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.

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Objective We evaluated the activity and safety of the combination of topotecan, cisplatin and bevacizumab in patients with recurrent or persistent carcinoma of the cervix. Methods Eligible patients had persistent or recurrent cervical cancer not amenable to curative intent treatment. No prior chemotherapy for recurrence was allowed. Treatment consisted of cisplatin 50 mg/m2 day 1, topotecan 0.75 mg/m2 days 1,2 and 3 and bevacizumab 15 mg/kg day 1 every 21 days until disease progression or limiting toxicity. The primary endpoint was progression free survival at 6 months. We explored PET/CT as a potential early indicator of response to therapy. Results Twenty-seven eligible patients received a median of 3 treatment cycles (range, 1–19). Median fallow-up was 10 months (range, 1.7–33.4). The 6-month PFS was 59% (80% CI: 46-70%). in 26 evaluable patients, we observed 1 CR (4%; 80% CI: 0.4–14%) and 8 PR (31%; 80% CI: 19–45%) lasting a median of 4.4 months. Ten patients had SD (39%; 80% CI: 25–53%) with median duration of 2.2 months. Median PFS was 7.1 months (80%; CI: 4.7–10.1) and median OS was 13.2 months (80% CI: 8.0–15.4). All patients were evaluated for toxicity. Grade 3–4 hematologic toxicity was common (thrombocytopenia 82% leukopenia 74%, anemia 63%, neutropenia 56%). Most patients (78%) required unanticipated hospital admissions for supportive care and/or management of toxicities. Conclusion The addition of bevacizumab to topotecan and cisplatin results in an active but highly toxic regimen. Future efforts should focus on identification of predictive biomarkers of prolonged response and regimen modifications to minimize toxicity.

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