cox2 pi3k  


Should aspirin be given to patients after a diagnosis of colorectal cancer?




Response from Nga T. Pham, PharmD 

Clinical Oncology Pharmacist, Ann B. Barshinger Cancer Institute, Lancaster, Pennsylvania


The current standard of treatment for colorectal cancer is dependent on the stage of cancer at the time of diagnosis but may involve chemotherapy, radiation, surgical resection, or a combination of these therapies. Aspirin, widely used for its antiplatelet and anti-inflammatory effects, has been studied as adjuvant therapy for colorectal cancer, with promising results. Earlier prevention studies demonstrated the efficacy of aspirin against the development of colorectal tumors,[1-3] prompting investigation into its potential treatment efficacy.


The proposed mechanism draws on the fact that certain colorectal tumors overexpress prostaglandin-endoperoxide synthase 2 -- better known as cyclooxygenase-2 (COX-2). Mutations of the sort seen in colorectal cancer are known to sustain tumor cell growth by preventing apoptosis.[4] By blocking COX-2, aspirin therapy is hypothesized to suppress tumor growth.


Studies uphold this hypothesis.[5,6] In a 2009 prospective cohort study involving 1279 participants with stage I, II, or III colorectal cancer, Chan and colleagues[5] reported a 29% risk reduction for colorectal cancer-related mortality among postdiagnosis aspirin users vs nonusers. Furthermore, regular aspirin use after diagnosis was associated with a 21% greater mortality benefit among prediagnosis nonusers compared with prediagnosis users -- highlighting the heterogeneity of colorectal cancer types. The investigators suggest that perhaps tumors developing in former users are of a type not prevented by aspirin use alone. And as hypothesized, the mortality benefits were limited to tumors that overexpressed COX-2 as obtained from tumor specimens.


Because inhibition of COX-2 may result in downstream inhibition of PIK3CA, Liao and colleagues[6] explored the mortality benefits of aspirin use in patients with PIK3CA-mutated colorectal cancer. The data were obtained from 964 patients in 2 cohorts: the Nurses' Health Study and the Health Professionals Follow-up Study. The results echoed trends in Chan and colleagues' study, with an even greater effect size: Regular aspirin use after diagnosis was associated with an 82% risk reduction in cancer-specific mortality vs nonusers in this patient population.

In addition, as hypothesized, the mortality benefits were limited to tumors with the PIK3CA mutation vs wild-type tumors. Among participants with PIK3CA-mutated tumors, 26% of postdiagnosis nonusers died within 5 years of diagnosis compared with 3% of users; the data on wild-type PIK3CA tumors indicate no difference in cancer-related mortality between users and nonusers.

The association of aspirin and colorectal cancer cell mutations continues to be evaluated.[7-9] For example, a recent study found that BRAF wild-type colonic neoplastic cells may be more sensitive than BRAF-mutant cells to the antineoplastic effects of aspirin.[7]

Clinical guidelines to date have not made any recommendation to initiate aspirin as adjuvant therapy for colorectal cancer.[10] Certainly, consideration of its use in current practice should take into account patients' tumor mutation status, because the available studies suggest it is an independent predictor of mortality benefit with adjuvant aspirin use. Although aspirin is widely used and generally safe in nononcology patients, there may be unknown risks associated with daily use in this population. At this stage, a clinical decision may be reached by way of dialogue with the patient candidate about the potential benefits in light of the limited data.


  1. Baron JA, Cole BF, Sandler RS, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med. 2003;348:891-899. Abstract

  2. Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med. 2007;356:2131-2142. Abstract

  3. Sandler RS, Halabi S, Baron JA, et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med. 2003;348:883-890. Abstract

  4. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell. 1998;93;705-716. Abstract

  5. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA. 2009;302:649-658.Abstract

  6. Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012;367:1596-1606. Abstract

  7. Nishihara R, Lochhead P, Kuchiba A, et al. Aspirin use and risk of colorectal cancer according to BRAF mutation status. JAMA. 2013;309:2563-2571. Abstract

  8. Kunzmann A, Murray LL, Cardwell CR, McShane CM, McMenamin UC, Cantwell MM. PTGS2 (cyclooxygenase-2) expression and survival amongst colorectal cancer patients: a systematic review. Cancer Epidemiol Biomarkers Prev. 2013 June 27. [Epub ahead of print]

  9. McCowan C, Munro AJ, Donnan PT, Steele RJ. Use of aspirin post-diagnosis in a cohort of patients with colorectal cancer and its association with all-cause and colorectal cancer specific mortality. Eur J Cancer. 2013;49:1049-1057. Abstract

  10. National Comprehensive Cancer Network. NCCN Guidelines® for Colon Cancer. V.3.2013. Accessed June 6, 2013.


    快樂小藥師 發表在 痞客邦 留言(0) 人氣()