Comprehensive Molecular Profiling in Primary Hepatobiliary Cancers: Fortune Favors the Brave in the Veterans Administration's National Precision Oncology Efforts

Abstract Background A fraction of patients referred for complex molecular profiling of biopsied tumors may harbor germline variants in genes associated with the development of hereditary cancer syndromes (HCS). Neither the bioinformatic analysis nor the reporting of such incidental germline findings are standardized. Methods Data from Next-Generation Sequencing (NGS) of biopsied tumor samples referred for complex molecular profiling were analyzed for germline variants in HCS-associated genes. Analysis of variant origin was performed employing bioinformatic algorithms followed by manual curation. When possible, the origin of the variant was validated by Sanger sequencing of the sample of normal tissue. The variants’ pathogenicity was assessed according to ACMG/AMP. Results Tumors were sampled from 183 patients (Males: 75 [41.0%]; Females: 108 [59.0%]; mean [SD] age, 57.7 [13.3] years) and analysed by targeted NGS. The most common tumor types were colorectal (19%), pancreatic (13%), and lung cancer (10%). A total of 56 sequence variants in genes associated with HCS were detected in 40 patients. Of them, 17 variants found in 14 patients were predicted to be of germline origin, with 6 variants interpreted as pathogenic (PV) or likely pathogenic (LPV), and 9 as variants of uncertain significance (VUS). For the 41 out of 42 (97%) missense variants in HCS-associated genes, the results of computational prediction of variant origin were concordant with that of experimental examination. We estimate that Sanger sequencing of a sample of normal tissue would be required for ~ 1–7% of the total assessed cases with PV or LPV, when necessity to follow with genetic counselling referral in ~ 2–15% of total assessed cases (PV, LPV or VUS found in HCS genes). Conclusion Incidental findings of pathogenic germline variants are common in data from cancer patients referred for complex molecular profiling. We propose an algorithm for the management of patients with newly detected variants in genes associated with HCS.

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Assessing real-world outcomes in precision oncology by linking clinical genomic testing to electronic medical records.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e18091 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e18091-e18091

Author(s):

Debajyoti Datta ◽

Theodore Goldstein ◽

Atul Butte

Keyword(s):

Next Generation Sequencing ◽

Cancer Patients ◽

Relational Database ◽

Real World ◽

Molecular Profiling ◽

Genomic Testing ◽

Precision Oncology ◽

Clinical Sequencing ◽

Clinical Genomic ◽

Generation Sequencing

e18091 Background: With an ever-widening array of targeted therapies for cancer patients, clinical genomic testing has expanded rapidly in recent years. Tumor molecular profiling by next-generation sequencing is now considered a cornerstone of precision oncology, with the potential to offer patients with advanced cancers new therapeutic options. However, the overall impact of this testing remains unclear, and evidence demonstrating improvement in patient outcomes is lacking. The objective of this study is to assess the utility of clinical sequencing on the management of cancer patients. Methods: We present the development of a database that combines results of tumor mutation profiling using various next-generation sequencing panels (both external commercial tests and our institution’s internal sequencing panel), with a variety of data points from a de-identified representation of our institution’s electronic medical record (EMR). Assembling this data from different sources into a common relational database permits efficient retrospective analysis of real-world outcomes in patients with advanced cancers. Results: This study included over 3000 patients seen at UCSF Comprehensive Cancer Center since 2013. With this linked data set we analyzed the rate at which tumor molecular profiling affected clinical decision making, identified barriers to the efficient use of testing, and assessed for disparities in utilization. For example, by measuring patient survival relative to the clinical intervention of genomic testing for the subset of patients with a date of death recorded in our EMR, we found that a small fraction of patients died before results returned and any action could be taken, especially in cases of pancreatic cancer. Conclusions: We demonstrate that a common relational database combining clinical sequencing results with real-world EMR data provides insights into the optimal clinical use of tumor molecular profiling. This provides new opportunities for advancing precision oncology initiatives and improving patient care, such as identifying which cancer patients should get genomic testing and efficiently matching patients to clinical trials.

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Individualized Molecular Profiling for Allocation to Clinical Trials Singapore Study—An Asian Tertiary Cancer Center Experience

JCO Precision Oncology ◽

10.1200/po.20.00261 ◽

2021 ◽

pp. 859-875

Author(s):

Amanda O. L. Seet ◽

Aaron C. Tan ◽

Tira J. Tan ◽

Matthew C. H. Ng ◽

David W. M. Tai ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Tumor Tissue ◽

