Clinical Cancer Research最新文献

{"title":"Abstract PS3-08-03: The mystery of ER-negative/PR-positive breast cancer: revisiting the endocrine therapy controversy using national data","authors":"S. M. Doss, P. Raval","doi":"10.1158/1557-3265.sabcs25-ps3-08-03","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps3-08-03","url":null,"abstract":"Background: The existence of estrogen receptor-negative (ER-), progesterone receptor-positive (PR+) breast cancer is rare, biologically confusing, and often attributed to technical artifact. Previous national analyses found no benefit from endocrine therapy (ET) in ER-/PR+ tumors, but more recent data suggest a survival benefit. To explore this inconsistency, we analyzed the association between receiving ET and survival in ER-/PR+ early-stage breast cancer treated with chemotherapy over time. Methods: We used the National Cancer Database (NCDB) to identify women age 40 and older diagnosed with stage I-III, ER-/PR+ breast cancer from 2010 to 2020 who received chemotherapy. Multivariate logistic regression evaluated factors associated with ET omission. Multivariate Cox regression analyzed the association between ET receipt and three-year overall survival (OS), stratified by diagnosis period (2010-2017 vs. 2018-2020) based on 2018 changes for prognostic staging and NCDB site-specific factors. Analyses adjusted for stage at diagnosis, age, comorbidity, HER2 status, race/ethnicity, grade, facility type, and zip code income. Robustness was tested using propensity score matching (PSM), landmark analysis, and HER2-negative subgroup analysis. Results: We identified 24,198 (0.94%) cases of ER-/PR+ breast cancer, of which 18,788 (77.6%) were stage I-III at diagnosis. Of these, 13,957 (74.3%) received chemotherapy, and 11,558 with complete covariate data were analyzed. Most cases were HER2-negative (60.2%) and high grade (75.1%). Stage distribution was 38.5% stage I, 43.5% stage II, and 18.0% stage III. Two-year overall survival was 93.3% for patients diagnosed from 2010-2017 and 92.9% for 2018-2020. ET was omitted in 33.8% of patients (median age 58 vs. 57 among ET recipients). In multivariate logistic regression, factors associated with omission of ET were diagnosis from 2018-2020 (adjusted odds ratio [aOR] 1.95, 95% CI 1.75-2.17, p<0.001), increasing age (age 70-80 vs. 40-50: aOR 1.34, 95% CI 1.16-1.55, p<0.001), and high grade (aOR 1.15, 95% CI 1.03-1.28, p=0.02). In multivariate Cox regression, receiving ET was associated with improved three-year OS for patients diagnosed from 2010-2017 (n=7,517; adjusted hazard ratio [aHR] 0.54, 95% CI 0.47-0.62, p<0.001) and 2018-2020 (n=4,041; aHR 0.60, 95% CI 0.48-0.77, p<0.001). Interaction testing for diagnosis period and ET benefit was not significant (p=0.59). After PSM by all covariates, OS benefit remained for both 2010-2017 (n=5,696; aHR 0.55, 95% CI 0.47-0.65, p<0.001) and 2018-2020 (n=2,344; aHR 0.64, 95% CI 0.48-0.86, p=0.003). Conclusions: Omission of ET in ER-/PR+ early-stage breast cancer treated with chemotherapy was associated with worse overall survival, both before and after 2018. The biological and technical uncertainty of this subtype remains unresolved, but these findings warrant further investigation. Citation Format: S. M. Doss, P. Raval. The mystery of ER-neg","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"66 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146231084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS3-01-09: Associations of genetically predicted metabolites with mammographic breast density and breast cancer risk in premenopausal women","authors":"G. Pourali, L. Lyu, X. Guo, A. Toriola","doi":"10.1158/1557-3265.sabcs25-ps3-01-09","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps3-01-09","url":null,"abstract":"Background: Genome-wide association studies (GWAS) have identified genetic loci associated with mammographic breast density (MBD) and breast cancer risk, but the mechanisms underlying these associations remain unclear. Metabolite quantitative trait loci (mQTL) analyses can map genetic loci associated with metabolites, potentially offering insight into mechanisms involved in risk, but there is limited data on how genetically predicted metabolites are associated with MBD and breast