Telomere fusion threshold identifies a poor prognostic subset of breast cancer patients.
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ABSTRACT:
SUBMITTER: Simpson K
PROVIDER: S-EPMC4449122 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The clinical utility and prognostic impact of presumed primary breast or ovarian cancer among patients with an unfavorable subset of cancer of unknown primary site (CUP) remains unclear. We aimed to evaluate the clinical relevance of the presumed primary site of CUP and the clinical outcome of site-specific therapy based on such presumptions.Patients referred to our center who were diagnosed with unfavorable-subset CUP and treated between April 2007 and March 2015 were enrolled in this study. Data were collected retrospectively from the hospital database and electronic medical records. Presumptive primary breast or ovarian cancer was based on histological and immunohistochemical analyses and metastatic patterns. The outcomes of patients with unfavorable-subset CUP with a putative primary site in the breast or ovary (P-CUP) and of patients with unfavorable-subset CUP, but without P-CUP (U-CUP), were assessed.A total of 780 patients were referred to our hospital with malignancy of unknown origin. Of these, 409 patients were diagnosed with CUP and 344 patients with unfavorable-subset CUP. Following clinicopathological examination, 40 (11.6%) of the 344 patients had P-CUP and the remaining 303 (88.3%) patients had U-CUP. In total, 136 patients received chemotherapy (22 with P-CUP and 114 with U-CUP). Among the 22 patients with P-CUP, three received hormonal therapy for breast cancer, and 19 received chemotherapy based on the presumed primary organ (breast, 4; ovaries, 15). Conventional platinum-based chemotherapy was administered to 105 patients with U-CUP and non-platinum drug treatment to nine patients. The objective response rates were 61.1% (95% confidence interval [CI]: 38.6-83.6) and 41.1% (95% CI: 31.8-50.4) for patients with P-CUP and U-CUP, respectively. The median overall survival durations were 50.0 months and 16.9 months (log-rank: P?=?0.002) for patients with P-CUP and U-CUP, respectively. P-CUP was identified as an independent predictor of good prognosis according to multivariate analysis.Patients with P-CUP had higher response rates and a better prognosis compared with patients with U-CUP. It might thus be reasonable to classify this subset as a new category of CUP with a favorable prognosis.
| S-EPMC5809895 | biostudies-literature
Project description:The bone marrow (BM) is a major organ of breast cancer (BC) dormancy and a common source of BC resurgence. Gap junctional intercellular communication (GJIC) between BC cells (BCCs) and BM stroma facilitates dormancy. This study reports on a hierarchy of BCCs with the most immature subset (Oct4(hi)/CD44(hi/med)/CD24(-/+)) demonstrating chemoresistance, dormancy, and stem cell properties: self-renewal, serial passaging ability, cycling quiescence, long doubling time, asymmetric division, high metastatic and invasive capability. In vitro and in vivo studies indicated that this subset was responsible for GJIC with BM stroma. Similar BCCs were detected in the blood of patients despite aggressive treatment and in a patient with a relatively large tumor but no lymph node involvement. In brief, these findings identified a novel BCC subset with stem cell properties, with preference for dormancy and in the circulation of patients. The findings establish a working cellular hierarchy of BCCs based on phenotype and functions.
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Project description:Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women's risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80-0.88) and 0.81 (95% CI: 0.76-0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk.
