Effect of age and ethnicity on the tumor location, nuclear accumulation of p53 and clinical outcome in colorectal adenocarcinoma.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 559-559
Author(s):  
Ravi Kumar Paluri ◽  
Michael Behring ◽  
James Posey ◽  
Upender Manne
Keyword(s):  
Overall Survival ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Tumor Location ◽  
Genetic Alterations ◽  
Proximal Colon ◽  
Nuclear Accumulation ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Race Ethnicity

559 Background: The race/ethnicity based research in colorectal cancer (CRC) care continues to remain a high priority in developing personalized medicine, and to improve overall clinical outcomes. The role of p53 abnormalities in prognostication of CRC has been evaluated earlier. The incidence of nuclear accumulation of p53 (p53nac) and its prognostic relevance in African American (AA) and non-Hispanic white patients (pts) have been investigated, and it was suggested that the clinical consequences of p53nac in CRC varies with anatomic location of the tumor and the race of the patient. However, the clinical value of p53nac in relation to age, the tumor location, and race together is not assessed. Thus, we evaluated prognostic significance of p53nac by considering the tumor location, age, race/ethnicity and p53nacin CRCs in AA and white pts. Methods: Formalin fixed paraffin embedded CRC tissues from 242 AAs and 346 whites who underwent surgery were assessed for p53nac by routine immunohistochemistry (IHC). The routine (not antigen retrieval) IHC will identify the majority of genetic alterations ( > 95% missense point mutations) and have significant association with patient survival in CRC. The association between phenotypes, p53nac status, clinicopathologic features, and overall survival were evaluated using the x2 test and Cox regression analyses. Results: Approximately equivalent proportions of distal (52%) and proximal adenocarcinomas (48%) were positive for p53nac in AA pts. In contrast, distal CRC from whites more frequently were positive for p53nac than from the proximal colon (67% vs. 34%, x2 P = 0.006). p53nac was found to be a strong predictor of poor overall survival in young ( < 65 yr) white pts with proximal tumors [hazard ratio (HR) = 2.8, 95% Confidence Intervals (CI):1.2-6.4] but not in AAs (HR = 0.7, 95% CI: 0.41-1.21). Conclusions: The findings of this study suggest that p53nac is a strong prognostic marker for young white pts with proximal colon adenocarcinomas. Our findings are clinically relevant because several small-molecule inhibitors of mutant p53 are under investigation. These studies were supported by a pilot project grant by the UAB Comprehensive Cancer center.

66 Complex markers of survival from pembrolizumab: the potential predictive role of tumor mutational burden (TMB) and KRAS

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A71-A71
Author(s):  
Yong Hee Lee ◽  
Carrie Hoefer ◽  
Paul DePietro ◽  
Mary Nesline
Keyword(s):  
Overall Survival ◽  
Survival Benefit ◽  
Cox Regression ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
High Status ◽  
Cox Regression Analysis ◽  
Risk Of Death ◽  
Mutational Status ◽  
Increased Risk

