Abstract
Increasing evidence indicates that the tumor microenvironment plays a critical role in regulating the biologic behavior of breast cancer. In veterinary oncology, there is a need for improved prognostic markers to accurately identify dogs at risk for local and distant (metastatic) recurrence of mammary gland carcinoma and therefore would benefit from adjuvant therapy. Collagen density and fiber organization have been shown to regulate tumor progression in both mouse and human mammary tumors, with certain collagen signatures predicting poor outcomes in women with breast cancer. We hypothesized that collagen signatures in canine mammary tumor biopsies can serve as prognostic biomarkers and potential targets for treatment. We used second harmonic generation imaging to evaluate fibrillar collagen density, the presence of a tumor-stromal boundary, tumor associated collagen signatures (TACS) and individual collagen fiber characteristics (width, length and straightness) in grade I/II and grade III canine mammary tumors. Collagen density, as well as fiber width, length and straightness, were inversely correlated with patient overall survival time. Notably, grade III cases were less likely to have a tumor-stromal boundary and the lack of a boundary predicted poor outcome. Importantly, a lack of a defined tumor-stromal boundary and an increased collagen fiber width were associated with decreased survival even when tumor grade, patient stage, ovariohysterectomy status at the time of mammary tumor excision, and histologic evidence of lymphovascular invasion were considered in a multivariable model, indicating that these parameters could augment current methods to identify patients at high risk for local or metastatic progression/recurrence. Furthermore, these data, which identify for the first time, prognostic collagen biomarkers in naturally occurring mammary gland neoplasia in the dog, support the use of the dog as a translational model for tumor-stromal interactions in breast cancer.
Highlights
In spite of major advances in diagnosis and treatment over the past several decades, breast cancer remains a major cause of morbidity and premature death for both human and veterinary patients throughout the world
We examined the potential role of fibrillar collagen in modulating the biologic behavior of canine mammary gland tumors
We demonstrate that specific collagen signatures, revealed by second harmonic generation (SHG) imaging in primary canine mammary carcinomas, are predictive of aggressive clinical outcomes
Summary
In spite of major advances in diagnosis and treatment over the past several decades, breast cancer remains a major cause of morbidity and premature death for both human and veterinary patients throughout the world. Physicians, and other scientific health and environmental professionals has been promoted in an initiative known as “One Health” to improve the lives of all species through the integration of human and veterinary medical research [7]. This “One Health” approach may more efficiently and simultaneously transform breast cancer treatment in women and female dogs. This approach applies novel diagnostics and therapeutics to veterinary oncologic patients from cutting-edge human breast cancer medical strategies, and informs human medicine through the unique advantages of the spontaneous, naturally occurring canine breast cancer model. The lack of accurate prognostic indicators results in increased morbidity and mortality due to both over-treatment of patients bearing malignant tumors with low metastatic potential and inadequate therapies for those requiring early, aggressive intervention
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