Breast cancer (BC) is the leading cause of cancer in women worldwide with rising incidence in low- and middle-income countries (LMIC). We examined trends in reproductive and lifestyle factors for breast cancer across birth cohorts of Nigerian women. We conducted a cross-sectional analysis of 2,309 female control participants (mean age, 42.5 ± 13.0 years) recruited between 1998 and 2017 as part of the Nigerian Breast Cancer Study (NBCS), an ongoing case-control study. Birth cohort was modeled as an ordinal predictor to evaluate temporal trends. Reproductive and lifestyle factors were analyzed across six birth cohorts (< 1940, 1940–1949, 1950–1959, 1960–1969, 1970–1979, and ≥ 1980). Analyses of reproductive variables were repeated among women aged ≥ 40 years, and hormonal contraceptive use was additionally evaluated among women aged ≥ 30 years. Among all women, mean age at menarche declined from 16.0 years among women born before 1940 to 15.1 years among those born in or after 1980 (P for trend = 0.001), whereas age at thelarche remained stable across birth cohorts. Among women aged ≥ 40 years, mean parity declined from 6.1 to 4.1 live births, and cumulative lifetime breastfeeding duration decreased from 114 to 75 months (both P for trend < 0.001). Mean breastfeeding duration per live birth showed only a modest decline. Among women aged ≥ 30 years, the prevalence of ever hormonal contraceptive use increased from 7.2

10572 Background: Breast cancer outcomes in sub-Saharan Africa are marked by early onset, advanced stage at diagnosis, and high mortality. Although prior studies demonstrate a high burden of inherited cancer susceptibility variants in African populations, access to ancestry-informed genetic counseling and testing remains limited due to infrastructure constraints and poor integration into routine oncology care. The GenCAF program was developed to translate prior genomic evidence from Nigeria into a scalable, clinically embedded cancer genomics implementation model in African settings. Methods: Consecutive breast cancer patients were prospectively enrolled and offered genetic counseling and testing regardless of age or family history. Germline testing was performed using the Color Hereditary Cancer Test (Color Health Inc). Counseling and result disclosure were delivered by locally trained oncology nurses or breast health specialists using a structured protocol. Clinical and tumor characteristics were correlated with genetic findings. The program was designed for scalability across English- and French-speaking sites. Results: Among 263 participants, 235 unrelated index breast cancer cases underwent germline testing. Overall, 43.0% (101/235) had a reportable germline finding, including 21.7% (51/235) with pathogenic or likely pathogenic (P/LP) variants and 21.3% (50/235) with variants of uncertain significance (VUS). Among genes present in ≥5% of cases with variant calls, VUS were most frequent in APC, ATM, PALB2, PMS2 , and BRCA2 , with several moderate-penetrance DNA repair genes exhibiting disproportionately high VUS burden, representing key candidates for future reclassification as African-ancestry reference data and gene–environment context expand. P/LP variants were most common in BRCA1 (n = 22), BRCA2 (n = 13), ATM (n = 4), and PALB2 (n = 4). P/LP carriers tended to be diagnosed before age 30 (13.7% vs 7.6%) and were more frequently diagnosed with advanced-stage disease (stage III–IV, 30.6%). Mean age did not differ overall; however, BRCA1 P/LP carriers had an earlier onset (mean age 40.1 years). Conclusions: These findings support integrating germline cancer genetics into routine breast cancer care in Africa through a scalable, nurse-led counseling model. The substantial VUS burden underscores the need for ancestry-informed interpretation and future reclassification efforts incorporating population-specific and environmental data. Planned implementation of point-of-care next-generation and long-read sequencing will further strengthen local diagnostic capacity and enable sustainable, locally driven precision prevention and oncology through risk-informed care. Age Group (yrs) P/LP (%) VUS (%) <30 13.7 7.6 30–39 15.7 23.9 40–49 23.5 23.4 50–59 27.5 26.6 ≥60 15.6 19.0