cancer risk in premenopausal women. To address this, we performed mQTL analyses in non-Hispanic White (NHW) and non-Hispanic Black (NHB) women and examined their overlap with established GWAS loci for MBD and breast cancer. Methods: Our analysis included 494 NHW and 163 NHB women who had screening mammograms at Washington University in St. Louis. Plasma metabolomic profiling (Metabolon®) identified 1,074 metabolites, and genotyping (Infinium microarray, Illumina) covered 2,028,571 loci. Metabolite data were batch-normalized, metabolites with >10% missingness were excluded, and remaining missing values were imputed. We conducted mQTL mapping using linear regression in PLINK 2.0, stratified by race and adjusted for age, body mass index, alcohol use, oral contraceptive use, and first five genotype principal components. Significant mQTLs (FDR-p<0.05) were compared to GWAS loci for breast cancer, two fine mapping studies, and GWAS of MBD. Results: In NHW women, 30 mQTLs were associated with 54 metabolites overlapping breast cancer GWAS loci. Key pathways included xenobiotics (anti-inflammatory/immunosuppressant drugs, chemicals, tobacco metabolites), lipid (fatty acid, corticosteroid, bile acid metabolism), and amino acid (tryptophan, methionine/cysteine, tyrosine metabolism). In NHB women, 2 mQTLs were associated with 3 metabolites overlapping breast cancer GWAS loci: rs16866849 (diltiazem, ß =0.2, FDR-p=1.6×10-6, cardiovascular drug), and rs9397068 with two metabolites (2-hydroxyibuprofen, ß=5.3, FDR-p=9.6×10-3, analgesics; and 2,2'-methylenebis(6-tert-butyl-p-cresol), ß=14.6, FDR-p=9.6×10-3, chemical). Additionally, in NHW women, 5 mQTLs were associated with 5 metabolites overlapping GWAS loci of MBD. For dense area, these included rs150249911 (levulinate (4-oxovalerate), ß=6.5, FDR-p=2.3×10-7, food component/plant), rs150249911 (N-acetyltyrosine, ß=5.0, FDR-p=3.3×10-4, tyrosine metabolism), rs2042239 (5-acetylamino-6-formylamino-3-methyluracil, ß=1.3, FDR-p=3.3×10-2, xanthine metabolism), and rs833472 (3-hydroxystachydrine, ß=11.0, FDR-p=2.5×10-3, food component/plant). For percent mammographic density, rs61941038 (3-hydroxystachydrine, ß=10.4, FDR-p=7.4×10-3, food component/plant) was associated. For non-dense area, rs78395856 (taurochenodeoxycholic acid 3-sulfate, ß=3.7, FDR-p=3.3×10-2, bile acid metabolism) was associated. Conclusions: Our novel study identified genetic loci associated with metabolites that overlap with established MBD and breast cancer r","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"8 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146231086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS3-06-16: Mapping neutrophil architecture with integrative spatial analysis to reveal clinically relevant functional heterogeneity","authors":"Y. Xu, D. Ma, X. Wu, Z. Qiu, L. Dai, H. Zhang, S. Zhao, Y. Xiao, Y. Jiang, Z. Shao","doi":"10.1158/1557-3265.sabcs25-ps3-06-16","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps3-06-16","url":null,"abstract":"Background: Neutrophils are increasingly recognized as a key component of the tumor microenvironment. However, their spatial organization and interactions with other cells remain poorly characterized. The clinical and biological significance of these spatial patterns requires further exploration. Our study aims to identify clinically relevant neutrophil spatial architectures in breast cancer and elucidate their biological underpinnings. Methods: We established a large-scale breast cancer cohort covering all standard therapeutic regimens (adjuvant setting, n = 629; neoadjuvant setting, n = 381), with matched hematoxylin and eosin (H&E)-stained whole slide images (WSIs). We refined an artificial intelligence-based computational pathology framework we had proposed1 to identify neutrophils in WSIs and characterize their spatial patterns (i.e., their spatial relationships with neighboring cell types). Then we studied the correlation between these patterns and patient outcomes. To investigate the biology basis of distinct neutrophil spatial patterns, we performed single-cell spatial transcriptomics profiling (n = 104) and integrative analysis, with functional validation using patient-derived organoids (PDOs). Results: We found neutrophil spatial