Abstract 1103: Aspirin reduces the incidence of metastasis in a preclinical study of Braf mutant colorectal cancer
Authors: Kane Alexandra , Liu Cheng , Fennell Lochlan , McKeone Diane , Borowsky Jennifer , Leggett Barbara , Whitehall Vicki 
Published: September 2020

Background. Aspirin is a well-studied chemopreventive agent for the prevention of conventional colorectal adenomas and cancer. Post hoc analyses of cardiovascular prevention trials demonstrate a long-term reduction in colorectal cancer incidence and mortality with aspirin treatment. Randomized controlled trials have shown a long-term benefit for reducing colorectal cancer incidence in patients with Lynch Syndrome, a form of hereditary colorectal cancer. These findings have led to the recommendation of aspirin as a chemopreventive for colorectal cancer by the U.S. Preventive Services Task Force and Cancer Council Australia. However, future research questions have noted a lack of knowledge of the differential benefits of aspirin in preventing sessile serrated lesions versus conventional adenomas and cancer. In our study, we hypothesized that aspirin will be an effective long-term treatment for the prevention of colorectal cancer resulting from sessile serrated lesions. We aimed to investigate this in a preclinical study utilizing a murine model of Braf mutant serrated neoplasia with a primary end-point investigating cancer incidence.

Methods. BrafV637E/+/Villin-CreERT2/+ mice were injected with tamoxifen (i.p. 75mg/kg) at 2 weeks of age to activate the Braf mutation within the intestine, then commenced on an aspirin-supplemented (n=78) or control standard (n=83) diet at wean. Aspirin was supplemented into the diet and provided ad libitum, at a human equivalent dose of 80-120mg per day, until sacrifice at 14 months. The gastrointestinal tract was excised and evaluated for the presence of carcinoma. In addition, the peritoneal and thoracic cavities were inspected for metastatic disease. A gastrointestinal pathologist (CL) assessed all histology sections.

Results. At sacrifice, 14 months post induction of mutant Braf, all mice developed murine serrated lesions reminiscent of human sessile serrated lesions. We observed a carcinoma incidence of 31% (26/83) of which 35% (9/26) had metastasized to the liver or peritoneal cavity. When mice were treated with an aspirin-supplemented diet there was no significant reduction in carcinoma incidence (22/78, 28%, P = 0.7315). However, there was a significant reduction in the incidence of metastasis (1/22, 5%, P = 0.0134). Mice in the control group had lesions of a significantly greater size when compared to aspirin treated mice (P=0.0032).

Conclusions. Aspirin resulted in a 7-fold decrease in metastases. This study demonstrates that the benefit of aspirin in preventing Braf mutant serrated neoplasia occurs at the carcinoma-metastasis phase of colorectal carcinogenesis. This could have potential clinical benefit in reducing recurrence and mortality.

Citation Format: Alexandra Kane, Cheng Liu, Lochlan Fennell, Diane McKeone, Jennifer Borowsky, Barbara Leggett, Vicki Whitehall. Aspirin reduces the incidence of metastasis in a preclinical study of Braf mutant colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1103.