BackgroundPembrolizumab, with or without chemotherapy, is NCCN guideline-recommended treatment for NSCLC cancer patients depending on tumor PD-L1 status by IHC. PD-L1 IHC provides guidance for treatment selection for response, but does not accurately predict survival benefit from pembrolizumab. Emerging evidence suggests TMB and other genomic markers (KRAS, STK11, TP53 mutations), may have clinical utility for predicting survival benefit.MethodsWe identified a cohort of metastatic EGFR/ALK wild type NSCLC patients (n=116) whose tumors underwent comprehensive profiling (June 2017-March 2019) for genomic variants, TMB and PD-L1 IHC 22C3 prior to selection of pembrolizumab (n=43), pembrolizumab + chemotherapy (n=41), or chemotherapy only (excluding subsequent targeted therapy or immunotherapy) (n=32) at Roswell Park Comprehensive Cancer Center, with at least one year of follow up. TMB was assessed using a 1.75 Mb capture of 409 oncogenes with full exon coverage (DNA-Seq), with ‘high’ TMB interpreted as ≥10 mutations/Mb. Electronic pharmacy records were curated to create pre and post-test treatment histories for each patient. Cox regression analysis evaluated OS with pembrolizumab monotherapy or pembrolizumab + chemotherapy vs chemotherapy only, adjusting for covariates including oncogenic driver mutations, TMB, PD-L1 IHC demographics, clinicopathologic characteristics, prior treatment, and performance status. Using the same model, we then assessed overall survival for each treatment group by TMB, KRAS, STK11, and TP53 mutant status.ResultsOverall, 47% of tumors were PD-L1 high, 47% TMB high, 34% KRAS mutant (codons 12, 13, 60, 61), 52% TP53 mutant and 16% STK11 mutant. As expected, pembrolizumab with or without chemotherapy significantly improved overall survival (OS) compared to chemotherapy alone; with TMB, smoking, and ECOG status identified as significant covariates. PD-L1 IHC status was not associated with OS for any treatment. TMB high status was significant for OS benefit with pembrolizumab either as monotherapy [HR=0.02; CI=0.01–0.40; p=0.01] or in combination with chemotherapy [HR=0.20; CI=0.04–0.95; p=0.04]. KRAS mutant status was independently significant for OS benefit from pembrolizumab + chemotherapy [HR=0.01; CI=0.01–0.79; p=0.04] but not for pembrolizumab monotherapy or chemotherapy alone. Among patients who received pembrolizumab monotherapy, there was a trend toward increased risk of death in those with STK11 mutations [HR=17.54; CI=0.35–1,000; p=0.15], whereas TP53 mutant status trended toward survival benefit [HR=0.18; CI=0.02–1.53; p=0.11].ConclusionsData comparing pembrolizumab treatments with chemotherapy and independent marker associations suggest TMB has predictive power for determining overall survival benefit from pembrolizumab, while KRAS, STK11, and TP53 mutational status demonstrated potential prognostic relevance for NSCLC.

scholarly journals IMPDH2 and HPRT expression and a prognostic significance in preoperative and postoperative patients with osteosarcoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Parunya Chaiyawat ◽  
Areerak Phanphaisarn ◽  
Nutnicha Sirikaew ◽  
Jeerawan Klangjorhor ◽  
Viraporn Thepbundit ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cox Regression ◽  
Expression Patterns ◽  
Prognostic Significance ◽  
Drug Repurposing ◽  
Survival Times ◽  
Metabolizing Enzymes ◽  
Hypoxanthine Guanine Phosphoribosyltransferase ◽  
High Grade Osteosarcoma ◽  
Enneking Stage

AbstractOsteosarcoma is one of the most aggressive bone tumors in children and adolescents. Development of effective therapeutic options is still lacking due to the complexity of the genomic background. In previous work, we applied a proteomics-guided drug repurposing to explore potential treatments for osteosarcoma. Our follow-up study revealed an FDA-approved immunosuppressant drug, mycophenolate mofetil (MMF) targeting inosine-5′-phosphate dehydrogenase (IMPDH) enzymes, has an anti-tumor effect that appeared promising for further investigation and clinical trials. Profiling of IMPDH2 and hypoxanthine–guanine phosphoribosyltransferase (HPRT), key purine-metabolizing enzymes, could deepen understanding of the importance of purine metabolism in osteosarcoma and provide evidence for expanded use of MMF in the clinic. In the present study, we investigated levels of IMPDH2, and HPRT in biopsy of 127 cases and post-chemotherapy tissues in 20 cases of high-grade osteosarcoma patients using immunohistochemical (IHC) analysis. Cox regression analyses were performed to determine prognostic significance of all enzymes. The results indicated that low levels of HPRT were significantly associated with a high Enneking stage (P = 0.023) and metastatic status (P = 0.024). Univariate and multivariate analyses revealed that patients with low HPRT expression have shorter overall survival times [HR 1.70 (1.01–2.84), P = 0.044]. Furthermore, high IMPDH2/HPRT ratios were similarly associated with shorter overall survival times [HR 1.67 (1.02–2.72), P = 0.039]. Levels of the enzymes were also examined in post-chemotherapy tissues. The results showed that high IMPDH2 expression was associated with shorter metastasis-free survival [HR 7.42 (1.22–45.06), P = 0.030]. These results suggest a prognostic value of expression patterns of purine-metabolizing enzymes for the pre- and post-chemotherapy period of osteosarcoma treatment.