architectures demonstrated significant prognostic and predictive value, particularly in triple-negative breast cancer (TNBC). Specifically, we identified two clinically relevant patterns in TNBC: (1) Neutrophils in closer proximity to tumor cells predicted improved prognosis, which was validated in independent cohorts. Mechanistically, neutrophils upregulated MHC class I on tumor cells via secreted factors (e.g., TNFα), thereby enhancing CD8+ T cell-mediated recognition and cytotoxicity. This process was further corroborated by evidence from a neutrophil-PDO-CD8+ T cell co-culture system. (2) Neutrophils neighboring immune cells correlated with superior response to neoadjuvant immunotherapy. These neutrophils developed potent antigen-presenting capabilities through concurrent upregulation of MHC class I and II molecules. They primed CD4+ naive T cells and expanded CD8+ effector/memory T cells, thus fostering an immunotherapy-responsive microenvironment. Conclusion: Our study delineates the spatial heterogeneity of neutrophils, mapping their functional plasticity to spatial patterns with clinical relevance. These findings may inform the development of clinically actionable biomarkers for prognosis stratification and treatment response prediction in breast cancer patients. References 1Zhao, S. et al. Single-cell morphological and topological atlas reveals the ecosystem diversity of human breast cancer. Nat Commun 14, 6796, doi:10.1038/s41467-023-42504-y (2023). Citation Format: Y. Xu, D. Ma, X. Wu, Z. Qiu, L. Dai, H. Zhang, S. Zhao, Y. Xiao, Y. Jiang, Z. Shao. Mapping neutrophil architecture with integrative spatial analysis to reveal clinically relevant functional heterogeneity [abstract]. In: Proceedings of","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"5 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146230760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS3-06-15: A Retrospective Study on a Predictive Model to Probe the Impact of Atmospheric Environment on Breast Cancer Prognosis: A Cohort of 17,438 Patients","authors":"Y. Yuan, A. Yuan, W. Wang, Z. Hu, C. Zheng, Z. Zheng, W. Liang, Y. Zhang, Y. Pan, C. Zhang","doi":"10.1158/1557-3265.sabcs25-ps3-06-15","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps3-06-15","url":null,"abstract":"Background: In survival analysis tasks, DeepSurv, DeepHit, etc., are deep learning-based models designed to handle one-dimensional time series data. Their primary objective is to predict an individual's survival probability and its relationship with time. However, traditional one-dimensional data processing methods may overlook certain spatial structural information inherent in the data—a limitation that is particularly significant for specific types of biomedical or clinical data. Therefore, we propose an innovative approach: converting one-dimensional data into grayscale images. This conversion introduces additional spatial features, enabling the model to better capture complex patterns in the data. Our aim is to develop a predictive analysis model for the impact of atmospheric environment on breast cancer prognosis. Methods: This study is a multi-center retrospective cohort study on breast cancer, involving 17,438 breast cancer patients. The endpoint outcome is disease-free survival (DFS). The features include age, gender, HDI, history of malignant tumors, family history of breast cancer, ki67, pathological type, molecular subtype, TNM staging, O3, PM2.5, monthly average precipitation, monthly average wind speed, and monthly average temperature. Firstly, we expand the dimensionality of one-dimensional survival data by mapping it to grayscale images, making it compatible with the input format of convolutional neural networks (CNNs) for processing image data. Through this conversion, we can effectively extract spatial features using convolutional operations, thereby enhancing the model's predictive capability. Subsequently, we develop a CNN-based deep neural network model that incorporates convolutional layers to process these grayscale image data while retaining the core concepts of survival analysis. This model aims to predict an individual's relative risk value by learning deep patterns in the data and can handle prognostic data with high complexity and non-linear relationships. Citation Format: Y. Yuan, A. Yuan, W. Wang, Z. Hu, C. Zheng, Z. Zheng, W. Liang, Y. Zhang, Y. Pan, C. Zhang. A Retrospective Study on a Predictive Model to Probe the Impact of Atmospheric Environment on Breast Cancer Prognosis: A Cohort of 17,438 Patients [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl): nr PS3-06-15.