Colorectal cancer is the predominant and recurring cancer leading to the second largest cause of mortality, globally. Abnormal regulation of oncogenes and deactivation of tumor suppressor genes over an extended period were key mechanisms underlying colon tumorigenesis. As a result, an effective drug targeting these genes should be explored to combat this disease. We aim to explore the effects of Valproic acid (VPA), a histone deacetylase inhibitor (HDACi), and Zebularine (ZEB), DNA methyltransferase inhibitor, on the expression of the Krüppel-like factor 4 (KLF4) and CTNNB1 (β-catenin) in an early-stage colon cells (SW480 cells) and a late-stage colon cell (DLD-1 cells). Using several in-vitro assays including cell viability, proliferation assay, single cell imaging and analysis and molecular assays including qPCR, protein expression analysis, we have assessed the anticancer properties of both drugs, VPA and ZEB. The synergistic effect of VPA and ZEB could effectively inhibit the proliferation of colon cells than their independent doses. The gene expression profile revealed 2-fold increase in the expression of KLF4 in SW480 cells, with increase to about 22-fold in DLD-1 cells. Notably, CTNNB1 was downregulated than KLF4 in a dose dependent manner, potentially leading to antitumorigenic and anti-proliferative properties of the combinatorial drug. Cellular localization of KLF4 and CTNNB1 protein expression in cytoplasm and nucleus with morphological changes of the cancer cells revealed the onset of programmed cell death. qPCR analysis also showed the downregulation of KLF4 and CTNNB1 upon synergistic activity of ZEB and VPA treated colon cancer cells. Microscopic analysis confirmed the upregulation of KLF4 in ZEB treatment cells leading to DNA methylation. Finally, single cell image analysis has shown the reduced expression of both KLF4 and CTNNB1. Overall, the analysis confirmed that synergistic effect of ZEB and VPA served as a potential anti-colon cancer agent.

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.

58 Background: The incidence of early-onset colorectal cancer (EOCRC) has increased across sub-Saharan Africa, but data describing the features of EOCRC in this region is limited. We characterized the demographics, clinicopathologic features, and survival outcomes of EOCRC patients in South Africa (SA). Methods: The Colorectal Cancer in South Africa (CRCSA) study is a longitudinal cohort study that enrolled CRC patients from five academic teaching hospitals affiliated with the University of the Witwatersrand between 2016 and 2019. We excluded patients with known mismatch repair deficiency and treated patients with multiple primary tumors as distinct cases. We stratified the cohort by age at CRC diagnosis (<50 vs ≥50 years) and performed a multivariable Cox proportional hazards analysis to compare overall survival (OS) between EOCRC and average-onset CRC (AOCRC). We performed a principal component analysis of self-reported diet data to identify dietary patterns and used a multivariable linear regression model to test the association of diet with age at CRC diagnosis. Results: In our cohort of 704 CRC cases, 179 were EOCRC (25.4%). EOCRC accounted for a greater proportion of CRC cases in Black patients than in non-Black patients (32.1% vs 18.4%, p < 0.001). Rectal cancer accounted for 55.8% of all tumors with no difference by age at diagnosis (p = 0.737). Metastatic disease was present at diagnosis in 47.4% of EOCRC cases and 38.0% of AOCRC cases (p = 0.042). EOCRC tumors were more likely to be KRAS WT (78.6% of EOCRC vs 48.3% of AOCRC, p = 0.041), although only 10% of tumors were tested. In a multivariable Cox proportional hazards model, EOCRC was not associated with OS (adjusted HR 1.12; 95% CI 0.88-1.42). Black race (adjusted HR 1.43; 95% CI 1.13-1.81) and male gender (adjusted HR 1.46; 95% CI 1.17-1.82) were associated with worse OS. In a multivariable linear regression model, patients in the highest quartile of adherence to a Western diet were diagnosed 4.19 years earlier than those in the lowest quartile (p = 0.005). Conclusions: In SA, EOCRC and AOCRC have comparable presentations, although EOCRC is more common in Black South Africans and is more likely to present with metastatic disease. Survival outcomes are similar across age groups after adjusting for relevant factors. Increased adoption of a Western diet may contribute to the rising burden of EOCRC in SA, but larger prospective studies of lifestyle factors are needed. Multivariable Cox regression model evaluating the association of age at CRC diagnosis with overall survival in the Colorectal Cancer in South Africa (CRCSA) study (2016-2019). Hazard Ratio* (95% CI)(n = 578) Age at Diagnosis Early-Onset 1.12 (0.88-1.42) Average-Onset 1.00 Race Black 1.43 (1.13-1.81) Non-Black 1.00 Gender Male 1.46 (1.17-1.82) Female 1.00 *The model also adjusted for BMI, socioeconomic status, and stage at diagnosis (data not shown).

