Aspirin and breast cancer recurrence

Jacob Schor ND FABNO

September 5, 2011

 

 

 

 

Introduction:

 

Aspirin for CVD

In recent years many medical authorities have suggested daily use of low dose aspirin to large segments of the population for the purpose of lowering risk of stroke and hemorrhage.  Current guidelines from the U.S. Preventive Services Task Force now encourage women at high risk of stroke age 55 to 79 years to use aspirin unless there is high risk of gastrointestinal hemorrhage. The American College of Chest Physicians now strongly suggest daily aspirin doses for almost all patients with coronary artery disease.  The rare contraindication against use is allergy to aspirin.    In 2010 Americans bought more than 44 million packages of low-dose aspirin marketed for heart protection.

 

As a result, data on the effects of these daily doses of aspirin on large cohorts of the population over extended periods of time have accumulated and have allowed analysis seeking associations and impacts on other diseases in particular cancer.

 

Of great interest is the association with cancer.  This article will focus on the information as it relates to breast cancer.  

 

 

The Last Chapter First

Rather than beginning with areview of past literature, this discussion will skip ahead to what might be described as the last chapter, or at least the current chapter, and review the recent study by Holmes et al so that you can appreciate what the excitement is about.

 

 

Holmes et al:

In March 2010 the Journal of Clinical Oncology published a study by Michelle Holmes and colleagues at Harvard University.  Their results suggest that taking daily aspirin may significantly reduce the risk of breast cancer recurrence.

 

Theirs was a prospective observational study based on data from 4,164 female nurses who took part in the Nurses' Health Study and who were diagnosed with breast cancer between 1976 and 2002.  Holmes and her colleagues tracked these women either until death or June 2006, whichever came first. The researchers calculated risk of death from breast cancer and compared it with the number of days during the week these women took aspirin. 

 

There were 341 breast cancer deaths among the women being tracked.  Taking aspirin more than once a week decreased the risk of dying from breast cancer.  Those women who reported taking aspirin 2 to 5 times a week had a 64% lower risk

(0.36; 95% CI, 0.24 to 0.54), of dying from the disease.  Those taking aspirin 6 to 7 days a week had a 71% lower risk compared to those not taking aspirin (0.29; 95% CI, 0.16 to 0.52).

 

Holmes’ group also reported that taking regular aspirin also reduced the chances of a distant metastasis.  Taking aspirin 2 to five times a week reduced risk of metastasis by 60% (0.40; 95% CI, 0.24 -0.65) and taking aspirin 6 to 7 times a week, reduced risk by a bit less, a 43% reduction in risk of distant recurrence (0.57; 95% CI, 0.39 - 0.82).

 

These results would suggest that the benefits of taking aspirin are in the same range of effectiveness as other medical therapies used to treat breast cancer, including standard forms of chemotherapy and radiation.

 

That aspirin use might increase survival among women with breast cancer is not a surprise. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) inhibit production of prostaglandins and cyclooxygenase and it has been postulated for years that they would have anticancer effect.  Numerous studies, in vitro, ex vivo and analysis of epidemiologic data from large population cohorts, have sought an association between aspirin intake and breast cancer risk and progression.

 

In vitro studies tell us that aspirin can inhibit breast cancer cell growth and decrease the tumor cells’ invasiveness, reduce cytokines involved in metastasis and stimulate immune responsiveness. Of particular interest from a clinical practitioner’s viewpoint, is that aspirin reverses the immune suppression caused by radiation therapy used to treat breast cancer.  Lowering cyclooxygenase activity appears to be beneficial in breast cancer.  Mice bred so that they don’t make cyclooxygenase or who were fed NSAIDs, which blocked cyclooxygenase, have less tumor growth. COX-2 overexpression has been associated with breast cancer metastasis in animals and humans.  

 

 

 

The results of this study by Holmes et al certainly stand out and beg consideration.  Should we now encourage breast cancer patients to take daily aspirin? 

 

With this introduction it is time to backup and start this story from the beginning.

