Abstract P3-06-24: Early activation of IFN/STAT signaling in tumor cells of patient-derived triple negative breast cancer xenografts predicts tumor sensitivity to chemotherapy

Abstract

Triple negative breast cancer (TNBC) is a tumor subtype characterized by the absence of overexpressed estrogen receptor-alpha (ER), progesterone receptor (PR), and HER2 receptor, encoded by ERBB2, a known proto-oncogene. This type of tumors account for approximately 15–25% of breast cancers at diagnosis, and is one of the most aggressive subtypes, with 77% of patients that live free of disease 5 years post-diagnosis. One of the most reliable predictive markers of patient outcome is the pathological complete response (pCR), which indicates that the surgical specimen removed after neoadjuvant chemotherapy contains no viable tumor cells detectable at histopathological level. For patients with pCR, the probability of surviving the disease is very high, however, pCR is observed only in about 20–30% of TNBC. On the other hand, for patients with no pCR the probablity of developing recurrent disease at 5 years is 50%.\ud \ud As pCR is strongly correlated with treatment efficacy, it is mandatory to develop methods that allow to tell as quick as possible if the treatment chosen for a given patient is efficiently working or if it should be abandoned in favor of an alternative strategy that could prove more efficacious. XenTech collection of breast cancer patient-derived xenografts (PDXs) includes 25 models of TNBC that display heterogeneous response to different chemotherapy agents. We used our models to investigate if transcriptional changes could be detected in PDXs that responded well to genotoxic agents. To do this we analyzed the gene expression profile of laser-microdissected residual tumor nodules interspersed in the murine stroma upon very efficient response to Adriamycin/Cyclophosphamide (AC). When doing so, we identified several genes of the IFN/STAT1 pathway that were over-expressed when compared to untreated tumors. This activation seems to be a transient event, as it was lost in tumors relapsing after the residual tumor nodule stage.\ud \ud The finding that residual cells from tumors strongly responding to AC treatment over-expressed IFN/STAT1 pathway-related genes prompted us to investigate whether this effect could be detected as an early event upon tumor exposure to chemotherapy. All TNBC models tested that were good responders to AC treatment displayed over-expression of IFN/STAT1 pathway-related genes as early as 3 days post-treatment, most of them reaching a plateau of intensity at day 7 post-treatment. By contrast, TNBC insensitive or low responders to AC treatment failed to show over-expression of IFN/STAT1 pathway-related genes.\ud \ud To verify if the selective over-expression of these genes in TNBC models sensitive to AC was independent of the treatment administered, Irinotecan and Capecitabine were used to treat TNBC models with heterogeneous response to these drugs. Again, we found that overexpression of IFN/STAT1 pathway-related genes was specifically identified at early stages only in TNBC models that responded well to these drugs.\ud \ud These results suggest that genes of the IFN/STAT1 pathway ...

One mouse, one patient paradigm: New avatars of personalized cancer therapy

“…Identification of IFN/STAT signaling as a predictor of therapeutic response to cyclophosphamide chemotherapy in triple negative breast cancer[91]…”

Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease

“…The genes were chosen from literature review on the basis of their being identified as (i) possible prognostic factors in residual disease at protein (4,(6)(7)(8)(9)(10) or mRNA level (11), (ii) as significantly up-or downregulated, but of unknown prognostic value in residual disease (12)(13)(14)(15)(16)(17)(18)(19)(20), (iii) as predictive of chemotherapy resistance (6,11,16,19,(21)(22)(23)(24)(25)(26)(27)(28)(29), and/or (iv) identified as possible prognostic factors over several previous datasets (26,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). In addition to the previously established prognostic factors ESR1 and ERBB2, the genes were also chosen to represent different pathways and biological processes of known implication in tumor progression or response to therapy, such as stemcellness (ALDH1A1, CD44, and STAT3), proliferation (TOP2A, MKI67, and AURKA), apoptosis (BCL2, BCL2L1, and PAWR), immunologic response (CD3D, CXCL13, and STAT1), epithelial-to-mesenchymal transition (EMT; SNAI1, SNAI2, SOX9, and TWIST), stromal activation (DECORIN, ...…”