Background This study investigates the metabolic alterations associated with breast cancer progression and elucidates the underlying mechanisms. Adenine nucleotide translocase 2 (ANT2), a mitochondrial protein essential for cellular energy metabolism, facilitates the exchange of ADP and ATP across the inner mitochondrial membrane. The role of ANT2, particularly its interaction with the ATP synthasome, in breast cancer metastasis remains poorly understood. Methods We analyzed ANT2 in breast cancer using genetic and clinical methods, validating its expression in human tissues. Gene enrichment studies and functional assays assessed ANT2's role in mitochondrial function and cancer metabolism. Knockdown experiments and pharmacogenomic screening evaluated ANT2's impact on metastasis and identified potential inhibitors in 3D cultures and orthotopic mouse models. Results ANT2 was significantly overexpressed in metastatic breast cancer, correlating with reduced survival. Knockdown of ANT2 impaired cell migration and invasion, reduced ATP production, and diminished oxidative phosphorylation (OXPHOS) activity in MCF7-F4 cells. In vivo, siRNA-mediated ANT2 silencing in JC-M3 cells decreased tumor growth and lung metastases in mice. Pharmacogenomic analysis identified cymarin as an ANT2 inhibitor, reducing spheroid formation in 3D cultures and tumor burden in vivo, alongside downregulation of epithelial-to-mesenchymal transition (EMT) and OXPHOS markers. ANT2 colocalized with ATP5B, forming an ATP synthasome that enhanced energy flux in hyperinvasive cells. Conclusions ANT2 drives breast cancer metastasis by enhancing mitochondrial energy production via the ATP synthasome. Its inhibition, particularly with cymarin, disrupts tumor bioenergetics and metastatic potential, positioning ANT2 as a promising therapeutic target.

Hormone receptor-positive metastatic breast cancer remains a major clinical burden and is characterized by sequential endocrine resistance over the disease course. In 2023, the Taiwan Breast Cancer Society (TBCS) published an expert consensus to support real-world decision-making in Taiwan. Subsequently, rapid advances in biomarker-informed strategies (e.g., estrogen receptor 1 and PI3K/AKT pathway alterations), endocrine partners, estrogen receptor (ER)-targeting agents (including oral selective ER degraders and emerging protein degraders), and the expanding role of antibody-drug conjugates based on human epidermal growth factor receptor 2 expression categories have materially increased the complexity of treatment selection and sequencing. Therefore, TBCS convened an expert panel to update the previous consensus while preserving its foundational framework and eight-chapter structure: risk evaluation and biomarker testing (I/II), first-line treatment selection (I/II), second-line treatment selection (I/II), and treatment options other than endocrine-based approaches (I/II). A multidisciplinary panel conducted a systematic literature review and iterative discussions using a modified Delphi process to identify the key clinical questions, update and refine statements where new evidence was practice-changing, and maintain continuity with the 2023 Consensus. The panel formulated updated recommendations, assigned levels of evidence and strengths of recommendations, and the key updates were integrated into practical treatment algorithms reflecting Taiwan's practice considerations. This updated consensus provides a continuity-based, yet evidence-responsive framework to facilitate the integration of emerging therapies into clinical practice in Taiwan and the Asia-Pacific region.

ABSTRACT Background Cyclin‐dependent kinase (CDK) 4/6 inhibitors are standard for treating hormone receptor‐positive metastatic breast cancer when combined with endocrine therapy. However, comparisons of first‐line treatments are scarce. Aims In this retrospective study, we aimed to determine the effects and safety of ribociclib and palbociclib as first‐line treatments for metastatic hormone receptor‐positive breast cancer in real‐world settings at two tertiary medical centers. Methods and Results This retrospective observational study, conducted in two tertiary medical centers, included patients receiving palbociclib or ribociclib in combination with endocrine therapy. Treatment responses were assessed by imaging studies according to RECIST 1.1 criteria. The primary endpoint was 24‐month progression‐free survival (PFS). Safety outcomes were also recorded and compared between the treatment groups. The median follow‐up times for the ribociclib and palbociclib groups were 19.7 and 24.6 months, respectively. The 24‐month PFS rates were comparable between the ribociclib and palbociclib cohorts (55.4% vs. 55.2%, respectively; hazard ratio [HR] = 1.110, 95% confidence interval [CI]: 0.605–2.035; p = 0.736), but the objective response rate was significantly higher in the palbociclib group than in the ribociclib group (43.2% vs. 30.2%, p = 0.035). A high rate of dose reduction was observed in both cohorts due to treatment‐related toxicities (41.2% in the palbociclib group vs. 47.2% in the ribociclib group). The adverse effect profiles were comparable, although the incidence of grade 1 fatigue was slightly higher in the ribociclib group than in the palbociclib group ( p = 0.043). Conclusion In Taiwanese real‐world practice, ribociclib and palbociclib demonstrated comparable 24‐month efficacy. Our findings show that dose reductions do not compromise targeted treatment efficacy, supporting proactive toxicity‐guided dose to optimize patient tolerability without sacrificing oncological outcomes in Asian populations.

