NPJ Breast Cancer最新文献

{"title":"PARP inhibition with olaparib and talazoparib for HER2-negative advanced breast cancer-Results from the prospective PRAEGNANT registry.","authors":"Manuel Hörner, Andreas Hartkopf, Nelson John, Philipp Ziegler, Lothar Häberle, Sabrina Uhrig, Chloë Goossens, Niklas Amann, Jan-Philipp Cieslik, Lara M Tretschock, Dominik Dannehl, Thomas M Deutsch, Moritz Dimpfl, Max Ehlert, Kathleen Eichstädt, Alexander Englisch, Melitta B Köpke, Annika Krückel, Theresa Link, Annika Müller, Kristin Reinhardt, Jonas Roth, Henning Schäffler, Lea Sych, Nikolas Tauber, Christian M Tegeler, Catharina Wichmann, Maggie Banys-Paluchowski, Henriette Princk, Achim Rody, Sara Y Brucker, Nina Ditsch, Johannes Ettl, Tanja Fehm, Carolin C Hack, Peyman Hadji, Alexander Hein, Wolfgang W Janni, Hans-Christian Kolberg, Diana Lüftner, Michael P Lux, Volkmar Müller, Florin-Andrei Taran, Hans Tesch, Diethelm Wallwiener, Frederik Marmé, Stephan Seitz, Erik Belleville, Laura L Michel, Markus Wallwiener, Peter A Fasching, Andreas Schneeweiss, Christian Maurer","doi":"10.1038/s41523-026-00947-8","DOIUrl":"10.1038/s41523-026-00947-8","url":null,"abstract":"<p><p>Germline BRCA1 and BRCA2 mutations enable targeted therapies in human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). The two poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors olaparib and talazoparib were introduced into clinical practice in 2018. Limited evidence about their routine clinical use highlights the importance of this analysis. We provide a real-world analysis for PARP-inhibitor use in ABC patients treated within the prospective German PRAEGNANT registry (NCT02338167). 152 patients with ABC receiving a PARP-inhibitor were included. Real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) were calculated for all patients using the Kaplan-Meier method. Subgroups (line of therapy, metastasis timing, hormone receptor (HR) status, treatment: olaparib, talazoparib, among others), germline BRCA1, BRCA2 and PALB2 mutations and adverse events (AEs) were analyzed. The median rwPFS was 6.2 months (95% CI, 4.8-7.9) and the median rwOS was 17.1 months (95% CI, 14.4-22.3). Line of therapy, HR status and treatment (olaparib versus talazoparib) appeared to especially affect both rwPFS and rwOS. Among patients with a reported germline mutation, 36.1% had a BRCA1, 62.9% a BRCA2 and 1.0% a PALB2 mutation. In summary, outcomes were comparable to those reported in pivotal trials despite later-line use of PARP-inhibitors in this analysis.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13087296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147662864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stromal-based proteome data improve stratification of hormone receptor-positive breast cancer.","authors":"Kenneth Finne, Silje Kjølle, Magdalena Ríos Romero, Even Birkeland, Heidrun Vethe, Sura Aziz, Gøril Knutsvik, Elisabeth Wik, Linda Sofie Lindström, Lars A Akslen","doi":"10.1038/s41523-026-00943-y","DOIUrl":"https://doi.org/10.1038/s41523-026-00943-y","url":null,"abstract":"<p><p>Breast cancers are biologically and clinically diverse. While large-scale gene expression analyses have enabled epithelial-centered molecular classifications, studies of the tumor microenvironment (TME) remain limited, especially at the proteome level using tissue-specific resolution. By laser capture microdissection and mass spectrometry-based proteomics followed by unsupervised clustering of the stromal proteome, we discovered three patient subgroups. The largest cluster revealed the most discrete representation of stromal proteins, including a 35-protein (35P) panel linked to extracellular matrix biology, tumor progression programs, and increased abundance of tumor-associated macrophages (TAM) by single-cell profiling. Clinical validation of 35P, using whole tissue protein and mRNA values from different cohorts of ER+/HER2- breast cancer, including a large randomized controlled trial (STO), identified that more aggressive (or 'high-grade') stromal features were independent of current molecular subtypes. The 35P stromal panel may reflect important clinical information by improving patient stratification beyond current epithelial-based classification of breast cancer.