COVID-19 infection and impact on cancer recurrence: Comprehensive results from over 32,000 patients with breast cancer

Background: The impact of COVID-19 infection on breast cancer recurrence remains poorly understood. SARS-CoV-2 infection is associated with systemic immune dysregulation, including lymphopenia, chronic inflammation, and altered interferon signaling, which may compromise tumor immune surveillance. We aimed to evaluate the association between COVID-19 infection and recurrence outcomes in patients with breast cancer. Methods: We identified patients diagnosed with localized breast cancer between 1/1/2011 and 12/31/2024 using ICD-10 codes, excluding those with metastatic disease codes prior to or at initial diagnosis, at an academic center. COVID-19 infection was identified through diagnostic codes. Recurrence was defined by ICD codes for metastatic disease occurring after initial diagnosis, and time to recurrence was measured from first breast cancer diagnosis to first metastatic code. Sites of recurrence were determined using specific ICD-10 codes. Hazard ratios were estimated using Cox proportional hazards models. Kaplan-Meier curves were generated for time-to-event analyses, and log-rank tests were used for group comparisons. Results: Of 32,871 eligible patients, 18,297 had tumors that were ER positive (ER+), 3,563 were ER negative (ER-), and 11,011 had unknown ER status. Median age at diagnosis was 63. Median follow-up time was 47 months. Of the entire cohort, 3325 (10.12%) developed distant or lymph node metastasis. Among 2,449 patients with COVID-19 after breast cancer diagnosis, 11.15% experienced distant recurrence and 15.35% experienced any recurrence, compared with 7.65% and 9.69%, respectively, in patients without post-diagnosis COVID-19. COVID-19 infection was associated with higher risk of any recurrence (HR 1.21; 95% CI 1.08-1.34; p<0.001). Subtype analyses showed higher risk of any recurrence associated with COVID-19 in ER+ patients (HR 1.42; p<0.001) and a trend towards higher risk in ER- patients (HR 1.18; p=0.169). Five-year invasive disease-free survival was lower in patients who had COVID-19 (85.7% vs. 88.6%; p<0.001). Bulk RNA sequencing from rapid autopsy studies demonstrated downregulation of HLA and p53 creating an immunosuppressive and pro-tumorigenic microenvironment, facilitating cancer growth and disease recurrence. Conclusions: COVID-19 infection following breast cancer diagnosis was associated with increased risk of recurrence, particularly in patients with ER+ disease, mediated in part by downregulation of tumor suppressor and immunosurveillance-related genes. These findings underscore the need for continued clinical surveillance and mechanistic studies exploring immune recovery and tumor progression in breast cancer survivors affected by COVID-19.