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Abstract Background Socioeconomic status (SES) is known to be positively associated with breast cancer risk but its relationship with mammographic density, a marker of susceptibility to breast cancer, is unclear. This study aims to investigate whether mammographic density varies by SES and to identify the underlying anthropometric, lifestyle and reproductive factors leading to such variation. Methods In a cross-sectional study of mammographic density in 487 pre-menopausal women, SES was assessed from questionnaire data using highest achieved level of formal education, quintiles of Census-derived Townsend scores and urban/rural classification of place of residence. Mammographic density was measured on digitised films using a computer-assisted method. Linear regression models were fitted to assess the association between SES variables and mammographic density, adjusting for correlated variables. Results In unadjusted models, percent density was positively associated with SES, with an absolute difference in percent density of 6.3% (95% CI 1.6%, 10.5%) between highest and lowest educational categories, and of 6.6% (95% CI -0.7%, 12.9%) between highest and lowest Townsend quintiles. These associations were mainly driven by strong negative associations between these SES variables and lucent area and were attenuated upon adjustment for body mass index (BMI). There was little evidence that reproductive factors explained this association. SES was not associated with the amount of dense tissue in the breast before or after BMI adjustment. The effect of education on percent density persisted after adjustment for Townsend score. Mammographic measures did not vary according to urban/rural place of residence. Conclusions The observed SES gradients in percent density paralleled known SES gradients in breast cancer risk. Although consistent with the hypothesis that percent density may be a mediator of the SES differentials in breast cancer risk, the SES gradients in percent density were mainly driven by the negative association between SES and BMI. Nevertheless, as density affects the sensitivity of screen-film mammography, the higher percent density found among high SES women would imply that these women have a higher risk of developing cancer but a lower likelihood of having it detected earlier.

The South African Breast Cancer and HIV Outcomes prospective cohort (SABCHO) study was established to investigate survival determinants among HIV-positive and HIV-negative SA women with breast cancer. This paper describes common and unique characteristics of the cancer centres and their participants, examining disparities in pathways to diagnosis, treatment resources and approaches adopted to mitigate resource constraints. The Johannesburg (Jhb), Soweto (Sow), and Durban (Dbn) sites treat mainly urban, relatively better educated and more socioeconomically advantaged patients whereas the Pietermaritzburg (Pmb) and Empangeni (Emp) sites treat predominantly rural, less educated and more impoverished communities The Sow, Jhb, and Emp sites had relatively younger patients (mean ages 54 ±14.5, 55±13.7 and 54±14.3 respectively), whereas patients at the Dbn and Pmb sites, with greater representation of Asian Indian women, were relatively older (mean age 57 ±13.9 and 58 ±14.6 respectively). HIV prevalence among the cohort was high, ranging from 15%-42%, (Cohort obesity (BMI ≥ 30 kg/m2) at 60%, self-reported hypertension (41%) and diabetes (13%). Direct referral of patients from primary care clinics to cancer centre occurred only at the Sow site which uniquely ran an open clinic and where early stage (I and II) proportions were highest at 48.5%. The other sites relied on indirect patient referral from regional hospitals where significant delays in diagnostics occurred and early-stage proportions were a low (15%- 37.3%). The Emp site referred patients for all treatments to the Dbn site located 200km away; the Sow site provided surgery and endocrine treatment services but referred patients to the Jhb site 30 Km away for chemo- and radiation therapy. The Jhb, Dbn and Pmb sites all provided complete oncology treatment services. All treatment centres followed international guidelines for their treatment approaches. Findings may inform policy interventions to address national and regional disparities in breast cancer care., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mapanga et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: In low- and middle-income countries (LMICs), advanced-stage diagnosis of breast cancer (BC) is common, and this contributes to poor survival. Understanding the determinants of the stage at diagnosis will aid in designing interventions to downstage disease and improve survival from BC in LMICs., Methods: Within the South African Breast Cancers and HIV Outcomes (SABCHO) cohort, we examined factors affecting the stage at diagnosis of histologically confirmed invasive breast cancer at five tertiary hospitals in South Africa (SA). The stage was assessed clinically. To examine the associations of the modifiable health system, socio-economic/household and non-modifiable individual factors, hierarchical multivariable logistic regression with odds of late-stage at diagnosis (stage III-IV), was used., Results: The majority (59%) of the included 3497 women were diagnosed with late-stage BC disease. The effect of health system-level factors on late-stage BC diagnosis was consistent and significant even when adjusted for both socio-economic- and individual-level factors. Women diagnosed in a tertiary hospital that predominantly serves a rural population were 3 times (OR = 2.89 (95% CI: 1.40-5.97) as likely to be associated with late-stage BC diagnosis when compared to those diagnosed at a hospital that predominantly serves an urban population. Taking more than 3 months from identifying the BC problem to the first health system entry (OR = 1.66 (95% CI: 1.38-2.00)), and having luminal B (OR = 1.49 (95% CI: 1.19-1.87)) or HER2-enriched (OR = 1.64 (95% CI: 1.16-2.32)) molecular subtype as compared to luminal A, were associated with a late-stage diagnosis. Whilst having a higher socio-economic level (a wealth index of 5) reduced the probability of late-stage BC at diagnosis, (OR = 0.64 (95% CI: 0.47-0.85))., Conclusion: Advanced-stage diagnosis of BC among women in SA who access health services through the public health system was associated with both modifiable health system-level factors and non-modifiable individual-level factors. These may be considered as elements in interventions to reduce the time to diagnosis of breast cancer in women., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mapanga et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The presence of preexisting morbidities poses a challenge to cancer patient care. There is little information on the profile and prevalence of multi-morbidities in breast cancer patients across middle income countries (MIC) to lower income countries (LIC) in sub-Saharan Africa (SSA). The African Breast Cancer-Disparities in Outcomes (ABC-DO) breast cancer cohort spans upper MICs South Africa and Namibia, lower MICs Zambia and Nigeria and LIC Uganda. At cancer diagnosis, seven morbidities were assessed: obesity, hypertension, diabetes, asthma/chronic obstructive pulmonary disease, heart disease, tuberculosis and HIV. Logistic regression models were used to assess determinants of morbidities and the influence of morbidities on advanced stage (stage III/IV) breast cancer diagnosis. Among 2189 women, morbidity prevalence was the highest for obesity (35%, country-specific range 15-57%), hypertension (32%, 15-51%) and HIV (16%, 2-26%) then for diabetes (7%, 4%-10%), asthma (4%, 2%-10%), tuberculosis (4%, 0%-8%) and heart disease (3%, 1%-7%). Obesity and hypertension were more common in upper MICs and in higher socioeconomic groups. Overall, 27% of women had at least two preexisting morbidities. Older women were more likely to have obesity (odds ratio: 1.09 per 10 years, 95% CI 1.01-1.18), hypertension (1.98, 1.81-2.17), diabetes (1.51, 1.32-1.74) and heart disease (1.69, 1.37-2.09) and were less likely to be HIV positive (0.64, 0.58-0.71). Multi-morbidity was not associated with stage at diagnosis, with the exception of earlier stage in obese and hypertensive women. Breast cancer patients in higher income countries and higher social groups in SSA face the additional burden of preexisting non-communicable diseases, particularly obesity and hypertension, exacerbated by HIV in Southern/Eastern Africa., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Multimorbidity in women with breast cancer may delay presentation, affect treatment decisions and outcomes. We described the multimorbidity profile of women with breast cancer, its determinants, associations with stage at diagnosis and treatments received. We collected self-reported data on five chronic conditions (hypertension, diabetes, cerebrovascular diseases, asthma/chronic obstructive pulmonary disease, tuberculosis), determined obesity using body mass index (BMI) and tested HIV status, in women newly diagnosed with breast cancer between January 2016 and April 2018 in five public hospitals in South Africa. We identified determinants of ≥2 of the seven above-mentioned conditions (defined as multimorbidity), multimorbidity itself with stage at diagnosis (advanced [III-IV] vs. early [0-II]) and multimorbidity with treatment modalities received. Among 2,281 women, 1,001 (44%) presented with multimorbidity. Obesity (52.8%), hypertension (41.3%), HIV (22.0%) and diabetes (13.7%) were the chronic conditions that occurred most frequently. Multimorbidity was more common with older age (OR = 1.02; 95% CI 1.01-1.03) and higher household socioeconomic status (HSES) (OR = 1.06; 95% CI 1.00-1.13). Multimorbidity was not associated with advanced-stage breast cancer at diagnosis, but for self-reported hypertension there was less likelihood of being diagnosed with advanced-stage disease in the adjusted model (OR 0.80; 95% CI 0.64-0.98). Multimorbidity was associated with first treatment received in those with early-stage disease, p = 0.003. The prevalence of multimorbidity is high among patients with breast cancer. Our findings suggest that multimorbidity had a significant impact on treatment received in those with early-stage disease. There is need to understand the impact of multimorbidity on breast cancer outcomes., (© 2019 UICC.)

