Background:

While periodontal disease has been linked to increased cancer risk, studies regarding an association with breast cancer are limited.

Methods:

We examined the relationship between self-reported diagnosis of periodontal bone loss and incidence of breast cancer in a large, prospective cohort study, the Nurses' Health Study (1998–2014). We calculated HRs using Cox proportional hazards modeling, adjusting for risk factors common to both periodontal disease and breast cancer.

Results:

During 1,023,647 person-years of follow-up, 5,110 of breast cancer cases were reported. We observed no association between periodontal disease and overall breast cancer risk (HR, 1.02; 95% confidence interval: 0.94–1.10); the association was not modified by smoking status, or other breast cancer risk factors or by breast tumor subtypes.

Conclusions:

We did not observe any association between periodontal disease and breast cancer risk.

Impact:

Given inconsistent findings in the literature, further research with standardized clinical measures of periodontitis is warranted.

Periodontal disease (PD) is a multifactorial inflammatory disease associated with other chronic systemic diseases (1). There is evidence of associations of PD with increased risk of cancer, including oral, esophageal, head and neck, pancreatic, and lung cancers (2). While there are some indications that PD is also associated with breast cancer risk, evidence is more limited (3). In the Women's Health Initiative study of postmenopausal women, we recently showed an association of PD with breast cancer risk, particularly among smokers who had quit within the last 20 years [hazard ratio (HR): 1.36, 95% confidence interval (CI): 1.05–1.77] but not among never smokers (HR: 1.06, 95% CI: 0.91–1.24). Here we examined the association between periodontal bone loss and breast cancer incidence in the Nurses' Health Study (NHS).

The NHS is a prospective cohort, established in 1976, of 121,700 female nurses ages 30–55 years (4). Participants completed a questionnaire on lifestyle factors and medical history every 2 years. Breast cancers were self-reported or identified through death records and then confirmed by physician review of medical records. In addition to invasive breast cancer cases, in situ cases were also included in these analyses. For the analyses of incident disease, we excluded women who reported a diagnosis of cancer at or before baseline for this analysis, died before baseline, or were missing information on PD; there were 77,541 eligible participants. The study protocol was approved by the Institutional Review Boards of the Brigham and Women's Hospital (Boston, MA) and Harvard T.H. Chan School of Public Health (Boston, MA), and those of participating registries as required.

In 1998, participants reported whether they had ever been diagnosed with mild, or moderate/severe periodontal bone loss. In 2000, participants reported whether in the last 2 years they had been diagnosed with periodontal bone loss. Person-years were calculated from the baseline questionnaire return date (1998) to the date of breast cancer diagnosis, death or the end of follow-up (June 2014), whichever occurred first. Although there has not been validation of the self-report in the NHS, a similar question regarding periodontal bone loss in the Health Professionals Follow-Up Study showed a positive predictive value of 0.80 and negative predictive value was 0.68 among non-dentists in comparisons with medical records or radiography (5).

We used Cox proportional hazards models to estimate age- and multivariable-adjusted HRs and 95% CIs. Periodontal bone loss was categorized as a binary variable (no/yes) and their status was updated if they reported PD in the last two years in 2000, and then further evaluated in relation to severity reported in 1998 (no/mild/moderate and severe). We adjusted the model for race, body mass index (BMI) at age 18, weight change since age 18, age at menarche, age at first birth and parity, age at menopause and menopausal status, menopausal hormone therapy use, first-degree family history of breast cancer, history of benign breast disease, alcohol consumption (g/day), physical activity level [metabolic equivalent task (MET)-hours/week], smoking status, pack years smoking, oral contraceptive use, and current mammographic screening. Furthermore, we examined for additional adjustment for aspirin or NSAID use because aspirin/NSAIDs can reduce periodontal bone loss. We also examined whether the association differed among tumor hormone receptor status (ER+ vs. ER and ER+/PR+ vs. ER+/PR vs. ER/PR). Finally, we evaluated whether the associations varied by age (<64 years old and ≥64 years old), smoking status (never, former, current smoker), BMI (<25 kg/m2 and ≥25 kg/m2), aspirin/NSAID use (none, aspirin only, NSAID only), hormone therapy (never, ever), and number of natural teeth (0–16 teeth, 16–24 teeth, 25–32 teeth). We used a Wald test to examine whether the coefficients of the cross-product terms between these variables and each of periodontal disease measures were statistically significant.

