Publications by authors named "Eric A Collisson"

75 Publications

Implementation of an Embedded In-Clinic Genetic Testing Station to Optimize Germline Testing for Patients with Pancreatic Adenocarcinoma.

Oncologist 2021 Sep 10. Epub 2021 Sep 10.

Division of Hematology and Oncology, University of California San Francisco, San Francisco, California, USA.

Background: Germline genetic testing is universally recommended for patients with pancreatic cancer, but testing remains infrequent. In May 2018, we implemented a systematic patient intake workflow featuring an in-clinic genetic testing station (GTS) at the University of California San Francisco (UCSF) to expedite genetic counseling and facilitate sample collection. We sought to determine the impact of this innovation on rates of genetic counseling and testing.

Methods: Medical records, patient intake records, and genetic test reports were retrospectively reviewed for new patients with pancreatic cancer eligible for germline testing at UCSF from May 2018 to May 2019. Primary outcomes included the rate of offered genetic counseling and confirmed germline testing. Data were compared for periods before and after GTS implementation. Associations between demographic characteristics and testing rates were assessed.

Results: Genetic counseling/testing was offered to 209 (94%) of 223 eligible patients, and 158 (71%) completed testing (135 at UCSF, 23 elsewhere). Compared with a traditional referral-based genetic counseling model, confirmed testing increased from 19% to 71%, patient attrition between referral and genetics appointment decreased from 36% to 3%, and rate of pathogenic variant detection increased from 20% to 33%. Patients who were younger, identified as non-Hispanic White, and spoke English as a primary language were more likely to complete testing.

Conclusions: Implementation of a systematic patient intake workflow and in-clinic GTS resulted in the highest reported real-world rate of germline testing for patients with pancreatic cancer. Health care disparities were identified and will guide future innovation. This report provides a model for other centers to create a similar testing infrastructure.

Implications For Practice: This study demonstrates that a systematic patient intake workflow and associated in-clinic genetic testing station improve delivery of genetic counseling and completion of germline testing for patients with pancreatic cancer. This study achieved, to the authors' knowledge, the highest real-world rate of confirmed genetic testing in this patient population. This article describes this innovation in detail to guide replication at other medical centers and facilitate guideline-concordant care for patients with pancreatic cancer. This infrastructure can also be applied to other cancers for which germline testing is recommended.
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http://dx.doi.org/10.1002/onco.13968DOI Listing
September 2021

Single-cell transcriptome analysis defines heterogeneity of the murine pancreatic ductal tree.

Elife 2021 May 19;10. Epub 2021 May 19.

Diabetes Center, University of California, San Francisco, San Francisco, United States.

To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA-sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify osteopontin as a regulator of this fate decision as well as human duct cell dedifferentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.
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http://dx.doi.org/10.7554/eLife.67776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184217PMC
May 2021

State of the structure address on MET receptor activation by HGF.

Biochem Soc Trans 2021 04;49(2):645-661

Cardiovascular Research Institute, University of California - San Francisco, San Francisco, CA 94158, U.S.A.

The MET receptor tyrosine kinase (RTK) and its cognate ligand hepatocyte growth factor (HGF) comprise a signaling axis essential for development, wound healing and tissue homeostasis. Aberrant HGF/MET signaling is a driver of many cancers and contributes to drug resistance to several approved therapeutics targeting other RTKs, making MET itself an important drug target. In RTKs, homeostatic receptor signaling is dependent on autoinhibition in the absence of ligand binding and orchestrated set of conformational changes induced by ligand-mediated receptor dimerization that result in activation of the intracellular kinase domains. A fundamental understanding of these mechanisms in the MET receptor remains incomplete, despite decades of research. This is due in part to the complex structure of the HGF ligand, which remains unknown in its full-length form, and a lack of high-resolution structures of the complete MET extracellular portion in an apo or ligand-bound state. A current view of HGF-dependent MET activation has evolved from biochemical and structural studies of HGF and MET fragments and here we review what these findings have thus far revealed.
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http://dx.doi.org/10.1042/BST20200394DOI Listing
April 2021

Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway.

