Background: The occurrence of spontaneous tumors in pet animals has been estimated in a few European and North American veterinary cancer registries with dissimilar methodologies and variable reference populations.Objectives: The Animal Tumor Registry (ATR) of Genoa, Italy, was established in 1985 with the aim of estimating the occurrence of spontaneous tumors in dogs.Methods: Six thousand seven hundred and forty-three tumor biopsy specimens were received from local veterinarians in the Municipality of Genoa between 1985 and 2002. Three thousand and three hundred and three (48.9%) biopsy specimen samples were diagnosed as cancer and were coded according to the International Statistical Classification of Diseases (ICD-9).Results: Mammary cancer was the most frequently diagnosed cancer in female dogs, accounting for 70% of all cancer cases. Incidence of all cancers was 99.3 per 100,000 dog-years (95% CI: 93.6-105.1) in male dogs and 272.1 (95% CI: 260.7-283.6) in female dogs. The highest incidence rates were detected for mammary cancer (IR 5 191.8, 95% CI: 182.2-201.4) and for non-Hodgkin's lymphoma (IR 5 22.9, 95% CI: 19.7-26.5) in bitches and for non-Hodgkin's lymphoma (IR 5 19.9, 95% CI: 17.4-22.7) and skin cancer (IR 5 19.1, 95% CI: 16.6-21.8) in male dogs. All cancer IR increased with age ranging between 23.7 (95% CI: 18.4-30.1) and 763.2 (95% CI: 700.4-830.1) in bitches and between 16.5 (95% CI: 12.8-21.1) and 237.6 (95% CI: 209.1-269.0) in male dogs aged 3 years and 49-11 years.Conclusion: This study summarizes the work done by the ATR of Genoa, Italy, between 1985 and 2002. All cancer incidence was 3 times higher in female than in male dogs, a difference explained by the high rate of mammary cancer observed in bitches. Because a biopsy specimen was required to make a cancer diagnosis, cancer rates for internal organs cancers, such as respiratory and digestive tract cancers may have been underestimated in the study population.

Background Src activation is associated with cell migration, proliferation and metastasis. Saracatinib is an oral, tyrosine kinase inhibitor (TKI) selective for Src. We performed this trial to evaluate the efficacy and safety of saracatinib monotherapy in patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative, metastatic breast cancer. Patients and Methods Patients with ≤1 prior chemotherapy regimen for measurable, ER- and PR-negative metastatic breast cancer received saracatinib 175 mg orally daily. The primary endpoint was disease control defined as complete response (CR) + partial response (PR) + stable disease (SD) >6 months. Secondary endpoints included toxicity and progression-free survival. Levels of circulating tumor cells in response to therapy were measured over time. Results Nine patients were treated on study. After a median of 2 cycles (range 1–3), no patients achieved CR, PR, or SD >6 months. The median time to treatment failure was 82 days (12–109).The majority (89%) of patients discontinued saracatinib because of disease progression. One patient developed potentially treatment-related grade 4 hypoxia with interstitial infiltrates and was removed from study. Common adverse events included fatigue, elevated liver chemistries, nausea, hyponatremia, dyspnea, cough, and adrenal insufficiency. Conclusions These efficacy results were not sufficiently promising to justify continued accrual to this study. Based on this series, saracatinib does not appear to have significant single-agent activity for the treatment of patients with ER(−)/PR(−) metastatic breast cancer.

Purpose:Tipifarnib is a farnesyl transferase (FTase) inhibitor that has activity in metastatic breast cancer and enhances the efficacy of cytotoxic agents in preclinical models. We evaluated the biological effects of tipifarnib in primary breast cancers in vivo, whether adding tipifarnib to preoperative chemotherapy increased the pathologic complete response rate (pCR) at surgery, and determined whether biomarkers predictive of pCR could be identified. Experimental Design: Forty-four patients with stage IIB-IIIC breast cancer received up to four cycles of neoadjuvant doxorubicin-cyclophosphamide (AC) every 2 weeks plus tipifarnib and filgrastim followed by surgery. Enzymatic assays measuring FTase activity and Western blotting for phospho (p)-signal transducer and activator of transcription 3 (STAT3), phospho-extracellular signal-regulated kinase, p-AKT, and p27 were done in 11 patients who agreed to optional tissue biopsies before therapy and 2 hours after the final dose of tipifarnib during the first cycle, and predictive biomarkers were evaluated by immunohistochemistry in 33 patients. The trial was powered to detect an improvement in breast pCR rate of 10% or less expected for AC alone to 25% for AC-tipifarnib (a = 0.05, b = 0.10). Results: Eleven patients had a breast pCR (25%; 95% confidence interval, 13-40%). FTase enzyme activity decreased in all patients (median, 91%; range, 24-100%) and p-STAT3 expression decreased in 7 of 9 (77%) patients. Low tumor Ki-67 expression (below the median of 60%) at baseline was significantly associated with resistance to therapy (P = 0.01). Conclusion: Tipifarnib inhibits FTase activity in human breast tumors in vivo, is associated with down-regulation of p-STAT3, and enhances the breast pCR rate, thus meriting further evaluation.

Tipifarnib may be safely combined with dose-dense AC using a dose and schedule that significantly inhibits FTase enzyme activity in human breast cancer in vivo and may enhance the pCR rate after four cycles of preoperative dose-dense AC.