H3K27M-mutant Diffuse Midline Gliomas should be Further Molecularly Stratified: An Integrated Analysis of 669 Patients

2021 ◽  
Author(s):  
Huy Gia Vuong ◽  
Hieu Trong Le ◽  
Tam N.M. Ngo ◽  
Kar-Ming Fung ◽  
James D. Battiste ◽  
...  
Keyword(s):  
Cox Regression ◽  
Fatal Outcome ◽  
Extent Of Resection ◽  
Tumor Location ◽  
Genetic Alterations ◽  
Integrated Analysis ◽  
Prognostic Impact ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
The Impact

Abstract Introduction: H3K27M-mutated diffuse midline gliomas (H3-DMGs) are aggressive tumors with a fatal outcome. This study integrating individual patient data (IPD) from published studies aimed to investigate the prognostic impact of different genetic alterations on survival of these patients.Methods: We accessed PubMed and Web of Science to search for relevant articles. Studies were included if they have available data of follow-up and additional molecular investigation of H3-DMGs. For survival analysis, Kaplan-Meier analysis and Cox regression models were utilized, and corresponding hazard ratios (HR) and 95% confidence intervals (CI) were computed to analyze the impact of genetic events on overall survival (OS).Result: We included 30 studies with 669 H3-DMGs. TP53 mutations were the most common second alteration among these neoplasms. In univariate Cox regression model, TP53 mutation was an indicator of shortened survival (HR = 1.446; 95% CI = 1.143-1.829) whereas ACVR1 (HR = 0.712; 95% CI = 0.518-0.976) and FGFR1 mutations (HR = 0.408; 95% CI = 0.208-0.799) conferred prolonged survival. In addition, ATRX loss was also associated with a better OS (HR = 0.620; 95% CI = 0.386-0.996). Adjusted for age, gender, tumor location, and the extent of resection, the presence of TP53 mutations, the absence of ACVR1 or FGFR1 mutations remained significantly poor prognostic factors.Conclusions: We outlined the prognostic importance of additional genetic alterations in H3-DMGs and recommended that these neoplasms should be further molecularly segregated. It could help neuro-oncologists better evaluate the risk stratification of patients and consider pertinent treatments.

scholarly journals Differential Characteristics and Prognosis of PD-L1–Positive Endometrial Carcinomas: A Retrospective Chart Review

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1047
Author(s):  
Justin Z. Amarin ◽  
Razan Mansour ◽  
Sura Al-Ghnimat ◽  
Maysa Al-Hussaini
Keyword(s):  
Overall Survival ◽  
Tumor Cells ◽  
Chart Review ◽  
Prognostic Significance ◽  
Retrospective Chart Review ◽  
Cancer Center ◽  
High Grade ◽  
Endometrial Carcinomas

Women with endometrial carcinomas that express PD-L1 may respond better to immunotherapy. Our aim was to investigate the differential characteristics of PDL1–positive endometrial carcinomas and the prognostic significance of PDL1. We performed a retrospective chart review of 231 women with endometrial carcinomas who were managed at King Hussein Cancer Center (2007–2016) and performed immunohistochemistry for MLH1, PMS2, MSH2, MSH6, p53, and PD-L1. Overall, 89 cases (38.5%) were MMR-deficient. PD-L1 was expressed in 49 cases (21.2%) and its expression was significantly associated with MLH1/PMS2 deficiency (p = 0.044) but not MSH2/MSH6 deficiency (p = 0.59). p53 was mutant in 106 cases (46.5%), and its mutation was significantly associated with MMR proficiency (p < 0.001) but not PDL1 expression (p = 0.78). In women with endometrioid adenocarcinomas, PD-L1 expression was significantly associated with the Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) grade (p = 0.008). Overall, PDL1 expression did not significantly predict overall survival in unadjusted or adjusted analyses (p = 0.92 and 0.54, respectively). In conclusion, tumors with MLH1/PMS2 loss and high-grade endometrioid adenocarcinomas were more likely to express PDL1 in tumor cells. Further research is required to investigate whether the presence of either characteristic signals a higher likelihood of a favorable response if immunotherapy is administered.

scholarly journals Incidence, Survival, and Associated Factors Estimation in Osteosarcoma Patients with Lung Metastasis: A Single-center Experience of 11 Years in Tianjin, China

2021 ◽  
Author(s):  
Chao Zhang ◽  
Haixiao Wu ◽  
Guijun Xu ◽  
Wenjuan Ma ◽  
Lisha Qi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
Regression Analysis ◽  
Prognostic Factors ◽  
Lung Metastasis ◽  
Associated Factors ◽  
Cox Regression ◽  
Cancer Center ◽  
Single Center ◽  
Cox Regression Analysis

