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Introduction: Cigarette 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., Methods: The 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 (cm 3 ), absolute breast dense volume (DV, cm 3 ) 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., Results: An inverse association between smoking exposure and VPD emerged (Diff% -7.96%, p <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., Discussion: This 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bendinelli, Caini, Assedi, Ermini, Pastore, Facchini, Gilio, Duroni, Fontana, Querci, Ambrogetti, Saieva and Masala.)

Aim: The analyses here reported aim to compare the screening performance of digital tomosynthesis (DBT) versus mammography (DM)., Methods: MAITA is a consortium of four Italian trials, REtomo, Proteus, Impeto, and MAITA trial. The trials adopted a two-arm randomised design comparing DBT plus DM (REtomo and Proteus) or synthetic-2D (Impeto and MAITA trial) versus DM; multiple vendors were included. Women aged 45 to 69 years were individually randomised to one round of DBT or DM., Findings: From March 2014 to February 2022, 50,856 and 63,295 women were randomised to the DBT and DM arm, respectively. In the DBT arm, 6656 women were screened with DBT plus synthetic-2D. Recall was higher in the DBT arm (5·84% versus 4·96%), with differences between centres. With DBT, 0·8/1000 (95% CI 0·3 to 1·3) more women received surgical treatment for a benign lesion. The detection rate was 51% higher with DBT, ie. 2·6/1000 (95% CI 1·7 to 3·6) more cancers detected, with a similar relative increase for invasive cancers and ductal carcinoma in situ. The results were similar below and over the age of 50, at first and subsequent rounds, and with DBT plus DM and DBT plus synthetic-2D. No learning curve was appreciable. Detection of cancers >= 20 mm, with 2 or more positive lymph nodes, grade III, HER2-positive, or triple-negative was similar in the two arms., Interpretation: Results from MAITA confirm that DBT is superior to DM for the detection of cancers, with a possible increase in recall rate. DBT performance in screening should be assessed locally while waiting for long-term follow-up results on the impact of advanced cancer incidence., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paolo Giorgi Rossi reports financial support was provided by Italian Ministry of Health. Pierpaolo Pattacini reports was provided by Emilia-Romagna Regional Health Authority. Antonio Ponti reports financial support was provided by Piedmont Region (Department of Health). Antonio Ponti reports financial support was provided by foundation Edo Tempia (a non-profit organisation). Antonio Ponti reports equipment, drugs, or supplies was provided by Regional Consortium for Informative Systems (CSI). Antonio Ponti reports financial support was provided by University of Turin. Paola Mantellini reports financial support was provided by Tuscany Region. Pierpaolo Pattacini reports equipment, drugs, or supplies and travel were provided by GE Healthcare. Antonio Ponti reports equipment, drugs, or supplies was provided by im3D S.p.A Torino. Stephen Duffy has received indirect funding in the past from Hologic Inc. Valentina Iotti, Andrea Nitrosi reports travel was provided by GE Healthcare. Pierpaolo Pattacini, Valentina Iotti, Andrea Nitrosi, Francesco Sardanelli reports a relationship with GE Healthcare that includes: speaking and lecture fees. Valentina Iotti reports a relationship with Bayer that includes: speaking and lecture fees. Paolo Giorgi Rossi, Livia Giordano, Stephen Duffy, and Francesco Sardanelli are members of the European Commission Initiative on Breast Cancer working groups. They contributed to the development of new breast cancer screening recommendations and quality assurance scheme. Livia Giordano is past president of the Gruppo Italiano Screening Mammografico, the Italian scientific society on breast cancer screening. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: We retrospectively investigated clinical, radiological, and pathological features of B3 lesions associated with the risk of subsequent upgrade to malignancy., Methods: We included consecutive vacuum-assisted biopsies (VABs) performed during 2011-2020 on suspicious microcalcifications not associated with other radiological signs diagnosed as B3 lesions and followed by surgical excision (SE) with definitive histological examination. Multiple logistic regression models were fitted to identify independent predictors of malignancy., Results: Out of the 366 B3 lesions included, 56 (15.3 %, 95 % CI 11.8-19.4 %) had upgraded to malignancy at SE: of these, 42/366 (11.5 %, 95 % CI 8.4-15.2 %) and 14/366 (3.8 %, 95 % CI 2.1-6.3 %) were in situ and invasive carcinoma, respectively. At univariate analysis, variables positively associated with upgrade to malignancy were age ≥ 60 years (p = 0.008), mixed morphology (p = 0.018), scattered distribution (p = 0,001), extension of microcalcifications > 10 mm (p = 0.001), and mixed B3 lesion (p = 0.017). Among B3 subtypes, the highest rates of upgrade were observed for AIDEP, LCIS/LIN2, FEA + AIDEP, FEA + LCIS/LIN2, and FEA + AIDEP + LCIS/LIN2 (24.6 %, 21.4 %, 25.3 %, 20.0 % and 40.0 % respectively), while FEA and ALH/LIN1 had a lower rates of upgrade (7.5 % and 3.7 %, respectively). Multiple logistic regression analysis confirmed as risk factors older age (p = 0.029), larger extension (p = 0.001) and mixed morphology (p = 0.007) of microcalcifications, AIDEP (p = 0.011) among pure B3 lesions, and FEA + AIDEP (p = 0.001) and FEA + AIDEP + LCIS/LIN2 (p = 0.037) among mixed B3 lesions., Conclusions: Based on our findings, vacuum-assisted excision is reasonable as definitive management for FEA and ALH/LIN1, while SE should remain the mainstay of treatment for AIDEP and LCIS/LIN2, whose upgrade rates are too high to safely recommend VAE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: High mammographic breast density (MBD) is an established risk factor for breast cancer (BC). Body fatness conveys an increased BC risk in postmenopause but is associated with less dense breasts. Here, we studied the relationship between body fatness and breast composition within the FEDRA (Florence-EPIC Digital mammographic density and breast cancer Risk Assessment) longitudinal study., Methods: Repeated anthropometric data and MBD parameters (obtained through an automated software on BC screening digital mammograms) were available for all participants, as well as information on other BC risk factors. Multivariate linear regression and functional data analysis were used to longitudinally evaluate the association of body fatness, and changes thereof over time, with dense (DV) and non-dense (NDV) breast volumes and volumetric percent density (VPD)., Results: A total of 5,262 women were included, with anthropometric data available at 20 and 40 years of age, at EPIC baseline (mean 49.0 years), and an average of 9.4 years thereafter. The mean number of mammograms per woman was 3.3 (SD 1.6). Body fatness (and increases thereof) at any age was positively associated with DV and NDV (the association being consistently stronger for the latter), and inversely associated with VPD. For instance, an increase by 1 kg/year between the age of 40 years and EPIC baseline was significantly associated with 1.97% higher DV, 8.85% higher NDV, and 5.82% lower VPD., Conclusion: Body fatness and its increase from young adulthood until midlife are inversely associated with volumetric percent density, but positively associated with dense and non-dense breast volumes in postmenopausal women., (© 2023. The Author(s).)

