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STAT1 Signalling Predicts Response to Chemotherapy in Oestrogen Receptor-Negative Breast Cancer

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STAT1 Signalling Predicts Response to Chemotherapy in Oestrogen Receptor-Negative Breast Cancer FULL PAPER British Journal of Cancer (2016) 114, 177–187 | doi: 10.1038/bjc.2015.398 Keywords: STAT1; ER-negative breast cancer; IFN; chemotherapy; predictive signature Activation of IFN/STAT1 signalling predicts response to chemotherapy in oestrogen receptor-negative breast cancer Marie-Emmanuelle Legrier1, Ivan Bie` che2, Julie Gaston1, Arnaud Beurdeley1, Vanessa Yvonnet1, Olivier De´as1, Aure´ lie Thuleau3, Sophie Chaˆ teau-Joubert4, Jean-Luc Servely4,5, Sophie Vacher2, Myriam Lassalle1, Ste´ phane Depil6, Gordon C Tucker6, Jean-Jacques Fontaine4, Marie-France Poupon1, Sergio Roman-Roman3, Jean-Gabriel Judde1, Didier Decaudin3,7, Stefano Cairo*,1,8,9 and Elisabetta Marangoni*,3,9 1XenTech, 4 rue Pierre Fontaine, Evry 91000, France; 2Genetics Department, Hospital, Institut Curie, 26 rue d’Ulm, Paris 75005, France; 3Translational Research Department, Institut Curie, 26 rue d’Ulm, Paris 75005, France; 4Department of Pathology, Veterinary School of Alfort, Maisons-Alfort 94704, France; 5INRA, Phase Department, Nouzilly, France; 6Institut de Recherches Servier, PIT Oncology, Croissy-sur-Seine 78290, France; 7Medical Oncology Department, Institut Curie, 26 rue d’Ulm, Paris 75005, France and 8University of Ferrara, LTTA Centre, Department of Morphology, Surgery and Experimental Medicine, Ferrara, Italy Background: Oestrogen receptor-negative (ER À ) breast cancer is intrinsically sensitive to chemotherapy. However, tumour response is often incomplete, and relapse occurs with high frequency. The aim of this work was to analyse the molecular characteristics of residual tumours and early response to chemotherapy in patient-derived xenografts (PDXs) of breast cancer. Methods: Gene and protein expression profiles were analysed in a panel of ER À breast cancer PDXs before and after chemotherapy treatment. Tumour and stromal interferon-gamma expression was measured in xenografts lysates by human and mouse cytokine arrays, respectively. Results: The analysis of residual tumour cells in chemo-responder PDX revealed a strong overexpression of IFN-inducible genes, induced early after AC treatment and associated with increased STAT1 phosphorylation, DNA-damage and apoptosis. No increase in IFN-inducible gene expression was observed in chemo-resistant PDXs upon chemotherapy. Overexpression of IFN- related genes was associated with human IFN-g secretion by tumour cells. Conclusions: Treatment-induced activation of the IFN/STAT1 pathway in tumour cells is associated with chemotherapy response in ER À breast cancer. Further validations in prospective clinical trials will aim to evaluate the usefulness of this signature to assist therapeutic strategies in the clinical setting. Neoadjuvant chemotherapy (NAC) is currently being used in correlates with favourable long-term outcome (von Minckwitz breast cancer patients with locally advanced disease, and it has et al, 2012). Differences in survival between patients with or increasing applications in patients with initially operable breast without a pCR were largest in patients with HER2 þ /oestrogen cancer but aggressive pathological features (high grade, high receptor-negative (ER À ) and triple-negative breast cancer proliferation, triple-negative or HER2-positive (HER2 þ ) breast (TNBC) (von Minckwitz et al, 2012). carcinoma). Several trials have shown that achievement of a Despite initial chemosensitivity, patients with TNBC and pathological complete response (pCR) after chemotherapy strongly HER2 þ /ER À subtypes have worse distant disease-free survival *Correspondence: Dr E Marangoni; E-mail: [email protected] or Dr S Cairo; E-mail: [email protected] 9These authors contributed equally to this work. Revised 7 October 2015; accepted 15 October 2015; published online 22 December 2015 & 2016 Cancer Research UK. All rights reserved 0007 – 0920/16 www.bjcancer.com | DOI:10.1038/bjc.2015.398 177 BRITISH JOURNAL OF CANCER IFN signature and chemotherapy response and overall survival than those with the luminal subtypes. In HER2 þ breast cancer, adding trastuzumab to chemotherapy METHODS significantly increases pCR (Buzdar et al, 2005). For TNBC, however, about 70% of patients do not achieve pCR after PDX establishment and in vivo efficacy studies. All patients had neo-adjuvant chemotherapy and suffer a dramatically worse previously given their verbal informed consent, at the time of first outcome, with a higher probability of metastatic relapse and a consultation at the Institut Curie, for experimental research on 3-year OS of only 60–70% (Carey et al, 2007; Liedtke et al, 2008). residual tumour tissue available after histophatological analyses. As a majority of