Purpose: COVID-19 affected care access, treatment options, and cancer outcomes. We assessed stage at diagnosis and 2-year overall survival among South African women with breast cancer (BC) pre- (1 January 2017 to 31 December 2018) and during COVID-19 (01 April 2020 to 31 March 2022). Methods: 1772 participants were enrolled at two Johannesburg academic hospitals, 978 pre- and 794 during COVID-19. Cox proportional hazard models examined risk factors of mortality. Results: Late-stage (III+IV) diagnosis increased by 7% during COVID-19. Two-year crude survival was 72.4% overall. Diagnosis during COVID-19 decreased mortality risk (Hazard ratio (HR)=0.71, 95% Confidence Interval (CI): 0.58-0.87). A family history of BC protected against late-stage diagnosis during both periods. Pre-COVID-19, unemployment (OR=1.47 95%CI 1.07-2.03) and household poverty (OR=1.37 95% CI 1.03-1.82) and being single during COVID-19 increased late-stage odds (OR=1.31 95%CI 1.05-1.62). Being unemployed increased mortality risk (HR=1.36, 95%CI: 1.09-1.69 pre-COVID-19; HR=1.43, 95%CI: 1.06-1.93 COVID-19) as did poor education pre-COVID-19 and tobacco use during COVID-19 (HR=1.60, 95% CI:1.10-2.33). Late-stage BC increased mortality risk (HR = 2.65, 95%CI: 1.95-3.61 pre-COVID; HR = 1.81, 95%CI: 1.31-2.51 COVID) as did high tumor proliferation rates (Ki67 ≥20%) (HR =1.53, 95%CI: 1.22-1.91 pre-COVID; HR = 1.43, 95%CI: 1.03-2.00 COVID). BC subtypes during the pandemic, HR-/HER2+ (HR=1.59, 95%CI: 1.04-2.42) and TNBC (HR=1.60, 95%CI: 1.16-2.19) and positive HIV status pre-COVID (HR=1.61, 95%CI: 1.28-2.02) increased mortality risk. Versus surgery as first treatment, no treatment and neoadjuvant modalities increased mortality risk. Conclusions : Health system and socioeconomic factors negatively impacted access to care; HIV and cancer treatment changes during COVID-19, contributed to improved 2-year survival.

Background Breast cancer survival rates in sub-Saharan Africa are low. In a prospective, multi-center cohort study, we estimated 5-year overall survival rates, overall survival determinants, and mediating effects between socioeconomic status on overall survival among South African women diagnosed with invasive BC. Patients and methods Patients from 4 public hospitals were enrolled between July 1, 2015 and January 31, 2019. Survival determinants were assessed using Cox proportional hazard models adjusted for age, background mortality, and treatments. Socioeconomic pathway effects on overall survival were determined through generalized structural equation models. Results Of 2838 participants, 58% had advanced-stage (III/IV) disease. Five-year crude overall survival was 44.3% (95% CI 42.5-46.2). Significant mortality risks were late stage at diagnosis (hazard ratio [HR] = 2.31 [95% CI 1.99-2.69] [stage III]; 4.79 [95% CI 3.96-5.80] [stage IV]), HIV-positive status (HR = 1.45 [95% CI 1.25-1.67]), unemployment HR = 1.25 [95% CI 1.09-1.44], and low education HR 1.19 [95% CI 1.04-1.37]). Age and treatment-adjusted socioeconomic status effects on overall survival were mediated through HIV status (81.7% of the effect) and stage at diagnosis (81.7%), both P < .001. Poor breast cancer knowledge had an indirect effect on overall survival, accounting for 77.6% of the total effect (P = .001), fully mediated by late-stage presentation. Socioeconomic status had no significant direct path to mortality after accounting for these mediators. Conclusion Interventions should prioritize early breast cancer detection. For patients with low socioeconomic status, particularly those with comorbid HIV, we must mitigate multifaceted barriers to healthcare access, including limited awareness and knowledge of breast cancer.

