Abstract
Research now suggests that regular aspirin use protects against breast cancer, possibly lowering risk of development and, more significantly, preventing disease recurrence. Study data from Holmes et al have shown a clinically significant protective effect against breast cancer recurrence to the degree that recommendations to take aspirin may become more common despite some inconsistencies in past research. Potential risks vs. possible benefits should now be considered in women at high risk for primary breast cancer, and especially in those women at risk of recurrence.
Introduction
In recent years medical authorities have suggested daily use of low-dose aspirin for the purpose of lowering risk of myocardial infarction (MI) and stroke. Current guidelines from the U.S. Preventive Services Task Force (USPSTF) recommend the use of aspirin to reduce the risk of MI in men ages 45–79. Aspirin use is recommended for women ages 55–79 when the potential benefit of a reduction in ischemic strokes outweighs the potential harm of an increase in gastrointestinal hemorrhage risk. The USPSTF recommends against the use of aspirin for stroke prevention in women younger than 55 years.1
The American College of Chest Physicians suggests daily aspirin doses for most patients with coronary artery disease. The contraindication against use is the rare allergy to aspirin.2 In 2010 US consumers purchased more than 44 million packages of low-dose aspirin for heart protection.3 As a result, data on the effects of these daily doses of aspirin on large cohorts of the population over extended time periods have allowed analysis seeking association with and impact on other diseases—in particular cancer.
This article focuses on the information as it relates to breast cancer. (Click here to read NMJ’s coverage of aspirin and colon cancer.)
History of Aspirin
Aspirin-like substances have a long history of medicinal use. Ancient Assyrian and Egyptian physicians used preparations made from the bark and leaves of willow and poplar trees to remedy pain, fever, and inflammation.4,5 Over the last few hundred years, the chemicals in these early preparations have gone through a gradual process of extraction, refinement, and modification. Reverend Edward Stone conducted what is described as the first “clinical trial,” giving ground willow bark to 50 of his parishioners in 1763.6,7 Thomas MacLagan, a Scottish physician, conducted a phase I trial on himself, taking a 2 gram dose of willow salicin in 1874. In 1874, 2 Germans, Kolbe and Lautemann, devised an inexpensive method that opened the door for commercial production of salicylic acid, which became a popular treatment for inflammatory conditions like rheumatic fever, rheumatoid arthritis, and gout. Unfortunately, patients frequently found the drug intolerable due to unwanted side effects including gastric irritation and an unpleasant taste. Among the patients who couldn’t tolerate salicylic acid was the father of chemist Felix Hoffman, who worked for Friedrich Bayer and Company. This inspired Hoffman to find a more tolerable version of the drug, and in August 1897 he produced acetylsalicylic acid. Hoffmann’s boss at Bayer, Heinrich Dreser, is given credit for naming the compound, registering the name Aspirin on February 1, 1899.8
Despite the long history of use, it wasn’t until 1971 that John Vane explained a mechanism of action of aspirin: It inhibits prostaglandin synthesis, and in particular it blocks the enzyme cyclooxygenase.9 It is aspirin’s ability to block cyclooxygenase that led researchers to look for an anticancer effect.
Holmes et al
In March 2010 the Journal of Clinical Oncology published a study by Michelle Holmes et al. The results suggest that taking daily aspirin may significantly reduce the risk of breast cancer recurrence and death.
The prospective observational study utilized data from 4,164 women who took part in the Nurses' Health Study and who were diagnosed with breast cancer between 1976 and 2002. The researchers tracked these women either until death or June 2006, whichever came first, and then compared risk of death from breast cancer with the number of days during the week that these women reported taking aspirin.
Among the women being tracked, 341 breast cancer deaths occurred. The women who reported taking aspirin 2 to 5 times a week had a 64% lower risk of dying (0.36; 95% CI: 0.24–0.54). The women who reported taking aspirin 6 to 7 days a week had a 71% lower risk of dying compared to those not taking aspirin (0.29; 95% CI: 0.16–0.52).
Holmes reported that taking regular aspirin reduced the chances of distant metastasis. Taking aspirin 2 to 5 times a week reduced risk of metastasis by 60% (0.40; 95% CI: 0.24–0.65). Taking aspirin 6 to 7 times a week reduced risk by 43% (0.57; 95% CI: 0.39–0.82).10
These findings were notable because the Nurses' Health Study did not find an association between aspirin use and breast cancer incidence. However, the authors note that prevention of recurrence may be different.
