Herbert Cubasch

Breast cancer receptor status and stage at diagnosis in over 1,200 consecutive public hospital patients in Soweto, South Africa: a case series

IntroductionEstimates of the proportion of estrogen receptor negative (ERN) and triple-negative (TRN) breast cancer from sub-Saharan Africa are variable and include high values. Large studies of receptor status conducted on non-archival tissue are lacking from this region.MethodsWe identified 1218 consecutive women (91% black) diagnosed with invasive breast cancer from 2006–2012 at a public hospital in Soweto, South Africa. Immunohistochemistry based ER, progesterone receptor (PR) and human epidermal factor 2 (HER2) receptors were assessed at diagnosis on pre-treatment biopsy specimens. Mutually adjusted associations of receptor status with stage, age, and race were examined using risk ratios (RRs). ER status was compared with age-stratified US Surveillance Epidemiology and End Results program (SEER) data.Results35% (95% confidence interval (CI): 32–38) of tumors were ERN, 47% (45–52) PRN, 26% (23–29) HER2P and 21% (18–23) TRN. Later stage tumors were more likely to be ERN and PRN (RRs 1.9 (1.1-2.9) and 2.0 (1.3-3.1) for stage III vs. I) but were not strongly associated with HER2 status. Age was not strongly associated with ER or PR status, but older women were less likely to have HER2P tumors (RR, 0.95 (0.92-0.99) per 5 years). During the study, stage III + IV tumors decreased from 66% to 46%. In black women the percentage of ERN (37% (34–40)) and PRN tumors (48% (45–52)) was higher than in non-black patients (22% (14–31) and 34% (25–44), respectively, P = 0.004 and P = 0.02), which remained after age and stage adjustment. Age-specific ERN proportions in black South African women were similar to those of US black women, especially for women diagnosed over age 50.ConclusionAlthough a greater proportion of black than non-black South African women had ER-negative or TRN breast cancer, in all racial groups in this study breast cancer was predominantly ER-positive and was being diagnosed at earlier stages over time. These observations provide initial indications that late-stage aggressive breast cancers may not be an inherent feature of the breast cancer burden across Africa.

Stage at breast cancer diagnosis and distance from diagnostic hospital in a periurban setting: a South African public hospital case series of over 1,000 women.

Advanced stage at diagnosis contributes to low breast cancer survival rates in sub‐Saharan Africa. Living far from health services is known to delay presentation, but the effect of residential distance to hospital, the radius at which this effect sets in and the women most affected have not been quantified. In a periurban South African setting, we examined the effect of a geographic information system (GIS)‐measured straight‐line distance, from a patients residence to diagnostic hospital, on stage at diagnosis in 1,071 public‐sector breast cancer patients diagnosed during 2006–2012. Generalized linear models were used to estimate risk ratios for late stage (stage III/IV vs. stage I/II) associated with distance, adjusting for year of diagnosis, age, race and socioeconomic indicators. Mean age of patients was 55 years, 90% were black African and diagnoses were at stages I (5%), II (41%), III (46%) and IV (8%). Sixty‐two percent of patients with distances >20 km (n = 338) had a late stage at diagnosis compared to 50% with distances <20 km (n = 713, p = 0.02). Risk of late stage at diagnosis was 1.25‐fold higher (95% CI: 1.09, 1.42) per 30 km. Effects were pronounced in an underrepresented group of patients over age 70. This positive stage–distance association held to 40 km, and plateaued or slightly reversed in patients (9%) living beyond this distance. Studies of woman and the societal and healthcare‐level influences on these delays and on the late stage at diagnosis distribution are needed to inform interventions to improve diagnostic stage and breast cancer survival in this and similar settings.

Racial Comparison of Receptor-Defined Breast Cancer in Southern African Women: Subtype Prevalence and Age–Incidence Analysis of Nationwide Cancer Registry Data

Background: Receptor-defined breast cancer proportions vary across Africa. They have important implications for survival prospects and research priorities. Methods: We studied estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor statuses in two multiracial Southern African countries with routine diagnostic immunohistochemistry. A total of 12,361 women with histologically confirmed breast cancer diagnosed at age ≥20 years during (i) 2009–2011 from South Africas national cancer registry (public sector) and (ii) 2011–2013 from Namibias only cancer hospital were included. Crude, age, and age + laboratory–adjusted ORs of receptor status were analyzed using logistic regression, and age–incidence curves were analyzed using Poisson regression. Results: A total of 10,047 (81%) women had known ER status. Ranking of subtypes was consistent across races: ER+/PR+HER2− was most common (race-specific percentage range, 54.6%–64.8%), followed by triple-negative (17.4%–21.9%), ER+/PR+HER2+ (9.6%–13.9%), and ER−PR−HER2+ (7.8%–10.9%). Percentages in black versus white women were 33.8% [95% confidence (CI), 32.5–35.0] versus 26.0% (24.0–27.9) ER−; 20.9% (19.7–22.1) versus 17.5% (15.4–19.6) triple-negative; and 10.7% (9.8–11.6) versus 7.8% (6.3–9.3) ER−PR−HER2+. Indian/Asian and mixed-ancestry women had intermediate values. Age–incidence curves had similar shapes across races: rates increased by 12.7% per year (12.2–13.1) across ER subtypes under the age of 50 years, and thereafter slowed for ER+ (1.95%) and plateaued for ER− disease (−0.1%). Conclusions: ER+ breast cancer dominates in all Southern African races, but black women have a modest excess of aggressive subtypes. Impact: On the basis of the predominant receptor-defined breast tumors in Southern Africa, improving survival for the growing breast cancer burden should be achievable through earlier diagnosis and appropriate treatment. Cancer Epidemiol Biomarkers Prev; 23(11); 2311–21. ©2014 AACR.

