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BACKGROUND: Studies have shown increased mortality among women living with HIV diagnosed with breast cancer compared with HIV-negative women with breast cancer. We aimed to examine how this HIV differential varies by patient or breast tumour characteristics. METHODS: The African Breast Cancer-Disparities in Outcomes (ABC-DO) study is a prospective cohort of women (aged ≥18 years) with incident breast cancer recruited consecutively at diagnosis (2014-17) from hospitals in Namibia, Nigeria, South Africa, Uganda, and Zambia. Detailed clinical and epidemiological data, including self-reported or tested HIV status, were collected at baseline. Participants were actively followed up via telephone calls every 3 months. The primary outcome was all-cause mortality, assessed in all women who had at least one updated vital status after baseline interview. Using Cox regression, we examined differences in overall survival by HIV status in the cohort, and across country and patient subgroups, adjusted for age, tumour grade, and tumour stage at cancer diagnosis. FINDINGS: Between Sept 8, 2014, and Dec 31, 2017, we recruited 2154 women with primary breast cancer, 519 of whom were excluded due to their countries having small numbers of women with HIV for comparison. Among the remaining 1635 women, 313 (19%) were living with HIV, 1184 (72%) were HIV negative, and 138 (9%) had unknown HIV status. At breast cancer diagnosis, women with HIV were younger and had lower body-mass index (BMI) than their HIV-negative counterparts, but had similar tumour stage, grade, and receptor subtypes. At the end of the follow-up (Jan 1, 2019), a higher proportion of women with HIV (137 [44%] of 313) had died than had HIV-negative women (432 [37%] of 1184). Crude 3-year survival was 9% lower for women with HIV (46% [95% CI 40-53]) than for HIV-negative women (55% [52-59]; hazard ratio (HR) 1·41 [1·15-1·74]). The HIV survival differential did not differ by age, BMI, tumour subtype, or tumour grade, but was stronger in women with non-metastatic disease (3-year survival 52% HIV-positive vs 63% HIV-negative women, adjusted HR 1·65 [1·30-2·10]), whereas women with metastatic cancer had low survival, regardless of HIV status. INTERPRETATION: The larger survival deficit among women with HIV with non-metastatic breast cancer calls for a better understanding of the reasons underlying this differential (eg, biological mechanisms, health behaviours, detrimental HIV-breast cancer treatment interactions, or higher HIV background mortality) to inform strategies for reducing mortality among this patient group. FUNDING: Susan G Komen, International Agency for Research on Cancer, National Cancer Institute, and UK-Commonwealth Scholarships.

Summary Background The contribution of alcohol to the large burden of oesophageal squamous cell carcinoma (ESCC) in east Africa remains uncertain and difficult to assess owing to complex consumption patterns of traditional and commercial drinks. We aimed to assess whether alcohol drinking, overall and at specific intake levels, contributes to ESCC risk in east Africa. Methods We did a hospital-based case-control study in Kenya, Tanzania, and Malawi, which included comprehensive assessment of a variety of locally consumed alcohol that we used to classify drinkers as exclusively low alcohol-by-volume (ABV

Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. Mutational profiles were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining differences in ESCC incidence. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures single-base substitution (SBS)2 and SBS13 were present in 88% and 91% of cases, respectively, and accounted for 25% of the mutation burden on average, indicating that APOBEC activation is a crucial step in ESCC tumor development.

Despite women being disproportionally affected by cancer deaths at young ages, there are no global estimates of the resulting maternal orphans, who experience health and education disadvantages throughout their lives. We estimated the number of children who became maternal orphans in 2020 due to their mother dying from cancer in that year, for 185 countries worldwide and by cause of cancer-related death. Female cancer deaths-by country, cancer type and age (derived from GLOBOCAN estimates)-were multiplied by each woman's estimated number of children under the age of 18 years at the time of her death (fertility data were derived from United Nations World Population Prospects for birth cohort), accounting for child mortality and parity-cancer risk associations. Globally, there were 1,047,000 such orphans. Over half of these were orphans due to maternal deaths from breast (258,000, 25%), cervix (210,000, 20%) and upper-gastrointestinal cancers (136,000, 13%), and most occurred in Asia (48%: India 15%, China 10%, rest of Asia 23%) and Africa (35%). Globally, there were 40 new maternal orphans due to cancer per 100,000 children, with a declining trend with a higher Human Development Index (range: 121 in Malawi to 15 in Malta). An estimated 7 million children were prevalent maternal orphans due to cancer in mid-2020. Accelerating the implementation of the World Health Organization's cervical and breast cancer initiatives has the potential to avert not only millions of preventable female cancer deaths but also the associated, often-overlooked, intergenerational consequences of these deaths.

Background: Early age at menarche and tall stature are associated with increased breast cancer risk. We examined whether these associations were also positively associated with mammographic density, a strong marker of breast cancer risk. Methods: Participants were 10,681 breast-cancer-free women from 22 countries in the International Consortium of Mammographic Density, each with centrally assessed mammographic density and a common set of epidemiologic data. Study periods for the 27 studies ranged from 1987 to 2014. Multi-level linear regression models estimated changes in square-root per cent density (√PD) and dense area (√DA) associated with age at menarche and adult height in pooled analyses and population-specific meta-analyses. Models were adjusted for age at mammogram, body mass index, menopausal status, hormone therapy use, mammography view and type, mammographic density assessor, parity and height/age at menarche. Results: In pooled analyses, later age at menarche was associated with higher per cent density (β√PD = 0.023 SE = 0.008, P = 0.003) and larger dense area (β√DA = 0.032 SE = 0.010, P = 0.002). Taller women had larger dense area (β√DA = 0.069 SE = 0.028, P = 0.012) and higher per cent density (β√PD = 0.044, SE = 0.023, P = 0.054), although the observed effect on per cent density depended upon the adjustment used for body size. Similar overall effect estimates were observed in meta-analyses across population groups. Conclusions: In one of the largest international studies to date, later age at menarche was positively associated with mammographic density. This is in contrast to its association with breast cancer risk, providing little evidence of mediation. Increased height was also positively associated with mammographic density, particularly dense area. These results suggest a complex relationship between growth and development, mammographic density and breast cancer risk. Future studies should evaluate the potential mediation of the breast cancer effects of taller stature through absolute breast density. This work was supported by the US National Cancer Institute at the National Institutes of Health [R03CA167771]; the International Agency for Research on Cancer; the University of Western Australia [Research Collaboration Award] and the Cancer Council Western Australia [Capacity Building and Collaboration Grant]. Original studies were supported, according to country by: Australia VicHealth; Cancer Council Victoria; Australian National Health and Medical Research Council [209057, 251,553 and 504711]; Australian National Breast Cancer Foundation [to JSt]; Canada the National Cancer Institute of Canada [to NFB]; Chile Fondecyt [11100238 to MLG, 1120326, 1130277, 3130532]; World Cancer Research Fund [2010/245]; Ellison Medical Foundation Grant [to AP]; Iran Isfahan University of Medical Sciences; Israel The Israel Cancer Association; Republic of Korea Asan Medical Center [2010-0811]; Malaysia Sime Darby LPGA Tournament; Ministry of Education University Malaya [High Impact Research Grant UM.C/HIR/MOHE/06]; University Malaya [Research Grant UMRG RP046B-15HTM]; Mexico National Council of Science and Technology (Mexico); the American Institute for Cancer Research [10A035]; Netherlands EPIC-NL-Europe against Cancer Programme of the European Commission (SANCO); Dutch Ministry of Health; Dutch Cancer Society; ZonMW the Netherlands Organisation for Health Research and Development; World Cancer Research Fund (WCRF); Poland Polish-Norwegian Research Programme [PNRF-243-AI-1/07]; Singapore National Medical Research Council [Clinician Scientist Award]; National University Cancer Institute Singapore (NCIS) Centre grant programme from National Medical Research Council; South Africa Pink Drive; Spain Spain’s Health Research Fund (Fondo de Investigacion Santiaria) [PI060386 and PS09/0790]; Spanish Federation of Breast Cancer Patients (FECMA) [EPY1169-10]; Turkey-Roche Mustahzarlari San. A.S., Istanbul, Turkey; UK UK Engineering and Physical Sciences Research Council [EP/K020439/1 to JHi]; Breast Cancer Campaign [2007MayPR23], Cancer Research UK [G186/11 and C405/A14565]; Da Costa Foundation UK; USA National Cancer Institute [R01CA85265, R37 CA54281, R01 CA97396, P50 CA116201, R01 CA177150 and R01 CA140286]; Cancer Center Support Grant [CA15083; CA131332, CA124865, UM1 CA186107 and UM1 CA176726]; the Susan G. Komen Foundation. Sí

