Breast Cancer Research最新文献

Purpose: Endocrine therapy (ET) with or without abemaciclib/ribociclib is the current standard for intermediate- and high-risk hormone receptor (HR)-positive/HER2-negative early breast cancer (EBC) patients. The NATALEE trial showed that adding 3 years of ribociclib to ET improves the 4-year invasive Disease-Free Survival (iDFS) by 4.9% compared with ET alone. Real world data on long-term risk of relapse is crucial when taking decisions about the prescription of new adjuvant drugs.

Methods: This is a retrospective analysis of 8,825 HR-positive/HER2-negative EBC patients recruited from 5 adjuvant GEICAM trials enrolled from 1999 to 2010 and El Álamo IV registry (diagnosed between 2002 and 2005). To estimate their long-term outcomes, patients were grouped into 3 cohorts: cohort 1 (high-risk, stage III); cohort 2 (intermediate-risk, T0-2N1, T3N0 or T2N0 and either histological grade (G)3, or GX/G2 with Ki-67 ≥ 20%); and cohort 3 (low-risk, stage I and T2N0 and either G1, or GX/G2 with Ki-67 < 20%).

Results: The distribution was 20.0% of patients in cohort 1, 36.0% in cohort 2 and 44.0% in cohort 3. With a median follow-up of 10.7 years, the 10-year iDFS were 53.8%, 73.8% and 84.0%, 10-y distant Disease-Free Survival were 56.3%, 77.3% and 87.8%, and 10-year overall survival (OS) were 66.7%, 84.6% and 91.9%, in cohorts 1, 2 and 3 respectively. In cohort 1, invasive relapse rate (IRR) and distant relapse rate (DDR) had a peak in years 2-3 and a second peak in year 7, while in cohorts 2 and 3 the rates increased steadily (higher at all time-points in cohort 2). In cohort 1, death rate (DR) had a soft peak in years 3-4 and years 7-8 while in cohorts 2 and 3 they increased steadily (also higher at all time-points in cohort 2).

Conclusions: Intermediate-risk patients have a 10-year iDFS of 73.8%, and 10-year OS of 84.6%. The IRR, DDR and DR increased steadily in cohort 2 (as in cohort 3), in contrast to cohort 1. Further follow-up of the NATALEE trial is needed to determine the true benefit of adjuvant ribociclib in intermediate-risk patients and to decide the best ET strategy for these patients. Trial registration number ClinTrials.gov: GEICAM/9805: NCT00121992 (Study Registration Date: 2005-07-18); GEICAM/9906: NCT00129922 (Study Registration Date: 2005-08-10); GEICAM/2003-02: NCT00129389 (Study Registration Date: 2005-08-10); GEICAM/ 2003-10: NCT00129935 (Study Registration Date: 2005-08-11) and GEICAM/ 2006-10: NCT00543127 (Study Registration Date: 2007-10-11).

Background: Triple-negative breast cancer (TNBC) remains difficult to treat because of poor immunogenicity and an immunosuppressive tumor microenvironment (TME). Pyroptotic signaling can enhance antitumor immunity through inflammatory cytokine release, but upstream regulators linking this process to macrophage phenotypic remodeling in TNBC remain incompletely understood. We investigated whether zinc finger protein 831 (ZNF831) restrains TNBC progression in association with enhanced NLR family pyrin domain containing 3 (NLRP3)-related pyroptotic signaling and macrophage phenotypic remodeling.

Methods: We integrated The Cancer Genome Atlas (TCGA-BRCA), Gene Expression Omnibus bulk datasets (GSE103091, GSE176078), and breast cancer single-cell RNA-sequencing datasets from Tumor Immune Single-cell Hub 2 (BRCA_GSE114727_inDrop, BRCA_GSE148673, BRCA_GSE150660, and BRCA_GSE161529) to evaluate ZNF831 expression, prognosis, pathway enrichment, and macrophage-related immune features. ZNF831 was overexpressed or silenced in MDA-MB-231 and 4T1-luc cells to assess macrophage recruitment, macrophage phenotypic changes, NLRP3-associated pyroptotic signaling, and IL-1β/IL-18 release. Chromatin immunoprecipitation (ChIP)-qPCR, actinomycin D chase assays, and RNA immunoprecipitation (RIP)-qPCR were performed primarily in MDA-MB-231 cells to evaluate promoter association, mRNA stability, and transcript interaction. In vivo efficacy was assessed in 6-week-old female BALB/c mice bearing orthotopic 4T1-luc tumors treated intratumorally with MCC950 or PBS.

