330 research outputs found

    Ras/Raf-1/MAPK pathway mediates response to tamoxifen but not chemotherapy in breast cancer patients

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    <b>Purpose</b>: The expression and activation of the Ras/Raf-1/mitogen-activated protein kinase (MAPK) pathway plays an important role in the development and progression of cancer, and may influence response to treatments such as tamoxifen and chemotherapy. In this study we investigated whether the expression and activation of the key components of this pathway influenced clinical outcome, to test the hypothesis that activation of the MAPK pathway drives resistance to tamoxifen and chemotherapy in women with breast cancer. <b>Experimental Design</b>: Breast tumors from patients at the Glasgow Royal Infirmary and others treated within the BR9601 trial were analyzed for expression of the three Ras isoforms, total Raf-1, active and inactive forms of Raf-1 [pRaf(ser338) and pRaf(ser259), respectively], MAPK, and phospho-MAPK using an immunohistochemical approach. Analyses were done with respect to disease free-survival and overall survival. <b>Results</b>: Expression and activation of the Ras pathway was associated with loss of benefit from treatment with tamoxifen but not chemotherapy. Overexpression of pRaf(ser338) was associated with shortened disease-free and overall survival time in univariate analyses. Multivariate analysis suggested pRaf(ser338) was independent of known prognostic markers in predicting outcome following tamoxifen treatment (<i>P</i>=0.03). <b>Conclusion</b>: This study suggests that activation of the Ras pathway predicts for poor outcome on tamoxifen but not chemotherapy, and identifies pRaf(ser338) as a potential marker of resistance to estrogen receptor–targeted therapy. In addition, it suggests that expression of pRaf(ser338) could identify patients for whom tamoxifen alone is insufficient adjuvant systemic therapy, but for whom the addition of chemotherapy may be of benefit

    Determining lines of therapy in patients with solid cancers: a proposed new systematic and comprehensive framework

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    The complexity of neoplasia and its treatment are a challenge to the formulation of general criteria that are applicable across solid cancers. Determining the number of prior lines of therapy (LoT) is critically important for optimising future treatment, conducting medication audits, and assessing eligibility for clinical trial enrolment. Currently, however, no accepted set of criteria or definitions exists to enumerate LoT. In this article, we seek to open a dialogue to address this challenge by proposing a systematic and comprehensive framework to determine LoT uniformly across solid malignancies. First, key terms, including LoT and ‘clinical progression of disease’ are defined. Next, we clarify which therapies should be assigned a LoT, and why. Finally, we propose reporting LoT in a novel and standardised format as LoT N (CLoT + PLoT), where CLoT is the number of systemic anti-cancer therapies (SACT) administered with curative intent and/or in the early setting, PLoT is the number of SACT given with palliative intent and/or in the advanced setting, and N is the sum of CLoT and PLoT. As a next step, the cancer research community should develop and adopt standardised guidelines for enumerating LoT in a uniform manner

    Subgroup analyses from a phase 3, open-label, randomized study of eribulin mesylate versus capecitabine in pretreated patients with advanced or metastatic breast cancer

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    Purpose and methods: Our secondary analyses compared survival with eribulin versus capecitabine in various patient subgroups from a phase 3, open-label, randomized study. Eligible women aged ≥18 years with advanced/metastatic breast cancer and ≤3 prior chemotherapies (≤2 for advanced/metastatic disease), including an anthracycline and taxane, were randomized 1:1 to intravenous eribulin mesylate 1.4 mg/m² on days 1 and 8 or twice-daily oral capecitabine 1250 mg/m² on days 1–14 (21-day cycles). Results: In the intent-to-treat population (eribulin 554 and capecitabine 548), overall survival appeared longer with eribulin than capecitabine in various subgroups, including patients with human epidermal growth factor receptor 2-negative (15.9 versus 13.5 months, respectively), estrogen receptor-negative (14.4 versus 10.5 months, respectively), and triple-negative (14.4 versus 9.4 months, respectively) disease. Progression-free survival was similar between the treatment arms. Conclusions: Patients with advanced/metastatic breast cancer and human epidermal growth factor receptor 2-, estrogen receptor-, or triple-negative disease may gain particular benefit from eribulin as first-, second-, and third-line chemotherapies

