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AspIrin's role in reducing cancer risks

AM4CCCAspirin may slow the spread of some types of colon and pancreatic cancer cells, found a US study, while a Chinese study and meta-analysis found that regular aspirin use was associated with decreased risk of pancreatic cancer. Meanwhile, a multicentre US study found that although non-steroidal anti-inflammatory drugs are better than all the other compared therapies for preventing recurrence of adenomatous polyps following removal, aspirin had nearly as good of results, with much less additional risk.

Platelets are blood cells involved with clotting. They promote the growth of cancerous cells by releasing growth factors and increasing the response of certain proteins that regulate tumour cell development (oncoproteins). Low doses of aspirin, an anti-platelet drug, have been shown to reduce the risk of some types of gastrointestinal cancers, but the process by which aspirin hampers tumour growth has been unclear. "The current study was designed to determine the effect of inhibition of platelet activation and function by aspirin therapy on colon and pancreatic cancer cell proliferation," the researchers wrote.

The research team combined activated platelets primed for the clotting process with three groups of cancer cells: • metastatic colon cancer (cells that have spread outside the colon), • non-metastatic colon cancer (cells that grow only within the colon) and • non-metastatic pancreatic cancer cells.

When they added aspirin to the mixture, they found that the platelets were no longer able to stimulate growth and replication in the pancreatic and non-metastatic colon cancer cells. The metastatic colon cancer cells continued to multiply when treated with aspirin.

In pancreatic cancer cells, low doses of aspirin stopped the platelets from releasing growth factor and hampered the signalling of the oncoproteins that cause cancer to survive and spread. Only very high doses – larger than are possible to take orally – were effective in stopping growth in the metastatic colon cells, explained the researchers.

The findings detail the interaction among platelets, aspirin and tumour cells and are promising for the future treatment of non-metastatic cancer, according to the researchers. "Our study reveals important differences and specificities in the mechanism of action of high- and low-dose aspirin in metastatic and non-metastatic cancer cells with different tumour origins and suggests that the ability of aspirin to prevent platelet-induced c-MYC [an oncoprotein] expression might be selective for a non-metastatic phenotype."

Aspirin, an anti-inflammatory and anti-thrombotic drug, has become the focus of intense research as a potential anti-cancer agent owing to its ability to reduce tumor proliferation in vitro and to prevent tumorigenesis in patients. Studies have found an anti-cancer effect of aspirin when used in low, anti-platelet doses. However, the mechanism(s) through which low dose aspirin works is poorly understood. In this study we aimed to determine the effect of aspirin on the crosstalk between platelets and cancer cells. For our study we used 2 colon cancer cell lines isolated from the same donor but characterized by different metastatic potential, SW480 (nonmetastatic) and SW620 (metastatic) cancer cells, and a pancreatic cancer cell line, PANC-1 (nonmetastatic). We found that SW480 and PANC-1 cancer cell proliferation was potentiated by human platelets in manner dependent upon the upregulation and activation of the oncoprotein c-MYC. The ability of platelets to upregulate c-MYC and cancer cell proliferation was reversed by an anti-platelet concentration of aspirin. In conclusion, we show for the first time that inhibition of platelets by aspirin can affect their ability to induce cancer cell proliferation through the modulation of the c-MYC oncoprotein.

Annachiara Mitrugno, Joanna L Sylman, Anh TP Ngo, Jiaqing Pang, Rosalie C Sears, Craig Williams, Owen JT McCarty


And in another study, researchers found that regular use of aspirin by people living in Shanghai, China, was associated with decreased risk for developing pancreatic cancer. Data from the new study and meta-analysis of data from 18 other studies suggest that over the past two decades, as the general population's use of aspirin has increased, the effect of aspirin in decreasing pancreatic cancer risk has become more pronounced.

"Pancreatic cancer is one of the deadliest types of cancer – fewer than 8% of patients survive five or more years after diagnosis – so it is crucial that we find ways to prevent it," said Dr Harvey A Risch, professor of epidemiology in the department of chronic disease epidemiology at the Yale School of Public Health, Yale School of Medicine, and Yale Cancer Centre in New Haven, Connecticut. "We found that regular use of aspirin by a large group of people in Shanghai cut risk of pancreatic cancer almost in half."