Results: Across cohorts, higher ZNF831 expression was associated with favorable outcome, an M1-skewed macrophage signature, and enrichment of pyroptosis-related pathways. In vitro, ZNF831 overexpression enhanced macrophage recruitment, shifted macrophage phenotypes toward a more pro-inflammatory M1-like state while suppressing M2-like features, promoted NLRP3-associated pyroptotic signaling, and increased IL-1β and IL-18 release, whereas ZNF831 knockdown produced opposite trends. Mechanistically, ZNF831 showed association with the NLRP3 promoter and selective enrichment of NLRP3 mRNA, consistent with multi-level regulation of NLRP3 expression. In vivo, pharmacologic inhibition with MCC950 attenuated the antitumor effects and macrophage-related changes associated with ZNF831 overexpression.

Conclusions: These findings support a role for the ZNF831-NLRP3 axis in shaping a more inflammatory TNBC microenvironment and suggest that ZNF831 may contribute to macrophage M1-like phenotypic remodeling through NLRP3-associated pyroptotic signaling.

Background: TP53 mutation is a critical driver of breast cancer, yet its relationship with treatment outcomes for breast cancer remains unclear. This study investigates the association between TP53 mutation and response to CDK4/6 inhibitors (CDK4/6i) and immune checkpoint inhibitors (ICI) in breast cancer using real-world data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) cohort, focusing on age-related differences.

Methods: METABRIC (n = 1355) was used for initial survival analysis, and gene set enrichment analysis (GSEA) was performed to identify pathways enriched in TP53-mutated ER-positive/HER2-negative breast cancers. Clinical and genomic data of metastatic breast cancer (mBC) patients in Japan were analyzed in the C-CAT (n = 1668) cohort. Treatment duration was used as a real-world surrogate endpoint reflecting treatment exposure and potential clinical benefit. Patients were stratified by age into four groups: Adolescents and Young Adults (AYA; 15-39 years), perimenopausal (40-54 years), menopausal (55-64 years), and older (≥ 65 years).

Results: TP53 mutations were associated with poor prognosis in the METABRIC cohort. GSEA showed TP53-mutated tumors were enriched with gene sets related to cell proliferation and immune response, while TP53 wild-type tumors enriched for estrogen response pathways. In the C-CAT cohort, TP53 mutations were linked to shorter CDK4/6i treatment duration with similar trends observed for both abemaciclib and palbociclib. However, TP53 mutations were not associated with ICI treatment duration. Patients in the AYA group had the shortest treatment duration, with TP53 mutation prevalence decreasing with age. In age-stratified analyses, TP53 mutation was associated with shorter treatment duration in perimenopausal, menopausal, and older groups but not in the AYA group. However, formal interaction testing did not detect a significant interaction between TP53 mutation and age group.

Conclusion: TP53 mutation is associated with shorter CDK4/6i treatment duration, highlighting the importance of considering both genomic and age-related clinical context when interpreting treatment duration in ER-positive/HER2-negative breast cancer.