Molecular Profiling ◽

Tumor Board ◽

Cancer Center ◽

Precision Oncology ◽

Molecular Tumor Board ◽

Tumor Types ◽

Tertiary Cancer Center

PURPOSE Precision oncology has transformed the management of advanced cancers through implementation of advanced molecular profiling technologies to identify increasingly defined subsets of patients and match them to appropriate therapy. We report outcomes of a prospective molecular profiling study in a high-volume Asian tertiary cancer center. PATIENTS AND METHODS Patients with advanced cancer were enrolled onto a prospective protocol for genomic profiling, the Individualized Molecular Profiling for Allocation to Clinical Trials Singapore study, at the National Cancer Center Singapore. Primary objective was to identify molecular biomarkers in patient's tumors for allocation to clinical trials. The study commenced in February 2012 and is ongoing, with the results of all patients who underwent multiplex next-generation sequencing (NGS) testing until December 2018 presented here. The results were discussed at a molecular tumor board where recommendations for allocation to biomarker-directed trials or targeted therapies were made. RESULTS One thousand fifteen patients were enrolled with a median age of 58 years (range 20-83 years). Most common tumor types were lung adenocarcinoma (26%), colorectal cancer (15%), and breast cancer (12%). A total of 1,064 NGS assays were performed, on fresh tumor tissue for 369 (35%) and archival tumor tissue for 687 (65%) assays. TP53 (39%) alterations were most common, followed by EGFR (21%), KRAS (14%), and PIK3CA (10%). Of 405 NGS assays with potentially actionable alterations, 111 (27%) were allocated to a clinical trial after molecular tumor board and 20 (4.9%) were enrolled on a molecularly matched clinical trial. Gene fusions were detected in 23 of 311 (7%) patients tested, including rare fusions in new tumor types and known fusions in rare tumors. CONCLUSION Individualized Molecular Profiling for Allocation to Clinical Trials Singapore demonstrates the feasibility of a prospective broad molecular profiling program in an Asian tertiary cancer center, with the ability to develop and adapt to a dynamic landscape of precision oncology.

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Precision cancer therapy by molecular profiling – A Theoretical Study

10.31219/osf.io/jkfmy ◽

2021 ◽

Author(s):

V. Sah

Keyword(s):

Large Scale ◽

Clinical Decision Making ◽

Single Cell Analysis ◽

Clinical Decision ◽

Molecular Profiling ◽

Outcome Analysis ◽

Precision Oncology ◽

Liquid Biopsies ◽

Next Generation Sequencing Technology ◽

Genomic Studies

The amount of druggable tumor-specific molecular aberrations has increased significantly over the last decade, with biomarker-matched therapies demonstrating a major survival advantage in many cancer forms. Therefore, molecular pathology has been critical not just for tumor detection and prognosis, but also for clinical decision-making in everyday practice. The advent of next-generation sequencing technology and the proliferation of large-scale tumor molecular profiling services through universities worldwide have transformed the area of precision oncology. When systematic genomic studies become more accessible in clinical and laboratory environments, healthcare professionals face the difficult challenge of outcome analysis and translation. This study summarizes existing and future methods to implementing precision cancer medicine, outlining the obstacles and possible strategies for facilitating the understanding and maximization of molecular profiling findings. Beyond tumor DNA sequencing, we discuss innovative molecular characterization techniques such as transcriptomics, immunophenotyping, epigenetic profiling, and single-cell analysis. Additionally, we discuss present and future uses of liquid biopsies for evaluating blood-based biomarkers such as circulating tumor cells and nucleic acids. Finally, the shortcomings of genotype-based treatments give insight into opportunities to extend personalized medicine beyond genomics.

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Pragmatic precision oncology: the secondary uses of clinical tumor molecular profiling

Journal of the American Medical Informatics Association ◽

10.1093/jamia/ocw002 ◽

2016 ◽

Vol 23 (4) ◽

pp. 773-776 ◽

Cited By ~ 2

Author(s):

Matthew J Rioth ◽

Ramya Thota ◽

David B Staggs ◽

Douglas B Johnson ◽

Jeremy L Warner

Keyword(s):

Science Research ◽

Molecular Profiling ◽

Molecular Profile ◽

Data Repository ◽

Precision Oncology ◽

Profile Data ◽

Secondary Use ◽

Discovery Science ◽

Real Time Database ◽

One Year

Abstract Background Precision oncology increasingly utilizes molecular profiling of tumors to determine treatment decisions with targeted therapeutics. The molecular profiling data is valuable in the treatment of individual patients as well as for multiple secondary uses. Objective To automatically parse, categorize, and aggregate clinical molecular profile data generated during cancer care as well as use this data to address multiple secondary use cases. Methods A system to parse, categorize and aggregate molecular profile data was created. A naÿve Bayesian classifier categorized results according to clinical groups. The accuracy of these systems were validated against a published expertly-curated subset of molecular profiling data. Results Following one year of operation, 819 samples have been accurately parsed and categorized to generate a data repository of 10,620 genetic variants. The database has been used for operational, clinical trial, and discovery science research. Conclusions A real-time database of molecular profiling data is a pragmatic solution to several knowledge management problems in the practice and science of precision oncology.

