Early-onset breast cancer in East Africa : genetics, tumor characteristics and clinical management

<p dir="ltr">Background: Breast cancer is a leading cause of cancer-related mortality among women worldwide, with particularly poor outcomes in many low-and middle- income countries. In East Africa, patients are often young at diagnosis, present with advanced disease, and face major barriers to accessing timely and comprehensive cancer care. Knowledge about the underlying tumor biology and hereditary predisposition in these settings remains limited.</p><p dir="ltr">Aim: The overarching aim of this thesis was to evaluate the biological and genetic landscape of breast cancer, and access to breast cancer care in Ethiopia and Uganda, with a specific focus on early-onset disease among women.</p><p dir="ltr">Methods: This thesis comprises four studies. Study I was a multicenter retrospective observational study of breast cancer surgery in 29 hospitals across Uganda, used to estimate the national breast cancer surgery rate and unmet surgical need. Study II was a cross-sectional study including women aged 18-39 years and men >18 years with invasive breast cancer from Ethiopia (n = 100) and a comparable patient cohort from Sweden (n = 100), focusing on stage at diagnosis and tumor subtypes. In Study III, the Ethiopian cohort underwent multigene panel testing for 12 established breast cancer susceptibility genes to assess the type and prevalence of germline pathogenic variants. Study IV was a prospective observational study following the Ethiopian cohort for one year to evaluate initiation and completion of recommended multimodal treatment, as well as early recurrence and mortality.</p><p dir="ltr">Results: In Study I, after correction for missing data using multiple imputation, the annual breast cancer surgery rate was estimated at 137 procedures, corresponding to 5.7% of the national breast cancer incidence. Assuming that 80% of incident cases should receive surgery, the unmet surgical need was 92.9%. Most operations were performed at the National Referral Hospital by specialist surgeons.</p><p dir="ltr">In Study II, Ethiopian patients presented with substantially more advanced disease compared with Swedish patients. Ethiopian and Swedish participants were diagnosed in tumor stage I (3.3% vs 27.0%), stage II (33.7% vs 45.0%), stage III (44.6% vs 23.0%) and stage IV (18.5% vs 5.0%), representing a significant difference in stage distribution between the groups (p < 0.001). The majority of tumors in both cohorts were estrogen receptor-positive, and luminal-like tumors were the most prevalent subtype at both sites.</p><p dir="ltr">In Study III, genetic analysis was successfully performed in 89 Ethiopian patients. In total, 22 germline pathogenic variants were identified. Over one-fifth (21.3%) harbored a pathogenic variant in a high-risk gene (BRCA1, BRCA2 or PALB2), including seven BRCA1, eight BRCA2 and four PALB2 variants.</p><p dir="ltr">In Study IV, among patients with non-metastatic disease at diagnosis (n = 76), initiation of surgery and systemic therapy was relatively high, but only 20% completed the full recommended multimodal treatment. Early outcomes were poor: 29.2% of stage I-Ill patients experienced recurrence within one year, and among those with primary metastatic disease, the one-year mortality rate was 58.3%, with substantial loss to follow-up.</p><p dir="ltr">Conclusions: This thesis reveals gaps in access to surgical and multimodal breast cancer care in East Africa, alongside a substantial burden of advanced- stage and hereditary disease. In Uganda, only a small fraction of women and men with breast cancer undergo surgery, leaving the vast majority of cases untreated. In Ethiopia, patients present with markedly more advanced disease than patients in Sweden, despite estrogen receptor-positive tumors being the most common subtype in both regions and both cohorts being unscreened populations. A high proportion of Ethiopian patients carried germline pathogenic variants in high-risk breast cancer susceptibility genes, underscoring the importance of hereditary predisposition in the target population.</p><p dir="ltr">Major barriers to completing multimodal treatment, together with very limited access to radiotherapy and targeted therapies, likely contribute to high rates of early recurrence and mortality, highlighting an urgent need for strengthened cancer services in the region.</p><h3 dir="ltr">List of scientific papers</h3><p dir="ltr">I. <b>Ekdahl Hjelm T,</b> Matovu A, Mugisha N, Löfgren J. Breast cancer care in Uganda: A multicenter study on the frequency of breast cancer surgery in relation to the incidence of breast cancer. PLoS One 14:e0219601, 2019. <a href="https://doi.org/10.1371/journal.pone.0219601" rel="noreferrer" target="_blank">https://doi.org/10.1371/journal.pone.0219601</a></p><p dir="ltr">II. <b>Ekdahl Hjelm T*</b>, Gebremariam TY*, Weldearegay MF, Sori M, Bauer M, Ayele BG, Assefa M, Anberber E, Mohammed HY, Kantelhardt EJ, Margolin S, Lindblom A, Ashenafi S, Lofgren J. Stage at diagnosis and tumor characteristics among young women and men with breast cancer, in Ethiopia and Sweden, a descriptive cross- sectional study. BMC Cancer 25:1222, 2025. <a href="https://doi.org/10.1186/s12885-025-14614-x" rel="noreferrer" target="_blank">https://doi.org/10.1186/s12885-025-14614-x</a></p><p dir="ltr">III. <b>Ekdahl Hjelm T*</b>, Gebremariam TY*, Weldearegay MF, Ayele BG, Assefa M, Anberber E, Kvist A, Törngren T, Borg Å, Margolin S, Lindblom A, Ashenafi S, Löfgren J. Germline pathogenic variants in breast cancer predisposing genes among early-onset female and male breast cancer in Ethiopia. JCO Global Oncology. [Accepted]<br><br></p><p dir="ltr">IV. <b>Ekdahl Hjelm T,</b> Gebremariam TY, Weldearegay MF, Zenebe Y, Assefa M, Margolin S, Lindblom A, Ashenafi S, Löfgren J. Initiation of recommended oncological treatment in a cohort of young female and male breast cancer patients in Ethiopia: A one-year follow-up study. [Submitted]</p><p dir="ltr">* Shared first authorship.</p>