"These new data are consistent with what has been seen in other populations around the world," continued Risch. "Pancreatic cancer is relatively rare – just 1.5% of US adults will be diagnosed with it at some point during life – and regular aspirin use can cause appreciable complications for some. Therefore, a person should consult his or her doctor about aspirin use. Nevertheless, the balance of evidence shows that people who use aspirin to reduce risk for cardiovascular disease or colorectal cancer can feel positive that their use likely also lowers their risk for pancreatic cancer."

Risch and colleagues recruited patients newly diagnosed with pancreatic cancer at 37 Shanghai hospitals from December 2006 to January 2011. They also randomly selected controls from the Shanghai Residents Registry. The 761 patients with pancreatic cancer and 794 controls were interviewed in person to determine when they started using aspirin, the number of years they used aspirin, and when they stopped using aspirin, among other things. Almost all aspirin users used aspirin daily.

Among the patients with pancreatic cancer, 11% reported regular use of aspirin – 18% of the controls reported regular use of aspirin.

After adjusting for a number of factors, including body mass index, smoking history, and history of diabetes, the researchers found that ever having used aspirin regularly was associated with a 46% decreased risk for pancreatic cancer. Risk decreased by 8% for each year of aspirin use.

In reviewing the literature, Risch and colleagues found 18 other studies that had investigated aspirin use and pancreatic cancer risk. Meta-analysis of the data from these studies showed that if the studies were considered by the year at which the midpoint of when the aspirin exposures were ascertained in the study, the odds ratios for regular use of aspirin and pancreatic cancer risk significantly decreased by 2.3% per year through the present.

According to Risch, the main limitation of the Shanghai study is that it is a case-control study that relied on participants accurately reporting past aspirin use.

Background: Few options besides the avoidance of smoking and obesity are available to prevent pancreatic cancer. The association between aspirin use and risk of pancreatic cancer has been inconsistent across studies.
Methods: We performed a population-based study of 761 case and 794 control subjects frequency matched on sex and age during 2006 to 2011 in Shanghai, China. Participants were asked about episodes of regular use of aspirin, tablets per day or week, and ages that the use started and stopped. Data were analyzed by unconditional logistic regression, with adjustments for age, sex, education, body mass index, years of cigarette smoking, cigarettes smoked per day, Helicobacter pylori CagA seropositivity, ABO blood group, and history of diabetes mellitus. Meta-regression was carried out to summarize the literature.
Results: Ever-regular use of aspirin was associated with lowered risk of pancreatic cancer: OR = 0.54; 95% confidence interval (CI), 0.40–0.73; P = 10−4.2. Risk decreased 8% per each cumulative year of use: ORtrend = 0.92; 95% CI, 0.87–0.97; P = 0.0034. Across this and 18 published studies of this association, the OR for ever-regular use decreased with increasingly more recent mid-study year, for any aspirin type (Ptrend = 10−5.1), and for low-dose aspirin (Ptrend = 0.0014).
Conclusions: Regular use of aspirin thus appears to reduce risk of pancreatic cancer by almost half.
Impact: People who take aspirin for prevention of other diseases likely also reduce their risk of pancreatic cancer. Aside from benefits for both cardiovascular disease and certain cancers, long-term aspirin use entails some risks of bleeding complications, which necessitates risk–benefit analysis for individual decisions about use.

Harvey A Risch, Lingeng Lu, Samantha A Streicher, Jing Wang, Wei Zhang, Quanxing Ni, Mark S Kidd, Herbert Yu and Yu-Tang Gao


Also, Mayo Clinic researchers and a team of collaborating scientists from across the US have determined the comparative effectiveness of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin and several supplements in preventing the recurrence of advanced neoplasia (polyps that are the precursor of colorectal cancer) after polyp removal.

According to the World Cancer Research Fund, colorectal cancer is the third most common cancer in the world. In the US, more than one-third of people who develop colorectal cancer will die of the disease, with most of those cancers arising from advanced neoplasia (also known as advanced adenomas or adenomatous polyps).

In their study the research team showed that, for most patients, non-aspirin NSAIDs (ibuprofen) work better than aspirin or a host of nutritional supplements to prevent the growth of advanced adenomas. In the paper, they say that due to most colorectal cancers developing from this type of polyps, preventing them is a good proxy for colorectal cancer prevention.