Primary prevention is a key strategy to reducing the global burden of cancer, a disease responsible for ~ 9.6 million deaths per year and predicted to top 13 million by 2030. The role of environmental geochemistry in the aetiology of many cancers-as well as other non-communicable diseases-should not be understated, particularly in low- and middle-income countries where 70% of global cancer deaths occur and reliance on local geochemistry for drinking water and subsistence crops is still widespread. This article is an expansion of a series of presentations and discussions held at the 34th International Conference of the Society for Environmental Geochemistry and Health in Livingstone, Zambia, on the value of effective collaborations between environmental geochemists and cancer epidemiologists. Key technical aspects of each field are presented, in addition to a case study of the extraordinarily high incidence rates of oesophageal cancer in the East African Rift Valley, which may have a geochemical contribution. The potential merit of veterinary studies for investigating common geochemical risk factors between human and animal disease is also highlighted.

Background: Hot beverage consumption is a probable risk factor for esophageal squamous cell carcinoma (ESCC). No standardized exposure assessment protocol exists., Methods: To compare how alternative metrics discriminate distinct drinking habits, we measured sip temperatures and sizes in an international group of hot beverage drinkers in France ( n = 20) and hot porridge consumers ( n = 52) in a high ESCC incidence region of China. Building on the knowledge that sip size and temperature affect intraesophageal liquid temperature (IELT), IELTs were predicted by modeling existing data, and compared with first sip temperature and, across all sips, mean temperature and sip-weighted mean temperature., Results: Two contrasting exposure characteristics were observed. Compared with the international group, Chinese porridge consumers took larger first sips [mean difference +17 g; 95% confidence interval (CI), 13.3-20.7] of hotter (+9.5°C; 95% CI, 6.2-12.7) liquid, and their mean sip size did not vary greatly across sips, but the former groups increased in size as temperature decreased. This resulted in higher predicted IELTs (mean 61°C vs. 42.4°C) and sip-weighted temperatures (76.9°C vs. 56°C) in Chinese porridge consumers, and compared with first sip and mean temperature, these two metrics separated the groups to a greater extent., Conclusions: Distinguishing thermal exposure characteristics between these groups was greatly enhanced by measuring sip sizes. Temperature at first sip alone is suboptimal for assessing human exposure to hot foods and beverages, and future studies should include sip size measurements in exposure assessment protocols., Impact: This study provides a logistically feasible framework for assessing human exposure to hot beverages., (©2019 American Association for Cancer Research.)

Soil, water and food supply composition data have been combined to primarily estimate micronutrient intakes and subsequent risk of deficiencies in each of the regions studied by generating new data to supplement and update existing food balance sheets. These data capture environmental influences, such as soil chemistry and the drinking water sources to provide spatially resolved crop and drinking water composition data, where combined information is currently limited, to better inform intervention strategies to target micronutrient deficiencies. Approximately 1500 crop samples were analysed, representing 86 food items across 50 sites in Tanzania in 2013 and >230 sites in Western Kenya between 2014 and 2018. Samples were analysed by ICP-MS for 58 elements, with this paper focussing on calcium (Ca), copper (Cu), iron (Fe), magnesium (Mg), selenium (Se), iodine (I), zinc (Zn) and molybdenum (Mo). In general, micronutrient supply from food groups was higher from Kilimanjaro,Tanzania than Counties in Western Kenya, albeit from a smaller sample. For both countries leafy vegetable and vegetable food groups consistently contained higher median micronutrient concentrations compared to other plant based food groups. Overall, calculated deficiency rates were <1% for Cu and Mo and close to or >90% for Ca, Zn and I in both countries. For Mg, a slightly lower risk of deficiency was calculated for Tanzania at 0 to 1% across simplified soil classifications and for female/males, compared to 3 to 20% for Kenya. A significant difference was observed for Se, where a 3 to 28% risk of deficiency was calculated for Tanzania compared to 93 to 100% in Kenya. Overall, 11 soil predictor variables, including pH and organic matter accounted for a small proportion of the variance in the elemental concentration of food. Tanzanian drinking water presented several opportunities for delivering greater than 10% of the estimated average requirement (EAR) for micronutrients. For example, 1 to 56% of the EAR for I and up to 10% for Se or 37% for Zn could be contributed via drinking water.

There are no studies of oral health in relation to esophageal cancer in Africa, or of Eastern Africa's endemic dental fluorosis, an irreversible enamel hypo-mineralization due to early-life excessive fluoride intake. During 2014-18, we conducted a case-control study of squamous cell esophageal cancer in Eldoret, western Kenya. Odds ratios (AORs (95% confidence intervals)) were adjusted for design factors, tobacco, alcohol, ethnicity, education, oral hygiene and missing/decayed teeth. Esophageal cancer cases (N = 430) had poorer oral health and hygiene than controls (N = 440). Compared to no dental fluorosis, moderate/severe fluorosis, which affected 44% of cases, had a crude OR of 20.8 (11.6, 37.4) and on full adjustment was associated with 9.4-fold (4.6, 19.1) increased risk, whilst mild fluorosis (43% of cases) had an AOR of 2.3 (1.3, 4.0). The prevalence of oral leukoplakia and tooth loss/decay increased with fluorosis severity, and increased cancer risks associated with moderate/severe fluorosis were particularly strong in individuals with more tooth loss/decay. Using a mswaki stick (AOR = 1.7 (1.0, 2.9)) rather than a commercial tooth brush and infrequent tooth brushing also independently increased risk. Geographic variations showed that areas of high esophageal cancer incidence and those of high groundwater fluoride levels have remarkably similar locations across Eastern Africa. In conclusion, poor oral health in combination with, or as a result of, high-altitude susceptibility to hydro-geologically influenced dental fluorosis may underlie the striking co-location of Africa's esophageal cancer corridor with the Rift Valley. The findings call for heightened research into primary prevention opportunities of this highly fatal but common cancer., (© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Element deficiencies and excesses play important roles in non-communicable disease aetiology. When investigating their roles in epidemiologic studies without prospective designs, reverse-causality limits the utility of transient biomarkers in cases. This study aimed to investigate whether surrogate participants may provide viable proxies by assessing concentration correlations within households. We obtained spot urine samples from 245 Tanzanian and Kenyan adults (including 101 household pairs) to investigate intra-household correlations of urinary elements (As, Ba, Ca, Cd, Co, Cs, Cu, Fe, Li, Mn, Mo, Ni, Pb, Rb, S, Se, Sr, Tl, V and Zn) and concentrations (also available for: Bi, Ce, Sb, Sn and U) relative to external population-levels and health-based values. Moderate-strong correlations were observed for As (r = 0.65), Cs (r = 0.67), Li (r = 0.56), Mo (r = 0.57), Se (r = 0.68) and Tl (r = 0.67). Remaining correlations were <0.41. Median Se concentrations in Tanzania (29 µg/L) and Kenya (24 µg/L) were low relative to 5738 Canadians (59 µg/L). Exceedances (of reference 95th percentiles) were observed for: Co, Mn, Mo, Ni and U. Compared to health-based values, exceedances were present for As, Co, Mo and Se but deficiencies were also present for Mo and Se. For well correlated elements, household members in East African settings provide feasible surrogate cases to investigate element deficiencies/excesses in relation to non-communicable diseases.

