Association of tumor extracellular matrix density with recurrence in invasive lobular carcinoma.

Abstract

e15162 Background: Invasive lobular carcinoma (ILC) is associated with a unique pattern of dissemination and higher risk of late relapse ( > 10 years) compared with other invasive breast cancer types. However, the predictors of relapse in ILC are largely based on clinicopathological data. In numerous cancers, the tumor microenvironment (TME) is thought to play a significant role in the ability for tumor cells to spread. Several studies have shown that changes in the TME can assist in tumor dissemination and metastasis. However, there is a paucity in literature exploring the potential role of the TME in predicting clinical outcomes. Human replacement therapy (HRT) exposure is a known risk factor for ILC. Yet, the mechanisms by which HRT influences the TME and how these changes may predispose patients to ILC remain unclear. We sought to explore the association between tumor extracellular matrix (ECM), recurrence, and HRT exposure in ILC. Methods: Sections from a tissue microarray, constructed from 115 Formalin-Fixed Paraffin Embedded ILC patients samples from the GLACIER study cohort (REC: 18/SW/0052), were stained with PicroSirius Red solution and Weigert's Iron Hematoxylin. Tumor cell density (TCD) of the cores was extracted using QuPath. High density matrix (HDM) values were calculated as the proportion of image pixels corresponding to the matrix, using the ImageJ plugin ‘The Workflow Of Matrix BioLogy Informatics’ (TWOMBLI) (Wershof et al.). Logistic regression was used for both univariate and multivariate recurrence analysis. Covariates were included based on clinical relevance and previous literature. Cox Proportional Hazards model was employed to assess relapse free survival (RFS). Results: A total of 562 cores from 115 patients with ILC were included in the analysis (Invasive = 439, Normal = 80, lobular carcinoma in situ = 43). Among low TCD cores, the median HDM was higher in recurrence cases (0.78 vs. 0.75, p = 0.044), regression analysis yielded an odds ratio (OR) 3.89 [95%CI (1.26-7.50), (p = 0.018)]. When adjusting for stage and HER2 status, HDM had an even greater OR of 3.03 [95%CI (1.33-7.83), (p = 0.0012)]. There was also a borderline association with shorter RFS and higher HDM, hazard ratio (HR) 1.82 [95%CI (0.97- 3.43), (p = 0.064)] which became significant when adjusting for age, stage, HER2 status, ER status and histological subtype, HR 2.03 [95%CI (1.03-4.03), (p = 0.042). These associations with recurrence were not observed in high TCD cores (0.65 vs 0.67, p = 0.8). Among the low TCD cores, there was no statistical difference in HDM between women exposed to HRT compared to those without (0.75 vs 0.76) (p = 0.9). Nor was there a difference in the high TCD cores (0.66 vs 0.69, p = 0.5). Conclusions: This retrospective analysis of ILC samples reveals the potential role of stromal TME in ILC risk prognostication. Spatial profiling of these samples will be performed to explore these findings further.