In this issue, Mmbaga and colleagues present results of a case–control study to investigate environmental and lifestyle risk factors for esophageal cancer in Tanzania, East Africa. The results contribute to the early stage of a growing evidence base aimed to inform primary prevention of a major poor prognosis cancer in East Africa. In this commentary, we first discuss considerations needed to evaluate causality of associations, a feature needed for primary prevention. There is a need for further studies across the African esophageal cancer corridor, for more refined exposure assessment and a careful consideration of potential epidemiologic biases within study designs for real-life situations in the setting. This study also forms a prime example of the broader research needs for cancer in low- and middle-income countries and in Sub-Saharan Africa, a setting with distinct and underresearched cancers and exposure patterns. While this etiologic research is challenging, it is an essential component of the ground-shot approach to global health research needed to inform primary prevention. See related article by Mmbaga et al., p. 305

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.

The incidence of esophageal squamous cell carcinoma (ESCC) is disproportionately high in the eastern corridor of Africa and parts of Asia. Emerging research has identified a potential association between poor oral health and ESCC. One possible link between poor oral health and ESCC involves the alteration of the microbiome. We performed an integrated analysis of four independent sequencing efforts of ESCC tumors from patients from high- and low-incidence regions of the world. Using whole genome sequencing (WGS) and RNA sequencing (RNAseq) of ESCC tumors from 61 patients in Tanzania, we identified a community of bacteria, including members of the genera Fusobacterium, Selenomonas, Prevotella, Streptococcus, Porphyromonas, Veillonella and Campylobacter, present at high abundance in ESCC tumors. We then characterized the microbiome of 238 ESCC tumor specimens collected in two additional independent sequencing efforts consisting of patients from other high-ESCC incidence regions (Tanzania, Malawi, Kenya, Iran, China). This analysis revealed similar ESCC-associated bacterial communities in these cancers. Because these genera are traditionally considered members of the oral microbiota, we next explored whether there was a relationship between the synchronous saliva and tumor microbiomes of ESCC patients in Tanzania. Comparative analyses revealed that paired saliva and tumor microbiomes were significantly similar with a specific enrichment of Fusobacterium and Prevotella in the tumor microbiome. Together, these data indicate that cancer-associated oral bacteria are associated with ESCC tumors at the time of diagnosis and support a model in which oral bacteria are present in high abundance in both saliva and tumors of some ESCC patients.

In some countries of sub-Saharan Africa, the prevalence of HIV exceeds 20%; in South Africa, 20.4% of people are living with HIV. We examined the impact of HIV infection on the overall survival (OS) of women with nonmetastatic breast cancer (BC) enrolled in the South African Breast Cancer and HIV Outcomes (SABCHO) study. We recruited women with newly diagnosed BC at six public hospitals from 1 July 2015 to 30 June 2019. Among women with stages I-III BC, we compared those with and without HIV infection on sociodemographic, clinical, and treatment factors. We analyzed the impact of HIV on OS using multivariable Cox proportional hazard models. Of 2367 women with stages I-III BC, 499 (21.1%) had HIV and 1868 (78.9%) did not. With a median follow-up of 29 months, 2-year OS was poorer among women living with HIV (WLWH) than among HIV-uninfected women (72.4% vs 80.1%, P .001; adjusted hazard ratio (aHR) 1.49, 95% confidence interval (CI) = 1.22-1.83). This finding was consistent across age groups ≥45 years and45 years, stage I-II BC and stage III BC, and ER/PR status (all P .03). Both WLWH with50 viral load copies/mL and WLWH with ≥50 viral load copies/mL had poorer survival than HIV-uninfected BC patients [aHR: 1.35 (1.09-1.66) and 1.54 (1.20-2.00), respectively], as did WLWH who had ≥200 CD4+ cells/mL at diagnosis [aHR: 1.39 (1.15-1.67)]. Because receipt of antiretroviral therapy has become widespread, WLWH is surviving long enough to develop BC; more research is needed on the causes of their poor survival.

Most breast cancer patients in sub‐Saharan Africa are diagnosed at advanced stages after prolonged symptomatic periods. In the multicountry African Breast Cancer‐Disparities in Outcomes cohort, we dissected the diagnostic journey to inform downstaging interventions. At hospital presentation for breast cancer, women recalled their diagnostic journey, including dates of first noticing symptoms and health‐care provider (HCP) visits. Negative binomial regression models were used to identify correlates of the length of the diagnostic journey. Among 1429 women, the median (inter‐quartile range) length (months) of the diagnostic journey ranged from 11.3 (5.7‐21.2) in Ugandan, 8.2 (3.4‐16.4) in Zambian, 6.5 (2.4‐15.7) in Namibian‐black to 5.6 (2.3‐13.1) in Nigerian and 2.4 (0.6‐5.5) in Namibian‐non‐black women. Time from first HCP contact to diagnosis represented, on average, 58% to 79% of the diagnostic journey in each setting except Nigeria where most women presented directly to the diagnostic hospital with advanced disease. The median number of HCPs visited was 1 to 4 per woman, but time intervals between visits were long. Women who attributed their initial symptoms to cancer had a 4.1 months (absolute) reduced diagnostic journey than those who did not, while less‐educated (none/primary) women had a 3.6 months longer journey than more educated women. In most settings the long journey to breast cancer diagnosis was not primarily due to late first presentation but to prolonged delays after first presentation to diagnosis. Promotion of breast cancer awareness and implementation of accelerated referral pathways for women with suspicious symptoms are vital to downstaging the disease in the region., What's new? In sub‐Saharan Africa, most women with breast cancer are diagnosed long after symptoms first arise. Here, the authors studied the diagnostic journey for breast cancer among the African Breast Cancer‐Disparities in Outcome cohort. This is the largest study to quantify the length of the diagnostic journey across various settings in sub‐Saharan Africa. Time to final diagnosis decreased substantially when a woman recognized her symptoms as cancer. Most delays, they found, were due to extended time between first examination and final diagnosis. Promotion of breast cancer awareness among both women and healthcare providers could help reduce these delays.