Cell Rep 2021 02;34(5):108707

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(-) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(-) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(-) cases are required to understand this important LUAD subset.
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http://dx.doi.org/10.1016/j.celrep.2021.108707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009291PMC
February 2021

Metastatic Donor-derived Malignancies Following Simultaneous Pancreas-kidney Transplant: Three Case Reports and Management Strategies.

Transplant Direct 2021 Jan 8;7(1):e636. Epub 2020 Dec 8.

Department of Surgery, University of California, San Francisco, San Francisco, CA.

Stopping immunosuppression in a transplant patient with donor-derived malignancy offers the theoretical benefit that reconstitution of the patient's immune system will allow "rejection" of the malignancy, as the malignancy also originates from allogeneic tissue. However, this option exists with the caveat that the patient's allograft(s) will likely be rejected too. In simultaneous pancreas-kidney (SPK) recipients, the normal continued functioning and possible absence of malignancy in either the unaffected kidney or pancreas further complicate this decision.

Methods: The charts of 3 patients with donor-derived metastatic malignancies after SPK were retrospectively reviewed in detail. We provide treatment and management recommendations based on successful outcomes and a review of the existing literature.

Results: Consistent with a broad review of the literature, in all 3 cases, complete immunosuppression cessation, removal of both grafts, and in 1 case treatment with an immune checkpoint inhibitor to augment the immune response was successful. One patient is doing well 1 year after successfully undergoing kidney retransplantation, while a second patient is active on the waitlist for SPK retransplantation after no evidence of metastatic disease for 2 years.

Conclusion: The successful management of metastatic donor-derived malignancies requires allograft removal, immunosuppression cessation, and adjuvant therapy that includes occasional use of checkpoint inhibitors to augment the immune response.
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http://dx.doi.org/10.1097/TXD.0000000000001090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725258PMC
January 2021

Ferrous Iron-Dependent Pharmacology.

Trends Pharmacol Sci 2021 01 28;42(1):7-18. Epub 2020 Nov 28.

Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

The recent emergence of oxidation state selective probes of cellular iron has produced a more nuanced understanding of how cells utilize this crucial nutrient to empower enzyme function, and also how labile ferrous iron contributes to iron-dependent cell death (ferroptosis) and other disease pathologies including cancer, bacterial infections, and neurodegeneration. These findings, viewed in light of the Fenton chemistry promoted by ferrous iron, suggest a new category of therapeutics exhibiting ferrous iron-dependent pharmacology. While still in its infancy, this nascent field draws inspiration from the remarkable activity and tremendous clinical impact of the antimalarial artemisinin. Here, we review recent insights into the role of labile ferrous iron in biology and disease, and describe new therapeutic approaches designed to exploit this divalent transition metal.
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http://dx.doi.org/10.1016/j.tips.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754709PMC
January 2021

Molecular Insights in Transmission of Cancer From an Organ Donor to Four Transplant Recipients.

J Natl Compr Canc Netw 2020 11 2;18(11):1446-1452. Epub 2020 Nov 2.

11Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, San Francisco, California.

Organ donors are systematically screened for infection, whereas screening for malignancy is less rigorous. The true incidence of donor-transmitted malignancies is unknown due to a lack of universal tumor testing in the posttransplant setting. Donor-transmitted malignancy may occur even when not suspected based on donor or recipient factors, including age and time to cancer diagnosis. We describe the detection of a gastrointestinal adenocarcinoma transmitted from a young donor to 4 transplant recipients. Multidimensional histopathologic and genomic profiling showed a CDH1 mutation and MET amplification, consistent with gastric origin. At the time of writing, one patient in this series remains alive and without evidence of cancer after prompt organ explant after cancer was reported in other recipients. Because identification of a donor-derived malignancy changes management, our recommendation is to routinely perform short tandem repeat testing (or a comparable assay) immediately upon diagnosis of cancer in any organ transplant recipient. Routine testing for a donor-origin cancer and centralized reporting of outcomes are necessary to establish a robust evidence base for the future development of clinical practice guidelines.
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http://dx.doi.org/10.6004/jnccn.2020.7622DOI Listing
November 2020

Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix.

J Clin Invest 2020 09;130(9):4704-4709

Division of Hematology and Oncology, Department of Medicine and Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.

