November 2013, Vol 2, No 7

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Next-Generation Sequencing Identifies Actionable Genomic Alterations in Solid Tumors


Next-generation sequencing (NGS) is a valuable tool to identify actionable genomic alterations that may be present in a tumor sample, said Gary A. Palmer, MD, JD, MPH, senior vice president of medical affairs at Foundation Medicine Inc, Cambridge, Massachusetts, at the second annual, Global Biomarkers Consortium conference.

NGS techniques can overcome many of the shortcomings associated with conventional sequencing of clinical cancer samples, and routine use of NGS 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/deletions, focal amplification, homozygous deletion, and gene fusion) increases. Performing multiple tests may exhaust the biopsy material. “NGS can find all of these different types of alterations,” Palmer said.

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,” he 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 about 20%, “so if you have a mutant allele that’s less than 20% of the tumor DNA, you’re not likely to find it with Sanger sequencing,” Palmer said. In the first 107 cases of non–small cell lung cancer for which NGS was used at Foundation Medicine, 55% of biologic driver alterations were present in <20% of tumor DNA.

With NGS, alterations can be found using small amounts of tissue (50 ng of DNA, the equivalent of 8-10 microscope slides of tissue) in a clinically relevant time frame (approximately 2 weeks).

The sample gene list that Foundation is looking at numbers 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,” he said. “These alterations are not restricted to 1 tumor type.” HER2 alterations have been found in over 15 solid tumors, for example.

Keys to making NGS work routinely are the availability of tissue that has viable DNA and issuing relevant results to oncologists – “the biologic drivers of the particular tumor.” Not all will be targetable at present but may become targetable with the discovery of new agents. 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 FDA-approved drugs for the alteration found as well as FDA-approved drugs for a different tumor type, potentially supporting off-label use of a drug, and relevant clinical trials based on genomic alterations identified.

The initial experience with NGS at Foundation Medicine consists of 2200 solid tumor cases in which gene alterations have been found. More than 80% had actionable findings, many with off-label drugs or drugs being tested in clinical trials. The mean number of reportable alterations was 3 to 4, with 1.6 actionable alterations per sample.

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

Of the 2200 cases, 116 had ERBB2 alterations. “We’re up to 18 solid tumors in which we found what we feel are biologically important ERBB2 alterations,” he said. The majority has been found in breast cancer, but a sizable number of ERBB2 alterations have been found in lung cancer as well. In the lung cancers, 17 have been activating point mutations, “the great majority post amplification,” he 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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Uncategorized - December 3, 2013

Bench to Bedside, Gene to Drug Discovery Defines New Era of Precision Medicine

The next decade in anticancer drug discovery promises to be a complicated era of attempts to further define and overcome tumor heterogeneity, cancer evolution, and drug resistance, said Paul Workman, PhD, DSc, at the second annual Global Biomarkers Consortium conference. Killing off multiple cancer cell populations early in the disease [ Read More ]