 

 

Aspirin History:

 

The use of medicinal preparations made from the bark and leaves of willow and poplar trees have been used to remedy pain, fever and inflammation far back in history.  Stone tablets dating to the Sumerian period, inform us that Assyrian physicians, used willow leaves to treat rheumatic disease.  The Ebers papyrus, dated to about 1500 BC, tell us that ancient Egyptians knew of the fever reducing property of willow leaves and used them to treat various inflammatory disorders.  These same uses are mentioned in the writings of Hippocrates, Dioscorides, Celsus, Pliny the Elder and Galen. Other sources suggest that the ancient Chinese, early Native Americans and Southern African Hottentots also employed these plants for similar purpose.

 

An English clergyman named Edward Stone is usually given credit for conducting the first "clinical trial" of these ‘drugs’ in 1763.  Reverend Stone, while walking through the meadows near his rectory in Chipping Norton, on tasting a piece of willow bark, was struck by its extreme bitter taste.  Likening the taste to that of Cinchona bark, he wondered if it would produce similar therapeutic actions.  His was the time when the “Doctrine of Signatures” was given serious consideration in the practice of medicine.   He wrote,

 

"As this tree delights in a moist or wet soil, where agues chiefly abound, the general maxim that many natural maladies carry their cures along with them or that their remedies lie not far from their causes was so very apposite to this particular case that I could not help applying it; and that this might be the intention of Providence here, I must own, had some little weight with me."

 

Acting on this simple logic, he set up an experiment; he gathered and dried a pound of willow bark then ground it to a powder which he gave to about fifty of his parishioners. Stone reported that feedback from his test subjects suggested willow was a, ‘powerful astringent and very efficacious in curing agues and intermitting disorders.’ Stone reported these findings in a letter sent Lord Macclesfield, President of the Royal Society on April 25, 1763.  

 

Salicin was first isolated from willow in pure form in 1829 by the French pharmacist Henri Leroux who demonstrated its antipyretic property.

 

Some give credit to Thomas MacLagan, a Scottish physician, as having conducted the first clinical trials on salicin in 1874.  That is if we call his personally consuming about 2 grams of the compound without ill effect, a ‘phase 1 trial.’  Reassured as to salicin’s safety by his own survival, MacLagan moved on to a phase 2 trial by giving salicin to a patient with rheumatic fever. The patient's fever, pain, and inflammation subsided, confirming the antipyretic effect of salicylates, as well as their analgesic and anti-inflammatory effects.   MacLagan may have been late in his reporting.  Nearly forty years earlier, Raffaele Piria, an Italian chemist, had hydrolyzed salicin to salicylic alcohol and with a bit more chemical manipulation produced salicylic acid in 1838.

 

In 1874 two Germans, Kolbe and Lautemann, figured out a simpler way to make salicylic acid, which cost only about 10% what extracting it from willow bark did.  This made salicylic acid commercially available and it became popular for treating inflammatory conditions, including rheumatic fever, rheumatoid arthritis, and gout.  Their salicylic acid came with some unwanted side effects, including gastric irritation and an unpleasant taste.  Many patients found the drug intolerable, including the father of a young chemist named Felix Hoffman who at the time worked at Friedrich Bayer and Company.

 

His father’s arthritis inspired Hoffman to produce a more tolerable version of salicylic acid.   He succeeded in August 1897 producing acetylsalicylic acid.

 

Heinrich Dreser, Hoffmann’s boss at Bayer, is given credit both for recognizing the commercial potential of Hoffman’s discovery and also for naming the compound. Dresser named the compound Aspirin, registering the name on February 1, 1899.

 

The name Aspirin is thus the trade name of Bayer Aspirin and we should probably always write it with a capital A, the same way we would choose a capital X in describing a specific brand of photocopier.  Yet we will follow common format and use the small a in aspirin when referring to acetylsalicylic acid unless referring to Bayer’s brand name product.

 

Various theories exist to explain Dresser’s choice of name, the more common that he derived the name from Spirea, the Latin genus for meadowsweets, the source of salicylaldehyde.  A more pleasing explanation though is that he named the drug after St. Aspirinius, the patron saint of headaches.

 

We should note that it wasn’t until 1971 that John Vane explained that these drugs worked by inhibiting prostaglandin synthesis. Until than no mechanism of action was known.

