Aspirin for Treating Breast Cancer

by Jacob Schor, ND, FABNO

There are obviously differences between natural medicines and pharmaceutical drugs. Patients differentiate us from “regular” doctors by our preference for the former and avoidance of the later when we suggest therapies. Patients often want “natural medicines” as an expression of their faith in nature’s ability to heal, rather than for the more pragmatic reasons such as being safer, cheaper or more effective.

While a boundary line exists between these two groupings, natural versus drug, that line is less clearly defined in my mind than in some of my patients’ minds. Once it was easy to tell them apart; the things purchased in a health-food store are natural medicines and things purchased in a drug store are pharmaceuticals. As most, if not all, “drugstores” now sell natural supplements and as more supplements are the end result of pharmaceutical-grade refinement and distillation, this definition no longer works.

These questions were pushed to the forefront of my ruminations when yet another study was published on the potential impact aspirin has on risk of cancer recurrence. In the last few years there have been at least four major papers on aspirin, each of which should have been a game-changer; each strongly suggests that it would be prudent for more of our patients to take aspirin regularly. Is aspirin a natural medicine or is it a drug? Even if it is a drug, are we doing our patients a disservice by not encouraging more of them to use it?

While the possibility that aspirin might reduce deaths from cancer was first noticed back in the 1970s, let’s mention just a few of the recent papers, in particular those by Rothwell, Holmes, Choe, and Liao.¹

Let’s start in late 2010 with Peter Rothwell et al. and their meta-analysis published in Lancet. These Oxford University researchers combined data from eight separate prospective clinical trials in which aspirin had been used as an intervention hoping for protection against cardiovascular disease (CVD). While these trials were not originally set up to look at cancer, information on cause of death was obtained through national death certification and cancer registries. The combined data revealed that those study participants given aspirin had significantly fewer deaths, about 21% lower, due to cancer (in 25,570 patients; OR 0.79, CI 0.68–0.92, P = 0.003). This benefit only became apparent after 5 years. The effect was more pronounced for gastrointestinal cancer risk, which fell by 54% (all cancers HR 0.66, CI 0.5–0.87; GI cancers HR = 0.46, CI 0.27–0.77; P = 0.003).²

Rothwell’s group had a larger follow up study published in Lancet in April 2012.³ This time, data from 34 trials with a total of 69,224 participants was combined. Aspirin use reduced cancer deaths by 15% (562 vs. 664 deaths; odds ratio [OR] 0·85, 95% CI 0·76-0·96, p = 0·008). The longer participants took aspirin, the greater the benefit. Taking aspirin for three or more years reduced cancer risk by 25% in women (132 vs. 176; OR 0·75, 95% CI 0·59-0·94, p = 0·01) and 23% in men (OR 0·77, 95% CI 0·63-0·93, p = 0·008). Those taking aspirin five years or more reduced cancer death risk by 37% (92 vs. 145; OR 0·63, 95% CI 0·49–0·82, p = 0·0005).⁴

In March 2010 the Journal of Clinical Oncology published a study by Michelle Holmes et al. that reported regular aspirin use was associated with significantly lower risk of breast cancer recurrence and death. This 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. 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 also reported that 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).⁵

In the October 2012 Journal of Clinical Oncology, Choe et al. report that aspirin use reduces risk of death from prostate cancer. Data were analyzed from 5955 men, participants in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) Study, who had been diagnosed with localized adenocarcinoma of the prostate and who had been treated with either radiation therapy or radical prostatectomy. After a median follow-up time of 70 months, 193 of the men had died of prostate cancer. Of these men, 2175 (37%) had taken anticoagulant therapy. And of these, the majority (84%) had taken aspirin and about a fifth (21%) warfarin. At 7 years only 1 % of those taking anticoagulants had died of prostate cancer compared with 3% of those not taking anticoagulants. At 10 years these number had grown to 3% and 8%. Those taking anticoagulants also had significantly lower risk of disease recurrence and bone metastasis. The impact of anticoagulant use was more pronounced in those with high-risk disease. In this subgroup, prostate cancer specific mortality (PCSM) was 4% for those taking anticoagulants compared with 19% for those not. When the data was further analyzed using a Cox proportional hazards regression model, aspirin use was independently associated with lower PCSM (HR, 0.43; 95% CI, 0.21–0.87) while the use of other non-aspirin anticoagulants was not significantly associated with PCSM. It appears that all the benefit seen from anticoagulant use was from the aspirin and not the other drugs. Thus taking aspirin will reduce the risk of dying of prostate cancer in someone already treated by 57%.⁶