| S-EPMC8807602 | biostudies-literature
Project description:Breast cancer (BCa) molecular subtypes include luminal A, luminal B, normal-like, HER-2-enriched, and basal-like tumors, among which luminal B and basal-like cancers are highly aggressive. Biochemical pathways associated with patient survival or treatment response in these more aggressive subtypes are not well understood. With the limited availability of pathologically verified clinical specimens, cell line models are routinely used for pathway-centric studies. We measured the metabolome of luminal and basal-like BCa cell lines using mass spectrometry, linked metabolites to biochemical pathways using Gene Set Analysis, and developed a novel rank-based method to select pathways on the basis of their enrichment in patient-derived omics data sets and prognostic relevance. Key mediators of the pathway were then characterized for their role in disease progression. Pyrimidine metabolism was altered in luminal versus basal BCa, whereas the combined expression of its associated genes or expression of one key gene, ribonucleotide reductase subunit M2 (RRM2) alone, associated significantly with decreased survival across all BCa subtypes, as well as in luminal patients resistant to tamoxifen. Increased RRM2 expression in tamoxifen-resistant patients was verified using tissue microarrays, whereas the metabolic products of RRM2 were higher in tamoxifen-resistant cells and in xenograft tumors. Both genetic and pharmacological inhibition of this key enzyme in tamoxifen-resistant cells significantly decreased proliferation, reduced expression of cell cycle genes, and sensitized the cells to tamoxifen treatment. Our study suggests for evaluating RRM2-associated metabolites as noninvasive markers for tamoxifen resistance and its pharmacological inhibition as a novel approach to overcome tamoxifen resistance in BCa.
| S-EPMC4198742 | biostudies-literature
Project description:BackgroundPatients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) and disease-related poor prognostic factors are not well characterized. We aimed to describe patient demographics, disease characteristics, treatment patterns and patient-reported outcomes in a subset of HR+/HER2- ABC patients with these factors [at the time when cyclin-dependent kinase (CDK) 4 and 6 inhibitors were being introduced] and understand how these factors informed treatment decisions at the time of the survey.MethodsReal-world data were derived from a large, multinational, point-in-time survey of oncologists and their consulting patients with HR+/HER2- ABC in the EU5 and USA over March-June 2017, at the start of the changing treatment landscape. Analysis focused on four poor prognostic factors: visceral metastases, liver metastases (subset of visceral metastases), progesterone receptor-negative status and high tumor grade.ResultsIn total, 2259 patients with HR+/HER2- ABC had records eligible for this analysis. At least one poor prognostic factor was present in 63% of patients (most common visceral metastases; least common progesterone receptor-negative status), with varying degrees of overlap between factors. For physician-reported outcomes, pain increased, whereas performance status and activities of daily living declined with presence of poor prognostic factors, especially liver metastases. No clear trends were observed for patient-reported outcomes. Treatment with combined endocrine therapy plus CDK4 and 6 inhibitors was infrequent, as these agents were entering the market.ConclusionsMore than 60% of the HR+/HER2- ABC Adelphi Real World Disease Specific Programme™ sample had ≥1 disease-related poor prognostic factor, and patients appeared to be heterogeneous regarding occurrence and distribution of these factors. These patients typically have increased pain and reduced performance status, highlighting the importance of implementing effective therapy with CDK4 and 6 inhibitors. Future studies could inform how the treatment landscape has evolved over time with respect to patients with poor prognostic factors.
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Project description:BACKGROUND:The prognostic nutritional index (PNI), which is an easily calculated nutritional index, is significantly associated with patient outcomes in various solid malignancies. This study aimed to evaluate the prognostic impact of PNI changes in patients with breast cancer undergoing neoadjuvant chemotherapy (NAC). METHODS:We reviewed patients with breast cancer who underwent NAC and a subsequent surgery for breast cancer between 2005 and 2016. PNI before and after NAC were calculated using the following formula: 10?×?serum albumin (g/dl)?+?0.005?×?total lymphocyte count/mm3. The relationship between PNI and prognosis was retrospectively analyzed. RESULTS:In total, 191 patients were evaluated. There was no significant difference in disease-free survival (DFS) between the pre-NAC PNI high group and the pre-NAC PNI low group (cutoff: 53.1). However, PNI decreased in 181 patients (94.7%) after NAC and the mean PNI also significantly decreased after NAC from 52.6?±?3.8 pre-NAC to 46.5?±?4.4 post-NAC (p?<?0.01). The mean ?PNI, which was calculated as pre-NAC PNI minus post-NAC PNI, was 5.4. The high ?PNI group showed significantly poorer DFS than the low ?PNI group (cut off: 5.26) (p?=?0.015). Moreover, high ?PNI was an independent risk factor of DFS on multivariate analysis (p?=?0.042). CONCLUSIONS:High decrease of PNI during NAC predicts poor prognosis. Thus, maintaining the nutritional status during NAC may result in better treatment outcomes in patients with breast cancer.