Squamous cell esophageal cancer is common throughout East Africa, but its etiology is poorly understood. We investigated the contribution of alcohol consumption to esophageal cancer in Kenya, based on a hospital-based case-control study conducted from 08/2013 to 03/2018 in Eldoret, western Kenya. Cases had an endoscopy-confirmed esophageal tumor whose histology did not rule out squamous cell carcinoma. Age and gender frequency-matched controls were recruited from hospital visitors/patients without digestive diseases. Logistic regression was used to calculate odds ratios (ORs) and their 95% confidence intervals (CI) adjusting for tobacco (type, intensity) and 6 other potential confounders. A total of 422 cases (65% male, mean at diagnosis 60 (SD 14) years) and 414 controls were included. ORs for ever-drinking were stronger in ever-tobacco users (9.0, 95% CI: 3.4, 23.8, with few tobacco users who were never drinkers) than in never-tobacco users (2.6, 95% CI: 1.6, 4.1). Risk increased linearly with number of drinks: OR for >6 compared to >0 to ≤2 drinks/day were 5.2 (2.4, 11.4) in ever-tobacco users and 2.1 (0.7, 4.4) in never-tobacco users. Although most ethanol came from low ethanol alcohols (busaa or beer), for the same ethanol intake, if a greater proportion came from the moonshine chang'aa, it was associated with a specific additional risk. The population attributable fraction for >2 drinks per day was 48% overall and highest in male tobacco users. Alcohol consumption, particularly of busaa and chang'aa, contributes to half of the esophageal cancer burden in western Kenya., (© 2018 UICC.)

There is a growing population of older women living with HIV/AIDS (WLWHA). Breast cancer is a common cancer in women worldwide, but the global number of breast cancers in WLWHA is not known. We estimated, for each UN sub-region, the number and age distribution of WLWHA who were diagnosed with breast cancer in 2012, by combining IARC-GLOBOCAN estimates of age-country specific breast cancer incidence with corresponding UNAIDS HIV prevalence. Primary analyses assumed no HIV-breast cancer association, and a breast cancer risk reduction scenario was also considered. Among 16.0 million WLWHA aged 15+ years, an estimated 6,325 WLWHA were diagnosed with breast cancer in 2012, 74% of whom were in sub-Saharan Africa, equally distributed between Eastern, Southern and Western Africa. In most areas, 70% of HIV-positive breast cancers were diagnosed under age 50. Among all breast cancers (regardless of HIV status), HIV-positive women constituted less than 1% of the clinical burden, except in Eastern, Western and Middle Africa where they comprised 4-6% of under age 50 year old breast cancer patients, and in Southern Africa where this patient subgroup constituted 26 and 8% of breast cancers diagnosed under and over age 50 respectively. If a deficit of breast cancer occurs in WLWHA, the global estimate would reduce to 3,600. In conclusion, worldwide, the number of HIV-positive women diagnosed with breast cancer was already substantial in 2012 and with an expected increase within the next decade, early detection and treatment research targeted to this population are needed., (© 2018 UICC.)

Background: Case-control studies remain an important study design for aetiologic research on cancer, particularly when cohorts are not available. In addition to the potential biases inherent in this design, conducting fieldwork in settings with weak health care and information systems for cancer, such as in sub Saharan Africa, confer additional challenges which we present here with the aim to share experience to guide future studies., Methods: We undertook a hospital-based case-control study of squamous cell esophageal cancer at the Moi Teaching and Referral Hospital in Eldoret, West Kenya. Cases were recruited at endoscopy and controls from hospital wards, age and gender frequency-matched to cases. Urine, toenails, blood and tumour biopsy were collected and a questionnaire administered., Results: During this pilot phase, 143 cases and 155 controls were successfully recruited. Complete questionnaire data was obtained through e-data collection. Biospecimen collection was possible with support of an already existing equipped laboratory. We introduce changes made in the main study phase, including on expansion of the control groups to allow to consideration of selection bias., Conclusions: Extra attention and funding to train and monitor data quality and biospecimen collection and collaboration of a large group held together by strong leadership are essential. We recommend studies based on regional treatment centres with their more defined catchment areas rather than in the capital cities as referral routes in multi-level health care systems are severely attrition prone., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Esophageal squamous cell carcinoma (ESCC) remains the predominant histological subtype of esophageal cancer (EC) in many transitioning countries, with an enigmatic and geographically distinct etiology, and consistently elevated incidence rates in many Eastern and Southern African countries. To gain epidemiological insights into ESCC patterns across the continent, we conducted a systematic review and meta-analysis of male-to-female (M:F) sex ratios of EC age-standardised (world) incidence rates in Africa according to geography, time and age at diagnosis. Data from 197 populations in 36 countries were included in the analysis, based on data from cancer registries included in IARC's Cancer Incidence in Five Continents, Cancer in Africa and Cancer in Sub-Saharan Africa reports, alongside a systematic search of peer-reviewed literature. A consistent male excess in incidence rates overall (1.7; 95% CI: 1.4, 2.0), and in the high-risk Eastern (1.6; 95% CI: 1.4, 1.8) and Southern (1.8; 95% CI: 1.5, 2.0) African regions was observed. Within the latter two regions, there was a male excess evident in 30-39 year olds that was not observed in low-risk regions. Despite possible referral biases affecting the interpretability of the M:F ratios in place and time, the high degree of heterogeneity in ESCC incidence implies a large fraction of the disease is preventable, and directs research enquiries to elucidate early-age exposures among young men in Africa., (Copyright © 2018. Published by Elsevier Ltd.)

Purpose: Reported breast cancer incidence is rising in South Africa, where some women are diagnosed late and have poor outcomes. We studied patient and provider factors associated with clinical stage at diagnosis among women diagnosed at the Chris Hani Baragwanath Academic Hospital in Soweto, Johannesburg in 2015-2016., Methods: From face-to-face interviewer-administered questionnaires we compared self-reported socioeconomics, demographics, comorbidities, risk factors, personal and health system barriers, and from patient clinical records, clinical staging, receptor subtype, and tumor grade among 499 consecutive women newly diagnosed with advanced stage (III/IV) breast cancer versus those diagnosed early (stage 0/I/II). Logistic regression models were used to identify factors associated with advanced stage at diagnosis., Results: Among the women, 243 (49%) were diagnosed at early and 256 (51%) at advanced stages. In the multiple logistic regression adjusted model, completion of high school or beyond (odds ratio (OR) 0.59, and greater breast cancer knowledge and awareness (OR 0.86) were associated with lower stage of breast cancer at presentation. Advanced stage was associated with Luminal B (OR 2.25) and triple-negative subtypes (OR 3.17) compared to luminal A, with delays >3 months from first breast symptoms to accessing the health system (OR 2.79) and with having more than 1 visit within the referral health system (OR 3.19) for 2 visits; OR 2.73 for ≥3 visits)., Conclusions: Limited patient education, breast cancer knowledge and awareness, and health system inefficiencies were associated with advanced stage at diagnosis. Sustained community and healthcare worker education may down-stage disease and improve cancer outcomes.

