Aspirin Cuts Risk of BRAF Wild-Type Colorectal Cancer

Source: IMNG Medical Media

A new study suggests both men and women who use aspirin regularly have a significantly lower risk of developing colorectal cancer than aspirin nonusers.

Regular aspirin use has been linked to a lower risk of BRAF wild-type, but not BRAF mutated, colorectal cancer, according to a report in the June 26 issue of JAMA.
The absolute difference in risk was considered modest, so further investigation is required to clarify the clinical implications of these study findings. But the results do indicate that BRAF status may someday serve as a marker of sensitivity to aspirin therapy, said Reiko Nishihara, Ph.D., of the Dana-Farber Cancer Institute and Harvard University, Boston, and her associates.
Activating mutations in the BRAF oncogene occur in 10%-15% of colorectal cancers, and are thought to play a role in the upregulation and synthesis of certain prostaglandins. Since aspirin is an antiprostaglandin, “we hypothesized that BRAF-mutant colonic cells might be less sensitive to the antitumor effects of aspirin, whereas BRAF wild-type neoplastic cells might be more susceptible to its antitumor effects,” they said.
The study findings also could lead to new treatment strategies that are better tailored to tumor characteristics. And they “enhance understanding of the molecular pathogenesis of colorectal neoplasia and the mechanisms through which aspirin may exert its antineoplastic effects,” the investigators noted.
Dr. Nishihara and her colleagues examined the association between aspirin use and colorectal cancer’s BRAF mutation status using data from two large national prospective cohort studies that tracked participants’ aspirin use beginning in the 1980s. They analyzed data on 82,095 women in the Nurses' Health Study (NHS) and 45,770 men in the Health Professionals Follow-Up Study (HPFS), in which numerous dietary and other exposures were monitored in detail at 2-year intervals.
“Our detailed, updated exposure data allowed us to control for the effects of potential confounding by other dietary and lifestyle factors implicated in colorectal carcinogenesis,” they said.
The study participants used aspirin primarily to prevent cardiovascular disease and to treat arthritis, other musculoskeletal pain, and headache.
During 28 years (more than 3 million person-years) of follow-up, 1,226 of these subjects developed colorectal cancer. As expected, both men and women who used aspirin regularly showed a significantly lower risk of developing the disease than did aspirin nonusers.
DNA tissue was extracted from stored samples of tumor tissue so that BRAF status could be determined.
Aspirin use was associated with a significantly lower risk of BRAF-wild-type cancer. For this tumor, the age-adjusted incidence was 40.2 per 100,000 person-years among aspirin nonusers, compared with 30.5 per 100,000 person-years for aspirin users.
In contrast, aspirin use showed no relation to the risk of BRAF-mutated cancer. The age-adjusted incidence was 5.0 per 100,000 person-years among nonusers and 5.7 per 100,000 among aspirin users (JAMA 2013;309:2563-71).
In a sensitivity analysis that accounted for the concomitant use of cholesterol-lowering agents, antihypertensive medications, and NSAIDs, the results were unchanged.
Further investigation showed that the risk of BRAF-wild-type colorectal cancer decreased as the weekly dose of aspirin increased. In addition, this risk decreased as the duration of aspirin therapy increased.
In contrast, neither dose nor duration of aspirin therapy affected the risk for BRAF-mutated cancer.
“These findings support the hypothesis that BRAF-mutated cells may show resistance to the anticancer effects of aspirin due to upregulation of the [prostaglandin] pathway,” Dr. Nishihara and her associates said.
This study was supported by the National Institutes of Health, the Bennett Family Fund for Targeted Therapies Research, and the National Colorectal Cancer Research Alliance. Dr. Nishihara reported no financial conflicts. An associate reported ties to Bayer Healthcare, Millenium Pharmaceuticals, Pfizer, and Pozen.

Commentary – Confirm findings in black patients
Dr. Boris Pasche comments: This study identifies a biomarker of the tumor response to aspirin that is administered either preventively or therapeutically, and so may eventually help tailor both preventive and treatment approaches to colorectal cancer, said Dr. Boris Pasche.
One limitation was that the study population was 95%-98% white, whereas blacks have the highest incidence of colorectal cancer in the United States and stand to benefit the most from improvements in prevention and treatment. Thus, it will be important to determine whether these findings apply to black patients as well as white, he said.

Dr. Pasche is in the division of hematology/oncology at the University of Alabama at Birmingham and is a contributing editor at JAMA. He reported ties to Novartis, Amgen Vectibix, HudsonAlpha Institute, Hirslanden, and LACORE. These remarks were taken from his editorial accompanying Dr. Nishihara’s report (JAMA 2013;309:2598-9).

