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In spite of major advances over the past several decades in diagnosis and treatment, breast cancer remains a global cause of morbidity and premature death for both human and veterinary patients. Due to multiple shared clinicopathological features, dogs provide an excellent model of human breast cancer, thus, a comparative oncology approach may advance our understanding of breast cancer biology and improve patient outcomes. Despite an increasing awareness of the critical role of fibrillar collagens in breast cancer biology, tumor-permissive collagen features are still ill-defined. Here, we characterize the molecular and morphological phenotypes of type I collagen in canine mammary gland tumors. Canine mammary carcinoma samples contained longer collagen fibers as well as a greater population of wider fibers compared to non-neoplastic and adenoma samples. Furthermore, the total number of collagen cross-links enriched in the stable hydroxylysine-aldehyde derived cross-links was significantly increased in neoplastic mammary gland samples compared to non-neoplastic mammary gland tissue. The mass spectrometric analyses of type I collagen revealed that in malignant mammary tumor samples, lysine residues, in particular those in the telopeptides, were markedly over-hydroxylated in comparison to non-neoplastic mammary tissue. The extent of glycosylation of hydroxylysine residues was comparable among the groups. Consistent with these data, expression levels of genes encoding lysyl hydroxylase 2 (LH2) and its molecular chaperone FK506-binding protein 65 were both significantly increased in neoplastic samples. These alterations likely lead to an increase in the LH2-mediated stable collagen cross-links in mammary carcinoma that may promote tumor cell metastasis in these patients.

Breast cancer is the most common cause of cancer-related deaths in women worldwide. Identification of reliable prognostic indicators and therapeutic targets is critical for improving patient outcome. Cancer in companion animals often strongly resembles human cancers and a comparative approach to identify prognostic markers can improve clinical care across species. Feline mammary tumors (FMT) serve as models for extremely aggressive triple negative breast cancer (TNBC) in humans, with high rates of local and distant recurrence after resection. Despite the aggressive clinical behavior of most FMT, current prognostic indicators are insufficient for accurately predicting outcome, similar to human patients. Given significant heterogeneity of mammary tumors, there has been a recent focus on identification of universal tumor-permissive stromal features that can predict biologic behavior and provide therapeutic targets to improve outcome. As in human and canine patients, collagen signatures appear to play a key role in directing mammary tumor behavior in feline patients. We find that patients bearing FMTs with denser collagen, as well as longer, thicker and straighter fibers and less identifiable tumor-stromal boundaries had poorer outcomes, independent of the clinical variables grade and surgical margins. Most importantly, including the collagen parameters increased the predictive power of the clinical model. Thus, our data suggest that similarities with respect to the stromal microenvironment between species may allow this model to predict outcome and develop novel therapeutic targets within the tumor stroma that would benefit both veterinary and human patients with aggressive mammary tumors., Competing Interests: The authors have declared that no competing interests exist.

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.

Background: Ovarian hormones play crucial roles in mammary carcinogenesis. However, whether ovarian ablation by ovariohysterectomy (OHE) improves the prognosis in dogs with mammary carcinomas is unclear., Objectives: Determine if OHE at the time of mastectomy improves the prognosis in dogs with mammary carcinomas and evaluate if hormonal factors influence the effect of OHE., Animals: Sixty intact dogs with mammary carcinomas., Methods: Dogs were randomly assigned in a 1:1 ratio to undergo OHE (n = 31) or not (n = 29) at the time of tumor removal. Peri-surgical serum estradiol (E2) and progesterone concentrations were measured, tumor diagnosis was confirmed histologically, and tumor estrogen and progesterone receptor status was immunohistochemically determined. The dogs were monitored for recurrence and metastases every 3-4 months for at least 2 years. Uni- and multivariable survival analyses were performed with relapse and all-cause death as endpoints in addition to univariable subgroup analyses., Results: Overall, OHE did not significantly decrease hazard of relapse (hazard ratio [HR], 0.64; P = .18) or all-cause death (HR, 0.87; P = .64) in univariable analyses. In multivariable analysis OHE did not significantly influence the hazard of relapse (HR, 0.54; P = .12), but an interaction effect was identified between ER status and E2 (P = .037). Subgroup analysis identified decreased hazard of relapse in the OHE group compared to the non-OHE group in the subsets of dogs with increased E2 (HR, 0.22; P = .012) or grade 2 tumors (HR, 0.26; P = .02)., Conclusion: Dogs with grade 2, ER-positive tumors, or with increased peri-surgical serum E2 concentration represent a subset of dogs with mammary carcinomas likely to benefit from OHE., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Small to intermediate cell alimentary lymphoma was diagnosed in a cat after abdominal exploratory surgery with no prior history of pulmonary disease. Initial response to several chemotherapy regimens was poor, but a long-term remission was achieved with CCNU (lomustine) and corticosteroid therapy. After receiving a total cumulative CCNU dose of 552 mg m(-2) over 12 months, an acute episode of respiratory distress occurred and the cat died. Necropsy identified severe diffuse pulmonary fibrosis and no signs of lymphoma. This is the first report of pulmonary fibrosis following high cumulative dose nitrosourea chemotherapy in a cat.

