The Hygiene Hypothesis and breast cancer: A novel application of an etiologic
theory for allergies, asthma, and other immune disorders
Background: Efforts to understand breast cancer etiology more completely should focus on novel exposures that are consistent with breast cancer incidence patterns; that is, such factors should have increased in prevalence over prior decades, correspond with international, socioeconomic, and racial/ethnic incidence patterns and be compatible with established hormonal pathways to breast cancer causation. A group of factors meeting these criteria are microbial exposures studied as part of the "hygiene hypothesis" for allergic and autoimmune disease development. This idea holds that reduced, delayed, or otherwise inadequate exposures to microbes and other important immune challenges hamper the development of a healthy immune system which, in some persons, leads to the development of immune disorders.
Hypothesis: We hypothesize that reduced or delayed exposures to microbes or their byproducts, especially in early life, are associated with increased risk of breast cancer development. Factors indicative of reduced or delayed exposure to microbes include direct measures--no history or late age at infection with common viral, bacterial and parasitic infections--and indirect measures--no history of exposures consistently associated with allergic disease and factors otherwise thought to influence exposure to microbes, including exposure to furry pets, residence on farm or near animal pens, attendance at day care/nursery school, and other exposures to children. As examples, we hypothesize that a late age when first infected with chicken pox and childhood residence not near animal pens are associated with increased risk of breast cancer. Although the hygiene hypothesis has been considered in depth as regards the etiologies of allergic and autoimmune diseases and some cancers, no epidemiologic studies have addressed this concept as it might relate to breast cancer etiology. It appears to have been overlooked despite its epidemiologic consistencies, particularly its appropriateness to a disease with rising incidence and a positive socioeconomic gradient, and its biologic plausibility, given that reduced or delayed infections promote immune responses that act to chronically upregulate levels of steroid circulating hormone levels or that do not adequately monitor or clear nascent breast tumor cells.
Specific aims: The specific aim of this study is to evaluate whether risk of breast cancer in postmenopausal women is associated with direct and indirect measures of microbial exposures independently of reproductive characteristics and other established breast cancer risk factors. To the extent possible, we will also assess whether associations are influenced by select demographic or tumor characteristics, (e.g., race/ethnicity or tumor histology).
Methods: We propose to conduct a multiethnic case-control study including telephone interviews with 525 women aged 50-79 who have been recently diagnosed with incident invasive breast cancer (cases) and 525 community women without breast cancer (controls), matched on age and race, living in two diverse California counties (San Mateo and Monterey). Cases will be ascertained through the Greater Bay Area Cancer Registry and controls will be recruited through well-developed ethnic-specific random-digit dialing procedures. Our multidisciplinary team will develop and extensively pilot-test a structured questionnaire inquiring about established breast cancer risk factors and both direct and indirect measures of microbial exposures. Telephone interviews will be conducted in English and Spanish. We will assess associations between the exposures of interest and breast cancer risk by comparing distributions between cases and controls and quantifying the extent of association using odds ratios and 95% confidence intervals. Multiple logistic regression will be used to evaluate effects, adjusting for matching variables and possible confounders, particularly reproductive factors. We will explore subgroup differences by stratifying analyses. The impact of potential biases, including misclassification and selection bias, will be considered in the interpretation of results.
Relevance: Our incomplete understanding of breast cancer causes and the fact that there are no current means of primary prevention compel research into innovative etiologic hypotheses. Our hypothesis, grounded in epidemiologic consistency and biologic plausibility, thus represents an avenue for etiologic investigation that is novel, justifiable and testable. If associations were established for microbial exposures and breast cancer and then found to be causal, they could ultimately lead to feasible primary prevention efforts aimed at strengthening the immune response, perhaps through vaccination with harmless surrogates of important microbial factors. In addition, a finding that hygiene hypothesis-relevant exposures partly explain urban/rural, socioeconomic and racial/ethnic variation in breast cancer incidence could thereby provide novel means for understanding and addressing these kinds of disparities.
NCCC Principal Investigator: Christina Clarke, Ph.D.
Funding Source: Department of Defense (USA Medical Research Acquisition Activity) |