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarker, treatment patterns, and survival differences in metastatic triple-negative breast cancer by race in the United States.","authors":"Pegah Farrokhi, Leah Park, Howard Weston Schmutz, Samantha L Thompson, Clara Lam, Julian Bryan, David D Stenehjem","doi":"10.1038/s41523-026-00945-w","DOIUrl":"https://doi.org/10.1038/s41523-026-00945-w","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) disproportionately affects Black women, with higher incidence rates and worse outcomes compared with White women. This study included 670 adult patients with metastatic TNBC diagnosed between January 2017 and March 2022 from the Flatiron Clinico-Genomic database. All patients underwent NGS-based testing and were assessed for prevalence of BRCA1/2, PIK3CA, AKT1, and PTEN alterations; treatment patterns; and survival outcomes. Of 670 patients, 28% were Black and 72% White. Black patients had higher BRCA1/2 alteration prevalence (12% vs. 7%; p < 0.04) but similar rates of other mutations. First-line therapy rates were comparable between groups. No significant differences in overall survival were observed (median 13.7 months for Black patients vs. 18.9 months for White patients; p = 0.15). Black patients with metastatic TNBC were nearly twice as likely to have BRCA1/2 alterations, suggesting potential benefit from PARP inhibition. Although survival differences were not statistically significant, larger studies are needed to understand racial disparities in treatments and outcomes.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term prognostic value of ctDNA in early breast cancer: insights from the neoadjuvant ABCSG-34 Trial.","authors":"Daniel Egle, Dominik Hlauschek, Simon Peter Gampenrieder, Gabriel Rinnerthaler, Christian Singer, Georg Pfeiler, Rupert Bartsch, Gregor Huber, Angelika Pichler, Edgar Petru, Zsuzsanna Bago-Horvath, Anna-Sophia Kermanidis, Christian Fesl, Qing Zhou, Ricarda Graf, Sabrina Hammer, Nadia Dandachi, Martin Filipits, Michael Gnant, Ellen Heitzer, Marija Balic","doi":"10.1038/s41523-026-00934-z","DOIUrl":"https://doi.org/10.1038/s41523-026-00934-z","url":null,"abstract":"<p><p>Circulating tumor DNA (ctDNA) is a promising biomarker in early breast cancer for assessing treatment response, minimal residual disease (MRD), and recurrence risk. In the ABCSG-34 phase II trial, we previously reported that persistent ctDNA during neoadjuvant therapy (NAT) was associated with higher residual cancer burden and lower rates of pathological complete response. Here, we present long-term follow-up data evaluating the prognostic relevance of ctDNA dynamics. ABCSG-34 randomized 400 patients to chemotherapy or endocrine therapy, with or without the MUC1 vaccine tecemotide. Tumor-informed SiMSen-Seq assays were used to assess ctDNA at baseline, mid-therapy, and end-of-therapy. Of 145 patients with ctDNA data, 109 had long-term follow-up (median: 7.1 years). Baseline ctDNA positivity was significantly associated with inferior overall survival (HR 2.12, p = 0.043) and shorter survival durations across all endpoints. Trends toward improved outcomes were observed in patients who cleared ctDNA during NAT, though statistical significance was not reached-likely due to limited sample size. These findings support baseline ctDNA as a prognostic marker in early breast cancer. While ctDNA clearance may reflect treatment efficacy, further validation in larger trials is needed. Ongoing studies will determine the role of ctDNA in guiding therapy and monitoring MRD.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progesterone receptors drive advanced breast cancer phenotypes including circulating tumor- and stem-like cell expansion in the context of ESR1 mutation.","authors":"Thu H Truong, Noelle E Gillis, Amy R Dwyer, Rosemary J Huggins, Kyla M Hagen, Sai Harshita Posani, Nuri A Temiz, Carlos Perez Kerkvliet, Ellie M Piepgras, Julie H Ostrander, Geoffrey L Greene, Carol A Lange","doi":"10.1038/s41523-026-00939-8","DOIUrl":"10.1038/s41523-026-00939-8","url":null,"abstract":"<p><p>Endocrine therapy resistance remains a major challenge in the treatment of advanced estrogen receptor positive (ER+) breast cancer. This can be driven by acquired mutations in the estrogen receptor gene (ESR1), such as Y537S or D538G, that results in constitutive estrogen-independent ER activity. Progesterone receptors (PR) are important modifiers of ER activity, in part via direct binding. We previously showed that PR mediates expansion of cancer stem-like cell (CSC) populations. In this study, we sought to define whether PR function changes in the context of ESR1 mutations. PR readily interacted with wild type (WT), but not Y537S or D538G ERs. RNA-seq and ChIP-seq studies demonstrated that ER+ breast cancer models expressing Y537S ER exhibited a distinct response to progesterone. CSC populations were enhanced in Y537S ER+ cells compared to WT ER+ cells. PR knockdown demonstrated that this property required PR expression but was unresponsive to antiprogestins. Moreover, we identified PR-dependent transcriptional programs such as the unfolded protein response (UPR) that can be leveraged to target CSCs in Y537S ESR1-mutant breast cancer. Our findings demonstrate an interplay between PR and mutant ER function and provide insight into PR-driven pathways that can be exploited as potential therapeutic avenues in ER+ breast cancer.