Background: Histiocytic sarcoma is an aggressive neoplasm of dendritic cells that carries a grave prognosis. The efficacy of chemotherapy against this disease is unknown. The purpose of this study was to determine the efficacy of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in dogs with incompletely resected or metastatic histiocytic sarcoma, to describe the clinical characteristics of these dogs, and to identify factors affecting prognosis., Hypothesis: Our hypothesis is that CCNU has activity against canine histiocytic sarcoma and can improve survival in dogs with advanced disease., Animals: Included in analysis are dogs diagnosed with histiocytic sarcoma who had gross measurable or residual microscopic disease and who received CCNU., Methods: A multi-institutional, retrospective, single-arm cohort study was conducted. Available biopsy samples were tested with an antibody against CD18 when possible to confirm the diagnosis of histiocytic sarcoma., Results: Fifty-nine dogs were treated at 8 institutions. Twenty-three tumor specimens were confirmed to be CD18 positive. Treatment with CCNU at 60 to 90 mg/m2 resulted in an overall response rate of 46% in the 56 dogs with gross measurable disease. All 3 dogs with minimal residual disease experienced tumor relapse but lived 433 days or more after starting CCNU. The median survival of all 59 dogs was 106 days. Thrombocytopenia (< 100,000 platelets/microL) and hypoalbuminemia were found to be negatively associated with prognosis and were predictive of < 1 month survival., Conclusions and Clinical Importance: Results suggest that CCNU is active against canine histiocytic sarcoma and may be useful in the treatment of dogs without negative prognostic factors.

There is little information regarding mammary tumors in male cats. The purpose of this study was to characterize the clinical characteristics of mammary carcinoma in male cats, compare this malignancy to the disease in female cats, and identify prognostic factors. Thirty-nine male cats with mammary carcinoma were identified. One pathologist reviewed the biopsies from all cats, and complete follow-up information regarding outcome was available for 27 cats. Information collected included signalment, age at neutering, history of progestin therapy, age at tumor diagnosis, size of tumor, type of surgery (lumpectomy, simple mastectomy, or radical mastectomy), results of clinical staging, adjunctive therapies, time to local recurrence, survival, and cause of death. The mean age at tumor diagnosis (12.8 years) was slightly older than that reported in female cats. The incidence of local tumor recurrence in 9 of 20 (45%) cats was similar to that reported in females. A history of progestin therapy was present in 8 of 22 (36%) cats for which this information was known. The median time to local recurrence was 310 days (range 127-1,363 days), and overall median survival was 344 days (range 14-2,135 days). Tumor size and lymphatic invasion were identified as negative prognostic factors. This study indicates that mammary carcinoma in the male cat has many similarities to the disease in females, with an aggressive clinical course in most cats.

The clinical, histopathologic, and immunohistochemical features of 10 cats with epitheliotropic intestinal malignant lymphoma (EIL) are described. Intestinal biopsy samples were reviewed by 3 pathologists to confirm the diagnosis of EIL. These samples (n = 10) were compared to the intestinal biopsies of normal cats (n = 11), cats with inflammatory bowel disease (IBD; n = 7), and cats with non-EIL (n = 9) for quantification and immunophenotyping of intraepithelial lymphocytes. Immunophenotypic studies were performed with CD3 and CD79a antibody stains to assess for T- and B-cell immunoreactivity, respectively. EIL biopsies had markedly more intraepithelial lymphocytes than normal intestine (NRL) and samples from cats with IBD. However, no marked difference was observed in the number of intraepithelial lymphocytes in cats with non-EIL compared to cats with EIL. Regardless of the histologic diagnosis, the intraepithelial lymphocytes in all cats were small- to intermediate-sized T cells. Clinical findings and imaging studies in the cats identified minimal or nonspecific findings in affected cats. Most cats fit the typical profile of cats with IBD or alimentary malignant lymphoma. Nine of 10 cats with EIL were treated with prednisone with or without additional chemotherapy. Four cats were refractory to chemotherapy and were euthanized within 3.5 months. The remaining 5 cats had long-term survival times of 11 months or greater. The median survival time was 11 months. Additional studies are warranted to better characterize EIL and its relationship to IBD in cats and non-EIL and to identify optimal treatment strategies for this disease.

A retrospective evaluation was performed on 12 cats with nonresectable, histopathologically confirmed fibrosarcomas that were treated with doxorubicin and cyclophosphamide chemotherapy. All of the tumors were located in sites potentially used for vaccination. Six cats had a greater than 50% decrease in gross tumor burden. However, the responses were not durable, with a median response duration of 125 days. All cats developed progressive disease. When animals that received other treatments after doxorubicin-based chemotherapy were eliminated from the analysis, median survival time was significantly longer for cats that responded to chemotherapy compared with the median survival time for nonresponders (242 and 83 days, respectively). These findings may serve as a basis for further evaluating the role of chemotherapy in the treatment of vaccine-associated sarcomas.