Association of tumor infiltrating lymphocytes and proinflammatory biomarkers with breast cancer molecular subtypes: Analysis of the MEND study.

Background: The tumor microenvironment is characterized by tumor-infiltrating lymphocytes (TILs) and proinflammatory biomarkers/cytokines, factors that inform therapeutic options and predict treatment response and tumor progression. Breast tumors in Nigerian women are relatively more aggressive; however no prior study has characterized the landscape of TILs and proinflammatory biomarkers across molecular subtypes in this population. Materials and Methods : A total of 436 newly diagnosed, treatment-naïve BC patients from Nigeria were included in the study. BC molecular subtyping was determined by immunohistochemistry (IHC), and TILs were quantified on H&E-stained tumor slides using the International TILs Working Group criteria. Serum levels of proinflammatory biomarkers (IL-6, IL-8, IL-1B, TNF-alpha, and leptin) were assessed using immunoassays by Meso Scale Discovery. Descriptive statistics were used to evaluate the distribution of study covariates, and Spearman correlation was used to test the association of each proinflammatory biomarker and TILs. Multivariable logistic and multinomial regression models were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) for the association of TILs and proinflammatory biomarkers with molecular subtype. Results: The median age of study participants was 49, and 52.8% and 28.9% were diagnosed with grade 2 or 3 tumors respectively. The majority of BC tumors were of triple-negative subtype (43%), compared with 31% luminal A, 12% luminal B and 15% HER2-enriched subtype. Overall, BC patients had a median (Q1, Q3) TIL (%) of 10.0 (4.0, 21.0), with 49% categorized as low TIL (<10%), 41% categorized as intermediate TILs (10% ≤ TIL < 40%) and 10% categorized as high TIL (≥ 40%). Among a subset of 109 patients with proinflammatory biomarkers' data, TNF-alpha significantly correlated with TILs (ρ: 0.21; p = 0.026). Patients in high TIL category (vs low TIL category) were approximately 5-fold (OR: 5.03, 95% CI: 1.01, 24.94) more likely to be diagnosed with TNBC, while each standard deviation increase in TNF-alpha levels was significantly associated with 3.5-fold higher odds of TNBC (OR: 3.42, 95% CI: 1.32, 8.86) after adjusting for age, BMI, menopausal status, and all proinflammatory biomarkers. Other proinflammatory biomarkers showed no significant associations. Conclusion: Our study, first to our knowledge to characterize the TME by molecular subtype in Nigerian women, reveal strong associations of high TIL levels and TNF-alpha with TNBC subtype, highlighting opportunities for immunotherapy and the prognostic significance of TNF-alpha in this population.