    The Global Need for a Trastuzumab Biosimilar for Patients With HER2-Positive Breast Cancer

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    Trastuzumab improves survival outcomes for patients with HER2-positive (HER2+) breast cancer, yet not all such women receive this important therapy. Trastuzumab was approved by the US Food and Drug Administration in 1998 and the European Medicines Agency in 2000 as treatment for HER2+ metastatic breast cancer (MBC). Observational studies between 2000 and 2015 in patients with HER2+ MBC suggest that nearly 12% in the United States, 27% to 54% in Europe, and 27.1% to 49.2% in China did not receive trastuzumab or any other HER2-targeted agent as first- and/or later-line for treatment of metastatic disease. In 2006, both agencies approved trastuzumab as adjuvant therapy for patients with HER2+ early breast cancer (EBC). Observational studies on real-world treatment patterns for HER2+ EBC between 2005 and 2015 suggest that 19.1% to 59.5% of patients across regions of North America, Europe, Australia, New Zealand, and China did not receive (neo)adjuvant trastuzumab. Data suggest that some patient subgroups, including older patients, those with HER2+/hormone receptor-positive disease, and women with small and/or node-negative HER2+ tumors, were less likely to receive anti-HER2 therapy. Barriers to accessing trastuzumab are multifactorial and include issues related to drug funding and high treatment costs for patients that have been reported worldwide. Herein, we review available literature on the use of, and barriers to, treatment with trastuzumab in patients with HER2+ breast cancer. We also discuss how the availability of safe and effective biosimilars might increase access to trastuzumab and allow greater use of anti-HER2 therapy, potentially improving patient outcomes

    A phase I and pharmacokinetic study of the combination of capecitabine and docetaxel in patients with advanced solid tumours

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    Capecitabine and docetaxel are both active against a variety of solid tumours, while their toxicity profiles only partly overlap. This phase I study was performed to determine the maximum tolerated dose (MTD) and side-effects of the combination, and to establish whether there is any pharmacokinetic interaction between the two compounds. Thirty-three patients were treated with capecitabine administered orally twice daily on days 1–14, and docetaxel given as a 1 h intravenous infusion on day 1. Treatment was repeated every 3 weeks. The dose of capecitabine ranged from 825 to 1250 mg m–2twice a day and of docetaxel from 75 to 100 mg m–2. The dose-limiting toxicity (DLT) was asthenia grade 2–3 at a dose of 1000 mg m–2bid of capecitabine combined with docetaxel 100 mg m–2. Neutropenia grade 3–4 was common (68% of courses), but complicated by fever in only 2.4% of courses. Other non-haematological toxicities were mild to moderate. There was no pharmacokinetic interaction between the two drugs. Tumour responses included two complete responses and three partial responses. Capecitabine 825 mg m–2twice a day plus docetaxel 100 mg m–2was tolerable, as was capecitabine 1250 mg m–2twice a day plus docetaxel 75 mg m–2. © 2000 Cancer Research Campaig

    A phase II, multicentre, UK study of vinorelbine in advanced breast cancer.

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    Thirty-four evaluable patients were treated with vinorelbine, a novel, semisynthetic vinca alkaloid, as first-line chemotherapy for advanced breast cancer. They received vinorelbine 25 mg m-2 i.v. given weekly for a maximum of 16 cycles. Two patients achieved a complete remission and 15 a partial remission, giving a response rate of 17/34 (50%; 95% CI of 34-66%); median response duration was 5.8 months. The median progression-free interval was 4.4 months and median survival 9.9 months. Treatment was generally well tolerated. Fatigue was the most common side-effect. The main reason for dose adjustments was myelosuppression; 68% of patients had WHO grade 3 or 4 neutropenia and there was one death attributed to neutropenic sepsis. Nausea/vomiting and neuropathy were mild and alopecia was uncommon. This study confirms vinorelbine as a highly active, well-tolerated agent in advanced breast cancer worthy of evaluation in combination chemotherapy regimens
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