Desmoplasia describes the deposition of extensive extracellular matrix and defines primary pancreatic ductal adenocarcinoma (PDA). The acellular component of this stroma has been implicated in PDA pathogenesis and is being targeted therapeutically in clinical trials. By analyzing the stromal content of PDA samples from numerous annotated PDA data sets and correlating stromal content with both anatomic site and clinical outcome, we found PDA metastases in the liver, the primary cause of mortality to have less stroma, have higher tumor cellularity than primary tumors. Experimentally manipulating stromal matrix with an anti-lysyl oxidase like-2 (anti-LOXL2) antibody in syngeneic orthotopic PDA mouse models significantly decreased matrix content, led to lower tissue stiffness, lower contrast retention on computed tomography, and accelerated tumor growth, resulting in diminished overall survival. These studies suggest an important protective role of stroma in PDA and urge caution in clinically deploying stromal depletion strategies.
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http://dx.doi.org/10.1172/JCI136760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456216PMC
September 2020

Distinctions with a Difference: RNA Subtyping and Clinical Outcome in Pancreatic Cancer.

Authors:
Eric A Collisson

Clin Cancer Res 2020 09 13;26(18):4715-4716. Epub 2020 Jul 13.

University of California, San Francisco, San Francisco, California.

Pancreatic cancer patients are in desperate need of effective therapy virtually from the moment of their diagnosis. As we acquire more therapies, how best to deploy them, in what order and to which patients is emerging as an important clinical question. Pancreatic cancer subtypes, identifiable with common lab diagnostics in diagnostic biopsy samples, may be helpful in guiding therapy selection..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1062DOI Listing
September 2020

Theranostic Targeting of CUB Domain Containing Protein 1 (CDCP1) in Pancreatic Cancer.

Clin Cancer Res 2020 07 27;26(14):3608-3615. Epub 2020 Apr 27.

Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California.

Purpose: The recent emergence of radioligand therapies for cancer treatment has increased enthusiasm for developing new theranostic strategies coupling both imaging and cytotoxicity in the same entity. In this study, we evaluated whether CUB domain containing protein 1 (CDCP1), a single-pass transmembrane protein highly overexpressed in diverse human cancers, might be a target for cancer theranostics.

Experimental Design: The ectodomain of CDCP1 was targeted using radiolabeled forms of 4A06, a potent and specific recombinant human antibody that we developed. Imaging and antitumor assessment studies were performed in animal models of pancreatic cancer, including two patient-derived xenograft models we developed for this study. For antitumor assessment studies, the endpoints were death due to tumor volume >3,000 mm or ≥20% loss in body weight. Specific tracer binding or antitumor effects were assessed with an unpaired, two-tailed Student test and survival advantages were assessed with a log rank (Mantel-Cox) test. Differences at the 95% confidence level were interpreted to be significant.

Results: Zr-4A06 detected a broad dynamic range of full length or cleaved CDCP1 expression on seven human pancreatic cancer tumors ( = 4/tumor). Treating mice with single or fractionated doses of Lu-4A06 significantly reduced pancreatic cancer tumor volume compared with mice receiving vehicle or unlabeled 4A06 ( = 8; < 0.01). A single dose of Ac-4A06 also inhibited tumor growth, although the effect was less profound compared with Lu-4A06 ( = 8; < 0.01). A significant survival advantage was imparted by Ac-4A06 (HR = 2.56; < 0.05).

Conclusions: These data establish that CDCP1 can be exploited for theranostics, a finding with widespread implications given its breadth of overexpression in cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367754PMC
July 2020

Co-occurring Alterations in the RAS-MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer.

Clin Cancer Res 2020 01 23;26(2):439-449. Epub 2019 Sep 23.

Department of Medicine, University of California, San Francisco, California.

Purpose: Although patients with advanced-stage non-small cell lung cancers (NSCLC) harboring exon 14 skipping mutations (ex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.

Experimental Design: Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage ex14-mutated NSCLC.

Results: Prominent co-occurring RAS-MAPK pathway gene alterations (e.g., in ) were detected in NSCLCs with ex14 skipping alterations as compared with -mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS-MAPK pathway co-occurring alterations. In a preclinical model expressing a canonical ex14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by cotreatment with crizotinib and the MEK inhibitor trametinib.