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the contribution of rare non-coding variants in BRCA1, BRCA2 and PALB2 to hereditary breast cancer.","authors":"Qihong Zhao, Na Li, Evanny Marinovic, Simone McInerny, Maia Zethoven, Lisa Devereux, Daffodil M Canson, Amanda B Spurdle, Rodney J Scott, Paul A James, Ian G Campbell","doi":"10.1038/s41523-026-00942-z","DOIUrl":"https://doi.org/10.1038/s41523-026-00942-z","url":null,"abstract":"<p><p>Pathogenic coding variants in BRCA1, BRCA2 and PALB2 confer hereditary breast/ovarian cancer risk, yet these regions comprise less than 10% of the genomic footprint of these genes, leaving most sequence unexplored. We investigated the contribution of non-coding variation to hereditary breast cancer by analyzing intronic variants and 5' upstream regions of BRCA1, BRCA2 and PALB2 in the BEACCON case-control study of over 11,000 participants. Full-gene sequencing showed that 46.3% of cases carried at least one rare non-coding variant. This was associated with a modest increase in breast cancer risk (OR = 1.2, p < 0.0001), most likely reflecting the presence of a small proportion of pathogenic variants within a larger background of predominantly neutral variation. Stronger enrichment was observed for triple-negative disease, particularly for BRCA1 (OR = 1.5, p = 0.0001). Tumor sequencing of 42 high-priority variants identified 11 (26.2%) with wild-type allele loss and high homologous recombination deficiency. Functional CRISPR/Cas9 knock-in assays in MCF10A cells confirmed that two deep intronic variants created aberrant splice sites, disrupted splicing and impacted transcript expression.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147618887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TGF-α/EGFR-mediated lymphatic metastasis reveals a repositionable therapeutic target in breast cancer.","authors":"Wenyang Shi, Yueyun Pan, Bhavik Rathod, Yuhan Wang, Zhi Wang, Jianyu Shen, Francesca Gatto, Mingzhi Liu, Yizhe Sun, Margareta Wilhelm, Thomas Helleday, Maria H Ulvmar, Sara H Windahl, Mikael C I Karlsson, Jonas Fuxe","doi":"10.1038/s41523-026-00941-0","DOIUrl":"10.1038/s41523-026-00941-0","url":null,"abstract":"<p><p>The epidermal growth factor receptor (EGFR) is a well-established oncogenic driver in multiple epithelial cancers, yet its role in breast cancer remains elusive, with EGFR-targeted therapies showing limited clinical efficacy. Here, we demonstrate that EGFR promotes selective lymphatic dissemination in triple-negative breast cancer through a chemotactic mechanism involving the EGFR ligand TGF-α. Lymphatic endothelial cells (LECs) were identified as a tumor-associated source of TGF-α, both in a murine model and in human breast cancer, particularly upon stimulation with TGF-β1, a cytokine commonly overexpressed in breast tumors associated with lymph metastasis. We found that TGF-α-EGFR interactions elicit directional migration via STAT3 signaling, whereas the co-secreted ligand CTGF, enriched in blood endothelial cells, suppressed migration. Pharmacologic blockade of TGF-α with Fepixnebart, a first-in-class ligand-neutralizing antibody targeting TGF-α and previously not tested in oncologic indications, significantly inhibited early lymph metastasis of EGFR⁺ tumor cells. Furthermore, EGFR overexpression resulted in increased cellularity in tumor-draining lymph nodes and reduced CD8⁺ T-cell representation. Together, these findings reveal a role for the TGF-α/EGFR axis in lymph metastasis and propose a rationale for repositioning EGFR-targeted therapies toward targeting early metastatic spread and immunomodulation in breast cancer.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13057184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147616375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of body composition dynamics throughout treatment in patients with early-stage breast cancer.","authors":"Lauren E Rentz, McKinzey K Dierkes, Beth Vettiyil, Ida Holásková, Emidio E Pistilli","doi":"10.1038/s41523-026-00933-0","DOIUrl":"10.1038/s41523-026-00933-0","url":null,"abstract":"<p><p>This study characterized computed tomography (CT)-derived body composition and tissue morphology in females with non-metastatic breast cancer (BC), both cross-sectionally (n = 56) and longitudinally (n = 38), including comparisons with healthy women and cachexia-prone females with lung cancer. Morphologic changes occurred in the absence of pronounced muscle loss resultant of lean tissue reductions masked by concurrent increases in intra-muscular adipose. Longitudinal analyses suggest divergent phenotypes: non-cachectic patients (63% of BC cohort) demonstrated compositional shifts amid stable muscle quantity, whereas cachectic patients (37%) exhibited wasting of both muscle and adipose quantities alongside remodeling of externally-deposited adipose. Independent of weight, 32 of 38 patients with BC (84%) demonstrated clinically-relevant declines in muscle quantity and/or quality. Findings highlight the discordance between weight loss and underlying tissue dynamics, suggesting that conventional cachexia definitions may under-detect clinically relevant remodeling in early-stage BC. CT-based phenotyping may therefore refine risk stratification to better inform supportive interventions across cancer populations.