Consolidated BRCA1/2 Variant Interpretation by MH BRCA Correlates with Predicted PARP Inhibitor Efficacy Association by MH Guide

Publications

Consolidated BRCA1/2 Variant Interpretation by MH BRCA Correlates with Predicted PARP Inhibitor Efficacy Association by MH Guide

BRCA1/2 variants are prognostic biomarkers for hereditary breast and/or ovarian cancer (HBOC) syndrome and predictive biomarkers for PARP inhibition. In this study, we benchmarked the classification of BRCA1/2 variants from patients with HBOC-related cancer using MH BRCA, a novel computational technology that combines the ACMG guidelines with expert-curated variant annotations.

 

Evaluation of BRCA1/2 variants (n = 1040) taken from four HBOC studies showed strong concordance within the pathogenic (98.1%) subset. Comparison of MH BRCA’s ACMG classification to ClinVar submitter content from ENIGMA, the international consortium of investigators on the clinical significance of BRCA1/2 variants, the ARUP laboratories, a clinical testing lab of the University of UTAH, and the German Cancer Consortium showed 99.98% concordance (4975 out of 4976 variants) in the pathogenic subset. In our patient cohort, refinement of patients with variants of unknown significance reduced the uncertainty of cancer-predisposing syndromes by 64.7% and identified three cases with potential family risk to HBOC due to a likely pathogenic variant BRCA1 p.V1653L (NM_007294.3:c.4957G > T; rs80357261). To assess whether classification results predict PARP inhibitor efficacy, contextualization with functional impact information on DNA repair activity were performed, using MH Guide. We found a strong correlation between treatment efficacy association and MH BRCA classifications. Importantly, low efficacy to PARP inhibition was predicted in 3.95% of pathogenic variants from four examined HBOC studies and our patient cohort, indicating the clinical relevance of the consolidated variant interpretation.

 

View full text: https://www.mdpi.com/1422-0067/21/11/3895/htm.

Radioimmunotherapy in Non-Hodgkin’s Lymphoma: Retrospective Adverse Event Profiling of Zevalin and Bexxar

Publications

Radioimmunotherapy in Non-Hodgkin’s Lymphoma: Retrospective Adverse Event Profiling of Zevalin and Bexxar

by Christos Sachpekidis, David B. Jackson and Theodoros G. Soldatos

 

The power of RWD integration at Molecular Health – insights into the utility and safety of Radioimmunotherapy in Non-Hodgkin’s Lymphoma patients.

The development of monoclonal antibodies has dramatically changed the outcome of patients with non-Hodgkin’s lymphoma (NHL), the most common hematological malignancy. However, despite the satisfying results of monoclonal antibody treatment, only few NHL patients are permanently cured with single-agent therapies. In this context, radioimmunotherapy, the administration of radionuclides conjugated to monoclonal antibodies, is aimed to augment the single-agent efficacy of immunotherapy in order to deliver targeted radiation to tumors, particularly CD20+ B-cell lymphomas. Based on evidence from several trials in NHL, the radiolabeled antibodies 90Y-ibritumomab tiuxetan (Zevalin, Spectrum Pharmaceuticals) and 131I-tositumomab (Bexxar, GlaxoSmithKline) received FDA approval in 2002 and 2003, respectively. However, none of the two radioimmunotherapeutic agents has been broadly applied in clinical practice. The main reason for the under-utilization of radioimmunotherapy includes economic and logistic considerations. However, concerns about potential side effects have also been raised. Driven by these developments, we performed retrospective analysis of adverse events reporting Zevalin or Bexxar, extracted from the FDA’s Adverse Event Reporting System (FAERS) and the World Health Organization’s VigiBase repository. Our results indicate that the two radioimmunotherapeutic agents have both related and distinct side effect profiles and confirm their known toxicological considerations. Our work also suggests that computational analysis of real-world post-marketing data can provide informative clinical insights. While more prospective studies are necessary to fully characterize the efficacy and safety of radioimmunotherapy, we expect that it has not yet reached its full therapeutic potential in modern hematological oncology.

 

Pharmaceuticals 201912(4), 141; https://doi.org/10.3390/ph12040141

Precision Oncology – The Quest for Evidence.

Publications

Precision Oncology – The Quest for Evidence.

The molecular characterization of patient tumors provides a rational and highly promising approach for guiding oncologists in treatment decision-making. Notwithstanding, genomic medicine still remains in its infancy, with innovators and early adopters continuing to carry a significant portion of the clinical and financial risk. Numerous innovative precision oncology trials have emerged globally to address the associated need for evidence of clinical utility. These studies seek to capitalize on the power of predictive biomarkers and/or treatment decision support analytics, to expeditiously and cost-effectively demonstrate the positive impact of these technologies on drug resistance/response, patient survival, and/or quality of life. Here, we discuss the molecular foundations of these approaches and highlight the diversity of innovative trial strategies that are capitalizing on this emergent knowledge. We conclude that, as increasing volumes of clinico-molecular outcomes data become available, in future, we will begin to transition away from expert systems for treatment decision support (TDS), towards the power of AI-assisted TDS-an evolution that may truly revolutionize the nature and success of cancer patient care.

