Elsevier

Cancer Epidemiology

Volume 49, August 2017, Pages 156-160
Cancer Epidemiology

Tumor characteristics and family history in relation to mammographic density and breast cancer: The French E3N cohort

https://doi.org/10.1016/j.canep.2017.07.003Get rights and content

Highlights

  • Mammographic density and breast cancer risk examined in a large French cohort.

  • Stronger association in women with than without a family history of breast cancer.

  • No heterogeneity in the relation by tumor characteristics.

  • Shared genetic factors may account for familial breast cancer and breast density.

Abstract

Background

Mammographic density is a known heritable risk factor for breast cancer, but reports how tumor characteristics and family history may modify this association are inconsistent.

Methods

Dense and total breast areas were assessed using Cumulus™ from pre-diagnostic mammograms for 820 invasive breast cancer cases and 820 matched controls nested within the French E3N cohort study. To allow comparisons across models, percent mammographic density (PMD) was standardized to the distribution of the controls. Odds ratios (OR) and 95% confidence intervals (CI) of breast cancer risk for mammographic density were estimated by conditional logistic regression while adjusting for age and body mass index. Heterogeneity according to tumor characteristic and family history was assessed using stratified analyses.

Results

Overall, the OR per 1 SD for PMD was 1.50 (95% CI, 1.33–1.69). No evidence for significant heterogeneity by tumor size, lymph node status, grade, and hormone receptor status (estrogen, progesterone, and HER2) was detected. However, the association of PMD was stronger for women reporting a family history of breast cancer (OR1SD = 2.25; 95% CI, 1.67–3.04) than in women reporting none (OR1SD = 1.41; 95% CI, 1.24–1.60; pheterogeneity = 0.002). Similarly, effect modification by FHBC was observed using categories of PMD (pheterogeneity = 0.02) with respective ORs of 15.16 (95% CI, 4.23–54.28) vs. 3.14 (95% CI, 1.89–5.22) for ≥50% vs. <10% PMD.

Conclusions

The stronger association between mammographic density and breast cancer risk with a family history supports the hypothesis of shared genetic factors responsible for familial aggregation of breast cancer and the heritable component of mammographic density.

Introduction

Mammographic density, measured as absolute dense area (DA) or percent mammographic density (PMD), is a well-established breast cancer risk factor [1], [2]. As age and body mass index (BMI) act as negative confounders, PMD always needs to be adjusted for both factors. The role of non-dense breast area (NDA) is less clear; it was inversely associated with breast cancer risk under the assumption that fatty breast tissue influences breast cancer risk, but not related under the assumption that fat in the breast is a surrogate marker of adiposity [3]. A recent meta-analysis reported no difference by HER2 status [4] and the findings for estrogen receptor (ER) status are inconsistent [4], [5], [6], [7]. In a pooled analysis, PMD was more strongly associated with the risk of large vs. small and lymph node positive vs. negative tumors [8].

The presence of a family history of breast cancer (FHBC) in first-degree relatives (FDR) consistently shows an approximately 2-fold higher breast cancer risk [9], [10], [11]. Of familial risk of breast cancer, around 28% is due to low penetrance common variants and another 20% due to higher penetrance loci [12], but a large proportion still needs to be explained. Twin studies have shown that mammographic density has a strong heritable component [13]; it has been estimated that 50–60% of the variance of mammographic density that predicts breast cancer risk is due to undiscovered genetic factors [14]. Given that shared genetic factors may be related to mammographic density and hereditary breast cancer risk, it has been proposed that mammographic density may mediate the effect of FHBC on breast cancer risk [10]. In fact, recent reports have identified several such genes [15], [16]. Findings for a possible effect modification by FHBC are inconsistent; some studies were supportive [11], [17], [18] and others indicated independent associations of FHBC and mammographic density on breast cancer risk without a significant interaction [10], [19], [20]. The current analysis builds on a case-control study nested within the E3N French cohort to estimate the associations between mammographic density and breast cancer by tumor characteristics, i.e., tumor size, lymph node status, grade, hormone receptor status, as well as FHBC.

Section snippets

Study design

The French E3N cohort study is a prospective cohort study of 98,995 women aged 40–65 years at baseline who were recruited between 1990 and 1994 [21]. The French Commission for Data Protection and Privacy approved the study. At baseline, participants completed questionnaires asking about demographic characteristics, anthropometric measures, lifestyle factors, FHBD in FDR, and diet. Follow-up questionnaires updated lifestyle factors and medical events every 2–3 years with stable response rates at

Results

The breast cancer cases were diagnosed between 1990 and 2010 at a mean age of 59.2 ± 6.3 years (Table 1); mammograms were performed between 1988 and 2007 on average 1 year before the reference age for cases and controls. A higher proportion of cases than controls (18 vs. 14%) reported a FHBC in FDR (OR = 1.35; 95% CI, 1.03–1.78). DA and PMD were significantly higher in cases than in their matched controls (p < 0.0001), while NDA values were lower in cases than controls (p = 0.04). Among cases with

Discussion

In this nested case-control study of mammographic density and breast cancer risk among French women, we confirmed that DA and PMD, after adjustment for age and BMI, are risk factors for breast cancer, whereas NDA adjusted for age and BMI is inversely associated with BC risk. The associations did not vary by any of the six tumor characteristics that were examined. The inverse association between NDA and BC risk was more pronounced in women with than without a FHBC in FDR, resulting in a stronger

Authors contributions

FC, LD, and SD were instrumental in the acquisition of data, conceived and designed the study; GM was responsible for the breast density assessment; LB performed the statistical analysis; LB and GM drafted the manuscript; LD, SD, JLH, and FC contributed to the interpretation of the data, critically reviewed the content of the paper, and offered input for revision. All authors provided final approval of the version to be published.

Financial support

The E3N case-control study was funded by a grant from Fondation ARC pour la recherche sur le cancer (Francoise Clacel-Chapelon). The E3N cohort was funded by MGEN (Mutuelle Générale de l’Education Nationale) (FCC), Ligue contre le Cancer, Gustave Roussy and Institut National de la Santé et de la Recherche Médicale (Inserm) (FCC). Laura Baglietto was supported by a Marie Curie International Incoming Fellowship within the 7th European Community Framework Programme.

Conflict of interest

None.

Acknowledgment

We thank Maxime Valdenaire for the management of the mammographic data.

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