Background: Some clinicians and radiologists in South Africa (SA) suspect that aggressive subtypes of breast cancer are becoming more prevalent and that patients are presenting at younger ages. Objectives: This study aimed to analyse the prevalence and trends in female breast cancer presentations at a Breast Unit in Johannesburg, SA, by comparing data from 2012 and 2022. Method: A retrospective study was conducted at a tertiary hospital in Johannesburg. Records of female patients diagnosed with breast cancer between 2012 and 2022 were analysed. Demographic data, ultrasound or mammography findings, and tumour characteristics were compared. Results: A total of 493 records were reviewed: 165 (33.5%) from 2012 and 328 (66.5%) from 2022. The mean ± standard deviation (s.d.) age at presentation was 56.8 ± 16.8 years in 2012 and 54.1 ± 13.6 years in 2022 (p = 0.056). Tumours were smaller in 2022 (mean ± s.d., 35.0 mm ± 24.0 mm) compared to 2012 (48.1 mm ± 21.5 mm) (p 0.001). A higher proportion of women had positive oestrogen receptor status in 2022 (p = 0.005). No differences were observed in molecular subtypes. Conclusion: No significant change was found in the mean age at presentation, suggesting a stable demographic profile. However, reproductive, hormonal, and lifestyle factors may contribute to the rising prevalence among women aged 40–49 years. Smaller tumours likely reflect increased awareness and clinical breast examinations at local clinics. Contribution: This single-institution study underscores the need for broader national research to inform breast cancer screening and imaging guidelines.

Background. Monitoring quality indicators to improve breast cancer care is well established in high-income countries. This is the first evaluation of diagnostic and surgical quality indicators for initial benchmarking of breast cancer care in South Africa (SA). Objective. To measure the adherence rates to quality indicators among women with breast cancer in SA. Methods. Ten quality indicators were evaluated for 3 545 breast cancer patients across four SA surgical breast units using a shared electronic patient record system. Data quality and adherence rates with differences between units were determined. The effect of HIV status on adherence was assessed by multivariate Poisson regression analyses. Results. Our electronic patient record reliably measured most quality indicators. Rates of positive margins (5.7%), overall axillary surgery (95.8%) and appropriate treatment sequencing in locally advanced breast cancer patients (98.4%) consistently reached minimum international standards. Rates of multidisciplinary team discussion (72.2%), radiotherapy (66.7%) and sentinel node biopsy (39.6%) showed wide cross-site variance. Histopathology reporting (62.0%), breast-conserving surgery (19.4%) and number of nodes excised with axillary dissection (47.3%) and sentinel node biopsy (82.7%) were consistently below minimum standards. Unit volumes were achieved consistently in Gauteng Province, but only for some years in KwaZulu-Natal Province; surgeon volumes were achieved across all units. HIV status did not affect adherence levels. Most quality indicators were well measurable, but data quality on reoperations and surgeon volumes was poor. Conclusion. We evaluated local quality indicators for an initial benchmark, and the most emergent gaps in care are the receipt of radiotherapy and underutilisation of sentinel node biopsy.

11158 Background: Sub-Saharan Africa (SSA) has very low breast cancer (BC) survival. South Africa, unlike most SSA countries, is an upper middle-income country where patients are less burdened with cancer diagnostic and treatment costs. We aimed to provide five-year overall survival (OS) estimates and determinants among South African women with BC diagnosed and treated within the public health system. Methods: The South African Breast Cancer and HIV Outcomes prospective cohort study enrolled adult women recently diagnosed with invasive BC from four South African academic hospitals. We collected detailed sociodemographic, clinical, treatment, and outcomes data. Women were followed for five years or until December 31, 2023, whichever was earlier, and our primary outcome was five-year OS. Impacts of potential determinants on OS were assessed using individual Cox proportional hazard models focused on nine variable domains ( i.e., treating hospital, social status, BC risk factors, smoking, cardiovascular disease (CVD), HIV status, BC type, BC treatments, and age) and a combined model that also included adjustments for background mortality. Results: Between July 2015 and Feb 2019, we enrolled 2,838 women newly diagnosed with histopathologically confirmed invasive BC, of whom 58% had III or IV disease. At the end of follow-up, 1555 (55%) of the women had died, 1191 (42%) survived for five years, 33 (1%) were censored at study’s end, and 59 (2%) were lost to follow up. The five-year OS was 44.3% (95% CI 42.5-46.2). In the full model, the variables with the largest impact on five-year survival were late-stage at diagnosis (HR 2.4 [95% CI 2.0-2.7] for stage III and HR 5.0 [95% CI 4.1-6.1] for stage IV disease, both compared with stage I/II) and differing degree of treatments received (no treatment received: HR 8.2 [95% CI 5.9-11.3]; chemotherapy and endocrine therapy: HR 1.9 [95% CI 1.4-2.6]; endocrine therapy only: HR 2.2 [95% CI 1.6-3.2]; chemotherapy only: HR 4.8 [95% CI 3.4-6.6]; surgery only: HR 3.0 [95% CI 1.9-4.8]; surgery and chemotherapy: HR 1.8 [95% CI 1.3-2.5], all compared with surgery and endocrine treatments). Other variables significantly associated with survival were treating hospital, relationship status, employment, education, family history of cancer, CVD, and HIV infection. Conclusions: Interventions to improve BC survival in South Africa’s public health system should prioritize earlier diagnosis of cancer and expansion of the infrastructure supporting diagnostic and treatment services. Concurrently, South African BC patients with low socioeconomic status, HIV infection, and/or comorbid CVD are uniquely vulnerable and their barriers to accessing care must be better understood.

