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