Faculty Bibliography

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. Amongst 16.0 million WLWHA aged 15+ years, an estimated 6325 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 <1% of the clinical burden, except in Eastern, Western and Middle Africa where they comprised 4 to 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 3600. 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.

BACKGROUND:About half of births in rural Tanzania are assisted by skilled providers. Point-of-care mobile phone applications hold promise in boosting job support for community health workers aiming to ensure safe motherhood through increased facility delivery awareness, access and uptake. We conducted a controlled comparison to evaluate a smartphone-based application designed to assist community health workers with data collection, education delivery, gestational danger sign identification, and referrals. METHODS:Community health workers in 32 randomly selected villages were cluster-randomized to training on either smartphone (intervention) or paper-based (control) protocols for use during household visits with pregnant women. The primary outcome measure was postnatal report of delivery location by 572 women randomly selected to participate in a survey conducted by home visit. A mixed-effects model was used to account for clustering of subjects and other measured factors influencing facility delivery. FINDINGS/RESULTS:The smartphone intervention was associated with significantly higher facility delivery: 74% of mothers in intervention areas delivered at or in transit to a health facility, versus 63% in control areas. The odds of facility delivery among women counseled by smartphone-assisted health workers were double the odds among women living in control villages (OR, 1.96; CI, 1.21-3.19; adjusted analyses). Women in intervention areas were more likely to receive two or more visits from a community health worker during pregnancy than women in the control group (72% vs. 60%; chi-square = 6.9; p < 0.01). Previous facility delivery, uptake of antenatal care, and distance to the nearest facility were also strong independent predictors of facility delivery. INTERPRETATION/CONCLUSIONS:Community health worker use of smartphones increased facility delivery, likely through increased frequency of prenatal home visits. Smartphone-based job aids may enhance community health worker support and effectiveness as one component of intervention packages targeting safe motherhood. TRIAL REGISTRATION/BACKGROUND:NCT03161184.

Breast cancer survival rates in lower-income countries like Bangladesh are approximately 50%, versus over 80% in high income countries. Anecdotal reports suggest that, beyond economic and health system barriers, sociocultural factors may influence a woman's care-seeking behavior and resultant early stage diagnoses. To understand these barriers, we conducted 63 interviews (43 women with breast cancer symptoms and 20 men) in Khulna, Bangladesh. We identified socio-cultural barriers like neglect and indifference toward women, women's lack of power to use resources, and reduced support from family due to stigma. Interventions must address these barriers and improve the status of women in Bangladesh.

PURPOSE/OBJECTIVE:Mammographic density is a risk factor for breast cancer but the mechanism behind this association is unclear. The receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL) pathway has been implicated in the development of breast cancer. Given the role of RANK signaling in mammary epithelial cell proliferation, we hypothesized this pathway may also be associated with mammographic density. Osteoprotegerin (OPG), a decoy receptor for RANKL, is known to inhibit RANK signaling. Thus, it is of interest to evaluate whether OPG levels modify breast cancer risk through mammographic density. METHODS:We quantified serum OPG levels in 57 premenopausal and 43 postmenopausal women using an enzyme-linked immunosorbent assay (ELISA). Cumulus was used to measure percent density, dense area, and non-dense area for each mammographic image. Subjects were classified into high versus low OPG levels based on the median serum OPG level in the entire cohort (115.1 pg/mL). Multivariate models were used to assess the relationship between serum OPG levels and the measures of mammographic density. RESULTS:; P = 0.02) compared to those with high serum OPG levels after covariate adjustment. CONCLUSIONS:These findings suggest that low OPG levels may be associated with high mammographic density, particularly in postmenopausal women. Targeting RANK signaling may represent a plausible, non-surgical prevention option for high-risk women with high mammographic density, especially those with low circulating OPG levels.

BACKGROUND:Physical activity is inversely associated with the risk of breast cancer among women in the general population. It is not clear whether or not physical activity is associated with the risk of BRCA-associated breast cancer. METHODS:We conducted a case-control study of 443 matched pairs of BRCA mutation carriers to evaluate the association between physical activity and breast cancer risk. Moderate and vigorous physical activities at ages 12-13, ages 14-17, ages 18-22, ages 23-29 and ages 30-34 were determined using the Nurses' Health Study II Physical Activity Questionnaire. We estimated mean metabolic equivalent task hours/week for moderate, vigorous and total physical activities overall (ages 12-34), during adolescence (ages 12-17) and during early adulthood (ages 18-34). Logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for total, moderate and strenuous recreational physical activities and breast cancer risk, by menopausal status. RESULTS:Overall, there was no significant association between total physical activity and subsequent breast cancer risk (ORQ4 vs. Q1 = 1.01, 95% CI 0.69-1.47; P-trend = 0.72). Moderate physical activity between ages 12-17 was associated with a 38% decreased risk of premenopausal breast cancer (ORQ4 vs. Q1 = 0.62; 95% CI 0.40-0.96; P-trend = 0.01). We found no association between exercise and breast cancer diagnosed after menopause. CONCLUSIONS:These findings suggest that early-life physical activity is associated with a reduced risk of premenopausal breast cancer among BRCA mutation carriers. IMPACT/CONCLUSIONS:Future prospective analyses, complemented by mechanistic evidence, are warranted in this high-risk population.

For premenopausal women with primary ER + breast cancer, oophorectomy (OvX) is an evidence-based cost-effective option and is standard treatment in many countries. However, there is virtually no data describing the effects of OvX on breast tumour biology. We therefore, characterised the endocrine and genome-wide transcriptional impact of OvX in 56 premenopausal women with ER + breast cancer for 2 weeks prior to mastectomy. Plasma estradiol concentrations decreased from 406 ± 41 to 20.7 ± 2.6 pmol/l (mean ± sem) 24 h after OvX, and to 8.1 ± 0.8 pmol/l 2 weeks later at mastectomy. Ki67 decreased in 33/36 (91.7%) tumours. The expression of 655 genes changed significantly (FDR < 1%) with an absolute mean fold-change (FC) ≥ 1.25 (257 up, 398 down). Archetypal oestrogen-regulated genes (TFF1, GREB1, PGR and PDZK1) showed large decreases in expression (FC = 0.20-0.69; p < 1e-6-1e-7). Proliferation-associated genes (e.g. TOP2A, AURKA and UBE2C) were also strongly downregulated (FC = 0.38-0.56; p < 1e-7) along with putative progesterone-regulated genes (e.g. FKBP4, MYB; FC = 0.64-0.68; p < 1e-4-1e-7). The gene expression changes did not differ according to HER2 status and correlated strongly with the changes reported previously after aromatase inhibitor (AI) treatment in postmenopausal women (rho = 0.55, p < 1e-04). However, after OvX the mean FC was significantly higher compared to AI (p < 1e-04). In conclusion, changes in tumoural gene expression after OvX were largely similar, but of a greater magnitude to those observed after AI in postmenopausal patients; however, OvX appeared to have a greater effect on progesterone-regulated genes than AI.

We already know what causes cervical cancer, how to prevent it, and how to treat it, even in resource-constrained settings. Inequitable access to human papillomavirus vaccine for girls and screening and precancer treatment for women in low- and middle-income countries is unacceptable on ethical, social, and financial grounds. The burden of cervical cancer falls on the poor and extends beyond the narrow bounds of the family, affecting national economic development and community life, as family resources are drained and poverty tightens its grip. Proven solutions are available and the priorities for the next few years are clear, as shown by the papers in this Supplement. Sustained political commitment and strategic investments in cervical cancer prevention can not only save millions of lives over the next 10 years, but can also pave the way for the broader fight against all cancers.