The breast cancer (BC)-related mortality is higher and the immunity is altered in women living with HIV (WLWH) compared to HIV-negative women. Therefore, tumor samples of 296 black BC patients from South Africa and Namibia with known age, HIV status, tumor stage, hormone receptor and HER2 status and overall survival (OS) are analyzed for components of the tumor microenvironment (TME). WLWH ( n = 117), either with suppressed viral activity (HR = 1.25) or with immune suppression (HR = 2.04), have a shorter OS. HIV status is associated with increased numbers of CD8 + T cells in the TME compared to HIV-negative patients; no correlation is found with CD4 + T cell numbers in the blood. Moreover, an increased expression of CD276/B7-H3 and a more pronounced IFN-γ signaling in the tumors are found in WLWH, independent of age, stage, and BC subtypes. In conclusion, altered T cell composition and CD276 expression in WLWH may contribute to inferior survival and can be used for targeted treatment.

BACKGROUND:Women diagnosed with breast cancer at young ages (younger than 40 years) generally have lower survival than their older counterparts. With its young population structure, sub-Saharan Africa provides an informative setting to examine survival among young patients with breast cancer, including consideration of the extended reproductive lives and HIV comorbidities. METHODS:We established a prospective cohort of women aged 18 years and older newly diagnosed with breast cancer in five sub-Saharan African countries during 2014-2017, who were actively followed for up to 7 years. Overall survival, net survival, and Cox model hazard ratios (HRs) were used to assess the association between age at diagnosis and all-cause mortality. RESULTS:Among 2093 women, 459 (21.9%) were diagnosed under age 40 years ("young" women). Five-year net survival was 36% (95% confidence interval [CI] = 31% to 40%) in these young women, which was 8-14 percentage points lower than that for those diagnosed in their 40s, 50s, 60s, and 70s or older, being 43%, 45%, 47%, and 50%, respectively. Compared with women diagnosed at age 40-59 years, young women had 1.17-fold (95% CI = 1.02 to 1.35) higher mortality rates, unexplained by triple-negative breast cancer and HIV which were both less prevalent in young women than in those aged 40-59 years. Adjustment for sociodemographic, clinical, and treatment factors hardly altered results, except for adjustment for having had a pregnancy within the past 3 years (HR = 1.09, 95% CI = 0.93 to 1.28). CONCLUSION:Early onset breast cancer in sub-Saharan Africa was associated with lower survival compared with women aged 40-59 years. This excess mortality was restricted to young women whose breast cancer was diagnosed within 3 years postpartum, thus identifying a patient group with specific early detection, treatment support and research needs.

