Subtype-dependent prognostic relevance of an interferon-induced pathway metagene in human node negative breast cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Callari Maurizio
PROVIDER: S-ECPF-GEOD-37181 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:The majority of gene expression signatures developed to predict the likelihood to relapse in breast cancer (BC) patients assigns a high risk score to patients with Estrogen Receptor (ER) negative or highly proliferating tumors. We aimed to identify a signature of differentially expressed (DE) metagenes, rather than single DE genes, associated with distant metastases beyond classical risk factors. We used 105 gene expression profiles from consecutive BCs to identify metagenes whose prognostic role was defined on an independent series of 92 ESR1+/ERBB2- node-negative BCs (42 cases developing metastases within 5 years from diagnosis and 50 cases metastasis-free for more than 5 years, comparable for age, tumor size, ER status and surgery). Findings were validated on publicly available datasets of 684 node-negative BCs including all the subtypes. Only a metagene containing interferon-induced genes (IFN metagene) proved to be predictive of distant metastasis in our series of patients with ESR1+/ERBB2- tumors (P = 0.029), and such a finding was validated on 457 ESR1+/ERBB2- BCs from public datasets (P = 0.0424). Conversely, the IFN metagene was associated with a low risk of metastasis in 104 ERBB2+ tumors (P = 0.0099) whereas it did not prove to significantly affect prognosis in 123 ESR1-/ERBB2- tumors (P = 0.2235). A complex prognostic interaction was revealed in ESR1+/ERBB2- and ERBB2+ tumors when the association between the IFN metagene and a T-cell metagene was considered. The study confirms the importance of analyzing prognostic variables separately within BC subtypes, highlights the advantages of using metagenes rather than genes, and finally identifies in node-negative ESR1+/ERBB2- BCs, the unfavorable role of high IFN metagene expression.
| S-EPMC5528564 | biostudies-literature
Project description:We identified and validated the pivotal role for a metagene containing IFN-induced genes in association to higher metastatic potential as a function of the specific molecular subtype Fresh frozen primary tumors were collected at the time of diagnosis from 123 patients with operable breast cancer previously untreated and undergoing radical or conservative surgery at the Istituto Nazionale Tumori of Milano (INTM) between1990 and 1998. All patients were pathologically defined as axillary node negative and were not submitted to any type of adjuvant systemic treatment until relapse. Patients were selected in order to have a comparable pattern of classical risk factors (age, tumor size).
2014-05-01 | E-GEOD-37181 | biostudies-arrayexpress
Project description:We identified and validated the pivotal role for a metagene containing IFN-induced genes in association to higher metastatic potential as a function of the specific molecular subtype
2014-05-01 | GSE37181 | GEO
Project description:Clinical data and samples from patients diagnosed, more than 10 years previously, with operable node-negative breast cancer (participants in the Scottish Adjuvant Tamoxifen trial), were revisited. Cases with two distinct categories of outcome were selected; more than 10 years disease-free survival ('good outcome') or distant relapse within 6 years of diagnosis ('poor outcome'). An initial set of cases was analysed for a range of putative prognostic markers and a prognostic index, distinguishing the two outcome categories, was calculated. This index was then validated by testing its predictive power on a second, independent set of cases. A combination of histological grade plus immunochemical staining for BCL-2, p27 and Cyclin D1, generated a useful prognostic index for tamoxifen-treated patients but not for those treated by surgery alone. The value of the index was confirmed in a second set of tamoxifen-treated, early stage breast cancers. Overall, it correctly predicted good and poor outcome in 79 and 74% of cases, respectively (odds ratio 11.0). Other markers assessed added little to prediction of outcome. In the case of molecular assays, sensitivity and reliability were compromised by the age of the tissue specimens and the variability of fixation protocols. In selecting patients for adjuvant systemic chemotherapy, the proposed index improves considerably on current international guidelines and matches the performance reported for 'gene-expression signature' analysis.
