Characterisation of multifocal breast cancer using the 70-gene signature in clinical low-risk patients enrolled in the EORTC 10041/BIG 03-04 MINDACT trial

2017 ◽  
Vol 79 ◽  
pp. 98-105 ◽  
Author(s):  
K.C. Aalders ◽  
A. Kuijer ◽  
M.E. Straver ◽  
L. Slaets ◽  
S. Litiere ◽  
...  
2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 500-500
Author(s):  
Josephine Lopes Cardozo ◽  
Caroline Drukker ◽  
Marjanka Schmidt ◽  
Laura van 't Veer ◽  
Annuska Glas ◽  
...  

500 Background: Gene signatures have proven successful in identifying patients with a low risk of distant recurrence who could forego chemotherapy (CT) and are currently included in international treatment guidelines for breast cancer. For the 70-gene signature (MammaPrint) an additional threshold was established within the low risk category to identify patients with an ultralow risk of distant recurrence. In independent cohorts, these patients had excellent breast cancer specific survival at 15 years, suggesting that ultralow risk cancers represent indolent disease (Esserman, JAMA Oncol 2017, Delahaye, BC Res Treat 2017). Here we evaluate survival of patients with an ultralow risk 70-gene signature who participated in the randomized phase 3 MINDACT trial (Piccart, Lancet Oncol 2021). Methods: Of the 6,693 patients enrolled in the MINDACT trial (EORTC 10041/BIG 3-04) between 2007-2011, profiling revealed an ultralow risk 70-gene signature in 1,000 patients (15%). We assessed 5- and 8-year distant metastasis free interval (DMFI) and breast cancer specific survival (BCSS) in patients stratified by 70-gene signature result (high, low, ultralow), and within the ultralow risk group stratified by clinical risk. For these exploratory analyses, we used Kaplan-Meier estimates for time to event endpoints and Cox-regression models to calculate hazard ratio’s (HR). Results: Median follow-up was 8.7 years. Among the ultralow risk patients (n = 1,000), 67% were ≥50 years, 81% had tumors < 2cm, 80% were lymph node negative, 96% had grade 1 or 2 tumors and 99% were ER-positive. Systemic therapy was received by 83% of patients (69% endocrine therapy (ET), 14% ET + CT) and 16% received no adjuvant systemic treatment (AST). Survival estimates for all endpoints are shown in the table; 8-year DMFI was 97.0% (95% CI 95.8-98.1) for ultralow risk. The 8-year DMFI in ultralow risk patients who received no AST or ET only was 97.8% (95% CI 95.3-100) and 97.4% (95% CI 96.1-98.7), respectively. The HR for DMFI was 0.66 (95% CI 0.46-0.95) for ultralow vs low risk, after adjusting for tumor and treatment characteristics (preliminary results). Conclusions: In this prospective study, patients with an ultralow risk 70-gene signature have an excellent prognosis with 8-year BCSS above 99% regardless of clinical risk status, and with an 8-year DMFI of 95-98%.[Table: see text]


2021 ◽  
Vol 12 ◽  
Author(s):  
Mengdi Chen ◽  
Deyue Liu ◽  
Weilin Chen ◽  
Weiguo Chen ◽  
Kunwei Shen ◽  
...  

BackgroundThe 21-gene assay recurrence score (RS) provides additional information on recurrence risk of breast cancer patients and prediction of chemotherapy benefit. Previous studies that examined the contribution of the individual genes and gene modules of RS were conducted mostly in postmenopausal patients. We aimed to evaluate the gene modules of RS in patients of different ages.MethodsA total of 1,078 estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients diagnosed between January 2009 and March 2017 from Shanghai Jiao Tong University Breast Cancer Data Base were included. All patients were divided into three subgroups: Group A, ≤40 years and premenopausal (n = 97); Group B, &gt;40 years and premenopausal (n = 284); Group C, postmenopausal (n = 697). The estrogen, proliferation, invasion, and HER2 module scores from RS were used to characterize the respective molecular features. Spearman correlation and analysis of the variance tests were conducted for RS and its constituent modules.ResultsIn patients &gt;40 years, RS had a strong negative correlation with its estrogen module (ρ = −0.76 and −0.79 in Groups B and C) and a weak positive correlation with its invasion module (ρ = 0.29 and 0.25 in Groups B and C). The proliferation module mostly contributed to the variance in young patients (37.3%) while the ER module contributed most in old patients (54.1% and 53.4% in Groups B and C). In the genetic high-risk (RS &gt;25) group, the proliferation module was the leading driver in all patients (ρ = 0.38, 0.53, and 0.52 in Groups A, B, and C) while the estrogen module had a weaker correlation with RS. The impact of ER module on RS was stronger in clinical low-risk patients while the effect of the proliferation module was stronger in clinical high-risk patients. The association between the RS and estrogen module was weaker among younger patients, especially in genetic low-risk patients.ConclusionsRS was primarily driven by the estrogen module regardless of age, but the proliferation module had a stronger impact on RS in younger patients. The impact of modules varied in patients with different genetic and clinical risks.