PURPOSEBreast cancer is the leading cause of death in Nigerian women. Clinical trials are required to provide evidence for treatment. We aimed to generate efficacy data to support the shift in local practice of neoadjuvant therapy for breast cancer.METHODSA one-stage, phase II feasibility, single-arm study design was used. Treatment-naïve patients with clinically nonmetastatic human epidermal growth factor receptor 2 (HER2)–positive breast cancer received four cycles of neoadjuvant docetaxel with subcutaneous trastuzumab (T + scH). Patients with complete clinical response underwent surgery. Patients with stable disease/partial response received three further cycles of 5-fluorouracil, epirubicin, and cyclophosphamide + scH before surgery. Responders completed 18 scH cycles. The primary end point was pathologic complete response (pCR). The secondary end points were toxicity and invasive disease-free survival.RESULTSA total of 53 female patients age 18-70 years were enrolled. The median age of the 47 evaluable female patients was 50 years. pCR was achieved in 25 of 47 patients (53% [95% CI, 38.1 to 67.9]; P < .001). Forty-two percent of patients were estrogen receptor+ and 40% were progesterone receptor+ (95% CI, 20.3 to 66.5 and 21.5 to 69.2, respectively). All were HER2+, with 40% stage II and 60% stage III disease. Three patients (6.4%) experienced grade 3 myelosuppression, one (2.1%) experienced grade 3 diarrhea, two (4.3%) had a grade 4 adverse event, and two developed hepatitis while on the study medications. The reporting of disease-free and overall survival awaits future analysis.CONCLUSIONThis phase II study showed that neoadjuvant chemotherapy with T + scH resulted in pCR of 53%, surpassing the planned cutoff for success of 40%. This is comparable with the rates and other efficacy end points that follow data from phase II international trials. This regimen may be useful in the absence of pertuzumab and warrants further investigation.

Breast cancer (BC) is a heterogenous disease, and the rising global epidemic of premenopausal BC remains poorly understood. Mutational landscape and evolutionary dynamics of BC from diverse geography and populations are largely unknown, preventing the global acceleration of progress towards precision prevention. To examine etiology and heterogeneity of BC in indigenous Africans, 43 multi-region tumor samples and blood samples from 18 Nigerian women with BC (mean age 53 +/-12.7) were analyzed. Whole Genome Sequencing (WGS) was performed to identify somatic single nucleotide variants, insertions and deletions (ID), copy number alterations (CN), and structural variants (SV). Five mutational signature types (single base substitutions (SBS), double base substitutions (DBS), ID, CN, and SV), were analyzed and compared to COSMIC human cancer signatures. Multi-DPclust was used to classify mutations to clonal and subclonal cluster and create mutational phylogenetic trees. Driver gene analysis highlighted key driver genes, such as TP53, GATA3, and PIK3CA, corroborating prior findings. The most common signature was clock-like (CL) SBS5, followed by APOBEC-related SBS2 and SBS13. Other notable signatures included hypoxia-linked SBS18 and HRD-related DBS13. Signature profiles showed moderate heterogeneity across samples, with distinct patterns observed across mutational clusters. Intra-cluster correlation coefficients for signatures within samples from same patient range from 0.37 to 0.99 (median 0.84). TP53 and GATA3 mutations are common in clonal (early) clusters, with GATA3 often appearing in consecutive subclones. The CL SBS5 signature was prevalent early, while SBS18, linked to hypoxia, became prominent late, highlighting evolving mutational processes across disease progression. Distinct BC subtypes also displayed unique mutational profiles. HR+/HER2+ tumors exhibited higher levels of signature SBS91, while HR-/HER2- tumors exhibited higher levels of the HRD signature SBS3 compared to the rest of the tumors. HR-/HER2- tumors demonstrated lower levels of the mismatch repair-related signature ID1 but higher levels of the HRD signature ID6 and TOP2A signature ID8. Significant differences were observed in SV signatures, with higher SV9 signature activities in HR+/HER2+ tumors and elevated BRCA-related SV3 signature activities in HR-/HER2- tumors. Heterogeneity was also evident in the DBS and CN mutational signatures, further highlighting tumor complexity. This analysis sheds light on the diverse mutational dynamics within and across molecular subtypes, providing insights into the mutational evolution of BC in a non-screen detected young onset population. Ongoing work integrating WGS and transcriptome data will be presented at the conference. Avraam Tapinos, Toshio Yoshimatsu, Ilona Siljander, Mustapha A. Ajan, Ayodele Sanni, Atara Ntekim, Abayomi Odetunde, Elisabeth Sveen, Jeffrey Mueller, Galina Khramtsova, Sulin Wu, Dorothy Nyamai, Mihai Giurcanu, Dezheng Huo, Yonglan Zheng, David C. Wedge, Olufunmilayo I. Olopade. Multi-sample whole genome sequencing unveils complex mutational dynamics and clonal evolutionary patterns in young onset breast cancer from Nigeria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3892.