The challenges of managing breast cancer in the developing world - a perspective from sub-Saharan Africa

Communicable diseases are the major cause of mortality in lower-income countries. Consequently, local and international resources are channelled mainly into addressing the impact of these conditions. HIV, however, is being successfully treated, people are living longer,and disease patterns are changing. As populations age, the incidence of cancer inevitably increases. The World Health Organization has predicted a dramatic increase in global cancer cases during the next 15 years, the majority of which will occur in low- and middle-income countries. Cancer treatment is expensive and complex and in the developing world 5% of global cancer funds are spent on 70% of cancer cases. This paper reviews the challenges of managing breast cancer in the developing world, using sub-Saharan Africa as a model.

African Breast Cancer—Disparities in Outcomes (ABC-DO): protocol of a multicountry mobile health prospective study of breast cancer survival in sub-Saharan Africa

Introduction Sub-Saharan African (SSA) women with breast cancer (BC) have low survival rates from this potentially treatable disease. An understanding of context-specific societal, health-systems and woman-level barriers to BC early detection, diagnosis and treatment are needed. Methods The African Breast Cancer—Disparities in Outcomes (ABC-DO) is a prospective hospital-based study of overall survival, impact on quality of life (QOL) and delays along the journey to diagnosis and treatment of BC in SSA. ABC-DO is currently recruiting in Namibia, Nigeria, South Africa, Uganda and Zambia. Women aged 18 years or older who present at participating secondary and tertiary hospitals with a new clinical or histocytological diagnosis of primary BC are invited to participate. For consented women, tumour characteristics, specimen and treatment data are obtained. Over a 2-year enrolment period, we aim to recruit 2000 women who, in the first instance, will be followed for between 1 and 3 years. A face-to-face baseline interview obtains information on socioeconomic, cultural and demographic factors, QOL, health and BC attitudes/knowledge, and timing of all prediagnostic contacts with caregivers in orthodox health, traditional and spiritual systems. Responses are immediately captured on mobile devices that are fed into a tailored mobile health (mHealth) study management system. This system implements the study protocol, by prompting study researchers to phone women on her mobile phone every 3 months and, failing to reach her, prompts contact with her next-of-kin. At follow-up calls, women provide updated information on QOL, care received and disease impacts on family and working life; date of death is asked of her next-of-kin when relevant. Ethics and dissemination The study was approved by ethics committees of all involved institutions. All participants provide written informed consent. The findings from the study will be published in peer-reviewed scientific journals, presented to funders and relevant local organisations and at scientific conferences.

Drivers of advanced stage at breast cancer diagnosis in the multicountry African breast cancer - disparities in outcomes (ABC-DO) study: Drivers of advanced stage at breast cancer diagnosis

Breast cancer (BC) survival rates in sub‐Saharan Africa (SSA) are low in part due to advanced stage at diagnosis. As one component of a study of the entire journey of SSA women with BC, we aimed to identify shared and setting‐specific drivers of advanced stage BC. Women newly diagnosed in the multicountry African Breast Cancer–Disparities in Outcomes (ABC‐DO) study completed a baseline interview and their stage information was extracted from medical records. Ordinal logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for advanced stage (I, II, III, IV) in relation to individual woman‐level, referral and biological factors. A total of 1795 women were included from Nigeria, Uganda, Zambia, and the multiracial populations of Namibia and South Africa, 1091 of whom (61%) were stage III/IV. Stage was lower in women with greater BC knowledge (OR 0.77 (95% CI: 0.70, 0.85) per point on a 6 point scale). More advanced stage was associated with being black (4.00 (2.79, 5.74)), having attended

Breast conservation surgery versus total mastectomy among women with localized breast cancer in Soweto, South Africa