1993 ◽  
Vol 11 (3) ◽  
pp. 454-460 ◽  
Author(s):  
M Kaufmann ◽  
W Jonat ◽  
U Abel ◽  
J Hilfrich ◽  
H Caffier ◽  
...  

PURPOSE We report two randomized trials of adjuvant systemic therapy in 747 patients < or = 65 years of age with histologically proven node-positive breast cancer. PATIENTS AND METHODS Patients were selected for the two trials on the basis of lymph node and hormone receptor status. The only stratification was based on the treating institution. In patients with a lower probability of recurrence (n = 276), a comparison between endocrine therapy (tamoxifen [Tam] 30 mg/d for 2 years) and chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [CMF] intravenously [IV], six cycles every 4 weeks) was performed. In patients with a higher risk of recurrence (n = 471), a comparison between chemotherapy alone (doxorubicin plus cyclophosphamide [AC] i.v., eight cycles every 3 weeks) and the same chemotherapy plus Tam was made. RESULTS Overall, we found that CMF and Tam are equally effective in a subgroup of patients with a relatively good prognosis (low-risk patients). However, in the subset of women < or = 49 years old, a significantly greater disease-free survival (DFS) rate (P = .01) and overall survival (OS) rate (P = .002) was observed following therapy with CMF compared with Tam. In patients > or = 50 years old, the opposite was found, and Tam appeared to be superior to CMF (DFS, P = .003; OSm P = .5). These results must be interpreted cautiously, since a post-hoc stratification of patients by age (< or = 49, > or = 50) was performed, and significantly more younger, low-risk patients were randomized to receive chemotherapy alone and more older patients to receive Tam alone. Among patients with a relatively poor prognosis (high-risk patients), a combination of AC plus Tam was equivalent to AC and, when women were analyzed by age, this was found to be true of patients < or = 49 years as well. However, the addition of Tam to AC in women age > or 50 years resulted in a statistically significantly higher DFS (P = .01) and a trend toward better OS compared with women who received AC alone. CONCLUSION Further trials are required to analyze the role of combined simultaneous or sequential chemoendocrine adjuvant treatment or each single therapy alone in defined risk-adapted subsets of node-negative and node-positive patients.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12046-e12046 ◽  
Author(s):  
Yao Yuan ◽  
Alison Len Van Dyke ◽  
Allison W. Kurian ◽  
Serban Negoita ◽  
Valentina I. Petkov

e12046 Background: OncotypeDX DCIS is a 12-gene assay designed to predict the 10-year risk of local recurrence and to guide treatment decisions, specifically the benefit of radiation therapy in breast ductal carcinoma in situ (DCIS). The test became available in December 2011 and is not currently recommended by guidelines. The Surveillance, Epidemiology and End Results (SEER) program captures cancer data at the population-level and has been conducting annual linkages with Genomic Health Clinical Laboratory, the only lab performing the test, to identify patients receiving the test. Methods: SEER cases diagnosed with in situ breast cancer (DCIS or papillary in situ) between 2011-2015 were included in the analysis. SEER data on patient demographics, tumor characteristics, and treatments were combined with linkage variables for OncotypeDX DCIS tests reported by Genomic Health. Logistic regression was used to identify which patient related factors were associated with having received the test and to evaluate the relationship between test generated risk categories and treatments. Results: Of the 68,826 in situ breast cancer cases, 2,155 were linked to DCIS test data. Test utilization increased from < 1% to 5.3% for patients diagnosed in 2011 vs. 2015. Patients were less likely to receive the test if they had larger and higher-grade tumors, were divorced, had Medicaid insurance, and were in the lowest socioeconomic status tertile. The majority of patients (68%) were at low risk, 17% intermediate, and 15% in the high risk group. Patients at intermediate or high risk were more likely to receive radiation (OR = 2.4, 95% CI: 1.8-3.2 and OR = 3, 95% CI: 2.3,4.1, respectively) than the low risk group. High risk patients were more likely than low risk patients to receive chemotherapy (OR = 4.3, 95% CI: 1.2, 14.4) and to undergo mastectomy than lumpectomy (OR = 1.47, 95% CI: 1.12-1.93). Conclusions: Clinical adoption of the OncotypeDX DCIS test has been slow. The association between multiple demographic factors and receiving the test indicated disparities in the US population. Clinical factors also influenced whether patients received the test. OncotypeDX DCIS results appeared to guide clinical decisions.