Conclusions: Our study provides a genomic landscape of co-occurring alterations in advanced-stage ex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980768PMC
January 2020

Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer.

Nat Commun 2019 07 11;10(1):3055. Epub 2019 Jul 11.

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, 94158, USA.

KRAS mutations are present in over 90% of pancreatic ductal adenocarcinomas (PDAC), and drive their poor outcomes and failure to respond to targeted therapies. Here we show that Leukemia Inhibitory Factor (LIF) expression is induced specifically by oncogenic KRAS in PDAC and that LIF depletion by genetic means or by neutralizing antibodies prevents engraftment in pancreatic xenograft models. Moreover, LIF-neutralizing antibodies synergize with gemcitabine to eradicate established pancreatic tumors in a syngeneic, Kras-driven, PDAC mouse model. The related cytokine IL-6 cannot substitute for LIF, suggesting that LIF mediates KRAS-driven malignancies through a non-STAT-signaling pathway. Unlike IL-6, LIF inhibits the activity of the Hippo-signaling pathway in PDACs. Depletion of YAP inhibits the function of LIF in human PDAC cells. Our data suggest a crucial role of LIF in KRAS-driven pancreatic cancer and that blockade of LIF by neutralizing antibodies represents an attractive approach to improving therapeutic outcomes.
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http://dx.doi.org/10.1038/s41467-019-11044-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624260PMC
July 2019

Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.

Nature 2019 05 17;569(7754):131-135. Epub 2019 Apr 17.

Department of Surgery, Division of Surgical Oncology, University of California San Diego School of Medicine, La Jolla, CA, USA.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance. Furthermore, PSC activation occurs very early during PDAC tumorigenesis, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.
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http://dx.doi.org/10.1038/s41586-019-1130-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565370PMC
May 2019

Molecular subtypes of pancreatic cancer.

Nat Rev Gastroenterol Hepatol 2019 04;16(4):207-220

Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, Scotland, UK.

Cancers that appear morphologically similar often have dramatically different clinical features, respond variably to therapy and have a range of outcomes. Compelling evidence now demonstrates that differences in the molecular pathology of otherwise indistinguishable cancers substantially impact the clinical characteristics of the disease. Molecular subtypes now guide preclinical and clinical therapeutic development and treatment in many cancer types. The ability to predict optimal therapeutic strategies ahead of treatment improves overall patient outcomes, minimizing treatment-related morbidity and cost. Although clinical decision making based on histopathological criteria underpinned by robust data is well established in many cancer types, subtypes of pancreatic cancer do not currently inform treatment decisions. However, accumulating molecular data are defining subgroups in pancreatic cancer with distinct biology and potential subtype-specific therapeutic vulnerabilities, providing the opportunity to define a de novo clinically applicable molecular taxonomy. This Review summarizes current knowledge concerning the molecular subtyping of pancreatic cancer and explores future strategies for using a molecular taxonomy to guide therapeutic development and ultimately routine therapy with the overall goal of improving outcomes for this disease.
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http://dx.doi.org/10.1038/s41575-019-0109-yDOI Listing
April 2019

Stromal Content Is Correlated With Tissue Site, Contrast Retention, and Survival in Pancreatic Adenocarcinoma.

JCO Precis Oncol 2018 16;2018. Epub 2018 Jan 16.

Department of Medicine, University of California, San Francisco, USA.

Purpose: Desmoplastic stroma is a cardinal feature of primary pancreatic ductal adenocarcinoma (PDAC), but its effects on the biology, prognosis and therapeutic outcomes are not known. We developed an automated method to assess tumor stroma density (TSD) and investigated computed tomography (CT)-correlates of stroma in PDAC.

Patients And Methods: We collected PDAC samples from rapid autopsy and resection series and digitally annotated samples to quantify TSD. A series of resected patients also underwent preoperative multiphasic CT.

