Breast Cancer Risk Reduction: No Pain, No Gain?
Authors: Clifford A. Hudis, Kotha Subbaramaiah, Patrick G. Morris, Andrew J. Dannenberg
Journal: Journal of Clinical Oncology (2012)

The notion that lifestyle practices or the routine use of specific supplements, foods, or medications might modify the risks of cancer and its progression is attractive to many in the general public and the scientific community. Unfortunately, there are significant challenges to investigators who seek to explore such relationships. These include the depth of our understanding of the presumed molecular targets, the efficiency of available agents at altering the activity of the target, and, especially in the prevention setting, the relatively low rate of events even in high-risk groups. When exploring an intervention’s impact, the gold standard is the prospective, randomized, placebo-controlled trial, but such studies can be expensive and slow to conduct. When the anticipated effect size is modest and possibly confounded by differences in screening and detection, and the intervention is chronic and possibly associated with toxicities, the need for this rigorous study design is perhaps greatest, even as the feasibility is compromised. In addition, some patients and their family members may be reluctant to accept random assignment, which requires that they self-administer a drug with potential toxicities over many years, when the predicted risk is low and distributed across many years. Conversely, if we could identify a high-risk subset with a targetable causative factor, perhaps random assignment would be more acceptable and the costs and duration of such a study would be reduced. The article by Zhang et al that accompanies this editorial raises these questions and is relevant to this discussion. Breast cancer is the most common life-threatening malignancy in high-income countries. Its known causes and risk factors are complex, and it is comprised of three main subtypes: hormonally dependent, human epidermal growth factor receptor 2 dependent, and triple negative. Phenotyping and genotyping reveal additional reproducible subsets, and the known causative factors associated with each of them vary. For example, although age is a dominant risk factor and the majority of diagnoses are made after menopause, hormone receptor expression is common in this age group, with most of the tumors in this older population being sensitive to hormonal therapies. The association of older age with greater likelihood of hormonally driven breast cancers can seem to be a paradox: if circulating estradiol falls after menopause, why are hormonally responsive breast cancers more common when circulating levels of this growth-stimulating hormone are diminished? The recent discovery of a common inflammatory process in the white adipose tissue of the breast may be critical for solving this puzzle and provides a new way to view the data on antiinflammatory agents and breast and other cancers. There are reasons to hypothesize that the risks of several common malignancies could be reduced using widely available anti-inflammatory agents, and previous epidemiologic studies have suggested such benefits. At the same time, when testing aspirin, nonsteroidal anti-inflammatory drugs(NSAIDs),selectivecyclooxygenase-2(COX-2)inhibitors,andothers, the practical challenges include the fact that they are prescribed and used for specific reasons, some of which could plausibly relate to the risks of malignancy, that many of the untreated control patients would during their years on a study have good reasons to use the investigational drugs episodically, and, as suggested above, that their beneficial effects may only be detectable in a specific and identifiable subset of at-risk patients. In addition to uneven risk distribution across subpopulations, it is also possible that the impact of anti-inflammatory drugs could be dependent on breast cancer subtypes. Given these challenges, it could be difficult to detect a benefit using a broad and unselected approach, even if the patients were followed prospectively over many years. In the article that accompanies this editorial, Zhang et al report on the association of the use of aspirin, other NSAIDs, and acetaminophen and postmenopausal breast cancer. Their stated goal was to examine the “associations with breast cancer, both overall and by molecular subtype” in postmenopausal women, informed by evidence that COX-derived prostaglandins induce aromatase activity and therefore estradiol production. To this end, they observed 84,602 women who were initially free of cancer in 1980 through June 2008, collecting data every other year on analgesic use and other medication and health behaviors. They identified 4,734 incident cases of invasive breast cancer and found no statistically significant difference in incidence between regular aspirin users (two or more standardized dose tablets per week for 2 decades) and nonusers, with no difference by breast cancer phenotype. Usage of other NSAIDs and acetaminophen was not significantly associated with breast cancer risk. Interestingly, the authors did find a modestly lower risk of estrogen receptor–positive/ progesterone receptor–positive breast cancer in women who used aspirin at a dose of six or more tablets per week for at least 10 years. This latter observation certainly does not exclude a potentially important impact, if the right dose and high-risk patient populations were to be combined. In the end, Zhang et al conclude that, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 28 OCTOBER 1 2012