Aspirin and Colorectal Cancer - Clinical Cancer Research

Aspirin and Colorectal Cancer - Clinical Cancer Research

Published OnlineFirst December 10, 2013; DOI: 10.1158/1078-0432.CCR-13-2563 Clinical Cancer Research Perspectives Aspirin and Colorectal Cancer: Ba...

521KB Sizes 0 Downloads 9 Views

Recommend Documents

Colorectal Cancer Screening Clinical Practice Guideline - Kaiser
NATIONAL CLINICAL PRACTICE GUIDELINE. Colorectal Cancer Screening. Clinical Practice Guideline. These guidelines are inf

resistance in esophageal cancer - Clinical Cancer Research
Mar 4, 2015 - Randy L. Johnson5, Mien-Chie Hung2,7, Jaffer A. Ajani1. 1Department of ...... Itakura Y, Sasano H, Shiga C

Suppression of Colorectal Cancer Liver Metastasis - Cancer Research
Oct 1, 2004 - Hyun-Kyung Yu,1 Jang-Seong Kim,1 Ho-Jeong Lee,1 Jin-Hyung Ahn,1 Suk-Keun Lee,2 Soon-Won Hong,3 and. Yeup Y

Reporting colorectal cancer - NCBI
The resulting confusion that surrounds the Dukes classification may make it ... surgery for rectal cancer has been devel

[18F]fluoropropyl - Clinical Cancer Research
Aug 14, 2012 - Sora Baek,1 Chang-Min Choi,2 Sei Hyun Ahn,3 Jong Won Lee,3 Gyungyub Gong,4. Jin-Sook Ryu,1 Seung Jun Oh,1

Colorectal Cancer Pathway Acknowledgements - Cancer Care Ontario
external Cancer Care Ontario (CCO) website and they consent to their names being ... Kitchener, Ontario .... Director Di

Intestinal Inflammation and Colorectal Cancer Social Events
9.00 Bus departure from Hotel Meliá Sevilla and Hotel Tryp Macarena. City tour of ... 15.00 After lunch visit to the Al

Cancer Registration - Cancer Research UK
Achievements made possible by cancer registration information: • research showing that there are at least. 10 differen

Improving colorectal cancer screening rates
Aim. Methods. Lessons Learned. References: 1. Final Update Summary: Colorectal Cancer: Screening. U.S. Preventive Servic

international cancer research conference - Windsor Cancer Research
Nov 22, 2014 - Justin Peterson*, Adam Farag, Trevor Szekeres, Eli Gibson, Aaron Ward, Joseph Chin, Stephen. Pautler, Gle

Published OnlineFirst December 10, 2013; DOI: 10.1158/1078-0432.CCR-13-2563

Clinical Cancer Research

Perspectives

Aspirin and Colorectal Cancer: Back to the Future David Tougeron1, Dan Sha3, Sashidhar Manthravadi1, and Frank A. Sinicrope1,2,3

Abstract Abundant epidemiologic evidence indicates that regular and long-term use of aspirin is associated with a significant reduction in the incidence of colorectal cancer. The long duration of aspirin needed to prevent colorectal cancer is believed to be due to inhibition of precursor lesions known as adenomas, the recurrence of which is inhibited by aspirin in randomized trials. Aspirin intake has also been associated with a statistically significant improvement in patient survival after curative resection of colorectal cancer in large observational studies. In these cohorts, the survival benefit of aspirin was shown to depend upon the level of COX-2 expression in the primary colorectal cancer. More recent analysis of patient tumors from these observational cohorts suggests that the benefit of aspirin may be limited to specific molecular subtypes. Aspirin intake following colorectal cancer resection was associated with a significant improvement of survival in patients whose tumors carried mutant, but not wild-type, copies of the phosphoinositide 3-kinase (PI3KCA) gene, especially tumors that overexpressed COX-2. A mechanistic explanation is suggested by the finding that inhibition of COX-mediated prostaglandin E2 synthesis by aspirin attenuates PI3K signaling activity that is known to regulate cancer cell proliferation and survival. Aspirin has also been shown to reduce the incidence of colorectal cancers bearing wild-type, but not mutant alleles of the BRAFV600E oncogene. Although provocative, the potential utility of these molecular markers for predicting aspirin efficacy awaits prospective evaluation in clinical trials. If validated, these findings may support a personalized approach to using aspirin for the therapy of colorectal cancer. Clin Cancer Res; 20(5); 1087–94. 2013 AACR.

Acetylsalicylic acid was first synthesized in 1853 and used for its analgesic and anti-inflammatory properties. Aspirin acts on COX enzymes that regulate the synthesis of prostaglandins (PG) and related eicosanoids from arachidonic acid (Fig. 1). It inhibits constitutively expressed COX-1 as well as the inducible COX-2 isoform, which is upregulated at sites of inflammation (1). Selective COX-2 inhibitors were developed to reduce gastrointestinal injury but were later found to have cardiovascular toxicities (2). Large observational studies have demonstrated an association of regular and long-term aspirin intake with a significant reduction in the incidence (3–5) and mortality from colorectal cancer (3, 6). Cohorts from the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) of 130,274 total participants provided data on aspirin use from a questionnaire administered every 2 years. Among these cohorts, there were 636 incident colorectal cancers of which 67% were found to overexpress COX-2 proteins when analyzed retrospectively. Regular use of aspirin (two 325-mg tablets/wk) was shown to significantly reduce the incidence of colorectal cancers overexpresAuthors' Affiliations: Departments of 1Medicine and 2Oncology, and 3 Cancer Center, Mayo Clinic, Rochester, Minnesota Corresponding Author: Frank A. Sinicrope, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-255-5713; Fax: 507 255 6318; E-mail: [email protected] doi: 10.1158/1078-0432.CCR-13-2563 2013 American Association for Cancer Research.