Purpose: Breast cancer is the most common cancer among females in Taiwan, accounting for 28.5% of all newly diagnosed cancers in women. The risk of breast cancer can vary from person to person and is influenced by a combination of genetic, environmental, and lifestyle factors. Currently, mammography was the main modality of breast cancer screening in Taiwan. A polygenic risk score (PRS) is a numerical score that is calculated based on an individual's genetic information, specifically their DNA sequence variants, in order to estimate their risk for developing a particular disease or condition. To calculate a PRS, genetic variants that have been identified as being associated with the disease or trait of interest are combined and weighted according to their effect sizes. These effect sizes represent the strength of the association between the genetic variant and the disease or trait. The weighted genetic variants are then summed to create an overall score that represents an individual's genetic risk for the disease or trait. We designed a prospectively study to recall the patients with high PRS for receiving breast examination to determinate the correlation of PRS and breast cancer in Taiwan and demonstrate the real world practice. Materials and Methods: The PRS of the study were estimated using genotyping data from the Taiwan Precision Medicine Initiative (registered number SF19153A). We supposed top 10% population (totally 1001 patients) for the definition of high PRS, and targeted the patient between 35 to 60 years old. We tried to call back these patients to receive breast examination since 1st April, 2023, and collected their baseline characteristics by structured questionnaire. Breast sonography is the main modality for examination, if the patient is older than 45 years old or 40 years old with family history of breast cancer, mammography is also performed. Results: Total 599 patients between 35 to 60 years old were selected as high PRS. We contacted all of them, but only 140 patients (23.5%) came back to our hospital and received breast examination. The other patients refused to receive examination (n=69, 11.5%), visited other hospital (n=60, 10%), or had incomplete contact information (n=330, 55%). The median age of these 140 patients was 46.7 years old, and the youngest patient was 39 years old. Eventually, 5 cases (3.6%) were diagnosed as breast cancer. Family history of cancer, menopause status, exposure to contraceptive agents, less times of pregnancy and delivery, lack of exercise, and alcohol consumption seemed like risk factors for breast cancer in this screening program, but had no statistically significant difference. Conclusion: In real world practice, it was still a predicament that the called-back rate of PRS breast cancer screen program was still low (23.5%). Nevertheless, the breast cancer detection rate for high PRS in our study was 3.6%, which is higher than the mammography-based screening program in Taiwan (0.5%). There is a long way to go to promote this program and make it a useful and effective tool for breast cancer screening. Citation Format: Yu-Wen Weng, I-Chen Tsai, Jie-Ru Yang, Tzu-Hung Hsiao, Chih-Chiang Hung, Chia-Hua Liu. The Real World Practice of Prospectively Breast Cancer Screening Program for High Polygenic Risk Score Population in Taiwan [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-10-13.

BACKGROUND:Breast cancer treatments often have negative effects on fertility, which pose challenges among patients who want to be parents in the future. This study aimed to examine the efficacy of oocyte cryopreservation, embryo cryopreservation, and ovarian tissue cryopreservation in patients with breast cancer. METHODS:This retrospective review evaluated 42 patients with breast cancer who underwent fertility preservation at our center from January 2012 to December 2022. This review encompassed the demographic characteristics of the patients, cancer stages, treatment details, and types of fertility preservation procedures and their outcomes. RESULTS:The average age at disease diagnosis was 33.4 years. Approximately 90.4% of patients presented with early-stage cancer (≤2). Of 42 patients, 26 underwent oocyte cryopreservation; 17, embryo cryopreservation; and 2, ovarian tissue cryopreservation. Further, three patients received mixed treatment. The overall live birth rate was 63.2%. There are more live births in embryo cryopreservation group. The successful pregnancy group was significantly younger and had a remarkably higher quantity of preserved oocytes/embryos than the nonsuccessful pregnancy group. The oocyte and embryo utilization rates in cryopreservation were 7.69% and 52.94%, respectively. These findings underscored the importance of prompt, informed discussions about fertility preservation options. CONCLUSION:Fertility preservation in patients with breast cancer have promising reproductive outcomes, with embryo cryopreservation being particularly effective. Prompt counseling and individualized fertility preservation strategies are important for improving the likelihood of posttreatment pregnancy. Nevertheless, future research on the long-term psychological and emotional effects of different fertility preservation methods must be performed.

