstone role:the DESTINY-Breast05 trial showed that adjuvant T-DXd reduced the hazard ratio (HR) for invasive disease-free survival (iDFS) to 0.47 in high-risk early HER2+disease,while DESTINY-Breast09 lowered the HR for progression-free survival (PFS) to 0.56 in first-line metastatic HER2+disease. In addition,the Chinese-led phase 3 PHILA trial demonstrated that pyrotinib plus trastuzumab and docetaxel as first-line treatment for HER2+metastatic breast cancer achieved a median PFS of 24.3 months vs. 10.4 months in the control group(HR=0.36) (1). More importantly,the benefit of T-DXd has extended to patients with HER2-low and HER2-ultralow expression,overturning the decades-old binary HER2 classification.