Objectives: Mining and processing of chrysotile, an established carcinogen, has been undertaken in Asbest, Russian Federation since the late 1800s. Dust concentrations were routinely recorded at the open-pit mine and its asbestos-enrichment factories. We examined the temporal trends in these dust concentrations from 1951 to 2001., Methods: Analyses included 89290 monthly averaged gravimetric dust concentrations in six factories (1951-2001) and 1457 monthly averaged concentrations in the mine (1964-2001). Annual percent changes (APC) in geometric mean dust concentrations were estimated for each factory and the mine separately from linear mixed models of the logarithmic-transformed monthly averaged concentrations., Results: Dust concentrations declined significantly in the mine [APC: -1.6%; 95% confidence interval (CI): -3.0 to -0.2] and Factories 1-5 but not 6. Overall factory APCs ranged from -30.4% (95% CI: -51.9 to -8.9; Factory 1: 1951-1955) to -0.6% (95% CI: -1.5 to 0.2; Factory 6: 1969-2001). Factory trends varied across decades, with the steepest declines observed before 1960 [APCs: -21.5% (Factory 2) and -17.4% (Factory 3)], more moderate declines in the 1960s and 1970s [APCs from -10% in Factory 2 (1960s) to -0.3% (not statistically significant) in Factory 4 (1970s)], and little change thereafter. Mine dust concentrations increased in the 1960s (APC: +9.7%; 95% CI: 3.6 to 15.9), decreased in the 1990s (APC: -5.8%; 95% CI: -8.1 to -3.5) and were stable in between., Conclusions: In this analysis of >90000 dust concentrations, factory dust concentrations declined between 1951 and 1979 and then stabilized. In the mine, dust levels increased in the 1960s, declined in the 1990s and were unchanged in the interim., (Published by Oxford University Press on behalf of the British Occupational Hygiene Society 2017.)

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in most Eastern and Southern African countries, but its etiology has been understudied to date. To inform its research agenda, we undertook a review to identify, of the ESCC risk factors which have been established or strongly suggested worldwide, those with a high prevalence or high exposure levels in any ESCC-affected African setting and the sources thereof. We found that for almost all ESCC risk factors known to date, including tobacco, alcohol, hot beverage consumption, nitrosamines and both inhaled and ingested PAHs, there is evidence of population groups with raised exposures, the sources of which vary greatly between cultures across the ESCC corridor. Research encompassing these risk factors is warranted and is likely to identify primary prevention strategies., (© 2016 IARC/WHO.)

Background: Inter-women and intra-women comparisons of mammographic density (MD) are needed in research, clinical and screening applications; however, MD measurements are influenced by mammography modality (screen film/digital) and digital image format (raw/processed). We aimed to examine differences in MD assessed on these image types., Methods: We obtained 1294 pairs of images saved in both raw and processed formats from Hologic and General Electric (GE) direct digital systems and a Fuji computed radiography (CR) system, and 128 screen-film and processed CR-digital pairs from consecutive screening rounds. Four readers performed Cumulus-based MD measurements (n = 3441), with each image pair read by the same reader. Multi-level models of square-root percent MD were fitted, with a random intercept for woman, to estimate processed-raw MD differences., Results: Breast area did not differ in processed images compared with that in raw images, but the percent MD was higher, due to a larger dense area (median 28.5 and 25.4 cm 2 respectively, mean √dense area difference 0.44 cm (95% CI: 0.36, 0.52)). This difference in √dense area was significant for direct digital systems (Hologic 0.50 cm (95% CI: 0.39, 0.61), GE 0.56 cm (95% CI: 0.42, 0.69)) but not for Fuji CR (0.06 cm (95% CI: -0.10, 0.23)). Additionally, within each system, reader-specific differences varied in magnitude and direction (p < 0.001). Conversion equations revealed differences converged to zero with increasing dense area. MD differences between screen-film and processed digital on the subsequent screening round were consistent with expected time-related MD declines., Conclusions: MD was slightly higher when measured on processed than on raw direct digital mammograms. Comparisons of MD on these image formats should ideally control for this non-constant and reader-specific difference.

Purpose: Bimodal age distributions at diagnosis have been widely observed among US and European female breast cancer populations. To determine whether bimodal breast cancer distributions are also present in a sub-Saharan African population, we investigated female breast cancer in South Africa., Methods: Using the South African National Cancer Registry data, we examined age-at-diagnosis frequency distributions (density plots) for breast cancer overall and by their receptor (oestrogen, progesterone and HER2) determinants among black and white women diagnosed during 2009-2011 in the public healthcare sector. For comparison, we also analysed corresponding 2010-2011 US SEER data. We investigated density plots using flexible mixture models, allowing early/late-onset membership to depend on receptor status., Results: We included 8857 women from South Africa, 7176 (81 %) with known oestrogen receptor status, and 95064 US women. Bimodality was present in all races, with an early-onset mode between ages 40-50 years and a late-onset mode among ages 60-70 years. The early-onset mode was younger in South African black women (age 38), compared to other groups (45-54 years)., Conclusions: Consistent patterns of bimodality and of its receptor determinants were present across breast cancer patient populations in South Africa and the US. Although the clinical spectrum of breast cancer is well acknowledged as heterogeneous, universal early- and late-onset age distributions at diagnosis suggest that breast cancer etiology consists of a mixture two main types.

Mammographic density (MD) is a quantitative trait, measurable in all women, and is among the strongest markers of breast cancer risk. The population-based epidemiology of MD has revealed genetic, lifestyle and societal/environmental determinants, but studies have largely been conducted in women with similar westernized lifestyles living in countries with high breast cancer incidence rates. To benefit from the heterogeneity in risk factors and their combinations worldwide, we created an International Consortium on Mammographic Density (ICMD) to pool individual-level epidemiological and MD data from general population studies worldwide. ICMD aims to characterize determinants of MD more precisely, and to evaluate whether they are consistent across populations worldwide. We included 11755 women, from 27 studies in 22 countries, on whom individual-level risk factor data were pooled and original mammographic images were re-read for ICMD to obtain standardized comparable MD data. In the present article, we present (i) the rationale for this consortium; (ii) characteristics of the studies and women included; and (iii) study methodology to obtain comparable MD data from original re-read films. We also highlight the risk factor heterogeneity captured by such an effort and, thus, the unique insight the pooled study promises to offer through wider exposure ranges, different confounding structures and enhanced power for sub-group analyses., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The association between leisure-time physical activity (LTPA) and male breast cancer risk is unclear. In the Male Breast Cancer Pooling Project, with 449 cases and 13,855 matched controls, we used logistic regression with study stratification to generate adjusted ORs and 95% confidence intervals (CI) for LTPA tertiles and male breast cancer risk. Compared with low LTPA, medium and high LTPA were not associated with male breast cancer risk (OR, 1.01; 95% CI, 0.79-1.29; 0.90, 0.69-1.18, respectively). In joint-effects analyses, compared with the referent of high body mass index (BMI; ≥25 kg/m(2))/low LTPA, neither medium nor high PA was associated with risk among high BMI men, but normal BMI men (<25 kg/m(2)) with low or medium LTPA were at a nonsignificant ∼16% reduced risk and those with high LTPA were at a 27% reduced risk (OR, 0.73; 95% CI, 0.50-1.07). Physical activity alone may not confer protection against male breast cancer risk., (©2015 American Association for Cancer Research.)