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Plasma ctDNA sequencing supplementary to tissue-based molecular profiling as a source of additional actionable information in advanced cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15554 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15554-e15554

Author(s):

Bradley Allen Hancock ◽

Swee Seong Wong ◽

Saloni Sinha ◽

Tom Barber ◽

Benjamin A. Salisbury ◽

...

Keyword(s):

Liquid Biopsy ◽

Tumor Tissue ◽

Brca1 Mutation ◽

Molecular Data ◽

Parp Inhibitors ◽

Molecular Profiling ◽

Tumor Board ◽

Precision Oncology ◽

Sequencing Data ◽

Targeted Interventions

e15554 Background: The standard for tumor molecular profiling in precision oncology is the tissue-based biopsy. However, tissue biopsies are limited in the ability to capture the bulk of heterogeneity in advanced cancers. The integration of liquid biopsy diagnostics complementary to tissue-based sequencing may provide a broader perspective of heterogeneity and actionability. Methods: Patients with metastatic solid tumors were evaluated in the Indiana University Health Precision Genomics (PG) Program. We retrospectively analyzed existing genomic data from matched plasma and tissue that were collected within a 90-day window. Plasma sequencing was generated with a CLIA-certified test: FoundationACT/FoundationLiquid. Tumor tissue sequencing was performed either with CLIA-grade whole exome or a gene-panel. All sequencing data was reviewed by a molecular tumor board for the determination of a personalized treatment strategy. Molecular data for this analysis was concatenated and analyzed for mutations present in ctDNA but absent in tissue. Clinical actionability was defined based on clinical evidence of a biomarker to guide therapy or match a patient to a clinical trial. Results: 288 subjects with tissue- and plasma-derived mutation data were analyzed. Discordance, defined by the presence of a somatic mutation in the plasma that was not present in the tumor tissue, was detected in 156/288 (54%) of pairs. Interestingly, the discordance was clinically actionable in 26/288 (9%) subjects. In the 32 gene-level instances of actionable discordance, the 3 top mutated genes were PIK3CA (7), PTEN (4), and EGFR (4). Discordant mutations in ATM and CHEK2, which are actionable with PARP inhibitors, but also frequently mutated in clonal hematopoiesis of indeterminant potential (CHIP) represented 4/26 (15%) instances. A complete and formal CHIP analysis is ongoing. As a result of plasma discordance, targeted interventions were employed in 3/26 (12%) subjects targeting high TMB with immunotherapy, an ERBB2 mutation with ado-trastuzumab emtansine, and a BRCA1 mutation with olaparib. All 3 patients were non-responders. Conclusions: Discordant mutations that appear in ctDNA but not in matched tumor tissue is a common occurrence. The majority of these mutations are either not druggable or variants of unknown significance, but a significant subset would be deemed clinically actionable. Clinical efficacy of targeted intervention based on actionable liquid biopsy discordance warrants further investigation.

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Precision Oncology: Who, How, What, When, and When Not?

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_174176 ◽

2017 ◽

pp. 160-169 ◽

Cited By ~ 5

Author(s):

Lee Schwartzberg ◽

Edward S. Kim ◽

David Liu ◽

Deborah Schrag

Keyword(s):

Cost Effective ◽

Molecular Profiling ◽

Molecular Testing ◽

Precision Oncology ◽

High Quality ◽

Tissue Samples ◽

Development Of Resistance ◽

Target Drug ◽

Number Of Patients ◽

Next Generation Sequencing Ngs

Precision oncology, defined as molecular profiling of tumors to identify targetable alterations, is rapidly developing and has entered the mainstream of clinical practice. Genomic testing involves many stakeholders working in a coordinated fashion to deliver high-quality tissue samples to high-quality laboratories, where appropriate next-generation sequencing (NGS) molecular analysis leads to actionable results. Clinicians should be familiar with the types of genomic variants reported by the laboratory and the technology used to determine the results, including limitations of current testing methodologies and reports. Interpretation of genomic results is best undertaken with multidisciplinary input to reduce uncertainty in clinical recommendations relating to a documented variant. Non–small cell lung cancer has emerged as a prototype disease where genomic data from at least several well-documented alterations with approved targeted agents are essential for optimal treatment from diagnosis of advanced disease. Due to the development of resistance to targeted therapies, resampling and retesting of tumors, including using liquid biopsy technology after clinical progression, may be important in making treatment decisions. The value of molecular profiling depends on avoiding both underutilization for well-documented variant target-drug pairs and overutilization of variant-drug therapy without proven benefit. As techniques evolve and become more cost effective, the use of molecular testing may prove to add more specificity and improve outcomes for a larger number of patients.

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