Results: Automated and manual assessments of TSD were highly correlated (ρ= 0.65, < 0.001). Solid organ metastases had a lower median TSD than primary tumors ( < 0.001). Patients with high TSD enjoyed prolonged recurrence free survival (RFS) ( = 0.003; HR = 0.51) and overall survival ( = 0.008, HR = 0.57). In another independent dataset, patients with high TSD had decreased risk for recurrence ( = 0.003, HR = 0.03) and death ( 0.003, HR = 0.03) at time of resection, however the protective effect diminished over time. Patients with normalized portovenous phase CT tumor enhancement ratio ≥0.40 had a longer RFS following resection ( = 0.020). Normalized portovenous phase CT tumor enhancement ratio was significantly correlated with TSD ( = 0.003).

Conclusions: Objective quantitative assessment of stroma in PDAC revealed several clinically relevant observations. Firstly, stroma was less abundant in metastatic PDAC, the cause of most PDAC mortality. Secondly, high stromal content correlates with favorable outcome in resected cases, implying a protective effect of stroma and suggesting careful consideration of active stromal depletion therapies. Finally, standard multiphase CT imaging correlates with stroma content as well as clinical outcome, indicating that non-invasive assessment of stroma is a feasible sensitivity enrichment approach in PDAC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262879PMC
http://dx.doi.org/10.1200/PO.17.00121DOI Listing
January 2018

Referral frequency, attrition rate, and outcomes of germline testing in patients with pancreatic adenocarcinoma.

Fam Cancer 2019 04;18(2):241-251

Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA, 94143, USA.

Hereditary predisposition is estimated to account for 10% of all pancreatic cancer cases. However, referral patterns and clinical workflow for germline testing in this disease differ significantly by institution, and many at-risk patients may not undergo appropriate counseling and testing. We undertook an analysis of patients diagnosed with pancreatic cancer (PDAC) who were referred to the Clinical Genetics program of a high-volume academic center over a 3-year period to assess referral frequency, evaluate the yield of germline testing in this selected patient cohort, and elucidate the reasons individuals did not undergo recommended germline testing. Medical records of patients with PDAC referred for genetic counseling between January 2015 and October 2017 were reviewed for demographic, medical/family history, and disease-specific data. If testing did not occur, reasons were documented. Genetic test results were categorized as negative, variants of unknown significance, or established pathogenic mutations. Descriptive statistics included means with standard deviations; associations were analyzed with t test and Fisher's exact test. 32% (137 of 432) of PDAC patients were referred for genetic counseling, but only 64% attended their appointment and 60% ultimately underwent germline testing. Common reasons for attrition included worsening disease severity, lack of patient follow-up, insurance concerns, and logistic/travel challenges. Pathogenic germline mutations were detected in 20% (16 of 82) of patients tested, distributed across races/ethnicities, and significantly associated with younger age and positive family history of breast cancer. PDAC patients frequently do not undergo genetic counseling/germline testing despite appropriate referrals, highlighting a need to develop streamlined processes to engage more patients in testing, especially those with high-risk features.
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http://dx.doi.org/10.1007/s10689-018-0106-2DOI Listing
April 2019

Bringing Pancreas Cancer into the Lab.

Authors:
Eric A Collisson

Cancer Discov 2018 09;8(9):1062-1063

Hematology Oncology, Department of Medicine, University of California, San Francisco, San Francisco, California.

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http://dx.doi.org/10.1158/2159-8290.CD-18-0811DOI Listing
September 2018

APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa.

Sci Transl Med 2018 08;10(455)

Fundación DEBRA Chile, Santiago 7760099, Chile.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin and mucous membrane fragility disorder complicated by early-onset, highly malignant cutaneous squamous cell carcinomas (SCCs). The molecular etiology of RDEB SCC, which arises at sites of sustained tissue damage, is unknown. We performed detailed molecular analysis using whole-exome, whole-genome, and RNA sequencing of 27 RDEB SCC tumors, including multiple tumors from the same patient and multiple regions from five individual tumors. We report that driver mutations were shared with spontaneous, ultraviolet (UV) light-induced cutaneous SCC (UV SCC) and head and neck SCC (HNSCC) and did not explain the early presentation or aggressive nature of RDEB SCC. Instead, endogenous mutation processes associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) deaminases dominated RDEB SCC. APOBEC mutation signatures were enhanced throughout RDEB SCC tumor evolution, relative to spontaneous UV SCC and HNSCC mutation profiles. Sixty-seven percent of RDEB SCC driver mutations was found to emerge as a result of APOBEC and other endogenous mutational processes previously associated with age, potentially explaining a >1000-fold increased incidence and the early onset of these SCCs. Human papillomavirus-negative basal and mesenchymal subtypes of HNSCC harbored enhanced APOBEC mutational signatures and transcriptomes similar to those of RDEB SCC, suggesting that APOBEC deaminases drive other subtypes of SCC. Collectively, these data establish specific mutagenic mechanisms associated with chronic tissue damage. Our findings reveal a cause for cancers arising at sites of persistent inflammation and identify potential therapeutic avenues to treat RDEB SCC.
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http://dx.doi.org/10.1126/scitranslmed.aas9668DOI Listing
August 2018