Background: The etiology of male breast cancer is poorly understood, partly due to its relative rarity. Although tobacco and alcohol exposures are known carcinogens, their association with male breast cancer risk remains ill-defined., Methods: The Male Breast Cancer Pooling Project consortium provided 2,378 cases and 51,959 controls for analysis from 10 case-control and 10 cohort studies. Individual participant data were harmonized and pooled. Unconditional logistic regression was used to estimate study design-specific (case-control/cohort) ORs and 95% confidence intervals (CI), which were then combined using fixed-effects meta-analysis., Results: Cigarette smoking status, smoking pack-years, duration, intensity, and age at initiation were not associated with male breast cancer risk. Relations with cigar and pipe smoking, tobacco chewing, and snuff use were also null. Recent alcohol consumption and average grams of alcohol consumed per day were also not associated with risk; only one subanalysis of very high recent alcohol consumption (>60 g/day) was tentatively associated with male breast cancer (ORunexposed referent = 1.29; 95% CI, 0.97-1.71; OR>0-<7 g/day referent = 1.36; 95% CI, 1.04-1.77). Specific alcoholic beverage types were not associated with male breast cancer. Relations were not altered when stratified by age or body mass index., Conclusions: In this analysis of the Male Breast Cancer Pooling Project, we found little evidence that tobacco and alcohol exposures were associated with risk of male breast cancer., Impact: Tobacco and alcohol do not appear to be carcinogenic for male breast cancer. Future studies should aim to assess these exposures in relation to subtypes of male breast cancer., (©2014 American Association for Cancer Research.)

Introduction: Estimates of the proportion of estrogen receptor negative (ERN) and triple-negative (TRN) breast cancer from sub-Saharan Africa are variable and include high values. Large studies of receptor status conducted on non-archival tissue are lacking from this region., Methods: We identified 1218 consecutive women (91% black) diagnosed with invasive breast cancer from 2006–2012 at a public hospital in Soweto, South Africa. Immunohistochemistry based ER, progesterone receptor (PR) and human epidermal factor 2 (HER2) receptors were assessed at diagnosis on pre-treatment biopsy specimens. Mutually adjusted associations of receptor status with stage, age, and race were examined using risk ratios (RRs). ER status was compared with age-stratified US Surveillance Epidemiology and End Results program (SEER) data., Results: 35% (95% confidence interval (CI): 32-38) of tumors were ERN, 47% (45-52) PRN, 26% (23-29) HER2P and 21% (18-23) TRN. Later stage tumors were more likely to be ERN and PRN (RRs 1.9 (1.1-2.9) and 2.0 (1.3-3.1) for stage III vs. I) but were not strongly associated with HER2 status. Age was not strongly associated with ER or PR status, but older women were less likely to have HER2P tumors (RR, 0.95 (0.92-0.99) per 5 years). During the study, stage III + IV tumors decreased from 66% to 46%. In black women the percentage of ERN (37% (34-40)) and PRN tumors (48% (45-52)) was higher than in non-black patients (22% (14-31) and 34% (25-44), respectively, P = 0.004 and P = 0.02), which remained after age and stage adjustment. Age-specific ERN proportions in black South African women were similar to those of US black women, especially for women diagnosed over age 50., Conclusion: Although a greater proportion of black than non-black South African women had ER-negative or TRN breast cancer, in all racial groups in this study breast cancer was predominantly ER-positive and was being diagnosed at earlier stages over time. These observations provide initial indications that late-stage aggressive breast cancers may not be an inherent feature of the breast cancer burden across Africa.

Background: Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures., Methods: We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and nondense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, BMI, and menopausal status., Results: Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (P = 0.00005) and adjusted percent density (P = 0.001), whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (P = 0.003), but not with adjusted dense area (P = 0.07)., Conclusion: We identified two common breast cancer susceptibility variants associated with mammographic measures of radiodense tissue in the breast gland., Impact: We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association., (©2012 AACR)

Background: Primary prevention measures are needed for Africa's cancer burden (715,000 new cases and 542,000 deaths in 2008), a burden projected to double by 2030 due to demographic changes alone. Control of cancer-causing infections and lifestyle-related carcinogens will play a significant role in prevention, but less often addressed are environmental and occupational contributions., Methods: We review environmental issues that contribute to Africa's Cancer burden., Results: We demonstrate evidence of the impact of environmental carcinogens on the cancer burden as of now and that circumstances present today may increase their contribution further. Suboptimal implementation and monitoring of environmental protection and of occupational health standards, including in the informal sector, use of outdated technologies in industry and lack of awareness of potential hazards in the specific employment structure give rise to high levels of exposures. Carcinogens of concern include (i) those that have been long present (e.g. indoor air pollution) whose contribution may increase as life-expectancy increases and long latency periods for cancer are realised, (ii) exposures in mining and agricultural sectors and (iii) modern environmental hazards, including urban air pollution and agents arising from the mis-management of hazardous waste from local, industrial and trans-boundary sources., Conclusions: Actions taken to reduce exposures and research to fill gaps in knowledge, adapted to local settings, could help mitigate the cancer burden., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Substantial increases in height have occurred concurrently with economic development in most populations during the last century. In high-income countries, environmental exposures that can limit genetic growth potential appear to have lessened, and variation in height by socioeconomic position may have diminished. The objective of this study is to investigate inequalities in height in a cohort of children born in the early 1990s in England, and to evaluate which factors might explain any identified inequalities., Methods and Findings: 12,830 children from The Avon Longitudinal Study of Parents and Children (ALSPAC), a population based cohort from birth to about 11.5 years of age, were used in this analysis. Gender- and age-specific z-scores of height at different ages were used as outcome variables. Multilevel models were used to take into account the repeated measures of height and to analyze gender- and age-specific relative changes in height from birth to 11.5 years. Maternal education was the main exposure variable used to examine socioeconomic inequalities. The roles of parental and family characteristics in explaining any observed differences between maternal education and child height were investigated. Children whose mothers had the highest education compared to those with none or a basic level of education, were 0.39 cm longer at birth (95% CI: 0.30 to 0.48). These differences persisted and at 11.5 years the height difference was 1.4 cm (95% CI: 1.07 to 1.74). Several other factors were related to offspring height, but few changed the relationship with maternal education. The one exception was mid-parental height, which fully accounted for the maternal educational differences in offspring height., Conclusions: In a cohort of children born in the 1990s, mothers with higher education gave birth to taller boys and girls. Although height differences were small they persisted throughout childhood. Maternal and paternal height fully explained these differences.

Purpose: To investigate the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) lower lung cancer risk., Methods: We analysed pooled individual-level data from seven case-control and one cohort study in the International Lung Cancer Consortium (ILCCO). Relative risks for lung cancer associated with self-reported history of aspirin and other NSAID use were estimated within individual studies using logistic regression or proportional hazards models, adjusted for packyears of smoking, age, calendar period, ethnicity and education and were combined using random effects meta-analysis., Results: A total of 4,309 lung cancer cases (mean age at diagnosis 65 years, 45% adenocarcinoma and 22% squamous-cell carcinoma) and 58,301 non-cases/controls were included. Amongst controls, 34% had used NSAIDs in the past (81% of them used aspirin). After adjustment for negative confounding by smoking, ever-NSAID use (affirmative answer to the study-specific question on NSAID use) was associated with a 26% reduction (95% confidence interval 8 to 41%) in lung cancer risk in men, but not in women (3% increase (-11% to 30%)). In men, the association was stronger in current and former smokers, and for squamous-cell carcinoma than for adenocarcinomas, but there was no trend with duration of use. No differences were found in the effects on lung cancer risk of aspirin and non-aspirin NSAIDs., Conclusions: Evidence from ILCCO suggests that NSAID use in men confers a modest protection for lung cancer, especially amongst ever-smokers. Additional investigation is needed regarding the possible effects of age, duration, dose and type of NSAID and whether effect modification by smoking status or sex exists.

Background: The global burden of cancer is projected to increase from 13.3 to 21.4 million incident cases between 2010 and 2030 due to demographic changes alone, dominated by a growing burden in low- and middle-income countries (LMICs). Lifestyle risk factors for cancer are also changing in these countries and may further influence this burden., Design: We consider examples of changes already occurring in population-level distributions of tobacco and alcohol consumption, body weight, and reproductive lives of women to gauge the magnitude of their projected impact on cancer incidence in future decades., Results: Trends in lifestyle factors vary greatly between settings and by sex. Some common trends point to considerable increases in cancers of the (i) lung in men due to tobacco smoking; (ii) upper aerodigestive tract (UADT) due to increasing tobacco and alcohol consumption, worse in men; (iii) colon from increasing body mass index, and alcohol and tobacco consumption; and (iv) in women, breast due particularly to consistent international trends of younger age at menarche, smaller family size, and, at postmenopausal ages, increasing body weight., Conclusions: In many LMICs, the future cancer burden will be worsened by changing lifestyles. Affected common cancer sites likely to experience the largest increases are lung, colon, UADT, and breast.

