Publications by authors named "Janessa Laskin"

108 Publications

NTRK2 Fusion driven pediatric glioblastoma: Identification of oncogenic Drivers via integrative Genome and transcriptome profiling.

Clin Case Rep 2021 Mar 10;9(3):1472-1477. Epub 2021 Feb 10.

Division of Anatomic Pathology Children's and Women's Health Centre of British Columbia Vancouver BC Canada.

This is the first report of a NACC2-NTRK2 fusion in a histological glioblastoma. Oncogenomic analysis revealed this actionable fusion oncogene in a pediatric cerebellar glioblastoma, which would not have been identified through routine diagnostics, demonstrating the value of clinical genome profiling in cancer care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ccr3.3804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981675PMC
March 2021

Tumor infiltrating neutrophils and gland formation predict overall survival and molecular subgroups in pancreatic ductal adenocarcinoma.

Cancer Med 2021 02 28;10(3):1155-1165. Epub 2020 Dec 28.

Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, BC, Canada.

Background: RNA-sequencing-based classifiers can stratify pancreatic ductal adenocarcinoma (PDAC) into prognostically significant subgroups but are not practical for use in clinical workflows. Here, we assess whether histomorphological features may be used as surrogate markers for predicting molecular subgroup and overall survival in PDAC.

Methods: Ninety-six tissue samples from 50 patients with non-resectable PDAC were scored for gland formation, stromal maturity, mucin, necrosis, and neutrophil infiltration. Prognostic PDAC gene expression classifiers were run on all tumors using whole transcriptome sequencing data from the POG trial (NCT02155621). Findings were validated using digital TCGA slides (n = 50). Survival analysis used multivariate Cox proportional-hazards tests and log-rank tests.

Results: The combination of low gland formation and low neutrophil infiltration was significantly associated with the poor prognosis PDAC molecular subgroup (basal-like or squamous) and was an independent predictor of shorter overall survival, in both frozen section (n = 47) and formalin-fixed paraffin-embedded (n = 49) tissue samples from POG patients, and in the TCGA samples. This finding held true in the subgroup analysis of primary (n = 17) and metastatic samples (n = 79). The combination of high gland formation and high neutrophils had low sensitivity but high specificity for favorable prognosis subgroups.

Conclusions: The assessment of gland formation and neutrophil infiltration on routine histological sections can aid in prognostication and allow inferences to be made about molecular subtype, which may help guide patient management decisions and contribute to our understanding of heterogeneity in treatment response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897949PMC
February 2021

Matching methods in precision oncology: An introduction and illustrative example.

Mol Genet Genomic Med 2021 01 25;9(1):e1554. Epub 2020 Nov 25.

Canadian Centre for Applied Research in Cancer Control, Cancer Control Research, BC Cancer, Vancouver, BC, Canada.

Background: Randomized controlled trials (RCTs) are uncommon in precision oncology. We provide an introduction and illustrative example of matching methods for evaluating precision oncology in the absence of RCTs. We focus on British Columbia's Personalized OncoGenomics (POG) program, which applies whole-genome and transcriptome analysis (WGTA) to inform advanced cancer care.

Methods: Our cohort comprises 230 POG patients enrolled between 2014 and 2015 and matched POG-naive controls. We generated our matched cohort using 1:1 propensity score matching (PSM) and genetic matching prior to exploring survival differences.

Results: We find that genetic matching outperformed PSM when balancing covariates. In all cohorts, overall survival did not significantly differ across POG and POG-naive patients (p > 0.05). Stratification by WGTA-informed treatment indicated unmatched survival differences. Patients whose WGTA information led to treatment change were at a reduced hazard of death compared to POG-naive controls in all cohorts, with estimated hazard ratios ranging from 0.33 (95% CI: 0.13, 0.81) to 0.41 (95% CI: 0.17, 0.98).

Conclusion: These results signal that clinical effectiveness of precision oncology approaches will depend on rates of genomics-informed treatment change. Our study will guide future evaluations of precision oncology and support reliable effect estimation when RCT data are unavailable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.1554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963415PMC
January 2021

Uncovering Clinically Relevant Gene Fusions with Integrated Genomic and Transcriptomic Profiling of Metastatic Cancers.

Clin Cancer Res 2021 Jan 4;27(2):522-531. Epub 2020 Nov 4.

Department of Medical Oncology, BC Cancer, Vancouver, Canada.

Purpose: Gene fusions are important oncogenic drivers and many are actionable. Whole-genome and transcriptome (WGS and RNA-seq, respectively) sequencing can discover novel clinically relevant fusions.

Experimental Design: Using WGS and RNA-seq, we reviewed the prevalence of fusions in a cohort of 570 patients with cancer, and compared prevalence to that predicted with commercially available panels. Fusions were annotated using a consensus variant calling pipeline (MAVIS) and required that a contig of the breakpoint could be constructed and supported from ≥2 structural variant detection approaches.

Results: In 570 patients with advanced cancer, MAVIS identified 81 recurrent fusions by WGS and 111 by RNA-seq, of which 18 fusions by WGS and 19 by RNA-seq were noted in at least 3 separate patients. The most common fusions were in thoracic malignancies (9/69, 13%), and in colorectal cancer (4/73, 5.5%). Combined genomic and transcriptomic analysis identified novel fusion partners for clinically relevant genes, such as (novel partners: , and (novel partners: ).

Conclusions: Utilizing WGS/RNA-seq facilitates identification of novel fusions in clinically relevant genes, and detected a greater proportion than commercially available panels are expected to find. A significant benefit of WGS and RNA-seq is the innate ability to retrospectively identify variants that becomes clinically relevant over time, without the need for additional testing, which is not possible with panel-based approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-1900DOI Listing
January 2021

Establishing a Framework for the Clinical Translation of Germline Findings in Precision Oncology.

JNCI Cancer Spectr 2020 Oct 29;4(5):pkaa045. Epub 2020 May 29.

Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.

Inherited genetic variation has important implications for cancer screening, early diagnosis, and disease prognosis. A role for germline variation has also been described in shaping the molecular landscape, immune response, microenvironment, and treatment response of individual tumors. However, there is a lack of consensus on the handling and analysis of germline information that extends beyond known or suspected cancer susceptibility in large-scale cancer genomics initiatives. As part of the Personalized OncoGenomics program in British Columbia, we performed whole-genome and transcriptome sequencing in paired tumor and normal tissues from advanced cancer patients to characterize the molecular tumor landscape and identify putative targets for therapy. Overall, our experience supports a multidisciplinary and integrative approach to germline data management. This includes a need for broader definitions and standardized recommendations regarding primary and secondary germline findings in precision oncology. Here, we propose a framework for identifying, evaluating, and returning germline variants of potential clinical significance that may have indications for health management beyond cancer risk reduction or prevention in patients and their families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jncics/pkaa045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583151PMC
October 2020

Subtype-Discordant Pancreatic Ductal Adenocarcinoma Tumors Show Intermediate Clinical and Molecular Characteristics.

Clin Cancer Res 2021 Jan 13;27(1):150-157. Epub 2020 Oct 13.

Pancreas Centre BC, Vancouver, British Columbia, Canada.

Purpose: RNA-sequencing-based subtyping of pancreatic ductal adenocarcinoma (PDAC) has been reported by multiple research groups, each using different methodologies and patient cohorts. "Classical" and "basal-like" PDAC subtypes are associated with survival differences, with basal-like tumors associated with worse prognosis. We amalgamated various PDAC subtyping tools to evaluate the potential of such tools to be reliable in clinical practice.

Experimental Design: Sequencing data for 574 PDAC tumors was obtained from prospective trials and retrospective public databases. Six published PDAC subtyping strategies (Moffitt regression tools, clustering-based Moffitt, Collisson, Bailey, and Karasinska subtypes) were used on each sample, and results were tested for subtype call consistency and association with survival.

Results: Basal-like and classical subtype calls were concordant in 88% of patient samples, and survival outcomes were significantly different ( < 0.05) between prognostic subtypes. Twelve percent of tumors had subtype-discordant calls across the different methods, showing intermediate survival in univariate and multivariate survival analyses. Transcriptional profiles compatible with that of a hybrid subtype signature were observed for subtype-discordant tumors, in which classical and basal-like genes were concomitantly expressed. Subtype-discordant tumors showed intermediate molecular characteristics, including subtyping gene expression ( < 0.0001) and mutant allelic imbalance ( < 0.001).

Conclusions: Nearly 1 in 6 patients with PDAC have tumors that fail to reliably fall into the classical or basal-like PDAC subtype categories, based on two regression tools aimed toward clinical practice. Rather, these patient tumors show intermediate prognostic and molecular traits. We propose close consideration of the non-binary nature of PDAC subtypes for future incorporation of subtyping into clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-2831DOI Listing
January 2021

Genome and Transcriptome Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Solid Tumors.

Clin Cancer Res 2021 Jan 5;27(1):202-212. Epub 2020 Oct 5.

Department of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.

Purpose: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid tumors with dramatic and durable responses seen across multiple tumor types. However, identifying patients who will respond to these drugs remains challenging, particularly in the context of advanced and previously treated cancers.

Experimental Design: We characterized fresh tumor biopsies from a heterogeneous pan-cancer cohort of 98 patients with metastatic predominantly pretreated disease through the Personalized OncoGenomics program at BC Cancer (Vancouver, Canada) using whole genome and transcriptome analysis (WGTA). Baseline characteristics and follow-up data were collected retrospectively.

Results: We found that tumor mutation burden, independent of mismatch repair status, was the most predictive marker of time to progression ( = 0.007), but immune-related CD8 T-cell and M1-M2 macrophage ratio scores were more predictive for overall survival (OS; = 0.0014 and 0.0012, respectively). While [programmed death-ligand 1 (PD-L1)] gene expression is comparable with protein levels detected by IHC, we did not observe a clinical benefit for patients with this marker. We demonstrate that a combination of markers based on WGTA provides the best stratification of patients ( = 0.00071, OS), and also present a case study of possible acquired resistance to pembrolizumab in a patient with non-small cell lung cancer.

Conclusions: Interpreting the tumor-immune interface to predict ICI efficacy remains challenging. WGTA allows for identification of multiple biomarkers simultaneously that in combination may help to identify responders, particularly in the context of a heterogeneous population of advanced and previously treated cancers, thus precluding tumor type-specific testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-1163DOI Listing
January 2021

Delving into Early-onset Pancreatic Ductal Adenocarcinoma: How Does Age Fit In?

Clin Cancer Res 2021 Jan 21;27(1):246-254. Epub 2020 Sep 21.

BC Cancer, Vancouver, British Columbia, Canada.

Purpose: With the rising incidence of early-onset pancreatic cancer (EOPC), molecular characteristics that distinguish early-onset pancreatic ductal adenocarcinoma (PDAC) tumors from those arising at a later age are not well understood.

Experimental Design: We performed bioinformatic analysis of genomic and transcriptomic data generated from 269 advanced (metastatic or locally advanced) and 277 resectable PDAC tumor samples. Patient samples were stratified into EOPC (age of onset ≤55 years; = 117), intermediate (age of onset 55-70 years; = 264), and average (age of onset ≥70 years; = 165) groups. Frequency of somatic mutations affecting genes commonly implicated in PDAC, as well as gene expression patterns, were compared between EOPC and all other groups.