Early Response Assessment in Pancreatic Ductal Adenocarcinoma Through Integrated PET/MRI.

AJR Am J Roentgenol 2018 11 31;211(5):1010-1019. Epub 2018 Jul 31.

2 Department of Medicine, University of California San Francisco, San Francisco, CA.

Objective: The purpose of this study is to investigate early changes in F-FDG PET/MRI metrics after treatment in patients with advanced pancreatic ductal adenocarcinoma (PDAC) and to correlate those changes with eventual tumor response at standard-of-care CT.

Subjects And Methods: Thirteen patients with advanced PDAC underwent integrated FDG PET/MRI before and 4 weeks after treatment initiation. Patients were classified as responders or nonresponders according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at subsequent CT performed 8-12 weeks after treatment initiation. Changes in the primary tumor's maximum standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) determined at PET and apparent diffusion coefficient (ADC) determined at DWI at 4 weeks were compared between responders and nonresponders.

Results: Seven patients had a partial response according to RECIST, and six did not. Responders displayed significantly greater decreases in MTV (p = 0.003) and TLG (p = 0.006) in the primary pancreatic tumor at 4 weeks. Responders also displayed a greater increase in the mean (p = 0.004) and minimum (p = 0.024) ADC of the primary tumors. Tumor size change at 4 weeks was not significantly different between responders and nonresponders (p = 0.11). PET responders enjoyed longer progression-free survival (PFS) (p = 0.0004) and overall survival (OS) (p = 0.013) than did nonresponders, using either a 60% reduction in MTV or 65% reduction in TLG as a threshold. MRI responders had significantly longer PFS (p = 0.0002) and OS (p = 0.027) than did nonresponders, using a 20% increase in either mean or minimum ADC as a threshold.

Conclusion: Integrated PET/MRI can provide early response assessment in patients with advanced PDAC, thus potentially allowing early treatment adaptation in nonresponders.
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http://dx.doi.org/10.2214/AJR.18.19602DOI Listing
November 2018

Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma.

Nat Commun 2018 05 14;9(1):1894. Epub 2018 May 14.

Department of Dermatology, University of California, San Francisco, CA, 94115, USA.

Sebaceous carcinomas (SeC) are cutaneous malignancies that, in rare cases, metastasize and prove fatal. Here we report whole-exome sequencing on 32 SeC, revealing distinct mutational classes that explain both cancer ontogeny and clinical course. A UV-damage signature predominates in 10/32 samples, while nine show microsatellite instability (MSI) profiles. UV-damage SeC exhibited poorly differentiated, infiltrative histopathology compared to MSI signature SeC (p = 0.003), features previously associated with dissemination. Moreover, UV-damage SeC transcriptomes and anatomic distribution closely resemble those of cutaneous squamous cell carcinomas (SCC), implicating sun-exposed keratinocytes as a cell of origin. Like SCC, this UV-damage subclass harbors a high somatic mutation burden with >50 mutations per Mb, predicting immunotherapeutic response. In contrast, ocular SeC acquires far fewer mutations without a dominant signature, but show frequent truncations in the ZNF750 epidermal differentiation regulator. Our data exemplify how different mutational processes convergently drive histopathologically related but clinically distinct cancers.
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http://dx.doi.org/10.1038/s41467-018-04008-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951856PMC
May 2018

Hybrid Capture-Based Tumor Sequencing and Copy Number Analysis to Confirm Origin of Metachronous Metastases in Mutant Cholangiocarcinoma Harboring a Novel Fusion.