 

 

 

Aspirin and breast cancer

 

A number of studies have sought to detect an association between aspirin use and risk of developing breast cancer over the last dozen or so years.  Two of these studies have demonstrated strong benefit.

 

In 1999 Harris et al from Ohio State University reported a significant decrease in breast cancer risk in women who took aspirin regularly. This was a prospective cohort study of NSAID use and breast cancer among 32,505 women lasting five years. A total of 393 cases were detected. “Breast cancer rates decreased by about 50% with regular ibuprofen intake (p<0.01), and by about 40% with regular aspirin intake (p<0.05).”

 

In 2008, Ready et al, in a joint study between researchers at Bastyr University (The Naturopathic College in Seattle) and Fred Hutchinson Cancer Research Center, also found a strong protective effect. In their data, taking low-dose aspirin 4 or more days/week over ten years decreased risk of breast cancer by about 35% (HR = 0.65; CI 0.43-0.97).

 

In what is currently the most recent study on the subject, Bardia et al reported, in February 2011, the results of comparing data from a cohort of 26,580 women, 1,581 of who were diagnosed with breast cancer. Women who regularly took aspirin had a 20% lower risk of breast cancer (RR = 0.80; 95% CI: 0.71-0.90).

 

The risk decreased with increasing frequency of use, dropping by 29% in women taking aspirin 6 or more times/week compared to those who never took aspirin. (RR = 0.71 P trend = 0.00001). Interestingly in this study, use of other NSAIDs was not associated with breast cancer incidence overall (RR = 0.95; 95% CI: 0.85-1.07).

 

Not all of the research suggests this kind of benefit.  Four other large studies found less or no protective effect. 

 

In 1996, Egan et al, also from Harvard, in a prospective study on aspirin use in the Nurses Health Study, found no protective effect against breast cancer in those taking aspirin.  They had followed a group of 89,528 female nurses.  Starting in 1980 using mailed questionnaires they obtained information on breast cancer risk factors and aspirin use. Follow-up questionnaires were mailed every 2 years until 1992. Cases of breast cancer were identified through questionnaire responses, and medical records were obtained to confirm the diagnoses. Egan’s group was able to analyze aspirin use in 2,414 cases of invasive breast cancer of which 2,303 cases were confirmed through medical records.  Regular aspirin use was not associated with breast cancer risk.

 

 

Jacobs et al in 2007 reported that regular aspirin use lowered risk of some cancers in men including, colorectal and prostate, but the decrease in breast cancer risk seen in their data did not reach statistical significance. 

 

Also in 2007, Gill et al from Hawaii found no protective effect of aspirin but did find a protective effect by long-term regular use of other NSAIDs.  Interestingly this protective effect varied by ethnic groups.

 

Gierach reported in 2008 a modest, but statistically significant, 16% reduction in risk for ER positive breast cancer in women taking regular aspirin (RR = 0.84; 95% CI = 0.71 to 0.98).

 

On the other hand, Friis et al, analyzing Danish cohort data, reported in 2008 that regular aspirin use actually increased risk of breast cancer by 38% (RR = 1.38; 95% CI, 1.12-1.69).

 

Probably what should be considered to be the most definitive study to date was the 10-year long Women's Health Study by Cook et al published in 2005. This was a randomized placebo controlled trial conducted by researchers from Harvard University.   From 1992 to 2004, a cohort of 39,876 women aged over 45 years old were randomly assigned to take either 100 mg of aspirin every other day or placebo and then followed for an average of 10.1 years.  No protective effect was seen against breast cancer (RR = 0.98; 95% CI: 0.87-1.09; P = .68). 

 

Meta-analysis

Although these individual studies do not provide strong support for aspirin use to prevent breast cancer, meta-analysis of these trials did find a 9 to 30% reduction in breast cancer incidence.

 

Bosetti et al reported in 2006 a 9% reduction in breast cancer for regular aspirin takers.   Mangiapane et al, after combining data from 10 studies reported in 2006 that regular aspirin use reduced risk of breast cancer by 25% (RR = 0.75; 95%CI: 0.64 - 0.88).