Results: EOPC tumors showed significantly lower frequency of somatic single-nucleotide variant (SNV)/insertions/deletions (indel) in ( = 0.0017), and were more likely to achieve biallelic mutation of through homozygous copy loss as opposed to heterozygous copy loss coupled with a loss-of-function SNV/indel mutation, the latter of which was more common for tumors with later ages of onset ( = 1.5e-4). Transcription factor forkhead box protein C2 () was significantly upregulated in EOPC tumors ( = 0.032). Genes significantly correlated with in PDAC samples were enriched for gene sets related to epithelial-to-mesenchymal transition (EMT) and included ( = 1.8e-8), ( = 6.5e-5), and ( = 2.4e-2).

Conclusions: Our comprehensive analysis of sequencing data generated from a large cohort of PDAC patient samples highlights a distinctive pattern of biallelic mutation in EOPC tumors. Increased expression of in EOPC, with the correlation between and EMT pathways, represents novel molecular characteristics of EOPC..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-1042DOI Listing
January 2021

EGFR circulating tumour DNA testing: identification of predictors of ctDNA detection and implications for survival outcomes.

Transl Lung Cancer Res 2020 Aug;9(4):1084-1092

Department of Medical Oncology, BC Cancer, Vancouver, Canada.

Background: EGFR T790M testing is the standard of care for activating EGFR mutation (EGFRm) non-small cell lung cancer (NSCLC) progressing on 1st/2nd generation TKIs to select patients for osimertinib. Despite sensitive assays, detection of circulating tumour deoxyribonucleic acid (ctDNA) is variable and influenced by clinical factors. The number and location of sites of progressive disease at time of testing were reviewed to explore the effect on EGFR ctDNA detection. The prognostic value of EGFR ctDNA detection on survival outcomes was assessed.

Methods: Following extraction of cell-free DNA from plasma using the QIAamp Circulating Nucleic Acid Kit, custom droplet digital polymerase chair reaction (ddPCR) assays were used to assess EGFR ctDNA using the Bio-Rad QX200 system. The ddPCR assay has a limit of detection of ≤0.15% variant allele fraction. Baseline characteristics and imaging reports at time of EGFR ctDNA testing were reviewed retrospectively for a 1 year period.

Results: The study included 177 patients who had an EGFR ctDNA test. Liver (aOR 3.13) or bone (aOR 2.76) progression or 3-5 sites of progression (aOR 2.22) were predictive of EGFR ctDNA detection. The median OS from first ctDNA test after multiple testing iterations was 12.3 m undetectable EGFR ctDNA, 7.6 m for original EGFR mutation only and 24.1 m with T790M (P=0.001).

Conclusions: Patients with liver or bone progression and 3-5 progressing sites are more likely to have informative EGFR ctDNA testing. Detection of EGFR ctDNA is a negative prognostic indicator in the absence of a T790M resistance mutation, potentially reflecting the disease burden in the absence of targeted therapy options.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/tlcr-19-581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481591PMC
August 2020

Therapeutic Potential of Afatinib in NRG1 Fusion-Driven Solid Tumors: A Case Series.

Oncologist 2021 01 23;26(1):7-16. Epub 2020 Sep 23.

University of British Columbia, BC Cancer, Vancouver, British Columbia, Canada.

Background: Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors.

Patients And Methods: This report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib.

Results: The six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day.

Conclusion: This report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors.

Key Points: NRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2020-0379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794194PMC
January 2021

Evaluating genomic biomarkers associated with resistance or sensitivity to chemotherapy in patients with advanced breast and colorectal cancer.

J Oncol Pharm Pract 2020 Aug 26:1078155220951845. Epub 2020 Aug 26.

BC Cancer Agency, Vancouver, Canada.

Introduction: Carcinogenesis is driven by an array of complex genomic patterns; these patterns can render an individual resistant or sensitive to certain chemotherapy agents. The Personalized Oncogenomics (POG) project at BC Cancer has performed integrative genomic analysis of whole tumour genomes and transcriptomes for over 700 patients with advanced cancers, with an aim to predict therapeutic sensitivities. The aim of this study was to utilize the POG genomic data to evaluate a discrete set of biomarkers associated with chemo-sensitivity or-resistance in advanced stage breast and colorectal cancer POG patients.

Methods: This was a retrospective multi-centre analysis across all BC CANCER sites. All breast and colorectal cancer patients enrolled in the POG program between July 1, 2012 and November 30, 2016 were eligible for inclusion. Within the breast cancer population, those treated with capecitabine, paclitaxel, and everolimus were analyzed, and for the colorectal cancer patients, those treated with capecitabine, bevacizumab, irinotecan, and oxaliplatin were analyzed. The expression levels of the selected biomarkers of interest (, , , , , , , , , , , , , , , , and ) were reported as mRNA percentiles.

Results: For the breast cancer population, there were 32 patients in the capecitabine cohort, 15 in the everolimus cohort, and 12 in the paclitaxel cohort. For the colorectal cancer population, there were 29 patients in the bevacizumab cohort, 12 in the oxaliplatin cohort, 29 in the irinotecan cohort, and 6 in the capecitabine cohort. Of the biomarkers evaluated, the strongest associations were found between Bevacizumab-based therapy and (P = 0.0445); and between capecitabine therapy and (P = 0.0553).

Conclusions: Among breast cancer patients, higher expression was associated with sensitivity to capecitabine. Among colorectal cancer patients, higher expression was associated with sensitivity to bevacizumab-based therapy. This study supports further assessment of the potential predictive value of mRNA expression of these genomic biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1078155220951845DOI Listing
August 2020

Efficacy of Selpercatinib in -Altered Thyroid Cancers.