Summary Background Breast cancer has distinct causes, prognoses, and outcomes and effects in patients at premenopausal and postmenopausal ages. We sought to assess the global burden and trends in breast cancer by menopausal status. Methods We did a population-based analysis of global breast cancer incidence and mortality among premenopausal and postmenopausal women. Menopausal status was defined using age as a proxy, whereby breast cancer cases or deaths at age 50 years or older were regarded as postmenopausal. Age-standardised breast cancer incidence and mortality in 2018 were calculated using GLOBOCAN data. Incidence trends for 1998–2012 were assessed in 44 populations from 41 countries using the Cancer in Five Continents plus database, by calculating the annual average percent change. Findings Approximately 645 000 premenopausal and 1·4 million postmenopausal breast cancer cases were diagnosed worldwide in 2018, with more than 130 000 and 490 000 deaths occurring in each menopausal group, respectively. Proportionally, countries with a low UNDP human development index (HDI) faced a greater burden of premenopausal breast cancer for both new cases and deaths compared with higher income countries. Countries with a very high HDI had the highest premenopausal and postmenopausal breast cancer incidence (30·6 and 253·6 cases per 100 000, respectively), whereas countries with low and medium HDI had the highest premenopausal and postmenopausal mortality, respectively (8·5 and 53·3 deaths per 100 000, respectively). When examining breast cancer trends, we noted significantly increasing age-standardised incidence rates (ASIRs) for premenopausal breast cancer in 20 of 44 populations and significantly increasing ASIRs for postmenopausal breast cancer in 24 of 44 populations. The growth exclusively at premenopausal ages largely occurred in high-income countries, whereas the increasing postmenopausal breast cancer burden was most notable in countries under transition. Interpretation We provide evidence of a rising burden of both premenopausal and postmenopausal breast cancer worldwide. Although early diagnosis and access to treatment remain crucial in low-income and middle-income countries, primary prevention efforts seeking to decrease exposure to known breast cancer risk factors are warranted in all world regions to curb the future breast cancer burden. Funding None.

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.

Consumption of very-hot beverages/food is a probable carcinogen. In East Africa, we investigated esophageal squamous cell carcinoma (ESCC) risk in relation to four thermal exposure metrics separately and in a combined score.From the ESCCAPE case-control studies in Blantyre, Malawi (2017-20) and Kilimanjaro, Tanzania (2015-19), we used logistic regression models adjusted for country, age, sex, alcohol and tobacco, to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for self-reported thermal exposures whilst consuming tea, coffee and/or porridge.The study included 849 cases and 906 controls. All metrics were positively associated with ESCC: temperature of drink/food (OR 1.92 (95% CI: 1.50, 2.46) for 'very hot' vs 'hot'), waiting time before drinking/eating (1.76 (1.37, 2.26) for2 vs 2-5 minutes), consumption speed (2.23 (1.78, 2.79) for 'normal' vs 'slow') and mouth burning (1.90 (1.19, 3.01) for ≥6 burns per month vs none). Amongst consumers, the composite score ranged from 1 to 12, and ESCC risk increased with higher scores, reaching an OR of 4.6 (2.1, 10.0) for scores of ≥9 vs 3.Thermal exposure metrics were strongly associated with ESCC risk. Avoidance of very-hot food/beverage consumption may contribute to the prevention of ESCC in East Africa.

Geophagia, the intentional practice of consuming soil, occurs across the African esophageal cancer corridor, particularly during pregnancy. We investigated whether this practice is linked to endemic esophageal squamous cell carcinoma (ESCC) in this region. We conducted ESCC case-control studies in Tanzania, Malawi and Kenya. Cases were patients with incident histologically/clinically confirmed ESCC and controls were hospital patients/visitors without digestive diseases. Participants were asked if they had ever eaten soil (never/regularly/pregnancy-only). Odds ratios (OR) are adjusted for sex, age, tobacco, alcohol, country, religion and marital status. Overall, 934 cases (Malawi 535, Tanzania 304 and Kenya females 95) and 995 controls provided geophagia information. Among controls, ever-geophagia was common in women (Malawi 49%, Kenya 43% and Tanzania 29%) but not in men (10% Malawi

Spot urinary elemental concentrations are presented for 357 adults from Western Kenya collected between 2016 and 2019 as part of a wider environmental geochemical survey. The aim of this study was to establish population level urinary elemental concentrations in Western Kenya for micronutrients and potentially harmful elements for inference of health status against established thresholds. For elements where thresholds inferring health status were not established in the literature using urine as a non-invasive matrix, this study generated reference values with a 95% confidence interval (RV95s) to contextualise urinary elemental data for this population group. Data are presented with outliers removed based upon creatinine measurements leaving 322 individuals, for sub-categories (e.g. age, gender) and by county public health administrative area. For Western Kenya, reference values with a 95% confidence interval (RV95s) were calculated as follows (μg/L): 717 (I), 89 (Se), 1753 (Zn), 336 (Mo), 24 (Cu), 15.6 (Ni), 22.1 (As), 0.34 (Cd), 0.47 (Sn), 0.46 (Sb), 7.0 (Cs), 13.4 (Ba and 1.9 (Pb). Urinary concentrations at the 25th/75th percentiles were as follows (μg/L): 149/368 (I), 15/42 (Se), 281/845 (Zn), 30/128 (Mo), 6/13 (Cu), 1.7/6.1 (Ni), 2.0/8.2 (As). 0.1/0.3 (Cd), 0.05/0.22 (Sn), 0.04/0.18 (Sb), 1.2/3.6 (Cs), 0.8/4.0 (Ba) and 0.2/0.9 (Pb). Urinary concentrations at a population level inferred excess intake of micronutrients I, Se, Zn and Mo in 38, 6, 57 and 14% of individuals, respectively, versus a bioequivalent (BE) upper threshold limit, whilst rates of deficiency were relatively low at 15, 15, 9 and 18%, respectively. Each of the administrative counties showed a broadly similar range of urinary elemental concentrations, with some exceptions for counties bordering Lake Victoria where food consumption habits may differ significantly to other counties e.g. I, Se, Zn. Corrections for urinary dilution using creatinine, specific gravity and osmolality provided a general reduction in RV95s for I, Mo, Se, As and Sn compared to uncorrected data, with consistency between the three correction methods.