Esophageal squamous cell carcinoma (ESCC) is a disease with limited tools for early screening and a poor prognosis. Symptoms typically appear late, and early cancer is hard to detect without endoscopic screening, which is inaccessible in most high-risk areas. Saliva is easily accessible, and its microbiome composition can serve as a marker for upper gastrointestinal tract disease. We studied the potential utility of an oral microbiome signature for ESCC in South Africa, a region with a high incidence of the disease. In a cohort of 48 ESCC patients and 110 controls, we found marked alterations in the oral microbiome in patients with ESCC, including significantly reduced alpha diversity and increased Fusobacterium nucleatum. We devised machine learning models that classify ESCC using microbiome data, finding good performance on held-out samples (area under receiver operating characteristic curve of 0.96), and demonstrated generalization to data across independent studies conducted in different geographic regions (0.64-0.81). Overall, our results demonstrate the potential of the oral microbiome to serve as a non-invasive screening tool for ESCC.

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.

PURPOSEIn South Africa, breast care lacks governance and standardization, necessitating urgent improvements in patient outcomes. Quality improvement initiatives are urgently needed in low- and middle-income countries (LMICs), but requirements for breast centers in lower resource settings remain undefined and must be tailored to local environments. This consensus document outlines the role and requirements of breast centers in LMICs and presents a step-by-step implementation plan.METHODSThe literature was systematically reviewed, and the primary review team tabulated international accreditation standards alongside the 2018 South African Clinical Guidelines for Breast Cancer Control and Management from the South African National Department of Health, along with proposed South African standards. The broader consensus panel consisted of 29 clinical experts and representatives from societies, advocacy, and funders.RESULTSWe categorized requirements into eight broader categories and achieved unanimous consensus on all requirement components, except for 1 abstention in the general specialist and expertise category. We were unable to reach consensus on the patient volume requirements for radiologists as well as for medical and clinical/radiation oncologists. Volume requirements for clinical and radiation oncologists were later provided by the South African Society of Clinical and Radiation Oncology (SASCRO), along with the volume requirements submitted by the participating radiologists. We also achieved unanimous consensus for the Breast Interest Group of Southern Africa (BIGOSA) to house the initial project implementation. This consensus document is endorsed by BIGOSA, SASCRO, and the Cancer Association of South Africa.CONCLUSIONWe emphasize the importance and necessity of breast centers in resource-constrained environments, outline the first set of requirements for breast centers tailored to LMICs in sub-Saharan Africa, and present a feasible and detailed plan for initial implementation.

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.

1518 Background: Lung cancer is the most common cancer and cause of cancer death, encompassing for 16.8% of all cancer-related deaths worldwide. Anti-PD(L)1 Immune Checkpoint Inhibitors (ICIs) as monotherapy currently represent the standard of care (SoC) for advanced Non-Small Cell Lung Cancer with high (≥50%) PD-L1 expression in high-income countries. Despite their efficacy, ICIs remain largely inaccessible in low- and middle-income countries (LMICs), with affordability being a significant barrier. Providing evidence on cost-effective (CE) price ranges for ICIs in LMICs is critical for global health policymakers to devise strategies to enhance access. Methods: A partitioned-survival model was used to estimate CE price targets for three ICIs (atezolizumab, cemiplimab, and pembrolizumab) as single agents compared to platinum-based combination chemotherapy (current SoC in several LMICs). Treatment duration was assumed of up to 35 cycles or until disease progression. Cost-effectiveness thresholds were set at 1, 2, and 3 times the gross domestic product (GDP) per capita per quality-adjusted life year (QALY) gained. Case studies were modelled in two LMICs (India and South Africa – not all ICIs were registered in both countries) to determine the maximum price at which ICIs would be CE from the perspective of publicly-funded health systems. Primary efficacy data were sourced from phase III clinical trials (KEYNOTE-024, IMpower110, and EMPOWER-Lung 1), and country-specific data were collected through interviews with key technical stakeholders. Values were reported in USD for 2023. Results: The analysis determined that the maximum acquisition costs for ICIs to be cost-effective at 1-, 2-, and 3-times GDP per capita in India and South Africa, range from $14.20 to $648.00 per cycle per patient. Current reference prices would require discounts of up to 93.3% to meet the 3 GDP threshold. Dose-optimization strategies such as low-dose and vial sharing were identified as feasible and evidence-based approaches to achieve partial price reduction (sensitivity analysis will be provided). Conclusions: To make ICIs cost-effective in LMICs, significant discounts from current reference prices are needed. Similar price reductions (up 93%) have been achieved for other monoclonal antibodies, such as trastuzumab, in India and South Africa, also driven by the availability and uptake of quality-assured biosimilars. A comprehensive approach, combining accelerated biosimilar availability, also leveraging voluntary licensing and technology transfer, with dose and treatment-duration optimization strategies could help achieve target price levels and improve accessibility. Country WTP threshold (xGDP) Pembrolizumab Atezolizumab Cemiplimab India 1 $72.6 $74.2 $66.5 2 $199.7 $166.9 $181.5 3 $308.6 $259.6 $300.0 South Africa 1 $51.5 $53.1 $14.2 2 $349.9 $289.0 $314.7 3 $648.2 $525.0 $615.2

