1. 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., Appl. Immunohistochem. Mol. Morphol. 19,
[2] Davison Z. et al., Neoplasia. 13,
[3] Hartog H. et al., Breast Cancer Res. Treat. 129,
[4] Iqbal J. et al., Histopathology, 61,
[5] King E. et al., Recent Pat. Anticancer Drug Discov
[6] Litzenburger B.C. et al., Clin. Cancer Res. 17,
[7] Papa et al., Cancer Res. 53,
[8] Taromaru GCM. et al., 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
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