Breast Cancer Research最新文献

Background: Our goal was to evaluate the impact of level of androgen receptor (AR) expression on outcomes in women with estrogen receptor α (ER) positive breast cancer. We sought to corroborate our preclinical findings that AR-agonists were efficacious in patients with ER-positive tumors that also expressed high levels of AR.

Methods: Tissue microarrays (TMAs) were prepared from primary tumor blocks from patients entered on a prospective randomized adjuvant trial of tamoxifen (Tam) alone or combined with fluoxymesterone (Flu), an AR-agonist, (NCCTG 89-30-52). TMAs were stained for ER and AR and expression examined in decile increments (0-100%) of positive invasive tumor nuclei. The primary endpoint was relapse-free survival (RFS).

Results: 301 (59%) of the 514 patients had sufficient tissue to determine ER and AR expression, where nuclear staining of > 70% was considered "enriched" and nuclear staining of ≤ 70% was considered "poor/moderate". Eleven (4%) of these patients had poor/moderate ER staining and were excluded from these analyses. The proportion of the ER-enriched tumors that also had AR-enriched expression levels was 56.3% in the Tam arm and 51.8% in the Tam + Flu arm. Within the AR-enriched patients, the cumulative incidence of RFS events showed an advantage for Tam + Flu over Tam alone that reached significance (Gray's test p = 0.0472).

Conclusions: Our findings suggest that an AR-agonist may be of value in AR-enriched, ER-enriched breast cancers and should be studied in future trials because of the availability of new, more tolerable AR-agonists.

Background: Currently, the primary methods for detecting HER2 expression levels are immunohistochemistry (IHC) and in situ hybridization (ISH), with the traditional standard being a HER2-positive score of 3 + accompanied by ERBB2 gene amplification detected through ISH. However, a new entity has recently emerged: HER2-low, defined as HER2 IHC 1 + or 2 + with negative ISH. HER2-low breast cancer, representing 45-60% of all HER2-negative tumors, has distinct biological characteristics and uncertain responses to conventional HER2-targeted therapies. Recent studies suggest varied clinical outcomes, highlighting the need for further investigation into the impact of HER2-low status on treatment efficacy and prognosis.

Objective: This meta-analysis evaluates the difference in complete pathological response (pCR), disease-free survival (DFS), and overall survival (OS) between HER2-low and HER2-zero phenotypes.

Methods: We systematically searched the main databases PubMed, Scopus, and Web of Science for articles evaluating women in neoadjuvant therapy expressing HER2-low and HER2-zero. We computed odds ratios (ORs) or hazard ratios (HRs) using DerSimonian and Laird random-effect models for all endpoints, with 95% confidence intervals (CIs). We assessed the heterogeneity using I² statistics. R, version 4.2.3, was used for statistical analyses.

Results: 38 studies totaling 70,104 patients were included. The HER2-low group accounted for 61.3% of patients while HR + status represented 52.4% in the whole research. In 67,839 women, the pCR was analyzed, which in the overall cohort analysis favored the HER2-zero group (OR 0.84; 95% CI 0.78-0.90; p = 0.000005; I² = 15%). Subgroup analyses for triple-negative breast cancer (TNBC) and HR + patients also favored HER2-zero expression, with an OR of 0.91 (95% CI 0.83-1.0; p < 0.041; I² = 12%) and 0.75 (95% CI 0.70-0.81; p < 0.000001; I² = 0%), respectively. In the multivariate analysis across all patients, both DFS and OS outcomes were significantly favorable for the HER2-low expression group, with HR 0.8317 (95% CI 0.7036-0.9832; p = 0.031) for DFS and HR 0.806 (95% CI 0.663-0.979; p = 0.03) for OS.

Conclusion: Based on our findings, HER2-zero status is associated with a significantly higher pathological complete response (pCR) rate compared to HER2-low in early-stage breast cancer, and other survival outcomes. These results suggest that HER2-zero should be considered a prognostic factor in early-stage breast cancer and taken into account in neoadjuvant treatment planning and future clinical research.

Background: Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancers and carries a worse prognosis relative to other breast cancer subtypes. This systematic review and meta-analysis evaluated the prognostic value of circulating tumor DNA (ctDNA) in early-stage TNBC.