Mammographic breast density (MBD) is a strong independent risk factor for breast cancer (BC). We investigated the association between volumetric MBD measures, their changes over time, and BC risk in a cohort of women participating in the FEDRA (Florence-EPIC Digital mammographic density and breast cancer Risk Assessment) study. The study was carried out among 6148 women with repeated MBD measures from full-field digital mammograms and repeated information on lifestyle habits, reproductive history, and anthropometry. The association between MBD measures (modeled as time-dependent covariates), their relative annual changes, and BC risk were evaluated by adjusted Cox models. During an average of 7.8 years of follow-up, 262 BC cases were identified. BC risk was directly associated with standard deviation increments of volumetric percent density (VPD, HR 1.37, 95%CI 1.22-1.54) and dense volume (DV, HR 1.29, 95%CI 1.18-1.41). An inverse association emerged with non-dense volume (NDV, HR 0.82, 95%CI 0.69-0.98). No significant associations emerged between annual changes in VPD, DV, NDV, and BC risk. Higher values of MBD measures, modeled as time-dependent covariates, were positively associated with increased BC risk, while an inverse association was evident for increasing NDV. No effect of annual changes in MBD emerged.

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., "fruit-vegetable-cereal" and "salad-sauce-pasta/grains" 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.

Several biomarkers of healthy aging have been proposed in recent years, including the epigenetic clocks, based on DNA methylation (DNAm) measures, which are getting increasingly accurate in predicting the individual biological age. The recently developed "next-generation clock" DNAmGrimAge outperforms "first-generation clocks" in predicting longevity and the onset of many age-related pathological conditions and diseases. Additionally, the total number of stochastic epigenetic mutations (SEMs), also known as the epigenetic mutation load (EML), has been proposed as a complementary DNAm-based biomarker of healthy aging. A fundamental biological property of epigenetic, and in particular DNAm modifications, is the potential reversibility of the effect, raising questions about the possible slowdown of epigenetic aging by modifying one's lifestyle. Here, we investigated whether improved dietary habits and increased physical activity have favorable effects on aging biomarkers in healthy postmenopausal women. The study sample consists of 219 women from the "Diet, Physical Activity, and Mammography" (DAMA) study: a 24-month randomized factorial intervention trial with DNAm measured twice, at baseline and the end of the trial. Women who participated in the dietary intervention had a significant slowing of the DNAmGrimAge clock, whereas increasing physical activity led to a significant reduction of SEMs in crucial cancer-related pathways. Our study provides strong evidence of a causal association between lifestyle modification and slowing down of DNAm aging biomarkers. This randomized trial elucidates the causal relationship between lifestyle and healthy aging-related epigenetic mechanisms., (© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mammographic breast density (MBD) is a strong independent risk factor for breast cancer (BC). We designed a matched case-case study in the EPIC Florence cohort, to evaluate possible associations between the pre-diagnostic metabolomic profile and the risk of BC in high- versus low-MBD women who developed BC during the follow-up. A case-case design with 100 low-MBD (MBD ≤ 25%) and 100 high-MDB BC cases (MBD > 50%) was performed. Matching variables included age, year and type of mammographic examination. 1 H NMR metabolomic spectra were available for 87 complete case-case sets. The conditional logistic analyses showed an inverse association between serum levels of alanine, leucine, tyrosine, valine, lactic acid, pyruvic acid, triglycerides lipid main fraction and 11 VLDL lipid subfractions and high-MBD cases. Acetic acid was directly associated with high-MBD cases. In models adjusted for confounding variables, tyrosine remained inversely associated with high-MBD cases while 3 VLDL subfractions of free cholesterol emerged as directly associated with high-MBD cases. A pathway analysis showed that the "phenylalanine, tyrosine and tryptophan pathway" emerged and persisted after applying the FDR procedure. The supervised OPLS-DA analysis revealed a slight but significant separation between high- and low-MBD cases. This case-case study suggested a possible role for pre-diagnostic levels of tyrosine in modulating the risk of BC in high- versus low-MBD women. Moreover, some differences emerged in the pre-diagnostic concentration of other metabolites as well in the metabolomic fingerprints among the two groups of patients.