sing COX-2 [relative risk (RR), 0.64; 95% confidence interval (CI), 0.52–0.78; P ¼ 0.02], but not those with weak or absent COX-2 expression in the primary tumor (Table 1). Importantly, the ability of aspirin to reduce colorectal cancer incidence became evident only after regular use for more than 10 years (multivariate RR, 0.59; 95% CI, 0.42– 0.82; Ptrend < 0.001). The RR was further reduced as the number of aspirin tablets (325 mg) taken per week increased (0.5–1.5 vs. 2–5 vs. 6–14 vs. > 14; Ptrend ¼ 0.001), indicating that the chemopreventive effect was dependent upon both the dose and duration of aspirin intake (7), suggesting the importance of cumulative dosage as a determinant of aspirin efficacy in these settings. The explanation to why a prolonged duration of aspirin intake, varying between studies from 4 years to greater than 10 years (5, 8), is needed to reduce the incidence of colorectal cancer is likely due to a chemopreventive effect of aspirin on colorectal adenomas that are precursor lesions of colorectal cancer. In preclinical models, aspirin inhibits the development of colorectal adenomas and their progression to carcinoma (9). Using colorectal adenomas as a surrogate endpoint for colorectal cancer, earlier randomized and controlled trials of aspirin for the chemoprevention of colorectal cancer were negative (10, 11). However, more recent randomized trials have consistently demonstrated the ability of aspirin to decrease adenoma recurrence in patients with prior colorectal adenomas or cancer (12, 13) (Table 1), although the minimally effective dose remains unclear (14). The failure of earlier studies to detect a

www.aacrjournals.org

Downloaded from clincancerres.aacrjournals.org on March 8, 2018. © 2014 American Association for Cancer Research.

1087

Published OnlineFirst December 10, 2013; DOI: 10.1158/1078-0432.CCR-13-2563

Tougeron et al.

chemopreventive effect of aspirin may be due, in part, to the need for prolonged follow-up as studies reporting no reduction in colorectal cancer incidence initially (11, 15, 16) often noticed an effect after a longer interval ranging from 56 months to around 17 years (8, 17). A recent study involving 39,876 women ages 45 years or older who were enrolled in the Women’s Health Study found that alternate day dosing of low-dose aspirin (100 mg) taken for 10 or more years significantly reduced the incidence of colorectal cancer in women (HR, 0.80; 95% CI, 0.67– 0.97; P ¼ 0.021), especially in the proximal colon (17). After 18 years, the incidence of colorectal cancer was 20% lower in the aspirin group than in the placebo group and was accompanied by a significant increase in self-reported gastrointestinal toxicities (HR for gastrointestinal bleeding 1.14; 95% CI, 1.06–1.22; P < 0.001). In a high-risk population, i.e., patients with prior colon cancer, a prospective study involving 635 participants found that treatment with 325 mg/d aspirin over a mean duration

Translational Relevance Aspirin has been shown to reduce the incidence of colorectal cancer, and accumulating evidence suggests that aspirin may improve the clinical outcome of patients with colorectal cancer following surgical resection. Recent data from large observational studies indicate that the survival benefit of aspirin may be confined to specific molecular subsets defined by phosphoinositide 3-kinase (PI3KCA) mutation status and COX-2 expression levels. Furthermore, regular aspirin intake was found to be associated with a reduced risk of developing colorectal cancers with wild-type BRAF alleles, but not tumors with activating V600E point mutations. Together, these data suggest that aspirin may selectively exert its antitumor effects in specific molecular subsets, thereby identifying potential predictive biomarkers for aspirin efficacy in patients with colorectal cancer.

– COX-2

– COX-2 Aspirin

PGE2

Aspirin

EGFR

EP-4

EP-2 γ

β

γ

PI3K

αs

α

Axin GSK3β β

PGE2

APC

GSK3β

– P

APC

β

Src

Akt

mToR

Ras

β-Arrestin

Raf

– –

AMPK Aspirin



BIM –

MEK

β-Catenin

Src

Cytoplasm

NF-κB

Transcription Antiapoptosis factors BCL-2

Nucleus

Proapoptosis factors BIM, NOXA, PUMA

TCF4 β-Catenin

β-Catenin

HIF1

MAPK

CREB

Proliferation Factors c-myc, c-jun, cyclin D1, PPARδ, COX-2 Angiogenesis VEGF, bFGF

Figure 1. Molecular pathways regulated by PGE2 that are inhibited by aspirin. PGE2 promotes cancer cell growth by binding to its receptors (EP1–4) and modulating signaling pathways downstream of its receptors. In addition to binding Axin (57), the EP4 receptor activates PI3K, which phosphorylates GSK-3b to promote b-catenin–mediated transcription (40). PGE2 signaling is also implicated in c-Src and b-arrestin–mediated transactivation of EGFR and upregulation of the RAS–RAF–MAPK pathway (58).

1088

Clin Cancer Res; 20(5) March 1, 2014

Clinical Cancer Research

Downloaded from clincancerres.aacrjournals.org on March 8, 2018. © 2014 American Association for Cancer Research.