BACKGROUND/AIM:Matrix metalloproteinase-9 (MMP-9) has been associated with the development and progression of breast cancer (BCa). However, the relationship between MMP-9 genetic variants and BCa susceptibility remains contentious and inconclusive. This study aimed to evaluate the association of MMP-9 rs3918242 promoter polymorphisms with BCa, with a particular focus on the risk of triple-negative breast cancer (TNBC). MATERIALS AND METHODS:A case-control study was conducted involving 1,232 BCa patients and 1,232 healthy controls. The MMP-9 rs3918242 genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS:The genotype distribution of MMP-9 rs3918242 among the control group adhered to Hardy-Weinberg equilibrium (p=0.3265). No statistically significant differences were observed in the genotype frequencies between BCa cases and controls (p for trend=0.2555). Although the homozygous variant genotype (TT) showed a potential risk-increasing effect, this was not statistically significant [odds ratio (OR)=1.43, 95% confidence interval (CI)=0.88-2.36, p=0.1869]. Similarly, allele frequency analysis indicated no significant association between the variant T allele and overall BCa risk (OR=1.13, 95%CI=0.97-1.33, p=0.1265). Additionally, no interaction was detected between MMP-9 rs3918242 genotypes and the age of BCa onset (both p>0.05). Notably, the TT genotype of MMP-9 rs3918242 was significantly associated with an increased risk of TNBC (OR=2.49, 95%CI=1.32-4.72, p=0.0072). CONCLUSION:The MMP-9 rs3918242 TT genotype may serve as a potential predictive biomarker for TNBC in the Taiwanese population.

BACKGROUND/AIM:Breast cancer (BC) remains the leading cause of cancer-related mortality among women worldwide. Interleukin-12 (IL-12), a cytokine pivotal in immune regulation, has shown antitumor properties and may contribute to BC pathogenesis. MATERIALS AND METHODS:This study investigated the association between IL-12B rs3212227 polymorphism and BC risk in a Taiwanese population comprising 1,232 BC patients and 1,232 age-matched cancer-free controls. RESULTS:Genotype frequencies among controls conformed to Hardy-Weinberg equilibrium (p=0.0581). Compared to the AA genotype, carriers of the AC (OR=0.88, 95%CI=0.73-1.06, p=0.2105) and CC (OR=0.84, 95%CI=0.68-1.04, p=0.1307) genotypes exhibited a non-significant reduction in BC susceptibility. Similarly, neither dominant (AC+CC versus AA: OR=0.87, 95%CI=0.73-1.03, p=0.1225) nor recessive (CC versus AA+AC: OR=0.90, 95%CI=0.75-1.09, p=0.3198) models reached statistical significance. Allelic analysis showed a marginally reduced risk associated with the C allele (OR=0.91, 95%CI=0.81-1.02, p=0.1038). Notably, age-stratified analysis revealed significant protective effects of the AC (OR=0.79, 95%CI=0.64-0.98, p=0.0331) and CC (OR=0.68, 95%CI=0.52-0.87, p=0.0034) genotypes in individuals aged ≤55 years, but not in older subjects. No significant associations were found between IL-12B rs3212227 and risk of triple-negative BC (TNBC) or non-TNBC subtypes (p for trend=0.2072 and 0.8291, respectively). CONCLUSION:IL-12B rs3212227 is not a major genetic determinant of overall BC susceptibility in this population but may exert age-dependent protective effects. Further studies integrating IL-12 expression profiling and additional IL-12 pathway variants are warranted to clarify the immunogenetic basis of BC.

Recurrent breast cancer survivors often experience diverse symptom clusters (SCs) that impact their quality of life (QOL). Identifying these SCs is essential for developing targeted interventions to improve symptom management and care. This study aimed to identify and compare SCs in recurrent breast cancer survivors with local-regional and distant recurrence. In this cross-sectional study, adult women diagnosed with recurrent breast cancer within the past 10 years completed the National Comprehensive Cancer Network-Breast Cancer Symptom Index Questionnaire-16. Latent profile analysis (LPA), guided by the Bayesian Information Criterion, identified distinct SCs based on groups of individuals with similar symptom patterns. Symptom frequency and severity were analyzed to determine the predominant symptoms for each recurrence type. This study analyzed data from 165 recurrent breast cancer survivors. Among participants with local-regional recurrence, 2 distinct SCs were identified, with sleep disturbances and worsening worry being the most prominent symptoms. By contrast, 3 SCs emerged among those with distant recurrence. While no single symptom was universally predominant, pain and sleep disturbances were consistently present in 2 of the 3 clusters for this group. This study highlights the utility of LPA in identifying distinct SCs among recurrent breast cancer survivors, linked to local-regional and distant recurrence. The findings suggest that healthcare providers should prioritize managing sleep disturbances and worsening worry in survivors with local-regional recurrence, and pain and sleep disturbances in those with distant recurrence. Addressing these SCs through personalized care strategies may improve QOL for this population.