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147574879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disparities in breast cancer incidence and survival by age, race, and molecular subtype in US women.","authors":"Lin Wang, Zhihao Wan, Vikramjit Dhillon, Xin Wang, Yin Zheng, Chika F Ezeana, Polly Niravath, Akshjot Puri, Kai Sun, Jenny Chang, Stephen T C Wong","doi":"10.1038/s41523-026-00935-y","DOIUrl":"https://doi.org/10.1038/s41523-026-00935-y","url":null,"abstract":"<p><p>Using SEER datasets spanning nearly five decades, we identified a striking longitudinal shift in the breast cancer mortality burden from older to younger women, revealing an evolving risk landscape that warrant challenges to prevailing assumptions about age-related vulnerability. Leveraging contemporary data (2010-2022), we examined how molecular subtype, race, and age intersect jointly to shape survival disparities. As expected, young Black women with triple-negative breast cancer (HR-/HER2-) exhibited significantly elevated hazard ratios, underscoring their urgent need for targeted interventions and prevention strategies. Importantly, we also uncovered disproportionately high mortality risks among Asian women: those under 50 years experienced poorer outcomes for triple-negative breast cancer. These findings suggest that distinct biological, hormonal, and sociodemographic factors may contribute to heterogeneity in cancer progression and survival across populations. In addition, demographic analyses revealed that Asian and Hispanic women have steadily increased in proportional representation, surpassing Black patients recently, underscoring critical population shifts in the breast cancer burden. Together, these results not only broaden current understanding of how age, ancestry, and molecular subtype converge to drive disparities, but also underscore the urgent need to embed these dimensions into personalized prevention, precision diagnostics, and tailored therapeutic strategies to reduce inequities in breast cancer outcomes.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147531280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multi-ancestry genome-wide study of tamoxifen metabolism and breast cancer recurrence.","authors":"Chiea Chuen Khor, Whee Sze Ong, Elaine Hsuen Lim, Etienne Chatelut, Sylvia Chen, Thomas E Muerdter, Jean E Abraham, Natalia Sutiman, Joanne Siok Liu Lim, Sze Sing Lee, Cecile Arellano, Zheng Li, Kar Seng Sim, Diana M Eccles, William J Tapper, Tom Maishman, Nathalie K Zgheib, Stefan Winter, Boian Ganchev, Leila Dorling, Qi Guo, Carlos Caldas, Helena M Earl, Louise Hiller, Janet Dunn, Raymond Chee Hui Ng, Yoon Sim Yap, Mabel Wong, Fuh Yong Wong, Nan Soon Wong, Peter Cher Siang Ang, Rebecca Dent, Peter Krippl, Uwe Langsenlehner, Tanja Langsenlehner, Arafat Tfayli, Elke Schaeffeler, Michel Eichelbaum, Ute Hamann, Peter A Fasching, Matthias W Beckmann, Florence Dalenc, Melanie White-Koning, Hiltrud B Brauch, Werner Schroth, Wilfried Renner, Matthias Schwab, Fabienne Thomas, Balram Chowbay","doi":"10.1038/s41523-026-00931-2","DOIUrl":"https://doi.org/10.1038/s41523-026-00931-2","url":null,"abstract":"<p><p>Tamoxifen's pharmacokinetics are strongly influenced by the highly polymorphic CYP2D6, while the influence of other genetic variants has been inconclusive. To further delineate this genotypic-phenotypic impact, we conducted a multi-ancestry genome-wide association study in 636 hormone-receptor-positive (HR+) breast cancer (BC) patients treated with 20 mg tamoxifen daily for ≥8 weeks and validated these genetic determinants in another 869 patients. Association with clinical outcomes was examined in 1326 non-metastatic HR+ patients receiving adjuvant tamoxifen. A genome-wide significant association with Z-endoxifen levels was observed at the CYP2D6 locus on chromosome 22 and its downstream region of TCF20 rs932376 A > G. Both CYP2D6 metabolizer status and TCF20 rs932376 A > G were independent predictors of endoxifen levels in multivariable analysis. CYP2D6 metabolizer status accounted for greater variability of mean endoxifen levels compared to TCF20 rs932376 A > G (91.2% vs 48.8%). These findings were replicated in validation cohorts. Neither TCF20 rs932376 nor CYP2D6 metabolizer status was significantly associated with BC outcomes after adjustment for known prognostic factors. Our study confirmed that CYP2D6 metabolizer status remains as the prime predictor of steady-state Z-endoxifen levels, while TCF20 rs932376 A > G has a smaller, independent effect. Both genetic factors were not associated with BC clinical outcomes.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147491343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}