Peripheral Absolute Lymphocyte Count and Mortality Across Breast Cancer Subtypes, Race, and Ethnicity

Background: Among patients with triple-negative breast cancer (TNBC), higher tumor infiltrating lymphocytes (TILs) are associated with increased overall mortality (OM). We previously found that low peripheral absolute lymphocyte count (ALC) is associated with increased OM and breast cancer-specific mortality (BCSM) in a sample of mostly non-Hispanic White (NHW) patients with TNBC. Here, we investigated the association between low ALC and OM across different breast cancer subtypes and whether the association is potentially modified by race and ethnicity. Methods: We used the Oncoshare database, which links electronic medical records (EMRs) data to the California Cancer Registry (CCR), and assessed women diagnosed with stage I-III breast cancer between 2000-2017, who had at least one ALC measurement and were treated across two different healthcare systems in California. Patient and tumor characteristics were obtained from the CCR and laboratory testing results from EMRs. Patients with metastatic disease and chemotherapy receipt after one year of diagnosis were excluded. Multivariable logistic models assessed factors associated with “low ALC” (<1 K/µL, ever vs. never). We applied Cox models to evaluate the association between “min ALC” (lowest ALC value after diagnosis) and OM within each breast cancer subtype (estrogen receptor (ER) and/or progesterone receptor (PR)-positive, HER2-negative (ER/PR+, HER2-), any ER and PR status, HER2-positive (HER2+) and ER, PR and HER 2-negative or triple-negative, TNBC), and further explored the interaction between min ALC and race and ethnicity. All models were adjusted for low absolute neutrophil count, demographics, and tumor features. Results: Among 17,670 women analyzed, those with ‘low ALC’ were more likely to have public rather than private insurance (odds ratio, OR 1.10, p= 0.029) and to have TNBC (OR 1.26, p< 0.001). Cox models demonstrated that higher min ALC was associated with lower OM for all breast cancer subtypes: TNBC (hazard ratio, HR 0.31), HER2+ (HR 0.42), and ER/PR+, HER2- (HR 0.49) (all p<0.001). Additionally, race and ethnicity significantly modified the association between min ALC and OM (interaction-p < 0.001) across all subtypes. In particular, the association between higher min ALC and lower mortality was strongest among Black (HR=0.31, p=0.047), Asian (HR=0.32, p<0.001), and Hispanic (HR=0.38, p=0.002) women compared to NHW women (HR=0.52). Conclusions: Low peripheral ALC, a routinely measured clinical laboratory result, strongly predicts higher OM across breast cancer subtypes, beyond TNBC. The association between min ALC and OM was stronger among Hispanic, Black, and Asian women than NHW women, suggesting that maintaining normal ALC during breast cancer treatment may reduce OM, especially for women from racial and ethnic minoritized groups. Future research should investigate differences in ALC and immune response in diverse populations.