Background: Few randomized trials have been carried out to evaluate the effect of lifestyle modifications on mammographic breast density (MBD). The randomized 2 × 2 factorial Diet, physical Activity and MAmmography trial aimed to evaluate whether MBD can be reduced in postmenopausal women with high baseline MBD by a 24-month dietary and/or physical activity (PA) interventions., Methods: We randomized healthy postmenopausal women, attending the Florence (Italy) mammographic screening program, ages 50 to 69 years, nonsmokers, with MBD > 50% and no recent hormone therapy, to (i) a dietary intervention focused on plant foods, with a low glycemic load, low in saturated fats and alcohol; (ii) a PA intervention combining daily moderate intensity activities and one weekly supervised session of more strenuous activity; (iii) both interventions; (iv) general recommendations. We evaluated changes in MBD based on Volpara estimates comparing baseline and follow-up digital mammograms by an intention-to-treat-analysis., Results: MBD measures were available for 226 participants. An interaction emerged between treatments and thus we run analyses by arms. A decrease in volumetric percent density emerged for women in the dietary intervention (ratio 0.91; 95% CI, 0.86-0.97; P = 0.002) and in the PA intervention arm (0.93; 95% CI, 0.87-0.98; P = 0.01) in comparison with controls. No clear effect emerged in the double intervention arm., Conclusions: This intervention trial suggests that a 24-month dietary or PA intervention may reduce MBD in postmenopausal women., Impact: A modification of dietary habits or an increase in PA in postmenopausal women may reduce MBD. Further studies are needed to confirm these findings for planning breast cancer preventive strategies., (©2018 American Association for Cancer Research.)

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.

Purpose: Mammographic breast density (MBD) has been consistently associated with breast cancer (BC) risk, and at the same time it is modulated by established BC risk factors related to reproductive and hormonal history and to lifestyle. We aimed to evaluate the association between the clinical breast imaging reporting and data system (BI-RADS), a qualitative MBD classification used in clinical setting, and BC risk through a case-control nested in the EPIC Florence cohort where baseline information on reproductive history, lifestyle and anthropometry were collected., Methods: The study includes 136 newly diagnosed BC cases and 635 controls from the 10,083 healthy women enroled in the cohort between 1993 and 1998 and followed for 6 years on average. MBD was assessed on a negative mammogram performed at least one year before diagnosis in cases and on a mammogram performed in the same period for controls matched for age, enrolment date and menopausal status. Multivariate analyses adjusted for education, body mass index, parity, number of children, breastfeeding, BC family history, history of breast biopsies and Hormone Replacement Therapy use were performed., Results: An increase in BC risk across BI-RADS categories emerged with adjusted odds ratios (OR) 1.79 (95% CI 1.06-3.01), OR 2.09 (95% CI 1.17-3.74) and OR 2.67 (95% CI 1.08-6.62) for categories 2, 3 and 4 in comparison with the reference category (p for trend = 0.008)., Conclusions: We confirm in this Mediterranean population the association of increasing MBD, classified according to BI-RADS with BC risk also taking into account other well-known risk factors for this neoplasm.

