Canine invasive mammary carcinoma as a spontaneous model for IGF-1R-overexpressing triple negative breast cancer L. Jaillardon1,2, F. Nguyen1,2, D.Loussouarn3, T. Godard1,2, J. Abadie1,2, B. Siliart1,2, M. Campone4. 1Oniris, AMaROC-LDHvet, Ecole Nationale Vétérinaire, Agroalimentaire et de l’Alimentation Nantes Atlantique, Nantes, France, 2Université Nantes-Angers-Le Mans, France, 3Hopital G&R Laënnec, Nantes, France, 4Institut de Cancérologie de l’Ouest, Saint Herblain-Nantes cedex, France Introduction Results Discussion IGF-1R expression in TN-CMC Dogs spontaneously develop invasive mammary carcinoma with a high prevalence of the triple-negative subtype (ER-Estrogen Receptor and PR-Progesterone Receptor negative, not HER2-Human Epidermal Growth Factor Receptor 2 overexpressing), making this model relevant for the investigation of new therapeutic pathways. IGF-1R (Insulin-like Growth Factor-1 Receptor) is frequently overexpressed in triple-negative breast cancer [1] [6] and extensively involved in malignant transformation, proliferation and survival [2]. Multiple preclinical trials have used IGF-1R inhibitors in various cancer types, including triple-negative breast cancer, with encouraging results [5]. IGF-1R expression in TN-CMC As in its human counterpart [3] [6], IGF-1R is frequently highly expressed in the canine triple negative invasive mammary carcinoma. Even if IGF-1R expression is generally associated with estrogen receptor expression in breast cancer [7], recent papers showed that not only triple-negative breast cancer cell lines expressed IGF-1R, but their proliferation and survival were stimulated by IGF-1 [2] and inhibited by anti-IGF-1R therapy [6]. Prognostic value of IGF-1R expression in TN-CMC Strong expression of IGF-1R is associated with shorter overall and specific survivals in univariate analysis as well as in multivariate models including well-known prognostic factors involved in canine invasive mammary carcinoma. In human breast cancer, the prognostic value of IGF-1R expression depends on ER status: IGF-1R overexpression is a good prognostic factor in ER+ breast cancer while it is associated with a poor outcome and early recurrence in triple-negative breast carcinomas [3] [4]. IGF-1R score Emboli and IGF-1R expression (% TN-CMC) Score 2+ Score 3+ Score 0 Score 1+ Score 3+ Score 0/1+/2+ 45.2% (n=47) of TN-CMC overexpressed IGF-1R Of which 70.2% basal-like TN-CMC 61.7 % de grade III (Elston & Ellis) EMBOLI NO EMBOLI IGF-1R overexpression is associated with the presence of emboli in TN-CMC % (n) of TN-CMC according to IGF-1R expression To quantify IGF-1R expression in naturally-occurring triple-negative canine mammary carcinomas (TN-CMC) To assess the prognostic value of IGF-1R in TN-CMC in terms of overall (OS), specific (SS) and disease-free survivals (DFS) defined as the interval from mastectomy to the first local recurrence or lymph node metastasis To validate the dog as a spontaneous model for anti-IGF-1R therapies in triple-negative breast cancer Objectives Prognostic value of IGF-1R expression in TN-CMC Univariate analysis Disease-free survival (%) Specific survival (%) Median specific survival Median disease-free survival Median overall survival Overall survival (%) 374 d 477 d 1 d 842 d > 50% alive 1011 d 348 d 598 d 1049 d 163 d 332 d 278 d P < 0.001 P = 0.04 P < 0.001 Time since mastectomy (days) Time since mastectomy (days) Time since mastectomy (days) IGF-1R-overexpression (3+) is associated with a shorter overall, specific and disease-free survival Summary Material and Methods Multivariate analysis Positive prognostic factor Negative prognostic factor Parameters Overall survival Specific survival Disease-free survival HR p IGF-1R Score 0 Score 1+ Score 2+ Score 3+ - 0.49 0.30 0.60 (1.00) 0.008 NS 0.002 0.03 0.57 0.16 0.79 0.04 0.006 3.31 0.47 0.71 0.05 Grade Elston & Ellis I II III 0.29 0.94 Emboli No emboli 1.77 0.02 4.15 <0.001 Complete excision Incomplete excision 0.39 < 0.001 0.48 0.45 Androgen receptor < 1% Androgen receptor > 1% 2.78 0.001 1) IGF-1R overexpression is common in canine triple negative mammary carcinoma. 2) IGF-1R overexpression is related to a poor clinical outcome in canine triple-negative mammary carcinoma. 3) Dog is a relevant naturally-occurring model in triple- negative breast cancer overexpressing IGF-1R Inclusion: 104 naturally-occurring TN-CMC. Follow-up ≥ 2 years after mastectomy Immunophenotype: Triple-negative (ER-, PR-, not HER2-overexpressing) Basal-like (Cytokeratin-CK 5/6 positive and/or Epidermal Growth Factor Receptor-EGFR positive). N = 71 Non-basal-like (CK 5/6 and EGFR negative). N = 33 Immunohistochemical expression of IGF-1R (clone G11) and scoring [8]: Score 0 Score 1+ Score 2+ Score 3+ References: [1] Bharghava R. et al., 2011. Appl. Immunohistochem. Mol. Morphol. 19, 218-225 [2] Davison Z. et al., 2011. Neoplasia. 13, 504-515 [3] Hartog H. et al., 2011. Breast Cancer Res. Treat. 129, 725-736 [4] Iqbal J. et al., 2012. Histopathology, 61, 652-659 [5] King E. et al., 2012. Recent Pat. Anticancer Drug Discov. 7 14-30 [6] Litzenburger B.C. et al., 2011. Clin. Cancer Res. 17, 2314-2327 [7] Papa et al., 1993. Cancer Res. 53, 3736-3740 [8] Taromaru GCM. et al., 2012. Oncol. Lett. 3, 682-6 No membrane staining or < 10% of the cells Partial and slight membrane staining >10% of the cells Total and moderate membrane staining >10% of the cells Total and marked membrane staining >10% of the cells CONCLUSIONS Absence of IGF-1R overexpression correlates with longer OS and SS Total absence of IGF-1R expression correlates with a shorter DFS Printed by