Background: Cancer is one of the major risk factors for venous thromboembolism (VTE). The prevalence of incidental VTE among cancer patients in South Africa is unknown. Aim: To determine the presence and location of VTE, find out if VTE is more common in certain cancer types, and to determine the role of human immunodeficiency virus (HIV) in the incidental finding of VTE among cancer patients. Setting: This study was conducted at the Radiology Department at the Charlotte Maxeke Johannesburg Academic Hospital located in Johannesburg, South Africa. Methods: There were 214 staging computed tomography (CT) scans of eligible adult cancer patients from January 2018 to June 2018. These were identified using a picture archiving and communication system (PACS) and analysed retrospectively by three consultant radiologists. Univariate analysis and multivariable logistic regression models were used to investigate associations between VTE and HIV, age, gender, ethnicity and common cancers. Results: The mean age was 53 years (standard deviation [s.d.] 13.98) with the age range being 18–86 years, and 64% of these patients were female. Incidental VTE was 14.9% (95% confidence interval [CI] 10.7% – 20.4%). Pulmonary embolism (PE) accounted for 11.2%, while abdominal deep vein thrombosis (ADVT) accounted for 3.7%. Moreover, HIV-positive cancer patients were three times more likely to have VTE compared to HIV-negative cancer patients, with adjusted odds’ ratio 3.2 (1–10), p = 0.04. There was no association found between cancer type and VTE. Conclusion: This study revealed cancer and HIV infection as risk factors for patients developing VTE. Pulmonary embolism was more common than ADVT. Actively search for VTE in cancer patients when reviewing staging CT scans. Contribution: This is the first research in South Africa to determine the prevalence of incidental VTE among cancer patients.

Background: Cancer patients in Sub-Saharan Africa (SSA) are diagnosed late partly due to community lack of knowledge about the disease, social and cultural factors, health system challenges, and inadequate health care worker knowledge. These delays in diagnosis as well as inadequate treatment options contribute to the high mortality from lung cancer in SSA. Quality of life (QoL) is an important outcome measure for cancer patients undergoing treatment. Objective: To describe the quality of life among lung cancer patients in three teaching hospitals in SSA. Methods: This is a prospective cross-sectional study of lung cancer patients at three teaching hospitals in Sub-Saharan Africa (SSA- Kenya (BMC), Tanzania (MTRH) and South Africa (The Lung Laboratory Research and Intervention Unit Helen Joseph Hospital (Wits-Core)). Trained interviewers collected data on demographics, clinical information and performance status using the Eastern Cooperative Oncological Group Performance Scale (ECOG-PS). Patients' QoL was assessed using the 30-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30).   Results: A total of 210 lung cancer patients consented and were enrolled across the three sites. Global Health Status in this cohort is low, the median score was 41.7 (range: 0-100) and differed between sites. The Wits-Core patients had higher social functioning, while BMC and MTRH had higher financial difficulty scores. Poor ECOG-PS score (3-4) was associated with poorer Global QoL (GqoL) score (aOR = 2.9; 95% CI: 1.4 - 5.9), and patients with higher symptom burden had poorer GQoL. Conclusion: The QoL among lung cancer patients in the three sites is low. Poor QOL in the study is associated with level of education, performance status, fatigue, pain, dyspnoea, insomnia, loss of appetite and constipation.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementNo financial disclosure### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approval was obtained from the University of Witwatersrand Human Research Ethics Committee (Medical) (Ref: M180436), MTRH Institutional Research and Ethics Committee IREC (0004048), BMC/CUHAS Ethics & Review Committee (Certificate number CREC/278/2018) and National Institute for Medical Research (Certificate number MR/53/100/598).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesThe data used to support the research findings is included as part of the supporting information.