We evaluated whether Apolipoprotein E (APOE) ε2 homozygosity, a germline variant associated with lower LDL cholesterol, is linked to reduced risk of breast cancer. We analyzed data from 234,857 cancer-free and dementia-free women in the UK Biobank. APOE genotypes were classified as ε2 homozygotes, ε2 heterozygotes, and non-ε2 carriers. Incident breast cancer was assessed via national registry linkage. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs). Subgroup analyses were conducted by lifestyle, metabolic, and female-specific factors. Over a median follow-up of 12.3 years, 7,961 first primary breast cancers occurred. Compared to non-ε2 carriers, ε2 homozygotes had significantly lower breast cancer risk (HR, 0.64; 95% CI 0.45-0.90). The protective association of ε2/ε2 was stronger in participants with smoking history. APOE ε2 homozygosity was associated with reduced risk of breast cancer, particularly under inflammatory stress. These findings suggest that genetically determined lipid and inflammatory regulation may influence breast cancer susceptibility.

Background: The PAM50 classifier predicts breast cancer prognosis but requires 50 genes and specialised platforms. We derived CorePAM, the smallest data-driven PAM50 subset maintaining non-inferior prognostic performance relative to a full 50-gene Cox elastic-net model, without pre-specifying gene count.

Methods: Cox elastic-net regression ([Formula: see text]) with deterministic 10-fold cross-validation was applied in the SCAN-B cohort (N = 3069; GSE96058). Gene selection followed a pre-specified non-inferiority margin (ΔC-index = 0.010). External validation used four independent cohorts: TCGA-BRCA (N = 1072; RNA-seq), METABRIC (N = 1978; microarray; disease-specific survival), GSE20685 (N = 327; microarray), and GSE1456 (N = 159; microarray). Incremental value over a clinical model (CORE-A: age and ER status) was assessed by bootstrap ΔC-index. Secondary analyses evaluated pathologic complete response (pCR) prediction in four neoadjuvant cohorts (N = 697) plus I-SPY2 (N = 986).

Results: CorePAM comprises 24 genes with an out-of-fold C-index of 0.670 (gap vs 50-gene maximum: 0.009). The score was independently associated with survival in all validation cohorts: TCGA-BRCA (HR = 1.20), METABRIC DSS (HR = 1.41), GSE20685 (HR = 1.40), GSE1456 (HR = 1.71); all [Formula: see text]. Random-effects meta-analysis (K = 4) yielded pooled HR = 1.37 (95% CI 1.24-1.52; [Formula: see text] = 38.2%; [Formula: see text]). CorePAM provided incremental value beyond CORE-A and remained significant after adjustment for T-stage and nodal status. For pCR, pooled OR 1.69 (95% CI 1.39-2.05; [Formula: see text] = 0%; [Formula: see text]).

Conclusions: CorePAM-a 24-gene PAM50-derived score-met the pre-specified ΔC-index non-inferiority criterion relative to a 50-gene Cox elastic-net comparator in derivation and retained prognostic discrimination across four external RNA-seq and microarray cohorts, remained significant after anatomical staging adjustment, and was associated with pCR in secondary neoadjuvant analyses. This reduction from 50 to 24 genes may simplify future assay development, although platform-specific analytical validation is required before clinical deployment.

Background: Tamoxifen (TAM) resistance remains a challenge in estrogen receptor-positive breast cancer treatment. Current research suggested that mesenchymal stem cells (MSCs) derived exosomes may mediate chemoresistance, but the underlying mechanisms are unclear. This study investigates how exosomes from tamoxifen-pretreated MSCs (Tt-MSC-exos) promote tamoxifen resistance through the miR-137/SERPINA3 axis.

Methods: We isolated exosomes using ultracentrifugation. To investigate the effect of Tt-MSC-exos on TAM resistance, we co-cultured Tt-MSC-exos with ER-positive breast cancer cells and evaluated the cellular functional changes and apoptosis levels. Second-generation transcriptome sequencing was used to analyze the key genes for TAM resistance, and a dual luciferase reporter assay was used to detect the upstream factors of the key genes. The results were further validated by cellular function assays, xenograft modeling studies, and database analysis.

Results: We demonstrated that Tt-MSC-exos promote TAM resistance in ER-positive breast cancer cells. Next-generation sequencing revealed that the key gene for Tt-MSC-exos promoting resistance was SERPINA3. Downregulation of SERPINA3 expression enhances TAM resistance in breast cancer cells. In addition, we found that miR-137, which was highly expressed in Tt-MSC-exos, could bind to the 3' UTR region of SERPINA3 in breast cancer cells and thus inhibit the expression of SERPINA3.