 

Zhao et al reported in 2009 of finding only a slight decrease in risk from NSAID use but a 9% decrease in women who used aspirin regularly (RR = 0.91; 95% CI: 0.83-0.98).

 

Takkouche et al combined data from 38 studies to include   2,788,715 women and reported that regular aspirin use reduced risk of breast cancer by 13% (RR = 0.87; 95% CI = 0.82 - 0.92).

 

 

The difficulty in demonstrating significant and substantial benefits in these earlier studies should be kept in mind as the results of this paper by Holmes et al are considered. 

 

The studies mentioned so far attempt to discern whether aspirin use prevents against breast cancer.  Holmes et al have a different focus, whether aspirin changes the course of the disease once a woman has breast cancer, changing risk of metastasis or recurrence and changing risk of death from the disease. It may be that protecting against breast cancer and changing the course of the disease are very different actions. 

 

One other study has asked a similar question as Holmes et al, whether aspirin use will change the course of breast cancer and the data yielded different answers.

 

Kwan et al from Kaiser Permanante examined the association between NSAID use and breast cancer recurrence in a prospective cohort of 2,292 early-stage breast cancer survivors diagnosed from 1997 to 2000 participating in the Life After Cancer Epidemiology (LACE) Study.  They reported in 2007 an insignificant increase in risk of recurrence in those women taking aspirin. While ibuprofen decreased risk by 44% (RR, 0.56; 95% CI, 0.32-0.98), aspirin increased it by 9% (RR, 1.09; 95% CI, 0.74-1.61).  Statistical insignificant increase may mean no increase at all, but these results from Kwan are clearly not the protective effect seen in Holmes et al.

 

 

Discussion [and Ruminations]

One can, by selectively quoting references, argue strongly for regular use of aspirin to both prevent and treat breast cancer.  One can also selectively quote references to argue against aspirin use.

 

Risks:

This is without factoring in risks of regular aspirin use, which may despite our common opinion be relatively low.  Use of high dose aspirin (>500 mg/day) is associated with significant problems but cases of toxicity from low doses (<500 mg/day) are less well documented.   Sibilia et al in a review published in 2003 concluded that low dose aspirin are relatively safe. Analysis of data from 8 randomized studies suggests that low dose aspirin do not increase gastric or duodenal ulcers. GI bleeds are the most significant complication and occur in only 3% of cases.   Combining data from 16 low-dose aspirin studies did find a significant increase in bleeding ulcers (Odds Ratio = 1.77, P = 0.04). Nevertheless, these complications still only occurred in rare cases (less than 3% of patients) and most often were minor.  

 

 

Inconsistencies:

 

Before reaching that conclusion though the inconsistencies between some of these studies require some explanation.

 

Cook et al’s 2005 analysis of data from the Women’s Health Study stands as the strongest argument that regular aspirin use does not prevent cancer.  But they may have simply used too low a dose of aspirin in their study to be effective.  Recall that women in the cook study took 100 mg every other day, averaging 50 mg/day.  While in Din et al, 2010 report, 75 mg/day of aspirin did appear to lower risk of colorectal cancer by 22% (OR 0.78 95% CI 0.65 to 0.92, p=0.004), most studies have looked at the effect of higher doses.   The Din study seems to be an exception.  In most studies that report strong anti-cancer effect from aspirin, they have looked at full strength daily adult doses of 325mg.  For example Jacobs et al in their 2007 paper were talking about the effect of full dose aspirin. In their analysis, long-term daily aspirin use was associated with 32% lower risk of colorectal cancer (RR = 0.68, 95% CI = 0.52 to 0.90) and 19% lower risk of prostate cancer (RR = 0.81, 95% CI = 0.70 to 0.94).

 

 

Kwan et al also looked for aspirin benefit for women after breast cancer diagnosis as did Homes but found none.  There are some fundamental differences in the studies. The Kwan study had fewer participants than (2,292 vs. 4,164) and shorter follow-up time than (6 vs. 26 years).  In effect the Kwan analyzed only 13,752 person years against Homes’ who had data from108,212 person years.  Holmes and her colleagues had far greater power to detect an effect if there was one present.  Thus at this point in time, given the many uncertainties of discerning truth in the murky world of science, the results from Holmes et al, should be considered a real possibility.