Background: Triple-negative breast cancer (TNBC) is associated with a poor prognosis. The KEYNOTE-522 study established the combination of pembrolizumab and neoadjuvant chemotherapy (NAC) as the recommended treatment for early TNBC. However, real-world evidence, especially in the Taiwanese population, is lacking. This multicenter retrospective study aimed to identify clinical characteristics and treatment variables associated with response to pembrolizumab plus NAC in early TNBC. Methods: We retrospectively reviewed the multicenter medical records of patients with early TNBC who were treated with pembrolizumab plus NAC between May 2018 and October 2023. The primary endpoint was pathologic complete response (pCR). Kaplan-Meier curves were used to evaluate event-free survival (EFS) and overall survival (OS). Statistical analyses included two-sample t-test, chi-square test, and univariate analysis with a significance threshold of 0.05. Results: Among the 72 patients in our study, the pCR rate was 51.4% (37/72). Median age at diagnosis was 50.5 years old (IQR 43.5–57.6), and mean body weight showed 58.1±9.4 kg. The rates of pCR for Stage II and Stage III patients were 56% and 41%, respectively. Kaplan-Meier curves for EFS according to pCR status after neoadjuvant treatment demonstrated a significant difference (log-rank test p = 0.003), although no significant difference was observed in overall survival (OS) with a median follow-up of 1.6 years (IQR 1.0–2.3). The probability of recurrence events was significantly associated with pCR (p = 0.001). In the pCR group, the recurrence rate was 0% (0/37), whereas in the non-pCR group, it was 25.7% (9/35). Additionally, optimizing neoadjuvant pembrolizumab dosage in a 100 mg setting of patients showed a remarkable difference in pCR rate, achieving 68% (p = 0.01) with a per-weight dose exceeding 1.8 mg/kg. Only achieve four NAC cycles of anthracyclines along with cyclophosphamide were shown to be substantially linked with achieving pCR, with a rate of 88% (p = 0.023) in univariate analysis. Conclusions: This real-world study provides valuable insights into the efficacy and tolerability of pembrolizumab in early TNBC. It highlights the importance of optimizing neoadjuvant pembrolizumab dosage to a per-weight dose exceeding 1.8 mg/kg in the 100 mg setting, which significantly improves the pCR rate and the completion of AC regimen cycles necessary for achieving pCR in Asian patients with early TNBC. Citation Format: Yu-Ting Lin, Liang-Chih Liu, Chin-Yao Lin, Chiann-Yi, Hsu, Chih-Chiang Hung, Ting-Yi, Liao. Effectiveness of Combined Neoadjuvant Pembrolizumab and Chemotherapy in Early Triple-Negative Breast Cancer: Real-World Evidence from Multiple Centers in Asia [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-08-13.

Background/Objectives: This research presents a novel analytical method for breast tumor characterization and tissue classification by leveraging intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) combined with hyperspectral imaging techniques and deep learning. Traditionally, dynamic contrast-enhanced MRI (DCE-MRI) is employed for breast tumor diagnosis, but it involves gadolinium-based contrast agents, which carry potential health risks. IVIM imaging extends conventional diffusion-weighted imaging (DWI) by explicitly separating the signal decay into components representing true molecular diffusion (D) and microcirculation of capillary blood (pseudo-diffusion or D*). This separation allows for a more comprehensive, non-invasive assessment of tissue characteristics without the need for contrast agents, thereby offering a safer alternative for breast cancer diagnosis. The primary purpose of this study was to evaluate different methods for breast tumor characterization using IVIM-DWI data treated as hyperspectral image stacks. Dice similarity coefficients and Jaccard indices were specifically used to evaluate the spatial segmentation accuracy of tumor boundaries, confirmed by experienced physicians on dynamic contrast-enhanced MRI (DCE-MRI), emphasizing detailed tumor characterization rather than binary diagnosis of cancer. Methods: The data source for this study consisted of breast MRI scans obtained from 22 patients diagnosed with mass-type breast cancer, resulting in 22 distinct mass tumor cases analyzed. MR images were acquired using a 3T MRI system (Discovery MR750 3.0 Tesla, GE Healthcare, Chicago, IL, USA) with axial IVIM sequences and a bipolar pulsed gradient spin echo sequence. Multiple b-values ranging from 0 to 2500 s/mm2 were utilized, specifically thirteen original b-values (0, 15, 30, 45, 60, 100, 200, 400, 600, 1000, 1500, 2000, and 2500 s/mm2), with the last four b-value images replicated once for a total of 17 bands used in the analysis. The methodology involved several steps: acquisition of multi-b-value IVIM-DWI images, image pre-processing, including correction for motion and intensity inhomogeneity, treating the multi-b-value data as hyperspectral image stacks, applying hyperspectral techniques like band expansion, and evaluating three tumor detection methods: kernel-based constrained energy minimization (KCEM), iterative KCEM (I-KCEM), and deep neural networks (DNNs). The comparisons were assessed by evaluating the similarity of the detection results from each method to ground truth tumor areas, which were manually drawn on DCE-MRI images and confirmed by experienced physicians. Similarity was quantitatively measured using the Dice similarity coefficient and the Jaccard index. Additionally, the performance of the detectors was evaluated using 3D-ROC analysis and its derived criteria (AUCOD, AUCTD, AUCBS, AUCTD-BS, AUCODP, AUCSNPR). Results: The findings objectively demonstrated that the DNN method achieved superior performance in breast tumor detection compared to KCEM and I-KCEM. Specifically, the DNN yielded a Dice similarity coefficient of 86.56% and a Jaccard index of 76.30%, whereas KCEM achieved 78.49% (Dice) and 64.60% (Jaccard), and I-KCEM achieved 78.55% (Dice) and 61.37% (Jaccard). Evaluation using 3D-ROC analysis also indicated that the DNN was the best detector based on metrics like target detection rate and overall effectiveness. The DNN model further exhibited the capability to identify tumor heterogeneity, differentiating high- and low-cellularity regions. Quantitative parameters, including apparent diffusion coefficient (ADC), pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (PF), were calculated and analyzed, providing insights into the diffusion characteristics of different breast tissues. Analysis of signal intensity decay curves generated from these parameters further illustrated distinct diffusion patterns and confirmed that high cellularity tumor regions showed greater water molecule confinement compared to low cellularity regions. Conclusions: This study highlights the potential of combining IVIM-DWI, hyperspectral imaging techniques, and deep learning as a robust, safe, and effective non-invasive diagnostic tool for breast cancer, offering a valuable alternative to contrast-enhanced methods by providing detailed information about tissue microstructure and heterogeneity without the need for contrast agents.