Abstract Background: Osteosarcoma is the most common primary malignant bone tumor. The current study was conducted to describe the general condition of patients with primary osteosarcoma in a single cancer center in Tianjin, China and to investigate the associated factors in osteosarcoma patients with lung metastasis. Methods: From February 2009 to October 2020, patients from Tianjin Medical University Cancer Institute and Hospital, China were retrospectively analyzed. The Kaplan–Meier method was used to evaluate the overall survival of osteosarcoma patients. Prognostic factors of patients with osteosarcoma were identified by the Cox proportional hazard regression analysis. Risk factor of lung metastasis in osteosarcoma were investigated by the logistic regression model. Results: A total of 203 patients were involved and 150 patients were successfully followed up for survival status. The 5-year survival rate of osteo-sarcoma patients was 70.0%. Surgery, bone and lung metastasis were the significant prognostic factors in multivariable Cox regression analysis. Twenty-one (10.3%) patients showed lung metastasis at the diagnosis of osteosarcoma and 67 (33%) lung metastases during the later course. T3 stage (OR=11.415, 95%CI 1.362-95.677, P=0.025) and synchronous bone metastasis (OR=6.437, 95%CI 1.69-24.51, P=0.006) were risk factors of synchronous lung metastasis occurrence. Good necrosis (≥90%, OR=0.097, 95%CI 0.028-0.332, P=0.000) and elevated Ki-67 (≥50%, OR=4.529, 95%CI 1.241-16.524, P=0.022) were proved to be significantly associated with metachronous lung metastasis occurrence. Conclusion: The overall survival, prognostic factors and risk factors for lung metastasis in this single center provided insight about osteosarcoma management.

Delays in time to antibiotics in inpatient oncologic neutropenic fever do not predict decreased overall survival.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18765-e18765
Author(s):  
Jordan Villars ◽  
Christopher Anand Gardner ◽  
Tingting Zhan ◽  
Adam F Binder
Keyword(s):  
Overall Survival ◽  
Black People ◽  
Cox Regression ◽  
Adverse Outcomes ◽  
Neutropenic Fever ◽  
Cancer Center ◽  
Common Disease ◽  
Inpatient Setting ◽  
Oncologic Patients ◽  
Time To Antibiotics

e18765 Background: Neutropenic fever (NF) is relatively common oncologic emergency. Present expert consensus is that anti-pseudomonas gram-negative antibiotics should be administered within 60 minutes of detecting NF. To date studies investigating this relationship in neutropenic fever patients have been either limited in size, or have failed to reliably establish a relationship between time to antibiotics (TTA) and clinical outcomes.While some studies have shown an association between TTA and outcomes in NF patients admitted from the Emergency Department, such studies do not control for the time that patients may have been febrile in the community. To address these factors, we conducted a retrospective study on the effect of TTA on mortality in oncologic patients who developed NF as inpatients. Methods: We performed retrospective chart review of all cases of NF at an NCI designated Cancer Center between 7/1/2016 and 3/27/2019. NF was defined as temperature of 101˚ F on one occasion, or 100.4˚ F sustained over 60 minutes, with an absolute neutrophil count (ANC) less than 500. TTA and survival were calculated via chart abstraction; patients lost to follow up within 180 days were censored to the 180-day mortality group. Relationship between TTA and overall survival (OS) was analyzed via multivariable Cox regression. We excluded patients that had non-cancer related NF, were transferred from another institution with NF, were admitted from the ED with NF, or transitioned to hospice. Only the first instance of NF in any admission was analyzed. Results: A total of 187 eligible cases were identified during the study period, mean age was 57.6 +/- 13.6, 100 (53.5%) cases were in males, 114 (61.0%) cases in Caucasians, 53 (28.3%) in Black People. The 3 most common disease subtypes were acute leukemia (42.8%), plasma cell dyscrasias (27.8%), and lymphoma (16.6%). TTA showed no significant correlation with OS at any timeframe studied. Low Charlson Comorbidity Index ( < 3) correlated with increased survival through ̃360 days, however the effect was non-significant at longer timeframes. Immediate antibiotic treatment ( < 40 mins) correlated with poorer patient prognosis and significantly decreased OS (HR 3.08;CI: 1.30-7.28; p 0.010). Conclusions: TTA was not associated with OS in our study. For inpatients with NF, even hours long TTA may not be long enough to result in adverse clinical outcomes. Unlike NF patients presenting to the ED, where true TTA may often be many hours or even days prior to arrival, a few hours-long TTA in the hospital may not be sufficiently long enough to cause significant patient harm. Interestingly, in our cohort, those who received antibiotics quickly had adverse outcomes. It may be that in patients who were clinically unstable, TTA was shorter given the urgency of the situation. Ultimately, this study’s findings question the applicability of the 60-minute guideline when used in the inpatient setting.

