171MO Inflammatory profiling of individuals with germline TP53 mutations (gTP53m) and its relationship to subsequent cancer development

Abstract

Individuals with gTP53m have nearly 24 times higher incidence of any cancer than the general population, of which breast cancer (BC) comes first. Beside prophylactic mastectomy, no preventative measures are currently available. Nothing or very little is known regarding the role of immune and inflammatory factors. We aimed to search for predictors of the development of new subsequent cancers (NSC) among inflammatory and immune cytokines, in patients (pts) with gTP53m from the prospective LIFSCREEN MRI screening trial (NCT01464086). All pts with gTP53m who entered the LIFSCREEN trial at Gustave Roussy 11/2011 - 12/2014, with frozen serum samples available were eligible. We analysed inflammatory cytokines and chemokines on samples collected sequentially at accrual month (M) 0 and at M12 using multiplex immunoassay of serum analytes (Bio-Plex Pro™ 40-plex, Bio-Rad). Primary objective was potential associations between M0 and M12 biomarkers and the incidence of any NSC. We used Wilcoxon-Mann Whitney tests and logistic regressions. Among 107 pts, 42 had serum stored and were eligible. Median age 35.5 (7-67), 67% females. Median follow-up 100 months (95% CI 83-117). 24 pts (57%) had already had cancer before entering the study, of which 7 BC. 11 NSC were diagnosed. At M0, a Th1-like profile (high serum IL-2 (>2 pg/ml) (p=0.03; overall) and CXCL9 levels (>50 pg/ml) (p=0.01; without history of cancers)) was associated with the incidence of NSC. In logistic regression, the Th1 CXCL9 and CXCL10 chemokines were associated with a higher probability of NSC (p=0.03 and 0.04, respectively). At M12, high levels of the follicular T helper cell CXCL13 (>25 pg/ml) chemokine were protective against NSC (p=0.04). Individuals with a significant drop between M0 and M12 of neutrophil and T cell-chemoattracting factors (such as CXCL1 and IFNg/CXCL16 respectively) did not develop cancer. This exploratory study identifies a disbalance between Th1 and TFH soluble markers in Li Fraumeni deemed to experience additional neoplasia among pts carrying gTP53m. These findings warrant further validation and could be actionable for cancer interception.