BACKGROUND:There are few estimates of breast cancer survival and its determinants at 5 years and beyond in sub-Saharan Africa. We aimed to estimate survival up to 7 years, estimate annual mortality risk, and apportion 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 hospital with suspected breast cancer. Vital status was updated telephonically once every 3 months for 7 years. We collected detailed sociodemographic, clinical, and treatment data. The primary outcome was overall survival. We estimated age-standardised net survival, conditional survival, and predicted survival gains if there were favourable shifts in the distribution of prognostic factors aligned with the WHO Global Breast Cancer Initiative (GBCI). FINDINGS:Between Sept 8, 2014, and Dec 31, 2017, 2313 women were recruited and followed up to Jan 1, 2022, and for a further year in South Africa. We excluded 87 women without breast cancer, 14 women from small racial groups (eight White and six Asian women in South Africa), 57 women with previous treatment or possible recurrences, and two women without follow-up data. The remaining 2153 (93%) women were categorised by country and race, as follows: three groups in Namibia (60 White women, 50 mixed race women, and 367 Black women), two in South Africa (37 mixed race women and 638 Black women), and one group of Black women in each of Uganda (419 women), Zambia (198 women), and Nigeria (384 women). During follow-up to at most 7 years, 1323 (61%) of 2153 women died, 672 (31%) were alive at administrative censoring, and 158 (7%) were lost to follow-up, giving crude survival at 3 years, 5 years, and 7 years of 51%, 40%, and 33%, respectively. Large between-country variations in 5-year age-standardised net survival were observed: 35-42% in Zambia and Nigeria; 52-58% in Black women in Uganda, South Africa, and Namibia; and over 83% in non-Black Namibian women. The annual probability of death (1-year conditional net survival, censored before the COVID-19 pandemic) declined generally from 2-3 years after diagnosis, but remained at 8-21% for Black women in Namibia, Uganda, and Nigeria during the fifth year after diagnosis. Reaching the GBCI 60% stage I or II target and accessing treatment would lead to an approximate reduction in deaths by a third among Black women in Namibia, Nigeria, South Africa, Uganda, and Zambia. INTERPRETATION:Survival after breast cancer is poor in several sub-Saharan African countries, with a substantial risk of death even among women who have survived beyond 3 years after diagnosis. Understanding and preventing deaths among longer-term breast cancer survivors requires further research. FUNDING:National Cancer Institute, Susan G Komen, and International Agency for Research on Cancer. TRANSLATIONS:For the Yoruba, Hausa, Igbo, Luganda and French translations of the abstract see Supplementary Materials section.

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BACKGROUND:There is an urgent need to improve breast cancer survival in sub-Saharan Africa. Geospatial barriers delay diagnosis and treatment, but their effect on survival in these settings is not well understood. We examined geospatial disparities in 4-year survival in the African Breast Cancer-Disparities in Outcomes cohort. METHODS:In this prospective cohort study, women (aged ≥18 years) newly diagnosed with breast cancer were recruited from eight hospitals in Namibia, Nigeria, South Africa, Uganda, and Zambia. They reported sociodemographic information in interviewer-administered questionnaires, and their clinical and treatment data were collected from medical records. Vital status was ascertained by contacting participants or their next of kin every 3 months. The primary outcome was all-cause mortality in relation to rural versus urban residence, straight-line distance, and modelled travel time to hospital, analysed using restricted mean survival time, Cox proportional hazards, and flexible parametric survival models. FINDINGS:2228 women with breast cancer were recruited between Sept 8, 2014, and Dec 31, 2017. 127 were excluded from analysis (58 had potentially recurrent cancer, had previously received treatment, or had no follow-up; 14 from minority ethnic groups with small sample sizes; and 55 with missing geocoded home addresses). Among the 2101 women included in analysis, 928 (44%) lived in a rural area. 1042 patients had died within 4 years of diagnosis; 4-year survival was 39% (95% CI 36-42) in women in rural areas versus 49% (46-52) in urban areas (unadjusted hazard ratio [HR] 1·24 [95% CI 1·09-1·40]). Among the 734 women living more than 1 h from the hospital, the crude 4-year survival was 37% (95% CI 32-42) in women in rural areas versus 54% (46-62) in women in urban areas (HR 1·35 [95% CI 1·07-1·71] after adjustment for age, stage, and treatment status). Among women in rural areas, mortality rates increased with distance (adjusted HR per 50 km 1·04, 1·01-1·07) and travel time (adjusted HR per h 1·06, 1·02-1·10). Among women with early-stage breast cancer receiving treatment, women in rural areas had a strong survival disadvantage (overall HR 1·54, 1·14-2·07 adjusted for age and stage; >1 h distance adjusted HR 2·14, 1·21-3·78). INTERPRETATION:Geospatial barriers reduce survival of patients with breast cancer in sub-Saharan Africa. Specific attention is needed to support patients with early-stage breast cancer living in rural areas far from cancer treatment facilities. FUNDING:US National Institutes of Health (National Cancer Institute), Susan G Komen for the Cure, and the International Agency for Research on Cancer.