The last paper that requires mention is the October 25, 2012, report from Liao et al. published in the New England Journal of Medicine. In a study of more than 900 patients with colorectal cancer, taking aspirin improved survival in patients with tumors that contained a mutation in the PIK3CA gene. Five-year survival for those taking aspirin was 97% compared to only 74% for those not taking aspirin. Regular aspirin use by patients with tumors having mutated PIK3CA genes reduced cancer related death by 82% (multivariate hazard ratio for cancer-related death, 0.18; 95% confidence interval [CI], 0.06 to 0.61; P<0.001 by the log-rank test).⁷ It is not yet clear how common these PIK3CA mutations are. A recent survey of 478 patients in Sardinia reports an incidence rate that varied from 10% to 24% by location but had a mean in all locations of 17%.⁸ This degree of benefit in this size of a subpopulation of colon cancer patients is consistent with the Rothwell data that suggests a smaller protective effect when aspirin are used in all colon cancer patients regardless of genetic typing.

These papers provide a strong argument for breast or prostate cancer patients to start taking aspirin and for colon cancer patients to either take aspirin or, since Liao et al.’s study, to ask to be tested for the PIK3CA gene. Yet, when I mention aspirin to patients, I notice their expressions change; their eyes get a glazed look, an off in the distance stare, that suggests they’ve stopped paying attention; they’ve put their foot down on some mental clutch pedal and their awareness is no longer engaged; whatever you say to them, it doesn’t matter.

Who can blame them? They came to me for “natural medicine,” not generic drugs; what they want is some not quite pleasant-tasting berry ferried from a tropical rainforest by natives paddling a boat made of bark and twigs. They are hoping for something exciting, exotic, and containing a magical potency to treat themselves with, something that fits their image of “natural medicine.” They did not come to a naturopath to be told to take aspirin.

From a pragmatic, “let’s keep our patients alive and well” point of view, this aspirin research is important and should shift what our patients do. In reality, many will not want to hear about it. Their response would be far more enthusiastic if you told them about some orange fungus you found under a rock.

The odd thing with aspirin is that, despite its image as a drug, it isn’t that far removed from being natural. Probably it’s best to describe aspirin as an analogue to a natural medicinal substance that was long and widely used. After all, nearly the same chemical is found in certain plants that have a very long history of medicinal use. The difference is that aspirin is slightly modified and this is done to decrease the unwanted side effects, in particular the gastric irritation, which high doses of salicylic acid would cause.

Perhaps aspirin is not so “unnatural” as people think it is. With only slight nudging, we could perhaps push it back across the line between natural and drug, or at least into some gray area close to the line.

There is another aspect to using aspirin that we might pause to consider.

These thoughts come from a lecture that the late Wade Boyle, ND, gave in 1990. In speaking about botanical medicine, he drew a line between naturopathic and allopathic botanical medicine. In naturopathic practice, botanical medicines are chosen to stimulate the vis medicatrix naturae, and in allopathic medicine, herbs are chosen the way drugs are, to suppress symptoms. By Boyle’s definition, aspirin would seem to be in the latter category: it suppresses pain, fever, and inflammation.

But that’s in high doses. What about low doses? Does baby aspirin act the same? We naturopathic physicians, perhaps more than most other medical professionals, are aware of the theory of hormesis: that low doses of a substance may have the opposite effect of high doses.

At least one of the more recent papers on aspirin and cancer question the standard assumption that aspirin’s anti-inflammatory action via COX-2 is what changes cancer risk. In particular Liao et al. suggest that the amount of baby aspirin being used in the CVD trials is not high enough to change COX-2 activity. In their paper, they theorize that the benefits may derive from elsewhere, perhaps from some change in platelet behavior that lowers potential for metastasis. At this point we don’t know. While aspirin was “invented” in 1897, it took 74 years until a plausible mechanism of action was proposed.⁹ At this point we don’t know why aspirin lowers cancer risk.¹⁰ For all we know, aspirin could act via hormetic pathways triggering an adaptive response, a possibility that would be congruent with naturopathic principles.

Ruminations of this sort are probably best kept to ourselves and not shared with our patients. The bottom line is simple. Our obligation is to provide good advice. For patients with cancer, it looks like taking baby aspirin will improve their chances of staying both cancer free and alive. If these patients balk at the idea, believing that aspirin is a drug, you might remind them that the chemical in aspirin was originally derived from willow bark and that the current chemical sold is only slightly changed from this ancient natural medicine.