Cancer Drug Resistance. (J Pers Med. 2019 Sep 5;9(3). Soldatos, Kaduthanam, Jackson. doi: 10.3390/jpm9030043.

Adverse Event Circumstances and the Case of Drug Interactions.

Publications

Adverse Event Circumstances and the Case of Drug Interactions.

Adverse events are a common and for the most part unavoidable consequence of therapeutic intervention. Nevertheless, available tomes of such data now provide us with an invaluable opportunity to study the relationship between human phenotype and drug-induced protein perturbations within a patient system. Deciphering the molecular basis of such adverse responses is not only paramount to the development of safer drugs but also presents a unique opportunity to dissect disease systems in search of novel response biomarkers, drug targets, and efficacious combination therapies. Inspired by the potential applications of this approach, we first examined adverse event circumstances reported in FAERS and then performed a molecular level interrogation of cancer patient adverse events to investigate the prevalence of drug-drug interactions in the context of patient responses. We discuss avoidable and/or preventable cases and how molecular analytics can help optimize therapeutic use of co-medications. While up to one out of three adverse events in this dataset might be explicable by iatrogenic, patient, and product/device related factors, almost half of the patients in FAERS received multiple drugs and one in four may have experienced effects attributable to drug interactions.

 

Healthcare Basel. 2019 Mar 19;7(1); Soldatos, Jackson. doi: 10.3390/healthcare7010045.

Target-Adverse Event Profiles to Augment Pharmacovigilance: A Pilot Study With Six New Molecular Entities

Publications

Target-Adverse Event Profiles to Augment Pharmacovigilance: A Pilot Study With Six New Molecular Entities

Peter Schotland, Rebecca Racz, David Jackson, Robert Levin, David G. Strauss and Keith Burkhart

In Silico Profiling of Clinical Phenotypes for Human Targets Using Adverse Event Data.

Publications

In Silico Profiling of Clinical Phenotypes for Human Targets Using Adverse Event Data.

We present a novel approach for the molecular transformation and analysis of patient clinical phenotypes. Building on the fact that drugs perturb the function of targets/genes, we integrated data from 8.2 million clinical reports detailing drug-induced side effects with the molecular world of drug-target information. Using this dataset, we extracted 1.8 million associations of clinical phenotypes to 770 human drug-targets. This collection is perhaps the largest phenotypic profiling reference of human targets to-date, and unique in that it enables rapid development of testable molecular hypotheses directly from human-specific information. We also present validation results demonstrating analytical utilities of the approach, including drug safety prediction, and the design of novel combination therapies. Challenging the long-standing notion that molecular perturbation studies cannot be performed in humans, our data allows researchers to capitalize on the vast tomes of clinical information available throughout the healthcare system.


Soldatos, Taglang, Jackson; High Throughput. 2018 Nov 23;7(4). doi: 10.3390/ht7040037.

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data.

Publications

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data.

Recent studies suggest that combining nivolumab with ipilimumab is a more effective treatment for melanoma patients, compared to using ipilimumab or nivolumab alone. However, treatment with these immunotherapeutic agents is frequently associated with increased risk of toxicity, and (auto-) immune-related adverse events. The precise pathophysiologic mechanisms of these events are not yet clear, and evidence from clinical trials and translational studies remains limited. Our retrospective analysis of ~7700 metastatic melanoma patients treated with ipilimumab and/or nivolumab from the FDA Adverse Event Reporting System (FAERS) demonstrates that the identified immune-related reactions are specific to ipilimumab and/or nivolumab, and that when the two agents are administered together, their safety profile combines reactions from each drug alone. While more prospective studies are needed to characterize the safety of ipilimumab and nivolumab, the present work constitutes perhaps the first effort to examine the safety of these drugs and their combination based on computational evidence from real world post marketing data.

Diagnostics (Basel). 2018 Oct 31;8(4); Soldatos TG. doi: 10.3390/diagnostics8040076.

Association Between Serotonin Syndrome and Second-Generation Antipsychotics via Pharmacological Target-Adverse Event Analysis

Publications

Association Between Serotonin Syndrome and Second-Generation Antipsychotics via Pharmacological Target-Adverse Event Analysis

Racz, Soldatos, Jackson, Burkhart. Clin Transl Sci (2018) 00, 1–8; doi:10.1111/cts.12543

Bioinformatory-assisted analysis of next-generation sequencing data for precision medicine in pancreatic cancer.

Publications

Bioinformatory-assisted analysis of next-generation sequencing data for precision medicine in pancreatic cancer.

Stecker, Huelsewig, Brock, Jackson. 2017; Mol Oncol. 2017 Oct;11(10):1413-1429.

Comprehensive Benchmarking of SNV Callers for Highly Admixed Tumors

Publications

Comprehensive Benchmarking of SNV Callers for Highly Admixed Tumors

Bohnert R, Vivas S, Jansen G; 2017, PLoS ONE 12(10): e0186175. https://doi.org/10.1371/journal.pone.0186175.