Purpose Wide inter-individual variability is seen in the clinical outcomes of tamoxifen treatment, which may be attributable to cytochrome P450 genetic polymorphisms. To investigate this, we analysed data from an open-label three parallel arm trial with 36 healthy volunteers of African ancestry to whom a dose of 20 mg of tamoxifen had been administered and drug concentrations of tamoxifen and its three metabolites measured over 34 time points after administration. Methods The data was best described by a pharmacokinetic model, which focused on tamoxifen and its active metabolite endoxifen only. The model was described by a two-compartment model for the parent linked to a one-compartment model for the metabolite. Results Data exploration and estimated pharmacokinetic parameters for both compounds indicated wide variability between participants. The findings demonstrated high inter individual variability (99.3%) in the formation of endoxifen with no evidence to suggest that the CYP2D6 gene could explain this variation. Model diagnostic plots such as goodness of fit plots and visual predictive checks showed a good predictive performance of the model. Conclusion Age, BMI, CYP2D6, CYP3A4, CYP3A5, CYP2B6, CYP2C9 and CYP2C19 genotypes had no significant impact in explaining the variability in pharmacokinetic parameters for tamoxifen and endoxifen.

BACKGROUND:Breast cancer is the most common malignancy diagnosed among women in South Africa, with the aggressive triple-negative subtype comprising approximately 15% of breast cancers in this population. South Africa has the largest population of people with HIV in the world. This study aims to evaluate the association between HIV status and the proportion of patients with breast cancer with the triple-negative subtype. METHODS:We did a cross-sectional analysis of case-only data from the South African Breast Cancer and HIV Outcomes (SABCHO) study, a prospective cohort study recruiting patients with newly diagnosed breast cancer at six public hospitals in South Africa. We analysed data from patients who enrolled in SABCHO between Jan 1, 2015, and Jan 18, 2022. Women aged 18 years or older with newly diagnosed and histologically confirmed invasive breast cancer were eligible. Participants were classified as HIV-positive or HIV-negative by use of an ELISA-based HIV test done at the time of enrolment. We developed multivariable logistic regression models to test for an association between HIV status and the proportion of triple-negative relative to non-triple-negative breast cancers while adjusting for demographic and reproductive risk factors. FINDINGS:Of the 4122 patients enrolled in the SABCHO cohort within our study timeframe, 239 patients were excluded due to unknown breast cancer subtype (n=141), HIV status (n=97), or race (n=1). 3883 women with breast cancer were included in the study, of whom 637 (16·4%) had triple-negative breast cancer, 894 (23·0%) were HIV-positive, and 186 (4·8%) had triple-negative breast cancer and HIV. Triple-negative breast cancer accounted for 186 (20·8%) of 894 breast cancers among women who were HIV-positive and 451 (15·1%) of 2989 breast cancers among women who were HIV-negative (p<0·0001). In the fully adjusted logistic regression model, HIV-positive status was associated with an increased proportion of triple-negative breast cancer (adjusted odds ratio [OR] 1·39, 95% CI 1·12-1·74, compared with women who were HIV-negative). When compared with women who were HIV-negative, the association between HIV-positive status and the proportion of triple-negative breast cancer was strongest among the subgroup of women with a duration of HIV infection of 2 years or longer (1·57, 1·23-2·00) and those on antiretroviral therapy (ART; 1·47, 1·16-1·87). INTERPRETATION:Patients with breast cancer and chronic HIV who are on ART are more likely to have triple-negative breast cancer than patients with breast cancer without HIV. This association is independent of age, race, and reproductive factors. FUNDING:US National Institutes of Health, University of the Witwatersrand, South Africa Medical Research Council Common Epithelial Cancers Research Center, Conquer Cancer Foundation, and Varmus Global Scholars Fund.

Background Breast cancer survival in South Africa is low, but when diagnosed with breast cancer, many women in South Africa also have other chronic conditions. We investigated the impact of multimorbidity (≥ 2 other chronic conditions) on overall survival among women with breast cancer in South Africa. Methods Between 1 July 2015 and 31 December 2019, we enrolled women newly diagnosed with breast cancer at six public hospitals participating in the South African Breast Cancer and HIV Outcomes (SABCHO) Study. We examined seven chronic conditions (obesity, hypertension, diabetes, HIV, cerebrovascular diseases (CVD), asthma/chronic obstructive pulmonary disease, and tuberculosis), and we compared socio-demographic, clinical, and treatment factors between patients with and without each condition, and with and without multimorbidity. We investigated the association of multimorbidity with overall survival using multivariable Cox proportional hazard models. Results Of 3,261 women included in the analysis, 45% had multimorbidity; obesity (53%), hypertension (41%), HIV (22%), and diabetes (13%) were the most common individual conditions. Women with multimorbidity had poorer overall survival at 3 years than women without multimorbidity in both the full cohort (60.8% vs. 64.3%, p = 0.036) and stage groups: stages I–II, 80.7% vs. 86.3% ( p = 0.005), and stage III, 53.0% vs. 59.4% ( p = 0.024). In an adjusted model, women with diabetes (hazard ratio (HR) = 1.20, 95% confidence interval (CI) = 1.03–1.41), CVD (HR = 1.43, 95% CI = 1.17–1.76), HIV (HR = 1.21, 95% CI = 1.06–1.38), obesity + HIV (HR = 1.24 95% CI = 1.04–1.48), and multimorbidity (HR = 1.26, 95% CI = 1.13–1.40) had poorer overall survival than women without these conditions. Conclusions Irrespective of the stage, multimorbidity at breast cancer diagnosis was an important prognostic factor for survival in our SABCHO cohort. The high prevalence of multimorbidity in our cohort calls for more comprehensive care to improve outcomes for South African women with breast cancer.

