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Next-Generation Sequencing Identifies “Actionable” Genomic Alterations in Solid Tumors

November 2013, Vol 4, No 9

Boston, MA—Next-generation sequencing is a valuable tool to identify actionable genomic alterations that may be present in a tumor sample, said Gary A. Palmer, MD, JD, MBA, MPH, Senior Vice President of Medical Affairs and Commercial Development, Foundation Medicine, Cambridge, MA, at the Second Glob­al Biomarkers Consortium annual conference.

Next-generation sequencing techniques can overcome many of the shortcomings associated with conventional sequencing of clinical cancer samples, and routine use of next-generation sequencing in the clinic could potentially aid clinical trial enrollment and off-label drug treatment.

Matching the correct targeted therapy to the patient is diagnostically challenging as the number of clinically relevant genomic alterations (ie, base substitutions, mutations, short insertions and deletions, focal amplification, homozygous deletion, gene fusion) increases. Performing multiple tests may exhaust the biopsy material. “NGS [next-generation sequencing] can find all of these different types of alterations,” said Dr Palmer.

There are many potentially target­able alterations in any particular tumor type, “so I think that the days of panel testing, where you only test for 3 or 4 alterations in lung cancer and a different 3 or 4 in colon cancer, are probably rapidly coming to a close, because alterations tend to be shared across different solid tumors,” Dr Palmer said.

Many of the alterations are found in a small percentage of cancer cells, so a high degree of sensitivity is needed to find actionable alterations in a tumor sample. Sanger sequencing has a level of sensitivity of only approximately 20%, “so if you have a mutated allele that’s less than 20% of the tumor DNA, you’re not likely to find it with Sanger sequencing,” said Dr Palmer. In the first 107 cases of non–small-cell lung cancer for which next-generation sequencing was used at Foundation Medicine, 55% of biologic driver alterations were present in <20% of tumor DNA.

With next-generation sequencing, alterations can be found using small amounts of tissue in a clinically relevant time frame (approximately 2 weeks).

Foundation Medicine is looking at 236 genes. “You want a comprehensive list of genes you’ll be able to pick up in any particular solid tumor, those genes that have alterations that are clinically significant,” Dr Palmer said. “These alterations are not restricted to 1 tumor type.” HER2 alterations have been found in more than 15 types of solid tumors, for example.

The keys to making next-generation sequencing work routinely are the availability of tissue that has viable DNA and issuing relevant results to oncologists, “the biologic drivers of the particular tumor.” A high degree of specificity is also desirable.

Foundation Medicine’s report to the clinician includes the biologic drivers that are found and a table of “actionable” alterations. It also lists any US Food and Drug Administration (FDA)-approved drugs for the alteration that is found, as well as FDA-approved drugs for a different tumor type, potentially supporting the off-label use of a drug, and relevant clinical trials based on genomic alterations that are identified.

The initial experience with next-generation sequencing at Foundation Medicine consists of 2200 solid tumor cases in which gene alterations have been found.

The most frequently altered gene in cases in which alterations have been found is p53, which is present in approximately 50% of cases with alterations. Approximately 75% of specimens harbored ≥1 actionable gene. No 2 patients had the same findings, although many had similar alterations, Dr Palmer said. “That gives credence to this whole idea of personalized medicine.”

Table
Table: Distribution of 116 ErbB2 Alterations in 2200 Solid Tumors.
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Of the 2200 cases, 116 had ErbB2 alterations (Table). “We’re up to 18 solid tumors in which we found what we feel are biologically important ErbB2 alterations,” he said. The majority have been found in breast cancer, but a sizable number of ErbB2 alterations have been found in lung cancer as well. In the lung tumors, 17 have been activating point mutations, “the great majority postamplification,” Dr Palmer said. Whether anti-HER2 agents will work in solid tumors other than breast cancer will need to be determined, he added.

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