Published OnlineFirst December 10, 2013; DOI: 10.1158/1078-0432.CCR-13-2563

Aspirin and Colorectal Cancer

Table 1. Efficacy of aspirin in the secondary prevention of colorectal cancer Name of the study group

Type

Study population (N)

Aspirin dose used

Aspirin/Folate Polyp Prevention Study (14)

Randomized controlled trial

1,121 patients with prior colorectal adenomas

81 mg or 325 mg/d

The APACC Trial (59)

Randomized controlled trial

272 patients with prior colorectal adenomas

300 mg or 160 mg/d

Colorectal Adenoma Prevention Study (13)

Randomized controlled trial

635 patients with prior colorectal cancer

325 mg/d

of 30.9 months was associated with a statistically significant reduction in the risk of recurrent colorectal adenomas (Table 1) (13). Similar to aspirin, the selective COX-2 inhibitor, celecoxib, has been shown to effectively reduce adenoma recurrence in patients with prior adenomas in randomized trials (18, 19). In a 20-year follow-up of five randomized trials, aspirin at doses of at least 75-mg daily taken for several years reduced the long-term incidence and mortality from colorectal cancer, with the benefit being greatest for cancers of the proximal colon (3). The tumor site–related efficacy of aspirin is clinically important in that colonoscopy has been shown to be less effective at preventing right-sided versus left-sided colon cancers (20). Data also exist for the chemopreventive efficacy of aspirin in patients with Lynch syndrome who have an 80% lifetime risk of colorectal cancer that develops via defective DNA mismatch repair (21). Long-term aspirin treatment (600 mg/d for >2 years) was shown to significantly reduce the incidence of colorectal cancers (N ¼ 508; HR, 0.41; 95% CI, 0.19–0.86; P ¼ 0.02) in patients with Lynch syndrome during prolonged followup (mean, 55.7 months; range 1–128; ref. 8). In a recent report of patients within the NHS and HPFS who developed colorectal cancer, a potential predictive biomarker for aspirin efficacy was found. Regular aspirin intake was associated with a significant reduction in the incidence of colorectal cancers with wild-type (WT), but not mutant BRAFV600E (Table 2; ref. 22). Detailed analysis of the patients whose tumors carried WT–BRAF revealed

www.aacrjournals.org

Result from aspirin use [multivariate HR (95% CI)] In the 81-mg patient group: Unadjusted RR, 0.81 (95% CI, 0.69–0.96) for developing any adenoma. Adjusted RR, 0.83 (95% CI, 0.70–0.98) for developing any adenoma. In the 325-mg patient group: Unadjusted RR, 0.96 (95% CI, 0.81–1.13) for developing any adenoma. Adjusted RR, 0.95 (95% CI, 0.80–1.12) for developing any adenoma. In the 160-mg group: RR, 0.85 (95% CI, 0.57–1.26) for recurrent adenoma In the 300-mg group: RR, 0.61 (95% CI, 0.37–0.99) for recurrent adenoma Adjusted RR 0.65 (95% CI, 0.46–0.91) for any recurrent adenoma

that the preventive benefit of aspirin seemed to be concentrated in tumors overexpressing COX-2 proteins (multivariable HR, 0.67; 95% CI, 0.56–0.81; P ¼ 0.018). In contrast, aspirin failed to lower the risk of BRAFV600Emutated colorectal cancers irrespective of their level of COX-2 expression. Protection conferred by aspirin against the development of BRAF–WT colorectal cancers was not abrogated by mutations in PIK3CA exons 9 and 20 or KRAS exon 2 (22). Furthermore, aspirin benefit was unrelated to microsatellite instability status in incident colorectal cancers in the NHS and HPFS cohorts (A.T. Chan, Massachussets General Hospital, personal communication). Of note, chemopreventive efficacy for aspirin was reported in colorectal cancers from patients with Lynch syndrome that almost uniformly carry WT copies of BRAF (23). Activating mutations in the BRAFV600E oncogene, detected in up to 15% of colorectal cancers, are enriched in sporadic colorectal cancers with microsatellite instability due to epigenetic inactivation of MLH1 mismatch repair gene (24, 25). In separate studies, COX-2 inhibition was unable to suppress proliferation in KRASmutated cells, which suggests that this may also be the case in BRAFV600E-mutated colorectal cancer cells (26). The finding that aspirin can selectively reduce the incidence of BRAF–WT colorectal cancers awaits prospective validation, and studies to identify the specific mechanism underlying its potential predictive impact are awaited. In addition to its role in the prevention of colorectal cancer, data also indicate a role for aspirin as an adjuvant

Clin Cancer Res; 20(5) March 1, 2014

Downloaded from clincancerres.aacrjournals.org on March 8, 2018. © 2014 American Association for Cancer Research.

1089

Published OnlineFirst December 10, 2013; DOI: 10.1158/1078-0432.CCR-13-2563

Tougeron et al.

Table 2. Potential biomarkers indicating aspirin efficacy in colorectal cancer Name of the study group

Study population (N)

Aspirin Biomarker dose under study used Results [multivariate HR (95% CI)]