This study had several limitations. It was an observational study, rather than a controlled clinical trial. The study was limited by use of self-reporting for aspirin intake, treatment, and distant recurrence. In addition, the study did not include any information on aspirin dose, although most regular use was likely for heart disease prevention at the 81 mg/day level, the authors suggested.
Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) inhibit production of prostaglandins and the activity of cyclooxygenase enzymes. It has been postulated that they would have anticancer effect for those reasons. Numerous studies, including in vitro, ex vivo, and analysis of epidemiologic data from large population cohorts, have sought an association.
In vitro studies reveal that aspirin can inhibit breast cancer cell growth and decrease the tumor cells’ invasiveness, reduce cytokines involved in metastasis, and stimulate immune responsiveness.11,12 Of interest to a clinical practitioner, Blomgren et al reported that aspirin reverses the immune suppression caused by radiation therapy used to treat breast cancer.13 Lowering cyclooxygenase activity appears to be beneficial in breast cancer. Both knockout mice, bred so that they don’t produce cyclooxygenase, and standard mice treated with NSAIDs to block cyclooxygenase have less tumor growth.14 COX-2 over-expression is associated with breast cancer metastasis in animals and humans.15
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 prospective cohort study of NSAID use and breast cancer among 32,505 women lasted 5 years and detected a total of 393 cases. “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).”16
In 2008, Ready et al, in a joint study between researchers at Bastyr University 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 10 years decreased risk of breast cancer by about 35% (HR=0.65; CI: 0.43–0.97).17
In a February 2011 study, Bardia et al reported the results of analyzing data from a cohort of 26,580 women, 1,581 of whom 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). Their 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).18
Not all of the research has reported benefit. Four studies have found less or no protective effect.
In 1996, Harvard researchers Egan et al conducted a prospective study on aspirin use in the Nurses Health Study cohort and found no protective effect against breast cancer for those taking aspirin. Egan et al had followed a group of 89,528 female nurses. Starting in 1980 and using mailed questionnaires, they collected 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.19 Like the Holmes et al paper, this one utilized a cohort from the Nurses Health Study; however it should be noted that this paper looked at aspirin for primary prevention, whereas Holmes et al looked at aspirin for prevention of recurrence and death.
Jacobs et al reported in 2007 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.20
Also in 2007, Gill et al from Hawaii found no protective effect from aspirin, though they did find a protective effect from long-term, regular use of other NSAIDs. Interestingly this protective effect varied by ethnic groups.21
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: 0.71–0.98).22
Some reports actually suggest increased risk for people taking aspirin. 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).23
Probably the most definitive study to date is the 10-year 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 ages 45 years and older 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=0.68).24
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%–30% reduction in breast cancer incidence.
Bosetti et al reported in 2006 a 9% reduction in breast cancer for regular aspirin takers.25 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).26
In 2009, Zhao et al reported finding only a slight decrease in breast cancer risk associated with NSAID use but a 9% decrease in women who used aspirin regularly (RR=0.91; 95% CI: 0.83–0.98).27
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).28
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 breast cancer. Holmes et al had a different focus. Instead they questioned 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 asked a similar question to Holmes et al, and the data yielded a different answer. Kwan et al from Kaiser Permanente 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 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).29 This statistically insignificant increase may mean no increase at all, but these results from Kwan are clearly not the protective effect seen by Holmes et al.30
Aspirin Risks
Do the potential risks of taking daily aspirin outweigh the possible benefits? Despite commonly expressed concerns about the safety of aspirin, the actual risks appear to be relatively low. Although use of high-dose aspirin (>500 mg/day) is associated with significant problems, documented cases of toxicity from low doses (<500 mg/day) are far less common. Sibilia et al in a review published in 2003 concluded that low-dose aspirin is relatively safe. Analysis of data from 8 randomized studies suggests that low-dose aspirin does 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 an increase in bleeding ulcers (OR=1.77; P=0.04). Nevertheless, these complications still only occurred in rare cases (less than 3% of patients) and most often were minor.31
Inconsistencies
The inconsistencies between some of these studies require further consideration.