Background: Mammographic density (MD) is a strong marker of breast cancer risk, but it is unclear whether tumors arise specifically within dense tissue., Methods: In 231 British women diagnosed with breast cancer after at least one negative annual screening during a mammographic screening trial, we assessed whether tumor location was related to localized MD 5 years prior to diagnosis. Radiologists identified tumor locations on digitised films. We used a validated algorithm to align serial images from the same woman to locate the corresponding point on the prediagnostic film. A virtual 1 cm square grid was overlaid on prediagnostic films and MD calculated for each square within a woman's breast (mean = 271 squares/film). Conditional logistic regression, matching on a woman's breast, was used to estimate the odds of a tumor arising in a square in relation to its prediagnostic square-specific MD., Results: Median (interquartile range) prediagnostic MD was 98.2% (46.8%-100%) in 1 cm-squares that subsequently contained the tumor and 41.0% (31.5%-53.9%) for the whole breast. The odds of a tumor arising in a 1 cm-square were, respectively, 6.1 (95% CI: 1.9-20.1), 16.6 (5.2-53.2), and 25.5-fold (8.1-80.3) higher for squares in the second, third, and fourth quartiles of prediagnostic MD relative to those in the lowest quartile within that breast (P(trend) < 0.001). The corresponding odds ratios were 2.3 (1.3-4.0), 3.9 (2.3-6.4), and 4.6 (2.8-7.6) if a 3 cm-square grid was used., Conclusion: Tumors arise predominantly within the radiodense breast tissue., Impact: Localized MD may be used as a predictor of subsequent tumor location within the breast., (©2011 AACR.)

The carcinogenicity of cigar and pipe smoking is established but the effect of detailed smoking characteristics is less well defined. We examined the effects on cancer incidence of exclusive cigar and pipe smoking, and in combination with cigarettes, among 102,395 men from Denmark, Germany, Spain, Sweden and the United Kingdom in the EPIC cohort. Hazard ratios (HR) and their 95% confidence intervals (CI) for cancer during a median 9-year follow-up from ages 35 to 70 years were estimated using proportional hazards models. Compared to never smokers, HR of cancers of lung, upper aerodigestive tract and bladder combined was 2.2 (95% CI: 1.3, 3.8) for exclusive cigar smokers (16 cases), 3.0 (2.1, 4.5) for exclusive pipe smokers (33 cases) and 5.3 (4.4, 6.4) for exclusive cigarette smokers (1,069 cases). For each smoking type, effects were stronger in current smokers than in ex-smokers and in inhalers than in non-inhalers. Ever smokers of both cigarettes and cigars [HR 5.7 (4.4, 7.3), 120 cases] and cigarettes and pipes [5.1 (4.1, 6.4), 247 cases] had as high a raised risk as had exclusive cigarette smokers. In these smokers, the magnitude of the raised risk was smaller if they had switched to cigars or pipes only (i.e., quit cigarettes) and had not compensated with greater smoking intensity. Cigar and pipe smoking is not a safe alternative to cigarette smoking. The lower cancer risk of cigar and pipe smokers as compared to cigarette smokers is explained by lesser degree of inhalation and lower smoking intensity.

Since 1987, the Gambia National Cancer Registry has provided nationwide cancer registration for the Gambia. We used data from 1998 to 2006 to assess age-standardized incidence rates (ASRs) of 2 common cancers in women, breast and cervix. With an ASR of 15.42 (95% CI [14.18-16.66]) for cervix and 5.86 (95% CI [5.12-6.59]) for breast per 10(5) person-years, these cancers ranked first and third, respectively, among Gambian women (the second most common being liver, ASR 14.90). Incidence of both cancers, breast and cervix, increased rapidly at young ages to reach a peak at ages 40-44 years. Significant differences were observed in relation to ethnicity. Using the Mandinka (42% of the population) as a reference, breast cancer incidence rates were 2.16-fold higher (95% CI [1.33-3.52]) in Jola (10% of the population), specially at early-onset ages (before 40 years). For cervix cancer, highest rates were observed in Fula (18% of the population; risk ratio (RR): 1.84 (95% CI [1.44-2.36])). In contrast, a significantly lower risk was observed in the Serrahuleh (9% of the population; RR: 0.54 (95% CI [0.31-0.96]). This study revealed a preponderance of early-onset breast cancer among Gambian women similar to that seen in African women in more developed countries but also demonstrates large ethnic variations. It points to the need for further studies on cancer determinants to improve prevention, early detection and therapeutic management of these diseases in a low-resource setting in West Africa.

Purpose: To compare and evaluate intensity-based registration methods for computation of serial x-ray mammogram correspondence., Methods: X-ray mammograms were simulated from MRIs of 20 women using finite element methods for modeling breast compressions and employing a MRI/x-ray appearance change model. The parameter configurations of three registration methods, affine, fluid, and free-form deformation (FFD), were optimized for registering x-ray mammograms on these simulated images. Five mammography film readers independently identified landmarks (tumor, nipple, and usually two other normal features) on pairs of diagnostic and corresponding prediagnostic digitized images from 52 breast cancer cases. Landmarks were independently reidentified by each reader. Target registration errors were calculated to compare the three registration methods using the reader landmarks as a gold standard. Data were analyzed using multilevel methods., Results: Between-reader variability varied with landmark (p < 0.01) and screen (p = 0.03), with between-reader mean distance (mm) in point location on the diagnostic/prediagnostic images of 2.50 (95% CI 1.95, 3.15)/2.84 (2.24, 3.55) for nipples and 4.26 (3.43, 5.24)/4.76 (3.85, 5.84) for tumors. Registration accuracy was sensitive to the type of landmark and the amount of breast density. For dense breasts (> or = 40%), the affine and fluid methods outperformed FFD. For breasts with lower density, the affine registration surpassed both fluid and FFD. Mean accuracy (mm) of the affine registration varied between 3.16 (95% CI 2.56, 3.90) for nipple points in breasts with density 20%-39% and 5.73 (4.80, 6.84) for tumor points in breasts with density < 20%., Conclusions: Affine registration accuracy was comparable to that between independent film readers. More advanced two-dimensional nonrigid registration algorithms were incapable of increasing the accuracy of image alignment when compared to affine registration.

Percent mammographic density (PMD) is a strong marker of breast cancer risk. It may be a correlate of the rate of breast tissue aging, as proposed by Pike to explain breast cancer age-incidence. We examined longitudinal changes in PMD in 645 breast screening attendees in London, UK, in which each had between 2 and 5 screens spanning 3-12 years at ages 50-65 years and compare these to Pike's model. Within-woman PMD declined during these ages, with a slowing rate of decline. Annual rates of decline were 1.4% (95% confidence interval: 1.2-1.6), 0.7% (0.6-0.9) and 0.1% (-0.2 to 0.4) at ages 50, 57 and 64. Dense area declined similarly, but the absolute magnitude of the rate of increase of nondense area was almost double that of dense area. PMD dropped by 2.4% (1.4-3.4) on menopausal transition and increased by 2.4% (1.4-3.5) with the use of hormone therapy. Higher body mass index, greater parity and being Afro-Caribbean or South Asian ethnicities were associated with lower PMD, but did not affect rate of change of PMD at these ages. Within-woman rank correlation of PMD was 0.80 for readings taken 9 years apart. Effects of menopause and parity and the lack of effect of menarche on age-specific PMD at these ages are consistent with the predicted determinants in Pike's model. A high degree of tracking of PMD indicates that at ages 50-65 years high-risk women could be identified by a single early screen at age older than 50.