Biomarkers predicting survival in established colorectal cancer Nurses' Health Study, Stage I–III (N ¼ 1,279) COX-2 325 mg COX-2–overexpressing tumors: HR, 0.39 (95% CI, Health Professionals 0.20–0.76) for colorectal cancer–specific mortality Follow-Up Study (7) COX-2–negative tumors: HR, 1.22 (0.36–4.18) for colorectal cancer–specific mortality Nurses' Health Study, Stage I–IV (N ¼ 964) PIK3CA 325 mg PIK3CA–WT tumors: HR, 0.93 (95% CI, 0.68–1.28) Health Professionals for colorectal cancer–specific mortality Follow-Up Study (37) PIK3CA-mutant tumors: HR, 0.18 (95% CI, 0.05–0.60) for colorectal cancer–specific mortality PIK3CA–WT and COX-2–positive tumors: Stage-adjusted HR, 0.97 (95% CI, 0.73–1.29) for OS PIK3CA-mutant and COX-2–positive tumorsa: Stage-adjusted HR, 0.34 (95% CI, 0.14–0.82) for OS Biomarkers predicting colorectal cancer incidence COX-2 325 mg RR, 0.64 (95% CI, 0.52 to 0.78) for incidence of Nurses' Health Study, NHS (N ¼ 82,911) COX-2–overexpressing tumors Health Professionals HPFS (N ¼ 47,363) RR, 0.96 (95% CI, 0.73 to 1.26) for incidence of Follow-Up Study (7) Stage I–IV (N ¼ 636) COX-2–negative tumors BRAF 325 mg HR, 1.03 (95% CI, 0.76–1.38) for incidence of Nurses' Health Study, NHS (N ¼ 82,095) BRAF-mutant colorectal cancer Health Professionals HPFS (N ¼ 45,770) HR, 0.73 (95% CI, 0.64–0.83) for incidence of Follow-Up Study (22) Stage I–IV (N ¼ 1,226) BRAF–WT colorectal cancer Effect on BRAF–WT tumors based on COX-2 expression: HR, 0.67 (95% CI, 0.56–0.81) for incidence of COX-2–overexpressing colorectal cancer HR, 0.86 (95% CI, 0.67–1.09) for incidence of COX-2–negative colorectal cancer The study recorded zero deaths in the cohort in which tumors were both PIK3CA-mutant and COX-2–expressing (n ¼ 23).

a

agent in patients with resected colorectal cancer (Table 3). Compelling data were obtained from the NHS and HPFS studies (27) in which 1,279 patients with nonmetastatic colorectal cancers were identified retrospectively, and then categorized on the basis of aspirin usage after diagnosis (two 325-mg tablets/wk). During a median follow-up of 11.8 years from diagnosis, aspirin use after diagnosis (N ¼ 549) was associated with a statistically significant reduction in both colorectal cancer–specific mortality (HR, 0.71; 95% CI, 0.53–0.95; P ¼ 0.02) and overall mortality (HR, 0.79; 95% CI, 0.65–0.97; P ¼ 0.03) compared with non-aspirin users. Stratifying tumors based on expression of COX-2 revealed that the survival benefit from aspirin use was confined to patients whose primary tumors overexpressed COX-2 proteins (colorectal cancer–specific multivariate HR, 0.39; 95% CI, 0.20– 0.76). In contrast, a subgroup analysis of study participants who reported aspirin use before a colorectal cancer diagnosis indicated no mortality reduction even when aspirin use was continued after diagnosis (n ¼ 21; Pinteraction ¼ 0.09; ref. 27), suggesting that exposure to aspirin prediagnosis may select for aspirin-resistant tumor cells.

1090

Clin Cancer Res; 20(5) March 1, 2014

In an earlier study, the same investigators reported a post hoc analysis of a subgroup of patients with stage III colon cancer enrolled in an adjuvant chemotherapy trial (CALGB 89803) in which aspirin users had lower rates of colon cancer recurrence and death compared with nonusers (28). Among 2,916 patients with colorectal cancer identified from the Health Informatics Centre registry in Scotland, aspirin use (median of 1.53 years) after diagnosis was associated with improved colorectal cancer–specific survival (multivariate HR, 0.58; 95% CI, 0.45–0.75; P < 0.001; Table 3; ref. 29). Similarly, a cancer registry study conducted in the Netherlands identified 1,451 patients with colorectal cancer in whom aspirin use after diagnosis (defined as physician-prescribed aspirin for at least 14 days) conferred a statistically significant survival benefit in patients with colon cancer (HR, 0.62; 95% CI, 0.48–0.80; P < 0.001), but not rectal cancer (30). Further support for an effect of aspirin on micrometastases derives from five different randomized trials of aspirin for the prevention of vascular events that showed that aspirin use (80–325 mg/d) decreased the risk of metastases from colorectal cancer at diagnosis, as well as

Clinical Cancer Research

Downloaded from clincancerres.aacrjournals.org on March 8, 2018. © 2014 American Association for Cancer Research.

Published OnlineFirst December 10, 2013; DOI: 10.1158/1078-0432.CCR-13-2563

Aspirin and Colorectal Cancer

Table 3. Efficacy of aspirin in patients with surgically resected colorectal cancer

Study population (N)

Aspirin dose used

Name of the study group

Type

CALGB 89803 (28)

Subgroup analysis in a randomized controlled trial

Stage III colorectal cancer (N ¼ 830)

325 mg

Nurses' Health Study and Health Professionals Follow-Up Study (27)

Prospective cohort study

Stage I–III colorectal cancer (N ¼ 1279)

325 mg

Eindhoven cancer registry and PHARMO prescription registry (30)

Retrospective cohort study

Stage I–IV colorectal cancer (N ¼ 4,481)

80 mg

Health Informatics Centre Registry, Scotland (29)

Retrospective cohort study

Stage I–IV colorectal cancer (N ¼ 2,916)