Methods: A literature search was conducted using Ovid Medline, Elsevier EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science Databases for publications up to 11/16/2023. Results were uploaded to Covidence and assessed by two independent reviewers. Studies assessing the use of ctDNA to predict recurrence free survival and related outcomes as well as overall survival were included. All recurrence outcomes were combined during analysis. Statistical analysis was performed using Revman Web. Log-hazard ratios (HR) were pooled for studies reporting recurrence and death as a time-to-event outcomes. Odds ratios (OR) were calculated and pooled for studies reporting patient-level data on recurrence, death, and pathological complete response (pCR). Prospero ID: CRD42023492529.

Results: A total of 3,526 publications were identified through our literature search, and 20 publications (n = 1202 patients) were included in the meta-analysis. In studies that reported recurrence as a time-to-event outcome, post-neoadjuvant (before or after surgery) ctDNA + status was associated with a higher likelihood of disease recurrence (HR 4.12, 95% confidence interval [CI] 2.81-6.04). For studies that reported patient-level data, post-neoadjuvant ctDNA + status was associated with higher odds of disease recurrence (OR 6.72, 95% CI 3.61-12.54). Pooled log-HR also revealed that ctDNA + status in the post-neoadjuvant setting (before or after surgery) was associated with worse overall survival (HR 3.26, 95% CI 1.88-5.63).

Conclusions: Our findings suggest that ctDNA could be used as a prognostic biomarker to anticipate the risk of relapse. However, it remains unclear if therapeutic intervention for patients who are ctDNA + can improve outcomes. While more studies are needed before incorporating ctDNA into clinical practice, the findings of this meta-analysis are reassuring and show the promise of ctDNA as a biomarker.

Background: The multicohort, open-label, phase 1b KEYNOTE-173 study was conducted to investigate pembrolizumab plus chemotherapy as neoadjuvant therapy for triple-negative breast cancer (TNBC). This exploratory analysis evaluated features of the tumor microenvironment that might be predictive of response.

Methods: Cell fractions from 20 paired samples collected at baseline and after one cycle of neoadjuvant pembrolizumab prior to chemotherapy initiation were analyzed by spatial localization (tumor compartment, stromal compartment, or sum of tumor and stromal compartments [total tumor]) using three six-plex immunohistochemistry panels with T-cell, myeloid cell, and natural killer cell components. Area under the receiver operating characteristic curve (AUROC) was used to assess associations between immune subsets and gene expression signatures (T-cell-inflamed gene expression profile [Tcell_infGEP] and 10 non-Tcell_infGEP signatures using RNA sequencing) and pathologic complete response (pCR).

Results: At baseline, six immune subsets quantitated within the tumor compartment showed AUROC with 95% CIs not crossing 0.5, including CD11c⁺ cells (macrophage and dendritic cell [DC]: AUROC, 0.85; 95% confidence interval [CI] 0.63-1.00), CD11c⁺/MHCII⁺/CD163^-/CD68^- cells (DC: 0.76; 95% CI, 0.53-0.99), CD11c⁺/MHCII^-/CD163^-/CD68^- cells (nonactivated/immature DC: 0.80; 95% CI 0.54-1.00), and CD11c⁺/CD163⁺ cells (M2 macrophage: 0.77; 95% CI 0.55-0.99). Other associations with pCR included baseline CD11c⁺/MHCII^-/CD163^-/CD68^- (nonactivated/immature DC) within the total tumor (AUROC, 0.76; 95% CI 0.51-1.00) and the baseline CD11c/CD3 ratio within the tumor compartment (0.75; 95% CI 0.52-0.98). Changes in immune subsets following one cycle of pembrolizumab were not strongly associated with pCR. Although T-cell associations were relatively weak, specific CD8 subsets trended toward association. The AUROC for discriminating pCR based on Tcell_infGEP was 0.55 (95% CI 0.25-0.85); when detrended by Tcell_infGEP, AUROC varied for the non-Tcell_infGEP signatures. Tcell_infGEP expression trended higher in responders than in nonresponders when evaluating pCR.

Conclusions: Myeloid cell populations within the tumor compartment at baseline and Tcell_infGEP show a promising trend toward an association with pCR in a small subgroup of patients with early-stage TNBC treated with neoadjuvant pembrolizumab plus chemotherapy.

Trial registration: ClinicalTrials.gov, NCT02622074; registration date, December 2, 2015.