Unlabelled: Aims and background. High mammographic breast density (MBD) is an established risk factor for breast cancer (BC). The influence of diet and physical activity (PA) on MBD has long been investigated. In an observational study of a cohort in Florence, we observed inverse associations between consumption of vegetables and olive oil and moderate leisure-time PA and MBD, while high alcohol intake and high glycemic load diets were positively associated with MBD. We set out to investigate whether dietary and PA interventions were able to reduce MBD in postmenopausal women with high MBD (>50%). Methods and study design. The DAMA (Diet, physical Activity and MAmmography) trial, a factorial randomized trial involving healthy nonsmoking postmenopausal women not using hormone replacement therapy and having MBD >50%, is aimed at evaluating the ability of a 24-month intervention based on moderate-intensity PA and/or dietary modification focused on plant foods with a low glycemic load, low in saturated fats and alcohol, and rich in antioxidants and fiber, to reduce the percent MBD. Participants have been randomized to 1 of 4 study arms (diet, PA, diet + PA, control). Dietary and PA habits and anthropometry are collected at baseline and at the end of the intervention phase together with repeated blood and urine samples. The primary outcome of the study is the absolute change in percent MBD as assessed on baseline and follow-up digital mammograms performed in the framework of the local screening program. Results. Of 728 eligible women, 234 (32.1%) agreed to participate. We did not observe any difference across study arms in the baseline distribution of variables of interest related to diet and lifestyle. Conclusions. The DAMA trial may contribute to a better understanding of MBD determinants. This will provide insight into the pathogenesis of BC and may allow the development of strategies for primary prevention focused on high-MBD groups that are easily identifiable in large-scale BC screening programs., Trial Registration Number: ISRCTN28492718.

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.

Background: Core needle biopsy (CNB) diagnoses of ductal carcinoma-in-situ (DCIS) may represent understaged invasive breast cancer (IBC). We aimed to develop a model that helps identify preoperatively women with IBC after a CNB diagnosis of DCIS., Methods: Retrospective study of all women with DCIS on vacuum-assisted CNB of microcalcifications (1999-2008), with prospective classification of imaging variables independently by two radiologists. Variables included lesion size and level of suspicion on imaging, morphology and distribution of microcalcifications, DCIS nuclear grade on CNB, number of cores, and age. Multivariate logistic regression models of the probability of IBC were developed; the accuracy of these models was examined for each radiologist., Results: Excision histology showed IBC in 77 (17.4%) of 442 subjects with DCIS on CNB. Lesion size on imaging yielded the best model fit and highest accuracy, and had the highest agreement between radiologists. Addition of grade to a model which included size improved model fit (P < 0.0001). However, model fit and accuracy were not improved by inclusion of any other variables. A model based on size and grade had similar areas under the receiver operating characteristic curve (accuracy of 74%) for each radiologist. Modeled sensitivity, specificity, and predictive values for different combinations of size and grade thresholds are reported. If the imaging lesion is >50 mm and the CNB grade is high, the model's positive predictive value is ≥50%., Conclusions: A model based on imaging size of microcalcifications and CNB nuclear grade can identify women at high risk of having IBC with moderate accuracy and may be used to guide informed preoperative discussion in women with newly diagnosed DCIS on CNB.

A protective effect of physical activity (PA) on breast cancer (BC) risk has been suggested. Few studies have examined the influence of PA on mammographic breast density (MBD), a strong risk factor for BC. In a prospective study in Florence, Italy, we identified 2,000 healthy women with a mammogram taken 5 years after enrollment. Individual mammograms were retrieved (83%) and MBD assessed according to Wolfe's classification. Detailed information on PA at work and during leisure time, reproductive history, lifestyle and anthropometric measurements at enrollment were available for 1,666 women. Information on hormone replacement therapy (HRT) was also obtained at mammogram. Women with high-MBD (P2 + DY Wolfe's patterns) were compared with women with low-MBD (N1 + P1) by multivariate logistic models. Overall, high-MBD was inversely associated with increasing levels of leisure time PA (p for trend = 0.04) and among peri-/postmenopausal women, also with increasing levels of recreational activities (p for trend = 0.02). An interaction between PA and HRT emerged, with a stronger inverse association of highest level of recreational activity with MBD among HRT nonusers (p for interaction = 0.02). A modifying effect by body mass index (BMI) was evident among 1,025 peri-/postmenopausal women who did not use HRT at the time of mammogram, with a stronger inverse association between recreational PA and MBD in the highest BMI tertile (OR = 0.34; 95% CI 0.20-0.57; p for interaction = 0.03). This large study carried out in Mediterranean women suggests that leisure time PA may play a role in modulating MBD, particularly in overweight/obese peri-/postmenopausal women.

Introduction: Axillary node fine needle aspiration cytology (FNAC) has the potential to triage women with operable breast cancer to initial nodal surgical procedure. Because of variability in the reported accuracy of this test its role and clinical utility in pre-operative staging remains controversial., Methods: We retrospectively evaluated the accuracy of ultrasound-guided axillary FNAC in all consecutive clinically T1-2 N0-1 breast cancers that had undergone this test (491 biopsies). We included subjects with clinically or sonographically indeterminate or suspicious nodes. Pathological node status was used as the reference standard (based on axillary dissection or sentinel node biopsy)., Results: Sensitivity of node FNAC was 72.6% (67.3-77.9) and specificity was 95.7% (92.5-98.8) for all cases, sensitivity was lower at 64.6% (59.3-70.0) if inadequate cytology was included as a negative result. FNAC sensitivity was highest in women with clinically suspicious nodes [92.5% (88.2-96.7)] and lowest in women with sonographically abnormal and clinically negative nodes [50.0% (41.3-58.7)]. Specificity was high in both groups, 81.2% (54.5-96.0) and 97.2% (94.6-99.9), respectively. The false-negative rate was 15.3% (12.1-18.5), the false-positive rate was 1.4% (0.4-2.5), and the inadequacy rate was 10.8% (8.0-13.5). The likelihood of node FNAC being positive was significantly associated with tumour grade and stage, and the number of nodes involved with metastases., Discussion: Our data show that axillary FNAC has moderate sensitivity (which varies according to selection criteria for the test) and consistently high specificity, is associated with low inadequacy and very few false positives. We estimate that its use would have improved triage to initial nodal procedure in about one quarter of our cases. If one accepts the premise that initial surgical staging of the axilla should be based on all information available through pre-operative diagnosis, then axillary FNAC should be adopted routinely into clinical practice.