75 mg

the risk of subsequent metastasis at follow-up in patients who were initially metastasis-free (HR, 0.26; 95% CI, 0.11–0.57; P ¼ 0.0008; ref. 31). As was seen for its chemopreventive effects, the presumed antimetastatic effects of aspirin also seem to be dose-dependent in that an increase in postdiagnosis aspirin dosage from 0.5 to 5 to >6 tablets per week led to a modest improvement in survival benefit in the NHS and HPFS patient cohorts (Ptrend ¼ 0.04; ref. 27). Taken together, these studies suggest that aspirin warrants further evaluation as an adjuvant agent to eradicate micrometastases. In this regard, the ASCOLT study is the first prospective randomized placebo-controlled trial to evaluate aspirin as adjuvant therapy in resected colorectal cancer. In this study, 200 mg aspirin is administered daily for 3 years as adjuvant treatment in patients with resected stage III or high-risk stage II colorectal cancer (32). Recent data suggest the potential utility of PIK3CA mutation status in colorectal cancers for the prediction of clinical benefit from aspirin in the adjuvant setting. Mutations in the PIK3CA gene are detected in 15% to 20%

www.aacrjournals.org

Result from aspirin use after diagnosis [multivariate HR (95% CI)] HR, 0.48 (95% CI, 0.24–0.99) for disease-free survival HR, 0.52 (95% CI, 0.19–1.46) for death (OS) HR, 0.71 (95% CI, 0.53–0.95) for colorectal cancer–specific mortality HR, 0.79 (95% CI, 0.65–0.97) for overall mortality In aspirin nonusers before diagnosis: HR, 0.53 (95% CI, 0.33–0.86) for colorectal cancer–specific mortality In aspirin users before diagnosis: HR, 0.89 (95% CI, 0.59–1.35) for colorectal cancer–specific survival RR, 0.77 (95% CI, 0.63–0.95) for colorectal cancer–specific mortality RR, 0.65 (95% CI, 0.50–0.84) for colon cancer mortality RR, 1.03 (95% CI, 0.75–1.40) for rectal cancer mortality HR, 0.67 (95% CI, 0.57–0.79) for colorectal cancer–specific mortality HR, 0.72 (95% CI, 0.57–0.91) for colon cancer mortality HR, 0.80 (95% CI, 0.58–1.11) for rectal cancer mortality

of colorectal cancers (33) and lead to constitutive activation of the PI3K–Akt pathway. An uncertain role exists for PIK3CA mutations in prognosis (34) and in predicting resistance to anti-EGFR–targeted therapy (35, 36). A retrospective analysis of patients with colorectal cancer from the NHS and HPFS cohorts detected PIK3CA mutations in 161 of 964 (17%) nonmetastatic tumors. Patients were then categorized on the basis of aspirin usage after diagnosis and at a median follow-up of 153 months, aspirin intake (two 325-mg tablets/wk) in PIK3CA mutation carriers was associated with a statistically significant increase in survival (multivariate HR, 0.18; 95% CI, 0.06–0.61; P < 0.001), whereas patients whose tumors had WT alleles (N ¼ 803) did not derive any benefit (Table 2; ref. 37). Among patient tumors with PIK3CA mutations, the survival benefit associated with aspirin was most evident in tumors with overexpression of COX-2 (N ¼ 55/161; 34%). Similar findings were recently reported in a post hoc analysis of a clinical trial (VICTOR) evaluating rofecoxib as adjuvant therapy of stage II and III colon cancers (38). Patient tumors were categorized by

Clin Cancer Res; 20(5) March 1, 2014

Downloaded from clincancerres.aacrjournals.org on March 8, 2018. © 2014 American Association for Cancer Research.

1091

Published OnlineFirst December 10, 2013; DOI: 10.1158/1078-0432.CCR-13-2563

Tougeron et al.

PIK3CA mutation status and aspirin usage was recorded at the time of study enrollment. Patients taking <100 mg of aspirin daily were not excluded and were allowed to continue this therapy during the clinical trial. In patients whose tumors carried PIK3CA mutations (N ¼ 104), aspirin usage (n ¼ 14) was associated with a statistically significant improvement in recurrence-free survival (RFS; multivariate HR, 0.11, 95% CI, 0.001–0.832; P ¼ 0.027) at a median follow-up of 61.5 months (38). A modest improvement in overall survival (OS) was also found that did not reach statistical significance (multivariate HR, 0.29, 95% CI, 0.04–2.330; P ¼ 0.260). In contrast to aspirin, rofecoxib treatment was not associated with a difference in RFS (multivariate HR, 1.22; 95% CI, 0.50– 2.98; P ¼ 0.473). Although the duration of aspirin use before study enrollment was not reported, the median duration of rofecoxib use was 7.4 months. Despite the pronounced survival benefit of aspirin in PIK3Ca mutation carriers observed in the VICTOR trial, these data derive from a very small number of patients who reported aspirin usage. The lack of efficacy of the selective COX-2 inhibitor rofecoxib suggests that inhibition of constitutive COX-1 is mechanistically important. Furthermore, the ability of aspirin to inhibit platelet aggregation that is mediated by COX-1 may be important in its antitumor effect (39). Acting through its cell surface receptors EP1–EP4, PGE2 regulates cellular processes important in cancer development (Fig. 1). PGE2 acts through EP4 to activate Tcf/Lef signaling through a PI3K-dependent pathway (40). Inhibition of PGE2 signaling by aspirin may, therefore, attenuate PI3K activity in PIK3CA mutant cancers (41). In addition to inhibiting PGE2, aspirin has been shown to inhibit mTOR, a downstream effector of the PI3K pathway by activation of adenosine monophosphate–activated protein kinase (AMPK) in colorectal cancer cells (42). The mechanisms underlying the antitumor properties of aspirin include both COX-dependent and -independent effects (43). PGE2 stimulates angiogenesis by induction of VEGF and bFGF (basic fibroblast growth factor; ref. 44), and can modulate the WNT/ b-catenin pathway to enable an epithelial-to-mesenchymal transition, a critical event for metastasis (45). COXindependent mechanisms contribute to the antitumor effects of aspirin by inhibiting PPARd (46) and the NFkB pathway (47–49). Aspirin can also exert immunomodulatory effects by altering chemokines (CCL2 and CXCL10) that lead to decreased numbers of myeloidderived suppressor cells and an increase in cytotoxic CD8þ T cells (50). Both aspirin and selective COX-2 inhibitors can modulate apoptosis (51, 52) in tissues, including human colorectal epithelia (53), and cancer stem cells may be more sensitive to NSAID-induced apoptosis relative to differentiated cells that is relevant to eradicating micrometastases (54). From a clinical perspective, identifying the lowest dose of aspirin that can achieve antitumor effects, whereas minimizing potential toxicities is critical. In a prior study,