When it Comes to Colonoscopies, Recession and Co-Pays Matter

Image via Wikipedia

Source: http://blogs.wsj.com/health/
By Katherine Hobson By a number of indicators, people have been using fewer medical services during the economic downturn. Screening colonoscopies apparently aren’t immune to that trend, according to a study appearing in the March issue of Clinical Gastroenterology and Hepatology. The study finds that during the recent recession, commercially insured Americans had fewer of the tests to screen for cancer — a test that saves lives, according to research published just this week. According to the analysis, there were about 500,000 fewer screening colonoscopies among commercially-insured people aged 50 to 64 than you’d expect during the most recent recession, which officially lasted from December 2007 to June 2009. (The study used the National Bureau of Economic Research’s official designation for the recession.) The U.S. Preventive Services Task Force recommends colorectal cancer screening using several methods, including colonoscopy, for adults aged 50 to 75. The analysis didn’t find that people forgoing colonoscopy were instead using other, cheaper methods, such as fecal occult blood tests or sigmoidoscopy. Researchers looked at the rates of screening before and after the recession, then applied their findings to population data to come up with an estimate of 516,309 colonoscopies that would have occurred absent the downturn. Data came from 106 health plans and added up to a nationally representative picture of the commercially insured population, the authors say. It doesn’t include people who didn’t have a screening colonoscopy because they lost insurance coverage during the recession, says Spencer Dorn, an author of the study and an assistant professor of medicine in the division of gastroenterology at the University of North Carolina at Chapel Hill. And it doesn’t include Medicare or Medicaid beneficiaries. The analysis also found that when it comes to colonoscopy, cost sharing appears to be a deterrent. No matter the economic climate, people with higher out-of-pocket costs — $300 or more for the procedure — were less likely to be screened than those with lower costs, defined as $50 or less. That gap “widened during the recession,” says Dorn. Under the health-care overhaul law, colonoscopy — and other preventive services — must be covered with no cost sharing by Medicare, Medicaid and new private-insurance plans. (“Grandfathered” plans that haven’t significantly changed their design are exempt.) The drop in utilization seen in the study “could have negative consequences down the line,” says Dorn, in terms of cancers being caught at a later stage. (The screening study out this week suggests it might also lead to deaths from the disease.) The CDC last year reported an increase in screening rates for colorectal cancer from 2002 to 2010, but that estimate included all 50- to 75-year-olds and didn’t break down what happened during the intervening years.

Related articles

• When it Comes to Colonoscopies, Recession and Co-Pays Matter (blogs.wsj.com)
• Among People With Health Insurance, The Recession And High Co-Pays Tied To Fewer Colonoscopy Screenings (medicalnewstoday.com)
• Recession and high co-pays tied to fewer colonoscopy screenings among people with health insurance (medicalxpress.com)
• Recession and high co-pays tied to fewer colonoscopy screenings among people with health insurance (eurekalert.org)
• Many Cancer Deaths Prevented by Colonoscopy (webmd.com)
• CT Colonography Shown to be Comparable to Standard Colonoscopy for People Ages 65 and Over (multivu.com)
• Study Supports CT-Based 'Virtual' Colonoscopy to Spot Colon Cancer (news.health.com)
• Colon Cancer Alliance and American College of Radiology demand Medicare cover virtual colonoscopy (eurekalert.org)
• Fewer Americans Received Life-Saving Cancer Screenings During Recession (thinkprogress.org)
• Colorectal cancer death risk cut in half through colonoscopies, study shows - CBS News (cbsnews.com)

Independent Events

                       Image via WikipediaIndependent Events

I was speaking with a patient recently who was explaining why he thought that colon cancer screening with fecal occult blood testing (FOBT) was equivalent to colonoscopy. He wished to avoid colonoscopy for all the usual reasons, but also believed logically that it was not a superior test.

I won't get into the actual evidence behind the two methods of screening; that is not an issue for this post. Instead, I want to discuss his argument. He assumed that colonoscopy had a sensitivity (probability of the test being positive in someone with a significant colon lesion) of 98%, and this figure is in the ballpark of believable numbers. Let's assume that the sensitivity of FOBT is around 35% (also a reasonable ballpark figure). At that rate, he said, since colonoscopy is performed once every 10 years, and FOBT is performed yearly, after 10 years the performance of the two tests is similar with FOBT having a cumulative sensitivity of 99%.

There are two important problems with this argument. The first, which I will just mention in passing, is also the more obvious. If a test has to be repeated for 10 years to detect a cancer, that cancer may grow and become incurable during the testing period. Had it been found at year 1, it might have had a better chance of being cured.