Introduction HIV-positive women with breast cancer (BC) have worse overall survival than HIV-negative women with BC, and poor adherence to prescribed tamoxifen is known to contribute to poor survival. We, therefore, investigated the association of HIV infection with adherence to adjuvant tamoxifen among women with localized hormone receptor (HR)-positive breast cancer in South Africa. Methods Among 4,097 women diagnosed with breast cancer at six hospitals in the prospective South African Breast Cancer and HIV Outcomes (SABCHO) cohort study between July 2015 and December 2020, we focused on women with stages I-III HR-positive breast cancer who were prescribed 20mg of adjuvant tamoxifen daily for ≥3 months during the study period. We collected venous blood once from each participant during a routine clinic visit and analyzed concentrations of tamoxifen and its metabolites using a triple quadruple mass spectrometer. We defined non-adherence as a tamoxifen level < 60ng/mL after 3 months of prescribed daily tamoxifen use. We compared socio-demographic, lifestyle factors, tamoxifen-related side effects, and concurrent medication use among women with and without HIV and developed multivariable logistic regression models of tamoxifen non-adherence. Results Among 369 participants, 78 (21.1%) were HIV-positive and 291 (78.9%) HIV-negative. After a median (interquartile range) time of 13.0 (6.2-25.2) months since tamoxifen initiation, the tamoxifen serum concentration ranged between 1.54 and 943.0ng/mL, with a median of 52.3ng/mL. In the full cohort, 208 women (56.4%) were non-adherent to tamoxifen; only 161 (43.6%) were adherent. Women < 40 years of age were less likely to adhere to tamoxifen than women >60 years (73.4% vs 52.6%, odds ratio (OR)=2.49, 95% confidence interval (CI)=1.26-4.94); likewise, HIV-positive women (70.5% vs 52.6%, OR=2.16, 95% CI=1.26-3.70) were less likely to adhere than HIV-negative women. In an adjusted model, only HIV was associated with non-adherence; HIV-positive women had twice the odds of non-adherence to tamoxifen, compared to HIV-negative women (OR=2.40, 95% CI=1.11-5.20). Conclusion Non-adherence to tamoxifen may limit the overall survival of women with HR-positive breast cancer; in our study, especially in HIV-positive women. Citation Format: Oluwatosin A Ayeni, Shingirai Chiwambutsa, Wenlong Carl Chen, Nyasha N. Kapungu, Comfort Kanji, Roslyn Thelingwani, Nivashni Murugan, Rophiwa Mathiba, Boitumelo Phakathi, Sarah Nietz, Duvern Ramiah, Daniel S. O’Neil, Judith S. Jacobson, Paul Ruff, Herbert Cubasch, Tobias Chirwa, Maureen Joffe, Collen Masimirembwa, Alfred I. Neugut. The impact of HIV on non-adherence for tamoxifen among women with breast cancer in South Africa [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-03.

Clinical outcomes of tamoxifen (TAM) treatment show wide interindividual variability. Comedications and genetic polymorphisms of enzymes involved in TAM metabolism contributes to this variability. Drug–drug and drug–gene interactions have seldom been studied in African Black populations. We evaluated the effects of commonly co‐administered medicines on TAM pharmacokinetics in a cohort of 229 South African Black female patients with hormone‐receptor positive breast cancer. We also investigated the pharmacokinetic effects of genetic polymorphism in enzymes involved in TAM metabolism, including the variants CYP2D6*17 and *29 , which have been mainly reported in people of African descent. TAM and its major metabolites, N‐desmethyltamoxifen (NDM), 4‐OH‐tamoxifen, and endoxifen (ENDO), were quantified in plasma using the liquid chromatography‐mass spectrometry. The GenoPharm open array was used to genotype CYP2D6 , CYP3A5 , CYP3A4 , CYP2B6 , CYP2C9 , and CYP2C19 . Results showed that CYP2D6 diplotype and CYP2D6 phenotype significantly affected endoxifen concentration ( P < 0.001 and P < 0.001). CYP2D6*17 and CYP2D6*29 significantly reduced the metabolism of NDM to ENDO. Antiretroviral therapy had a significant effect on NDM levels and the TAM/NDM and NDM/ENDO metabolic ratios but did not result in significant effects on ENDO levels. In conclusion, CYP2D6 polymorphisms affected endoxifen concentration and the variants CYP2D6*17 and CYP2D6*29 significantly contributed to low exposure levels of ENDO. This study also suggests a low risk of drug–drug interaction in patients with breast cancer on TAM.