1092

Clin Cancer Res; 20(5) March 1, 2014

we reported that the 81-mg daily aspirin dose suppressed PGE2 levels equally as did the 650-mg daily dosage in the colorectal mucosa of patients with prior adenomas (55). The antitumor benefits of aspirin are achieved with a trade-off of increased toxicities, as described in a metaanalysis of 22 randomized trials of aspirin for vascular disease prevention. Most notable are the risks of gastrointestinal toxicities, mainly ulcers and gastrointestinal bleeding (RR, 1.62; 95% CI, 1.25–2.09), or intracranial bleeding (RR, 1.65; 95% CI, 1.06–5.99). In the metaanalysis, there was no difference in the rate of adverse events between patients receiving low-dose (75–162.5 mg/d) versus standard-dose (162.5–325 mg/d) aspirin (56). The risks versus potential benefits of aspirin must always be considered when advocating its use in patients. Although aspirin is currently not recommended for patients at average risk of developing colorectal cancer or in patients with removal of prior adenomatous polyps, its use in high-risk patients such as those with advanced adenomas or prior colorectal cancer may be warranted on an individualized basis. However, unresolved issues include the minimally effective dose, optimal duration, and the role of aspirin in patients already undergoing colonoscopic surveillance. For the adjuvant therapy of colorectal cancer, existing data justify the prospective evaluation of aspirin in this setting and a clinical trial (ASCOLT) is ongoing. Furthermore, the addition of celecoxib to standard chemotherapy with FOLFOX is being studied in an ongoing phase III adjuvant therapy trial (CALBG 80702). More than a century after it was first synthesized, the therapeutic benefits of aspirin continue to emerge. Aspirin has been shown to protect against the recurrence of colorectal adenomas and carcinomas, and compelling evidence suggests its efficacy as an adjuvant agent in a molecular subset. Specifically, aspirin may selectively and potently inhibit colon cancer recurrence and improve survival in patient tumors with PI3KCA mutations. Although this finding is compelling, the modest number of patients whose tumors carried PIK3CA mutations and who also used aspirin in these studies necessitates caution in their interpretation and underscores the need for prospective validation. Aspirin is currently being studied as adjuvant therapy in an ongoing trial in patients with colorectal cancer (ASCOLT), and another adjuvant study evaluates the benefit of adding celecoxib to FOLFOX in patients with node-positive colon cancer (CALGB80702). In both trials, a comparison of survival based on PIK3CA mutation status will be performed and will yield further efficacy data. Prospective evaluation will be challenging due to the relatively small number of patients whose tumors carry the PIK3Ca mutation, and studies will also need to address the issue of duration of aspirin therapy needed to achieve clinical benefit. Research into the mechanistic basis of the efficacy of aspirin in PIK3CAmutated colorectal cancers is eagerly awaited. In an era of targeted therapy that is increasing health care costs, aspirin is an inexpensive and well-tolerated drug that may

Clinical Cancer Research

Downloaded from clincancerres.aacrjournals.org on March 8, 2018. © 2014 American Association for Cancer Research.

Published OnlineFirst December 10, 2013; DOI: 10.1158/1078-0432.CCR-13-2563

Aspirin and Colorectal Cancer

prove to be an effective agent to prevent colon cancer recurrence. Disclosure of Potential Conflicts of Interest

Writing, review, and/or revision of the manuscript: D. Tougeron, D. Sha, S. Manthravadi, F.A. Sinicrope Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): D. Tougeron, D. Sha, F.A. Sinicrope Study supervision: D. Sha, F.A. Sinicrope

No potential conflicts of interest were disclosed.

Authors' Contributions

Grant Support

Conception and design: D. Tougeron, D. Sha, S. Manthravadi, F.A. Sinicrope Development of methodology: D. Tougeron, D. Sha, F.A. Sinicrope Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): D. Tougeron, D. Sha, F.A. Sinicrope Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): D. Tougeron, D. Sha, F.A. Sinicrope

This work was supported by the National Cancer Institute (K05CA142885; Senior Scientist Award to F.A. Sinicrope).

Received September 17, 2013; revised November 6, 2013; accepted November 27, 2013; published OnlineFirst December 10, 2013.