Background: Imlunestrant is a next-generation, brain-penetrant, oral SERD and pure estrogen receptor (ER) antagonist that delivers continuous ER inhibition, including in ESR1-mutant cancers. Methods: This phase-3, randomized, open-label trial (NCT04975308) enrolled patients (pts) with ER+, HER2- ABC that recurred or progressed on/after an aromatase inhibitor, alone or with a CDK4/6 inhibitor (CDK/6i). No other prior therapy for ABC was allowed. Pts were randomized 1:1:1 to imlunestrant (400 mg once daily [QD]), physician’s choice standard-of-care (SOC) ET (fulvestrant or exemestane per label), or imlunestrant (400 mg QD) + abemaciclib (150 mg twice daily). Primary endpoints were investigator-assessed PFS of imlunestrant vs SOC in pts with ESR1 mutations (ESR1m) and all pts and of imlunestrant + abemaciclib vs imlunestrant in all concurrently randomized pts. Secondary endpoints included OS (tested if the corresponding PFS was statistically significant), PFS by BICR, ORR, and safety. Results: Overall, 874 pts were randomized (imlunestrant, n=331; SOC, n=330; imlunestrant + abemaciclib, n=213), 60% received prior CDK4/6i (imlunestrant, 59%; SOC, 57%; imlunestrant + abemaciclib, 65%). A total of 256 pts had ESR1m (imlunestrant, n=138; SOC, n=118). Imlunestrant significantly improved PFS vs SOC in pts with ESR1m (HR, 0.62; 95% CI, 0.46-0.82; P<0.001; median PFS [mPFS] 5.5 vs 3.8 months). Imlunestrant did not significantly improve PFS in the overall population (n=661; HR, 0.87; 95% CI, 0.72-1.04; P=0.12). Imlunestrant + abemaciclib significantly improved PFS vs imlunestrant in all pts (n=426; HR, 0.57; 95% CI, 0.44-0.73; P<0.001; mPFS 9.4 vs 5.5 months), with benefit observed regardless of ESR1m or PI3K pathway mutation status and in CDK4/6i pretreated pts. Investigator and BICR assessments were consistent across all endpoints. In all pts with measurable disease, ORR was 12% for imlunestrant; 8% for SOC; and 27% for imlunestrant + abemaciclib. All OS analyses were immature and ongoing; favorable trends were observed for imlunestrant vs SOC in pts with ESR1m (31% events; HR, 0.55; 95% CI, 0.35-0.86; P<0.01 [not statistically significant]) and in all pts (23% events; HR, 0.69; 95% CI, 0.50-0.96; [not inferentially tested]). OS analyses were less mature for imlunestrant + abemaciclib vs imlunestrant (15% events; HR, 1.34; 95% CI, 0.81-2.21; P=0.25). In post-hoc analyses, imlunestrant had lower 12-month cumulative incidence of central nervous system progression vs SOC in pts with ESR1m (2% vs 7%; HR, 0.18; 95% CI, 0.04-0.90) and all pts (2% vs 3%; HR, 0.47; 95% CI, 0.16-1.38), though absolute numbers were small. Common all-grade TEAEs with imlunestrant were fatigue (23% vs 13% SOC), diarrhea (21% vs 12%), and nausea (17% vs 13%), mostly grade 1. Notably, all-grade bradycardia (2% vs 0% SOC), photopsia (0% each), and dyslipidemia (7% vs 9%) were infrequent or not observed with imlunestrant. Common grade ≥3 TEAEs with imlunestrant were anemia (2% vs 3% SOC), and neutropenia (2% each). Common all-grade/grade ≥3 TEAEs with imlunestrant + abemaciclib were diarrhea (86%/8%), nausea (49%/2%), and neutropenia (48%/20%). Grade ≥3 TEAEs rates were 17% for imlunestrant, 21% for SOC and 49% for imlunestrant + abemaciclib. Discontinuation of imlunestrant and imlunestrant + abemaciclib due to AEs was low (4% and 6%, respectively). Conclusion: Imlunestrant significantly improved PFS vs SOC in pts with ESR1m, and imlunestrant + abemaciclib significantly improved PFS vs imlunestrant in all pts regardless of ESR1m status. Imlunestrant had a favorable safety profile alone and combined with abemaciclib, thus providing an all-oral targeted therapy option for ET-pretreated pts with ER+, HER2- ABC. Citation Format: Komal Jhaveri, Patrick Neven, Monica Lis Casalnuovo, Sung-Bae Kim, Eriko Tokunaga, Philippe Aftimos, Cristina Saura, Joyce O’Shaughnessy, Nadia Harbeck, Lisa A. Carey, Giuseppe Curigliano, Antonio Llombart-Cussac, Elgene Lim, María de la Luz García Tinoco, Joohyuk Sohn, André Mattar, Qingyuan Zhang, Chiun-Sheng Huang, Chih-Chiang Hung, Jorge Luis Martinez Rodriguez, Manuel Ruiz Borrego, Rikiya Nakamura, Kamnesh R. Pradhan, Christoph Cramer von Laue, Emily Barrett, Shanshan Cao, Xuejing Aimee Wang, Lillian M. Smyth, François-Clément Bidard. Imlunestrant, an Oral Selective Estrogen Receptor Degrader (SERD), as Monotherapy & Combined with Abemaciclib, for Patients with ER+, HER2- Advanced Breast Cancer (ABC), Pretreated with Endocrine Therapy (ET): Results of the Phase 3 EMBER-3 trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr GS1-01.