Conclusions: In this study, we clarified that Tt-MSC-exos inhibit the expression level of SERPINA3 in cancer cells by delivering miR-137 to ER-positive breast cancer cells, which in turn leads to TAM resistance in breast cancer. This study provides a new idea to overcome endocrine therapy resistance in ER-positive breast cancer.

Background:  Mammographic density (MD) is a known predictor of breast cancer risk and may be influenced by modifiable lifestyle factors. This study aimed to assess the association between adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations prior to diagnosis and MD in women diagnosed with breast cancer.

Methods:  We analyzed data from 759 breast cancer patients recruited from eight Spanish hospitals enrolled in the case-case Breast Cancer & Density Association Study. Participants completed an epidemiological and a food frequency questionnaire. A standardized score was constructed to assess adherence to six WCRF/AICR recommendations. MD percentage was measured using the validated DM-Scan software on the digital mammogram of the contralateral, tumor-free, breast obtained prior to any treatment. Standardized prevalences and standardized prevalence ratios (SPRs) for four MD categories and for MD ≥ 50% across categories of adherence to the WCRF/AICR recommendations were estimated based on multinomial and binary multivariable logistic regression models.

Results:  Overall, adherence to the WCRF/AICR recommendations was not consistently associated with MD. However, the standardized prevalence of MD ≥ 50% was higher among women with high adherence compared to those with low adherence (SPR _{high vs. low} = 1.73; 95% CI = 1.03-2.91). This positive association was particularly evident with the physical activity recommendation (SPR _{fully met vs. no/partially met} = 1.51; 95% CI = 1.02-2.25).

Conclusions:  Breast cancer participants with greater adherence to the WCRF/AICR recommendations prior to diagnosis, particularly to physical activity guidelines, showed higher percent MD at diagnosis. This association likely reflects lower absolute breast adiposity rather than a greater amount of fibroglandular tissue, and would therefore not imply an increased carcinogenic risk. These findings highlight the complex relationship between lifestyle behaviors and breast tissue composition.

Background: Cryoablation is an emerging minimally invasive ablative technique for selected patients with early-stage breast cancer. The FIRST (FreezIng bReaST cancer in Brazil) trial was designed to evaluate the pathological efficacy and safety of cryoablation followed by surgery, to assess the accuracy of imaging modalities in predicting complete pathological response, and to explore technical predictors of successful tumor ablation.

Methods: This prospective, multicenter, non-randomized, single-arm phase II study enrolled adults with unifocal invasive breast cancer ≤ 2.5 cm, clearly visible on ultrasound and eligible for upfront surgery. All patients underwent ultrasound-guided cryoablation using a 2.4-mm cryoprobe, followed by standard surgical resection 14-28 days later. Complete ablation was defined as the absence of residual invasive or in situ carcinoma on final pathology. Secondary outcomes included imaging-pathology correlation and the association between tumor size, ice-ball dimensions, and ablation success.

Results: Among 48 evaluable patients, the invasive complete ablation rate was 97.9%, with 100% success in tumors ≤ 2.0 cm on MRI. The complete ablation rate was 89.6%, increasing to 96.9% for tumors ≤ 2.0 cm and 100% for tumors ≤ 1.0 cm. Only one patient (2.1%) had residual invasive disease (3 mm). Residual ductal carcinoma in situ was observed in 12.5% of patients, with a mean size of 2.2 mm. Cryoablation was well tolerated, with one minor skin burn (2.1%) and no serious adverse events. MRI demonstrated high predictive accuracy for complete response (negative predictive value, 93.0%), whereas ultrasound and mammography were less accurate (negative predictive values, 9.3% and 34.9%, respectively). Ice-ball margins ≥ 1 cm beyond the tumor were associated with complete ablation in most cases.