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Project description:Systemic chemotherapy in the adjuvant setting can cure breast cancer in some patients that would otherwise recur with incurable, metastatic disease. However, since only a fraction of patients would have recurrence after surgery alone, the challenge is to stratify high-risk patients (who stand to benefit from systemic chemotherapy) from low-risk patients (who can safely be spared treatment related toxicities and costs).We focus here on risk stratification in node-negative, ER-positive, HER2-negative breast cancer. We use a large database of publicly available microarray datasets to build a random forests classifier and develop a robust multi-gene mRNA transcription-based predictor of relapse free survival at 10 years, which we call the Random Forests Relapse Score (RFRS). Performance was assessed by internal cross-validation, multiple independent data sets, and comparison to existing algorithms using receiver-operating characteristic and Kaplan-Meier survival analysis. Internal redundancy of features was determined using k-means clustering to define optimal signatures with smaller numbers of primary genes, each with multiple alternates.Internal OOB cross-validation for the initial (full-gene-set) model on training data reported an ROC AUC of 0.704, which was comparable to or better than those reported previously or obtained by applying existing methods to our dataset. Three risk groups with probability cutoffs for low, intermediate, and high-risk were defined. Survival analysis determined a highly significant difference in relapse rate between these risk groups. Validation of the models against independent test datasets showed highly similar results. Smaller 17-gene and 8-gene optimized models were also developed with minimal reduction in performance. Furthermore, the signature was shown to be almost equally effective on both hormone-treated and untreated patients.RFRS allows flexibility in both the number and identity of genes utilized from thousands to as few as 17 or eight genes, each with multiple alternatives. The RFRS reports a probability score strongly correlated with risk of relapse. This score could therefore be used to assign systemic chemotherapy specifically to those high-risk patients most likely to benefit from further treatment.
| S-EPMC3961800 | biostudies-other
Project description:BackgroundWe aimed to evaluate the prognostic value of the lymph node ratio (LNR) in patients with axillary lymph node-positive triple-negative breast cancer (TNBC).MethodsThe prognostic efficacy was investigated in the first cohort from the Surveillance, Epidemiology, and End Results (SEER) dataset (n=4114) and was further validated in an independent cohort from Fudan University Shanghai Cancer Center (n=417). Patients were classified into low-, medium- and high-risk LNR groups.ResultsMultivariate analysis revealed that the LNR was an independent predictor of overall survival (hazard ratio (HR) for high-risk LNR: 3.24; 95% confidence interval (CI): 2.56 to 4.09) and breast cancer-specific survival (HR for high-risk LNR: 3.57; 95% CI: 2.76 to 4.62) in the SEER population and also for disease-free survival (HR for high-risk LNR: 4.29; 95% CI: 2.24-8.21) in the validation population. Subgroup analysis revealed that patient classification according to the LNR could discriminate among groups of patients with different survival rates based on pathological nodal (pN) staging.ConclusionThe LNR shows potential for use as an additional prognostic factor for TNBC patients with positive lymph node involvement. Considering the heterogeneity of TNBC, use of the LNR might allow for optimization of the pN staging system and should be considered when making treatment decisions.
| S-EPMC5546527 | biostudies-literature
Project description:IntroductionThe overall survival rate is good for lymph-node-negative breast cancer patients, but they still suffer from serious over- and some undertreatments. Prognostic and predictive gene signatures for node-negative breast cancer have a high number of genes related to proliferation. The prognostic value of gene sets from commercial gene-expression assays were compared with proliferation markers.MethodsIllumina WG6 mRNA microarray analysis was used to examine 94 fresh-frozen tumour samples from node-negative breast cancer patients. The patients were divided into low- and high-risk groups for distant metastasis based on the MammaPrint-related genes, and into low-, intermediate- and high-risk groups based on the recurrence score algorithm with genes included in Oncotype DX. These data were then compared to proliferation status, as measured by the mitotic activity index, the expressions of phosphohistone H3 (PPH3), and Ki67.ResultsKaplan-Meier survival analysis for distant-metastasis-free survival revealed that patients with weak and strong PPH3 expressions had 14-year survival rates of 87% (n=45), and 65% (n=49, p=0.014), respectively. Analysis of the MammaPrint classification resulted in 14-year survival rates of 80% (n=45) and 71% (n=49, p=0.287) for patients with low and high risks of recurrence, respectively. The Oncotype DX categorization yielded 14-year survival rates of 83% (n=18), 79% (n=42) and 68% (n=34) for those in the low-, intermediate- and high-risk groups, respectively (p=0.52). Supervised hierarchical cluster analysis for distant-metastasis-free survival in the subgroup of patients with strong PPH3 expression revealed that the genes involved in Notch signalling and cell adhesion were expressed at higher levels in those patients with distant metastasis.ConclusionThis pilot study indicates that proliferation has greater prognostic value than the expressions of either MammaPrint- or Oncotype-DX-related genes. Furthermore, in the subgroup of patients with high proliferation, Notch signalling pathway genes appear to be expressed at higher levels in patients who develop distant metastasis.