Background: Socioeconomic status (SES) is known to be positively associated with breast cancer risk but its relationship with mammographic density, a marker of susceptibility to breast cancer, is unclear. This study aims to investigate whether mammographic density varies by SES and to identify the underlying anthropometric, lifestyle and reproductive factors leading to such variation., Methods: In a cross-sectional study of mammographic density in 487 pre-menopausal women, SES was assessed from questionnaire data using highest achieved level of formal education, quintiles of Census-derived Townsend scores and urban/rural classification of place of residence. Mammographic density was measured on digitised films using a computer-assisted method. Linear regression models were fitted to assess the association between SES variables and mammographic density, adjusting for correlated variables., Results: In unadjusted models, percent density was positively associated with SES, with an absolute difference in percent density of 6.3% (95% CI 1.6%, 10.5%) between highest and lowest educational categories, and of 6.6% (95% CI -0.7%, 12.9%) between highest and lowest Townsend quintiles. These associations were mainly driven by strong negative associations between these SES variables and lucent area and were attenuated upon adjustment for body mass index (BMI). There was little evidence that reproductive factors explained this association. SES was not associated with the amount of dense tissue in the breast before or after BMI adjustment. The effect of education on percent density persisted after adjustment for Townsend score. Mammographic measures did not vary according to urban/rural place of residence., Conclusions: The observed SES gradients in percent density paralleled known SES gradients in breast cancer risk. Although consistent with the hypothesis that percent density may be a mediator of the SES differentials in breast cancer risk, the SES gradients in percent density were mainly driven by the negative association between SES and BMI. Nevertheless, as density affects the sensitivity of screen-film mammography, the higher percent density found among high SES women would imply that these women have a higher risk of developing cancer but a lower likelihood of having it detected earlier.

Background: Mammographic density is a strong risk factor for breast cancer, usually measured by an area-based threshold method that dichotomizes the breast area on a mammogram into dense and nondense regions. Volumetric methods of breast density measurement, such as the fully automated standard mammogram form (SMF) method that estimates the volume of dense and total breast tissue, may provide a more accurate density measurement and improve risk prediction., Methods: In 2000-2003, a case-control study was conducted of 367 newly confirmed breast cancer cases and 661 age-matched breast cancer-free controls who underwent screen-film mammography at several centers in Toronto, Canada. Conditional logistic regression was used to estimate odds ratios of breast cancer associated with categories of mammographic density, measured with both the threshold and the SMF (version 2.2beta) methods, adjusting for breast cancer risk factors., Results: Median percent density was higher in cases than in controls for the threshold method (31% versus 27%) but not for the SMF method. Higher correlations were observed between SMF and threshold measurements for breast volume/area (Spearman correlation coefficient = 0.95) than for percent density (0.68) or for absolute density (0.36). After adjustment for breast cancer risk factors, odds ratios of breast cancer in the highest compared with the lowest quintile of percent density were 2.19 (95% confidence interval, 1.28-3.72; P(t) <0.01) for the threshold method and 1.27 (95% confidence interval, 0.79-2.04; Pt = 0.32) for the SMF method., Conclusion: Threshold percent density is a stronger predictor of breast cancer risk than the SMF version 2.2beta method in digitized images.

Mammographic density is strongly associated with breast cancer risk, and endogenous hormones, which are risk factors for breast cancer, may be involved in the mechanism. This cross-sectional study of 494 premenopausal women is the first to account for cyclic variations in estrogen levels, by measuring urinary estrone glucuronide (E1G) in the periovulatory and luteal phases of the menstrual cycle, and to assess the role of androgens. Computer-assisted density readings were obtained from digitized mammograms. Mean ovulatory E1G level and daily E1G load were both positively associated with percent density before adjustment for body mass index (BMI), with women in the top fourth having 10.2% (95% CI: 2.9%, 18.1%) and 8.9% (1.7%, 16.7%), respectively, higher density than those in the bottom fourth (Ptrend before/after BMI adjustment=0.006/0.11 and 0.01/0.13, respectively). Neither the peak nor luteal E1G levels were predictive of density after adjustment for E1G levels at other points in the cycle. The plasma androgens testosterone, androstenedione, and dehydroepiandrosterone sulfate were negatively associated with density. In mutually adjusted analyses, density was positively associated with insulin-like growth factor (IGF)-I and negatively with IGF-II (Ptrend=0.006 for both) but not with IGF binding protein-3. There was also weak evidence of a positive association of prolactin with density. The study supports the hypothesis that endogenous hormones affect density in premenopausal women; in particular, it shows a positive association between estrogen levels and density and suggests that the mean level throughout the cycle is the most biologically relevant measure. Most of these hormone-density associations were attenuated with further adjustment for BMI.

To assess long-term health effects of ovarian-stimulation drugs we followed-up for over 20 years a British cohort of 7355 women with ovulatory disorders, 43% of whom were prescribed ovarian-stimulation drugs, and identified a total of 274 deaths and 367 incident cancers. Relative to the general population, the cohort experienced lower mortality from most causes, including from all neoplasms combined, and lower incidence of cervical cancer, but higher incidence of cancers of the breast (relative risk: 1.13; 95% CI 0.97, 1.30) and corpus uteri (2.02; 1.37, 2.87). There were, however, no significant differences in the risk of cancers of the breast, corpus uteri, ovary, or of any other site, between women who had been prescribed ovarian-stimulation drugs and those who had not. Further analyses by type of drug and dose revealed a dose-response gradient in the risk of cancer of the corpus uteri (P for linear trend=0.03), with women given >or=2250 mg of clomiphene having a 2.6-fold (2.62; 0.94, 6.82) increase in risk relative to those who were not treated. These findings do not support strong associations between ovulation-stimulation drugs and cancer risks, but they indicate the need for continued monitoring to establish whether risks are elevated in certain subgroups of users.

Purpose: To (a) compare the performance of full-field digital mammography (FFDM), using hard-copy image reading, with that of screen-film mammography (SFM) within a UK screening program (screening once every 3 years) for women aged 50 years or older and (b) conduct a meta-analysis of published findings along with the UK data., Materials and Methods: The study complied with the UK National Health Service Central Office for Research Ethics Committee guidelines; informed patient consent was not required, since analysis was carried out retrospectively after data anonymization. Between January 2006 and June 2007, a London population-based screening center performed 8478 FFDM and 31 720 SFM screening examinations, with modality determined by the type of machine available at the screening site. Logistic regression was used to assess whether breast cancer detection rates and recall rates differed between screening modalities. For the meta-analysis, random-effects models were used to combine study-specific estimates, if appropriate., Results: A total of 263 breast cancers were detected. After adjustment for age, ethnicity, area of residence, and type of referral, there was no evidence of differences between FFDM and SFM in terms of detection rates (0.68 [95% confidence interval {CI}: 0.47, 0.89] vs 0.72 [95% CI: 0.58, 0.85], respectively, per 100 screening mammograms; P = .74), recall rates (3.2% [95% CI: 2.8, 3.6] vs 3.4% [95% CI: 3.1, 3.6]; P = .44), positive predictive value (PPV) of an abnormal mammogram, or characteristics of detected tumors. Meta-analysis of data from eight studies showed a slightly higher detection rate for FFDM, particularly at 60 years of age or younger (pooled FFDM-SFM difference: 0.11 [95% CI: 0.04, 0.18] per 100 screening mammograms), but no clear modality differences in recall rates or PPVs., Conclusion: Within a routine screening program, FFDM with hard-copy image reading performed as well as SFM in terms of process indicators; the meta-analysis was consistent with FFDM yielding detection rates at least as high as those for SFM.