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"5 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146230769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS3-07-01: Ki67 change between diagnostic biopsy and surgery: impact of hormonal replacement therapy or contraception (HRT-HC) withdrawal at breast cancer diagnosis","authors":"L. Fontannaz, J. Sauser, B. Bisig, N. Dris, A. Kakourou, B. Giacomuzzi-Moore, A. Stravodimou, A. Liapi, C. Perrinjaquet, A. Dolcan, B. Wolf, E. Dubruc, D. Hastir, K. Zaman","doi":"10.1158/1557-3265.sabcs25-ps3-07-01","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps3-07-01","url":null,"abstract":"Background: Change in Ki67 expression between diagnostic biopsy and surgery of a breast cancer (BC) - the so-called window of opportunity - is commonly used as a surrogate marker of treatment response or to assess endocrine sensitivity as in the WSG-ADAPT HR+/HER2- trial. HRT-HC were shown to increase BC risk and are typically discontinued at BC diagnosis. Whether this withdrawal alone influences Ki67 dynamics remains unclear and may represent a potential confounding factor in the window of opportunity studies. Methods: This retrospective study included 382 female patients (pts) who underwent primary surgery at our breast center over a 4-year period (2020-2023). Clinical and tumor characteristics, including Ki67 levels at biopsy and surgery, were extracted from our institutional database. The primary objective was to compare the change in log Ki67 levels between the initial biopsy and the surgical specimen in pts with vs. without HRT-HC in HR+/HER2- BC (n=308). For this comparison, a linear regression adjusting for log Ki67 level at biopsy, HRT-HC use, age, menopausal status, year, stage, grade, expression levels of progesterone (PgR) and estrogen receptors, and histology was considered using the ratio of geometric means as an estimate of the effect of hormonal treatment. Results: Among patients with HR+/HER2- BC, 38% were premenopausal and 62% postmenopausal. At diagnosis, 27.9% of patients were receiving HRT-HC (39.3% of premenopausal and 20.9% of postmenopausal women). The distribution of Ki67 levels remained stable across the four years of assessment. Ki67 level was significantly correlated with the BC grade (1 vs. 2 vs. 3) and stage (I vs. II-III), at biopsy and at surgery. The correlation with menopausal status was significant only at surgery. No correlation was observed with PgR < vs. > 20%. Median time from biopsy to surgery was 39 days. Ki67 level was 9.2% lower at surgery than at biopsy (p=0.025). There was no significant difference in terms of Ki67 level at biopsy in pts with HRT-HC vs. without. However, the geometric mean of Ki67 at surgery for pts with HRT-HC was 29% lower than for pts without HRT-HC, adjusted for Ki67 level at biopsy (p=0.007). They also had a higher likelihood to present a Ki67 level <10% at surgery (estimate 0.52, p=0.015). This difference stayed significant in multivariable analysis (p<0.001). Conclusion: HR+/HER2- BC pts who interrupt HRT-HC upon BC diagnosis present a statistically significant drop in Ki67 level between diagnostic biopsy and surgery; a change which is not observed in patients HRT-HC naive. A significantly higher proportion of pts with HRT-HC also achieved a Ki67 level below 10% at surgery, a commonly used cutoff for decision. Thus, HRT-HC may act as a confounder factor when administrating a window of opportunity treatment to guide adjuvant systemic treatment or to predict a treatment efficacy based on Ki67 levels. These findings and their potential clinical relevance","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"10 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146230798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS1-04-17: Real-world patient (pt) and caregiver experiences with breast cancer (BC) risk of recurrence (ROR) in the US: Results of an Online