Canine invasive mammary carcinomas as models of human breast cancer. Part 2: immunophenotypes and prognostic significance

Abstract

PurposeRelevant animal models of human breast cancer are currently needed, especially for the aggressive triple-negative breast cancer subtype. Recent studies and our results (Part 1) indicate that spontaneous canine invasive mammary carcinomas (CMCs) resemble human breast cancer by clinics and pathology as well as behavior and prognostic indicators. We hypothesized that the current molecular classifications of human breast cancer, used for therapeutic decision, could be relevant to dogs.MethodsThree hundred and fifty female dogs with spontaneous CMC and a 2-year follow-up were retrospectively included. By immunohistochemistry, CMCs were classified according to Nielsen (Clin Cancer Res 10:5367–5374, 2004) and Blows (PlosOne doi: 10.1371/journal.pmed.1000279, 2010) into the subtypes of human breast cancer.ResultsFour immunophenotypes were defined either according to Nielsen classification (luminal A 14.3%, luminal B 9.4%, triple-negative basal-like 58.6%, and triple-negative nonbasal-like 17.7% CMCs); or to Blows classification (luminal 1−: 11.4%, luminal 1+: 12.3%, Core basal phenotype: 58.6%, and five-negative phenotype: 17.7%). No HER2-overexpressing CMC as defined by a 3 + immunohistochemical score was observed in our cohort. By univariate and multivariate analyses, both immunophenotypical classifications applied to CMCs showed strong prognostic significance: luminal A or luminal 1+ CMCs showed a significantly longer disease-free interval (HR = 0.46), Overall (HR = 0.47), and Specific Survival (HR = 0.56) compared to triple-negative carcinomas, after adjustment for stage.ConclusionsIn our cohort, triple-negative CMCs largely predominated (76%), were much more prevalent than in human beings, and showed an aggressive natural behavior after mastectomy. Dogs are thus potent valuable spontaneous models to test new therapeutic strategies for this particular subtype of breast cancer.

Deregulation of VEGFR-2 and PGFR expression and microvascular density in a triple-negative model of canine malignant mammary tumors with lymph node or lung metastasis

“…Regarding the nonmetastatic group, some patients with multiple tumors exhibited different molecular subtypes (data not shown), making it difficult to establish a prognosis based on the molecular subtype. Triple-negative tumors seem to be the most common molecular subtype in dogs [8]. This finding highlight the utility of dogs as a model for human triple-negative BC.…”

“…Immunohistochemistry was performed according to Abadie [8]. Then, we used a combination of ERα, PR, HER-2, Ki67, CK5/6 and EGFR to classify the different molecular phenotypes ( Figure 1).…”

“…Triple-negative tumors are very important as these tumors represent a therapeutic challenging, and limited therapeutic options are available compared with other subtypes [7]. Recently, a study evaluating a large number of cases subdivided CMT into molecular subtypes and found an increased prevalence of triple-negative tumors in dogs [8]. These results indicate that female dogs serve as a natural model for human BC.…”

Companion canines: an under-utilised model to aid in translating anti-metastatics to the clinic

“…The dog genome is well annotated and the human genome shares more ancestral sequence with the dog than the mouse [3], a reflection of which is that for many cancer-associated proteins there is a greater degree of sequence similarity between the human and canine homologs than between the human and mouse proteins [4]. At the protein level, antibodies used in humans for immunohistochemistry and flow cytometry often also work in dogs [5,6], whereas mice frequently require an antibody specific for the mouse protein, further emphasizing the similarity between human and dog genes. Importantly, many canine metastatic tumours show striking aetiological, epidemiological, genetic and histological similarity to their human counterparts [7].…”

Identification of oncolytic vaccinia restriction factors in canine high-grade mammary tumor cells using single-cell transcriptomics

“…If differences have been highlighted in complex carcinomas [24], simple canine carcinomas faithfully represent human breast carcinomas, both at the histological and molecular level [20,21]. This is particularly the case for the so called "triple negative carcinomas" (lack of estrogen and progesterone receptors and of epidermal growth factor receptor type 2) [22,25,26], for which therapeutic options are limited and unsatisfactory.…”