Black African populations are more genetically diverse than others, but genetic variants have been studied primarily in European populations. The present study examined the association of four single nucleotide polymorphisms (SNPs) of the fibroblast growth factor receptor 2, associated with breast cancer in non‑African populations, with breast cancer in Black, southern African women. Genomic DNA was extracted from whole blood samples of 1,001 patients with breast cancer and 1,006 controls (without breast cancer), and the rs2981582, rs35054928, rs2981578, and rs11200014 polymorphisms were analyzed using allele‑specific Kompetitive allele‑specific PCR™, and the χ2 or Fisher's exact tests were used to compare the genotype frequencies. There was no association between those SNPs and breast cancer in the studied cohort, although an association was identified between the C/C homozygote genotype for rs2981578 and invasive lobular carcinoma. These results show that genetic biomarkers of breast cancer risk in European populations are not necessarily associated with risk in sub‑Saharan African populations. African populations are more heterogenous than other populations, and the information from this population can help focus genetic risks of cancer in this understudied population.

PurposeBreast cancer is a heterogeneous disease with different gene expression profiles, treatment options and outcomes. In South Africa, tumors are classified using immunohistochemistry. In high-income countries multiparameter genomic assays are being utilized with implications for tumor classification and treatment.MethodsIn a cohort of 378 breast cancer patients from the SABCHO study, we investigated the concordance between tumor samples classified by IHC and the PAM50 gene assay.ResultsIHC classified patients as ER-positive (77.5%), PR-positive (70.6%), and HER2-positive (32.3%). These results, together with Ki67, were used as surrogates for intrinsic subtyping, and showed 6.9% IHC-A-clinical, 72.7% IHC-B-clinical, 5.3% IHC-HER2-clinical and 15.1% triple negative cancer (TNC). Typing using the PAM50 gave 19.3% luminal-A, 32.5% luminal-B, 23.5% HER2-enriched and 24.6% basal-like. The basal-like and TNC had the highest concordance, while the luminal-A and IHC-A group had the lowest concordance. By altering the cutoff for Ki67, and realigning the HER2/ER/PR-positive patients to IHC-HER2, we improved concordance with the intrinsic subtypes.ConclusionWe suggest that the Ki67 be changed to a cutoff of 20-25% in our population to better reflect the luminal subtype classifications. This change would inform treatment options for breast cancer patients in settings where genomic assays are unaffordable.

Because of potent antiretroviral therapy (ART), most women infected with HIV now live longer to ages when breast cancer incidence rates are high. Although not at increased risk of breast cancer, patients with HIV and breast cancer experience lower survival compared with their HIV-uninfected counterparts. A large US cancerand HIV-linked registry-based study of patients with cancer, the HIV/AIDS-Cancer Match study, showed that all-cause mortality and breast cancer–specific mortality were 4.6 times (hazard ratio [HR]; 95% CI, 3.9 to 5.5) and 2.6 times (2.1-3.3), respectively, higher among patients with HIV and breast cancer (n = 314) than among patients with breast cancer uninfected by HIV, after adjusting for ethnicity and age, year of diagnosis, and tumor stage at cancer diagnosis. Similarly, in Sub-Saharan Africa (SSA) where breast cancer survival is on average lower than that in highincome countries, we found that patients with breast cancer and HIV experience lower overall survival than patients with breast cancer uninfected by HIV. The absolute 3-year overall survival was 9% lower for patients with HIV and breast cancer (HR, 46%; 95% CI, 40 to 53) versus (HR, 55%; 95% CI, 52 to 59) for patients with breast cancer uninfected by HIV in the African Breast Cancer-Disparities in Outcomes (ABC-DO) study. The ABC-DO study and South African Breast Cancer and HIV Outcomes (SABCHO) study, to our knowledge, the two largest prospective cohorts of women newly diagnosed with breast cancer in SSA (n = 313 and 600 patients with HIV, respectively, with a small number contributing to both cohorts) reported ageand stage-adjusted all-cause mortality HRs in HIV-infected versus HIVuninfected patients with breast cancer of 1.41 (95% CI, 1.15 to 1.74) and 1.50 (95% CI, 1.22 to 1.85), respectively.