2021 ◽  
Vol 11 ◽  
Author(s):  
Nam Nhut Phan ◽  
Chih-Yi Hsu ◽  
Chi-Cheng Huang ◽  
Ling-Ming Tseng ◽  
Eric Y. Chuang

PurposeThe present study aimed to assign a risk score for breast cancer recurrence based on pathological whole slide images (WSIs) using a deep learning model.MethodsA total of 233 WSIs from 138 breast cancer patients were assigned either a low-risk or a high-risk score based on a 70-gene signature. These images were processed into patches of 512x512 pixels by the PyHIST tool and underwent color normalization using the Macenko method. Afterward, out of focus and pixelated patches were removed using the Laplacian algorithm. Finally, the remaining patches (n=294,562) were split into 3 parts for model training (50%), validation (7%) and testing (43%). We used 6 pretrained models for transfer learning and evaluated their performance using accuracy, precision, recall, F1 score, confusion matrix, and AUC. Additionally, to demonstrate the robustness of the final model and its generalization capacity, the testing set was used for model evaluation. Finally, the GRAD-CAM algorithm was used for model visualization.ResultsSix models, namely VGG16, ResNet50, ResNet101, Inception_ResNet, EfficientB5, and Xception, achieved high performance in the validation set with an overall accuracy of 0.84, 0.85, 0.83, 0.84, 0.87, and 0.91, respectively. We selected Xception for assessment of the testing set, and this model achieved an overall accuracy of 0.87 with a patch-wise approach and 0.90 and 1.00 with a patient-wise approach for high-risk and low-risk groups, respectively.ConclusionsOur study demonstrated the feasibility and high performance of artificial intelligence models trained without region-of-interest labeling for predicting cancer recurrence based on a 70-gene signature risk score.


2020 ◽  
Author(s):  
Qiang Cai ◽  
Shizhe Yu ◽  
Jian Zhao ◽  
Duo Ma ◽  
Long Jiang ◽  
...  

Abstract Background: Hepatocellular carcinoma (HCC) is heterogeneous disease occurring in the background of chronic liver diseases. The role of glycosyltransferase (GT) genes have recently been the focus of research associating with the development of tumors. However, the prognostic value of GT genes in HCC remains not elucidated. This study aimed to demonstrate the GT genes related to the prognosis of HCC through bioinformatics analysis.Methods: The GT genes signatures were identified from the training set of The Cancer Genome Atlas (TCGA) dataset using univariate and the least absolute shrinkage and selection operator (LASSO) Cox regression analyses. Then, we analyzed the prognostic value of GT genes signatures related to the overall survival (OS) of HCC patients. A prognostic model was constructed, and the risk score of each patient was calculated as formula, which divided HCC patients into high- and low-risk groups. Kaplan-Meier (K-M) and Receiver operating characteristic (ROC) curves were used to assess the OS of HCC patients. The prognostic value of GT genes signatures was further investigated in the validation set of TCGA database. Univariate and multivariate Cox regression analyses were performed to demonstrate the independent factors on OS. Finally, we utilized the gene set enrichment analysis (GSEA) to annotate the function of these genes between the two risk categories. Results: In this study, we identified and validated 4 GT genes as the prognostic signatures. The K-M analysis showed that the survival rate of the high-risk patients was significantly lower than that of the low-risk patients. The risk score calculated with 4 gene signatures could predict OS for 3-, 5-, and 7-year in patients with HCC, revealing the prognostic ability of these gene signature. In addition, Multivariate Cox regression analyses indicated that the risk score was an independent prognostic factor for HCC. Functional analysis further revealed that immune-related pathways were enriched, and immune status in HCC were different between the two risk groups.Conclusion: In conclusion, a novel GT genes signature can be used for prognostic prediction in HCC. Thus, targeting GT genes may be a therapeutic alternative for HCC.


2021 ◽  
Author(s):  
Menglin He ◽  
Cheng Hu ◽  
Jian Deng ◽  
Hui Ji ◽  
Weiqian Tian