The second problem is the focus of this post, and to examine it, we need to understand the calculation the patient was performing to get to a cumulative sensitivity of 99%. This is the same type of calculation that is often presented when thinking about the probability of an abnormal lab test due to chance alone in a battery of lab tests. The argument goes as follows:

We define "normal" in a lab test that has a continuous result (like serum sodium) as the range of values that captures 95% of healthy patients.
That means that 5% of healthy patients (or 1 in 20) will have an "abnormal" result on the test.
If we run a battery of different tests on a patient, each of which has a similarly defined normal range, the probability of a single abnormal result due to "chance" goes up.

The actual calculation of the likelihood of an abnormal test result typically confuses medical students and early residents until they've heard it presented repeatedly. A common assumption is that if there is a 1 in 20 chance of an abnormal result on each test, then if 20 tests are run there will definitely be an abnormal result. This is not the correct calculation. Under the usual assumptions that people make in thinking about this, the calculation would be that the probability of all the tests being normal is the probability of a single test being normal raised to the power of the number of tests.

Thus, for 20 tests it would be 0.95^20, which is 0.36. The probability that at least one such test will be abnormal due to "chance" is 1-0.36 or 0.64. Or, about 2/3 of normal patients would be expected to have at least one abnormal test on a battery of 20 tests under these assumptions.

So the patient utilizing FOBT for colon cancer screening was saying that, with a sensitivity of about 35%, he could expect a false negative rate of 0.65 per test but that 0.65^10 (for the ten years of testing) yielded a miss rate of 1%. This cumulative sensitivity would then be similar to that of a single colonoscopy, so why should he get the invasive procedure?

And so we come to the second problem with the patient's argument: each round of testing is not an independent event.

The calculations I described above for cumulative probabilities make the assumption that the individual events are independent from each other. That is, the result of one test has no influence on the others.

If you flip a fair penny three times and get three heads, there is still a 1 in 2 chance that it will come up heads on the fourth flip. But if you perform FOBT once for colon cancer and it is negative it might be in the setting of your particular precancerous lesion that doesn't tend to bleed. If so, it's less likely to be bleeding on subsequent FOBT than an "average" lesion and so the cumulative sensitivity cannot assume independence of events. This is not just a theoretical issue: based on some research, repeated testing is thought to actually have a cumulative sensitivity of around 85%, not 99%.

So the patient was miscalculating in his decision about how to be screened for colon cancer. I actually briefly discussed this with him during the appointment, but since the real issue was that he did not want a colonoscopy he was singularly uninfluenced by the math.

This plays out in other areas as well, though:

What about that standard example above regarding batteries of lab tests that all medical students and residents are taught? The tests in the battery, too, are clearly not independent events. Normal and abnormal tests tend to cluster and so it is likely that the probability of the 20th test being abnormal in a healthy patient is affected by whether the prior 19 tests included any abnormal results.

To contrast with the assumption of probabilities in the face of independent events, here we are talking about "conditional" probabilities where we want to know the likelihood of an event given some other set of events. However, in the real world we have very few data about these situations. If, for instance, I wanted to know how likely, due to random variation, a patient with an abnormal serum sodium and chloride is to have a high serum potassium, it is extremely unlikely that I could get a high quality answer without doing my own primary research.

This problem of not knowing conditional probabilities when faced with non-independent events has an important effect on how diagnostic strategies might be misinterpreted if clinicians really started utilizing a test parameter that is a favorite in the EBM community but has not really permeated the clinical world. I'll address this in a future post.

Related articles

• Blood test for colon cancer screening beneficial for some seniors, but not for many others (eurekalert.org)
• Proper Bowel Prep Key to Effective Colon Cancer Screening (nlm.nih.gov)
• Colorectal Screenings can be Lifesavers (cancerhelpandtreatment.wordpress.com)
• Colonoscopy screenings may occur more often than recommended; benefit uncertain in some older adults (eurekalert.org)
• Proper Health Screening Chart (checkupyourcheckup.wordpress.com)
• Screening Colonoscopies Done More Often Than Recommended On Medicare Beneficiaries (medicalnewstoday.com)
• Canadians too ‘squeamish’ about testing for colorectal cancers (theglobeandmail.com)
• Colorectal cancer screening rates on rise among Medicare beneficiaries due to expansion of coverage (scienceblog.com)
• Colorectal cancer cases on the rise: Report (calgaryherald.com)
• Colorectal cancer screening rates on rise among Medicare beneficiaries due to expansion of coverage (eurekalert.org)