Background: The ataxia-telangiectasia mutated (ATM) kinase phosphorylates and activates several downstream targets that are essential for DNA damage repair, cell cycle inhibition and apoptosis. Germline biallelic inactivation of the ATM gene causes ataxia-telangiectasia (A-T), and heterozygous pathogenic variant (PV) carriers are at increased risk of cancer, notably breast cancer. This study aimed to investigate whether DNA methylation profiling can be useful as a biomarker to identify tumors arising in ATM PV carriers, which may help for the management and optimal tailoring of therapies of these patients.

Methods: Breast tumor enriched DNA was prepared from 2 A-T patients, 27 patients carrying an ATM PV, 6 patients carrying a variant of uncertain clinical significance and 484 noncarriers enrolled in epidemiological studies conducted in France and Australia to investigate genetic and nongenetic factors involved in breast cancer susceptibility. Genome-wide DNA methylation analysis was performed using the Illumina Infinium HumanMethylation EPIC and 450K BeadChips. Correlation between promoter methylation and gene expression was assessed for 10 tumors for which transcriptomic data were available.

Results: We found that the ATM promoter was hypermethylated in 62% of tumors of heterozygous PV carriers compared to the mean methylation level of ATM promoter in tumors of noncarriers. Gene set enrichment analyses identified 47 biological pathways enriched in hypermethylated genes involved in neoplastic, neurodegenerative and metabolic-related pathways in tumor of PV carriers. Among the 327 differentially methylated promoters, promoters of ARHGAP40, SCGB3A1 (HIN-1), and CYBRD1 (DCYTB) were hypermethylated and associated with a lower gene expression in these tumors. Moreover, using three different deep learning algorithms (logistic regression, random forest and XGBoost), we identified a set of 27 additional biomarkers predictive of ATM status, which could be used in the future to provide evidence for or against pathogenicity in ATM variant classification strategies.

Conclusions: We showed that breast tumors that arise in women who carry an ATM PV display a specific genome-wide DNA methylation profile. Specifically, the methylation pattern of 27 key gene promoters was predictive of ATM PV status of the women. These genes may also represent new medical prevention and therapeutic targets for these women.

Background: Each year, millions of women undergo breast biopsies. Of these, 80% are negative for malignancy but some may be at elevated risk of invasive breast cancer (IBC) due to the presence of benign breast disease (BBD). Cellular senescence plays a complex but poorly understood role in breast cancer development and the presence or absence of these cells may have prognostic value.

Methods: We conducted a case-control study, nested within a cohort of 15,395 women biopsied for BBD at Kaiser Permanente Northwest between 1971 and 2006. Cases (n = 512) were women who developed a subsequent invasive breast cancer (IBC) at least one year after the BBD biopsy; controls (n = 491) did not develop IBC during the same follow-up period. Using H&E-stained biopsy images, we predicted senescence based on deep learning models trained on replicative senescence (RS), ionizing radiation (IR), and various drug treatments. Age-adjusted and multivariable odds ratios (ORs) and 95% confidence intervals (CI) were estimated using unconditional logistic regression.

Results: The RS- and IR-derived senescence scores for adipose tissue and the RS-derived score for epithelial tissue were positively associated with the risk of IBC (adipose tissue - RS model: OR_{q4 vs. q1}=1.69, 95% CI 1.03-2.77, and IR model: OR_{q4 vs. q1}=1.73, 95%CI 1.06-2.82; epithelial tissue- RS model: OR_{q4 vs. q1}=1.53, 95% CI 1.05-2.22). The results were stronger among postmenopausal women and women with epithelial hyperplasia with/without atypia, and postmenopausal women also showed a positive association for stromal tissue with the RS model (OR_{q4 vs. q1}=1.84, 95%CI 1.12-3.04). There was an elevated risk of IBC in those with higher senescence scores in both epithelial and adipose tissue compared with those with low senescence scores in both (IR epithelium-IR fat: OR_{q2-4 vs. q1}=2.14, 95% CI 1.30-3.51; and IR epithelium-RS fat: OR_{q2-4 vs. q1}= 2.24, 95% CI 1.15-4.35).

Conclusions: This study suggests that nuclear senescence scores predicted by deep learning models in breast epithelial and adipose tissue can predict the risk of breast cancer development among women with BBD.