N Engl J Med 2020 08;383(9):825-835

From Massachusetts General Hospital (L.J.W.) and Dana-Farber Cancer Institute (J. Lorch), Boston; Memorial Sloan Kettering Cancer Center, New York (E.S., A.D.); Royal North Shore Hospital, St. Leonards, NSW (B.R.), and Peter MacCallum Cancer Institute, Melbourne, VIC (B.S.) - both in Australia; University of California, San Francisco-Helen Diller Family Comprehensive Cancer Center, San Francisco (H.K.), David Geffen School of Medicine at UCLA, Los Angeles (J.W.G.), and Chao Family Comprehensive Cancer Center, University of California Irvine, Orange (V.W.Z.) - all in California; University of Michigan, Ann Arbor (F.W.), and START Midwest, Grand Rapids (N.L.) - both in Michigan; University of Pennsylvania, Philadelphia (M.B.); University of Chicago, Chicago (J.P.); Gustave Roussy, Villejuif (S.L.), Institut Bergonié, Bordeaux (Y.G.), Aix Marseille University, Centre National de la Recherche Scientifique, INSERM, Centre de Recherche en Cancérologie de Marseille, Assistance Publique-Hôpitaux de Marseille, Early Phase Cancer Trial Center CLIP2, Hospital La Timone, Marseille (F.B.), Centre Léon Bérard, Lyon (C.D.L.F.), and Hôpital Européen Georges-Pompidou, Faculté de Médecine Paris-Descartes, Paris (J.M.) - all in France; Mayo Clinic-Rochester, Rochester, MN (J.C.M.); Winship Cancer Institute of Emory University, Atlanta (T.K.O.); National Cancer Center Singapore, Singapore (D.S.W.T.); University of Bern, Bern, and Cantonal Hospital of Lucerne, Lucerne - both in Switzerland (O.G.); University of North Carolina-Chapel Hill, Chapel Hill (J.W.); University of Wisconsin-Carbone Cancer Center, Madison (M.E.B.); British Columbia Cancer Agency, Vancouver, Canada (J. Laskin); Oregon Health and Science University, Portland (M.H.T.); Universitätsklinikum Würzburg, Department of Internal Medicine I, Division of Endocrinology and Diabetology, Würzburg, Germany (M.K.); Sarah Cannon Research Institute-Tennessee Oncology, Nashville (T.M.B.); Johns Hopkins Kimmel Cancer Center, Washington, DC (B.L.); Fundación Jimenez Diaz, START-Madrid, Madrid (V.M.); Loxo Oncology, Stamford, CT (K.E., M.N., D.H., E.Y.Z., X.H., L.Y., J.K., S.M.R.); University of Texas M.D. Anderson Cancer Center, Houston (V.S., M.E.C.); and Ohio State University Comprehensive Cancer Center, Columbus (M.H.S.).

Background: mutations occur in 70% of medullary thyroid cancers, and fusions occur rarely in other thyroid cancers. In patients with -altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown.

Methods: We enrolled patients with -mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.

Results: In the first 55 consecutively enrolled patients with -mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with -mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events.

Conclusions: In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2005651DOI Listing
August 2020

Improved structural variant interpretation for hereditary cancer susceptibility using long-read sequencing.

Genet Med 2020 11 6;22(11):1892-1897. Epub 2020 Jul 6.

Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.

Purpose: Structural variants (SVs) may be an underestimated cause of hereditary cancer syndromes given the current limitations of short-read next-generation sequencing. Here we investigated the utility of long-read sequencing in resolving germline SVs in cancer susceptibility genes detected through short-read genome sequencing.

Methods: Known or suspected deleterious germline SVs were identified using Illumina genome sequencing across a cohort of 669 advanced cancer patients with paired tumor genome and transcriptome sequencing. Candidate SVs were subsequently assessed by Oxford Nanopore long-read sequencing.

Results: Nanopore sequencing confirmed eight simple pathogenic or likely pathogenic SVs, resolving three additional variants whose impact could not be fully elucidated through short-read sequencing. A recurrent sequencing artifact on chromosome 16p13 and one complex rearrangement on chromosome 5q35 were subsequently classified as likely benign, obviating the need for further clinical assessment. Variant configuration was further resolved in one case with a complex pathogenic rearrangement affecting TSC2.

Conclusion: Our findings demonstrate that long-read sequencing can improve the validation, resolution, and classification of germline SVs. This has important implications for return of results, cascade carrier testing, cancer screening, and prophylactic interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-0880-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605438PMC
November 2020

Endogenous Retrovirus Transcript Levels Are Associated with Immunogenic Signatures in Multiple Metastatic Cancer Types.

Mol Cancer Ther 2020 09 9;19(9):1889-1897. Epub 2020 Jun 9.

Pancreas Centre BC, Vancouver, British Columbia, Canada.

Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. Although expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across different types of metastatic cancer are not well established. We performed bioinformatics analysis of genomic, transcriptomic, and clinical data across an integrated cohort of 199 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma tumors. Within each cancer type, we identified a subgroup of viral mimicry tumors in which increased ERV levels were coupled with transcriptional signatures of autonomous antiviral response and immunogenicity. In addition, viral mimicry colorectal and pancreatic tumors showed increased expression of DNA demethylation gene Taken together, these data demonstrate the existence of an ERV-associated viral mimicry phenotype across three distinct metastatic cancer types, while indicating links between ERV abundance, epigenetic dysregulation, and immunogenicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-20-0094DOI Listing
September 2020

A phase IB study of durvalumab with or without tremelimumab and platinum-doublet chemotherapy in advanced solid tumours: Canadian Cancer Trials Group Study IND226.

Lung Cancer 2020 05 28;143:1-11. Epub 2020 Feb 28.

The Ottawa Hospital Cancer Centre, Division of Medical Oncology, Ottawa, ON, Canada.

