Gina Chan

An Integrated Genomic-Based Approach to Individualized Treatment of Patients With Advanced-Stage Ovarian Cancer

PURPOSE The purpose of this study was to develop an integrated genomic-based approach to personalized treatment of patients with advanced-stage ovarian cancer. We have used gene expression profiles to identify patients likely to be resistant to primary platinum-based chemotherapy and also to identify alternate targeted therapeutic options for patients with de novo platinum-resistant disease. PATIENTS AND METHODS A gene expression model that predicts response to platinum-based therapy was developed using a training set of 83 advanced-stage serous ovarian cancers and tested on a 36-sample external validation set. In parallel, expression signatures that define the status of oncogenic signaling pathways were evaluated in 119 primary ovarian cancers and 12 ovarian cancer cell lines. In an effort to increase chemotherapy sensitivity, pathways shown to be activated in platinum-resistant cancers were subject to targeted therapy in ovarian cancer cell lines. RESULTS Gene expression profiles identified patients with ovarian cancer likely to be resistant to primary platinum-based chemotherapy with greater than 80% accuracy. In patients with platinum-resistant disease, we identified expression signatures consistent with activation of Src and Rb/E2F pathways, components of which were successfully targeted to increase response in ovarian cancer cell lines. CONCLUSION We have defined a strategy for treatment of patients with advanced-stage ovarian cancer that uses therapeutic stratification based on predictions of response to chemotherapy, coupled with prediction of oncogenic pathway deregulation, as a method to direct the use of targeted agents.

MicroRNAs and their target messenger RNAs associated with ovarian cancer response to chemotherapy

OBJECTIVE Few successful therapeutic options exist for patients with recurrent ovarian cancer (OVCA). This is due in part to an incomplete understanding of the molecular determinants of chemotherapy-response. Recently, it has been shown that microRNAs (miRNAs) influence messenger-RNA (mRNA) post-transcriptional control and can contribute to human carcinogenesis. The objective of the current study was to explore the role of miRNAs, and their predicted mRNA targets, in OVCA in-vitro response to chemotherapy. METHODS The expression of 335 unique miRNAs was measured in 16 OVCA cell lines. In parallel, the sensitivity of these cell lines to 6 commonly used chemotherapeutic agents (cisplatin, doxorubicin, topotecan, paclitaxel, docetaxel, and gemcitabine) was evaluated by in-vitro cell proliferation assay. MiRNAs associated with cell line drug response were identified by linear regression analysis, and their predicted mRNA targets subject to functional biologic pathway analyses. RESULTS Twenty-seven miRNAs were found to be associated with response to the one or more of the 6 salvage chemotherapies tested (p<0.05). Predicted targets of these miRNAs included 52 mRNAs, previously reported to be associated with chemo-responsiveness, and which are also involved in functional biologic pathways that influence cancer cell cytotoxicity, carcinogenesis, cell mitosis, p53 signaling, and tumor cell growth and invasion. CONCLUSION We have identified miRNAs and their predicted target mRNAs associated with ovarian cancer cell response to chemotherapeutic agents. Our strategy of integrating miRNA and mRNA data may aid in the characterization of important molecular pathways associated with OVCA chemo-response.

Retraction: Genomic signatures to guide the use of chemotherapeutics

The authors wish to retract this article because they have been unable to reproduce certain crucial experiments showing validation of signatures for predicting response to chemotherapies, including docetaxel and topotecan.

Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12 (1294-1300))

The authors wish to retract this article because they have been unable to reproduce certain crucial experiments showing validation of signatures for predicting response to chemotherapies, including docetaxel and topotecan.

Corrigendum: Genomic signatures to guide the use of chemotherapeutics

Nat. Med. 12, 1294–1300 (2006); published online 22 October 2006; corrected after print 10 May and 10 October 2007 In the supplementary information initally published online to accompany this article, and in the revised supplementary information posted online on 10 May, the gene lists that make up the chemotherapy sensitivity signatures in Supplementary Table 1 contained errors.

Patient reported outcomes (PROs) in patients with human papilloma virus (HPV) positive versus negative head and neck cancer (HNC).

87 Background: HNC caused by HPV has become an epidemic. Treatment for HNC results in a tremendous symptom burden. The impact of HPV-status on quality of life (QOL) and how this effects illness perception and mood has not been described. We sought to explore differences in PROs in patients with HPV + vs. - HNC. METHODS This is a secondary analysis of data from a prospective, longitudinal intervention study of 60 patients with newly diagnosed HNC undergoing concurrent chemoradiation. 30 control patients received standard care followed by 30 intervention patients who received an educational intervention. Satisfaction (information satisfaction questionnaire (ISQ)), mood (Hospital Anxiety and Depression Scale (HADS)), illness perception (Brief Illness Perception Questionnaire (IPQ)), and QOL (MD Anderson Symptom Inventory- Head and Neck (MDASI-HN)) were evaluated at baseline and 3 weeks. Data were analyzed using linear regression models controlling for the effect of the intervention to assess the association between HPV status and changes in PROs. RESULTS From 8/2014 to 10/2015, we enrolled 60 patients (2 excluded for hospitalization or care elsewhere). 29/58 (50%) had HPV + HNC. 40 (69%) were men. 54 (93%) had stage III/IV disease. Compared to patients with HPV - HNC, patients with HPV + HNC reported an increase in symptom burden, symptom interference, and depressive symptoms, as well as a more threatening illness perception from baseline to 3 weeks. There were no differences in anxiety or satisfaction. Table 1 details the regression models. CONCLUSIONS Patients with HPV + HNC have a larger decrement in QOL during treatment than patients with HPV - HNC, which corresponds to a more threatening illness perception and more depressive symptoms. Interventions tailored to symptom management and mood should be developed for this unique population. [Table: see text].

Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature (2006) 12, (1294-1300))

Nat. Med. 12, 1294–1300 (2006); published online 22 October 2006; corrected after print 10 May and 10 October 2007 In the supplementary information initally published online to accompany this article, and in the revised supplementary information posted online on 10 May, the gene lists that make up the chemotherapy sensitivity signatures in Supplementary Table 1 contained errors.