Volumetric breast density and risk of advanced cancers after a negative screening episode: a cohort study

Abstract Background We evaluated the association between volumetric breast density (BD) and risk of advanced cancers after a negative screening episode. Methods A cohort of 16,752 women aged 49–54 years at their first screening mammography in the Florence screening programme was followed for breast cancer (BC) incidence until the second screening round. Volumetric BD was measured using fully automated software. The cumulative incidence of advanced cancer after a negative screening episode (including stage II or more severe cancer during the screening interval - on average 28 months - and at the subsequent round) was calculated separately for Volpara density grade (VDG) categories. Results BC incidence gradually increased with the increas in BD: 3.7‰, 5.1‰, 5.4‰ and 9.1‰ in the VDG categories 1–4, respectively (p trend < 0.001). The risk of advanced cancers after a negative screening episode was 1.0‰, 1.3‰, 1.1‰, and 4.2‰ (p trend = 0.003). The highest BD category, compared with the other three together, has double the invasive BC risk (RR = 2.0; 95% CI 1.5–2.8) and almost fourfold risk of advanced cancer (RR = 3.8; 95% CI 1.8–8.0). Conclusion BD has a strong impact on the risk of advanced cancers after a negative screening episode, the best early surrogate of BC mortality. Therefore, our results suggest that screening effectiveness is quite different among BD categories

Pre-diagnostic DNA methylation patterns differ according to mammographic breast density amongst women who subsequently develop breast cancer: a case-only study in the EPIC-Florence cohort

Purpose: Mammographic breast density (MBD) is a marker of increased breast cancer (BC) risk, yet much remains to be clarified about the underlying mechanisms. We investigated whether DNA methylation patterns differ between high- vs. low-MBD women who developed BC during an 8.9-year median follow-up in the Florence section of the European Prospective Investigation into Cancer and Nutrition. Methods: We analysed 96 pairs of women with BC arising on high- vs. low-MBD breasts (BI-RADS category III-IV vs. I). DNA methylation was determined on pre-diagnostic blood samples using the Illumina Infinium MethylationEPIC BeadChip assay. The statistical analysis was conducted by performing an epigenome-wide association study (EWAS), by searching differentially methylated regions (DMRs) in gene promoters (followed by functional enrichment and gene annotation analysis); and through a "candidate pathways" approach focusing on pre-defined inflammation-related pathways. Results: In EWAS, no single CpG site was differentially methylated between high- and low-MBD women after correction for multiple testing. A total of 140 DMRs were identified, of which 131 were hyper- and 9 hypo-methylated amongst high-MBD women. These DMRs encompassed an annotation cluster of 35 genes coding for proteins implicated in transcription regulation and DNA binding. The "apoptosis signalling" was the only inflammation-related candidate pathway differentially methylated between high- and low-MBD women. Conclusion: Pre-diagnostic methylation patterns differ between high- vs. low-MBD women who subsequently develop BC, particularly, in genes involved in the regulation of DNA transcription and cell apoptosis. Our study provides novel clues about the mechanisms linking MBD and BC

Dietary Patterns, Dietary Interventions, and Mammographic Breast Density: A Systematic Literature Review

Background: Breast cancer (BC) is the most common and deadliest malignancy among women. High mammographic breast density (MBD) is an established modifiable risk marker for BC, and it is of interest, for prevention purposes, to consider lifestyle factors that may modulate both MBD and BC risk. Here, we conducted a systematic review of the most up-to-date evidence on the association between diet as a whole and MBD. Methods: We considered as eligible for inclusion in our review (PROSPERO registration code CRD42022335289) the studies published until 31 December 2021, that reported on the association between a priori or a posteriori dietary patterns (in observational studies) or dietary interventions (in randomized controlled trials) and MBD. Results: In total, twelve studies were included. MBD tended to be inversely associated with adherence to dietary patterns characterized by high consumption of plant-based foods and low in meat, animal fats, and alcohol, defined both a priori (e.g., Mediterranean diet and WCRF/AICR guidelines) or a posteriori (e.g., &ldquo;fruit-vegetable-cereal&rdquo; and &ldquo;salad-sauce-pasta/grains&rdquo; patterns). Findings from intervention studies were in fair agreement with those from observational studies. Conclusions: While further studies are needed, we found suggestive evidence that the adoption of a healthy diet is associated with lower MBD

Glycemic Index, Glycemic Load and Mammographic Breast Density: The EPIC Florence Longitudinal Study