Survey and Social Media Analysis","authors":"H. S. Rugo, M. Chase, M. Rutt, M. Smith, S. Weldon, E. Pain, G. Vadnerkar, T. Sen, S. Padhi, N. Nadimpalli, L. Santarsiero, C. Auld, N. Harbeck, A. B. Chagpar","doi":"10.1158/1557-3265.sabcs25-ps1-04-17","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps1-04-17","url":null,"abstract":"Background: While most new HR+/HER2− BC cases are diagnosed (dx) as early BC (EBC), recurrences are an urgent concern as approximately 50% of recurrences occur in ≤5 years despite standard-of-care endocrine therapy and this risk can persist for decades after dx. Little has been published on the awareness and understanding of BC ROR from the pt and caregiver perspective and how this may influence shared decision-making and quality of life (QoL). Here, we present the results of an online survey of pts and subsequent social media analysis (SMA) of pts and caregivers including important insights on ROR. Methods: Female pts from France, Germany, Italy, the UK, and the US were invited to participate in a survey developed with input from medical experts and pt advocates on the Carenity platform, an online pt community, between Dec 1, 2021 and Jan 24, 2022; results from the US are presented. Additionally, deidentified data from publicly available posts by US pts and caregivers on social media sites, forums, and blogs between Apr 1, 2023 and Mar 31, 2025 were analyzed using the Sprinklr social media aggregator. Results: Of 220 US pts who responded to the Carenity survey, 57 (26%) reported being dx with HR+/HER2− BC, 39% with HER2+, and 22% with triple negative BC (TNBC). Among pts with HR+/HER2− BC, 38 pts (67%) were initially dx with EBC (stage I-III); of those, 11 pts (29%) recurred as metastatic BC (MBC). In the SMA, a screen of 3440 posts found 1622 relevant to EBC and ROR; 82% of conversations were driven by pts. In the Carenity survey, many pts initially dx with HR+/HER2− EBC wished they had received more relevant information on chances/duration of survival (32%) or emotional support options (26%) from their healthcare provider (HCP) at the time of dx, some of whom indicated they received no information at dx (chances/duration of survival: 22%; emotional support options: 67%). Many pts who reflected back on initial dx and wanted but had not received information on chances/duration of survival (75%) or emotional support options (40%) experienced a metastatic recurrence. This was reinforced by the SMA which identified recurrence rate and peer support as topics pts were seeking more information on. Posts related to ROR highlight pt and caregiver concerns about late recurrences, limited long-term monitoring, and persistent worries about unexpected recurrences. Pts also expressed feelings of being overwhelmed by the fear of BC recurrence. Within the Carenity survey, limiting risk of cancer metastasis and living as long as possible ranked high among treatment (tx) expectations. Similar themes emerged from the SMA, in which ROR was identified as one of the top aspects leading to positive perceptions of available tx. Surveyed pts with HR+/HER2− BC felt they had less access to services and support programs compared to pts with HER2+ or TNBC. In the SMA, pts discussed challenges and stressors associated with the lack of ROR knowledge within their support syst","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"7 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146231075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS2-13-08: Neoadjuvant Dalpiciclib Plus Letrozole Versus Standard Chemotherapy in High-Risk HR+/HER2- Negative Breast Cancer (DARLING-02): A Randomized Phase II Trial","authors":"C. Geng, L. Zhang, C. Yang, T. Zhou, L. Ma, R. Luo, Z. Song, Y. Qi, J. Yang, X. Wang, J. Han, J. Ma, Z. Zhang, Y. Li, C. Gao, L. Yang, J. Yu","doi":"10.1158/1557-3265.sabcs25-ps2-13-08","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps2-13-08","url":null,"abstract":"Background: Dalpiciclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has shown significant efficacy and a favorable safety profile when combined with endocrine therapy for advanced hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer. Building on this evidence, the present study evaluated the efficacy and safety of