Background Arm and shoulder problems (ASP), including lymphedema, were common among women with breast cancer in high-income countries before sentinel lymph node biopsy became the standard of care. Although ASP impair quality of life, as they affect daily life activities, their frequency and determinants in Sub-Saharan Africa remain unclear. Methods All women newly diagnosed with breast cancer at the Namibian, Ugandan, Nigerian, and Zambian sites of the African Breast Cancer-Disparities in Outcomes (ABC-DO) cohort study were included. At each 3-month follow-up interview, women answered the EORTC-QLQ-Br23 questionnaire, including three ASP items: shoulder/arm pain, arm stiffness, and arm/hand swelling. We estimated the cumulative incidence of first self-reported ASP, overall and stratified by study and treatment status, with deaths treated as competing events. To identify determinants of ASP, we estimated cause-specific hazard ratios using Cox models stratified by study site. Results Among 1476 women, up to 4 years after diagnosis, 43% (95% CI 40–46), 36% (33–38) and 23% (20–25), respectively, self-reported having experienced arm/shoulder pain, stiffness and arm/hand swelling at least once. Although risks of self-reported ASP differed between sites, a more advanced breast cancer stage at diagnosis, having a lower socioeconomic position and receiving treatment increased the risk of reporting an ASP. Conclusion ASP are very common in breast cancer survivors in Sub-Saharan Africa. They are influenced by different factors than those observed in high-income countries. There is a need to raise awareness and improve management of ASP within the African setting.

Background In high-income settings, delays from breast cancer (BC) diagnosis to initial treatment worsen overall survival (OS). We examined how time to BC treatment initiation (TTI) impacts OS in South Africa (SA). Methods We evaluated women enrolled in the South African BC and HIV Outcomes study between July 1, 2015 and June 30, 2019, selecting women with stages I-III BC who received surgery and chemotherapy. We constructed a linear regression model estimating the impact of sociodemographic and clinical factors on TTI and separate multivariable Cox proportional hazard models by first treatment (surgery and neoadjuvant chemotherapy (NAC)) assessing the effect of TTI (in 30-day increments) on OS. Results Of 1260 women, 45.6% had upfront surgery, 54.4% had NAC, and 19.5% initiated treatment >90 days after BC diagnosis. Compared to the surgery group, more women in the NAC group had stage III BC (34.8% vs 81.5%). Living further away from a hospital and having hormone receptor positive (vs negative) BC was associated with longer TTI (8 additional days per 100 km, P = .003 and 8 additional days, P = .01, respectively), while Ki67 proliferation index >20 and upfront surgery (vs NAC) was associated with shorter TTI (12 and 9 days earlier; P = .0001 and.007, respectively). Treatment initiation also differed among treating hospitals (P < .0001). Additional 30-day treatment delays were associated with worse survival in the surgery group (HR 1.11 [95%CI 1.003-1.22]), but not in the NAC group. Conclusions Delays in BC treatment initiation are common in SA public hospitals and are associated with worse survival among women treated with upfront surgery.

Context Oesophageal cancer (EC) is among the common causes of illness and death among all cancers worldwide. Advanced EC has a poor prognosis, with worse outcomes observed in low-income settings. Oesophageal squamous cell carcinoma (ESCC) is the most common EC histology reported globally, with the highest ESCC incidence rates in the ‘Asian Belt’ and the African EC corridor. While the aetiology of ESCC is well-documented in the ‘Asian belt’, data for the African EC corridor and the entirety of sub-Saharan Africa (SSA) are fewer. Objective To help address gaps in ESCC aetiology in SSA, we critically evaluated evidence of lifestyle, environmental, and epigenetic factors associated with ESCC risk and discussed prospects of defining ESCC exposome. Data inclusion Unlimited English and non-English articles search were made on PubMed Central and Web of Science databases from January 1970 to August 2021. In total, we retrieved 999 articles and considered meta-analyses, case-control, and cohort studies. The quality of individual studies was assessed using the Newcastle–Ottawa scale. Data extraction Details extracted include the year of publication, country of origin, sample size, comparators, outcomes, study subjects, and designs. Data analysis Together, we assessed 13 case-control studies and two meta-analyses for the effect of lifestyle or environmental exposures on ESCC risk. Again, we evaluated seven case-control studies and one meta-analysis regarding the role of epigenetics in ESCC tumorigenesis. Results In general, evidence of ESCC aetiology points to essential contributions of alcohol, tobacco, hot beverages, biomass fuel, and poor oral health/hygiene, although more precise risk characterisation remains necessary. Conclusion We conclude that ESCC in SSA is a multifactorial disease initiated by several external exposures that may induce aberrant epigenetic changes. The expanding aetiological research in this domain will be enhanced by evidence synthesis from classical and molecular epidemiological studies spanning the external and internal exposome.

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.

An important component of cancer control programs for the growing burden in sub-Saharan Africa is a population’s awareness of risk factors. Studies thereof have focused on single rather than multiple cancers and carcinogens. During March and April 2015, we undertook a survey to assess awareness of multiple cancer risk factors and symptoms in the Kilimanjaro Region, North Tanzania. General population (n = 620) and attendees at HIV care-and-treatment clinics (CTCs) were included (n = 207). Participants’ mean age was 43.8 (interquartile range 30–52) years; 58% were female. Awareness of cancer risk was highest for tobacco (90%) and alcoholic spirits (67%), but tended to be lower for infections (41% for HIV (42.2% and 41.4% for CTC and community group, respectively) and 16% for HPV (16.0% and 16.6% for CTC and community group, respectively)), while that of moldy maize and peanuts was 35% for both. Awareness of specific cancer signs and symptoms ranged between 70% and 90%. Awareness of alcohol and tobacco was higher in men than women (odds ratio = 1.82 (1.38, 2.40) and 3.96 (2.14, 7.31), respectively). In relation to cancer treatment, 70% preferred modern medicine and 10% preferred traditional medicine alone. Sixty percent was not aware of any local cancer early detection services. Only 20% had ever been examined for cancer, and of those screened, CTC group was 1.5 times more likely to screen than community participants. Awareness did not differ by age or HIV status. There are good levels of cancer risk factor awareness for certain lifestyle-related carcinogens in Tanzania; however, increased awareness is needed especially for infections and cancer warning symptom both in the general and HIV-positive population, as well as some myths to be dispelled.

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.