Breast core needle biopsy (CNB) is used for sampling breast lesions in both the screening and diagnostic context. We present the accuracy of breast CNB from a consecutive series of 4035 core biopsies, using methods that minimise selection and verification bias. We calculate accuracy and underestimation of malignancy for both automated (14G) and directional vacuum-assisted (11G) CNB performed under stereotactic or sonographic guidance. Overall sensitivity of CNB is 94.2% (92.9-95.5%) and specificity is 88.1% (86.6-89.6%), positive and negative predictive values are 84.8% (82.9-86.7%) and 95.6% (94.6-96.6%), respectively. In sampling microcalcification, the overall underestimation of malignancy is 26.6% (22.9-30.3%): underestimation is significantly higher for automated CB relative to VAB (chi2 ((df = 1)) = 8.90 , P = 0.002), the absolute difference in underestimation being 14% (5-23%); sensitivity is higher for VAB than automated CB (chi2 ((df = 1)) = 3.28, P = 0.06) but specificity is significantly higher for automated CB (14G) relative to VAB (11G) (chi2 ((df = 1)) = 6.37, P = 0.01), and the overall accuracy of the two methods is similar. Sensitivity of CNB improved with experience (over time and in relation to caseload). Accuracy was not substantially affected by lesion palpability or image-guidance method, and was similar for both masses and calcification but lower for lesions depicted as distortions on mammography. Inadequacy was very low and decreased with greater operator caseload, and was not associated with core gauge or image-guidance method. False negatives occurred in 4.4% (3.4-5.4%) of cases, and where core histology was benign but discordant with (suspicious) imaging and/or clinical findings the likelihood of malignancy was 33.1% (18.5-47.7%), emphasising the importance of correlating all test information in breast diagnosis.

Background: A review of the literature indicated variable underestimation rates for breast core-needle biopsy (CNB) based on generally small series. In this article, the authors present precise estimates for overall underestimation and for categories of histologic underestimates (including categories that reflect contemporary classification) and examine the effect of lesion and sampling variables., Methods: Among 4035 consecutive CNBs, the authors examined women whose CNB outcome represented a potential underestimate of malignancy (benign but of uncertain biologic or malignant potential or B3 and ductal carcinoma in situ [DCIS]). From 889 eligible women, all 758 women who had excision histology available were included., Results: Overall underestimation of CNB was 27.7% (95% confidence interval [95% CI], 24.5-30.9%). The following category-specific rates were used: B3 underestimates, 36.2% (95% CI, 30.6-41.8%); B3 underestimates (excluding atypical proliferations), 17.9% (95% CI, 10.8-24.9%); atypical ductal hyperplasia underestimates, 29.0% (95% CI, 21.4-36.6%; upgraded to DCIS) and 44.2% (95% CI, 36.0-52.5%; upgraded to DCIS or invasive cancer); and DCIS underestimates, 22.8% (95% CI, 19.0-26.5%). There was a significant trend toward greater underestimation of malignancy with increasing lesion size on imaging studies for overall underestimates (P = .00008), B3 underestimates (P = .009), and DCIS underestimates (P = .0007). Underestimation rates did not differ between masses (27.9%) and microcalcifications (27.6%; chi-square statistic with 1 degree of freedom = 3.02; P = .98) and were significantly lower for vacuum-assisted CNB (11-gauge) than for automated CNB (14-gauge; P = .001). Underestimation rates, when sampling microcalcifications, decreased with increasing number of cores collected, but this was mainly for DCIS underestimates., Conclusions: CNB results that were not definitely negative or were not positive for invasive cancer were associated with high rates of underestimation of disease and with target lesion size. Identifying imaging or sampling factors that affect underestimation rates of CNB may assist in reducing their occurrence and better predicting excision histology outcomes., ((c) 2007 American Cancer Society.)

