[show abstract][hide abstract] ABSTRACT: Developments in genomics, including next-generation sequencing technologies, are expected to enable a more personalized approach to clinical care, with improved risk stratification and treatment selection. In oncology, personalized medicine is particularly advanced and increasingly used to identify oncogenic variants in tumor tissue that predict responsiveness to specific drugs. Yet, the translational research needed to validate these technologies will be conducted in patients with late-stage cancer and is expected to produce results of variable clinical significance and incidentally identify genetic risks. To explore the experiential context in which much of personalized cancer care will be developed and evaluated, we conducted a qualitative interview study alongside a pilot feasibility study of targeted DNA sequencing of metastatic tumor biopsies in adult patients with advanced solid malignancies. We recruited 29/73 patients and 14/17 physicians; transcripts from semi-structured interviews were analyzed for thematic patterns using an interpretive descriptive approach. Patient hopes of benefit from research participation were enhanced by the promise of novel and targeted treatment but challenged by non-findings or by limited access to relevant trials. Family obligations informed a willingness to receive genetic information, which was perceived as burdensome given disease stage or as inconsequential given faced challenges. Physicians were optimistic about long-term potential but conservative about immediate benefits and mindful of elevated patient expectations; consent and counseling processes were expected to mitigate challenges from incidental findings. These findings suggest the need for information and decision tools to support physicians in communicating realistic prospects of benefit, and for cautious approaches to the generation of incidental genetic information.European Journal of Human Genetics advance online publication, 17 July 2013; doi:10.1038/ejhg.2013.158.
European journal of human genetics: EJHG 07/2013; · 3.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: The successes of targeted drugs with companion predictive biomarkers and the technological advances in gene sequencing have generated enthusiasm for evaluating personalized cancer medicine strategies using genomic profiling. We assessed the feasibility of incorporating real-time analysis of somatic mutations within exons of 19 genes into patient management. Blood, tumor biopsy and archived tumor samples were collected from 50 patients recruited from four cancer centers. Samples were analyzed using three technologies: targeted exon sequencing using Pacific Biosciences PacBio RS, multiplex somatic mutation genotyping using Sequenom MassARRAY and Sanger sequencing. An expert panel reviewed results prior to reporting to clinicians. A clinical laboratory verified actionable mutations. Fifty patients were recruited. Nineteen actionable mutations were identified in 16 (32%) patients. Across technologies, results were in agreement in 100% of biopsy specimens and 95% of archival specimens. Profiling results from paired archival/biopsy specimens were concordant in 30/34 (88%) patients. We demonstrated that the use of next generation sequencing for real-time genomic profiling in advanced cancer patients is feasible. Additionally, actionable mutations identified in this study were relatively stable between archival and biopsy samples, implying that cancer mutations that are good predictors of drug response may remain constant across clinical stages.
International Journal of Cancer 09/2012; · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Antiangiogenic strategies have demonstrated efficacy in epithelial ovarian cancer (EOC). Sorafenib is a novel multitargeted kinase inhibitor with antiangiogenic activity. Gemcitabine has known activity against EOC. A phase 1 clinical trial of this combination suggested activity in ovarian cancer with no dose-limiting toxicity. This phase 2 study was designed to examine the safety and efficacy of gemcitabine and sorafenib in patients with recurrent EOC.
Patients with recurrent EOC after platinum-based chemotherapy and who had subsequently received up to 3 prior chemotherapy regimens were eligible. Gemcitabine (1000 mg/m intravenous [IV]) was administered weekly for 7 of 8 weeks in the first cycle, then weekly for 3 weeks of each subsequent 4-week cycle. Sorafenib (400 mg p.o. bid) was given continuously. The primary end point for this trial was objective response rate by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included Gynecologic Cancer Intergroup (GCIG) CA-125 response, time to progression, overall survival, and toxicity.