"Approximately 85% of all colorectal cancers are thought to result from untreated adenomatous polyps," says Dr M Hassan Murad, a clinical epidemiologist and preventive medicine physician at Mayo Clinic, and the study's senior author. "If we can find a way to stop their growth, we could prevent a majority of these cases."

"We knew that aspirin and other NSAIDs have a protective effect, and that a number of other nutritional supplements have also been studied for their effectiveness in preventing cancer," says Murad. "What we didn't know is how they compared to each other."

The team conducted a meta-analysis (a statistical research method that involves combining data from multiple studies to obtain a single consolidated observation) of clinical trial data from 15 randomised control trials, reviewing information from 12,234 patients. These studies included low- and high-dose aspirin therapy, calcium, vitamin D and folic acid, and compared them each alone or in various combinations.

Murad and his colleagues showed that non-aspirin NSAIDs are better than all the other compared therapies for preventing recurrence of adenomatous polyps within three to five years following initial polyp removal. However, because of some of the other health risks of non-aspirin NSAIDs, they may not be the best choice for everyone.

Aspirin had nearly as good of results, with much less additional risk. Murad and his colleagues cautioned that, although low-dose aspirin was ranked second in preventive capabilities, "the excess benefit over risk might therefore be favourable for many patients."

"It is important that patients and doctors have a discussion on the various risks and benefits of any medication or other therapy," says Murad. "While a research publication may contain promising findings, it is generalised information, and each individual is different. So their care will be individualised, as well."

Objective: To assess the comparative efficacy and safety of candidate agents (low and high dose aspirin, non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), calcium, vitamin D, folic acid, alone or in combination) for prevention of advanced metachronous neoplasia (that is, occurring at different times after resection of initial neoplasia) in individuals with previous colorectal neoplasia, through a systematic review and network meta-analysis.
Data sources: Medline, Embase, Web of Science, from inception to 15 October 2015; clinical trial registries.
Study selection: Randomized controlled trials in adults with previous colorectal neoplasia, treated with candidate chemoprevention agents, and compared with placebo or another candidate agent. Primary efficacy outcome was risk of advanced metachronous neoplasia; safety outcome was serious adverse events.
Data extraction: Two investigators identified studies and abstracted data. A Bayesian network meta-analysis was performed and relative ranking of agents was assessed with surface under the cumulative ranking (SUCRA) probabilities (ranging from 1, indicating that the treatment has a high likelihood to be best, to 0, indicating the treatment has a high likelihood to be worst). Quality of evidence was appraised with GRADE criteria.
Results: 15 randomized controlled trials (12 234 patients) comparing 10 different strategies were included. Compared with placebo, non-aspirin NSAIDs were ranked best for preventing advanced metachronous neoplasia (odds ratio 0.37, 95% credible interval 0.24 to 0.53; SUCRA=0.98; high quality evidence), followed by low-dose aspirin (0.71, 0.41 to 1.23; SUCRA=0.67; low quality evidence). Low dose aspirin, however, was ranked the safest among chemoprevention agents (0.78, 0.43 to 1.38; SUCRA=0.84), whereas non-aspirin NSAIDs (1.23, 0.95 to 1.64; SUCRA=0.26) were ranked low for safety. High dose aspirin was comparable with low dose aspirin in efficacy (1.12, 0.59 to 2.10; SUCRA=0.58) but had an inferior safety profile (SUCRA=0.51). Efficacy of agents for reducing metachronous colorectal cancer could not be estimated.
Conclusions: Among individuals with previous colorectal neoplasia, non-aspirin NSAIDs are the most effective agents for the prevention of advanced metachronous neoplasia, whereas low dose aspirin has the most favorable risk:benefit profile.

Parambir S Dulai, Siddharth Singh, Evelyn Marquez, Rohan Khera, Larry J Prokop, Paul J Limburg, Samir Gupta, Mohammad Hassan Murad

[link url=""]American Physiological Society material[/link]
[link url=""]American Journal of Physiology – Cell Physiology abstract[/link]
[link url=""]Yale Cancer Centre material[/link]
[link url=""]Cancer Epidemiology Biomarkers and Prevention abstract[/link]
[link url=""]Mayo Clinic material[/link]
[link url=""]BMJ abstract[/link]

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