High Densities of Tumor-Associated Plasma Cells Predict Improved Prognosis in Triple Negative Breast Cancer

Breast cancer is the most common malignancy affecting women, but the heterogeneity of the condition is a significant obstacle to effective treatment. Triple negative breast cancers (TNBCs) do not express HER2 or the receptors for estrogen or progesterone, and so often have a poor prognosis. Tumor-infiltrating T cells have been well-characterized in TNBC, and increased numbers are associated with better outcomes; however, the potential roles of B cells and plasma cells have been large. Here, we conducted a retrospective correlative study on the expression of B cell/plasma cell-related genes, and the abundance and localization of B cells and plasma cells within TNBCs, and clinical outcome. We analyzed 269 TNBC samples and used immunohistochemistry to quantify tumor-infiltrating B cells and plasma cells, coupled with NanoString measurement of expression of immunoglobulin metagenes. Multivariate analysis revealed that patients bearing TNBCs with above median densities of CD38(+) plasma cells had significantly better disease-free survival (DFS) (HR = 0.44; 95% CI 0.26-0.77; p = 0.004) but not overall survival (OS), after adjusting for the effects of known prognostic factors. In contrast, TNBCs with higher immunoglobulin gene expression exhibited improved prognosis (OS p = 0.029 and DFS p = 0.005). The presence of B cells and plasma cells was positively correlated (p < 0.0001, R = 0.558), while immunoglobulin gene IGKC, IGHM, and IGHG1 mRNA expression correlated specifically with the density of CD38 plasma cells (IGKC p < 0.0001,R=0.647; IGHM p < 0.0001,R=0.580; IGHG1 p < 0.0001,R=0.655). Interestingly, after adjusting the multivariate analysis for the effect of intratumoral CD38(+) plasma cell density, the expression levels of all three genes lost significant prognostic value, suggesting a biologically important role of plasma cells. Last but not least, the addition of intratumoral CD38+ plasma cell density to clinicopathological features significantly increased the prognostic value for both DFS (Delta LR chi(2) = 17.28, p = 1.71E-08) and OS (Delta LR chi(2) = 10.03, p = 6.32E-08), compared to clinicopathological features alone. The best combination was achieved by integrating intratumoral CD38 plasma cell density and IGHG1 which conferred the best added prognostic value for DFS (Delta LR chi(2) = 27.38, p = 5.22E-10) and OS (Delta LR chi(2) = 21.29, p = 1.03E-08). Our results demonstrate that the role of plasma cells in TNBC warrants further study to elucidate the relationship between their infiltration of tumors and disease recurrence.