References 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

Siegel MI, McConnell RT, Cuatrecasas P. Aspirin-like drugs interfere with arachidonate metabolism by inhibition of the 12-hydroperoxy5,8,10,14-eicosatetraenoic acid peroxidase activity of the lipoxygenase pathway. Proc Natl Acad Sci U S A 1979;76:3774–8. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006;332:1302–8. Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010;376: 1741–50. Cooper K, Squires H, Carroll C, Papaioannou D, Booth A, Logan RF, et al. Chemoprevention of colorectal cancer: systematic review and economic evaluation. Health Technol Assess 2010;14:1–206. Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES, Curhan GC, Fuchs CS. Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA 2005;294:914–23. Coghill AE, Newcomb PA, Campbell PT, Burnett-Hartman AN, Adams SV, Poole EM, et al. Prediagnostic non-steroidal anti-inflammatory drug use and survival after diagnosis of colorectal cancer. Gut 2011;60:491–8. 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: 2131–42. Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein G, Olschwang S, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 2011;378:2081–7. Barnes CJ, Lee M. Chemoprevention of spontaneous intestinal adenomas in the adenomatous polyposis coli Min mouse model with aspirin. Gastroenterology 1998;114:873–7. Gann PH, Manson JE, Glynn RJ, Buring JE, Hennekens CH. Low-dose aspirin and incidence of colorectal tumors in a randomized trial. J Natl Cancer Inst 1993;85:1220–4. Cook NR, Lee IM, Gaziano JM, Gordon D, Ridker PM, Manson JE, et al. Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial. JAMA 2005; 294:47–55. Logan RF, Grainge MJ, Shepherd VC, Armitage NC, Muir KR. Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology 2008;134:29–38. Sandler RS, Halabi S, Baron JA, Budinger S, Paskett E, Keresztes R, et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 2003;348: 883–90. Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 2003;348:891–9. Burn J, Bishop DT, Mecklin JP, Macrae F, Moslein G, Olschwang S, et al. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N Engl J Med 2008;359:2567–78.

www.aacrjournals.org

16. Benamouzig R, Uzzan B, Deyra J, Martin A, Girard B, Little J, et al. Prevention by daily soluble aspirin of colorectal adenoma recurrence: 4-year results of the APACC randomised trial. Gut 2012;61: 255–61. 17. Cook NR, Lee IM, Zhang SM, Moorthy MV, Buring JE. Alternate-day, low-dose aspirin, and cancer risk: long-term observational follow-up of a randomized trial. Ann Intern Med 2013;159:77–85. 18. Arber N, Eagle CJ, Spicak J, Racz I, Dite P, Hajer J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006;355:885–95. 19. Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006;355:873–84. 20. Baxter NN, Goldwasser MA, Paszat LF, Saskin R, Urbach DR, Rabeneck L. Association of colonoscopy and death from colorectal cancer. Ann Intern Med 2009;150:1–8. 21. Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999;81:214–8. 22. Nishihara R, Lochhead P, Kuchiba A, Jung S, Yamauchi M, Liao X, et al. Aspirin use and risk of colorectal cancer according to BRAF mutation status. JAMA 2013;309:2563–71. 23. Domingo E, Laiho P, Ollikainen M, Pinto M, Wang L, French AJ, et al. BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet 2004;41:664–8. 24. Ogino S, Nosho K, Kirkner GJ, Kawasaki T, Meyerhardt JA, Loda M, et al. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut 2009;58:90–6. 25. Samowitz WS, Albertsen H, Herrick J, Levin TR, Sweeney C, Murtaugh MA, et al. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology 2005;129:837–45. 26. Sheng H, Williams CS, Shao J, Liang P, DuBois RN, Beauchamp RD. Induction of cyclooxygenase-2 by activated Ha-ras oncogene in Rat-1 fibroblasts and the role of mitogen-activated protein kinase pathway. J Biol Chem 1998;273:22120–7. 27. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA 2009;302:649–58. 28. C. Fuchs JAM, Heseltine DL, Niedzwiecki D, Hollis D, Chan AT, Saltz LB, et al. Influence of regular aspirin use on survival for patients with stage III colon cancer: findings from intergroup trial CALGB 89803. J Clin Oncol 2005;23(16S):3530. 29. McCowan C, Munro AJ, Donnan PT, Steele RJ. Use of aspirin postdiagnosis in a cohort of patients with colorectal cancer and its association with all-cause and colorectal cancer specific mortality. Eur J Cancer 2013;49:1049–57. 30. Bastiaannet E, Sampieri K, Dekkers OM, de Craen AJ, van Herk-Sukel MP, Lemmens V, et al. Use of aspirin postdiagnosis improves survival for colon cancer patients. Br J Cancer 2012;106:1564–70. 31. Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012; 379:1591–601.

Clin Cancer Res; 20(5) March 1, 2014

Downloaded from clincancerres.aacrjournals.org on March 8, 2018. © 2014 American Association for Cancer Research.

1093

Published OnlineFirst December 10, 2013; DOI: 10.1158/1078-0432.CCR-13-2563

Tougeron et al.

32. Ali R, Toh HC, Chia WK. The utility of Aspirin in Dukes C and High Risk Dukes B Colorectal cancer–the ASCOLT study: study protocol for a randomized controlled trial. Trials 2011;12:261. 33. Yamauchi M, Morikawa T, Kuchiba A, Imamura Y, Qian ZR, Nishihara R, et al. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut 2012;61:847–54. 34. Liao X, Morikawa T, Lochhead P, Imamura Y, Kuchiba A, Yamauchi M, et al. Prognostic role of PIK3CA mutation in colorectal cancer: cohort study and literature review. Clin Cancer Res 2012;18: 2257–68. 35. Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 2009;69:1851–7. 36. Prenen H, De Schutter J, Jacobs B, De Roock W, Biesmans B, Claes B, et al. PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res 2009;15:3184–8. 37. Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 2012;367:1596–606. 38. Domingo E, Church DN, Sieber O, Ramamoorthy R, Yanagisawa Y, Johnstone E, et al. Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer. J Clin Oncol 2013;31:4297–305. 39. Leese PT, Hubbard RC, Karim A, Isakson PC, Yu SS, Geis GS. Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: a randomized, controlled trial. J Clin Pharmacol 2000;40:124–32. 40. Fujino H, West KA, Regan JW. Phosphorylation of glycogen synthase kinase-3 and stimulation of T-cell factor signaling following activation of EP2 and EP4 prostanoid receptors by prostaglandin E2. J Biol Chem 2002;277:2614–9. 41. Uddin S, Ahmed M, Hussain A, Assad L, Al-Dayel F, Bavi P, et al. Cyclooxygenase-2 inhibition inhibits PI3K/AKT kinase activity in epithelial ovarian cancer. Int J Cancer 2010;126:382–94. 42. Din FV, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K, et al. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 2012;142:1504–15. 43. Cha YI, DuBois RN. NSAIDs and cancer prevention: targets downstream of COX-2. Annu Rev Med 2007;58:239–52. 44. Cheng T, Cao W, Wen R, Steinberg RH, LaVail MM. Prostaglandin E2 induces vascular endothelial growth factor and basic fibroblast growth factor mRNA expression in cultured rat Muller cells. Invest Ophthalmol Vis Sci 1998;39:581–91. 45. Brabletz T, Hlubek F, Spaderna S, Schmalhofer O, Hiendlmeyer E, Jung A, et al. Invasion and metastasis in colorectal cancer: epithelial–mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin. Cells Tissues Organs 2005;179: 56–65.