High mammographic breast density (H-MBD) has been associated with increased breast cancer (BC) risk, even after adjustment for established BC risk factors. Only a few studies have examined the influence of diet on MBD. In a longitudinal study in Florence, Italy, we identified about 2,000 women with a mammogram taken 5 years after enrollment, when detailed information on dietary and lifestyle habits and anthropometric measurements had been collected. Original mammograms have been identified and retrieved (1,668; 83%), and MBD was assessed by 2 experienced readers, according to Wolfe's classification and a semiquantitative scale. By logistic analysis, we compared women with H-MBD (P2 + DY according to Wolfe's classification) with those with low-MBD (N1 + P1). H-MBD was confirmed to be inversely associated with BMI, number of children and breast feeding, while it was directly associated with higher educational level, premenopausal status and a previous breast biopsy. In multivariate analyses adjusted for non-dietary variables, H-MBD was inversely associated with increasing consumption of vegetables (p for trend = 0.005) and olive oil (p for trend = 0.04). An inverse association was also evident between H-MBD and frequent consumption of cheese and high intakes of beta-carotene, vitamin C, calcium and potassium (p for trend < or = 0.05). On the other hand, we found a positive association with increasing consumption of wine (p for trend = 0.01). This large longitudinal study, the first carried out in Mediterranean women, suggests that specific dietary components may play a key role in determining MBD in this population, thus possibly modulating BC risk.

Purpose: To compare the performance of screen-film and digital mammography in the assessment of screen-detected breast lesions., Materials and Methods: A series of 100 consecutive mammographic screen-detected lesions (65 masses, 6 architectural distortions, 29 microcalcifications) deserving diagnostic assessment and judged to have a low positive predictive value underwent screen-film mammography (SFM) and digital mammography by a Fuji computed radiography system (FCR) (double exposure, same view, without removing compression) of the corresponding breast. Three sets of images (SFM, hard copy and soft copy FCR) were read, blind of assessment outcome, by three experienced radiologists. For the three different imaging modalities a contrast-detail analysis, dose evaluation and diagnostic accuracy by means of ROC analysis were performed. At the end of the diagnostic workup all suspicious cases (20) underwent surgical biopsy and were histologically confirmed as cancers and the cases which were negative or benign at assessment (80) were followed up for a period of 12-20 months. During the follow-up period two more cases proved to be cancers at subsequent examinations., Results: Contrast-detail analysis gives better image quality for FCR compared to SFM at the same delivered dose, whilst in ROC analysis the SFM (AUC 0.7158), hard copy FCR (AUC 0.7404) and soft copy FCR (AUC 0.7501) (chi(2)=1.30, p=0.5220) are equivalent., Conclusion: FCR has a diagnostic performance equivalent to SFM in the assessment of screen-detected lesions with a low positive predictive value for cancer and it may be safely included in routine screening practice.

Purpose: To compare the diagnostic accuracy of two commercial CAD systems (CADx and R2) and their impact as an aid to conventional reading of screening mammograms., Materials and Methods: The image set considered consisted of 120 mammograms, 89 confirmed negative and 31 with subsequent interval cancers (11 classified as false negatives (FN), 20 as "minimal signs" (MS)). The set was digitised and processed with CAD, and printouts obtained of the mammograms with indications of the areas warranting review. Six expert radiologists read the mammograms three times, once using conventional reading and twice using CAD reading with CADx and R2, respectively. The two CAD systems were compared in terms of diagnostic accuracy of the marks and the impact of CAD reading compared to conventional reading and to the use of independent second reading simulated by combining pairs of single conventional readings., Results: R2 highlighted more calcifications (218 vs 132, +65%) and CADx highlighted more masses (208 vs 105, +98%). CADx and R2 marked 15 and 17 out of 31 cancers, respectively (sensitivity 48.3% vs 54.8%, chi squared=6.4, p=0.79), 10 and 6 out of 11 FN (90.9% vs 54.5%, chi squared=2.0, p=0.15), respectively, and 5 and 11 out of 20 MS (25.0% vs 55.0%, chi squared=2.6, p=0.10), respectively. As for specificity, the false positive markings for masses were on average (per case) 1.60 for CADx and 0.75 for R2, those for calcifications were 1.08 for CADx and 1.77 for R2 and the total false positive markings were 2.68 for CADx and 2.52 for R2. CADx and R2 marked 73 and 63 of 89 negative controls (specificity = 0.18 vs 0.29, chi squared=2.52, p=0.11), respectively. All the radiologists showed greater sensitivity with CAD reading compared to conventional reading. On average, sensitivity with conventional reading was 58.6% (109/186), as against 70.9% (132/186) for CADx or R2 (chi squared=5.71, p=0.016). Sensitivity for FN cases was 71.2% (47/66) with conventional reading, 84.8% (56/66) with CADx (chi squared=2.82, p=0.09) and 80.3% (53/66) for R2 (chi squared=1.03, p=0.30) (CADx vs R2, chi squared=0.21, p=0.64). Sensitivity for MS cases was 51.6% (62/120) for conventional reading, 63.3% (76/120) for CADx (chi squared=2.88, p=0.08) and 65.8% (79/120) for R2 (chi squared=4.40, p=0.03) (CADx vs R2, chi squared=0.07, p=0.78). The recall rates were 18.1% (97/534) for conventional reading, 29.7% (159/534) for CADx (chi squared=5.72, p=0.01) and 24.3% (130/534) for R2 (chi squared=10.11, p=10-5) (CADx vs R2, chi squared=3.71, p=0.05). Double reading was significantly more sensitive than conventional reading (chi squared=29.6, p=10-6), CADx (chi squared=5.33, p=0.02) and R2 (chi squared=5.33, p=0.02). The recall rate for double reading was significantly higher than for conventional reading (chi squared=21.5, p=10-6) whereas no significant difference was detected when compared to CADx (chi squared=0.16, p=0.68) or R2 (chi squared=3.4, p=0.06)., Conclusions: Despite using different algorithms, the two CAD systems exhibit comparable levels of diagnostic accuracy and a similar positive impact on sensitivity when used as an aid to conventional reading. Single reading with either CAD system is as specific but not as sensitive to double independent reading: its use as an alternative to double reading cannot be recommended and should be investigated further by means of controlled prospective studies.