Importance:Most breast cancers in Africa are diagnosed at advanced stages. Improved risk prediction tools to optimize screening and earlier diagnosis are urgently needed. Objective:To build a comprehensive breast cancer risk estimation model by integrating a polygenic risk score (PRS), pathogenic variants (PVs) in high- or moderate-penetrance genes, and a questionnaire-based risk calculator. Design, Setting, and Participants:This multicenter case-control study initially enrolled women in Nigeria in 1998 and expanded to Cameroon and Uganda in 2011; enrollment ended in 2018. Women with breast cancer (hereafter cases) were enrolled through hospital oncology units, whereas women without breast cancer (hereafter controls) were recruited from other outpatient clinics and the community. Participants whose genetic data were used in PRS development were excluded from the development of the comprehensive breast cancer risk estimation model. Analyses were performed from September 2023 to January 2025. Exposures:Lifetime absolute risk estimation models that integrated a PRS only (previously developed using data from women of African ancestry and European ancestry), PRS plus PVs in high- or moderate-penetrance genes (BRCA1, BRCA2, PALB2, ATM, CHEK2, TP53, BARD1, RAD51C, and RAD51D), epidemiologic risk factors only (ascertained from NBCS questionnaires), and a combined model containing these 3 components. Main Outcomes and Measures:Lifetime absolute risk of breast cancer was estimated, accounting for an association between family history and genetic factors. Participants' lifetime estimated absolute risk was categorized by the following risk thresholds: lower than 3%, 3%, 5%, and 10% or higher. Results:A total of 1686 women, of whom 996 were cases (mean [SD] age at enrollment, 49.5 [12.2] years) and 690 were controls (mean [SD] age at enrollment, 41.5 [13.8] years), were included in the main analyses. The age-adjusted area under the receiver operating characteristic curve (AUROC) was 0.579 (95% CI, 0.549-0.610) for the PRS only model and 0.609 (95% CI, 0.579-0.638) for the PRS plus PV model. In the combined model containing both genetic and nongenetic risk factors, age-adjusted AUROC increased to 0.723 (95% CI, 0.698-0.748). Using a threshold of 10% or higher lifetime absolute risk, the combined model classified 12.0% of cases (120) as high risk compared with 3.7% of cases (37) using the epidemiologic factors only model and 5.0% of cases (50) using the PRS plus PV model. Conclusions and Relevance:In this case-control study, a breast cancer risk estimation model was developed that combines genetic and nongenetic factors and refines a previous model that includes epidemiologic risk factors. Further development and validation of this model are necessary to advance breast cancer risk assessment in sub-Saharan Africa.

Background/Objectives: Brazil has a highly admixed population. Polygenic risk scores (PRSs) have mostly been developed from European population studies, and their application to other populations is challenging. To assess the use of PRS for breast cancer (BC) risk in Brazil, we evaluated four PRSs in the Brazilian population. Methods: We analyzed a Brazilian cohort composed of 6206 women with a history of breast cancer and 8878 unphenotyped adults as controls. Genomic variants were imputed from exomes, and scores were calculated for all samples. Results: After individuals with known pathogenic or likely pathogenic variants in BRCA1, BRCA2, PALB2, PTEN, or TP53 genes, and first-degree relatives of the probands were excluded, 5598 cases and 8767 controls remained. Four PRS models were compared, and PRS3820 achieved the best performance, with an odds ratio (OR) of 1.43 per standard deviation increase (p value < 0.001) and an OR of 1.88 (p value < 0.001) for the top decile. PRS3820 also performed well for different ancestry groups: East Asian majority (OR 1.59, p value 0.004), Non-European majority (OR 1.45, p value < 0.001), and European majority (OR 1.43, p value < 0.001). Conclusions: Among the different PRSs, PRS313 and PRS3820 could be validated in our Brazilian cohort, with the latter exhibiting the best performance. While further clinical studies are necessary to guide clinical practice, this work represents an important step toward improving BC precision medicine in Brazil.

Supplementary Fig. S4. No Correlation with Immune Cell Infiltration in the Basal-like Subtype Tumors.

Supplementary Table S1: The PAM110 Genes

Supplementary Fig. S3. An Association with MKI67, ESR1, or ERBB2 Expression.

Supplementary Fig. S2. Correlation with Other Immune Modules.