Preclinical evaluation of anticancer drug efficacy utilizes 2D cell culture systems, tumoroids or experimental animal models, but it suffers from limitations such as inaccurate simulation of tumor microenvironments in living tumors, difficulty in regional analysis, and low throughput. Therefore, in this study, we developed a system named tumor-microenvironment-on-chip (TMoC) comprising a 3D dynamic tumor tissue culture system, which recreated diverse and heterogeneous cellular tumor microenvironments. In addition to the culture with a dynamic circulation, TMoC allowed users to perform real-time regional analysis, independently assessing the drug response from the normoxic area to the hypoxic area in a gradient manner. Through cell composition analysis and gene analysis, we proved that TMoC has a tumor environment with close resemblance to the original tumor environment. By comparing 15 drug testing results with animal experiments, we proved that TMoC is 93% consistent with the response results of animal experiments. In addition, we confirmed that either mouse- or patient-derived tumor cell lines can be cultured and tested in TMoC, indicating its immense potential for all aspects of preclinical drug evaluation.

Mammographic screening has contributed to a significant reduction in breast cancer mortality. Several studies have highlighted the correlation between breast density, as detected through mammography, and a higher likelihood of developing breast cancer. A polygenic risk score (PRS) is a numerical score that is calculated based on an individual's genetic information. This study aims to explore the potential roles of PRS as candidate markers for breast cancer development and investigate the genetic profiles associated with clinical characteristics in Asian females with dense breasts. This is a retrospective cohort study integrated breast cancer screening, population genotyping, and cancer registry database. The PRSs of the study cohort were estimated using genotyping data of 77 single nucleotide polymorphisms based on the PGS000001 Catalog. A subgroup analysis was conducted for females without breast symptoms. Breast cancer patients constituted a higher proportion of individuals in PRS Q4 (37.8% vs. 24.8% in controls). Among dense breast patients with no symptoms, the high PRS group (Q4) consistently showed a significantly elevated breast cancer risk compared to the low PRS group (Q1–Q3) in both univariate (OR = 2.25, 95% CI 1.43–3.50, P < 0.001) and multivariate analyses (OR: 2.23; 95% CI 1.41–3.48, P < 0.001). The study was extended to predict breast cancer risk using common low-penetrance risk variants in a PRS model, which could be integrated into personalized screening strategies for Taiwanese females with dense breasts without prominent symptoms.