SIDEBAR

A Short History of Aspirin

The use of bark and leaves from willow and poplar trees to treat pain, fever, and inflammation can be traced all the way back to the ancient Sumerians and Egyptians and from there to the writings of Hippocrates, Dioscorides, Celsus, Pliny the Elder, and Galen. According to stone tablets dating to the Sumerian period, Assyrian physicians used willow leaves to treat inflammatory rheumatic diseases.¹¹ According to the Ebers Papyrus (about 1500 BC), the ancient Egyptians were also aware that willow leaves possessed a fever-reducing property and used them to treat various inflammatory disorders.¹² Similar uses are documented in the ancient Chinese, early Native Americans, and Southern African Hottentots.¹³

The Reverend Edward Stone is credited with conducting the first “clinical trial” of these “drugs” in 1763. Struck by the bitter taste of willow bark, and so likening it to cinchona bark because of the taste, he wondered if it would have similar medicinal actions. Following this logic, he gathered and dried a pound of willow bark, ground it to a powder, and gave it to 50 of his church parishioners. Stone reported that, willow bark was a “powerful astringent and very efficacious in curing agues and intermitting disorders.”^14,15

The leaves and the bark of the willow contain salicylic acid. Salicin was first isolated in pure form in 1829 by the French pharmacist Henri Leroux, who demonstrated its antipyretic property. Raffaele Piria, an Italian chemist, hydrolyzed salicin to salicylic alcohol and with a bit further chemical manipulation produced salicylic acid in 1838¹⁶

In 1874, Thomas MacLagan, a Scottish physician, personally consumed a 2 gram dose of salicin without apparent ill effect and so gave a dose to a patient with rheumatic fever. The patient’s fever, pain, and inflammation subsided, thus confirming the antipyretic effect of salicylates, as well as their analgesic and anti-inflammatory effects. (Clinical trials were simpler back then.)

In the same year as MacLagan’s experiments, two Germans, Kolbe and Lautemann, figured out how to synthesize salicylic acid cheaply, for 90% less than extracting it from willow bark would cost. Their product became popular for treating inflammatory conditions, including rheumatic fever, rheumatoid arthritis, and gout. Salicylic acid, though cheap, came with 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 worked at Friedrich Bayer and Co.

Hoffman was inspired by his father’s arthritis and in August 1897 produced a version of salicylic acid that was relatively tolerable. His version was acetylsalicylic acid. Heinrich Dreser, Hoffman’s boss at Bayer, is credited for both recognizing the commercial potential of this discovery and naming the compound, Aspirin, registering the name on February 1, 1899. Various theories exist to explain this name, the more logical being that Spirea is the genus name for the herb meadowsweet, the source of salicylaldehyde. A more satisfying explanation is that the drug is named after St. Aspirinius, the patron saint of headaches.¹⁷

Note: The word Aspirin is actually part of the trademarked name Bayer Aspirin and deserves to be capitalized as we should capitalize the X in Xerox Copier.

END SIDEBAR

Notes

1. Kaiser J. Will an aspirin a day keep cancer away? Science. 21 September 2012:1471–1473.

2. Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011 Jan 1;377(9759):31–41. Epub 2010 Dec 6.

3. Rothwell PM, Price JF, Fowkes FG, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet. 2012 Apr 28;379(9826):1602–1612.

4. Ibid.

5. Holmes MD, Chen WY, Li L, Hertzmark E, Spiegelman D, Hankinson SE. Aspirin intake and survival after breast cancer. J Clin Oncol. 2010 Mar 20;28(9):1467–1472.

6. Choe KS, Cowan JE, Chan JM, Carroll PR, D’Amico AV, Liauw SL. Aspirin use and the risk of prostate cancer mortality in men treated with prostatectomy or radiotherapy. J Clin Oncol. 2012 Oct 1;30(28):3540–3544.

7. Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012 Oct 25;367(17):1596–1606.

8. Palomba G, Colombino M, Contu A, et al. Prevalence of KRAS, BRAF, and PIK3CA somatic mutations in patients with colorectal carcinoma may vary in the same population: clues from Sardinia. J Transl Med. 2012 Aug 29;10:178. doi:10.1186/1479-5876-10-178.

9. Lafont O. From the willow to aspirin. [In French]. Rev Hist Pharm (Paris). 2007 Jul;55(354):209–216.

10. Kaiser J. Wondering how the wonder drug works. Science. 21 September 2012:1472.

11. Jack DB. One hundred years of aspirin. Lancet. 1997 Aug 9;350(9075):437–439.

12. Mackowiak PA. Brief history of antipyretic therapy. Clin Infect Dis. 2000 Oct;31 Suppl 5:S154–S156.

13. Vane JR, Flower RJ, Botting RM. History of aspirin and its mechanisms of action. Stroke. 1990;21(Suppl 4):IV12–23.

14. Lafont. Op cit.

15. Norn S, Permin H, Kruse PR, Kruse E. From willow bark to acetylsalicylic acid. [In Danish]. Dan Medicinhist Arbog. 2009;37:79–98.

16. MacLagan TJ. The treatment of rheumatism by salicin and salicylic acid. Lancet. 1876;1:342–343.

17. Vane JR, Flower RJ, Botting RM. History of aspirin and its mechanism of action.

Stroke. 1990 Dec;21(12 Suppl):IV12–IV23.