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Project description:PurposeThe aim of this study was to investigate whether young age at onset of breast cancer is an independent prognostic factor in patients from the Japanese Breast Cancer Registry, after adjustment of known clinicopathological prognostic factors.MethodsOf the 53,670 patients registered between 2004 and 2006 and surveyed after a 5-year follow-up prognosis, 25,898 breast cancer patients (48.3 %), who were obtained prognostic data, were examined. Clinicopathological factors were compared between young adult (YA; <35 years), middle-aged adult (MA; 35-50 years), and older adult (OA; >50 years) patients. Five-year disease-free survival (DFS) and overall survival (OS) rates were studied.ResultsYA patients were associated with an advanced TNM stage and aggressive characteristics (e.g. human epidermal growth factor receptor 2 (HER2)-positive or oestrogen receptor (ER)-negative breast cancers) compared to MA and OA patients (P < 0.001). The 5-year DFS and OS rates were 79.4 % and 90.8, 88.5 and 95.0 %, and 87.8 % and 91.6 % for YA, MA, and OA patients, respectively. From the multivariable regression analysis, young age at onset was confirmed as an independent prognostic factor for both DFS (hazard ratio 1.73, 95 % confidence interval 1.42-2.10; P < 0.001) and OS (hazard ratio 1.58, 95 % confidence interval 1.16-2.15; P = 0.004).ConclusionsYoung age at onset is an independent negative prognostic factor in breast cancer. Further studies are required to develop new therapeutic strategies for YA breast cancer patients.
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Project description:BackgroundAccumulating evidences indicate that the signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) plays a key role in the development and progression of many human cancers. However, the underlying mechanism and prognosis value of SCUBE3 in breast cancer are still unclear.MethodsThe clinical data of 137 patients with breast cancer who underwent surgical resection in Taizhou Hospital of Zhejiang Province were retrospectively analyzed. We first conducted a comprehensive study on the expression pattern of SCUBE3 using the Tumor Immune Estimation Resource (TIMER) and UALCAN databases. In addition, the expression of SCUBE3 in breast tumor tissues was confirmed by immunohistochemistry. The protein-protein interaction analysis and functional enrichment analysis of SCUBE3 were analyzed using the STRING and Enrichr databases. Moreover, tissue microarray (TMA) was used to analyze the relationship between SCUBE3 expression levels and clinical-pathological parameters, such as histological type, grade, the status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2). We further supplemented and identified the above results using the UALCAN and bc-GenExMiner v4.4 databases from TCGA data. The correlation between the expression of SCUBE3 and survival was calculated by multivariate Cox regression analysis to investigate whether SCUBE3 expression may be an independent prognostic factor of breast cancer.ResultsWe found that the expression level of SCUBE3 was significantly upregulated in breast cancer tissue compared with adjacent normal tissues. The results showed that the distribution of breast cancer patients in the high expression group and the low expression group was significantly different in ER, PR, HER2, E-cadherin, and survival state (p < 0.05), but there was no significant difference in histologic grade, histologic type, tumor size, lymph node metastasis, TMN stage, subtypes, or recurrence (p > 0.05). In addition, the high expression of SCUBE3 was associated with relatively poor prognosis of ER- (p = 0.012), PR- (p = 0.029), HER2 + (p = 0.007). The multivariate Cox regression analysis showed that the hazard ratio (HR) was 2.80 (95% CI 1.20-6.51, p = 0.0168) in individuals with high SCUBE3 expression, and HR was increased by 1.86 (95% CI 1.06-3.25, p = 0.0300) for per 1-point increase of SCUBE3 expression.ConclusionsThese findings demonstrate that the high expression of SCUBE3 indicates poor prognosis in breast cancer. SCUBE3 expression may serve as a potential diagnostic indicator of breast cancer.