Abstract Introduction: Breast cancer is the most common cancer among women in Taiwan and the incidence rate of breast cancer has been increasing steadily over the past 30 years. To address this, a nationwide screening program with biennial mammography for women aged 40-69 was implemented in 2004, which has contributed to a significant reduction in breast cancer mortality. Asian women are more likely to have dense breast tissue, and studies have shown a correlation between breast density and the risk of developing breast cancer, with higher breast density values associated with increased risk. Polygenic risk scores (PRS) are calculated based on an individual's genetic information and can estimate their risk of developing a particular disease. Although PRS can identify low-penetrance risk variants, its use in breast cancer risk estimation is typically limited to gene-only models, and integration with breast cancer screening databases is rare. Hence, the aim of this specific study was to evaluate the predictive capacity of PRS in women with dense breast tissue by exploring potential genetic markers and constructing a PRS to investigate the genetic factors associated with clinical characteristics and the risk of developing breast cancer. Methods: The PRS was developed using genetic information from the Taiwan Precision Medicine Initiative genotyping data. A total of 6335 patients were enrolled, and 101 single nucleotide polymorphisms (SNPs) were selected as candidate markers based on the PGS Catalog (PGS000001). Clinical characteristics of the study cohort were summarised using median and range, or frequency and percentage. The distribution of characteristics between breast cancer and controls was estimated using an independent two-sample t-test, chi-square, and Fisher’s exact test. The association of the PRS and related characteristics with breast cancer risk in the study cohort was estimated using univariate and multivariate binomial logistic regression. Harrel’s C-index was reported to demonstrate the predictive performance of PRS in both univariate and multivariate models. All p-values were two-sided, and a p less than .05 is considered statistically significant. All analyses were performed using R 4.1.2 (R core team, 2023) Results: The results showed that breast cancer patients constituted a higher proportion of individuals in PRS Q4 (37.8% vs 24.8% in controls). The model's predictive performance for breast cancer risk increased from 0.565 (95% CI = 0.520-0.611) to 0.699 (95% CI = 0.644-0.755) by adding related clinical characteristics compared to the PRS-only model. Patients characterized with benign breast disease (OR = 0.50, 95% CI = 0.31-0.79, P = 0.004) showed a decreased breast cancer risk, and patients with mastalgia or palpable breast lesion (OR = 6.87, 95% CI = 4.29-10.8, P < 0.001) predicted significant greater breast cancer risk. Subgroup analysis of patients without breast symptoms was conducted as they may be overlooked or underestimated for breast cancer screening. For dense breast patients without symptoms, the high PRS group (Q4) consistently showed a significantly elevated breast cancer risk compared to the low PRS group (Q1-Q3) in both univariate (OR = 2.25, 95% CI = 1.43-3.50, P < 0.001) and multivariate analyses (OR = 2.22, 95% CI = 1.41-3.46, P < 0.001). Conclusion: Breast cancer screening has undergone a shift from a general approach to a personalized, risk-based approach. Besides breast cancer screening using family history as the only risk factor, our proposed model identifies both genetic and clinical risk factors using big data analyses including the EHR, cancer screening, and registry from a single institute. The study suggests that integrating PRS into personalized screening strategies could improve risk prediction for Taiwanese females with dense breasts without prominent symptoms. Table 1. Clinical characteristics of study cohort (n=6335). Table 2. Association of the PRS quartiles in breast cancer risk. Table 3. Predictive performance of PRS for breast cancer risk. Citation Format: Chih Yean Lum, Chih Chiang Hung, Chi-Cheng Huang, Tzu-Hung Hsiao, Sin-Hua Moi. Breast cancer risk prediction performance of polygenic risk score in Taiwanese female with dense breast: A nested case-control study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-10.

BACKGROUND:Imlunestrant is a next-generation, brain-penetrant, oral selective estrogen-receptor (ER) degrader that delivers continuous ER inhibition, even in cancers with mutations in the gene encoding ERα (ESR1). METHODS:In a phase 3, open-label trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer that recurred or progressed during or after aromatase inhibitor therapy, administered alone or with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Patients were assigned in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy, or imlunestrant-abemaciclib. Primary end points were investigator-assessed progression-free survival with imlunestrant as compared with standard therapy among patients with ESR1 mutations and among all patients and with imlunestrant-abemaciclib as compared with imlunestrant among all patients who had undergone randomization concurrently. RESULTS:Overall, 874 patients underwent randomization, with 331 assigned to imlunestrant, 330 to standard therapy, and 213 to imlunestrant-abemaciclib. Among 256 patients with ESR1 mutations, the median progression-free survival was 5.5 months with imlunestrant and 3.8 months with standard therapy. The estimated restricted mean survival time at 19.4 months was 7.9 months (95% confidence interval [CI], 6.8 to 9.1) with imlunestrant and 5.4 months (95% CI, 4.6 to 6.2) with standard therapy (difference, 2.6 months; 95% CI, 1.2 to 3.9; P<0.001). In the overall population, the median progression-free survival was 5.6 months with imlunestrant and 5.5 months with standard therapy (hazard ratio for progression or death, 0.87; 95% CI, 0.72 to 1.04; P = 0.12). Among 426 patients in the comparison of imlunestrant-abemaciclib with imlunestrant, the median progression-free survival was 9.4 months and 5.5 months, respectively (hazard ratio, 0.57; 95% CI, 0.44 to 0.73; P<0.001). The incidence of grade 3 or higher adverse events was 17.1% with imlunestrant, 20.7% with standard therapy, and 48.6% with imlunestrant-abemaciclib. CONCLUSIONS:Among patients with ER-positive, HER2-negative advanced breast cancer, treatment with imlunestrant led to significantly longer progression-free survival than standard therapy among those with ESR1 mutations but not in the overall population. Imlunestrant-abemaciclib significantly improved progression-free survival as compared with imlunestrant, regardless of ESR1-mutation status. (Funded by Eli Lilly; EMBER-3 ClinicalTrials.gov number, NCT04975308.).