<div><p>A few studies have evaluated the association between diet and mammographic breast density (MBD) and results are inconsistent. MBD, a well-recognized risk factor for breast cancer, has been proposed as a marker of cumulative exposure to hormones and growth factors. Diets with a high glycemic index (GI) or glycemic load (GL) may increase breast cancer risk, via an effect on the insulin-like growth factor axis. We have investigated the association between carbohydrate intake, GI, GL and MBD in a prospective study. We identified a large series of women, in the frame of the EPIC-Florence cohort, with a mammogram taken five years after enrolment, when detailed information on dietary and lifestyle habits and anthropometric measurements had been collected. Mammograms have been retrieved (1,668, 83%) and MBD assessed according to Wolfe’s classification. We compared women with high MBD (P2+DY Wolfe’s categories) with those with low MBD (N1+P1) through logistic models adjusted for age, education, body mass index, menopause, number of children, breast feeding, physical activity, non-alcohol energy, fibers, saturated fat and alcohol. A direct association between GL and high MBD emerged in the highest quintile of intake in comparison with the lowest quintile (OR = 1.73, 95%CI 1.13–2.67, p for trend = 0.048) while no association with glycemic index was evident. These results were confirmed after exclusion of women reporting to be on a diet or affected with diabetes, and when Hormone Replacement Therapy at the date of mammographic examination used to assess MBD was considered. The effect was particularly evident among leaner women, although no interaction was found. A positive association was suggested for increasing simple sugar and total carbohydrates intakes limited to the highest quintiles. In this Italian population we observed an association between glycemic load, total and rapidly absorbed carbohydrates and high MBD. These novel results warrant further investigations.</p></div

Mean and median values of selected lifestyle and dietary variables of 1,668 participants by low and high MBD (EPIC-Florence).

*<p>Metabolic equivalents (METs) for non occupational physical activity (including recreational and household activities).</p>**<p><i>P</i>-values were calculated from GLM.</p

Association between energy-adjusted total carbohydrate, simple sugars and starches and high MBD (1,628 EPIC-Florence women).

*<p>Crude ORs obtained by models including only the variable of interest (classified in quintiles).</p>**<p>Adjusted ORs obtained by multivariate logistic models including terms for age (years), education (university and secondary school yes/no), body mass index (normal weight/overweight/obese), menopausal status (pre−/post-menopausal), number of children (0; 1–2; ≥3), duration of breast feeding (≤8 months/>8 months), non-alcohol energy intake (kcal/day, continuous), leisure time physical activity (MET/week in continuous), alcohol (g/day), fiber (g/day) and saturated fat (g/day) intakes in quintiles.</p>∧<p>Included simultaneously in the crude and adjusted models.</p

Cigarette smoking and mammographic breast density in post-menopausal women from the EPIC Florence cohort

IntroductionCigarette smoking has been recognized as a risk factor for breast cancer (BC) also if the biological mechanism remains poorly understood. High mammographic breast density (MBD) is associated with BC risk and many BC risk factors, such as genetic, anthropometric, reproductive and lifestyle factors and age, are also able to modulate MBD. The aim of the present study was to prospectively explore, in post-menopausal women, the association between smoking habits and MBD, assessed using an automated software, considering duration and intensity of smoking.MethodsThe analysis was carried out in 3,774 women enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC) Florence cohort in 1993-98, participating in the 2004-06 follow up (FU) and with at least one full-field digital mammography (FFDM) performed after FU. For each woman, detailed information on smoking habits, anthropometry, lifestyle and reproductive history was collected at enrollment and at FU. Smoking information at baseline and at FU was integrated. The fully automated Volpara™ software was used to obtain total breast volume (cm3), absolute breast dense volume (DV, cm3) and volumetric percent density (VPD, %) from the first available FFDM (average 5.3 years from FU). Multivariable linear regression models were applied to evaluate the associations between smoking habits and VPD or DV.ResultsAn inverse association between smoking exposure and VPD emerged (Diff% -7.96%, p &lt;0.0001 for current smokers and -3.92%, p 0.01 for former smokers, compared with non-smokers). An inverse dose-response relationship with number of cigarettes/day, years of smoking duration and lifetime smoking exposure (pack-years) and a direct association with time since smoking cessation among former smokers emerged. Similar associations, with an attenuated effect, emerged when DV was considered as the outcome variable.DiscussionThis longitudinal study confirms the inverse association between active smoking, a known risk factor for BC, and MBD among post-menopausal women. The inclusion of smoking habits in the existing BC risk prediction models could be evaluated in future studies

Association between energy-adjusted GI and GL and high MBD by menopausal status and BMI (1,628 EPIC-Florence women).

*<p>Adjusted ORs obtained by multivariate logistic models including terms for age (years), education (university and secondary school yes/no), number of children (0; 1–2; ≥3), duration of breast feeding (≤8 months/>8 months), non -alcohol energy intake (kcal/day, continuous), leisure time physical activity (MET/week in continuous), alcohol (g/day), fiber (g/day) and saturated fat (g/day) intakes in quintiles and, alternatively, body mass index (normal weight/overweight/obese) and menopausal status (pre-/post-menopausal).</p

Association between energy-adjusted GI, GL and high MBD (1,628 EPIC-Florence women).

*<p>Crude ORs obtained by models including only the variable of interest (classified in quintiles).</p>**<p>Adjusted ORs obtained by multivariate logistic models including terms for age (years), education (university and secondary school yes/no), body mass index (normal weight/overweight/obese), menopausal status (pre−/post-menopausal), number of children (0; 1–2; ≥3), duration of breast feeding (≤8 months/>8 months), non-alcohol energy intake (kcal/day, continuous), leisure time physical activity (MET/week in continuous), alcohol (g/day), fiber (g/day) and saturated fat (g/day) intakes in quintiles.</p