scholarly journals Prognostic Significance of Sarcopenia in Patients with Unresectable Advanced Esophageal Cancer

2019 ◽  
Vol 8 (10) ◽  
pp. 1647 ◽  
Author(s):  
Sachiyo Onishi ◽  
Masahiro Tajika ◽  
Tsutomu Tanaka ◽  
Yutaka Hirayama ◽  
Kazuo Hara ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Prognostic Factor ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Japanese Patients ◽  
Independent Prognostic Factor ◽  
Cancer Center ◽  
Advanced Esophageal Cancer ◽  
Cox Regression Analysis ◽  
Group 2

The prognostic significance of sarcopenia in unresectable advanced esophageal cancer remains unclear. Our study retrospectively evaluated 176 consecutive Japanese patients with esophageal squamous cell carcinoma who had been diagnosed with unresectable advanced cancer in Aichi Cancer Center Hospital between January 2007 and December 2014. Skeletal muscle mass was calculated from abdominal computed tomography (CT) scans before treatment, and patients were divided into sarcopenic and non-sarcopenic groups. Sarcopenia was present in 101 patients (57.4%). Eighty-two patients in the sarcopenic group and 63 patients in the non-sarcopenic group died during follow-up (mean: 20.3 months). The overall survival (OS) rate was significantly lower in the sarcopenic group compared to the non-sarcopenic group (2-year OS: 9.8% vs. 23.7%, p < 0.01). Cox regression analysis revealed only pretreatment sarcopenia as an independent prognostic factor (hazard ratio (HR): 1.48, 95% confidence interval (CI): 1.04–2.10, p = 0.03). In the sarcopenic group, withdrawn cases, for whom the planned treatment was discontinued for some reason, showed a significantly lower OS rate compared to complete cases (1-year OS: 11.0% vs. 59.9%, p < 0.01). The most common reason for discontinuation was aspiration pneumonia (64.5%). Presence of sarcopenia was an independent prognostic factor for unresectable advanced esophageal cancer. Identifying the presence of sarcopenia prior to treatment may improve the prognosis.

scholarly journals Deep learning for glioblastoma segmentation using preoperative magnetic resonance imaging identifies volumetric features associated with survival

2020 ◽  
Vol 162 (12) ◽  
pp. 3067-3080
Author(s):  
Yizhou Wan ◽  
Roushanak Rahmat ◽  
Stephen J. Price
Keyword(s):  
Neural Network ◽  
Overall Survival ◽  
Convolutional Neural Network ◽  
Multiple Testing ◽  
Network Performance ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Ground Truth ◽  
Cox Regression Analysis ◽  
Volumetric Features

Abstract Background Measurement of volumetric features is challenging in glioblastoma. We investigate whether volumetric features derived from preoperative MRI using a convolutional neural network–assisted segmentation is correlated with survival. Methods Preoperative MRI of 120 patients were scored using Visually Accessible Rembrandt Images (VASARI) features. We trained and tested a multilayer, multi-scale convolutional neural network on multimodal brain tumour segmentation challenge (BRATS) data, prior to testing on our dataset. The automated labels were manually edited to generate ground truth segmentations. Network performance for our data and BRATS data was compared. Multivariable Cox regression analysis corrected for multiple testing using the false discovery rate was performed to correlate clinical and imaging variables with overall survival. Results Median Dice coefficients in our sample were (1) whole tumour 0.94 (IQR, 0.82–0.98) compared to 0.91 (IQR, 0.83–0.94 p = 0.012), (2) FLAIR region 0.84 (IQR, 0.63–0.95) compared to 0.81 (IQR, 0.69–0.8 p = 0.170), (3) contrast-enhancing region 0.91 (IQR, 0.74–0.98) compared to 0.83 (IQR, 0.78–0.89 p = 0.003) and (4) necrosis region were 0.82 (IQR, 0.47–0.97) compared to 0.67 (IQR, 0.42–0.81 p = 0.005). Contrast-enhancing region/tumour core ratio (HR 4.73 [95% CI, 1.67–13.40], corrected p = 0.017) and necrotic core/tumour core ratio (HR 8.13 [95% CI, 2.06–32.12], corrected p = 0.011) were independently associated with overall survival. Conclusion Semi-automated segmentation of glioblastoma using a convolutional neural network trained on independent data is robust when applied to routine clinical data. The segmented volumes have prognostic significance.