Conclusions: Cryoablation achieved high rates of complete tumor ablation with an excellent safety profile, particularly in tumors ≤ 2.0 cm, in carefully selected patients with early-stage invasive breast cancer. These findings provide robust pathological and imaging validation of cryoablation as an effective ablative approach; however, they do not support its use as a standalone definitive therapy or, even when combined with adjuvant treatments such as radiotherapy and endocrine therapy, as a standard of care at this stage. As a phase II study, these results are not practice-changing and warrant confirmation in randomized phase III trials to evaluate long-term oncologic outcomes and to define the potential role of cryoablation within surgical de-escalation strategies.

Trial registration: ClinicalTrials.gov Identifier NCT05398497 (Registration date May 26, 2022).

Background: Neoadjuvant chemotherapy (NAC) is a critical therapeutic strategy for locally advanced breast cancer; however, its clinical utility is constrained by tumor heterogeneity and a lack of reliable predictive biomarkers. Integrating single-omics, multimodal, and multi-omics technologies provides comprehensive insights into the tumor biology, while artificial intelligence (AI) facilitates the efficient integration and interpretation of these high-dimensional data.

Main body: Based on a comprehensive literature search, we review and synthesize existing literature on the progress of AI-driven data integration in the NAC of breast cancer. We highlight the significant role of AI in predicting treatment response, discovering biomarkers, and profiling tumor heterogeneity and immune microenvironment. We also discussed the major challenges, including data quality, model interpretability, ethical concerns, and clinical translation in AI-empowered multi-omics studies. Moreover, recent advances in spatial multi-omics and large language models to decode intratumoral heterogeneity and to support clinical decision were also discussed. However, despite these significant progressions, translation of these innovations into practice still requires data-sharing architectures and interdisciplinary collaboration.

Conclusions: AI empowered data integration holds profound potential to decode the complex molecular landscape of breast cancer, which will ultimately promote precise personalized NAC strategies and prognosis of patients.

Background and objective: Cancer-associated fibroblasts (CAFs), critical constituents of the tumor microenvironment, promote tumor progression and therapeutic resistance through exosome secretion. However, the mechanisms by which CAF-derived exosomes contribute to trastuzumab resistance in HER2-positive breast cancer remain unclear. This study investigated whether CAF-derived exosomes activate the YAP-USP8 axis to stabilize HER2 and induce trastuzumab resistance.

Methods: Primary CAFs and normal fibroblasts (NFs) were isolated from HER2-positive breast cancer specimens, and exosomes were characterized by TEM, nanoparticle tracking analysis, and immunoblotting of exosomal markers. HER2-positive breast cancer cells (HCC1954 and BT-474) were treated with CAF- or NF-derived exosomes in vitro. Mechanistic studies were performed mainly in HCC1954 cells, whereas BT-474 cells were used for validation. Cargo dependency was assessed using RNase/Proteinase K protection assays, and YAP pathway involvement was examined using Verteporfin. In vivo tumor growth was evaluated using xenograft models.

Results: CAF-derived exosomes reduced LATS1 and YAP phosphorylation (p < 0.001), enhanced nuclear YAP accumulation, and upregulated USP8 transcription, leading to HER2 stabilization (P < 0.001). Membrane disruption abolished Hippo suppression, indicating dependence on intravesicular cargo. CAF-exo treatment increased proliferation, elevated trastuzumab IC₅₀, reduced apoptosis, and accelerated tumor growth in vivo (all p < 0.001). These effects were reproduced in BT-474 cells and were reversed by YAP or USP8 silencing. Pharmacological inhibition of YAP similarly restored trastuzumab sensitivity. TCGA-BRCA analysis revealed positive correlations between YAP1 and USP8, and between USP8 and ERBB2, supporting the molecular relevance of this axis.

Conclusion: This study identified a novel CAF-exosome-YAP-USP8-HER2 signaling axis that drives trastuzumab insensitivity in HER2-positive breast cancer. Intervening in this pathway may represent a potential treatment approach to counteract microenvironment-induced chemoresistance.