NPJ Breast Cancer最新文献

Pregnancy-associated breast cancer (PABC), diagnosed during or shortly after pregnancy, is a challenging entity with an aggressive biology and poor prognosis. This study analyzed the clinicopathological characteristics and gene expression profile of 33 PABC and 26 non-PABC patients using the nCounter BC360 Panel (NanoString). Notably, PABC showed a higher prevalence of basal-like tumors than non-PABC (48.48% vs 15.38%, p = 0.012) and displayed 73 differentially expressed genes (e.g., DEPDC1, CCNA2, PSAT1, CDKN3, and FAM83D), enriched in DNA repair and cell proliferation pathways. Through the PPI network, we also identified a cluster of cell-cycle regulation genes like MYC, FOXM1, or PTEN. Interestingly, differences emerged when comparing patients diagnosed during gestation (PABC-GS) and the postpartum period (PABC-PP), with PABC-PP showing increased expression of immune-related genes, including PD-1, and greater immune cell infiltration (Tregs, macrophages, neutrophils, B-cells). These findings suggest an enhanced proliferative capacity and impaired DNA repair in PABC, and underscore the role of immune infiltration in postpartum cases; providing insights into its aggressive nature and potential targets.

Hormone receptor-positive/HER2-negative breast cancer (BC) is the most common subtype of BC and typically occurs as an early, operable disease. In patients receiving neoadjuvant chemotherapy (NACT), pathological complete response (pCR) is rare and multiple efforts have been made to predict disease recurrence. We developed a framework to predict pCR using clinicopathological characteristics widely available at diagnosis. The machine learning (ML) models were trained to predict pCR (n = 463), evaluated in an internal validation cohort (n = 109) and validated in an external validation cohort (n = 151). The best model was an Elastic Net, which achieved an area under the curve (AUC) of respectively 0.86 and 0.81. Our results highlight how simpler models using few input variables can be as valuable as more complex ML architectures. Our model is freely available and can be used to enhance the stratification of BC patients receiving NACT, providing a framework for the development of risk-adapted clinical trials.

Adjuvant CDK4/6 inhibitors (abemaciclib and ribociclib) associated with endocrine therapy reduced the risk of relapse for HR+/HER2- early breast cancer (eBC) patients in the monarchE and NATALEE trials. In this population-based study, we assess the real-life proportion, and long-term prognosis of patients treated for HR+/HER2- eBC between 2005 and 2015, and eligible for adjuvant CDK4/6 inhibitors according to these trial inclusion criteria. Among 3,103 patients, N = 440 (14.2%) would have been eligible for adjuvant abemaciclib, and N = 1068 (34.4%) for ribociclib. Node-negative patients who would have been eligible for adjuvant ribociclib represent 10.9% of the eligible population. 21.7% of patients now eligible for adjuvant abemaciclib, and 32.1% for ribociclib did not receive (neo)adjuvant chemotherapy. After a median follow-up of 144.7 months, 10-year overall survival confirms the prognostic relevance of the inclusion criteria used in pivotal trials. This study provides real-life insights into the prevalence, clinicopathological characteristics and long-term prognosis of HR+/HER2- eBC patients now eligible for adjuvant CDK4/6 inhibitors.

Early-stage and metastatic breast cancers (MBC) can exhibit genomic heterogeneity, even within the same individual. Response to therapy in metastatic breast cancer patients with multiple metastases can also be heterogeneous, with different degrees of responsiveness to the same drug(s) across metastatic sites, termed "mixed response," within the same patient. Whether this treatment response variability is influenced by factors such as intrinsic tumor characteristics of metastatic lesions and/or the microenvironment is unknown. Through genomic analysis of multiple metastases from the same patient, assayed in 6 different patients who had exhibited mixed response on imaging, we identified that higher regulatory T cells (T reg) and CDKN2A gene expression values correlate with non-response, while the KRAS gene, KRAS amplicon, and CD8T cells were associated with response in individual metastases. These genomic features may explain mixed clinical responses and provide valuable insights into intrapatient variations in treatment sensitivity.

Using a novel unsupervised method to integrate multi-omic data, we previously identified a breast cancer group with a poor prognosis. In the current study, we characterize the biological features of this subgroup, defined as the high-risk group, using various data sources. Assessment of three published hypoxia signatures showed that the high-risk group exhibited higher hypoxia scores (p < 0.0001 in all three signatures), compared to the low-risk group. Our analysis of the immune cell composition using CIBERSORT and leukocyte fraction showed significant differences between the high and low-risk groups across the entire cohort, as well as within PAM50 subtypes. Within the basal subtype, the low-risk group had a statistically significantly higher spatial fraction of tumor-infiltrating lymphocytes (TILs) compared to the high-risk group (p = 0.0362). Our findings indicate that this subgroup with poor prognosis is driven by a distinct biological signature with high activation of hypoxia-related genes as well as a low number of TILs.

