Abstract LB-074: Regression of duodenal neoplasia in familial adenomatous polyposis patients using COX and EGFR inhibition: A randomized placebo-controlled trial
Authors: Neklason Deborah W. , Delker Don A. , Boucher Kenneth M. , Kanth Priyanka , Byrne Kathryn , Bernard Philip , Samowitz Wade , Done Michelle W. , Berry Therese , Pappas Lisa , Smith Laurel , Sample Danielle , Davis Rian , Topham Matthew K. , Burt Randall W. , Kuwada Scott K. , Samadder N Jewel 
Published: July 2016

The objective of this trial was to test the effect of a combination of COX and EGFR inhibition on duodenal adenoma progression in patients with familial adenomatous polyposis (FAP). FAP is caused by mutations in the APC gene and is characterized by the development of hundreds of colorectal adenomas and colorectal cancer. FAP patients are also at increased risk for duodenal neoplasia with a ∼10% lifetime risk of duodenal carcinoma. Surgical and endoscopic management of duodenal neoplasia is difficult and chemoprevention has not been successful. Preclinical data has illustrated that a combination of cyclooxygenase (COX) and epidermal growth factor (EGFR) inhibition diminishes small intestinal adenoma development by 87% in mice with germline Apc mutations. Therefore, we conducted a double blind, randomized, placebo-controlled trial in which FAP patients received combination therapy with 150 mg sulindac twice per day and 75 mg erlotinib daily or placebo for 6 months (NCT01187901). The total number and diameter of polyps in a 10cm segment of the proximal duodenum were mapped at baseline and 6 months. The primary outcome was change in total polyp burden, calculated as the sum of the diameters of polyps. We also evaluated RNA expression in duodenal tissue and polyps at endpoint from 10 patients on drug and 10 patients on placebo by RNA sequencing. Seventy-three randomized patients were included in the intention to treat analysis. Over six months, the median change in total duodenal polyp burden was an increase of 8.0 mm from baseline burden in the placebo group (23.0 to 31.0 mm) and the median change in the sulindac-erlotinib group was a decrease of 8.5 mm (29.0 to 19.5 mm). The estimated net difference in change between the two groups was -19.0 mm (95% CI: -32.0, -10.9; P&lt;0.001). Grade 1 and 2 adverse events were more common in the sulindac-erlotinib group, with an acne-like rash observed in 87% of patients receiving treatment and 20% of patients receiving placebo (P&lt;0.001). We identified ∼ 750 differentially expressed genes (fold ≥ 2, false discovery rate &lt; 0.05) in polyps from patients on placebo as compared with patient-matched normal duodenum which were unchanged in polyps from patients on drug. These differentially expressed genes suggested increased EGFR, prostaglandin E2 (PGE2 or COX2) and WNT signaling in duodenal polyps from patients on placebo but not on drug. In duodenal tissue from patients on drug when compared to tissue from patients on placebo, we identified differentially expressed genes suggestive of a reactivated immune response including interferon gamma and interleukin 12 signaling; a possible mechanism for the regression of duodenal polyps observed in drug treated patients. In conclusion, combined chemoprevention with sulindac and erlotinib in FAP patients is effective to lower duodenal polyp burden, block COX2 and EGFR activity, and may reactivate immune surveillance. At the doses tested, however, frequent adverse events may limit the use of these medications.

Part of this abstract was presented as part of a preliminary presentation.

Citation Format: Deborah W. Neklason, Don A. Delker, Kenneth M. Boucher, Priyanka Kanth, Kathryn Byrne, Philip Bernard, Wade Samowitz, Michelle W. Done, Therese Berry, Lisa Pappas, Laurel Smith, Danielle Sample, Rian Davis, Matthew K. Topham, Randall W. Burt, Scott K. Kuwada, N Jewel Samadder. Regression of duodenal neoplasia in familial adenomatous polyposis patients using COX and EGFR inhibition: A randomized placebo-controlled trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-074.