Abstract CT065: A phase Ib biomarker trial of naproxen in patients at risk for DNA mismatch repair deficient colorectal cancer
Authors: Uribe Laura Reyes , Lin Ramona , Stoffel Elena M. , Samadder N. Jewel , Lynch Patrick , Kanth Priyanka , Milne Ginger , Marnett Lawrence J. , Sepeda Valerie , Liu Diane D , You Y. Nancy , Vornik Lana A. , Lee J. Jack , Richmond Ellen , Umar Asad , Perloff Marjorie , Lipkin Steven M. , Brown Powel H. , Vilar-Sanchez Eduardo 
Published: August 2018

Abstract
Background: Patients diagnosed with Lynch Syndrome (LS) have an approximately 70% lifetime risk of colorectal cancer (CRC) due to the presence of germline mutations in the mismatch repair (MMR) genes. Cyclooxygenases (COX) are key enzymes in the metabolism of Prostaglandins (PGs) being COX-2 induced at sites of inflammation as well as in ~85% of CRC and 50% of premalignant adenomas. Non-steroidal anti-inflammatory drugs (NSAIDs) such as Aspirin and Naproxen exert their therapeutic effects through the inhibition of both COX-1 and COX-2, which causes a reduction in PGs. However, other known non-canonical effects include inhibition of cell growth, induction of cell cycle arrest, and apoptosis. Aspirin has demonstrated chemopreventive properties in LS patients at high doses. Naproxen is widely used for the treatment of pain with an excellent safety profile. In addition, pre-clinical in vivo data using a genetically-engineered mouse model of Lynch Syndrome (Villin-Cre;Msh2LoxP/LoxP) has demonstrated that Naproxen is the most effective NSAID in preventing colorectal tumors and has shown to be superior to Aspirin. The present clinical trial was designed to assess the safety and tolerability of long-term chemoprevention with Naproxen in LS and also to discover novel biomarkers of drug activity.
Methods: LS patients at 4 participating sites (The University of Texas MD Anderson Cancer Center, Dana Farber Cancer Institute, The University of Michigan Comprehensive Cancer Center, and Huntsman Cancer Institute) were randomly assigned to Naproxen 440 mg, 220 mg, or placebo once daily for 6 months. To determine the safety profile and tolerability of Naproxen, adverse events (AEs) were reported using CTCAE V4.03. To assess the activity of the drug intervention we measured Prostaglandin E2 (PGE2) levels in normal colorectal mucosa, its metabolite in urine (PGE-M), levels of Naproxen in plasma and colorectal mucosa at baseline and 6 months after treatment. Response to treatment was defined as 30% reduction in PGE2 levels. Results: A total of 86 patients were registered to this study, 28 randomized to Placebo, 25 to Naproxen 440 mg, and 27 to Naproxen 220 mg. Mean age was 44.6 years, 64% of the patients were females, 53% were unaffected carriers, and MLH1 and MSH2 were the most frequently mutated genes. Fifty-eight completed the study (67%). A total of 183 AEs were recorded in 61 patients, 77% were unrelated or unlikely related to the treatment, only 8 were reported as grade 3 AEs and none of these were related to Naproxen. In the group that received Naproxen at 440 mg, the levels of Naproxen in plasma and normal colorectal mucosa were the highest and the levels of PGE2 and PGE-M were significantly lower when compared to patients in the Placebo arm (P=0.027). In addition, the response rate was the highest among patients receiving Naproxen at 440 mg daily compared to Naproxen at 220 mg and Placebo (87.5% vs 75% vs 13%, respectively).
Conclusions: The tolerance and safety of long-term chemoprevention with Naproxen at a dose of 440 mg for 6 months was excellent. There was evidence of decreased inflammatory activity among LS patients treated with high dose Naproxen compared to Placebo. Biomarker studies to discover novel non-canonical effects of Naproxen via modulation of miRNA and mRNA profiles using next-generation sequencing approaches are currently ongoing.
Citation Format: Laura Reyes Uribe, Ramona Lin, Elena M. Stoffel, N. Jewel Samadder, Patrick Lynch, Priyanka Kanth, Ginger Milne, Lawrence J. Marnett, Valerie Sepeda, Diane D Liu, Y. Nancy You, Lana A. Vornik, J. Jack Lee, Ellen Richmond, Asad Umar, Marjorie Perloff, Steven M. Lipkin, Powel H. Brown, Eduardo Vilar-Sanchez. A phase Ib biomarker trial of naproxen in patients at risk for DNA mismatch repair deficient colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT065.