Forty-three patients were enrolled, and 33 completed at least 1 cycle. Two patients had a partial response (Response Evaluation Criteria in Solid Tumors objective response rate = 4.7%). Ten patients (23.3%) maintained response or stable disease for at least 6 months. GCIG CA-125 response was 27.9%. The median time to progression was 5.4 months, and the median overall survival was 13.0 months. Hematologic toxicity was common but manageable. The most common nonhematologic adverse events were hand-foot syndrome, fatigue, hypokalemia, and diarrhea.
This trial of gemcitabine and sorafenib in recurrent EOC did not meet its primary efficacy end point, but the combination was associated with encouraging rates of prolonged stable disease and CA-125 response.
International Journal of Gynecological Cancer 07/2010; 20(5):787-93. · 1.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: Effective agents with a favorable toxicity profile are needed for women with advanced ovarian cancer. PEGylated liposomal doxorubicin (PLD) is safe and effective as monotherapy for advanced ovarian cancer. It was compared with topotecan in a large Phase III trial in this patient population and was found to be associated with less severe adverse events. In platinum-sensitive patients, PLD was associated with a statistically significant survival advantage over topotecan. PLD is currently under further investigation to expand its role in the treatment of ovarian cancer into combination regimens with carboplatin as first-line treatment, as maintenance therapy as a single-agent, and in combination with molecularly targeted agents in the salvage setting.
Expert Review of Obstetrics & Gynecology 12/2007; 3(1):21-31.
[show abstract][hide abstract] ABSTRACT: UCN-01 is a staurosporine analogue shown to abrogate the G2 checkpoint through inhibition of cyclin-dependent kinases. Preclinical evidence suggests synergy between UCN-01 and cytotoxic chemotherapy. Topotecan is an active agent in ovarian cancer. This phase II study was conducted to investigate the safety and efficacy of topotecan and UCN-01 in patients with advanced ovarian cancer.
A two-stage phase II trial was designed for patients with advanced ovarian cancer with progressive disease despite prior treatment with platinum and paclitaxel. Patients with advanced ovarian cancer were treated with topotecan, 1 mg/m(2) IV, days 1 to 5, and UCN-01 70 mg/m(2) on day 1 of the first cycle, and 35 mg/m(2) on day 1 of all subsequent cycles. Treatment was repeated on a 3-week cycle. The primary objective of this study was objective response rate while secondary objectives included rates of stable disease, duration of response, progression-free and overall survival, as well as toxicity. Tumor biopsy specimens were also collected where possible for molecular correlative studies.
Twenty-nine patients are evaluable for toxicity and efficacy. Three patients (10%) achieved a partial response. The median time to progression was 3.3 months (95% CI 1.5-NA), and the median overall survival was 9.7 months (95% CI: 7.5-15.3). The most common grade 3-4 toxicities were neutropenia (79%), anemia (41%), thrombocytopenia (14%), hyperglycemia (10%), and pain (10%).
The combination of UCN-01 and topotecan is generally well tolerated, however, this combination is not considered to have significant antitumor activity against advanced ovarian cancer.
[show abstract][hide abstract] ABSTRACT: Epidermal growth factor receptor (EGFR) is overexpressed by several solid tumors, including pancreatic cancer, and has become an important target for novel anticancer pharmacotherapy. Erlotinib (Tarceva, OSI-774) is an orally available small-molecule inhibitor of the EGFR tyrosine kinase. The addition of erlotinib to gemcitabine has been shown to prolong survival of patients treated for advanced pancreatic cancer in the National Cancer Institute of Canada PA.3 trial. This survival advantage is small yet noteworthy, in that numerous gemcitabine-containing combinations have failed to show a statistically significant survival advantage over gemcitabine alone. The most frequent toxicities associated with the addition of erlotinib are diarrhea and rash. Erlotinib-induced rash appears to be predictive of outcome. Further clinical studies of erlotinib in the treatment of pancreatic cancer are ongoing.