Showing papers by "Cheryl Gillett published in 2009"

The potential of optical proteomic technologies to individualize prognosis and guide rational treatment for cancer patients.

Abstract: Genomics and proteomics will improve outcome prediction in cancer and have great potential to help in the discovery of unknown mechanisms of metastasis, ripe for therapeutic exploitation. Current methods of prognosis estimation rely on clinical data, anatomical staging and histopathological features. It is hoped that translational genomic and proteomic research will discriminate more accurately than is possible at present between patients with a good prognosis and those who carry a high risk of recurrence. Rational treatments, targeted to the specific molecular pathways of an individual’s high-risk tumor, are at the core of tailored therapy. The aim of targeted oncology is to select the right patient for the right drug at precisely the right point in their cancer journey. Optical proteomics uses advanced optical imaging technologies to quantify the activity states of and associations between signaling proteins by measuring energy transfer between fluorophores attached to specific proteins. Forster resonance energy transfer (FRET) and fluorescence lifetime imaging microscopy (FLIM) assays are suitable for use in cell line models of cancer, fresh human tissues and formalin-fixed paraffin-embedded tissue (FFPE). In animal models, dynamic deep tissue FLIM/FRET imaging of cancer cells in vivo is now also feasible. Analysis of protein expression and post-translational modifications such as phosphorylation and ubiquitination can be performed in cell lines and are remarkably efficiently in cancer tissue samples using tissue microarrays (TMAs). FRET assays can be performed to quantify protein-protein interactions within FFPE tissue, far beyond the spatial resolution conventionally associated with light or confocal laser microscopy. Multivariate optical parameters can be correlated with disease relapse for individual patients. FRET-FLIM assays allow rapid screening of target modifiers using high content drug screens. Specific protein-protein interactions conferring a poor prognosis identified by high content tissue screening will be perturbed with targeted therapeutics. Future targeted drugs will be identified using high content/throughput drug screens that are based on multivariate proteomic assays. Response to therapy at a molecular level can be monitored using these assays while the patient receives treatment: utilizing re-biopsy tumor tissue samples in the neoadjuvant setting or by examining surrogate tissues. These technologies will prove to be both prognostic of risk for individuals when applied to tumor tissue at first diagnosis and predictive of response to specifically selected targeted anticancer drugs. Advanced optical assays have great potential to be translated into real-life benefit for cancer patients.

Prognosis of synchronous bilateral breast cancer.

Abstract: Background: The prognosis of patients with synchronous bilateral breast cancer (SBBC) is usually based on the tumour with the worst pathological features. There is little evidence in the literature for this assumption, potentially impairing reasoned decisions on optimal adjuvant therapy. Methods: This was a case–control study in which 68 women with SBBC were matched with 128 women with unilateral breast cancer. Both the GuysRisk prognostic model and the Nottingham Prognostic Index were used to determine the bilateral tumour with the poorer prognosis. Controls were matched for age, menopausal status, date of diagnosis, histological type and grade, and oestrogen receptor and axillary node status. Results: Both prognostic models indicated the same side tumour with the worst prognosis. Kaplan–Meier survival curves for both disease-free and overall survival showed no significant difference in outcome between the two groups. Conclusion: Prognosis was determined by the tumour with the worst prognosis, with no additional worsening of outcome incurred from the second tumour. Copyright © 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Microtubule Associated Protein Tau Expression as a Predictive and Prognostic Marker in a Trial Assessing Sequential Docetaxel as Adjuvant Chemotherapy for Early Breast Cancer (TACT).

Abstract: Objective: TACT, which compared sequential anthracycline-taxane (FEC-D) adjuvant chemotherapy with an anthracycline regimen of similar duration (Lancet 2009:373, 1681-1692) provides an opportunity to correlate tau expression levels with disease-free survival (DFS) and to explore the interaction between tau expression and docetaxel benefit. Patients and Methods: 4162 patients were randomized to FE 60 C (fluorouracil, epirubicin and cyclophosphamide,- 4 cycles) followed by docetaxel (4 cycles) or control. Control, determined by local centres, was FE 60 C (8 cycles) or epirubicin (4 cycles) followed by classical CMF (cyclophosphamide, methotrexate and fluorouracil - 4 cycles). Patients with hormone receptor positive tumours also received adjuvant endocrine treatment. Tissue blocks were obtained for 3610 TACT patients (87 % of total) to create tissue microarrays (TMA). Tau protein expression was assessed by immunohistochemistry (IHC). Tau was successfully scored by 2 observers (blinded to treatment allocation and clinical outcome), scoring 2 cores from separate TMAs for each of 2977 patients. Intensity (negative, weak, moderate or strong) and the proportion of tumour cells stained (in 5% increments) were recorded. Results: A very strong association was observed between level of intensity and proportion of staining (p Conclusion: Tau expression was associated with improved DFS but there was no evidence of an interaction between tau and docetaxel benefit. These results are similar to NSABP-B28, which evaluated addition of paclitaxel to doxorubicin/cyclophosphamide. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 607.