Esophageal sponge cytology is an endoscopy alternative well accepted by patients with extensive data for accuracy in the context of adenocarcinoma. Few studies have assessed its feasibility in asymptomatic community members, and fewer still in East Africa, where esophageal squamous cell carcinoma (ESCC) rates are high. We aimed to assess the feasibility of a capsule-based diagnosis of esophageal squamous dysplasia (ESD), an ESCC precursor, which may benefit epidemiological and early detection research. We collected Cytosponge collections in 102 asymptomatic adults from Kilimanjaro, Tanzania. Uptake, acceptability and safety were assessed. Participants scored acceptability immediately following the procedure and 7 days later on a scale of 0 (least) to 10 (most acceptable). Slides from paraffin-embedded cell clots were read by two pathologists for ESD and other pathologies. All participants (52 men, 50 women, aged 30-77) swallowed the device at first attempt, 100 (98%) of which gave slides of adequate cellularity. Acceptability scores were 10 (53%), 9 (24%), 8 (21%), 7 (2%) and 6 (1%), with no differences by age, sex or time of asking. Cytological findings were esophageal inflammation (4%), atypical squamous cells of uncertain significance (1%), low-grade dysplasia (1%), gastritis (22%) and suspected intestinal metaplasia (6%). Setting-specific logistical and ethical considerations of study implementation are discussed. We demonstrate the safety, acceptability and feasibility of Cytosponge sampling in this setting, paving the way for innovative etiology and early-detection research. Targeted sampling strategies and biomarker development will underpin the success of such initiatives. The study protocol is registered on ClinicalTrials.gov (NCT04090554).

Key Points Question How many maternal orphans resulted from every 100 breast cancer deaths in sub-Saharan African settings in 2014-2019? Findings In the African Breast Cancer–Disparities in Outcomes cohort study of women with breast cancer, there were 964 children (, Importance Low breast cancer survival in sub-Saharan Africa’s young population increases the likelihood that breast cancer deaths result in maternal orphans, ie, children (, This cohort study estimates the number of maternal orphans in 4 sub-Saharan Africa countries when women die of breast cancer.

Epigenetic mechanisms such as aberrant DNA methylation (DNAme) are known to drive esophageal squamous cell carcinoma (ESCC), yet they remain poorly understood. Here, we studied tumor-specific DNAme in ESCC cases from nine high-incidence countries of Africa, Asia, and South America. Infinium MethylationEPIC array was performed on 108 tumors and 51 normal tissues adjacent to the tumors (NAT) in the discovery phase, and targeted pyrosequencing was performed on 132 tumors and 36 NAT in the replication phase. Top genes for replication were prioritized by weighting methylation results using RNA-sequencing data from The Cancer Genome Atlas and GTEx and validated by qPCR. Methylome analysis comparing tumor and NAT identified 6,796 differentially methylated positions (DMP) and 866 differential methylated regions (DMR), with a 30% methylation (Δβ) difference. The majority of identified DMPs and DMRs were hypermethylated in tumors, particularly in promoters and gene-body regions of genes involved in transcription activation. The top three prioritized genes for replication, PAX9, SIM2, and THSD4, had similar methylation differences in the discovery and replication sets. These genes were exclusively expressed in normal esophageal tissues in GTEx and downregulated in tumors. The specificity and sensitivity of these DNAme events in discriminating tumors from NAT were assessed. Our study identified novel, robust, and crucial tumor-specific DNAme events in ESCC tumors across several high-incidence populations of the world. Methylome changes identified in this study may serve as potential targets for biomarker discovery and warrant further functional characterization. Significance: This largest genome-wide DNA methylation study on ESCC from high-incidence populations of the world identifies functionally relevant and robust DNAme events that could serve as potential tumor-specific markers.

We examined the geospatial dimension of delays to diagnosis of breast cancer in a prospective study of 1541 women newly diagnosed in the African Breast Cancer—Disparities in Outcomes (ABC‐DO) Study. Women were recruited at cancer treatment facilities in Namibia, Nigeria, Uganda and Zambia. The baseline interview included information used to generate the geospatial features: urban/rural residence, travel mode to treatment facility and straight‐line distances from home to first‐care provider and to diagnostic/treatment facility, categorized into country/ethnicity (population)‐specific quartiles. These factors were investigated in relation to delay in diagnosis (≥3 months since first symptom) and late stage at diagnosis (TNM: III, IV) using logistic regression, adjusted for population group and sociodemographic characteristics. The median (interquartile range) distances to first provider and diagnostic and treatment facilities were 5 (1‐37), 17 (3‐105) and 62 (5‐289) km, respectively. The majority had a delay in diagnosis (74%) and diagnosis at late stage (64%). Distance to first provider was not associated with delay in diagnosis or late stage at diagnosis. Rural residence was associated with delay, but the association did not persist after adjustment for sociodemographic characteristics. Distance to the diagnostic/treatment facility was associated with delay (highest vs lowest quartile: odds ratio (OR) = 1.56, 95% confidence interval (CI) = 1.08‐2.27) and late stage (overall: OR = 1.47, CI = 1.05‐2.06; without Nigerian hospitals where mostly local residents were treated: OR = 1.73, CI = 1.18‐2.54). These findings underscore the need for measures addressing the geospatial barriers to early diagnosis in sub‐Saharan African settings, including providing transport or travel allowance and decentralizing diagnostic services., What's new? Survival from breast cancer is poor in sub‐Saharan Africa, due largely to the high proportion of women who are diagnosed at advanced stages. In this study, the authors examined geospatial information to assess women's prediagnostic journey to breast cancer diagnosis, with special attention to delays in diagnosis, in the regions of Namibia, Nigeria, Uganda, and Zambia. Geospatial factors particularly long travel distances to diagnostic and treatment facilities were identified as major barriers to early diagnosis. The findings underscore the need for policies to address these barriers to ensure breast cancer diagnosis at a curable stage.

Summary Background Breast cancer is the second leading cause of death from cancer in women in sub-Saharan Africa, yet there are few well characterised large-scale survival studies with complete follow-up data. We aimed to provide robust survival estimates in women in this setting and apportion the survival gaps. Methods The African Breast Cancer-Disparities in Outcomes (ABC-DO) prospective cohort study was done at eight hospitals across five sub-Saharan African countries (Namibia, Nigeria, South Africa, Uganda, and Zambia). We prospectively recruited women (aged ≥18 years) who attended these hospitals with suspected breast cancer. Women were actively followed up by use of a telephone call once every 3 months, and a mobile health application was used to keep a dynamic record of follow-up calls due. We collected detailed sociodemographic, clinical, and treatment data. The primary outcome was 3-year overall survival, analysed by use of flexible proportional mortality models, and we predicted survival under scenarios of modified distributions of risk factors. Findings Between Sept 8, 2014, and Dec 31, 2017, 2313 women were recruited from these eight hospitals, of whom 85 did not have breast cancer. Of the remaining 2228 women with breast cancer, 58 women with previous treatment or recurrence, and 14 women from small racial groups (white and Asian women in South Africa), were excluded. Of the 2156 women analysed, 1840 (85%) were histologically confirmed, 129 (6%) were cytologically confirmed, and 187 (9%) were clinically confirmed to have breast cancer. 2156 (97%) women were followed up for up to 3 years or up to Jan 1, 2019, whichever was earlier. Up to this date, 879 (41%) of these women had died, 1118 (52%) were alive, and 159 (7%) were censored early. 3-year overall survival was 50% (95% CI 48–53), but we observed variations in 3-year survival between different races in Namibia (from 90% in white women to 56% in Black women) and in South Africa (from 76% in mixed-race women to 59% in Black women), and between different countries (44–47% in Uganda and Zambia vs 36% in Nigeria). 215 (10%) of all women had died within 6 months of diagnosis, but 3-year overall survival remained low in women who survived to this timepoint (58%). Among survival determinants, improvements in early diagnosis and treatment were predicted to contribute to the largest increases in survival, with a combined absolute increase in survival of up to 22% in Nigeria, Zambia, and Uganda, when compared with the contributions of other factors (such as HIV or aggressive subtypes). Interpretation Large variations in breast cancer survival in sub-Saharan African countries indicate that improvements are possible. At least a third of the projected 416 000 breast cancer deaths that will occur in this region in the next decade could be prevented through achievable downstaging and improvements in treatment. Improving survival in socially disadvantaged women warrants special attention. Funding Susan G Komen and the International Agency for Research on Cancer.