Background: Reports on beta thalassemia in the Nigerian population are conflicting, and the prevalence and role of beta thalassemia in Nigerian sickle cell disease (SCD) patients remain unclear. There is a need to set the records straight to ascertain the prevalence and effect of beta thalassemia in these patients. Methods: 123 SCD patients and 117 age- and sex- matched controls were recruited. For the cases, the age range was 3 to 69 years, median(IQR) = 16(9 -29). A separate cohort of 26 SCD patients were studied along. Full blood count was calculated, and the hemoglobin fractions were estimated by High Performance Liquid Chromatography. The 1.6kb beta-globin gene region was amplified from germline DNA and Sanger sequencing was performed. Single nucleotide polymorphisms (SNPs) were detected and annotated, and haplotypes were constructed. Results: Contrary to recent reports, the prevalence of beta thalassemia in this population is <1%. Aside the sickle, hemoglobin C and beta thalassemia mutations, eight other variants were identified. Only three of these variants were found in the SCD patients and are in linkage disequilibrium. The sickle and hemoglobin C mutations arose on the major ancestral haplotype, while the beta thalassemia intermedia mutation (rs33915217C>A) was found on the minor ancestral haplotype, atypical of Africa. Two rare variants (rs537944366T>C and rs33915217C>A) are reported for the first time in the Yoruba population. Conclusion: There is a need for a re-assessment of the diagnosis of beta thalassemia in this and other African populations for the proper management of SCD and other anemia-related cases. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study received funding from The Doris Duke Charitable Foundation ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Ethics Review Committee of the University of Ibadan/University College Hospital, Ibadan, and the Institutional Review Board at the University of Chicago gave ethical approval for this work. 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. Yes I 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). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript and supplementary materials. Further information needed are available upon reasonable request to the authors

Abstract Purpose: Black women experience the highest breast cancer mortality rate compared with women of other racial/ethnic groups. To gain a deeper understanding of breast cancer heterogeneity across diverse populations, we examined a VEGF-hypoxia gene expression signature in breast tumors from women of diverse ancestry. Experimental Design: We developed a NanoString nCounter gene expression panel and applied it to breast tumors from Nigeria (n = 182) and the University of Chicago (Chicago, IL; n = 161). We also analyzed RNA sequencing data from Nigeria (n = 84) and The Cancer Genome Atlas (TCGA) datasets (n = 863). Patient prognosis was analyzed using multiple datasets. Results: The VEGF-hypoxia signature was highest in the basal-like subtype compared with other subtypes, with greater expression in Black women compared with White women. In TCGA dataset, necrotic breast tumors had higher scores for the VEGF-hypoxia signature compared with non-necrosis tumors (P < 0.001), with the highest proportion in the basal-like subtype. Furthermore, necrotic breast tumors have higher scores for the proliferation signature, suggesting an interaction between the VEGF-hypoxia signature, proliferation, and necrosis. T-cell gene expression signatures also correlated with the VEGF-hypoxia signature when testing all tumors in TCGA dataset. Finally, we found a significant association of the VEGF-hypoxia profile with poor outcomes when using all patients in the METABRIC (P < 0.0001) and SCAN-B datasets (P = 0.002). Conclusions: These data provide further evidence for breast cancer heterogeneity across diverse populations and molecular subtypes. Interventions selectively targeting VEGF-hypoxia and the immune microenvironment have the potential to improve overall survival in aggressive breast cancers that disproportionately impact Black women in the African Diaspora.

Supplementary Fig. S1. Correlation with T-Cell Immune Module Scores.

Fifteen events displaying statistically significant IR expression correlation with methylation