 

Discussion: [What can we do with this information with our patients?]

Knowing if aspirin provides protection against breast cancer and convincing our breast cancer patients to take daily aspirin are two very different problems.  Assuming Holmes is correct will not necessarily convince our patients to take aspirin.  In truth the typical patient who comes to see a naturopathic physician will not appreciate this data.    How can we apply this information?  Here are some thoughts:

 

First, there are the patients who have been taking aspirin daily but who, after breast cancer diagnosis, have decided to discontinue the practice in order, “to be healthier”.  We should encourage them to continue use.

 

The challenge will be those patients who simply view aspirin as one more pharmaceutical drug and who for reasons of belief, have no interest in utilizing such products.  These patients may be partially swayed toward aspirin use if they were more familiar with the botanical origins of the product. 

 

These typical naturopathic patients might be even more inclined to take daily doses of willow bark concentrates rather than aspirin.  Point of fact, willow does appear to contain chemicals in adition to salicin that have anticancer effects. Willow extracts do have anticancer action.  El-Shemy  et al have demonstrated that willow leaf extract acts against Ehrlich Ascites Carcinoma Cells (EACC), acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) and concluded that, “… metabolites within the willow extract may act as tumor inhibitors that promote apoptosis.”   The salicin content of willow bark does not fully explain willow’s anti-cancer effect.  Thus while aspirin may work, willow bark extracts might work better.  Some patients unwilling to take aspirin might consider daily doses of willow.  There might be a specific market for aspirin enriched willow products designed for anti-cancer benefit.

 

Other COX-2 inhibitors:

Current theory suggests that aspirin act against cancer due to it blocks cyclooxygenase.  The naturopathic pharmacopeia certainly contains options that have similar action.  Curcumin, a popular plant extract in naturopathic oncology, has one of the strongest impacts on this same enzyme pathway when compared to other plant extracts.   It could be argued that curcumin might have a similar benefit to daily aspirin in cancer prevention or treatment.  Curcumin acts synergistically with other COX-2 inhibitors such as celecoxib .   This has led to a growing belief that using a combination of agents, natural and pharmaceutical, to target these inflammatory pathways may have greater benefit than individual agents alone.  

 

Such an approach could fit with together with naturopathic philosophy and be more congruent with our patient’s beliefs.  Thus the data from Holmes et al can be viewed as supporting a general anti-inflammatory approach to breast cancer treatment that might include daily aspirin along with other components that act synergistically on  COX-2 as part of an overall treatment strategy.

 

Quercetin, another plant compound often used in naturopathic oncology also acts against the same COX-2 pathway that aspirin does and so the same logic that supports aspirin use after breast cancer diagnosis could be applied to both quercetin and foods containing high amounts of quercetin.

 

While it is true that as naturopathic physicians, we have many agents at our disposal that may have synergistic effects with aspirin, these thoughts are something of a distraction. 

 

The bottom line is that, we cannot ignore Holmes’ findings.  We should, as Langley et al suggest in a August 2011 evaluation, admit that, “…recent epidemiological evidence demonstrating regular aspirin use after a diagnosis of cancer improves outcomes [and] suggests that it may have a role in the adjuvant setting ….”

 

Conclusions:

At this point, as it seems that the results of Holmes et al are true, we should be obligated to encourage regular aspirin use for most women with a history of breast cancer. The benefits certainly appear to outweigh the risks.

 

Over-expression of COX-2 occurs in about 40% of invasive breast cancer cases and is more common in large tumors, positive lymph nodes, ductal histology, high histological grade and hormone receptor negative tumors.   Thus it makes even more sense to suggest aspirin in women whose cancers fit these criteria. This writer will be carefully and cautiously encouraging regular aspirin use in women with a history of breast cancer who do not have other conditions that argue against usage.

 

 

Our eminent and wise colleague Tina Kaczor has already written an interesting and illuminating commentary on the protective effect of aspirin against colon cancer in the January 1, 2011 issue of this journal. http://www.naturalmedicinejournal.com/article_content.asp?article=26

 

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