When breast cancer is detected and treated early, the chances of survival are very high. However, women in many settings face complex barriers to early detection, including social, economic, geographic, and other interrelated factors, which can limit their access to timely, affordable, and effective breast health care services. Previously, the Breast Health Global Initiative (BHGI) developed resource-stratified guidelines for the early detection and diagnosis of breast cancer. In this consensus article from the sixth BHGI Global Summit held in October 2018, the authors describe phases of early detection program development, beginning with management strategies required for the diagnosis of clinically detectable disease based on awareness education and technical training, history and physical examination, and accurate tissue diagnosis. The core issues address include finance and governance, which pertain to successful planning, implementation, and the iterative process of program improvement and are needed for a breast cancer early detection program to succeed in any resource setting. Examples are presented of implementation, process, and clinical outcome metrics that assist in program implementation monitoring. Country case examples are presented to highlight the challenges and opportunities of implementing successful breast cancer early detection programs, and the complex interplay of barriers and facilitators to achieving early detection for breast cancer in real-world settings are considered.

Objectives: To assess the validity of self-reported HIV status, and investigate factors that influence accurate reporting of HIV-positive status, in a population tested and informed of their HIV test result. Design: Prospective cohort study. Methods: We compared self-reported HIV status with biomarker-confirmed HIV test status among participants of Karonga Health and Demographic Surveillance Site in rural northern Malawi. We linked information on HIV test results to subsequent self-reported HIV status, and calculated sensitivity, specificity, positive predictive value and negative predictive value for self-reported HIV status (considered as a diagnostic test). We used Poisson regression with robust variance estimators to examine predictors of accurate self-reporting of HIV-positive status. Results: Among 17 445 adults who tested for HIV, were recorded as having received their HIV test results, and had a subsequent self-reported HIV status between 2007 and 2018: positive predictive value of self-reported HIV status was 98.0% (95% confidence interval: 97.3–98.7); negative predictive value was 98.3 (98.1–98.5); sensitivity was 86.1% (84.5–87.7); and specificity was 99.8% (99.7–99.9). Among true HIV-positive people, those who were younger, interviewed in community settings, and had tested for HIV longer ago were more likely to misreport their HIV-positive status. Conclusion: In this setting, self-report provides good estimates of test-detected HIV prevalence, suggesting that it can be used when HIV test results are not available. Despite frequent HIV testing, younger people and those interviewed in community settings were less likely to accurately report their HIV-positive status. More research on barriers to self-reporting of HIV status is needed in these subgroups.

Introduction Cadmium (Cd) is a heavy metal, which is widespread in the environment and has been hypothesized to be a metalloestrogen and a breast cancer risk factor. Mammographic density (MD) reflects the composition of the breast and was proposed to be used as a surrogate marker for breast cancer. The aim of our study was to investigate association between cadmium concentration in urine and mammographic density. Methods A cross-sectional study included 517 women aged 40–60 years who underwent screening mammography in Łodź, Poland. Data were collected through personal interviews and anthropometric measurements. Spot morning urine samples were obtained. The examination of the breasts included both craniocaudal and mediolateral oblique views. Raw data (“for processing”) generated by the digital mammography system were analysed using Volpara Imaging Software, The volumetric breast density(%) and fibrograndular tissue volume(cm3) were determined. Cadmium concentration in urine was analysed using the standard ICP-MS method. Results After adjusting for key confounders including age, BMI, family breast cancer, mammographic device, season of the year of mammography, and age at menarche, an inverse association of Cd and volumetric breast density was found, which was attenuated after further adjustment for smoking. Associations of Cd with dense volume were null. Conclusions These findings suggest that Cd is not positively associated with breast density, a strong marker of breast cancer risk, when examined in a cross-sectional fashion.

IntroductionFor women of the same age and body mass index, increased mammographic density is one of the strongest predictors of breast cancer risk. There are multiple methods of measuring mammographic density and other features in a mammogram that could potentially be used in a screening setting to identify and target women at high risk of developing breast cancer. However, it is unclear which measurement method provides the strongest predictor of breast cancer risk.Methods and analysisThe measurement challenge has been established as an international resource to offer a common set of anonymised mammogram images for measurement and analysis. To date, full field digital mammogram images and core data from 1650 cases and 1929 controls from five countries have been collated. The measurement challenge is an ongoing collaboration and we are continuing to expand the resource to include additional image sets across different populations (from contributors) and to compare additional measurement methods (by challengers). The intended use of the measurement challenge resource is for refinement and validation of new and existing mammographic measurement methods. The measurement challenge resource provides a standardised dataset of mammographic images and core data that enables investigators to directly compare methods of measuring mammographic density or other mammographic features in case/control sets of both raw and processed images, for the purposes of the comparing their predictions of breast cancer risk.Ethics and disseminationChallengers and contributors are required to enter a Research Collaboration Agreement with the University of Melbourne prior to participation in the measurement challenge. The Challenge database of collated data and images are stored in a secure data repository at the University of Melbourne. Ethics approval for the measurement challenge is held at University of Melbourne (HREC ID 0931343.3).

Highlights • We conducted a review and meta-analysis of esophageal cancer sex ratios in mainland Africa using data from 197 populations in 36 countries. • We observed a consistent male excess in incidence rates overall and in the high-risk Eastern and Southern African regions. • A male excess was evident in 30–39 year olds in high-risk Eastern and Southern African regions. • Our findings suggest that a substantial fraction of the African EC burden could be avoided by targeting gender-specific exposures., 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.

