Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine.

Abstract:

:Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame BRAF deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC.Significance: Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. Cancer Discov; 8(9); 1096-111. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.

journal_name

Cancer Discov

journal_title

Cancer discovery

authors

Aguirre AJ,Nowak JA,Camarda ND,Moffitt RA,Ghazani AA,Hazar-Rethinam M,Raghavan S,Kim J,Brais LK,Ragon D,Welch MW,Reilly E,McCabe D,Marini L,Anderka K,Helvie K,Oliver N,Babic A,Da Silva A,Nadres B,Van Seventer EE,

doi

10.1158/2159-8290.CD-18-0275

subject

Has Abstract

pub_date

2018-09-01 00:00:00

pages

1096-1111

issue

9

eissn

2159-8274

issn

2159-8290

pii

2159-8290.CD-18-0275

journal_volume

8

pub_type

杂志文章
  • The Gut Microbiome Dictates Whether Predisposed Mice Develop Leukemia.

    abstract::An intact gut microbiome was needed to protect genetically vulnerable mice from developing leukemia. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-RW2020-139

    authors:

    更新日期:2020-11-01 00:00:00

  • Two Worlds Collide: Unraveling the Role of the Immune System in BRAF-MEK Inhibitor Responses.

    abstract::Although BRAF-MEK inhibition can enhance the immune recognition of melanoma cells, the mechanisms that underlie this remain poorly defined. In this issue of Cancer Discovery, Erkes and colleagues present new data showing that BRAF-MEK inhibition activates pyroptosis in melanoma cells through gasdermin E cleavage, lead...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-19-1441

    authors: Smalley KSM

    更新日期:2020-02-01 00:00:00

  • Arvinas, Pfizer Team Up on PROTACs.

    abstract::Biotechnology startup Arvinas is developing proteolysis-targeting chimeras (PROTAC) that combat cancer by degrading disease-causing proteins. The company's first PROTACs will target prostate and breast cancers, and a recent deal with Pfizer will allow Arvinas to develop PROTACs for other cancer types. ...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-NB2018-015

    authors:

    更新日期:2018-04-01 00:00:00

  • Molecular dissection of microsatellite instable colorectal cancer.

    abstract:UNLABELLED:Colorectal cancer was one of the first solid tumors to be classified on the basis of molecular profiling. Microsatellite instability has allowed researchers to distinguish a specific subtype of colorectal cancer that has a clearly identified molecular origin (mismatch repair deficiency), arises on a heredita...

    journal_title:Cancer discovery

    pub_type: 杂志文章,评审

    doi:10.1158/2159-8290.CD-12-0471

    authors: Vilar E,Tabernero J

    更新日期:2013-05-01 00:00:00

  • Relapse-Driving AML Cells Exhibit Pyrimidine-Synthesis Dependency.

    abstract::Residual acute myeloid leukemia (AML) cells required bone marrow stromal cell-derived aspartate. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-RW2020-118

    authors:

    更新日期:2020-10-01 00:00:00

  • Unfurling the Genetic Map of Sarcomas.

    abstract::An international team of researchers has uncovered multiple new germline mutations that may influence the development of sarcomas. Notably, they found that variants in several DNA damage sensing and repair genes contribute greatly to sarcoma risk, including BRCA2, ATM, ATR, and ERCC2. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2016-108

    authors:

    更新日期:2016-10-01 00:00:00

  • Pembrolizumab Shows Promise for NSCLC.

    abstract::Data from the KEYNOTE-001 trial show that pembrolizumab improves clinical outcomes for patients with advanced non-small cell lung cancer, and is well tolerated. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy. ...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-NB2015-057

    authors:

    更新日期:2015-06-01 00:00:00

  • Cancer "Clock" Opens New Therapeutic Avenues.

    abstract::Long ignored, the importance of circadian rhythms-the focus of this year's Nobel Prize in Physiology or Medicine-is beginning to gain attention from researchers interested in cancer prevention, drug discovery, and therapeutic optimization. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2017-149

    authors:

    更新日期:2017-12-01 00:00:00

  • Dramatic Responses Seen with TRK Inhibitor.

    abstract::Presenting data on 50 of 55 patients with advanced TRK fusion-positive tumors, researchers reported that 76% of patients responded to the selective pan-TRK inhibitor larotrectinib, and 12% of patients experienced complete responses; 93% of responders remain on therapy. The targeted therapy was well tolerated, with jus...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2017-084

    authors:

    更新日期:2017-08-01 00:00:00

  • Immunotherapy toxic in obese mice.

    abstract::New research shows immunotherapy can cause lethal inflammation in both young and aged mice that are obese. Restricting calories in aged mice protected them from toxicity, and giving young obese mice a drug for autoimmune disease prevented the fatal reactions. ...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-NB2014-171

    authors:

    更新日期:2015-01-01 00:00:00

  • Nanostars amplify ability to image cancer.