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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.

The discovery of novel and innovative therapeutic strategies for cancer treatment and management remains a major global challenge. Exosomes are endogenous nanoscale extracellular vesicles that have garnered increasing attention as innovative vehicles for advanced drug delivery and targeted therapy. The attractive physicochemical and biological properties of exosomes, including increased permeability, biocompatibility, extended half-life in circulation, reduced toxicity and immunogenicity, and multiple functionalization strategies, have made them preferred drug delivery vehicles in cancer and other diseases. Small interfering RNAs (siRNAs) are remarkably able to target any known gene: an attribute harnessed to knock down cancer-associated genes as a viable strategy in cancer management. Extensive research on exosome-mediated delivery of siRNAs for targeting diverse types of cancer has yielded promising results for anticancer therapy, with some formulations progressing through clinical trials. This review catalogs recent advances in exosome-mediated siRNA delivery in several types of cancer, including the manifold benefits and minimal drawbacks of such innovative delivery systems. Additionally, we have highlighted the potential of plant-derived exosomes as innovative drug delivery systems for cancer treatment, offering numerous advantages such as biocompatibility, scalability, and reduced toxicity compared to traditional methods. These exosomes, with their unique characteristics and potential for effective siRNA delivery, represent a significant advancement in nanomedicine and cancer therapeutics. Further exploration of their manufacturing processes and biological mechanisms could significantly advance natural medicine and enhance the efficacy of exosome-based therapies.

Intravenous pembrolizumab 400 mg every 6 weeks was approved across tumor types based on pharmacokinetic modeling, which showed exposures consistent with previous standard dosing of 200 mg or 2 mg/kg every 3 weeks, and early results of cohort B of the phase 1 KEYNOTE-555 study. Results after ≥1 year of potential follow-up for all patients in cohort B of KEYNOTE-555 are presented. Patients aged ≥18 years with previously untreated stage III/IV melanoma received pembrolizumab 400 mg every 6 weeks for ≤18 cycles. The primary endpoint was objective response rate per RECIST v1.1 by blinded independent central review. Secondary endpoints included duration of response, progression-free survival, pharmacokinetics, and safety. Overall, 101 patients received pembrolizumab. Median projected follow-up was 21.9 months (range, 17.0-25.7). The objective response rate was 50.5% (95% CI: 40.4-60.6; 19 complete responses, 32 partial responses). Median duration of response was not reached (NR; range, 2.4+ to 21.0+ months). Median progression-free survival was 13.8 months (95% CI: 4.1-NR). Observed pharmacokinetic exposures were consistent with model predictions for pembrolizumab 400 mg every 6 weeks and other approved and tested schedules (2 mg/kg or 200 mg every 3 weeks). Grade 3-4 treatment-related adverse events occurred in 13 patients (12.9%). No deaths were considered treatment related. These results support the pharmacokinetic modeling and demonstrate that the benefit-risk profile of pembrolizumab 400 mg Q6W is consistent with that of 200 mg or 2 mg/kg every 3 weeks. Clinically meaningful objective response rate and durable progression-free survival within the expected range for first-line pembrolizumab were observed. Clinical trial registry: ClinicalTrials.gov, NCT03665597.

