Effect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis

Samadder, N. Jewel; Neklason, Deborah W.; Boucher, Kenneth M.; Byrne, Kathryn R.; Kanth, Priyanka; Samowitz, Wade S.; Jones, David A.; Tavtigian, Sean V.; Done, Michelle W.; Berry, Therese; Jasperson, Kory; Pappas, Lisa M.; Smith, Lane F.; Sample, Danielle; Davis, R. Kim; Topham, Matthew K.; Lynch, Patrick M.; Strait, Elena G.; McKinnon, Wendy; Burt, Randall W.; Kuwada, Scott K.

doi:10.1001/jama.2016.2522

Cited by 125 publications

(106 citation statements)

References 31 publications

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“…established in tumorigenesis and they are targets for drugs in clinical use or under development. So far, only EGF signaling has been targeted in clinical trials for duodenal polyposis (16). Our data point to additional and novel opportunities for intervention but they also highlight the molecular genetic heterogeneity of duodenal adenomas.…”

Section: Discussionmentioning

confidence: 75%

“…Surgical treatments including ampullectomy, duodenectomy, and pancreatico-duodenectomy appear effective for cancer prevention but are associated with significant procedureassociated risks (7,11). Medical treatment using the cyclooxygenase (COX) inhibitors sulindac and celecoxib has proven less effective in the duodenum than the colorectum (12)(13)(14)(15), but a recent trail of combined COX and EGFR inhibition with sulindac and erlotinib demonstrated promising short-term effects on duodenal polyp burden (16). The efficacy of medical and surgical treatment or prevention of duodenal disease in MAP remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Burden and Profile of Somatic Mutation in Duodenal Adenomas from Patients with Familial Adenomatous- and MUTYH-associated Polyposis

Thomas

Hurley

Meuser

et al. 2017

Clinical Cancer Research

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Purpose: Duodenal polyposis and cancer are important causes of morbidity and mortality in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). This study aimed to comprehensively characterize somatic genetic changes in FAP and MAP duodenal adenomas to better understand duodenal tumorigenesis in these disorders.Experimental Design: Sixty-nine adenomas were biopsied during endoscopy in 16 FAP and 10 MAP patients with duodenal polyposis. Ten FAP and 10 MAP adenomas and matched blood DNA samples were exome sequenced, 42 further adenomas underwent targeted sequencing, and 47 were studied by array comparative genomic hybridization. Findings in FAP and MAP duodenal adenomas were compared with each other and to the reported mutational landscape in FAP and MAP colorectal adenomas.Results: MAP duodenal adenomas had significantly more protein-changing somatic mutations (P ¼ 0.018), truncating mutations (P ¼ 0.006), and copy number variants (P ¼ 0.005) than FAP duodenal adenomas, even though MAP patients had lower Spigelman stage duodenal polyposis. Fifteen genes were significantly recurrently mutated. Targeted sequencing of APC, KRAS, PTCHD2, and PLCL1 identified further mutations in each of these genes in additional duodenal adenomas. In contrast to MAP and FAP colorectal adenomas, neither exome nor targeted sequencing identified WTX mutations (P ¼ 0.0017).Conclusions: The mutational landscapes in FAP and MAP duodenal adenomas overlapped with, but had significant differences to those reported in colorectal adenomas. The significantly higher burden of somatic mutations in MAP than FAP duodenal adenomas despite lower Spigelman stage disease could increase cancer risk in the context of apparently less severe benign disease.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Burden and Profile of Somatic Mutation in Duodenal Adenomas from Patients with Familial Adenomatous- and MUTYH-associated Polyposis

Thomas

Hurley

Meuser

et al. 2017

Clinical Cancer Research

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“…Advances in understanding the convergence of Wnt and EGFR signalling in familial adenomatous polyposis, a disease characterised by germline mutations in APC , led to a breakthrough trial of combinatorial chemoprevention with erlotinib and sulindac after standard prophylactic colectomy, which reduced duodenal neoplasia, the leading cause of death. 46 The risk of myeloma is increased more than 30-fold in patients with the inherited lipid-storage disorder Gaucher disease, characterised by germline GBA mutations, due in part to lysolipid-induced chronic inflammation and genomic instability. Lysolipid substrate reduction in Gba1- deficient mice decreases the risk of gammopathies.…”

