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Purpose: The urokinase plasminogen activator (uPA) and the plasminogen activator inhibitor 1 (PAI-1) are associated with an aggressive course in breast cancer and are used to determine whether chemotherapy is needed in node-negative patients. The objective of the study was to evaluate the prognostic value of uPA and PAI-1 protein expression in advanced breast cancer patients treated with trastuzumab., Methods: Formalin-fixed paraffin-embedded tumor tissue samples were retrospectively collected from 230 patients with advanced breast cancer treated with trastuzumab and 130 patients treated with 1st line taxanes. uPA, PAI-1, ER, PgR, HER2 and Ki67 protein expression was evaluated by immunohistochemistry., Results: Central review of HER2 status revealed that only 144 (63 %) of the trastuzumab-treated patients were truly HER2-positive. Median survival was 50.7 months for the HER2-positive and 30.1 months for the HER2-negative patients (p = 0.006) treated with trastuzumab. In multivariate Cox regression analysis of the trastuzumab cohort, a significant interaction was found, in terms of survival, between HER2 status and PAI-1 protein expression in the stroma (Wald's p = 0.002). Positive PAI-1 protein expression in the stroma of HER2-negative patients was associated with lower risk of death (HR 0.35, 95 % CI 0.19-0.65, Wald's p = 0.0008). Such an association was not observed in HER2-positive patients treated with trastuzumab or in the non-trastuzumab (validation) cohorts., Conclusions: Our results suggest that positive stromal PAI-1 protein expression may identify a subgroup of HER2-negative advanced breast cancer patients who might benefit from treatment with trastuzumab. Further studies are warranted to validate these findings in larger cohorts.

Purpose: Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) bear a grave prognosis. There are unmet needs for the development of novel agents for this incurable disease. Angiogenesis is an important biological process in SCCHN. We, therefore, evaluated the activity and safety of sunitinib, an oral tyrosine kinase inhibitor that targets multiple receptors, in patients with RM-SCCHN., Patients and Methods: Seventeen patients were treated with sunitinib 50 mg per day administrated in 4-week cycles followed by a rest period of 2 weeks. Sunitinib and SU012662 plasma levels were determined based on a validated liquid chromatography-tandem mass spectrometry method and pharmacokinetic data were fitted in a non-compartmental analysis., Results: Totally, 28 6-week cycles of treatment with sunitinib were administered (median, 2 cycles). Only three patients demonstrated stabilization of the disease; therefore, the study had to be terminated prematurely due to futility. Grade 3 toxicities, apart from fatigue, were infrequent. Other frequently reported side effects were skin discoloration, neutropenia, and thrombocytopenia. Ten various bleeding complications were reported in seven patients. Mean maximum concentrations (C(max)) were reached during the first day of treatment for sunitinib at 38.98 (+ or - 22.66) ng/ml and for SU012662 at 11.12 (+ or - 24.57) ng/ml. Our results showed that SU012662 has a longer half-life and a larger volume of distribution than the parent drug sunitinib. None of the biological markers tested was of any prognostic value., Conclusions: According to our findings, sunitinib monotherapy was not proven active in RM-SCCHN, and no further development of the drug in this indication is warranted.