Background Sickle cell disease (SCD) is a hereditary hemoglobinopathy affecting ~100,000 individuals in the United States. While SCD increases the risk of hematologic malignancies, large cohort studies report the incidence of solid tumors—including breast cancer—remains below 2%, lower than in age-matched controls. This rarity likely reflects the chronic hypoxic, antiangiogenic, and inflammatory environment in SCD, which may suppress tumor angiogenesis and growth. As management improves and survival increases, age-related cancers are rising. This vignette illustrates diagnostic and management challenges of breast cancer in SCD and highlights emerging evidence on this rare co-occurrence.

Case Presentation A 58-year-old African American woman with homozygous SCD, hypertension, and proteinuria, compliant with routine screenings, underwent annual mammography. In 2022, grouped microcalcifications were detected in the left breast, but an initial biopsy was inconclusive. Repeat imaging and biopsy in 2024 revealed a 0.5 cm, moderately to poorly differentiated invasive ductal carcinoma (IDC) with high-grade ductal carcinoma in situ (DCIS) and microcalcifications. The tumor was hormone receptor-positive and HER2- negative. She underwent lumpectomy and re-excision; sentinel lymph nodes were negative. Oncotype DX testing showed a Recurrence Score of 38(0-100), calculated from RT-PCR analysis of 21 genes, corresponding to a 9-year distant recurrence risk of 26% (95% CI: 20%–34%) and chemotherapy benefit exceeding 15% (95% CI: 9%–37%). Due to concern about complications, she declined chemotherapy and received radiotherapy and anastrozole. She is eligible for Ribociclib plus endocrine therapy under NATALEE trial criteria, supporting its use as a new adjuvant option.

Discussion Recent population-based studies provide insights into cancer risk in SCD. A 23-year California registry analysis found SCD patients had a 38% lower risk of solid tumors, including breast cancer, despite a 72% higher risk of hematologic malignancies. Similar findings emerged from North Carolina, where only 1.9% of SCD patients developed solid tumors, with breast cancer a small minority. Mechanistic studies suggest chronic hypoxia in SCD upregulates hypoxia-inducible factors and alters immune function, potentially suppressing angiogenesis and modulating immune surveillance. Experimental data indicate the SCD microenvironment impairs neovascularization and may limit solid tumor growth and spread. However, as management advances and lifespan increases, cumulative risk of age-related malignancies, including breast cancer, is expected to rise. This case highlights individualized screening and treatment in SCD, balancing benefit with the risk of complications. It emphasizes the need for continued epidemiological surveillance and mechanistic research to clarify risk and guide treatment in this population.