Introduction: Mammographic breast density is one of the strongest known markers of susceptibility to breast cancer. To date research into density has relied on a single measure (for example, percent density (PD)) summarising the average level of density for the whole breast, with no consideration of how the radiodense tissue may be distributed. This study aims to investigate the spatial distribution of density within the breast using 493 mammographic images from a sample of 165 premenopausal women (~3 medio-lateral oblique views per woman)., Methods: Each breast image was divided into 48 regions and the PD for the whole breast (overall PD) and for each one of its regions (regional PD) was estimated. The spatial autocorrelation (Moran's I value) of regional PD for each image was calculated to investigate spatial clustering of density, whether the degree of clustering varied between a woman's two breasts and whether it was affected by age and other known density correlates., Results: The median Moran's I value for 165 women was 0.31 (interquartile range: 0.26, 0.37), indicating a clustered pattern. High-density areas tended to cluster in the central regions of the breast, regardless of the level of overall PD, but with considerable between-woman variability in regional PD. The degree of clustering was similar between a woman's two breasts (mean within-woman difference in Moran's I values between left and right breasts = 0.00 (95% confidence interval (CI) = -0.01, 0.01); P = 0.76) and did not change with aging (mean within-woman difference in I values between screens taken on average 8 years apart = 0.01 (95% CI = -0.01, 0.02); P = 0.30). Neither parity nor age at first birth affected the level of spatial autocorrelation of density, but increasing body mass index (BMI) was associated with a decrease in the degree of spatial clustering., Conclusions: This study is the first to demonstrate that the distribution of radiodense tissue within the breast is spatially autocorrelated, generally with the high-density areas clustering in the central regions of the breast. The degree of clustering was similar within a woman's two breasts and between women, and was little affected by age or reproductive factors although it declined with increasing BMI.

Introduction: Sex steroids, insulin-like growth factors (IGFs) and prolactin are breast cancer risk factors but whether their effects are mediated through mammographic density, one of the strongest risk factors for breast cancer, is unknown. If such a hormonal basis of mammographic density exists, hormones may underlie ethnic differences in both mammographic density and breast cancer incidence rates., Methods: In a cross-sectional study of 270 postmenopausal Caucasian and Afro-Caribbean women attending a population-based breast screening service in London, UK, we investigated whether plasma biomarkers (oestradiol, oestrone, sex hormone binding globulin (SHBG), testosterone, prolactin, leptin, IGF-I, IGF-II and IGF binding protein 3 (IGFBP3)) were related to and explained ethnic differences in mammographic percent density, dense area and nondense area, measured in Cumulus using the threshold method., Results: Mean levels of oestrogens, leptin and IGF-I:IGFBP3 were higher whereas SHBG and IGF-II:IGFBP3 were lower in Afro-Caribbean women compared with Caucasian women after adjustment for higher mean body mass index (BMI) in the former group (by 3.2 kg/m(2) (95% confidence interval (CI): 1.8, 4.5)). Age-adjusted percent density was lower in Afro-Caribbean compared with Caucasian women by 5.4% (absolute difference), but was attenuated to 2.5% (95% CI: -0.2, 5.1) upon BMI adjustment. Despite ethnic differences in biomarkers and in percent density, strong ethnic-age-adjusted inverse associations of oestradiol, leptin and testosterone with percent density were completely attenuated upon adjustment for BMI. There were no associations of IGF-I, IGF-II or IGFBP3 with percent density or dense area. We found weak evidence that a twofold increase in prolactin and oestrone levels were associated, respectively, with an increase (by 1.7% (95% CI: -0.3, 3.7)) and a decrease (by 2.0% (95% CI: 0, 4.1)) in density after adjustment for BMI., Conclusions: These findings suggest that sex hormone and IGF levels are not associated with BMI-adjusted percent mammographic density in cross-sectional analyses of postmenopausal women and thus do not explain ethnic differences in density. Mammographic density may still, however, be influenced by much higher premenopausal hormone levels.

It is not known whether the 20-30% lower breast cancer incidence rates in first-generation South Asian and Afro-Caribbean women relative to Caucasian women in the United Kingdom are reflected in mammographic density. The authors conducted a United Kingdom population-based multiethnic study of mammographic density at ages 50-64 years in 645 women. Data on breast cancer risk factors were obtained using a questionnaire/telephone interview. Threshold percent density was assessed on 5,277 digitized mammograms taken in 1995-2004 and was analyzed using multilevel models. Both ethnic minorities were characterized by more protective breast cancer risk factor distributions than Caucasians, such as later menarche, shorter stature, higher parity, earlier age at first birth, and less use of hormone therapy, but they had a higher mean body mass index; the last four factors were associated with lower mammographic density. Age-adjusted percent mammographic densities in Afro-Caribbeans and South Asians were 5.6% (95% confidence interval (CI): 3.5, 7.5) and 5.9% (95% CI: 3.6, 8.0) lower, respectively, than in Caucasians. Lower densities were partly attributed to higher body mass index, less use of hormone therapy, and a protective reproductive history, but these factors did not account entirely for ethnic differences, since fully adjusted mean densities were 1.3% (95% CI: -1.3, 3.7) and 3.8% (95% CI: 1.1, 6.3) lower, respectively. Ethnic differences in mammographic density are consistent with those for breast cancer risk.

Background: Mammographic density is one of the strongest risk factors for breast cancer. It is commonly measured by an interactive threshold method that does not fully use information contained in a mammogram. An alternative fully automated standard mammogram form (SMF) method measures density using a volumetric approach., Methods: We examined between-breast and between-view agreement, reliability, and associations of breast cancer risk factors with the threshold and SMF measures of breast density on the same set of 1,000 digitized films from 250 women who attended routine breast cancer screening by two-view mammography in 2004 at a London population-based screening center. Data were analyzed using random-effects models on transformed percent density., Results: Median (interquartile range) percent densities were 12.8% (5.0-22.3) and 21.8% (18.4-26.6) in the threshold and SMF methods, respectively. There was no evidence of systematic differences between left-right breasts or between views in either method. Reliability of a single measurement was lower in the SMF than in the threshold method (0.77 versus 0.92 for craniocaudal and 0.68 versus 0.89 for mediolateral oblique views). Increasing body mass index and parity were associated with reduced density in both methods; however, an increase in density with hormone replacement therapy use was found only with the threshold method., Conclusion: Established properties of mammographic density were observed for SMF percent density; however, this method had poorer left-right reliability than the threshold method and has yet to be shown to be a predictor of breast cancer risk.

Mammographic features are associated with breast cancer risk, but estimates of the strength of the association vary markedly between studies, and it is uncertain whether the association is modified by other risk factors. We conducted a systematic review and meta-analysis of publications on mammographic patterns in relation to breast cancer risk. Random effects models were used to combine study-specific relative risks. Aggregate data for > 14,000 cases and 226,000 noncases from 42 studies were included. Associations were consistent in studies conducted in the general population but were highly heterogeneous in symptomatic populations. They were much stronger for percentage density than for Wolfe grade or Breast Imaging Reporting and Data System classification and were 20% to 30% stronger in studies of incident than of prevalent cancer. No differences were observed by age/menopausal status at mammography or by ethnicity. For percentage density measured using prediagnostic mammograms, combined relative risks of incident breast cancer in the general population were 1.79 (95% confidence interval, 1.48-2.16), 2.11 (1.70-2.63), 2.92 (2.49-3.42), and 4.64 (3.64-5.91) for categories 5% to 24%, 25% to 49%, 50% to 74%, and > or = 75% relative to < 5%. This association remained strong after excluding cancers diagnosed in the first-year postmammography. This review explains some of the heterogeneity in associations of breast density with breast cancer risk and shows that, in well-conducted studies, this is one of the strongest risk factors for breast cancer. It also refutes the suggestion that the association is an artifact of masking bias or that it is only present in a restricted age range.