    abstract::A new nanoparticle design may make cancer detection possible without the use of molecular markers of tumor cells. The star-shaped probe detected five different cancers in mouse models, according to a new study. By using nanostars to boost surface-enhanced resonance Raman scattering signals, the technique highlighted t...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-NB2015-022

    authors:

    更新日期:2015-04-01 00:00:00

  • Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis.

    abstract::Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, and new strategies for prevention and treatment are urgently needed. We previously reported that histone H4 acetylation is elevated in pancreatic acinar cells harboring Kras mutations prior to the appearance of premalignant lesions. Because acetyl-CoA abunda...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-18-0567

    authors: Carrer A,Trefely S,Zhao S,Campbell SL,Norgard RJ,Schultz KC,Sidoli S,Parris JLD,Affronti HC,Sivanand S,Egolf S,Sela Y,Trizzino M,Gardini A,Garcia BA,Snyder NW,Stanger BZ,Wellen KE

    更新日期:2019-03-01 00:00:00

  • Shades of T790M: Intratumor Heterogeneity in EGFR-Mutant Lung Cancer.

    abstract::In the setting of recent exciting clinical results and numerous ongoing trials, Piotrowska and colleagues explore mechanisms of acquired resistance to the mutant-specific EGFR inhibitor rociletinib, and demonstrate that loss of T790M, EGFR amplification, and small-cell transformation are all clinically relevant mechan...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-15-0616

    authors: Ichihara E,Lovly CM

    更新日期:2015-07-01 00:00:00

  • Functional metabolic screen identifies 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 as an important regulator of prostate cancer cell survival.

    abstract:UNLABELLED:Alterations in metabolic activity contribute to the proliferation and survival of cancer cells. We investigated the effect of siRNA-mediated gene silencing of 222 metabolic enzymes, transporters, and regulators on the survival of 3 metastatic prostate cancer cell lines and a nonmalignant prostate epithelial ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-11-0234

    authors: Ros S,Santos CR,Moco S,Baenke F,Kelly G,Howell M,Zamboni N,Schulze A

    更新日期:2012-04-01 00:00:00

  • RNA Missplicing Triggers Antiviral Immune Response in Breast Cancer.

    abstract::Spliceosome inhibitors induced mRNA missplicing, retaining introns that formed double-stranded RNA. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-RW2021-008

    authors:

    更新日期:2021-01-22 00:00:00

  • Blocking IDO1 Helps Shrink Bladder, Cervical Tumors.

    abstract::Findings from a phase I/IIa study indicate that combining the investigational indoleamine 2,3-dioxygenase 1 inhibitor BMS-986205 with nivolumab is safe and boosts response rates among patients with bladder and cervical cancers. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2017-167

    authors:

    更新日期:2018-01-01 00:00:00

  • Durable Responses Achieved with AM0010.

    abstract::In a phase Ib trial, a combination of the experimental immunotherapy AM0010, a PEGylated form of the recombinant human cytokine IL10, and the anti-PD-1 checkpoint inhibitor pembrolizumab was well tolerated and effective at controlling tumors in some patients with advanced renal cell carcinoma, non-small cell lung canc...

    journal_title:Cancer discovery

    pub_type:

    doi:10.1158/2159-8290.CD-NB2016-125

    authors:

    更新日期:2016-12-01 00:00:00

  • ctDNA Reveals Targetable Alterations.

    abstract::In the plasmaMATCH trial, researchers performed circulating tumor DNA testing on patients with advanced breast cancer and matched those with ESR1, HER2, or AKT1 alterations to targeted therapies. Patients with HER2 and AKT1 mutations experienced response rates greater than 22% with durable benefit. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2020-013

    authors:

    更新日期:2020-05-01 00:00:00

  • By the Numbers: New Biologic License Application Filings and Drug Approvals, 2007-2016.

    abstract::The FDA approved 22 novel drugs in 2016, down from 45 in 2015. Four of the new therapies are for cancer treatment, and two are for cancer diagnosis. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2017-003

    authors:

    更新日期:2017-02-01 00:00:00

  • The Metabolic Basis of Kidney Cancer.

    abstract::Kidney cancer is not a single disease but represents several distinct types of cancer that have defining histologies and genetic alterations and that follow different clinical courses and have different responses to therapy. Mutation of genes associated with kidney cancer, such as VHL, FLCN, TFE3, FH, or SDHB, dysregu...

    journal_title:Cancer discovery

    pub_type: 杂志文章,评审

    doi:10.1158/2159-8290.CD-18-1354

    authors: Linehan WM,Schmidt LS,Crooks DR,Wei D,Srinivasan R,Lang M,Ricketts CJ

    更新日期:2019-08-01 00:00:00

  • New Guideline on Managing Colorectal Cancer.

    abstract::A multidisciplinary panel of experts has issued guidelines that consolidate current evidence on testing for molecular biomarkers in colorectal cancer. The guidelines aim to standardize molecular testing for patients with colorectal cancer and help clinicians identify patients most likely to benefit from targeted treat...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2017-030

    authors:

    更新日期:2017-04-01 00:00:00

  • Access to follicular dendritic cells is a pivotal step in murine chronic lymphocytic leukemia B-cell activation and proliferation.

    abstract:UNLABELLED:In human chronic lymphocytic leukemia (CLL) pathogenesis, B-cell antigen receptor signaling seems important for leukemia B-cell ontogeny, whereas the microenvironment influences B-cell activation, tumor cell lodging, and provision of antigenic stimuli. Using the murine Eμ-Tcl1 CLL model, we demonstrate that ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-14-0096

    authors: Heinig K,Gätjen M,Grau M,Stache V,Anagnostopoulos I,Gerlach K,Niesner RA,Cseresnyes Z,Hauser AE,Lenz P,Hehlgans T,Brink R,Westermann J,Dörken B,Lipp M,Lenz G,Rehm A,Höpken UE

    更新日期:2014-12-01 00:00:00

  • A genetic mouse model recapitulates immune checkpoint inhibitor-associated myocarditis and supports a mechanism-based therapeutic intervention.

    abstract::Immune checkpoint inhibitors (ICI) targeting CTLA-4 or PD-1/PD-L1 have transformed cancer therapy but are associated with immune-related adverse events (irAEs), including myocarditis. Here, we report a robust preclinical mouse model of ICI-associated myocarditis in which mono-allelic loss of Ctla4 in the context of co...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-20-0856

    authors: Wei SC,Meijers WC,Axelrod ML,Anang NAS,Screever EM,Wescott EC,Johnson DB,Whitley E,Lehmann L,Courand PY,Mancuso JJ,Himmel LE,Lebrun-Vignes B,Wleklinski MJ,Knollmann BC,Srinivasan J,Li Y,Atolagbe OT,Rao X,Zhao Y,Wa

    更新日期:2020-11-30 00:00:00

  • CD30-Targeted CAR T Cells Show Promise in Pretreated Hodgkin Lymphoma.

    abstract::CD30-directed CAR T cells were safe and produced a 62% overall response rate in Hodgkin lymphoma. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-RW2020-111

    authors:

    更新日期:2020-09-01 00:00:00

  • Global Cost of Smoking Passes $1 Trillion.

    abstract::A new report from the World Health Organization and the NCI estimates that the worldwide cost of smoking-due to health problems and lost productivity-exceeds $1 trillion annually, with the biggest economic burden falling on low- and middle- income countries. That's because proven interventions, such as tax and price i...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2017-014

    authors:

    更新日期:2017-03-01 00:00:00

  • The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial.

    abstract::CDK4/6 inhibition with endocrine therapy is now a standard of care for advanced estrogen receptor-positive breast cancer. Mechanisms of CDK4/6 inhibitor resistance have been described preclinically, with limited evidence from clinical samples. We conducted paired baseline and end-of-treatment circulating tumor DNA seq...

    journal_title:Cancer discovery

    pub_type: 杂志文章,随机对照试验

    doi:10.1158/2159-8290.CD-18-0264

    authors: O'Leary B,Cutts RJ,Liu Y,Hrebien S,Huang X,Fenwick K,André F,Loibl S,Loi S,Garcia-Murillas I,Cristofanilli M,Huang Bartlett C,Turner NC

    更新日期:2018-11-01 00:00:00

  • LXR agonism inhibits metastatic melanoma through activation of ApoE.

    abstract::Nuclear hormone receptor targeting suppresses melanoma progression in diverse preclinical models. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-RW2014-056

    authors:

    更新日期:2014-05-01 00:00:00

  • NK Cells Mediate T-cell Inflammation in the Tumor Microenvironment.

    abstract::IFNγ-producing NK cells induced TME remodeling and orchestrated T cell-mediated tumor control. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-RW2020-174

    authors:

    更新日期:2020-12-04 00:00:00

  • IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma.

    abstract::Pancreatic ductal adenocarcinoma (PDAC) is poorly responsive to therapies and histologically contains a paucity of neoplastic cells embedded within a dense desmoplastic stroma. Within the stroma, cancer-associated fibroblasts (CAF) secrete tropic factors and extracellular matrix components, and have been implicated in...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-18-0710

    authors: Biffi G,Oni TE,Spielman B,Hao Y,Elyada E,Park Y,Preall J,Tuveson DA

    更新日期:2019-02-01 00:00:00

  • BRCA1: a missing link in the Fanconi anemia/BRCA pathway.

    abstract::Domchek and colleagues provide a case report of a 28-year-old woman with congenital abnormalities, inherited ovarian cancer, and carboplatin hypersensitivity. Interestingly, the woman had validated germline mutations in both BRCA1 alleles. These findings further implicate BRCA1 in the Fanconi anemia/BRCA pathway and h...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-13-0044

    authors: D'Andrea AD

    更新日期:2013-04-01 00:00:00