1094

Clin Cancer Res; 20(5) March 1, 2014

46. He TC, Chan TA, Vogelstein B, Kinzler KW. PPARdelta is an APCregulated target of nonsteroidal anti-inflammatory drugs. Cell 1999;99: 335–45. 47. Stark LA, Reid K, Sansom OJ, Din FV, Guichard S, Mayer I, et al. Aspirin activates the NF-kappaB signalling pathway and induces apoptosis in intestinal neoplasia in two in vivo models of human colorectal cancer. Carcinogenesis 2007;28:968–76. 48. Din FV, Dunlop MG, Stark LA. Evidence for colorectal cancer cell specificity of aspirin effects on NF kappa B signalling and apoptosis. Br J Cancer 2004;91:381–8. 49. Stark LA, Din FV, Zwacka RM, Dunlop MG. Aspirin-induced activation of the NF-kappaB signaling pathway: a novel mechanism for aspirinmediated apoptosis in colon cancer cells. FASEB J 2001;15:1273–5. 50. Fujita M, Kohanbash G, Fellows-Mayle W, Hamilton RL, Komohara Y, Decker SA, et al. COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells. Cancer Res 2011;71: 2664–74. 51. Iglesias-Serret D, Pique M, Barragan M, Cosialls AM, Santidrian AF, Gonzalez-Girones DM, et al. Aspirin induces apoptosis in human leukemia cells independently of NF-kappaB and MAPKs through alteration of the Mcl-1/Noxa balance. Apoptosis 2010;15:219–29. 52. Greenhough A, Wallam CA, Hicks DJ, Moorghen M, Williams AC, Paraskeva C. The proapoptotic BH3-only protein Bim is downregulated in a subset of colorectal cancers and is repressed by antiapoptotic COX-2/PGE(2) signalling in colorectal adenoma cells. Oncogene 2010;29:3398–410. 53. Sinicrope FA, Half E, Morris JS, Lynch PM, Morrow JD, Levin B, et al. Cell proliferation and apoptotic indices predict adenoma regression in a placebo-controlled trial of celecoxib in familial adenomatous polyposis patients. Cancer Epidemiol Biomarkers Prev 2004;13:920–7. 54. Qiu W, Wang X, Leibowitz B, Liu H, Barker N, Okada H, et al. Chemoprevention by nonsteroidal anti-inflammatory drugs eliminates oncogenic intestinal stem cells via SMAC-dependent apoptosis. Proc Natl Acad Sci U S A 2010;107:20027–32. 55. Sample D, Wargovich M, Fischer SM, Inamdar N, Schwartz P, Wang X, et al. A dose-finding study of aspirin for chemoprevention utilizing rectal mucosal prostaglandin E(2) levels as a biomarker. Cancer Epidemiol Biomarkers Prev 2002;11:275–9. 56. McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Am J Med 2006;119:624–38. 57. Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS. Prostaglandin E2 promotes colon cancer cell growth through a Gsaxin-beta-catenin signaling axis. Science 2005;310:1504–10. 58. Buchanan FG, Wang D, Bargiacchi F, DuBois RN. Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J Biol Chem 2003;278:35451–7. 59. Benamouzig R, Deyra J, Martin A, Girard B, Jullian E, Piednoir B, et al. Daily soluble aspirin and prevention of colorectal adenoma recurrence: one-year results of the APACC trial. Gastroenterology 2003;125: 328–36.

Clinical Cancer Research

Downloaded from clincancerres.aacrjournals.org on March 8, 2018. © 2014 American Association for Cancer Research.

Published OnlineFirst December 10, 2013; DOI: 10.1158/1078-0432.CCR-13-2563

Aspirin and Colorectal Cancer: Back to the Future David Tougeron, Dan Sha, Sashidhar Manthravadi, et al. Clin Cancer Res 2014;20:1087-1094. Published OnlineFirst December 10, 2013.

Updated version

Cited articles Citing articles

E-mail alerts Reprints and Subscriptions Permissions

Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-13-2563

This article cites 59 articles, 21 of which you can access for free at: http://clincancerres.aacrjournals.org/content/20/5/1087.full#ref-list-1 This article has been cited by 6 HighWire-hosted articles. Access the articles at: http://clincancerres.aacrjournals.org/content/20/5/1087.full#related-urls

Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected] To request permission to re-use all or part of this article, use this link http://clincancerres.aacrjournals.org/content/20/5/1087. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.

Downloaded from clincancerres.aacrjournals.org on March 8, 2018. © 2014 American Association for Cancer Research.