Cook et al’s 2005 analysis of data from the Women’s Health Study provides the strongest argument that regular aspirin use does not prevent cancer. But the participants in this trial may have taken too low a dose of aspirin to be effective. Recall that women in this study took 100 mg every other day, averaging 50 mg/day.32 Other studies have suggested higher doses are required. In their 2010 report, Din et al did find that 75 mg/day of aspirin was associated with a lower risk of colorectal cancer (OR=0.78; 95% CI: 0.65–0.92; P=0.004).33 The Din study seems to be an exception. Most studies that report strong anti-cancer effect from aspirin have looked at full-strength daily adult doses of 325 mg. For example, in their 2007 paper Jacobs et al considered 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: 0.52–0.90) and 19% lower risk of prostate cancer (RR=0.81; 95% CI: 0.70–0.94).34
It is important for practitioners to be aware of the most recent research on aspirin and breast cancer, as they undoubtedly will be fielding questions from patients on this issue.
Kwan et al and Holmes also looked for aspirin benefit for women after breast cancer diagnosis but found none. There were some fundamental differences in the studies. The Kwan study had fewer participants (2,292 vs. 4,164) and shorter follow-up time than (6 vs. 26 years). In effect the Kwan study analyzed only 13,752 person years of data compared to Holmes’ 108,212 years. This gave Holmes far greater statistical power to detect an effect if one was 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 strongly.
Discussion
Knowing if aspirin provides protection against breast cancer and convincing our breast cancer patients to take daily aspirin are 2 very different considerations. Assuming the findings of Holmes’ study are correct will not necessarily convince our patients to take aspirin. The typical patient who comes to see a naturopathic physician may not readily accept this data. How can we apply this information?
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.” If appropriate, we should encourage them to continue aspirin use, as long as they are not undergoing chemotherapy and do not have other contraindications.
The challenge will be those patients who view aspirin as one more pharmaceutical drug and who for philosophical reasons have no interest in utilizing chemicals. These patients may be partially swayed toward aspirin use if they were more familiar with the botanical origins of the product.
Such patients might be more inclined to take daily doses of willow concentrates rather than aspirin. Salicin content of willow bark does not fully explain willow’s anticancer effect, and the effects of willow on breast cancer or breast cancer recurrence in humans has yet to be studied.35 Willow does contain chemicals in addition to salicin that have independent anticancer effects. 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), concluding that “metabolites within the willow extract may act as tumor inhibitors that promote apoptosis.”36,37
Other COX Inhibitors
Current theory suggests that aspirin acts against cancer because it blocks the cyclooxygenase enzymes, both COX-1 and COX-2. Our naturopathic pharmacopeia contains botanical options that have similar action, though they typically affect only COX-2 action and not COX-1. Curcumin, a popular plant extract in naturopathic oncology, has perhaps the strongest impact on these enzyme pathways when compared to other plant extracts.38 Curcumin acts synergistically with other COX-2 inhibitors, such as celecoxib.39 This has led to a growing belief that using a combination of agents, both natural and pharmaceutical, to target these inflammatory pathways may have greater benefit than using individual agents alone.40 At this point, there is no published long-term evidence establishing this action in humans, nor is there clinical trial data supporting the role of curcumin in cancer prevention or recurrence in humans.
Still such an approach could fit together with naturopathic philosophy and be more congruent with our patients’ beliefs. If the data from Holmes et al is viewed as supporting a general anti-inflammatory approach to breast cancer treatment, an overall treatment strategy might include daily aspirin along with other components that act synergistically on the cyclooxygenase enzymes.
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 it.41
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.”42
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, and tumors that are high histological grade or hormone receptor–negative. Thus it makes even more sense to attempt to affect COX activity in women whose cancers fit these criteria.43
Conclusion
While the findings by Holmes et al are promising for the role of aspirin therapy in the prevention of breast cancer recurrence and death, this research needs to be confirmed by further clinical trials. It is important for practitioners to be aware of the most recent research on aspirin and breast cancer, as they undoubtedly will be fielding questions from patients on this issue. I will be carefully and cautiously encouraging regular low-dose aspirin (81 mg/day) use in women with a history of breast cancer who have no other conditions that argue against usage.
For more research involving integrative oncology, click here.