Objective In low- and middle-income countries (LMICs), advanced-stage diagnosis of breast cancer (BC) is common, and this contributes to poor survival. Understanding the determinants of the stage at diagnosis will aid in designing interventions to downstage disease and improve survival from BC in LMICs. Methods Within the South African Breast Cancers and HIV Outcomes (SABCHO) cohort, we examined factors affecting the stage at diagnosis of histologically confirmed invasive breast cancer at five tertiary hospitals in South Africa (SA). The stage was assessed clinically. To examine the associations of the modifiable health system, socio-economic/household and non-modifiable individual factors, hierarchical multivariable logistic regression with odds of late-stage at diagnosis (stage III-IV), was used. Results The majority (59%) of the included 3497 women were diagnosed with late-stage BC disease. The effect of health system-level factors on late-stage BC diagnosis was consistent and significant even when adjusted for both socio-economic- and individual-level factors. Women diagnosed in a tertiary hospital that predominantly serves a rural population were 3 times (OR = 2.89 (95% CI: 1.40–5.97) as likely to be associated with late-stage BC diagnosis when compared to those diagnosed at a hospital that predominantly serves an urban population. Taking more than 3 months from identifying the BC problem to the first health system entry (OR = 1.66 (95% CI: 1.38–2.00)), and having luminal B (OR = 1.49 (95% CI: 1.19–1.87)) or HER2-enriched (OR = 1.64 (95% CI: 1.16–2.32)) molecular subtype as compared to luminal A, were associated with a late-stage diagnosis. Whilst having a higher socio-economic level (a wealth index of 5) reduced the probability of late-stage BC at diagnosis, (OR = 0.64 (95% CI: 0.47–0.85)). Conclusion Advanced-stage diagnosis of BC among women in SA who access health services through the public health system was associated with both modifiable health system-level factors and non-modifiable individual-level factors. These may be considered as elements in interventions to reduce the time to diagnosis of breast cancer in women.

Purpose Women living with HIV (WLWH) and breast cancer (BC) have worse overall survival than HIV-negative women with BC, and poor adherence to prescribed tamoxifen is known to contribute to poor survival. We therefore investigated the association of HIV infection with adherence to adjuvant tamoxifen among women with localized hormone receptor (HR)-positive breast cancer in South Africa. Methods Among 4,097 women diagnosed with breast cancer at six hospitals in the prospective South African Breast Cancer and HIV Outcomes (SABCHO) cohort study between July 2015 and December 2020, we focused on black women with stages I-III HR-positive breast cancer who were prescribed 20 mg of adjuvant tamoxifen daily. We collected venous blood once from each participant during a routine clinic visit, and analyzed concentrations of tamoxifen and its metabolites using a triple quadruple mass spectrometer. We defined non-adherence as a tamoxifen level < 60 ng/mL after 3 months of daily tamoxifen use. We compared tamoxifen-related side effects, and concurrent medication use among women with and without HIV and developed multivariable logistic regression models of tamoxifen non-adherence. Results Among 369 subjects, 78 (21.1%) were WLWH and 291 (78.9%) were HIV-negative. After a median (interquartile range) time of 13.0 (6.2-25.2) months since tamoxifen initiation, the tamoxifen serum concentration ranged between 1.54 and 943.0 ng/mL and 208 (56.4%) women were non-adherent to tamoxifen. Women < 40 years of age were more likely to be non-adherent than women > 60 years (73.4% vs 52.6%, odds ratio (OR) = 2.49, 95% confidence interval (CI) = 1.26-4.94); likewise, WLWH (70.5% vs 52.6%, OR = 2.16, 95% CI = 1.26-3.70) than HIV-negative women. In an adjusted model WLWH had twice the odds of non-adherence to tamoxifen, compared to HIV-negative women (OR = 2.40, 95% CI = 1.11-5.20). Conclusion High rates of non-adherence to adjuvant tamoxifen may limit the overall survival of black South African women with HR-positive breast cancer, especially among WLWH.