neoadjuvant dalpiciclib plus letrozole compared with standard chemotherapy in patients with high-risk HR+/HER2- early breast cancer. Methods: DARLING-02 was a multicenter, randomized, phase II non-inferiority trial (NCT06107673). Key eligibility criteria included women aged ≥18 years; Eastern Cooperative Oncology Group performance status 0-1; clinical stage T1c-2N1-2 or T3-4N0-2; estrogen receptor (ER) expression ≥50%; HER2- status; and Ki-67 level ≤30%. Patients were randomized 1:1 to receive 24-week treatment. The experimental arm received dalpiciclib 150 mg orally once daily (3 weeks on, 1 week off) plus letrozole 2.5 mg orally once daily. The control arm received epirubicin 100 mg/m2 plus cyclophosphamide 500 mg/m2 intravenously on day 1 every 3 weeks for 4 cycles, followed by docetaxel 100 mg/m2 intravenously on day 1 every 3 weeks for 4 cycles. The primary endpoint was objective response rate (ORR), assessed per Response Evaluation Criteria in Solid Tumors, version 1.1. Results: Between August 2023 and April 2025, 170 patients were screened; 158 met the eligibility criteria and were randomized to the dalpiciclib-letrozole (n = 80) or chemotherapy (n = 78) group. At the data cut-off date (September 17, 2025), 9 patients in the experimental arm and 10 in the control arm were still on neoadjuvant therapy. Among patients with completed short-term efficacy assessment, the ORR was 69.0% (49/71) with dalpiciclib-letrozole and 70.5% (48/68) with chemotherapy; total pathological complete response (tpCR) rate was 5.6% (4/71) and 1.5% (1/68), respectively. The proportion of patients with Preoperative Endocrine Prognostic Index (PEPI) score ≥4 was higher in the chemotherapy group (74.6% [44/59]) than in the dalpiciclib-letrozole group (53.3% [32/60]). Grade ≥3 adverse events were predominantly hematological toxicities and occurred less frequently with dalpiciclib-letrozole than with chemotherapy (decreased white blood cell count: 36.4% [28/77] vs 64.0% [39/61]; decreased neutrophil count: 74.0% [57/77] vs 86.9% [53/61]). Conclusions: These findings support dalpiciclib plus letrozole as a promising neoadjuvant option for patients with high-risk HR+/HER2- early breast cancer and warrant confirmation in phase III trials. Citation Format: C. Geng, L. Zhang, C. Yang, T. Zhou, L. Ma, R. Luo, Z. Song, Y. Qi, J. Yang, X. Wang, J. Han, J. Ma, Z. Zhang, Y. Li, C. Gao, L. Yang, J. Yu. Neoadjuvant Dalpiciclib Plus Letrozole Versus Standard Chemotherapy in High-Risk HR+/HER2- Negative Breast Cancer (DARLING-02): A Randomized Phase II Trial [abstract]. In: Proceedings of the San Antonio Breast Cance","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"30 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146231104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS2-09-30: Combination of a novel MELK inhibitor with standard of care treatment results in tumor regression and improved survival in a triple-negative inflammatory breast cancer xenograft model","authors":"M. Mughees, R. Pathania, N. Fowlkes, J. Wang, S. Krishnamurthy, S. Damodaran, W. Woodward, K. Hunt, A. Sahin, K. Dalby, B. Chandra","doi":"10.1158/1557-3265.sabcs25-ps2-09-30","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps2-09-30","url":null,"abstract":"Background Patients with highly aggressive breast cancers, such as triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC)—face clinical challenges, due to advanced stage at diagnosis, high risk for development of metastasis, and limited treatment options. Therefore, the development of novel treatment strategies is an urgent unmet need. We previously demonstrated that MELK is highly expressed in TNBC and IBC, and plays a key role in promoting stemness, epithelial-mesenchymal transition (EMT), and metastasis in a xenograft model. The inhibition of MELK reduced fibronectin (FN1) expression in vitro and in a xenograft mouse model, impairing the formation of extracellular fibronectin fibrils and ultimately decreasing cancer cell motility in TNBC/IBC cells. In the current study, we extended our investigation to patient samples to assess MELK expression, EMT markers, and macrophage infiltration in the tumor microenvironment. Additionally, to support clinical translation, we evaluated the efficacy of MELK inhibitors