TNBC patients endure the toxicity of cytotoxic PDX establishments have been performed after approval of the chemotherapy (CTX) without benefit, and as valuable time for a ethics committee of the Institut Curie. potentially more efficient alternative treatment is lost, there is a The care and use of animals used here was strictly applying strong rational for clinical and experimental research to identify European and National Regulation for the Protection of Vertebrate predictive markers of response and more efficient therapies. Animals used for Experimental and other Scientific Purposes in Several clinical studies reported gene expression changes force. This experiment complies with the procedure number 6 during NAC (Hannemann et al, 2005; Boidot et al, 2009). approved by the Ethical Committee CEEA-Ile de France Paris Hannemann et al (2005) showed that response of breast cancer to (official registration number 59). Swiss nude mice, 10-week-old NAC results in gene expression alterations. Gonzalez-Angulo et al female, were purchased from Charles River (Les Arbresles, France). (2012) analysed 21 paired tumour samples pre- and post-NAC in Establishment of PDX models from primary breast cancers and basal-like, HER2 þ and luminal breast cancer patients. in vivo responses to chemotherapies have previously been They reported significant changes in several kinase pathways, published (Marangoni et al, 2007). Adriamycin (DOX, Doxor- including PI3K and sonic hedghog, metabolism and immune- ubicin, Teva Pharmaceuticals, Paris, France), cisplatin (CDDP, related pathways. More recently, Balko et al (2012) profiled Teva Pharmaceuticals) and cyclophosphamide (Endoxan, Baxter, formalin-fixed tissues from 49 breast cancers using supervised Maurepas, France) were administered by intra-peritoneal (i.p.) À 1 NanoString gene expression analysis. They found low concentra- route at the doses of 2, 6 and 100 mg kg , respectively, every 3 tions of DUSP4 in basal-like breast cancer and demonstrated that weeks. Capecitabine (Xeloda, Roche Laboratories, Nutley, NJ, À 1 À 1 its overexpression was associated with CTX-induced apoptosis in USA) was administered per os at the dose of 540 mg kg day , cell lines. Korde et al (2010) reported changes in gene expression q5d  5 week and Irinotecan (Fresenius Kabi, Se`vres, France) by À 1 after one cycle of docetaxel and capecitabine NAC. They i.p. route at the dose of 50 mg kg at days 0, 3, 7 and 11. identified 71 differentially expressed gene sets, including DNA Ruxolitinib (RUX; Novartis, Rueil-Malmaison, France) was given À 1 À 1 repair and cell proliferation regulation pathways. By analysing per os at the dose of 30 mg kg 3 week . residual samples of tumours partially responsive to anthracyclin/ Histological analysis of the inter-scapular fad pad and in situ cyclophosphamide (AC) NAC, Koike Folgueira et al (2009) hybridisation of tumour residues. Histological analysis of showed that some of them retained their parental molecular residual tumours and in situ hybridisation of a human Alu probe signature, whereas others presented significant changes. All were performed, as previously described (Romanelli et al, 2012). studies found biological modifications between pretreatment Tumours with at least 40% of tumour content, as determined by and posttreatment tumours. However, no common signature histology, were included in the study. or pathway emerged, possibly reflecting patient heterogeneity and/or differences in the neo-adjuvant regimen, the percentage of Immunohistochemical (IHC) characterisation of xenografted non-tumour cells (normal, fibrotic and inflammatory tissue), tumours. Xenografted tumours were fixed in 10% neutral buffered the delay between the biopsy and the last chemotherapy cycle formalin, paraffin embedded and haematoxylin–eosin (H&E) or the technique used for analysis. In addition, no early gene stained to differentiate the human tumour components from the expression changes in post-NAC samples were generally captured murine stroma. Tumour tissues were analysed by IHC for in clinical studies. expression of the following biomarkers: P-STAT1Tyr701 (1/1000; Transplantable patient-derived xenografts (PDXs) are a Cell Signaling Ozyme, Saint Quentin en Yvelines, France), P-g- valuable preclinical tool to assess drug efficacy, study resistance H2AXSer139 (1/1000; Merck Millipore, Billerica, MA, USA). mechanisms and generate hypotheses that can be tested and P-STAT1Tyr701-positive tumour foci were counted in untreated translated to the clinic (Hidalgo et al, 2014; Marangoni and and RUX-treated tumour sections; mean±s.d., n ¼ 5 per group. Poupon, 2014). The panel of breast cancer PDX models used in Nuclear staining was considered positive for P-g-H2AX expression. this study reproduces the phenotypic and molecular hetero- For each tumour, the percentage of P-g-H2AX staining was geneity of clinical breast
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