Endocrine therapy with CDK4/6 inhibitors is standard for estrogen receptor-positive, HER2-negative metastatic breast cancer (ER+/HER2- MBC), yet clinical resistance develops. Previously, we demonstrated that low doses of palbociclib activate autophagy, reversing initial G1 cell cycle arrest, while high concentrations induce off-target senescence. The autophagy inhibitor hydroxychloroquine (HCQ) induced on-target senescence at lower palbociclib doses. We conducted a phase I trial (NCT03774472 registered in ClinicalTrials.gov on 8/20/2018) of HCQ (400, 600, 800 mg/day) with palbociclib (75 mg/day continuous) and letrozole, using a 3 + 3 design. Primary objectives included safety, tolerability, and determining the recommended phase 2 dose (RP2D) of HCQ. Secondary objectives included tumor response and biomarker analysis. Fourteen ER+/HER2- MBC patients were evaluable [400 mg (n = 4), 600 mg (n = 4), 800 mg (n = 6)]. Grade 3 adverse events (AEs) included hematological (3 at 800 mg), skin rash (2 at 600 mg), and anorexia (1 at 400 mg), with no serious AEs. The best responses were partial (2), stable (11), and progression (1). Tumor reductions ranged from 11% to 30%, with one 55% increase. The two partial responders sustained tumor size reductions of 30% to 55% over an extended treatment period, lasting nearly 300 days. Biomarker analysis in responders demonstrated significant decreases in Ki67, Rb, and nuclear cyclin E levels and increases in autophagy markers p62 and LAMP1, suggesting a correlation between these biomarkers and treatment response. This phase I study demonstrated that HCQ is safe and well-tolerated and the RP2D was established at 800 mg/day with continuous low-dose palbociclib (75 mg/day) and letrozole (2.5 mg/day). These findings suggest that adding HCQ could potentially enhance the efficacy of low-dose palbociclib and standard letrozole therapy, pending verification in larger randomized studies.

Special histologic subtypes of breast cancer (BC) exhibit unique phenotypes and molecular profiles with diagnostic and therapeutic implications, often differing in behavior and clinical trajectory from common BC forms. Novel methodologies, such as artificial intelligence may improve classification. Genetic predisposition plays roles in a subset of cases. Uncommon BC presentations like male, inflammatory and pregnancy-related BC pose challenges. Emerging therapeutic strategies targeting genetic alterations or immune microenvironment are being explored.

Cancer disrupts intratumoral innate-adaptive immune crosstalk, but how the systemic immune landscape evolves during breast cancer progression remains unclear. We profiled circulating immune cells in stage I-III and stage IV triple-negative breast cancer (TNBC) patients and healthy donors (HDs). Metastatic TNBC (mTNBC) patients had reduced T cells, dendritic cells, and differentiated B cells compared to non-metastatic TNBC patients and HDs, partly linked to prior chemotherapy. Vδ1 γδ T cells from mTNBC patients produced more IL17 than those from HDs. Chemotherapy-naïve mTNBC patients showed increased classical monocytes and neutrophils. Transcriptional, proteomic, and functional analyses revealed that neutrophils in mTNBC exhibited enhanced migratory capacity, elevated granule proteins, and higher ROS production. Some immune changes, such as reduced non-switched B cells and heightened neutrophil migration, were evident in earlier TNBC stages. This study comprehensively maps systemic immunity in TNBC, guiding future research on patient stratification and immunomodulation strategies.

Discrimination can contribute to worse health outcomes, but its prevalence in breast cancer is not well studied. We aimed to understand how women with stage I-III breast cancer faced discrimination in health care and everyday settings through the Everyday Discrimination Scale, cross-sectional survey. 296 women, 178 (60%) Non-Hispanic White (NHW), 76 (26%) Non-Hispanic Black (NHB), and 42 (14%) Hispanic participated. NHB women reported significantly more discrimination in everyday life compared to NHW women (score 20.1 vs 16.1, p < 0.001) and Hispanic women (score 20.1 vs 16.0, p < 0.001). In the health care setting, NHB had statistically more frequent reports of being ignored (23.7% vs. 5.6%), treated with less respect (21.1% vs. 7.3%), and treated with less courtesy (18.7% vs. 6.2%; all P = < 0.001) when compared to NHW women. NHB women experience a higher degree of discrimination both inside and outside of health care. Further research to understand discrimination on breast cancer outcomes is warranted.

Patients with metastatic breast cancer face reduced quality of life and increased mortality rates, necessitating more effective anti-cancer strategies. Building on previous research that identified metastatic-niche-specific metabolic vulnerabilities, we investigated how a ketogenic diet enhances estrogen receptor (ER)-positive liver metastatic breast cancer's response to Fulvestrant (Fulv) treatment. Using in vitro cell lines and in vivo xenograft metastasis mouse models, we examined the molecular mechanisms of combining ER targeting with a ketogenic diet. We found that Fulv treatment downregulates the ketogenesis pathway enzyme OXCT1, leading to β-hydroxybutyrate accumulation and decreased tumor cell viability. We also explored interactions between glucose, palmitic acid, and β-hydroxybutyric acid. These findings establish the molecular basis and clinical potential of a ketogenic diet to enhance Fulv efficacy in patients with ER+ liver metastatic breast cancer, potentially improving survival outcomes and quality of life in this population.