Purpose: To evaluate the diagnostic accuracy of 11-G vacuum-assisted stereotactic core biopsy (VAB) of isolated clusters of microcalcifications identified by mammography., Materials and Methods: Retrospective analysis of 364 consecutive procedures from February 1999 to June 2002. Final outcome was histological diagnosis at surgery or mammographic follow-up. Linkage with local cancer registry was available. Diagnostic accuracy and upgrading of atypical ductal hyperplasia (ADH) to carcinoma or of ductal carcinoma in situ (DCIS) to invasive carcinoma (INV) was evaluated. The positive predictive value (PPV) of radiological judgement (score 1 to 5) and of the cluster volume (only for unifocal lesions) for ADH or more severe lesions was also considered., Results: A total of 364 consecutive VAB procedures were evaluated (average age 54.9, range 33-81). VAB report was negative, ADH, DCIS or INV in 192, 22, 126 or 24 cases, respectively. Of 188 cases with ADH or more severe reports at VAB or surgical biopsy 16 had an originally negative VAB report, yielding a sensitivity of 91.4%. Upgrading at surgical biopsy for cases with follow-up was 29.4% (5/17) for ADH (DCIS=2, INV=3) and 17.3% (20/115) for DCIS. Of 221 cases with known outcome and mammograms available for review PPV was 37.1%, 65.9%, 90.9%, and 89.4% for radiological suspicion degrees 2,3,4 and 5, respectively (chi squared for trend = 32.44, p<10(-6)) and was 70.0%, 72.4% and 89.4% for cluster volumes of 0-60, 61-500 and >500 mmc, respectively (chi squared for trend= 2.36, p=0.12) among 195 unifocal clusters. No microcalcifications were found at core radiography in 20 cases (VAB negative=18, ADH=1, INV=1) with DCIS or INV occurring in 4 or 1 case, respectively, at further surgery., Conclusions: Core biopsy avoids unnecessary surgery in many subjects with suspicious microcalcifications, although it implies a non negligible risk of false negative report. Surgical biopsy in VAB negative cases could be indicated according to other variables (e.g. the degree of radiological suspicion). VAB has relevant limits in grading breast lesions, as ADH or DCIS are associated to a considerable risk of upgrading at surgical biopsy. VAB reports other than INV need to be confirmed at surgery before an individual treatment strategy may be defined.

Purpose: To evaluate the role of double reading of screening mammograms by expert radiologists., Material and Methods: We analyzed the results of independent readings of a proficiency test of screening mammography (140 cases, 32 cancers) performed by four expert radiologists. Double reading was simulated by matching the four original readings in 6 possible combinations. The impact of double reading over single reading was evaluated in terms of increased sensitivity and increased recall rate., Results: Of 32 carcinomas 22, 6, or 4 were identified by 4, 3, or 2 readers, respectively. Of 108 cases negative for cancer a recall for further investigations was suggested by 4, 3, 2, 1 or no reader(s) in 3, 3, 9, 14, or 79 cases, respectively. Inter-reader diagnostic repeatability was good (k = 0.65). Single readers achieved an average sensitivity of 89% (range 87.5-90.6%) and an average recall rate of 12.2% (range 7.4-16.6%). Simulated double reading achieved an average increase in sensitivity of 8.8% (range 6.2-10.95%) and an average increase of recall rate of 6.2% (range 3.8-8.3%)., Conclusions: Even though the relative increase of recall rate is relevant (+53.2%), the corresponding gain in sensitivity justifies the use of double reading, which was confirmed to be worthwhile also when expert radiologists are involved. This study confirms the opportunity of adopting double reading as a routine procedure in mammographic screening.