Background South Africa’s public healthcare system is better equipped to manage breast cancer than most other SSA countries, but survival rates are unknown. Methods A historical cohort of 602 women newly diagnosed with invasive breast carcinoma during 2009–2011 at Chris Hani Baragwanath Academic Hospital, Soweto, Johannesburg, was followed using health systems data to December 2014. ‘Overall survival’ time was defined from diagnosis to death or terminal illness. Cox regression was used to estimate hazard ratios (HR) associated with woman and tumour characteristics. Results During a median 2.1 years follow-up (IQR 0.5–3.8), 149 women died or were classified terminally ill; 287 were lost-to-follow-up. 3-year survival was 84% for early stage (I/II) and 56% for late stage (III/IV) tumours (late v early: HR 2.8 (95% confidence interval (CI): 1.9–4.1), however the 42% cumulative losses to follow-up over this period were greater for late stage, half of which occurred within 6 months of diagnosis. After mutual adjustment for stage, grade, age, receptor subtype and HIV status, lower survival was also associated with triple negative (HR 3.1 (95% CI: 1.9–5.0)) and HER2-enriched (2.5 (95% CI: 1.4–4.5)) compared to ER/PR+ HER2- tumours, but not with age or HIV-infection (1.4 (95% CI: 0.8, 2.3)). Conclusion In this South African cohort, breast cancer survival is suboptimal, but was better for early stage and hormone receptor-positive tumours. Efforts to reduce clinic losses in the immediate post-diagnosis period, in addition to early presentation and accelerated diagnosis and treatment, are needed to prevent breast cancer deaths, and survival improvements need to be monitored using prospective studies with active follow-up.

SummaryEarly diagnosis of cancer, followed by timely and appropriate therapy, are the cornerstones of the secondary prevention of cancer, thus the NHS has set a 2028 target to achieve 75% early stage (TNM I/II) at cancer diagnosis. In this context, Barclay et al. evaluated overall, sex, age and deprivation-group-specific progress towards this target based on 202,000 cancer patients diagnosis in 2015. Herein, we discuss their findings which form a valuable pre-COVID-19 pandemic status. We discuss the impact of the pandemic and the efforts being made in innovative early detection and diagnosis research.

BACKGROUND: The incidence of breast cancer in sub-Saharan Africa is relatively low, but as survival from the disease in the region is poor, mortality rates are as high as in high-income countries. Stage at diagnosis is a major contributing factor to poor survival from breast cancer. We aimed to do a systematic review and meta-analysis on stage at diagnosis of breast cancer in sub-Saharan Africa to examine trends over time, and investigate sources of variations across the region. METHODS: We searched MEDLINE, Embase, Web of Knowledge, and Africa-Wide Information to identify studies on breast cancer stage at diagnosis in sub-Saharan African women published before Jan 1, 2014, and in any language. Random-effects meta-analyses were done to investigate between-study heterogeneity in percentage of late-stage breast cancer (stage III/IV), and meta-regression analyses to identify potential sources of variation. Percentages of women with late-stage breast cancer at diagnosis in sub-Saharan Africa were compared with similar estimates for black and white women in the USA from the Surveillance, Epidemiology, and End Results database. FINDINGS: 83 studies were included, which consisted of 26 788 women from 17 sub-Saharan African countries. There was wide between-study heterogeneity in the percentage of late-stage disease at diagnosis (median 74·7%, range 30·3-100%, I2=93·3%, p

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.

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., What's new? To date, there are no comprehensive studies of oral health and esophageal cancer in Eastern Africa, nor of this area's endemic dental fluorosis, an irreversible enamel hypo‐mineralization due to early‐life excessive fluoride intake. Here, the authors found that moderate/severe fluorosis is associated with a ten‐fold increased cancer risk in Eastern Africa, particularly if tooth loss or decay is co‐present. The finding is striking because of the remarkable co‐location of Africa's esophageal cancer corridor with areas of high groundwater fluoride. Identification of the causal mechanisms will be critical to primary prevention of this common cancer.

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/m2)/low LTPA, neither medium nor high PA was associated with risk among high BMI men, but normal BMI men (

A historical cohort study in workers occupationally exposed to chrysotile was set up in the town of Asbest, the Russian Federation, to study their cause-specific mortality, with a focus on cancer. Chrysotile has different chemical and physical properties compared with other asbestos fibres; therefore it is important to conduct studies specifically of chrysotile and in different geographical regions to improve the knowledge about its carcinogenicity. Setting was the town of Asbest, Sverdlovsk oblast, the Russian Federation. Participants were all current and former employees with at least one year of employment between 1/1/1975 and 31/12/2010 in the mine, enrichment factories, auto-transport and external rail transportation departments, the central laboratory, and the explosives unit of the company. Of the 35,837 cohort members, 12,729 (35.5%) had died (2,373 of them of cancer, including 10 of mesothelioma), 18,799 (52.5%) were known to be alive at the end of the observation period (2015), and 4,309 (12.0%) were censored before the end of 2015. Mean follow-up duration was 21.7 years in men and 25.9 years in women. The mean age at death was 59.4 years in men and 66.5 years in women. This is the largest occupational cohort of chrysotile workers to date, and the only one with a large proportion of exposed female workers.

Oesophageal squamous cell carcinoma (ESCC) has markedly high incidence rates in Kenya and much of East Africa, with a dire prognosis and poorly understood aetiology. Consumption of hot beverages—a probable carcinogen to humans—is associated with increased ESCC risk in other settings and is habitually practiced in Kenya. We conducted a case–control study in Eldoret, western Kenya between August 2013 and March 2018. Cases were patients with endoscopically confirmed oesophageal cancer whose histology did not rule out ESCC. Age and sex‐matched controls were hospital visitors and hospital out and in‐patients excluding those with digestive diseases. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for self‐reported drinking temperatures; consumption frequency; mouth burning frequency and hot porridge consumption using logistic regression models adjusted for potential confounders. Drinking temperature association with tumour sub‐location was also investigated. The study included 430 cases and 440 controls. Drinkers of ‘very hot’ and ‘hot’ beverages (>95% tea) had a 3.7 (95% CI: 2.1–6.5) and 1.4‐fold (1.0–2.0) ESCC risk, respectively compared to ‘warm’ drinkers. This trend was consistent in males, females, never and ever alcohol/tobacco and was stronger over than under age 50 years. The tumour sub‐location distribution (upper/middle/lower oesophagus) did not differ by reported drinking temperature. Our study is the first comprehensive investigation in this setting to‐date to observe a link between hot beverage consumption and ESCC in East Africa. These findings provide further evidence for the role of this potentially modifiable risk factor in ESCC aetiology., What's new? Oesophageal squamous cell carcinoma (ESCC) has markedly high incidence rates in Kenya and much of East Africa, with a dire prognosis and poorly understood aetiology. Hot beverage consumption – a probable carcinogen to humans – is associated with increased ESCC risk in other settings. In this first comprehensive case‐control study to investigate the role of hot beverages in esophageal cancer in Kenya and East Africa, the authors find overall risks of 3.7 and 1.4‐fold for drinking “very hot” and “hot” beverages, respectively, compared to “warm” These findings will contribute to local and global prevention efforts by addressing this potentially modifiable risk factor.

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.