| S-EPMC8130162 | biostudies-literature
Project description:Breast cancer is one of the most common female malignancies worldwide. Due to its early metastases formation and a high degree of malignancy, the 10 year-survival rate of metastatic breast cancer does not exceed 30%. Thus, more precise biomarkers are urgently needed. In our study, we first estimated the tumor microenvironment (TME) infiltration using the xCell algorithm. Based on TME infiltration, the three main TME clusters were identified using consensus clustering. Our results showed that the three main TME clusters cause significant differences in survival rates and TME infiltration patterns (log-rank test, p = 0.006). Then, multiple machine learning algorithms were used to develop a nine-pathway-based TME-related risk model to predict the prognosis of breast cancer (BRCA) patients (the immune-related pathway-based risk score, defined as IPRS). Based on the IPRS, BRCA patients were divided into two subgroups, and patients in the IPRS-low group presented significantly better overall survival (OS) rates than the IPRS-high group (log-rank test, p < 0.0001). Correlation analysis revealed that the IPRS-low group was characterized by increases in immune-related scores (cytolytic activity (CYT), major histocompatibility complex (MHC), T cell-inflamed immune gene expression profile (GEP), ESTIMATE, immune, and stromal scores) while exhibiting decreases in tumor purity, suggesting IPRS-low patients may have a strong immune response. Additionally, the gene-set enrichment analysis (GSEA) result confirmed that the IPRS-low patients were significantly enriched in several immune-associated signaling pathways. Furthermore, multivariate Cox analysis revealed that the IPRS was an independent prognostic biomarker after adjustment by clinicopathologic characteristics. The prognostic value of the IPRS model was further validated in three external validation cohorts. Altogether, our findings demonstrated that the IPRS was a powerful predictor to screen out certain populations with better prognosis in breast cancer and may serve as a potential biomarker guiding clinical treatment decisions.
| S-EPMC9690299 | biostudies-literature
Project description:Medullary breast cancers (MBC) display a basal profile, but a favorable prognosis. We hypothesized that a previously published 368-gene expression signature associated with MBC might serve to define a prognostic classifier in basal cancers. We collected public gene expression and histoclinical data of 2145 invasive early breast adenocarcinomas. We developed a Support Vector Machine (SVM) classifier based on this 368-gene list in a learning set, and tested its predictive performances in an independent validation set. Then, we assessed its prognostic value and that of six prognostic signatures for disease-free survival (DFS) in the remaining 2034 samples. The SVM model accurately classified all MBC samples in the learning and validation sets. A total of 466 cases were basal across other sets. The SVM classifier separated them into two subgroups, subgroup 1 (resembling MBC) and subgroup 2 (not resembling MBC). Subgroup 1 exhibited 71% 5-year DFS, whereas subgroup 2 exhibited 50% (p=9.93E-05). The classifier outperformed the classical prognostic variables in multivariate analysis, conferring lesser risk for relapse in subgroup 1 (HR=0.52, p=3.9E-04). This prognostic value was specific to the basal subtype, in which none of the other prognostic signatures was informative. The IPC series contained frozen tumor samples obtained from 266 early breast cancer patients who underwent initial surgery in our institution between 1992 and 2004. They included 227 cases previously reported {Finetti, 2008 #1758} and 39 additional cases, all similarly profiled using Affymetrix U133 Plus 2.0 human oligonucleotide microarrays as previously described {Finetti, 2008 #1758}. The study was approved by the IPC review board, and informed consent was available for each case. Gene expression data of 266 BCs were quantified by using whole-genome DNA microarrays (HG-U133 plus 2.0, Affymetrix).
| S-ECPF-GEOD-21653 | biostudies-other