During 14 years of follow-up (1,023,647 person-years), there were 5,110 confirmed cases of breast cancer. Participants reporting periodontal bone loss were more likely to have osteoporosis, smoke more, drink more alcohol, and have a history of benign breast disease (Table 1). We did not find a statistically significant association between reported periodontal bone loss and breast cancer (HR: 1.02, 95% CI: 0.94–1.10; Table 2). We also examined number of teeth (restricted to periods > 1998) in association with breast cancer; there was no evidence of a statistically significant association (Table 2). Furthermore, we found no evidence of potential interactions between periodontal disease and smoking status, BMI, age, aspirin/NSAID use, and number of teeth on breast cancer risk (Supplementary Table S1). Furthermore, we did not find a statistically significant association between mild, moderate, or severe periodontal disease and breast cancer compared with women without a history of bone loss (Supplementary Table S2). We also did not find a statistically significant association by breast cancer hormone receptor status outcomes (Supplementary Table S3). We conducted an additional analysis to evaluated whether the association between periodontal bone loss and breast cancer differed by invasiveness using competing risk Cox models and found no difference in association between invasive and borderline cancers (Pheterogeneity = 0.91).

Table 1.

Age-adjusted baseline characteristics by categories of periodontal bone loss in the NHS in 1998.

Periodontal bone loss in 1998
CharacteristicNo (n = 61,135)Yes (n = 9929)
Age, yearsa 64.3 (7.2) 64.5 (6.9) 
Ever use of OCs, % 48 49 
Ever osteoporosis, % 17 
Ever hip fracture, % 
Ever had a mammogram, % 86 86 
Benign breast disease, % 41 45 
Ever family history of breast cancer, % 14 15 
Weight change since age 18 14.7 (13.2) 13.2 (12.9) 
BMI at age 18 years, kg/m2 21.3 (2.9) 21.4 (2.9) 
BMI, kg/m2 26.7 (5.3) 26.2 (5.1) 
Age at menarche, years 12.5 (1.8) 12.4 (1.8) 
Postmenopausal status, % 94 95 
Age at menopause, years 49.2 (4.8) 49.0 (4.7) 
Age at first birth, years 25.1 (3.3) 25.3 (3.4) 
Number of children 3+, % 60 58 
White, % 98 97 
Education, RN license without BSN, % 94 93 
Pack years of smoking 12.4 (19.2) 21.05 (23.2) 
Smoking status   
 Never smoker, % 47 30 
 Past smoker, % 43 53 
 Current smoker, % 10 18 
Ever postmenopausal hormone use, % 68 71 
Current aspirin/NSAID use >5 years, % 59 59 
Number of natural teeth 25–32, % 65 55 
Alcohol consumption, g/day 4.8 (8.9) 6.0 (10.0) 
Physical activity, MET-hours per week 17.3 (21.5) 17.5 (21.1) 
Antibiotic use, dental reason, % 16 25 
Periodontal bone loss in 1998
CharacteristicNo (n = 61,135)Yes (n = 9929)
Age, yearsa 64.3 (7.2) 64.5 (6.9) 
Ever use of OCs, % 48 49 
Ever osteoporosis, % 17 
Ever hip fracture, % 
Ever had a mammogram, % 86 86 
Benign breast disease, % 41 45 
Ever family history of breast cancer, % 14 15 
Weight change since age 18 14.7 (13.2) 13.2 (12.9) 
BMI at age 18 years, kg/m2 21.3 (2.9) 21.4 (2.9) 
BMI, kg/m2 26.7 (5.3) 26.2 (5.1) 
Age at menarche, years 12.5 (1.8) 12.4 (1.8) 
Postmenopausal status, % 94 95 
Age at menopause, years 49.2 (4.8) 49.0 (4.7) 
Age at first birth, years 25.1 (3.3) 25.3 (3.4) 
Number of children 3+, % 60 58 
White, % 98 97 
Education, RN license without BSN, % 94 93 
Pack years of smoking 12.4 (19.2) 21.05 (23.2) 
Smoking status   
 Never smoker, % 47 30 
 Past smoker, % 43 53 
 Current smoker, % 10 18 
Ever postmenopausal hormone use, % 68 71 
Current aspirin/NSAID use >5 years, % 59 59 
Number of natural teeth 25–32, % 65 55 
Alcohol consumption, g/day 4.8 (8.9) 6.0 (10.0) 
Physical activity, MET-hours per week 17.3 (21.5) 17.5 (21.1) 
Antibiotic use, dental reason, % 16 25 

