The “one size fits all” approach is not effective in the clinical management of cancer. The personalization of therapy for cancer requires molecular characterization of unique and shared genetic aberrations. For many patients with advanced cancer, either the standard of care is ineffective or no standard of care therapy exists. In such cases, patients often pursue clinical trials. Trials involving novel targeted therapies make up the majority of new approaches in oncology. While such trials are numerous, there are no standard means to comprehensively assess an individual’s tumor for genetic mutations and the likelihood of response to one particular therapy over another. Sequencing of tumors from such patients could offer clinicians and patients the opportunity to make decisions regarding clinical trials or targeted therapy based on the molecular characteristics of their cancer. The advantage of tumor sequencing, as opposed to directed gene evaluation, is the opportunity to characterize novel gene targets for patients with disease that do not have known or viable targets.
Growing technological advances in genomic sequencing has now made it possible to consider the use of sequence data in a clinical setting. For instance, comprehensive high-throughput sequencing may identify biomarkers for predictive or prognostic purposes and thereby inform treatment choices and prevention strategies. Thus, the translation of high throughput next generation sequencing would support a “personalized” strategy for cancer. The goal of our study is to comprehensively profile the genetic aberrations in an individual’s cancer tissue and identify “actionable” mutations in a subset of cancer patients through this effort and, importantly, develop systematic approaches to translate high-throughput sequencing technologies to the clinic.
Patient Recruitment and Clinical Sequencing
Patients with metastatic or refractory cancer, for whom standard therapies are not effective (per best clinical practices), will be identified and receive informed consent to undergo biopsy of their tumor and comprehensive genomic profiling of somatic and germline DNA. Due to the nature of genomic sequencing, there are unique features that must be adequately explained during the informed consent process. Therefore, patients will receive genetic counseling as part of informed consent, including discussion of possible return of results and privacy risk due to data sharing. Additionally, patients will be given the option to decline “incidental” results through specialized “flexible-default” consent.
We will use an “integrative sequencing approach” that will provide a comprehensive landscape of actionable and informative mutations in a tumor. This approach will enable the detection of molecular lesions such as point mutations, insertions/deletions, gene fusions and rearrangements, outlier expressed genes, and amplifications/deletions. Furthermore, we will identify certain germline alterations that may also be relevant. The study will gather and analyze sequencing data for the purpose of nominating candidate alterations using a number of computational pipelines that we have developed in house or have adapted from the public domain.
Interpretation and Return of Sequencing Results
The overall sequencing analysis will be presented in our “Precision Medicine Tumor Board” (PMTB) meetings. The multi-disciplinary PMTB, composed of members with expertise in clinical oncology, clinical pathology, cancer genetics, genome biology, bioinformatics, medical genetics and counseling and bioethics will provide oversight for the study and will be responsible for determining what results should be offered to patients. The Board will deliberate on whether results have clinical significance for patients using the flexible-default model for genomic results related to “cancer of interest” as well as “conditions other than cancer of interest.” The treating physicians of patients to be discussed at the PMTB will be informed of the meeting and encouraged to attend. Treating physicians will have access to actionable, tumor genomic results to guide therapeutic choices and clinical trial eligibility through a comprehensive molecular report. Treatment decisions will be made by the patient and their board-certified medical oncologist.
Physicians, please direct inquiries to our study coordinators at: email@example.com.