BACKGROUND/AIM:Matrix metalloproteinase-2 (MMP-2) has been implicated in the pathogenesis of breast cancer (BC). However, there is limited research on the role of MMP-2 genotypes in BC risk. This study aimed to investigate the associations between two MMP-2 promoter polymorphisms, rs243865 and rs2285053, and BC risk. MATERIALS AND METHODS:MMP-2 genotypes were analyzed using PCR-based RFLP methodology in a cohort comprising 1,232 BC cases and 1,232 controls. RESULTS:Genotypic frequencies of MMP-2 rs243865 and rs2285053 in controls were consistent with Hardy-Weinberg equilibrium (p=0.3702 and 0.2036, respectively). There were no significant differences in the distribution of rs243865 and rs2285053 genotypes between BC cases and controls (p for trend=0.1602 and 0.2170, respectively). Variant genotypes at rs243865 and rs2285053 appeared to confer a protective effect, although not statistically significant (all p>0.05). Similarly, the variant T allele at rs243865 and rs2285053 showed a non-significant trend towards decreased BC risk (OR=0.84 and 0.89, 95%CI=0.69-1.02 and 0.78-1.02, p=0.0811 and 0.1043, respectively). There was no interaction observed between MMP-2 rs243865 or rs2285053 genotypes and age. Stratified analysis did not reveal significant associations between MMP-2 rs243865 or rs2285053 genotypes and triple-negative breast cancer (TNBC) (p=0.6458 and 0.8745, respectively). Among both TNBC and non-TNBC cases, none of the variant genotypes at rs243865 or rs2285053 showed significant associations with TNBC (all p>0.05). CONCLUSION:MMP-2 rs243865 and rs2285053 genotypes appear to have a minimal impact on individual susceptibility to BC or TNBC.

Tissue inhibitor of metalloproteinase-2 (TIMP-2) is an endogenous inhibitor of matrix metalloproteinase-2 and is highly expressed in breast cancer (BC) cases at diagnosis. However, the genetic investigations for the association of TIMP-2 genotypes with BC risk are rather limited. In this study, contribution of TIMP-2 rs8179090, rs4789936, rs2009196 and rs7342880 genotypes to BC risk was examined among Taiwan’s BC population. TIMP-2 genotypic profiles were revealed among 1232 BC cases and 1232 controls about their contribution to BC using a PCR-based RFLP methodology. The TIMP-2 rs8179090 homozygous variant CC genotype was significantly higher in BC cases than controls (odds ratio (OR) = 2.76, 95% confidence interval (95%CI) = 1.78–4.28, p = 0.0001). Allelic analysis showed that C allele carriers have increased risk for BC (OR = 1.39, 95%CI = 1.20–1.62, p = 0.0001). Genotypic together with allelic analysis showed that TIMP-2 rs4789936, rs2009196 or rs7342880 were not associated with BC risk. Stratification analysis showed that TIMP-2 rs8179090 genotypes were significantly associated with BC risk among younger (≤55) aged women, not among those of an elder (>55) age. Last, rs8179090 genotypes were also associated with triple negative BC. This study sheds light into the etiology of BC in Taiwanese women. Rs8179090 may be incorporated into polygenic risk scores and risk prediction models, which could aid in stratifying individuals for targeted breast cancer screening.

Background: To evaluate the clinical feasibility of interstitial brachytherapy by intraoperative free-hand catheter implantation in the treatment of early breast cancer after breast-conserving surgery (BCS). Methods: Between January 2018 and December 2019, 44 patients with early breast cancer after BCS who met the inclusion criteria ≥45 years old, invasive carcinoma ≤3 cm or ductal carcinoma in situ <2.5 cm, estrogen receptor positive, lymph node negative, surgical margin negative, no distant metastasis, and an ECOG performance score ≤1 were enrolled in this phase II single-arm study. The postoperative irradiation field includes the tumor bed plus 2-cm margin in all directions, except in the anterior–posterior direction. The total prescribed tumor dose was 3400 cGy delivered in 10 fractions twice daily at 6-hour intervals. The primary endpoints were acute side effects, late treatment-related toxicity, and cosmetic outcome. The secondary endpoints were local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), and overall survival (OS). Results: The median follow-up time was 33.5 months (mean, 32.9 months; range, 20-43 months). The cosmetic results were good to very good in 92.3% of the questionnaire respondents. The acute toxicities were mild, and no acute grade 3-4 toxicity was noted. Wound infection was noted in two patients (4.5%). There was only one event of regional lymph node recurrence in one patient. The 3-year LRFS, DMFS, and OS were 100%, and RRFS was 94.7%. For two patients who had a positive lymph node based on their final pathology reports, postoperative irradiation, including whole breast and regional lymph nodes, was added. Conclusion: Accelerated partial breast irradiation using interstitial brachytherapy with the intraoperative free-hand catheter implantation technique provides an alternative method of postoperative radiotherapy for selected patients with early breast cancer after BCS with acceptable toxicities.