in combination with standard-of-care agents—paclitaxel (PT) and eribulin (ERB) in TNBC/IBC xenograft models. Materials and Methods We evaluated the efficacy and toxicity of MELK-inhibitors (MELK-In-17, MELK-In-30e, and OTS167), alone or in combination with paclitaxel or eribulin, using the 4T1(TNBC) and SUM149 (TN-IBC) mouse models. The multiplex immunofluorescence (mIF) staining was performed on tissue microarrays from 179-TNBC and 278-invasive breast cancer samples from the MD Anderson Breast Tumor Tissue Bank. The panel of markers included MELK, N-cadherin, E-cadherin, vimentin, fibronectin, PANCK, arginase1, CD163, IBA-1, CD206, and PD-L1. Results In the 4T1 model, MELK inhibitors alone or in combination with paclitaxel significantly reduced tumor growth compared to vehicle. MELK-In-30e was more effective than OTS167, though no synergistic effect was observed with paclitaxel combinations. All treatment groups showed reduction in FN1 and Ki67expression, with the greatest decrease in 30e and 30e+paclitaxel groups. In the SUM149 tumor model, treatment with 30e plus eribulin resulted in significantly greater tumor suppression compared to 30e alone (p = 0.02), while 30e plus paclitaxel did not demonstrate synergy. OTS167 showed modest tumor growth inhibition as a monotherapy and in combination with paclitaxel or eribulin showed limited effect. Survival was improved with 30e+paclitaxel and 30e+eribulin combinations. Ki-67 expression was reduced across all treatment groups, with the most substantial decrease in the 30e+eribulin group. 30e alone or 30e+eribulin also led to decreased expression of MELK, FN1, and vimentin. No significant toxicity was observed in the monotherapy or combination treatments. mIF staining of patient tissues revealed variable expression of MELK and EMT markers, with consistent moderate to high PDL1 expression and frequent infiltration of macrophages exhibiting immunosuppressive “M2”-like phenotypes fre","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146230768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS5-10-22: Allostatic Load and Risk of Obesity Related and Total Cancer in Postmenopausal Women","authors":"J. Chi, F. Wang, Y. Zong, M. Pennell, M. Yu, V. Nair, A. Vasbinder, D. Lane, A. Shadyab, C. Valencia, N. Saquib, J. Wactawski-Wende, P. Richey, M. Skiba, M. Simon","doi":"10.1158/1557-3265.sabcs25-ps5-10-22","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps5-10-22","url":null,"abstract":"Allostatic Load and Risk of Obesity-Related and Total Cancer in Postmenopausal Women: Insights from the Women’s Health InitiativeBackground: Allostatic load (AL), a composite biomarker of physiological stress, has been associated with chronic disease, but its relationship with cancer—particularly obesity-related cancers—remains understudied in large, diverse populations. In this analysis, we investigated the association between baseline AL and the incidence of obesity-related cancers and total cancer risk, among postmenopausal women in the Women’s Health Initiative (WHI). Methods: Among 161,805 WHI participants, we identified a final cohort of 28,102 women with information on AL after excluding individuals with delayed biomarker collection, or prior cancer diagnosis. AL was calculated using eight biomarkers (pulse, systolic and diastolic blood pressure, body mass index (BMI), waist circumference, C-reactive protein (CRP), fasting glucose, and total cholesterol). Participants were stratified into tertiles of AL (low: 0–2, medium: 3–5, and high: 6–8). Cox proportional hazards and Fine-Gray models were used to assess associations between AL and incident cancers, separately looking at the risk of 13 obesity related cancers and total cancer risk, and adjusting for sociodemographic, behavioral, and reproductive factors. Results: Over median follow up of 18. 