Lymphopenia in breast cancer and association with clinical outcomes: An analysis from over 30,000 patients.

640 Background: Lymphopenia is an independent prognostic factor for overall survival in patients with solid tumors. Low circulating lymphocytes represents impaired adaptive immunity, which can compromise antitumor immune responses and increase the risk of treatment-related toxicity. Despite having an ICD-10 code (D72.810), lymphopenia as a diagnosis might be often underrecognized and overlooked. We aimed to analyze the prevalence and concordance of lab-defined lymphopenia with the clinical diagnosis and the association of lab-defined lymphopenia with clinical outcomes in a large cohort of patients with breast cancer. Methods: We identified patients with breast cancer between 1/1/2011-12/31/2024 in a single institution using ICD-10 codes. Stage and subtype was determined using ICD codes, with recurrence defined by any ICD code for metastatic disease at least 6 months after initial diagnosis. Lab-defined lymphopenia was defined by absolute lymphocyte count (ALC) <1000 cells/µL. Baseline and on-treatment lymphopenia using ICD codes was compared to lab-defined baseline and on-treatment lymphopenia using Cohen’s κ concordance statistic (0-1). Univariate logistic regression was performed to evaluate the association of lab-defined lymphopenia with recurrence. Overall mortality was analyzed using Cox proportional hazards regression. Results: 36,496 patients with breast cancer were included in the analysis. Most (89.7%) patients had early-stage breast cancer and estrogen receptor (ER)-positive disease (50.5%). At breast cancer diagnosis, 2,368 (6.5%) patients had lab-defined lymphopenia and 56 (0.02%) had lymphopenia diagnoses, demonstrating significantly low concordance by ICD codes (κ = 0.0268). Similarly, on-treatment lymphopenia was also discordant by ICD codes, with lab-defined on-treatment lymphopenia occurring in 5,564 (15.2%) of patients and 257 (0.7%) by ICD codes (κ = 0.0459). In early-stage breast cancer, baseline lab-defined lymphopenia was associated with increased risk of recurrence (OR 1.74; 95% CI 1.42-2.06; p<0.001) and increased risk of mortality (HR 2.13; 95% CI 1.92-2.37; p<0.001). In the metastatic setting, baseline lab-defined lymphopenia was associated with increased risk of mortality (HR 1.50; 95% CI 1.32-1.69; p<0.001). Multivariable analysis demonstrated that lab-defined lymphopenia at diagnosis was associated with increased mortality (HR 2.47; 95% CI 2.01-3.02, p<0.001), after adjusting for ER status, stage, and type of treatment. Conclusions: Lymphopenia is significantly underdiagnosed during breast cancer treatment, and is independently associated with increased risk of recurrence and death. These findings highlight the need for improved recognition of lymphopenia as a prognostic factor and tailored strategies to augment systemic immunity and potentially improve long-term outcomes for patients.