Oncologist 2018 09 5;23(9):998-1003. Epub 2018 Apr 5.

Department of Medicine, University of California, San Francisco, San Francisco, California, USA

Biliary tract cancers such as cholangiocarcinoma represent a heterogeneous group of cancers that can be difficult to diagnose. Recent comprehensive genomic analyses in large cholangiocarcinoma cohorts have defined important molecular subgroups within cholangiocarcinoma that may relate to anatomic location and etiology [1], [2], [3], [4] and may predict responsiveness to targeted therapies in development [5], [6], [7]. These emerging data highlight the potential for tumor genomics to inform diagnosis and treatment options in this challenging tumor type. We report the case of a patient with a germline mutation who presented with a cholangiocarcinoma driven by the novel fusion. Hybrid capture-based DNA sequencing and copy number analysis performed as part of clinical care demonstrated that two later-occurring tumors were clonally derived from the primary cholangiocarcinoma rather than distinct new primaries, revealing an unusual pattern of late metachronous metastasis. We discuss the clinical significance of these genetic alterations and their relevance to therapeutic strategies.

Key Points: Hybrid capture-based next-generation DNA sequencing assays can provide diagnostic clarity in patients with unusual patterns of metastasis and recurrence in which the pathologic diagnosis is ambiguous.To our knowledge, this is the first reported case of a fusion in pancreaticobiliary cancer, and a very rare case of cholangiocarcinoma in the setting of a germline mutation.The patient's mutation and fusion constitute potential targets for future therapy.
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http://dx.doi.org/10.1634/theoncologist.2017-0645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192605PMC
September 2018

Ultrasensitive plasma ctDNA assay for detection, prognosis, and assessment of therapeutic response in patients with unresectable pancreatic ductal adenocarcinoma.

Oncotarget 2017 Nov 26;8(58):97769-97786. Epub 2017 Oct 26.

Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

Precision oncology requires sensitive and specific clinical biomarkers. Carbohydrate Antigen 19-9 (CA19-9) is widely used in pancreatic ductal adenocarcinoma (PDA) but lacks sensitivity and specificity. Nearly all PDAs harbor somatic mutations, nominating circulating tumor DNA (ctDNA) as an alternative disease biomarker, however, variable clinical performance has limited its clinical utility. We applied an ultrasensitive, PCR mutation enrichment, next generation sequencing ctDNA assay in a large cohort of patients with unresectable PDA ( = 189) recruited to the BIOPAC study between 2008-2015. Baseline and longitudinal serum CA19-9 and plasma ctDNA were correlated with time to progression (TTP) and overall survival (OS). Baseline ctDNA detection rate was 93.7% (86.4% in patients with non-elevated CA19-9). ctDNA and CA19-9 were positively correlated yet independently associated with TTP and OS (ctDNA = 0.0018 and 0.0014; CA19-9 = 0.0294 and 0.0007, respectively). A generated model quantitating longitudinal ctDNA correctly assessed greater than 80% of patient responses. Quantitative detection of ctDNA is an informative prognostic biomarker, complementary to CA19-9 in patients with unresectable PDA. Longitudinal ctDNA may inform therapeutic decision making and provides a kinetically dynamic and quantitative metric of patient response.
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http://dx.doi.org/10.18632/oncotarget.22080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716690PMC
November 2017

Advances in the Genetics and Biology of Pancreatic Cancer.

Cancer J 2017 Nov/Dec;23(6):315-320

Pancreatic ductal adenocarcinoma (PDA) remains one of the most devastating diagnoses in modern medicine. While the clinical management of the disease has improved, the complex biologic underpinnings of PDA enable both its aggressive nature and slow clinical translational progress. In this review, we provide an overview of the key features of PDA genetics and biology, highlighting translational challenges and providing a framework for improved diagnostic and therapeutic approaches.
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http://dx.doi.org/10.1097/PPO.0000000000000286DOI Listing
July 2018

Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma.

Cancer Res 2017 08 18;77(16):4498-4505. Epub 2017 May 18.