This multicenter phase Ib study aimed to establish a recommended phase II dose for durvalumab (Du) ± tremelimumab (Tr) in combination with standard platinum-doublet chemotherapy. Eligible patients were enrolled into one of six dose levels (DL) of Du ± Tr which included concomitant treatment with standard platinum-doublet regimens; (pemetrexed, gemcitabine, etoposide, (each with cisplatin or carboplatin) or nab-paclitaxel (with carboplatin)). Dose escalation was according to a Rolling Six type design. Both weight-based and fixed dosing of Du and Tr were explored. Du was continued until progression. Tr dosing was finite (up to 6 doses) with increasing dose and/or frequency by DL. 136 patients were enrolled. The majority of drug-related adverse events (AEs) were ≤ grade 2 and attributable to chemotherapy. AEs considered related to immunotherapy were mainly ≤ grade 2; the most frequent (occurring ≥10 %) were colitis/diarrhea, skin, and thyroid dysfunction. Seven patients had DLTs including pneumonitis, myocarditis, diarrhea, encephalitis, motor neuropathy, and enterocolitis. There were 2 treatment-related deaths. Tr and Du exposures did not appear affected by chemotherapy. Among the 73 non-small cell lung cancer (NSCLC) patients treated, the objective response rate was 51 % (95 %CI = 38.7-62.6 %) with a median progression-free and overall survival of 6.5 months (95 % CI = 5.5-9.4 months) and 19.8 months (95 % CI = 14.8 months - not yet reached) respectively. Anti-tumour activity was observed across PD-L1 subtypes. Du 1500 mg q3w and Tr 75 mg q3wx5 can be safely combined with platinum-doublet chemotherapy. Efficacy among NSCLC patients appears comparable to results from other immunotherapy and chemotherapy combination trials. NCT02537418.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2020.02.016DOI Listing
May 2020

Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution.

Nat Genet 2020 02 13;52(2):231-240. Epub 2020 Jan 13.

Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.

Pancreatic adenocarcinoma presents as a spectrum of a highly aggressive disease in patients. The basis of this disease heterogeneity has proved difficult to resolve due to poor tumor cellularity and extensive genomic instability. To address this, a dataset of whole genomes and transcriptomes was generated from purified epithelium of primary and metastatic tumors. Transcriptome analysis demonstrated that molecular subtypes are a product of a gene expression continuum driven by a mixture of intratumoral subpopulations, which was confirmed by single-cell analysis. Integrated whole-genome analysis uncovered that molecular subtypes are linked to specific copy number aberrations in genes such as mutant KRAS and GATA6. By mapping tumor genetic histories, tetraploidization emerged as a key mutational process behind these events. Taken together, these data support the premise that the constellation of genomic aberrations in the tumor gives rise to the molecular subtype, and that disease heterogeneity is due to ongoing genomic instability during progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0566-9DOI Listing
February 2020

Patient selection for a developmental therapeutics program using whole genome and Transcriptome analysis.

Invest New Drugs 2020 10 6;38(5):1601-1604. Epub 2020 Jan 6.

Department of Medical Oncology, BC Cancer, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada.

Introduction Given the high level of uncertainty surrounding the outcomes of early phase clinical trials, whole genome and transcriptome analysis (WGTA) can be used to optimize patient selection and study assignment. In this retrospective analysis, we reviewed the impact of this approach on one such program. Methods Patients with advanced malignancies underwent fresh tumor biopsies as part of our personalized medicine program (NCT02155621). Tumour molecular data were reviewed for potentially clinically actionable findings and patients were referred to the developmental therapeutics program. Outcomes were reviewed in all patients, including those where trial selection was driven by molecular data (matched) and those where there was no clear molecular rationale (unmatched). Results From January 2014 to January 2018, 28 patients underwent WGTA and enrolled in clinical trials, including 2 patients enrolled in two trials. Fifteen patients were matched to a treatment based on a molecular target. Five patients were matched to a trial based upon single-gene DNA changes, all supported by RNA data. Ten cases were matched on the basis of genome-wide data (n = 4) or RNA gene expression only (n = 6). With a median follow-up of 6.7 months, the median time on treatment was 8.2 weeks. Discussion When compared to single-gene DNA-based data alone, WGTA led to a 3-fold increase in treatment matching. In a setting where there is a high level of uncertainty around both the investigational agents and the biomarkers, more data are needed to fully evaluate the impact of routine use of WGTA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10637-020-00892-8DOI Listing
October 2020

Fluorouracil sensitivity in a head and neck squamous cell carcinoma with a somatic structural variant.

Cold Spring Harb Mol Case Stud 2020 02 3;6(1). Epub 2020 Feb 3.

Department of Medical Oncology, BC Cancer, Vancouver, British Columbia V5Z 4E6, Canada.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide and represents a heterogeneous group of tumors, the majority of which are treated with a combination of surgery, radiation, and chemotherapy. Fluoropyrimidine (5-FU) and its oral prodrug, capecitabine, are commonly prescribed treatments for several solid tumor types including HNSCC. 5-FU-associated toxicity is observed in ∼30% of treated patients and is largely caused by germline polymorphisms in , which encodes dihydropyrimidine dehydrogenase, a key enzyme of 5-FU catabolism and deactivation. Although the association of germline alterations with toxicity is well-described, the potential contribution of somatic alterations to 5-FU sensitivity has not been explored. In a patient with metastatic HNSCC, in-depth genomic and transcriptomic integrative analysis on a biopsy from a metastatic neck lesion revealed alterations in genes that are associated with 5-FU uptake and metabolism. These included a novel somatic structural variant resulting in a partial deletion affecting , a variant of unknown significance affecting , and homozygous deletion of There was no evidence of deleterious germline polymorphisms that have been associated with 5-FU toxicity, indicating a potential vulnerability of the tumor to 5-FU therapy. The discovery of the novel variant led to the initiation of 5-FU treatment that resulted in a rapid response lasting 17 wk, with subsequent relapse due to unknown resistance mechanisms. This suggests that somatic alterations present in this tumor may serve as markers for tumor sensitivity to 5-FU, aiding in the selection of personalized treatment strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/mcs.a004713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996515PMC
February 2020

Epidermal growth factor receptor mutation analysis in tissue and plasma from the AURA3 trial: Osimertinib versus platinum-pemetrexed for T790M mutation-positive advanced non-small cell lung cancer.