scholarly journals A Nomogram Based on a Three-Gene Signature Derived from AATF Coexpressed Genes Predicts Overall Survival of Hepatocellular Carcinoma Patients

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Jun Liu ◽  
Jianjun Lu ◽  
Zhanzhong Ma ◽  
Wenli Li
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Clinical Practice ◽  
Correlation Coefficient ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Gene Signature ◽  
Cancer Genome ◽  
Survival Prediction

Background. Hepatocellular carcinoma (HCC) is a common cancer with an extremely high mortality rate. Therefore, there is an urgent need in screening key biomarkers of HCC to predict the prognosis and develop more individual treatments. Recently, AATF is reported to be an important factor contributing to HCC. Methods. We aimed to establish a gene signature to predict overall survival of HCC patients. Firstly, we examined the expression level of AATF in the Gene Expression Omnibus (GEO), the Cancer Genome Atlas (TCGA), and the International Union of Cancer Genome (ICGC) databases. Genes coexpressed with AATF were identified in the TCGA dataset by the Poisson correlation coefficient and used to establish a gene signature for survival prediction. The prognostic significance of this gene signature was then validated in the ICGC dataset and used to build a combined prognostic model for clinical practice. Results. Gene expression data and clinical information of 2521 HCC patients were downloaded from three public databases. AATF expression in HCC tissue was higher than that in matched normal liver tissues. 644 genes coexpressed with AATF were identified by the Poisson correlation coefficient and used to establish a three-gene signature (KIF20A, UCK2, and SLC41A3) by the univariate and multivariate least absolute shrinkage and selection operator Cox regression analyses. This three-gene signature was then used to build a combined nomogram for clinical practice. Conclusion. This integrated nomogram based on the three-gene signature can predict overall survival for HCC patients well. The three-gene signature may be a potential therapeutic target in HCC.

scholarly journals Comparative Analysis of Public Knowledge Bases for Precision Oncology

2019 ◽  
pp. 1-8 ◽  
Author(s):  
Steffen Pallarz ◽  
Manuela Benary ◽  
Mario Lamping ◽  
Damian Rieke ◽  
Johannes Starlinger ◽  
...  
Keyword(s):  
Genetic Alterations ◽  
Knowledge Bases ◽  
Tumor Board ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Accurate Information ◽  
Precision Oncology ◽  
Cancer Genes ◽  
Qualitative Comparison ◽  
Data Set

PURPOSE Precision oncology depends on the availability of up-to-date, comprehensive, and accurate information about associations between genetic variants and therapeutic options. Recently, a number of knowledge bases (KBs) have been developed that gather such information on the basis of expert curation of the scientific literature. We performed a quantitative and qualitative comparison of Clinical Interpretations of Variants in Cancer, OncoKB, Cancer Gene Census, Database of Curated Mutations, CGI Biomarkers (the cancer genome interpreter biomarker database), Tumor Alterations Relevant for Genomics-Driven Therapy, and the Precision Medicine Knowledge Base. METHODS We downloaded each KB and restructured their content to describe variants, genes, drugs, and gene-drug associations in a common format. We normalized gene names to Entrez Gene IDs and drug names to ChEMBL and DrugBank IDs. For the analysis of clinically relevant gene-drug associations, we obtained lists of genes affected by genetic alterations and putative drug therapies for 113 patients with cancer whose cases were presented at the Molecular Tumor Board (MTB) of the Charité Comprehensive Cancer Center. RESULTS Our analysis revealed that the KBs are largely overlapping but also that each source harbors a notable amount of unique information. Although some KBs cover more genes, others contain more data about gene-drug associations. Retrospective comparisons with findings of the Charitè MTB at the gene level showed that use of multiple KBs may considerably improve retrieval results. The relative importance of a KB in terms of cancer genes was assessed in more detail by logistic regression, which revealed that all but one source had a notable impact on result quality. We confirmed these findings using a second data set obtained from an independent MTB. CONCLUSION To date, none of the existing publicly available KBs on gene-drug associations in precision oncology fully subsumes the others, but all of them exhibit specific strengths and weaknesses. Consideration of multiple KBs, therefore, is essential to obtain comprehensive results.

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