Abstract Background: Breast cancer (BC) is a kind of cancer with high incidence and mortality in female. Conventional clinical characteristics are far from accurate to predict individual outcomes. Therefore, we aimed to develop a novel signature to predict the survival of patients with BC. Methods: We analyzed the data of a training cohort from the TCGA database and a validation cohort from GEO database. After the applications of GSEA and Cox regression analyses, a glycolysis-related signature for predicting the survival of patients with BC was developed. The signature contains AK3, CACNA1H, IL13RA1, NUP43, PGK1, and SDC1. Then, we constructed a risk score formula to classify the patients into high and low-risk groups based on the expression levels of six-gene in patients. The receiver operating characteristic (ROC) curve and the Kaplan-Meier curve were used to assess the predicted capacity of the model. Next, a nomogram was developed to predict the outcomes of patients with risk score and clinical features in 1, 3, and 5 years. We further used Human Protein Atlas (HPA) database to validate the expressions of the six biomarkers in tumor and sample tissues.Results: We constructed a six-gene signature to predict the outcomes of patients with BC. The patients in high-risk group showed poor prognosis than that in low-risk group. The AUC values were 0.719 and 0.702, showing that the prediction performance of the signature is acceptable. Additionally, Cox regression analysis revealed that these biomarkers could independently predict the prognosis of BC patients without being affected by clinical factors. The expression levels of all six biomarkers in BC tissues were higher than that in normal tissues except AK3. Conclusion: We developed a six-gene signature to predict the prognosis of patients with BC. Our signature has been proved to have the ability to make an accurate and obvious prediction and might be used to expand the prediction methods in clinical.


2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Wei Hu ◽  
Mingyue Li ◽  
Qi Zhang ◽  
Chuan Liu ◽  
Xinmei Wang ◽  
...  

Abstract Background Copy number variation (CNVs) is a key factor in breast cancer development. This study determined prognostic molecular characteristics to predict breast cancer through performing a comprehensive analysis of copy number and gene expression data. Methods Breast cancer expression profiles, CNV and complete information from The Cancer Genome Atlas (TCGA) dataset were collected. Gene Expression Omnibus (GEO) chip data sets (GSE20685 and GSE31448) containing breast cancer samples were used as external validation sets. Univariate survival COX analysis, multivariate survival COX analysis, least absolute shrinkage and selection operator (LASSO), Chi square, Kaplan-Meier (KM) survival curve and receiver operating characteristic (ROC) analysis were applied to build a gene signature model and assess its performance. Results A total of 649 CNV related-differentially expressed gene obtained from TCGA-breast cancer dataset were related to several cancer pathways and functions. A prognostic gene sets with 9 genes were developed to stratify patients into high-risk and low-risk groups, and its prognostic performance was verified in two independent patient cohorts (n = 327, 246). The result uncovered that 9-gene signature could independently predict breast cancer prognosis. Lower mutation of PIK3CA and higher mutation of TP53 and CDH1 were found in samples with high-risk score compared with samples with low-risk score. Patients in the high-risk group showed higher immune score, malignant clinical features than those in the low-risk group. The 9-gene signature developed in this study achieved a higher AUC. Conclusion The current research established a 5-CNV gene signature to evaluate prognosis of breast cancer patients, which may innovate clinical application of prognostic assessment.


2020 ◽  
Vol 10 ◽  
Author(s):  
Youchao Xiao ◽  
Gang Cui ◽  
Xingguang Ren ◽  
Jiaqi Hao ◽  
Yu Zhang ◽  
...  

The overall survival of patients with lower grade glioma (LGG) varies greatly, but the current histopathological classification has limitations in predicting patients’ prognosis. Therefore, this study aims to find potential therapeutic target genes and establish a gene signature for predicting the prognosis of LGG. CD44 is a marker of tumor stem cells and has prognostic value in various tumors, but its role in LGG is unclear. By analyzing three glioma datasets from Gene Expression Omnibus (GEO) database, CD44 was upregulated in LGG. We screened 10 CD44-related genes via protein–protein interaction (PPI) network; function enrichment analysis demonstrated that these genes were associated with biological processes and signaling pathways of the tumor; survival analysis showed that four genes (CD44, HYAL2, SPP1, MMP2) were associated with the overall survival (OS) and disease-free survival (DFS)of LGG; a novel four-gene signature was constructed. The prediction model showed good predictive value over 2-, 5-, 8-, and 10-year survival probability in both the development and validation sets. The risk score effectively divided patients into high- and low- risk groups with a distinct outcome. Multivariate analysis confirmed that the risk score and status of IDH were independent prognostic predictors of LGG. Among three LGG subgroups based on the presence of molecular parameters, IDH-mutant gliomas have a favorable OS, especially if combined with 1p/19q codeletion, which further confirmed the distinct biological pattern between three LGG subgroups, and the gene signature is able to divide LGG patients with the same IDH status into high- and low- risk groups. The high-risk group possessed a higher expression of immune checkpoints and was related to the activation of immunosuppressive pathways. Finally, this study provided a convenient tool for predicting patient survival. In summary, the four prognostic genes may be therapeutic targets and prognostic predictors for LGG; this four-gene signature has good prognostic prediction ability and can effectively distinguish high- and low-risk patients. High-risk patients are associated with higher immune checkpoint expression and activation of the immunosuppressive pathway, providing help for screening immunotherapy-sensitive patients.


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