Cancer 2020 01 26;126(2):373-380. Epub 2019 Nov 26.

State Key Laboratory of South China, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, China.

Background: This study assesses different technologies for detecting epidermal growth factor receptor (EGFR) mutations from circulating tumor DNA in patients with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) from the AURA3 study (NCT02151981), and it evaluates clinical responses to osimertinib and platinum-pemetrexed according to the plasma T790M status.

Methods: Tumor tissue biopsy samples were tested for T790M during screening with the cobas EGFR Mutation Test (cobas tissue). Plasma samples were collected at screening and at the baseline and were retrospectively analyzed for EGFR mutations with the cobas EGFR Mutation Test v2 (cobas plasma), droplet digital polymerase chain reaction (ddPCR; Biodesix), and next-generation sequencing (NGS; Guardant360, Guardant Health).

Results: With cobas tissue test results as a reference, the plasma T790M positive percent agreement (PPA) was 51% (110 of 215 samples) by cobas plasma, 58% (110 of 189) by ddPCR, and 66% (136 of 207) by NGS. Plasma T790M detection was associated with a larger median baseline tumor size (56 mm for T790M-positive vs 39 mm for T790M-negative; P < .0001) and the presence of extrathoracic disease (58% for M1b-positive vs 39% for M0-1a-positive; P = .002). Progression-free survival (PFS) was prolonged in randomized patients (tissue T790M-positive) with a T790M-negative cobas plasma result in comparison with those with a T790M-positive plasma result in both osimertinib (median, 12.5 vs 8.3 months) and platinum-pemetrexed groups (median, 5.6 vs 4.2 months).

Conclusions: PPA was similar between ddPCR and NGS assays; both were more sensitive than cobas plasma. All 3 test platforms are suitable for routine clinical practice. In patients with tissue T790M-positive NSCLC, an absence of detectable plasma T790M at the baseline is associated with longer PFS, which may be attributed to a lower disease burden.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.32503DOI Listing
January 2020

Comparative Tumor RNA Sequencing Analysis for Difficult-to-Treat Pediatric and Young Adult Patients With Cancer.

JAMA Netw Open 2019 10 2;2(10):e1913968. Epub 2019 Oct 2.

CHOC Children's Hospital, Hyundai Cancer Institute, Orange, California.

Importance: Pediatric cancers are epigenetic diseases; therefore, considering tumor gene expression information is necessary for a complete understanding of the tumorigenic processes.

Objective: To evaluate the feasibility and utility of incorporating comparative gene expression information into the precision medicine framework for difficult-to-treat pediatric and young adult patients with cancer.

Design, Setting, And Participants: This cohort study was conducted as a consortium between the University of California, Santa Cruz (UCSC) Treehouse Childhood Cancer Initiative and clinical genomic trials. RNA sequencing (RNA-Seq) data were obtained from the following 4 clinical sites and analyzed at UCSC: British Columbia Children's Hospital (n = 31), Lucile Packard Children's Hospital at Stanford University (n = 80), CHOC Children's Hospital and Hyundai Cancer Institute (n = 46), and the Pacific Pediatric Neuro-Oncology Consortium (n = 24). The study dates were January 1, 2016, to March 22, 2017.

Exposures: Participants underwent tumor RNA-Seq profiling as part of 4 separate clinical trials at partner hospitals. The UCSC either downloaded RNA-Seq data from a partner institution for analysis in the cloud or provided a Docker pipeline that performed the same analysis at a partner institution. The UCSC then compared each participant's tumor RNA-Seq profile with more than 11 000 uniformly analyzed tumor profiles from pediatric and young adult patients with cancer, downloaded from public data repositories. These comparisons were used to identify genes and pathways that are significantly overexpressed in each patient's tumor. Results of the UCSC analysis were presented to clinical partners.

Main Outcomes And Measures: Feasibility of a third-party institution (UCSC Treehouse Childhood Cancer Initiative) to obtain tumor RNA-Seq data from patients, conduct comparative analysis, and present analysis results to clinicians; and proportion of patients for whom comparative tumor gene expression analysis provided useful clinical and biological information.

Results: Among 144 samples from children and young adults (median age at diagnosis, 9 years; range, 0-26 years; 72 of 118 [61.0%] male [26 patients sex unknown]) with a relapsed, refractory, or rare cancer treated on precision medicine protocols, RNA-Seq-derived gene expression was potentially useful for 99 of 144 samples (68.8%) compared with DNA mutation information that was potentially useful for only 34 of 74 samples (45.9%).

Conclusions And Relevance: This study's findings suggest that tumor RNA-Seq comparisons may be feasible and highlight the potential clinical utility of incorporating such comparisons into the clinical genomic interpretation framework for difficult-to-treat pediatric and young adult patients with cancer. The study also highlights for the first time to date the potential clinical utility of harmonized publicly available genomic data sets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2019.13968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822083PMC
October 2019

Emotional distress and psychosocial needs in patients with breast cancer in British Columbia: younger versus older adults.

Breast Cancer Res Treat 2020 Jan 19;179(2):471-477. Epub 2019 Oct 19.

University of British Columbia, Vancouver, Canada.

Purpose: This study evaluates the prevalence of emotional distress and psychosocial needs in young adult (YA, age 18-39) patients at the time of their breast cancer diagnosis compared to older patients.

Methods: Through a province-wide program, BC Cancer patients complete the PsychoSocial Scan for CANcer-Revised (PSSCAN-R) questionnaire, which screens for the presence of symptoms of anxiety and depression and assesses psychosocial needs using the Canadian Problem Checklist (CPC). The study population comprised all breast cancer patients who completed the questionnaire within 6 months of their cancer diagnosis between 2011 and 2016. Clinical information was retrospectively collected from electronic health records. Univariate and multivariate analyses using the X, Fisher's exact test, and logistical regression were used to compare patient age groups.