| S-EPMC3944091 | biostudies-literature
Project description:Analyses whether, and if so, gene expression can add prognostic information in the subgroups of patients with tumours with low or high proliferative activity. As proliferation measured with MAI and PPH3 has repeatedly been shown to be the best prognosticator in node-negative breast cancer (high sensitivity, little overtreatment). Total RNA were extracted from 94 lymph node negative breast cancer patients
| S-ECPF-GEOD-46563 | biostudies-other
Project description:BackgroundThe prognostic effect of tumor infiltrating CD8+ cytotoxic lymphocytes (CTLs) in breast cancer is controversial. We analyzed the association between CD8+ CTLs and survival of untreated node-negative breast cancer patients.Material and methodsCD8+ CTLs infiltrate was evaluated by immunostaining in a cohort of 332 node-negative breast cancer patients with a median follow-up of 152 months. The prognostic significance of CD8+ CTLs for disease-free survival (DFS) and breast cancer-specific overall survival (OS) was evaluated with Kaplan-Meier survival analysis as well as univariate analysis and multivariate Cox analysis adjusted for age at diagnosis, pT stage, histological grade, estrogen receptor (ER) status, progesterone receptor (PR) status, Ki-67 expression and human epidermal growth factor receptor 2 (HER-2) status.Results285 (85.8%) patients showed strong CD8+ CTLs infiltrate positive status. Univariate analysis showed that CD8+ CTLs had statistically significant association with DFS (P?=?0.004, hazard ratio [HR]?=?0.454, 95% confidence interval [CI]?=?0.265-0.777) and OS (P?=?0.014, HR?=?0.430, 95% CI?=?0.220-0.840) in the entire cohort. The significance of CD8+ CTLs was especially strong in ER negative, HER-2 negative and ER, PR, HER-2 triple-negative breast cancers. In Kaplan-Meier analysis, CD8+ CTLs had significant effect on prognosis of patients (Log-rank test: P?=?0.003 for DFS and P?=?0.011 for OS), independent of established clinical factors for DFS (P?=?0.002, HR?=?0.418, 95% CI?=?0.242-0.724) as well as for OS (P?=?0.009, HR?=?0.401, 95% CI?=?0.202-0.797).
| S-EPMC3990637 | biostudies-literature
Project description:BackgroundTriple-negative (TN) breast cancer, which is defined as being negative for the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER-2), represents a subset of breast cancer with different biologic behaviour. We investigated the clinicopathologic characteristics and prognostic indicators of lymph node-negative TN breast cancer.MethodsMedical records were reviewed from patients with node-negative breast cancer who underwent curative surgery at Seoul National University Hospital between Jan. 2000 and Jun. 2003. Clinicopathologic variables and clinical outcomes were evaluated.ResultsAmong 683 patients included, 136 had TN breast cancer and 529 had non-TN breast cancer. TN breast cancer correlated with younger age (< 35 y, p = 0.003), and higher histologic and nuclear grade (p < 0.001). It also correlated with a molecular profile associated with biological aggressiveness: negative for bcl-2 expression (p < 0.001), positive for the epidermal growth factor receptor (p = 0.003), and a high level of p53 (p < 0.001) and Ki67 expression (p < 0.00). The relapse rates during the follow-up period (median, 56.8 months) were 14.7% for TN breast cancer and 6.6% for non-TN breast cancer (p = 0.004). Relapse free survival (RFS) was significantly shorter among patients with TN breast cancer compared with those with non-TN breast cancer (4-year RFS rate 85.5% vs. 94.2%, respectively; p = 0.001). On multivariate analysis, young age, close resection margin, and triple-negativity were independent predictors of shorter RFS.ConclusionTN breast cancer had higher relapse rate and more aggressive clinicopathologic characteristics than non-TN in node-negative breast cancer. Thus, TN breast cancer should be integrated into the risk factor analysis for node-negative breast cancer.
| S-EPMC2577689 | biostudies-literature