Purpose Breast conserving surgery (BCS) has become the preferred surgical option for the management of patients with nonmetastatic breast cancer in high-income countries. However, little is known about the distribution and determinants of BCS in low-and middle-income countries, especially those with high HIV prevalence. Methods We compared demographic and clinical characteristics of female patients who received BCS and those who received total mastectomy (TM) for nonmetastatic invasive carcinoma of the breast in Soweto, South Africa, 2009–2011. We also developed a multivariable logistic regression model of predictors of type of surgery. Results Of 445 patients, 354 (80%) underwent TM and 91 (20%) BCS. Of 373 patients screened for HIV, 59 (15.8%) tested positive. Eighty-two of 294 patients with stage I/II disease (28%), but just 9 of 151 (6%) with stage III disease had BCS (p<0.001). All women who received BCS (except for seven who received completion mastectomy within 6 weeks of BCS) and 235 (66.4%) women who received TM were referred for radiation therapy (RT). In our multivariable analysis, age group 50–59 years (OR = 2.28, 95% CI = 1.1–4.8) and ≥70 years (OR = 9.55, 95% CI = 2.9–31.2) vs. age group <40 years, stage at diagnosis (stage II (OR = 3.79, 95% CI = 1.6–8.2) and stage III (OR = 27.8, 95% CI = 9.0–78.8) vs. stage 1, HIV (HIV positive (OR = 3.19, 95% CI = 1.3–7.9) vs. HIV negative) and HER2-enriched subtype (OR = 3.50, 95% CI = 1.2–10.1) vs. triple negative were independently associated with TM. Conclusion TM was more common than BCS among patients with nonmetastatic breast cancer in Soweto, not only among patients with locally advanced disease at diagnosis, but also among women with stage I and II disease.

South African Breast Cancer and HIV Outcomes Study: Methods and Baseline Assessment

Purpose In low- and middle-income, HIV-endemic regions of sub-Saharan Africa, morbidity and mortality from the common epithelial cancers of the developed world are rising. Even among HIV-infected individuals, access to antiretroviral therapy has enhanced life expectancy, shifting the distribution of cancer diagnoses toward non–AIDS-defining malignancies, including breast cancer. Building on our prior research, we recently initiated the South African Breast Cancer and HIV Outcomes study. Methods We will recruit a cohort of 3,000 women newly diagnosed with breast cancer at hospitals in high (average, 20%) HIV prevalence areas, in Johannesburg, Durban, Pietermaritzburg, and Empangeni. At baseline, we will collect information on demographic, behavioral, clinical, and other factors related to access to health care. Every 3 months in year 1 and every 6 months thereafter, we will collect interview and chart data on treatment, symptoms, cancer progression, comorbidities, and other factors. We will compare survival rates of HIV-infected and uninfected women with newly diagnosed breast cancer and their likelihood of receiving suboptimal anticancer therapy. We will identify determinants of suboptimal therapy and context-specific modifiable factors that future interventions can target to improve outcomes. We will explore molecular mechanisms underlying potentially aggressive breast cancer in both HIV-infected and uninfected patients, as well as the roles of pathogens, states of immune activation, and inflammation in disease progression. Conclusion Our goals are to contribute to development of evidence-based guidelines for the management of breast cancer in HIV-positive women and to improve outcomes for all patients with breast cancer in resource-constrained settings.

Barriers to early presentation of breast cancer among women in Soweto, South Africa

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

Neoadjuvant chemotherapy among patients treated for nonmetastatic breast cancer in a population with a high HIV prevalence in Johannesburg, South Africa

Background Neoadjuvant (primary) chemotherapy (NACT) is the standard of care for locally advanced breast cancer. It also allows for the short-term assessment of chemotherapy response; a pathological complete responses correspond to improved long-term breast cancer outcomes. In sub-Saharan Africa, many patients are diagnosed with large nonresectable tumors. We examined NACT use in breast cancer patients who visited public hospitals in Johannesburg, South Africa. Methods We assessed demographic characteristics, tumor stage and grade, hormone receptor status, and human immunodeficiency virus (HIV) status of female patients diagnosed with nonmetastatic invasive carcinoma of the breast at Chris Hani Baragwanath Academic Hospital between January 1, 2009, and December 31, 2011. The patients received neoadjuvant, adjuvant, or no chemotherapy. Trastuzumab was unavailable. We developed logistic regression models to analyze the factors associated with NACT receipt in these patients. Results Of 554 women with nonmetastatic breast cancer, the median age at diagnosis was 52 years (range: 28–88 years). Only 5.8% of patients were diagnosed with stage I disease; 49.3% and 44.9% were diagnosed with stages II and III, respectively. Most patients had hormone-responsive tumors: luminal A, 38.1%; luminal B1 (human epidermal growth factor receptor 2 [HER2]-negative and high grade), 12.5%, and luminal B2 (HER2-positive any grade), 11.6%; 11.6% had a HER2-enriched tumor and 20.6% a triple-negative tumor. Eighty (14.4%) patients were HIV-positive. In total, 195 patients (35.2%) received NACT, 264 (47.7%) patients received adjuvant chemotherapy, and 95 patients (17.1%) received no chemotherapy, including 62 (11.2%) patients who received only hormonal therapy. Of patients receiving NACT, 125 (64.1%) were evaluable for clinical response. Eighty (64.0%) patients had a clinically significant response; 19 (15.2%) patients had a stable disease, and 26 (20.8%) patients had a progressive disease. Multivariate analysis showed age <40 years and disease stage to be independently associated with the receipt of NACT. Conclusion Most women receiving NACT with available response data showed a clinical benefit. Stage III disease at diagnosis and age <40 years were predictors of neoadjuvant versus adjuvant chemotherapy treatment.