This study reports the results of some voluntary Italian radiologists performing 103 proficiency tests in clinical (100 patients, 32 cancers) and screening mammography (150 patients, 17 cancers). Relative to the average accuracy of a panel of expert radiologists, 12 of 49 readers (27%) and 32 of 54 readers (56%) passed the clinical and screening mammography test, respectively. The results were significantly correlated with the readers' previous experience (years of mammographic practice [< 2, 2-4, > 4] and number of mammograms read [< 5,000, 5-10,000, > 10,000]). The rate of passed test was: < 2 years = 0%, 2-4 years = 40%, > 4 years = 66.6% (P = 0.002); < 5,000 mammograms read = 15.3%, 5-10,000 = 28.5%, > 10,000 = 69.2% (P = 0.02). The best results were achieved by the readers with a previous reading experience of at least 10,000 mammograms, a figure which might be used as the reference for a future criterion of accreditation on a national basis. Proper training before reporting mammography is fundamental to ensure a good diagnostic performance. The low number of tests performed in most Italian mammographic practice facilities makes local training highly questionable and requires quite a long time. Reference centers, adequately equipped for training, should be identified for this purpose. Proficiency tests such as those described in the present study are useful to assess individual performance and should be a part of a training program.

The authors reviewed a series of 748 consecutive male patients referred for breast screening; their average age was 50.5 years. A malignant lesion was detected in 20 patients (18 infiltrating ductal carcinomas, 1 intraductal carcinoma and 1 myxosarcoma). Of 18 infiltrating carcinomas, 17 were found in patients over 60 years of age; pT classes were pT1c in 13 patients, pT2 in 2, pT4b in 1, pT4d in 1 and pTx in one patient. Biopsy demonstrated 92 benign lesions (74 gynecomastia cases and 18 other lesions), whereas 636 lesions were considered benign at direct or cancer registry follow-up. Sensitivity was 85% for palpation, 88.8% for mammography, 93.7% for cytology and 100% for US. Specificity was 95.3%, 94%, 95.6% and 97.9%, respectively. Combined palpation and mammography had 100% sensitivity. Sixty-five of 92 benign lesions were submitted to biopsy, even in the absence of suspicion, for psychological/cosmetic reasons. Negative cytology spared unnecessary biopsy in 9 cases, which were fairly suspicious at other exams. To conclude, we confirm the role of this multimodality clinical-instrumental diagnostic approach, with a special emphasis on the role of US. Cytology was as useful to avoid unnecessary open biopsy in men as it is in women. Male breast cancer has the same semiology as female breast cancer, though with a prevalence of opacities with blurred outline and in the absence of scirrhous-stellate patterns. The diagnostic protocol we used to diagnose breast cancer in women seems to be fully indicated also in men.

The authors report on a series of 1009 consecutive patients submitted to clinical examination, mammography, cytology and galactography for the presence of nipple discharge. Galactography was performed mainly in the presence of hematic nipple discharge. Surgical biopsy was performed in 392 cases, and 52 cancers (31 invasive and 21 intraductal lesions) were diagnosed, which were suspected at palpation, mammography, cytology and galactography in 17, 17, 18 and 31 cases, respectively. Forty of 52 cancers were suspected on the basis of combined exam findings, while 8 cancers (7 intraductal and 1 invasive lesions) were submitted to biopsy on the basis of a galactographic diagnosis of multiple benign papilloma, an (invasive) lesion with a diagnosis of single papilloma, and 3 (invasive) lesions because of persistent hematic discharge. Cancer was suspected with only one exam in 14 cases: 3 at cytology, 2 at mammography, 1 at clinical examination and 8 at galactography. Hematic discharge alone is not a sufficient reason to indicate surgery, because its positive predictive value for cancer is low (< or = 10%), while cytology is of limited help because of its poor sensitivity (34.6%). In contrast, galactography (59.6% sensitivity) gives a greater contribution to differential diagnosis and is always indicated in the presence of hematic discharge. Galactographic evidence suspicious for cancer (67.3% positive predictive value) or for multiple papilloma (9.7% positive predictive value) is sufficient to advise open biopsy. The surgical removal of single papillomas is of questionable benefit, since single papillomas are benign lesions, with no clear evidence of progression to cancer. In our series, only one cancer was misdiagnosed as a single papilloma at galactography (0.5% positive predictive value).

The diagnostic features are reported of 143 consecutive patients with breast cancer intramammary recurrences observed after conservative treatment, 1984 to 1994. Disease-free interval after surgery was 3.7 years on the average, being longer for the patients receiving postoperative breast irradiation (3.9 vs 3.1 years). The conserved breast was followed-up on a regular basis with palpation and mammography, whereas US and cytology were used only in selected suspicious cases. Palpation, mammography, cytology or US suspected the recurrence in 75, 64, 81 and 77% of cases, respectively. Mammographic false negatives were not explained by breast parenchymal density (Wolfe's pattern) or by breast irradiation, but were likely to be ascribed to the masking effect of surgical scars and distortion. Most failures at cytology were caused by inadequate sampling: when sampling was adequate, cytology exhibited the highest sensitivity (97%). In all, combined palpation + mammography, palpation + cytology and palpation + mammography + cytology diagnosed correctly 97, 98 and 100% of cases, respectively. Palpation should be always combined with mammography in the follow-up of the conserved breast, but US and aspiration cytology should be performed in case of any clinico-radiologic abnormality carrying even a minimal risk of recurrence.