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

Esophageal cancer is the eighth most common cancer worldwide and the sixth most common cause of cancer-related death; however, worldwide incidence and mortality rates do not reflect the geographic variations in the occurrence of this disease. In recent years, increased attention has been focused on the high incidence of esophageal squamous cell carcinoma (ESCC) throughout the eastern corridor of Africa, extending from Ethiopia to South Africa. Nascent investigations are underway at a number of sites throughout the region in an effort to improve our understanding of the etiology behind the high incidence of ESCC in this region. In 2017, these sites established the African Esophageal Cancer Consortium. Here, we summarize the priorities of this newly established consortium: to implement coordinated multisite investigations into etiology and identify targets for primary prevention; to address the impact of the clinical burden of ESCC via capacity building and shared resources in treatment and palliative care; and to heighten awareness of ESCC among physicians, at-risk populations, policy makers, and funding agencies.

A greater understanding of the nature and drivers of poor breast cancer (BC) awareness in sub-Saharan Africa (SSA) will inform much needed awareness programmes. We aimed to assess the level and nature of BC awareness in the multi-country African Breast Cancer—Disparities in Outcome (ABC-DO) cohort of women newly diagnosed with BC during 2014–2017. Awareness indicators were assessed during a baseline interview at/near diagnosis. Logistic/ordinal regression was used to estimate odds ratios (OR) for indicators of BC awareness in relation to woman-level characteristics for individual settings and then meta-analyzed. In the 1,451 women included, almost all Namibian non-black women (n = 104) knew of BC and its curability, while in Namibian black and Zambian women, one in 7 (~ 15%) had not previously heard of BC and 25–40% did not know it was curable. In Uganda and Nigeria awareness was lowest: one in four women had no BC awareness, and 2 in 3 had no knowledge of its cure potential. Low educational level, unskilled employment, low socioeconomic position, rural residence, older age, being unmarried, and in some settings HIV-positivity, were associated with lower BC awareness—e.g., having unskilled employment was associated with not having heard of BC (summary OR 3.37; 95% confidence interval (CI) 2.17–5.23), believing that it is incurable (2.43; 1.81–3.26), and not recognizing a breast lump symptom (1.85; 1.41–2.43) but with between-setting variation (I2 > 68% for all). The findings provide evidence of the level and difference in BC awareness and beliefs across different settings, highlighting the urgent need for context-specific education programmes in the SSA region.

Hot beverage consumption has been linked to oesophageal squamous cell cancer (EC), but its contribution to the poorly understood East African EC corridor is not known. In a cross-sectional study of general-population residents in Kilimanjaro, North Tanzania, tea drinking temperatures and times were measured. Using linear regression models, we compared drinking temperatures to those in previous studies, by socio-demographic factors and tea type (“milky tea” which can be 50 % or more milk and water boiled together vs “black tea” which has no milk). Participants started drinking at a mean of 70.6 °C (standard deviation 3.9, n = 188), which exceeds that in all previous studies (p ≤ 0.01 for each). Tea type, gender and age were associated with drinking temperatures. After mutual adjustment for each other, milky tea drinkers drank their tea 1.9 °C (95 % confidence interval: 0.9, 2.9) hotter than drinkers of black tea, largely because black tea cooled twice as fast as milky tea. Men commenced drinking tea 0.9 °C (−0.2, 2.1) hotter than women did and finished their cups 30 (−9, 69) seconds faster. 70 % and 39 % of milky and black tea drinkers, respectively, reported a history of tongue burning. Hot tea consumption, especially milky tea, may be an important and modifiable risk factor for EC in Tanzania. The contribution of this habit to EC risk needs to be evaluated in this setting, jointly with that of the many risk factors acting synergistically in this multi-factorial disease.

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– 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. Cancer Epidemiol Biomarkers Prev; 24(3); 520–31. ©2014 AACR.

The International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) have initiated a series of cancer-focused seminars [Scelo G, Hofmann JN, Banks RE et al. International cancer seminars: a focus on kidney cancer. Ann Oncol 2016; 27(8): 1382-1385]. In this, the second seminar, IARC and NCI convened a workshop in order to examine the state of the current science on esophageal squamous cell carcinoma etiology, genetics, early detection, treatment, and palliation, was reviewed to identify the most critical open research questions. The results of these discussions were summarized by formulating a series of 'difficult questions', which should inform and prioritize future research efforts.

Background Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. Methods and findings We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35–85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (–0.46 cm [95% CI: −0.53, −0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was −0.24 cm (95% CI: −0.34, −0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (−0.38 cm [95% CI: −0.44, −0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature. Conclusions Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction., Valerie McCormack and colleagues reveal reduced breast density with increased age in women from different ethnic groups; however increased breast density in young women is a cancer risk., Author summary Why was this study done? Breast density, a measure of the amount of dense to fatty tissue in the breast, is a strong marker of breast cancer risk. Breast density determinants have been studied in high-income countries, but not in women worldwide. What did the researchers do and find? We studied how breast density differed by age and menopausal status in diverse groups of women from 22 countries worldwide. For over 11,000 women, mammograms were read centrally and risk factor data harmonised. We found that, regardless of the country and ethnic group of women, breast density was much lower in postmenopausal than in premenopausal women of the same age. Additionally, as a relative proportion of breast area, breast density was lower in older women both among premenopausal and postmenopausal women. Among premenopausal women, breast density changed with age without an increase in breast area, but among postmenopausal women, the latter also increased. What do these findings mean? That this change in breast density with age is seen internationally suggests that the change is due to a universal biological mechanism inherent to all women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction.

Background In West Africa, trends and risk factors for breast cancer (BC) have been rarely studied. Methods Here we have analyzed trends of BC over two periods in two population-based cancer registries, in Mali-Bamako (1987–1997; 1998–2009) and in The Gambia (1988–1997; 1998–2006). We have conducted a case–control study ( n = 253 cases, 249 controls) on risk factors associated with reproductive life stratified by menopausal status in Bamako. Results Between the two periods, BC incidence rates increased by 20% (incidence rate ratio (IRR) 1.20 (95% CI [1.07–1.35])) in Bamako, with an annual percentage change of 2% (95% CI [0.4–3.6]). The increase was of 30% in women under 55 years (IRR 1.30 (95% CI [1.14–1.60])). A similar pattern was observed in The Gambia for women under 50 years (IRR 1.47 (95% CI [1.07–2.01])). Overall, pre-menopausal breast cancer was predominant in both countries. In contrary to what is well established, case–control study showed that late age at menarche (>14 years) increased the risk of BC among pre-menopausal women (OR: 2.02 (95% CI [1.08–3.78])) while it tended to be protective in post-menopausal women (OR: 0.61 (95% CI [0.29–1.29])). Later age at a first pregnancy (>20 years) was associated with a reduction of risk in pre-menopausal women (OR: 0.41 (95% CI [0.18–0.89])). Conclusion These results indicate that the burden of pre-menopausal BC is increasing in West African countries. These cancers appear to be associated with distinct reproductive risk factors, highlighting the need for better understanding the biological bases of early BC in African populations.