Abbreviations: BMI, body mass index; BSN, Bachelor of Science in Nursing; MET, metabolic equivalent; NSAID, nonsteroidal anti-inflammatory drugs; OCs, oral contraceptives; RN, registered nurse.

aValues are means (SD) for continuous variables, percentages for categorical variables.

Table 2.

Associations of periodontal bone loss and breast cancer during 14 years of follow-up (1,023,647 person years) in the NHS, 1998–2014.

Periodontal bone lossNumber of natural teeth
(n = 77,541)(n = 72,288)
NoYes25–32 teeth16–24 teeth0–16 teeth
No. of cases (n = 4,352) (n = 758) (n = 3,131) (n = 909) (n = 735) 
Age-adjusted 1.00 (reference) 1.06 (0.98–1.15) 1.00 (reference) 0.95 (0.88–1.02) 0.90 (0.83–0.98) 
Multivariable-adjusteda 1.00 (reference) 1.02 (0.94–1.10) 1.00 (reference) 0.97 (0.90–1.05) 0.96 (0.88–1.04) 
Multivariable-adjustedb 1.00 (reference) 1.02 (0.94–1.10) 1.00 (reference) 0.97 (0.90–1.05) 0.96 (0.88–1.04) 
Periodontal bone lossNumber of natural teeth
(n = 77,541)(n = 72,288)
NoYes25–32 teeth16–24 teeth0–16 teeth
No. of cases (n = 4,352) (n = 758) (n = 3,131) (n = 909) (n = 735) 
Age-adjusted 1.00 (reference) 1.06 (0.98–1.15) 1.00 (reference) 0.95 (0.88–1.02) 0.90 (0.83–0.98) 
Multivariable-adjusteda 1.00 (reference) 1.02 (0.94–1.10) 1.00 (reference) 0.97 (0.90–1.05) 0.96 (0.88–1.04) 
Multivariable-adjustedb 1.00 (reference) 1.02 (0.94–1.10) 1.00 (reference) 0.97 (0.90–1.05) 0.96 (0.88–1.04) 

Abbreviations: CI, confidence interval; HR, hazard ratio.

aMultivariable-adjusted models for the following covariates: age (months), race (nonwhite or white), body mass index at age 18 years [weight (kg)/height (m)2; <18.5, 18.5–24.9, 25.0–29.9, ≥30, or missing], age at menarche (<12, 12, 13, ≥14 years), age at first birth and parity combined (nulliparous, <25 years and 1 child, 25+ years and 1 child, <25 years and 2 children, 25+ years and 2 children, <25 years and >2 children, 25+ years and >2 children, or missing), age at menopause and menopausal status (premenopausal, <45 years and post-menopausal, 45–49 years and post-menopausal, 50–52 years and post-menopausal, 53+ years, or unknown status), first degree family history of breast cancer (yes, no, or missing), history of benign breast disease (ever/never), alcohol consumption (nondrinker, quartile 1, quartile 2, quartile 3, quartile 4, or missing), physical activity (<8 MET, 8–16 MET, 16–24 MET, 24+ MET, or missing), ever mammography (never/ever), smoking status (never, former, current smoker), pack years smoking (none, 0–10 years, 10–20 years, 20–30 years, 30–40 years, 40+ years, or unknown pack years), weight change since 18 (lost at least 2 kg, stable, gained 2–5 kg, gained 5–10 kg, gained 10–20 kg, gained 20–25 kg, gained >25 kg, or missing), menopausal hormone therapy (never or ever), and oral contraceptive use (never or ever).

bAdditionally adjusted for aspirin or NSAID use (never, <5 years, ≥5 years, or missing).