Forty methylation sites and their corresponding SNPs

Background: Circular RNAs (circRNAs) are a large class of RNAs derived from back splicing and subsequent circularization of precursor mRNAs. Due to their circular structures, circRNAs are protected from exonuclease-induced degradation and are thereby comparatively more stable than linear RNAs. circRNAs have been implicated in the progression of multiple types of cancers but few studies have systematically examined how circRNAs associate with different subtypes of breast cancer and prognosis. Methods: We conducted a nested case-control study of prospectively ascertained participants in the Chicago Multiethnic Breast Cancer Cohort (ChiMEC), in which patients without recurrence were matched with patients with recurrence on time to recurrence, age of diagnosis, tumor stage, and clinical subtype. We performed whole exome capture RNA sequencing on tumor samples that passed quality control. We then used CIRIquant to identify circRNAs by aligning back-splice junction (BSJ) reads to pseudo-circular reference sequences and retained circRNAs that had a BSJ read count of 2 or greater in at least 5 patients. After normalization using the trimmed mean of M-values method, we used edgeR to model circRNA expression via a negative binomial distribution and performed differential expression (DE) analyses of circRNAs by ER and HER2 status, as well as between Black (self-reported) and White patients. Furthermore, we conducted survival analyses for each circRNA using Cox proportional hazards models to assess how the expression of each circRNA associated with survival outcomes of invasive disease-free survival (IDFS) and overall survival, while adjusting for age at diagnosis, stage, and HER2 status. Results: A total of 123 of 126 sequenced patients were included in the analysis, including 56 Black patients, 59 White patients, and 8 patients from other racial groups. The mean age of diagnosis was 51.9 years of age (SD 13.2) with 68% ER+, 48% PR+, and 30% HER2+ patients. We identified 16,927 high-confidence circRNAs. In the crude DE analysis, we found 489 circRNAs differentially expressed between patients with ER+ compared to patients with ER- tumors and 33 circRNAs between HER2+ vs. HER2- at a false discovery rate of 0.05. After adjusting for race and grade, we discovered 187 circRNAs differentially expressed by ER status and 38 by HER2 status. In the DE analysis by race, we found 88 circRNAs that were differentially expressed between Blacks and Whites. After adjusting for grade, ER, PR, and HER2 status, 14 circRNAs remained significantly different between racial groups. After a median of follow up of 8 years, 41 patients died, 41 patients had invasive recurrent diseases, and 2 patients had second primary breast cancers, for a total of 57 events in the IDFS analysis. Because of the matching study design to limit the impact of known prognostic factors, none of known prognostic factors (stage, ER, PR, HER2, grade, and race) were statistically associated with IDFS. In the survival analyses, we discovered two circRNAs (hsa-GSK3B_0001 and hsa-CMPK1_0006) that met the Bonferroni threshold for significance for their associations with IDFS but did not detect any circRNAs that were significantly associated with overall survival after correction for multiple testing. Discussion: This preliminary study demonstrates that multiple candidate circRNAs were differentially expressed between BC subtypes and racial groups, and several circRNAs were associated with IDFS. Future studies are warranted to validate our findings and cement the portability of these circRNAs as prognostic biomarkers across populations. Citation Format: James L. Li, Toshio F. Yoshimatsu, Julian C. McClellan, Fangyuan Zhao, Yonglan Zheng, Olufunmilayo I. Olopade, Dezheng Huo. Circular RNAs express heterogeneously across different breast cancer subtypes and correlate with invasive disease-free survival [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 P5-03-13.

Forty methylation sites and their corresponding SNPs

Differential expression of 44 significant retained introns between races and four subtypes

Purpose:To externally evaluate a mammography-based deep learning (DL) model (Mirai) in a high-risk racially diverse population and compare its performance with other mammographic measures.Materials and Methods:A total of 6435 screening mammograms in 2096 female patients (median age, 56.4 years ± 11.2 [SD]) enrolled in a hospital-based case-control study from 2006 to 2020 were retrospectively evaluated. Pathologically confirmed breast cancer was the primary outcome. Mirai scores were the primary predictors. Breast density and Breast Imaging Reporting and Data System (BI-RADS) assessment categories were comparative predictors. Performance was evaluated using area under the receiver operating characteristic curve (AUC) and concordance index analyses.Results:Mirai achieved 1- and 5-year AUCs of 0.71 (95% CI: 0.68, 0.74) and 0.65 (95% CI: 0.64, 0.67), respectively. One-year AUCs for nondense versus dense breasts were 0.72 versus 0.58 (P = .10). There was no evidence of a difference in near-term discrimination performance between BI-RADS and Mirai (1-year AUC, 0.73 vs 0.68; P = .34). For longer-term prediction (2-5 years), Mirai outperformed BI-RADS assessment (5-year AUC, 0.63 vs 0.54; P < .001). Using only images of the unaffected breast reduced the discriminatory performance of the DL model (P < .001 at all time points), suggesting that its predictions are likely dependent on the detection of ipsilateral premalignant patterns.Conclusion:A mammography DL model showed good performance in a high-risk external dataset enriched for African American patients, benign breast disease, and BRCA mutation carriers, and study findings suggest that the model performance is likely driven by the detection of precancerous changes.Keywords: Breast, Cancer, Computer Applications, Convolutional Neural Network, Deep Learning Algorithms, Informatics, Epidemiology, Machine Learning, Mammography, Oncology, Radiomics Supplemental material is available for this article. © RSNA, 2023See also commentary by Kontos and Kalpathy-Cramer in this issue.