Breast Neoplasms: Verrill MW

Jones AL, Barlow M, Barrett-Lee PJ, Canney PA, Gilmour IM, Robb SD, Plummer CJ, Wardley AM, Verrill MW. · Department of Oncology, Royal Free and University College London Hospitals, UK. · Br J Cancer. · Pubmed #19259090 links to  free full text

Abstract: More women are living with and surviving breast cancer, because of improvements in breast cancer care. Trastuzumab (Herceptin) has significantly improved outcomes for women with HER2-positive tumours. Concerns about the cardiac effects of trastuzumab (which fundamentally differ from the permanent myocyte loss associated with anthracyclines) led to the development of cardiac guidelines for adjuvant trials, which are used to monitor patient safety in clinical practice. Clinical experience has shown that the trial protocols are not truly applicable to the breast cancer population as a whole, and exclude some women from receiving trastuzumab, even though they might benefit from treatment without long-term adverse cardiac sequelae. Consequently, five oncologists who recruited patients to trastuzumab trials, some cardiologists with whom they work, and a cardiovascular lead general practitioner reviewed the current cardiac guidelines in the light of recent safety data and their experience with adjuvant trastuzumab. The group devised recommendations that promote proactive pharmacological management of cardiac function in trastuzumab-treated patients, and that apply to all patients who are likely to receive standard cytotoxic chemotherapy. Key recommendations include: a monitoring schedule that assesses baseline and on-treatment cardiac function and potentially reduces the overall number of assessments required; intervention strategies with cardiovascular medication to improve cardiac status before, during, and after treatment; simplified rules for starting, interrupting and discontinuing trastuzumab; and a multidisciplinary approach to breast cancer care.

Barrett-Lee PJ, Dixon JM, Farrell C, Jones A, Leonard R, Murray N, Palmieri C, Plummer CJ, Stanley A, Verrill MW. · Breast Unit, Velindre Cancer Centre, Cardiff, UK. · Ann Oncol. · Pubmed #19153118 No free full text.

Abstract: Anthracyclines are considered to be among the most active agents for the treatment of breast cancer. However, their use is limited by cumulative, dose-related cardiotoxicity. Such cardiotoxicity results in a permanent loss of cardiac myocytes and a progressive reduction in cardiac function following each subsequent dose of anthracycline. Initially, damage to the heart is subclinical; however, increasingly impaired cardiac function can result in cardiovascular symptoms, with serious cardiac injury resulting in chronic heart failure. Since the early detection and treatment of cardiotoxicity can reduce its clinical effects, it is important that oncologists are aware of these adverse effects and manage them appropriately. This review examines the risk factors for anthracycline-associated cardiotoxicity and offers recommendations on strategies to reduce the cardiotoxicity of anthracyclines in the management of patients with advanced breast cancer.

Llombart-Cussac A, Martin M, Harbeck N, Anghel RM, Eniu AE, Verrill MW, Neven P, De Grève J, Melemed AS, Clark R, Simms L, Kaiser CJ, Ma D. · Hospital Universitario Arnau Vilanova, Lleida, Spain. · Clin Cancer Res. · Pubmed #17575230 links to  free full text

Abstract: PURPOSE: Pemetrexed has shown varied response rates in advanced breast cancer. This randomized, double-blind, phase II study was conducted to assess the efficacy and safety of two doses of pemetrexed in a homogeneous population. A secondary objective was to identify molecular biomarkers correlating with response and toxicity. EXPERIMENTAL DESIGN: Patients with newly diagnosed metastatic breast cancer or locally recurrent breast cancer received 600 mg/m(2) (P600 arm) or 900 mg/m(2) (P900 arm) of pemetrexed on day 1 of a 21-day cycle. All patients received folic acid and vitamin B(12) supplementation. RESULTS: The P600 (47 patients) and P900 (45 patients) arms had response rates of 17.0% (95% confidence interval, 7.7-30.8%) and 15.6% (95% confidence interval, 6.5-29.5%) with approximately 50% stable disease per arm, median progression-free survival of 4.2 and 4.1 months, and median times to tumor progression of 4.2 and 4.6 months, respectively. Both arms exhibited minimal toxicity (grade 3/4 neutropenia <20%, leukopenia <9%, and other toxicities <5%). Tumor samples from 49 patients were assessed for the expression levels of 12 pemetrexed-related genes. Folylpolyglutamate synthetase and thymidine phosphorylase correlated with efficacy. Best response rates and median time to tumor progression for high versus low thymidine phosphorylase expression were 27.6% versus 6.3% (P = 0.023) and 5.4 versus 1.9 months (P = 0.076), and for folylpolyglutamate synthetase were 37.5% versus 10.0% (P = 0.115) and 8.6 versus 3.0 months (P = 0.019), respectively. gamma-Glutamyl hydrolase expression correlated with grade 3/4 toxicities: 78.6% for high versus 27.3% for low gamma-glutamyl hydrolase (P = 0.024). CONCLUSION: The two pemetrexed doses yielded similar efficacy and safety profiles. Exploratory biomarker analysis identified efficacy and toxicity correlations and warrants further evaluation.

Jamieson D, Cresti N, Verrill MW, Boddy AV. · Northern Institute for Cancer Research, University of Newcastle upon Tyne, Paul O'Gorman Building, Medical School, Newcastle upon Tyne, NE2 4HH, UK. · J Immunol Methods. · Pubmed #19376123 No free full text.

Abstract: Trastuzumab is a therapeutic monoclonal antibody against the Her2 oncoprotein, which is over-expressed in approximately 30% of breast cancers, and is now used routinely in the management of early and metastatic Her2+ disease. However, not all Her2+ breast cancer patients respond to trastuzumab and the pharmacodynamic and pharmacokinetic parameters behind this variation in response are unknown. Pharmacological investigations into variable response to trastuzumab have been hampered by the lack of a published feasible method to determine trastuzumab concentration in plasma. Here we describe the development and validation of a cell-based ELISA to measure trastuzumab in human plasma. The assay specifically measures the interaction between trastuzumab and Her2 and has a dynamic range of between 10 and 120 microg/ml. The mean intra-assay and inter-assay variability of the ELISA was 9%. Trastuzumab in plasma was stable for at least 10 weeks at -20 degrees C and 72 h at 4 degrees C, and was unaffected by 5 freeze/thaw cycles. Having validated the assay, the trough plasma trastuzumab concentrations of 30 patients being treated for metastatic or early disease were measured. The median trough concentration was 62 (range 21 to 441) microg/ml. This cell-based ELISA method has undergone appropriate validation and is suitable for quantification of trastuzumab in the plasma of patients treated with Herceptin.