Section: Preventionmentioning

confidence: 99%

Future cancer research priorities in the USA: a Lancet Oncology Commission

Jaffee

Dang

Agus

et al. 2017

The Lancet Oncology

174

123

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We are in the midst of a technological revolution that is providing new insights into human biology and cancer. In this era of big data, we are amassing large amounts of information that is transforming how we approach cancer treatment and prevention. Enactment of the Cancer Moonshot within the 21st Century Cures Act in the USA arrived at a propitious moment in the advancement of knowledge, providing nearly US$2 billion of funding for cancer research and precision medicine. In 2016, the Blue Ribbon Panel (BRP) set out a roadmap of recommendations designed to exploit new advances in cancer diagnosis, prevention, and treatment. Those recommendations provided a high-level view of how to accelerate the conversion of new scientific discoveries into effective treatments and prevention for cancer. The US National Cancer Institute is already implementing some of those recommendations. As experts in the priority areas identified by the BRP, we bolster those recommendations to implement this important scientific roadmap. In this Commission, we examine the BRP recommendations in greater detail and expand the discussion to include additional priority areas, including surgical oncology, radiation oncology, imaging, health systems and health disparities, regulation and financing, population science, and oncopolicy. We prioritise areas of research in the USA that we believe would accelerate efforts to benefit patients with cancer. Finally, we hope the recommendations in this report will facilitate new international collaborations to further enhance global efforts in cancer control.

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“…Thus, upper gastrointestinal surveillance and chemopreventive measures should be continued even after extensive surgical procedures. Unfortunately, improvement of clinical outcomes after chemoprevention have been disappointing so far, with no consistent reduction of polyp burden after treatment for months (46). Further investigations should address long-term effectiveness by controlling side effects and improving clinical outcomes in a larger population.…”

Section: Discussionmentioning

confidence: 99%

Advanced duodenal neoplasia and carcinoma in familial adenomatous polyposis: outcomes of surgical management

Campos

Bustamante-Lopez

Kanno

et al. 2017

J. Gastrointest. Oncol.

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Background: In addition to the presence of neoplasia in the colon and rectum, patients with familial adenomatous polyposis (FAP) may develop numerous polyps and carcinoma within the upper gastrointestinal tract. Methods:The aim of the present paper was to review the incidence advanced duodenal polyposis or cancer and their surgical outcomes. A retrospective review of patients' records from our department was performed. respectively. Duodenal carcinomas occurred later (55.8 years) when compared to advanced adenomatosis (45.3 years). Three patients were diagnosed due to symptoms, while the others were detected under endoscopic surveillance. Age interval between FAP treatment and duodenal neoplasia diagnosis was 15.3 years . All but one patient underwent duodenopancreatectomy (DP). Two from the 7 patients undergoing DP died, one from pulmonary embolism 30 days after surgery and the other from recurrent T4N0 duodenal tumor. Thus, major operative morbidity and mortality were 12.5%. Conclusions:In this single-center Brazilian series of FAP patients: (I) advanced duodenal neoplasia or cancer requiring surgery occurred in 5.5% of patients; (II) when reaching the fifth decade of life, patients should be carefully evaluated to diagnose and treat early lesions; (III) in spite of the technical complexity of DP, operative morbidity is acceptable in experienced hands; and (IV) continuous surveillance is necessary during follow-up.

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Effect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis

Cited by 125 publications

References 31 publications

Burden and Profile of Somatic Mutation in Duodenal Adenomas from Patients with Familial Adenomatous- and MUTYH-associated Polyposis

Burden and Profile of Somatic Mutation in Duodenal Adenomas from Patients with Familial Adenomatous- and MUTYH-associated Polyposis

Future cancer research priorities in the USA: a Lancet Oncology Commission

Advanced duodenal neoplasia and carcinoma in familial adenomatous polyposis: outcomes of surgical management

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