522 Background: South African (SA) women living with comorbid estrogen receptor positive (ER+) breast cancer (BC) and HIV have higher mortality than other SA women with ER+ BC. We aimed to evaluate for associations between HIV status, psychosocial factors, and adjuvant endocrine therapy (AET) adherence as a potential contributor to this disparity. Methods: From Chris Hani Baragwanath Hospital, Johannesburg, we enrolled adult women with stage I-III ER+ BC in remission and currently prescribed tamoxifen or an aromatase inhibitor to a prospective cohort study. We performed AET pill counts at enrollment, 12 weeks, and 24 weeks, and calculated adherence ratios from the difference in pills between visits divided by the number of days between visits. Women completed questionnaires on sources of social support, beliefs about medication, health literacy, and self-efficacy at enrollment and questionnaires about mental health (depression, anxiety, and acute stress) symptom burden and AET-related side effects at the 12- and 24-week visits. We also collected household wealth data and clinical data on BC and HIV. AET adherence ratios were compared between women with and without comorbid HIV using Wilcoxon rank sum testing. We also used structural equation modeling techniques to refine and evaluate an a priori model of AET adherence with latent variables for mental health, socioeconomic (SES) status, healthcare savvy, and AET side effect burden and subgroup analyses of the resulting model in women with and without HIV. Results: Between April 26, 2022, and July 11, 2023, we enrolled 239 women, 63 (26.4%) of whom had co-morbid HIV. Adherence data was available from 106 women at 12 and 24 weeks, from 22 women at 12 weeks only, and from 111 women at 24 weeks only. Comparing women with and without HIV, median AET adherence ratio was 0.88 vs 0.89, respectively (p = 0.65). Our final model of AET adherence achieved good fit (comparative fit index = 0.96, RMSEA 90% CI: 0.03-0.06). In the full cohort, SES quintile showed a trend towards association with AET adherence (β 0.02, SE 0.01, p=0.09); mental health, healthcare savvy, and side effect burden latent variables were not significantly associated with adherence. In the subgroup of women living with HIV, SES quintile (β 0.04, SE 0.02, p=0.08) and mental health (β -0.02, SE 0.01, p=0.10) showed trends toward association with adherence; these relationships did not persist for women without HIV. Conclusions: HIV status is not predictive of AET adherence among SA women with ER+ BC, but in women with both diagnoses, decreasing SES status and increasing mental health symptoms trended towards an association with decreased adherence. Interventions to improve the mental health of SA breast cancer patients living with HIV may promote AET adherence.

Quality improvement (QI) programs have rapidly grown in health care over recent years. Despite increasing evidence of successful QI initiatives resulting in improved outcomes, the adoption and implementation of QI programs remain a challenge worldwide. This paper briefly describes political and administrative barriers that impede the implementation of QI programs, including political and ideological factors, socioeconomic and educational barriers, and barriers related to data collection, privacy, and security. Key political and administrative barriers identified include resource limitations due to inadequate public funding, stringent laws, and change resistance. Potential solutions include support and commitment from regional and national authorities, consultation of all involved parties during QI program development, and financial incentives. The barrier of limited resources is starker among low- and middle-income countries (LMICs) compared with high-income countries (HICs) due to the absence of adequate infrastructure, personnel equipped with QI-oriented skills, and analytical technology. Solutions that have facilitated QI programs in some LMICs include outreach and collaboration with other health centers and established QI programs in HICs. The lack of QI-specific training and education in medical curricula challenges QI implementation but can be mitigated through the provision of QI promotion webinars, QI-specific project opportunities, and formalized QI training modules. Finally, barriers related to data collection, privacy, and security include laws hindering the availability of quality data, inefficient data collection and processes, and outdated clinical information systems. Access to high-quality data, organized record-keeping, and alignment of data collection processes will help alleviate these barriers to QI program implementation. The multidimensional nature of these barriers means that proposed solutions will require coordination from multiple stakeholders, government support, and leaders across multiple fields.

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: The Hedgehog (HH) pathway is a key regulator of many important processes in vertebrate embryonic development, including stem cell maintenance, cell differentiation, tissue polarity and cell proliferation. During pathway activation, Ptch no longer inhibits Smo and the full length Gli translocates to the nucleus resulting in the transcription of oncogenes. When constitutively activated, this leads to tumorigenesis in several human cancers. Cyclopamine acts as an antagonist of the HH signalling pathway by directly binding to the Smo heptahelical domain. The involvement of this pathway in metastasis, and its presence in cancer stem cells (CSCs), makes it a valid option for developing a targeted therapeutic against it. Methods: CSC were isolated from DLD1 and HT29 cell lines using magnetic cell separation labelling the CD133 receptor. The growth patterns of isolated CSCs (CD133 positive) in comparison to non-stem cells (CD133 negative) were analysed using real-time cell impedance assays (RTCA). Thereafter, adhesion, invasion and migration assays were performed with the application of small molecule inhibitors. The expression levels of CD133 and SHH were evaluated using confocal microscopy following treatment with cyclopamine. Results and Discussion: Growth of CSCs appeared to be slower than non-CSCs. Adhesion, invasion and cell migration were inhibited when CSCs were pharmacologically treated either with cyclopamine or SANT-2 (a synthetic analogue of cyclopamine), small molecule inhibitors of the HH pathway. Using confocal microscopy the cell surface expression of Sonic Hedgehog (SHH) was significantly decreased following treatment with cyclopamine, while the expression of CD133 remained unaffected. Conclusion: Considering these in vitro results, small molecule inhibitors targeting the SHH pathway appear to be promising therapeutic tools for the treatment of metastatic colon CSCs.

Plasma-Select Sequence Mutations Gene List