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Dec 1, 2011

Sequencing Used to Identify Patients for Cancer Clinical Trials

  • Scientists have demonstrated the feasibility of using genomic and transciptional data resulting from integrative sequencing of tumors in a clinical setting as a means to match patients to drug trials. A Michigan Center for Translational Pathology team carried out a pilot study to explore the practical challenges associated with applying high-throughput sequencing in clinical oncology. They presented data from integrated DNA and transcriptome sequencing of patients’ tumors to a board of multidisciplinary experts for review. The review process by a panel of experts led to identification of potential mutations that could help identify which clinical trials would be most suitable. Arul M. Chinnaiyan, M.D., and colleagues reported their findings in Science Translational Medicine, in a paper titled “Personalized Oncology Through Integrative High-Throughput Sequencing: A Pilot Study.”

    The mutational landscape of an individual’s cancer can provide information to aid clinical decision making, such as the selection of targeted therapies, but translating high-throughput sequencing into a routine clinical setting to enable personalized management presents a number of logistic challenges, the researchers note. These include the initial identification of patients who would benefit, developing an informed consent process, carrying out cost-effective sequencing, implementing integrated computational pipelines for data analysis and deciding which results the patient should be told.

    To see whether these challenges could be met, the team set in motion an exploratory study, which they called the Michigan Oncology Sequencing Project (MI-ONCOSEQ). The study involved patients who were considering taking part in clinical trials, and for whom integrative sequencing would potentially be relevant clinically. The aim was to generate validated CLIA results within four weeks from biopsy, which is the standard length of washout period for patients enrolling in a new clinical trial.

    A sequencing tumor board (STB) was also established to review clinical and genetic data. Rather than a more traditional tumor board that focuses on a single tissue of origin and uses a molecular classification of cancer, the STB incorporated expertise in clinical oncology, pathology, cancer biology, bioethics, bioinformatics, and clinical genetics, researchers note.  

    The sequencing strategy involved whole genome sequencing, targeted whole-exome sequencing and transcriptome sequencing (RNA-seq), and included shallow (5× to 15×) paired-end whole-genome sequencing of the tumor, targeted exome sequencing of the tumor and matched germline samples (blood or buccal smear), and paired-end transcriptome sequencing of the tumor. For the first four patients participating in MI-ONCOSEQ, the estimated cost of reagents was $5,400 per patient.

    The process was evaluated initially on tumor xenografts from two living patients with metastatic prostate cancer that had been grown in mice, and a mock STB established to evaluate the sequencing results. Two patients were then enrolled in the MI-ONCOSEQ pilot study proper: The first was a male patient with metastatic colorectal cancer, who had taken part in a Phase I study evaluating the Aurora kinase B inhibitor TAK-901 (NCT00935844), but whose cancer had progressed after four cycles and was taken off the study. The second patient was a female with metastatic melanoma. For both patients integrative sequencing and analyses were completed and the findings presented to the STB within 24 days of biopsy.

    The authors report a complete set of results in their published paper, but note that sequencing data from the metastatic prostate cancer patient included identification of mutation and amplification of Aurka as a possible mechanism for his tumor progression while on an Aurora kinase inhibitor. Additional clinically relevant findings included the presence of NRAS and CDK8 alterations, which the STB suggested might, in future, be matched to clinical trials with MEK, PI3K, or CDK inhibitors.

    Results from sequencing of the metastatic melanoma patient’s tumor found no mutaitonis in the prevalent melanoma oncogenes BRAF, CKIT or NRAS, but among the potentially clinically relevant findings, an activating mutation in HRAS was nominated as a potential target for clinical trials with inhibitors of MEK, PI3K, and mTOR. “The HRAS activating mutation was surprising, because HRAS mutations have not been described in malignant melanoma, whereas NRAS mutations are common (15%),” the authors note.

    They suggest that while MI-ONCOSEQ used a combination of DNA and RNA sequencing to provide a broad view of genetic aberrations in cancer, they anticipate that adding global epigenetic and small RNA analyses, combined with bioinformatics algorithms, will provide additional information and allow cross-validation. “Integrative high-throughput sequencing of patients with advanced cancer generates a comprehensive, individual mutational landscape to facilitate biomarker-driven clinical trials in oncology,” they conclude. Moreover, the team adds, such an approach will facilitate the discovery of new genetic changes, such as the Aurka alteration in the prostate cancer patient, and can serve as a source of correlative data for trials with molecularly targeted therapies.

     


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