64 years, 14.1% of participants developed obesity-related cancers and 22.3% developed any cancer. In fully adjusted models, women in the highest AL tertile at WHI enrollment had significantly elevated risk of obesity-related cancer compared to the lowest tertile (HR 1.20; 95% CI: 1.01–1.42; p=0.044). A 1-point increase in AL score was associated with a 4% higher risk (HR 1.04; 95% CI: 1.00–1.07; p=0.028). Total cancer risk did not increase significantly with higher AL score (HR for high vs. low: 1.07; 95% CI: 0.92–1.24; p=0.388; per point: HR 1.02; 95% CI: 1.00–1.05; p=0.079). These associations did not differ significantly by race, ethnicity or income. Conclusions: Elevated allostatic load is independently associated with increased risk of obesity-related cancer among postmenopausal women in the WHI. These findings highlight the potential role of cumulative physiological stress in in cancer risk beyond obesity alone and suggest that AL may be a valuable biomarker incorporating social and metabolic stressors for cancer risk stratification in older women. Citation Format: J. Chi, F. Wang, Y. Zong, M. Pennell, M. Yu, V. Nair, A. Vasbinder, D. Lane, A. Shadyab, C. Valencia, N. Saquib, J. Wactawski-Wende, P. Richey, M. Skiba, M. Simon. Allostatic Load and Risk of Obesity Related and Total Cancer in Postmenopausal Women [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl): nr PS5-10-22.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"47 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146230796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS3-01-04: Single-cell transcriptomic and phenotypic profiling reveals T cell dysfunction in cancer-free BRCA1 germline mutation carriers","authors":"H. Chiang, R. Araya, L. Qi, H. Arestake, S. Martinez, A. Sanchez, I. Kalia, Y. Hu, A. Horvath, R. Li","doi":"10.1158/1557-3265.sabcs25-ps3-01-04","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps3-01-04","url":null,"abstract":"Women harboring germline mutations in BRCA1 have an approximately 80% lifetime risk of developing breast cancer. Extensive research on the breast epithelium, the cell of origin for BRCA1-related tumors, has shed light on the molecular functions of BRCA1 in tumor suppression. However, all somatic cells in a germline BRCA1 mutation carrier contain the same mutant allele, yet it remains unclear whether BRCA1 heterozygosity in stromal compartments could also contributes to the increased risk of BRCA1-associated cancer. To determine the impact of BRCA1 heterozygosity on T cells at the transcriptional and functional levels, we first investigated a cohort of T cells isolated from healthy individuals who are BRCA1 mutation carriers (BRCA1 mut/+ ) and non-carriers, using single cell RNA sequencing (scRNA-seq) and high-parametric spectral flow cytometry. Single-cell transcriptomic analysis revealed a significant enrichment of a gamma-delta (γδ) T cell subpopulation in BRCA1 mut/+ samples. A similar trend, albeit not statistically significant, was observed for a SOX4high T cell subpopulation. Functionally, BRCA1 mut/+ T cells exhibited a delayed response to CD3/CD28 costimulation and showed an enrichment of naïve cells in the CD4 compartment. In addition, the production of cytokine IL-17 is significantly reduced in BRCA1 mut/+ T cells after 24 hours of activation. To determine a causal effect of T-cell BRCA1 heterozygosity on tumorigenesis, we next deleted one allele Brca1 in mouse T lymphocytes. Implanted mammary tumors grew more robustly in T cell-specific Brca1 -/+ mice than their Brca +/+ counterparts, supporting the notion that Brca1 heterozygosity in mouse T lymphocytes compromises the antitumor immunity. Furthermore, mechanistic studies indicate that BRCA1 regulates T cell-related gene expression in conjunction with other transcriptional coregulators. In summary, our data from clinical samples and preclinical models suggest that the heterozygous BRCA1 mutation status leads to T cell-intrinsic functional alterations and compromised antitumor immunity. We propose that germline BRCA1 mutations exert a “double whammy” effect—contributing to elevated cancer risk through their presence in both the cell of origin and the surrounding stromal compartments. Citation Format: H. Chiang, R. Araya, L. Qi, H. Arestake, S. Martinez, A. Sanchez, I. Kalia, Y. Hu, A. Horvath, R. Li. Single-cell transcriptomic and phenotypic profiling reveals T cell dysfunction in cancer-free BRCA1 germline mutation carriers [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl): nr PS3-01-04.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"73 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146230840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}