Division of Hematology and Oncology, Department of Medicine and Helen Diller Family Comprehensive Cancer Center University of California, San Francisco, California.

Targeting somatically activated oncogenes has revolutionized the treatment of non-small cell lung cancer (NSCLC). Mutations in the gene mesenchymal-epithelial transition () near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (Δ14). Here, we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. Δ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a hepatocyte growth factor-dependent manner. In addition, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. In addition, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed toward Δ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an system for the study of Δ14 in an immunocompetent host. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004099PMC
August 2017

Pancreatic Cancer Genomics 2.0: Profiling Metastases.

Cancer Cell 2017 03;31(3):309-310

Departments of Pathology and Translational Molecular Pathology, Sheikh Ahmed Pancreatic Cancer Research Center, UT MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

Pancreatic ductal adenocarcinoma, even when diagnosed early, nearly always metastasizes. Recurrent mutations and genomic instability are early events in the disease. Two recent papers advance our understanding of how the cancer genome evolves as the primary tumor migrates from its origin in the pancreas to colonize distant metastatic sites.
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http://dx.doi.org/10.1016/j.ccell.2017.02.014DOI Listing
March 2017

Pancreatic Cancer: Progress and Challenges in a Rapidly Moving Field.

Cancer Res 2017 03 16;77(5):1060-1062. Epub 2017 Feb 16.

Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.

"Pancreatic Cancer: Advances in Science and Clinical Care," a Special Conference of the American Association for Cancer Research, was held in Orlando, FL, on May 12 to 15, bringing together more than 450 basic, translational, clinical, and epidemiologic pancreatic cancer researchers as well as pancreatic cancer patients, survivors, and advocates. Pancreatic cancer remains one of the great challenges in medicine, but the accelerating pace of research and early hints of clinical successes to come were palpable throughout the meeting. Prominent meeting themes included immunology and the tumor microenvironment, heterogeneity of both the epithelial and stromal compartments, personalized medicine efforts to integrate molecular information into clinical practice, new approaches to early detection, and clinical trials using a host of novel targeted therapies. Adding to the vibrant atmosphere of the meeting, a coalition of pancreatic cancer research and support foundations participated, with several innovative initiatives announced by individual organizations. We present here a summary of meeting highlights, a series of "success factors" that will benchmark the progress of the field over the next 2 years, and three challenges to the pancreatic cancer research community as it moves toward to the goal of extending patient survival. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2452DOI Listing
March 2017

Stromal cues regulate the pancreatic cancer epigenome and metabolome.

Proc Natl Acad Sci U S A 2017 01 17;114(5):1129-1134. Epub 2017 Jan 17.

Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037;

A fibroinflammatory stromal reaction cooperates with oncogenic signaling to influence pancreatic ductal adenocarcinoma (PDAC) initiation, progression, and therapeutic outcome, yet the mechanistic underpinning of this crosstalk remains poorly understood. Here we show that stromal cues elicit an adaptive response in the cancer cell including the rapid mobilization of a transcriptional network implicated in accelerated growth, along with anabolic changes of an altered metabolome. The close overlap of stroma-induced changes in vitro with those previously shown to be regulated by oncogenic Kras in vivo suggests that oncogenic Kras signaling-a hallmark and key driver of PDAC-is contingent on stromal inputs. Mechanistically, stroma-activated cancer cells show widespread increases in histone acetylation at transcriptionally enhanced genes, implicating the PDAC epigenome as a presumptive point of convergence between these pathways and a potential therapeutic target. Notably, inhibition of the bromodomain and extraterminal (BET) family of epigenetic readers, and of Bromodomain-containing protein 2 (BRD2) in particular, blocks stroma-inducible transcriptional regulation in vitro and tumor progression in vivo. Our work suggests the existence of a molecular "AND-gate" such that tumor activation is the consequence of mutant Kras and stromal cues, providing insight into the role of the tumor microenvironment in the origin and treatment of Ras-driven tumors.
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http://dx.doi.org/10.1073/pnas.1620164114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293019PMC
January 2017

The Authors Respond.

J Natl Compr Canc Netw 2016 Mar;14(3):lxviii

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March 2016
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