Results: The cohort included 10,734 breast cancer patients: median age 62, 4% YA, 99% female, and 96% presented with non-metastatic disease. After adjusting for clinical and demographic variables, YA patients were more likely to report depression (33.6% vs. 25.5%, OR 1.47, p = 0.001) and anxiety symptoms (58.6% vs. 35.7%, OR 2.49, p < 0.001) than older patients. Psychosocial needs regarding work/school (OR 3.79, p < 0.001), intimacy/sexuality (OR 2.82, p < 0.001), and finances (OR 2.78, p < 0.001) were more common among YA than older adults.

Conclusions: After a breast cancer diagnosis, YAs have higher levels of emotional distress compared to older patients. Differences in specific psychosocial needs likely reflect differences in life stage between these age groups. The data suggest that YAs warrant specific attention with respect to early psychosocial assessment and tailored intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-019-05468-6DOI Listing
January 2020

Altered Gene Expression along the Glycolysis-Cholesterol Synthesis Axis Is Associated with Outcome in Pancreatic Cancer.

Clin Cancer Res 2020 01 3;26(1):135-146. Epub 2019 Sep 3.

Pancreas Centre BC, Vancouver, British Columbia, Canada.

Purpose: Identification of clinically actionable molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcome. Intertumoral metabolic heterogeneity contributes to cancer survival and the balance between distinct metabolic pathways may influence PDAC outcome. We hypothesized that PDAC can be stratified into prognostic metabolic subgroups based on alterations in the expression of genes involved in glycolysis and cholesterol synthesis.

Experimental Design: We performed bioinformatics analysis of genomic, transcriptomic, and clinical data in an integrated cohort of 325 resectable and nonresectable PDAC. The resectable datasets included retrospective The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) cohorts. The nonresectable PDAC cohort studies included prospective COMPASS, PanGen, and BC Cancer Personalized OncoGenomics program (POG).

Results: On the basis of the median normalized expression of glycolytic and cholesterogenic genes, four subgroups were identified: quiescent, glycolytic, cholesterogenic, and mixed. Glycolytic tumors were associated with the shortest median survival in resectable (log-rank test = 0.018) and metastatic settings (log-rank test = 0.027). Patients with cholesterogenic tumors had the longest median survival. and -amplified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of the oncogenes (Wilcoxon rank sum test = 0.015). Glycolytic tumors had the lowest expression of mitochondrial pyruvate carriers and . Glycolytic and cholesterogenic gene expression correlated with the expression of prognostic PDAC subtype classifier genes.

Conclusions: Metabolic classification specific to glycolytic and cholesterogenic pathways provides novel biological insight into previously established PDAC subtypes and may help develop personalized therapies targeting unique tumor metabolic profiles..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-1543DOI Listing
January 2020

The pivotal role of sampling recurrent tumors in the precision care of patients with tumors of the central nervous system.

Cold Spring Harb Mol Case Stud 2019 08 1;5(4). Epub 2019 Aug 1.

Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.

Effective management of brain and spine tumors relies on a multidisciplinary approach encompassing surgery, radiation, and systemic therapy. In the era of personalized oncology, the latter is complemented by various molecularly targeting agents. Precise identification of cellular targets for these drugs requires comprehensive profiling of the cancer genome coupled with an efficient analytic pipeline, leading to an informed decision on drug selection, prognosis, and confirmation of the original pathological diagnosis. Acquisition of optimal tumor tissue for such analysis is paramount and often presents logistical challenges in neurosurgery. Here, we describe the experience and results of the Personalized OncoGenomics (POG) program with a focus on tumors of the central nervous system (CNS). Patients with recurrent CNS tumors were consented and enrolled into the POG program prior to accrual of tumor and matched blood followed by whole-genome and transcriptome sequencing and processing through the POG bioinformatic pipeline. Sixteen patients were enrolled into POG. In each case, POG analyses identified genomic drivers including novel oncogenic fusions, aberrant pathways, and putative therapeutic targets. POG has highlighted that personalized oncology is truly a multidisciplinary field, one in which neurosurgeons must play a vital role if these programs are to succeed and benefit our patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/mcs.a004143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6672021PMC
August 2019

Genomic characterization of a well-differentiated grade 3 pancreatic neuroendocrine tumor.

Cold Spring Harb Mol Case Stud 2019 06 3;5(3). Epub 2019 Jun 3.

Canada's Michael Smith Genome Science Centre, BC Cancer, Vancouver, British Columbia V5Z 4S6, Canada.

Pancreatic neuroendocrine neoplasms (PanNENs) represent a minority of pancreatic neoplasms that exhibit variability in prognosis. Ongoing mutational analyses of PanNENs have found recurrent abnormalities in chromatin remodeling genes (e.g., and ), and mTOR pathway genes (e.g., , , and ), some of which have relevance to patients with related familial syndromes. Most recently, grade 3 PanNENs have been divided into two groups based on differentiation, creating a new group of well-differentiated grade 3 neuroendocrine tumors (PanNETs) that have had a limited whole-genome level characterization to date. In a patient with a metastatic well-differentiated grade 3 PanNET, our study utilized whole-genome sequencing of liver metastases for the comparative analysis and detection of single-nucleotide variants, insertions and deletions, structural variants, and copy-number variants, with their biologic relevance confirmed by RNA sequencing. We found that this tumor most notably exhibited a -disrupting fusion, showed a novel fusion, and lacked any somatic variants in , , and .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/mcs.a003814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549554PMC
June 2019

ALK-Positive Lung Adenocarcinoma Arising in an Adolescent Treated for Relapsed Neuroblastoma.

J Thorac Oncol 2019 06;14(6):e132-e135

Division of Anatomical Pathology, British Columbia Children's Hospital; and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2019.02.010DOI Listing
June 2019

Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in Wild-Type Pancreatic Ductal Adenocarcinoma.

