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Comprehensive genome sequencing should be considered for advanced cancers to identify actionable gene mutations
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PARIS — Patients with advanced/refractory cancers who are candidates for clinical trials could benefit from efforts to identify eligibility for targeted drugs based on the clinically relevant genes in their specific tumor, according to a presenter at the WIN 2013 Symposium.
Prior studies have established that, for many patients with advanced cancer, the standard of care is ineffective or no standard therapy exists. These patients often choose to enroll in clinical trials, yet there are no standard means to assess which therapy likely will work best.
To better assess these patients, researchers from the Michigan Oncology Sequencing Center (MI-ONCOSEQ) launched an initiative to identify patients with advanced or refractory cancers who are eligible for clinical trials, then obtain biospecimens and perform integrative sequencing and analysis of their tumors.
Arul M. Chinnaiyan
“Targeted sequencing assays can often miss new drivers. I think one of the early goals of these approaches will be to molecularly enrich Phase 1 and 2 clinical trials of targeted therapies,” Arul M. Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology at the University of Michigan Medical School, said during a presentation. “Also, we will be able to characterize mechanisms of resistance because we have permission to not only biopsy before they go on to a targeted therapy clinical trial, but also once they potentially progress on that clinical trial.”
Chinnaiyan described cases in which comprehensive sequencing through MI-ONCOSEQ yielded unique and shared genetic aberrations.
One case involved a woman aged 44 years. A liver biopsy following post-operative radiation for anaplastic meningeal malignant solitary fibrous tumor/hemangiopericytoma revealed the NAB2-STAT6 gene fusion.
In collaboration with researchers from Memorial Sloan-Kettering Cancer Center, the researchers discovered that an entire cohort of patients with of solitary fibrous tumor (n=52) exhibited recurrent NAB2-STAT6 fusions.
Wu and colleagues reported a second case in Cancer Discovery. After performing a prospective clinical sequencing program for advanced cancers, MI-ONCOSEQ researchers identified four index cases that harbored gene rearrangements of FGFR2, including patients with cholangiocarcinoma, breast cancer and prostate cancer. Extending their assessment of FGFR rearrangements across multiple tumor cohorts, researchers were able to identify additional FGFR fusions with intact kinase domains in squamous cell carcinoma of the lung, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell carcinoma.
Although genetic sequencing of tumors from such patients could inform choices regarding clinical trials or targeted therapy, Chinnaiyan cautioned that several questions still must be addressed.
They include:
- What type of molecular aberrations should be monitored? Should genomic sequencing identify only point mutations, or should they include gene rearrangement and fusions, amplifications and deletions?
- What type of sequencing should be employed?
- How do researchers handle broad sequencing in the context of regulatory approval?
- How should future clinical trials be designed?
“In addition, how will we begin to match the combinations of mutations and pathways in an individual patient with potentially a combination of targeted therapies, similar to the successes that have been achieved in the context of HIV/AIDS in which a combination of drugs works so effectively?” Chinnaiyan said. “The problem, of course, with cancer is that we have a number of different diseases, and attempting to actually implement a rational combination therapy on an individual patient and running that in the context of a clinical trial can be a major challenge.”
For more information:
Chinnaiyan A.M #L1.01. Presented at: WIN 2103 Symposium; July 10-12, 2013; Paris, France.
Disclosure: Chinnaiyan served as a scientific advisory board member to Paradigm, Life Technologies and Molecular MD. He also reported a consulting relationship with Hologic.