In this prospective study, we found no association of reported periodontal bone loss with breast cancer risk. In previous prospective studies, an increased risk of breast cancer among those who report periodontal disease has been observed, although others have detected no relationship between periodontal disease and breast cancer risk (3). Periodontal disease was significantly associated with increased risk of breast cancer [relative risk (RR) = 1.22, 95% CI = 1.06–1.40] in a meta-analysis (3). When limited to prospective studies, the association was borderline significant (RR: 1.17, 95% CI: 0.97–1.41; ref. 3). In the Women's Health Initiative Observational Study, periodontal disease was significantly associated with breast cancer risk (HR = 1.14, 95% CI = 1.03–1.26), particularly among former smokers who quit within 20 years (HR = 1.36, 95% CI = 1.05–1.77; ref. 5). In the NHS, however, there was no association with risk of breast cancer including within strata of smoking status. Given the validity of self-reported periodontal bone loss, we did not observe a clear association between self-reported periodontal disease and overall breast cancer risk. However, more a more recent study suggests a heterogeneity in risk for invasive breast cancer versus ductal carcinoma in situ (DCIS), with periodontal disease being associated with a non-statistically significant higher incidence of invasive disease and lower incidence of DCIS (6).

Strengths of this study include the prospective design, large sample size, adjudication of breast cancer cases and extensive information on covariates. Limitations include that the main exposure was by self-report and therefore subject to error. Although self-reported periodontal bone loss has been validated in other health professional cohorts (5) and therefore, errors would be limited. However, there was no information on periodontal disease after 2000. This would most likely result in nondifferential misclassification of periodontal bone loss because the outcome was assessed prospectively, and lead to an attenuation in the estimate toward the null. In addition, while we adjusted for known breast cancer risk factors, unmeasured or residual confounding may persist, particularly by smoking. Smoking is a strong periodontal disease risk factor; however, the prevalence of smokers in 1998 was low, therefore this is not likely the explanation for our findings. We also did not have information on periodontal bone loss treatment; however, adjusting for antibiotic use for dental reasons in our study did not change the estimate. Finally, the cohort is generally educated, particularly regarding health, which may affect the distribution of exposures.

We did not observe any association between periodontal disease and breast cancer risk. Given inconsistent findings in the literature, studies with better clinical measures and examination of possible mechanisms in animal models are warranted.

A.H. Eliassen reports grants from NIH during the conduct of the study. J.L. Freudenheim reports grants from NIH during the conduct of the study, as well as grants from Windsong Cares Foundation outside the submitted work. No disclosures were reported by the other authors.

Z. Farhat: Data curation, software, methodology, writing–original draft, project administration, writing–review and editing. C. Cadeau: Supervision, investigation, visualization, methodology, writing–review and editing. A.H. Eliassen: Conceptualization, resources, supervision, validation, investigation, methodology, project administration, writing–review and editing. J.L. Freudenheim: Conceptualization, resources, supervision, funding acquisition, investigation, methodology, writing–review and editing.

This work was supported by the following grants from the NCI at the NIH: UM1 CA186107 (to A.H. Eliassen) and P01 CA87969 (to A.H. Eliassen). Funding for the project was supported in part by the Interdisciplinary Training in Cancer Epidemiology R25CA113951 (to J.L. Freudenheim and Z. Farhat) and the Interdisciplinary Training in Cancer Epidemiology T32CA113951 (to J.L. Freudenheim and Z. Farhat). This work was also supported by the Breast Cancer Research Foundation (BCRF; to A.H. Eliassen) and by a New York State Department of Health Peter T. Rowley Breast Cancer award: C33916GG (to J.L. Freudenheim).

We would like to thank the participants and staff of the Nurses' Health Study (NHS) for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. We would also like to thank the Channing Division of Network Medicine for access to NHS data.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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