Clin Cancer Res 2019 Aug 8;25(15):4674-4681. Epub 2019 May 8.

Pancreas Centre British Columbia, Vancouver, Canada.

Purpose: Gene fusions involving neuregulin 1 () have been noted in multiple cancer types and have potential therapeutic implications. Although varying results have been reported in other cancer types, the efficacy of the HER-family kinase inhibitor afatinib in the treatment of fusion-positive pancreatic ductal adenocarcinoma is not fully understood.

Experimental Design: Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving received afatinib treatment, with response measured by pretreatment and posttreatment PET/CT imaging.

Results: Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as wild type by whole-genome sequencing. All wild-type tumors were positive for gene fusions involving the ERBB3 ligand . Two of 3 patients with fusion-positive tumors were treated with afatinib and demonstrated a significant and rapid response while on therapy.

Conclusions: This work adds to a growing body of evidence that gene fusions are recurrent, therapeutically actionable genomic events in pancreatic cancers. Based on the clinical outcomes described here, patients with wild-type tumors harboring gene fusions may benefit from treatment with afatinib..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-0191DOI Listing
August 2019

Application of a Neural Network Whole Transcriptome-Based Pan-Cancer Method for Diagnosis of Primary and Metastatic Cancers.

JAMA Netw Open 2019 04 5;2(4):e192597. Epub 2019 Apr 5.

Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.

Importance: A molecular diagnostic method that incorporates information about the transcriptional status of all genes across multiple tissue types can strengthen confidence in cancer diagnosis.

Objective: To determine the practical use of a whole transcriptome-based pan-cancer method in diagnosing primary and metastatic cancers and resolving complex diagnoses.

Design, Setting, And Participants: This cross-sectional diagnostic study assessed Supervised Cancer Origin Prediction Using Expression (SCOPE), a machine learning method using whole-transcriptome RNA sequencing data. Training was performed on publicly available primary cancer data sets, including The Cancer Genome Atlas. Testing was performed retrospectively on untreated primary cancers and treated metastases from volunteer adult patients at BC Cancer in Vancouver, British Columbia, from January 1, 2013, to March 31, 2016, and testing spanned 10 822 samples and 66 output classes representing untreated primary cancers (n = 40) and adjacent normal tissues (n = 26). SCOPE's performance was demonstrated on 211 untreated primary mesothelioma cancers and 201 treatment-resistant metastatic cancers. Finally, SCOPE was used to identify the putative site of origin in 15 cases with initial presentation as cancers with unknown primary of origin.

Results: A total of 10 688 adult patient samples representing 40 untreated primary tumor types and 26 adjacent-normal tissues were used for training. Demographic data were not available for all data sets. Among the training data set, 5157 of 10 244 (50.3%) were male and the mean (SD) age was 58.9 (14.5) years. Testing was performed on 211 patients with untreated primary mesothelioma (173 [82.0%] male; mean [SD] age, 64.5 [11.3] years); 201 patients with treatment-resistant cancers (141 [70.1%] female; mean [SD] age, 55.6 [12.9] years); and 15 patients with cancers of unknown primary of origin; among the treatment-resistant cancers, 168 were metastatic, and 33 were the primary presentation. An accuracy rate of 99% was obtained for primary epithelioid mesotheliomas tested (125 of 126). The remaining 85 mesotheliomas had a mixed etiology (sarcomatoid mesotheliomas) and were correctly identified as a mixture of their primary components, with potential implications in resolving subtypes and incidences of mixed histology. SCOPE achieved an overall mean (SD) accuracy rate of 86% (11%) and F1 score of 0.79 (0.12) on the 201 treatment-resistant cancers and matched 12 of 15 of the putative diagnoses for cancers with indeterminate diagnosis from conventional pathology.

Conclusions And Relevance: These results suggest that machine learning approaches incorporating multiple tumor profiles can more accurately identify the cancerous state and discriminate it from normal cells. SCOPE uses the whole transcriptomes from normal and tumor tissues, and results of this study suggest that it performs well for rare cancer types, primary cancers, treatment-resistant metastatic cancers, and cancers of unknown primary of origin. Genes most relevant in SCOPE's decision making were examined, and several are known biological markers of respective cancers. SCOPE may be applied as an orthogonal diagnostic method in cases where the site of origin of a cancer is unknown, or when standard pathology assessment is inconclusive.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2019.2597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487574PMC
April 2019

Base excision repair deficiency signatures implicate germline and somatic aberrations in pancreatic ductal adenocarcinoma and breast cancer oncogenesis.

Cold Spring Harb Mol Case Stud 2019 04 1;5(2). Epub 2019 Apr 1.

Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia V5Z 4S6, Canada.

We report a case of early-onset pancreatic ductal adenocarcinoma in a patient harboring biallelic germline mutations, whose tumor featured somatic mutational signatures consistent with defective -mediated base excision repair and the associated driver transversion mutation p.Gly12Cys. Analysis of an additional 730 advanced cancer cases ( = 731) was undertaken to determine whether the mutational signatures were also present in tumors from germline heterozygote carriers or if instead the signatures were only seen in those with biallelic loss of function. We identified two patients with breast cancer each carrying a pathogenic germline variant with a somatic copy loss leading to the germline variant being homozygous in the tumor and demonstrating the same somatic signatures. Our results suggest that monoallelic inactivation of is not sufficient for C:G>A:T transversion signatures previously linked to deficiency to arise ( = 9), but that biallelic complete loss of function can cause such signatures to arise even in tumors not classically seen in -associated polyposis ( = 3). Although defective is not the only determinant of these signatures, germline variants may be present in a subset of patients with tumors demonstrating elevated somatic signatures possibly suggestive of deficiency (e.g., COSMIC Signature 18, SigProfiler SBS18/SBS36, SignatureAnalyzer SBS18/SBS36).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/mcs.a003681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549570PMC
April 2019