Background: Traditional surgical education is based on observation and assistance in surgical practice. Recently introduced deep learning (DL) techniques enable the recognition of the surgical view and automatic identification of surgical landmarks. However, there was no previous studies have conducted to develop surgical guide for robotic breast surgery. To develop a DL model for guiding the dissection plane during robotic mastectomy for beginners and trainees.

Methods: Ten surgical videos of robotic mastectomy procedures were recorded. Video frames taken at 1-s intervals were converted to PNG format. The ground truth was manually delineated by two experienced surgeons using ImageJ software. The evaluation metrics were the Dice similarity coefficient (DSC) and Hausdorff distance (HD).

Results: A total of 8,834 images were extracted from ten surgical videos of robotic mastectomies performed between 2016 and 2020. Skin flap dissection during the robotic mastectomy console time was recorded. The median age and body mass index of the patients was 47.5 (38-52) years and 22.00 (19.30-29.52) kg/m², respectively, and the median console time was 32 (21-48) min. Among the 8,834 images, 428 were selected and divided into training, validation, and testing datasets at a ratio of 7:1:2. Two experts determined that the DSC of our model was 0.828[Formula: see text]5.28 and 0.818[Formula: see text]6.96, while the HDs were 9.80[Formula: see text]2.57 and 10.32[Formula: see text]1.09.

Conclusion: DL can serve as a surgical guide for beginners and trainees, and can be used as a training tool to enhance surgeons' surgical skills.

Background: Lipid metabolic reprogramming is increasingly recognized as a hallmark of endocrine resistance in estrogen receptor-positive (ER+) breast cancer. In this study, we investigated alterations in lipid metabolism in ER + breast cancer cell lines with acquired resistance to common endocrine therapies and evaluated the efficacy of a clinically relevant fatty acid synthase (FASN) inhibitor.

Methods: ER + breast cancer cell lines resistant to Tamoxifen (TamR), Fulvestrant (FulvR), and long-term estrogen withdrawal (EWD) were derived. Global gene expression and lipidomic profiling were performed to compare parental and endocrine resistant cells. Lipid storage was assessed using Oil Red O (ORO) staining. The FASN inhibitor TVB-2640 was tested for its impact on lipid storage and cell growth. ¹³C₂-acetate tracing was used to evaluate FASN activity and the efficacy of TVB-2640.

Results: Endocrine resistant cells showed significant enrichment in lipid metabolism pathways and distinct lipidomic profiles, characterized by elevated triglyceride levels and enhanced cytoplasmic lipid droplets. ¹³C₂-acetate tracing revealed increased FASN activity in endocrine resistant cells, which was effectively reduced by TVB-2640. While TVB-2640 reduced lipid storage in most but not all cell lines, this did not correlate with decreased cell growth. Polyunsaturated fatty acids (PUFAs) containing 6 or more double bonds were elevated in endocrine resistant cells and remained unaffected or increased with TVB-2640.

Conclusion: Endocrine resistant breast cancer cells undergo a metabolic shift toward increased triglyceride storage and PUFAs with high degrees of desaturation. While TVB-2640 reduced lipid storage in most conditions, it had limited effects on the growth of endocrine resistant breast cancer cells. Targeting specific lipid metabolic dependencies, particularly pathways that produce PUFAs, represents a potential therapeutic strategy in endocrine resistant breast cancer.

Breast cancer (BRCA) is a common malignant tumor, and its immune microenvironment plays a crucial role in disease progression. In this research, we utilized single-cell RNA sequencing and bulk RNA sequencing technologies, combined with in vivo and in vitro experiments, to thoroughly investigate the immunological functions and mechanisms of FOLR2+ macrophages in BRCA. Our findings demonstrate a significant enhancement in the interaction between FOLR2+ macrophages and CD8⁺ T cells within the tumor tissues of BRCA patients. FOLR2 is closely associated with T cell infiltration in the tumor microenvironment of BRCA patients, particularly with CD8⁺ T cells. By secreting CXCL9 and engaging with CXCR3, FOLR2+ macrophages can activate the functionality of CD8⁺ T cells, thereby promoting cancer cell apoptosis. Further animal experiments confirm that FOLR2+ macrophages activate CD8⁺ T cells through the CXCL9-CXCR3 axis, exhibiting an antitumor immunity effect in BRCA. FOLR2+ macrophages play a crucial role in antitumor immunity in BRCA through the CXCL9-CXCR3 axis.