Abstract P1-08-15: Communication between tumor cells and fibroblasts as a prognostic factor of NACT in TNBC
Authors: Marcus Bauer, Martina Vetter, Ana Maia, Efstathios Vlachavas, Brigitta Michels, Mireia Berdiel-Acer, Kathleen Schüler, Alessandra Morselli, Manio Skarlatou, Christoph Thomssen, Stefan Wiemann
Journal: Cancer Research (2022)

Abstract Introduction. Neoadjuvant chemotherapy (NACT) is the standard of care in aggressive breast cancer, including triple negative breast cancer (TNBC). Cytotoxic drugs specifically target proliferating cells, however, patient outcome is variable. Tumor physiology and response to therapy are orchestrated by an intricate interplay between cancer, stromal and immune cells collectively forming the tumor microenvironment. We have recently uncovered a feedback mechanism of tumor cells and fibroblasts, involving IFNB1 signaling, that supports tumor cells in the recovery from chemotherapy-induced stress. Here, we wanted to assess whether targets of IFNB1 signaling in fibroblasts and tumor cells would qualify as predictive markers of pathological complete response (pCR) after neoadjuvant therapy (NACT) as prognostic markers for the course of the disease. Methods and Patients. RNA-sequencing data from in vitro experiments found the GO-term GO:0051607 ‘defense response to virus’ significantly enriched. Twentyfour genes intersected between differentially expressed genes and the genes of this GO-term. We selected three of the encoded proteins a) interferon induced with helicase C domain 1 IFIH1, b) interferon alpha-inducible protein ISG15, c) 2'-5'-oligoadenylate synthetase OAS1 to test their expression in human specimens of TNBCs after NACT by immunohistochemistry (IHC). None of the respective genes correlated with recurrence free survival when tested in treatment-naïve tumor biopsies (KM Plotter). A prospective consecutively enrolled cohort (2000 - 2021) was available with an overall pCR rate of 46%. pCR was defined by no invasive cancer cell in breast or axilla (ypT0 N0). The median follow-up for iDFS was 36.2 months (6-154) and for OS 39.3 months (6-214).Primary objective was the correlation between IFIH1, ISG15 and OAS1 protein expression in the residual tumor by non-pCR or in the tumor bed by pCR. Second objective was the association of IFIH1, ISG15 and OAS1 protein expression to invasive disease-free survival (iDFS) and overall survival (OS). Results. To date, IHC staining has been established for IFIH1, ISG15 and OAS1. In representative stainings of FFPE tissue samples with pCR we did not detect any positive signal for IFIH1 and ISG15 in stromal cells like fibroblast or lymphocytes. Slight to strong protein expression was detected by non-pCR in cancer cells, stromal cells and tumour infiltrating lymphocytes. In contrast OAS1 was expressed especially strong in lymphocytes by pCR or non-pCR. Cancer cell showed moderate OAS1 expression. IHC analysis and of the entire cohort is in progress including the analyses of the association of these markers to pCR, non-pCR and iDFS/OS. Conclusion. Using samples from our consecutive, multicentre enrolled cohort, an association between the expression of markers of an IFNB1-triggered antiviral response and pCR and survival was demonstrated in patients of the TNBC subgroup. Analysis of the entire cohort is necessary to potentially demonstrate applicability of an interferon-response as predictor of survival. Citation Format: Marcus Bauer, Martina Vetter, Ana Maia, Efstathios Vlachavas, Brigitta Michels, Mireia Berdiel-Acer, Kathleen Schüler, Alessandra Morselli, Manio Skarlatou, Christoph Thomssen, Stefan Wiemann. Communication between tumor cells and fibroblasts as a prognostic factor of NACT in TNBC [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-15.