In the Clinic

On Cancer: New Tumor Sequencing Test Will Bring Personalized Treatment Options to More Patients

By Eva Kiesler, PhD, Science Writer/Editor  |  Thursday, June 12, 2014
Pictured: Michael Berger Genomics researcher Michael Berger

A new genome-sequencing test developed at Memorial Sloan Kettering allows our doctors to quickly find out whether a patient’s tumor carries clinically useful mutations — including aberrations that make cancers vulnerable to particular drugs — and to match individual patients with available therapies or clinical trials that will most benefit them.

Until now, genomic testing of tumors has been done routinely only in certain cancers. For most cancers, the available tests have been limited to analyzing one or a handful of genes at a time, and within each gene, only the most common mutations could be detected.

The new test, called MSK-IMPACT™, makes the analysis far more comprehensive and can be used on any type of solid tumor, irrespective of where in the body the cancer is thought to have arisen. (A similar genomic test for blood cancers was recently co-developed by Memorial Sloan Kettering scientists and Foundation Medicine, a biotech company.)

“It’s an incredibly powerful test,” Memorial Sloan Kettering’s Department of Pathology Chair David S. Klimstra says of the MSK-IMPACT technology. He expects it will enable our physicians to rapidly extend the promise of precision medicine to many patients with difficult-to-treat cancers, including both common and rare tumor types.

Intensified Tumor Testing

“We are able to look at hundreds of genes in multiple patients simultaneously and collect an enormous amount of information about each of these genes,” adds genomics researcher Michael Berger, who led the development of MSK-IMPACT together with molecular pathologists Marc Ladanyi and Maria E. Arcila and bioinformatician Donavan Cheng of the Molecular Diagnostics Service in the Department of Pathology.  The assay will also be offered on a research basis in the newly launched Marie-Josée and Henry R. Kravis Center for Molecular Oncology.

Dr. Klimstra anticipates the new method will enable Memorial Sloan Kettering physicians to perform molecular pathology testing on tumors from up to 10,000 patients by the end of 2014. The bulk of tests will be done for patients with advanced disease, for whom results can help guide treatment choices.

Effective Sequencing

The MSK-IMPACT test is based on next-generation sequencing — cutting-edge technology that allows cancer genomes to be profiled very quickly and with great sensitivity. Next-generation sequencing makes it possible to analyze more types of genetic abnormalities than conventional DNA sequencing technologies. “For example, we can tell if a gene has been mutated or deleted, or if there are additional copies of it,” Dr. Berger says.

Until recently, this technology had mainly been used in the context of research studies, in which tumor samples of the highest quality are chosen. “The samples we deal with in the clinic are different and much more difficult to analyze,” Dr. Berger explains. “They may contain a mix of various tumor cells and noncancerous cells, and the cells’ DNA might be degraded.”

In developing MSK-IMPACT, Dr. Berger and his co-workers, with support from the Farmer Family Foundation, meticulously enhanced the next-generation sequencing protocols and computational methods for the clinical diagnostic laboratory setting, where many tissue samples need to be processed and analyzed simultaneously.

Actionable Targets

Rather than sequencing a tumor’s whole genome, or the entire part of the genome that codes for proteins, MSK-IMPACT analyzes 341 of the most important cancer genes, which are captured and sequenced on an instrument called Illumina HiSeqTM. This targeted sequencing approach makes the analysis of tumor tissue more feasible and effective and increases the chance of finding clinically relevant gene changes. 

“All important regions of these 341 genes are sequenced, rather than the more focused analysis of only the most frequently altered regions, or mutational ‘hot spots,’ allowed by earlier technology,” explains Dr. Klimstra. “This gives us a much more comprehensive picture of the full spectrum of genetic changes in a person’s cancer.”

The 341 genes covered by the test are ones that have been shown to play a role in the development or behavior of tumors. They represent all “actionable targets” — genes that can either be targeted with drugs or provide clinically relevant information about the disease if they are altered. Dr. Berger says the test will be updated periodically as new actionable targets are discovered.

A Wealth of Information

So what can the MSK-IMPACT test tell doctors about their patients’ diseases? A lot, according to Dr. Klimstra. “In fact,” he says, “the test will likely generate more molecular information about tumors than we will know what to do with initially.”

The 341 genes were selected by drawing connections between the genomic profiles and clinical data of past patients. For example, changes in some of the genes have been shown to indicate that a tumor is more likely to respond to a particular drug, while other gene changes may predict that a certain therapy will be of little or no benefit.

“The interaction of different altered genes can also be important in predicting the behavior of the tumor,” Dr. Klimstra says, “which is another reason why we needed a test to evaluate many genes simultaneously.”

In some cases, finding a specific mutation in a tumor can lead to a new clinical trial in which a patient is offered an experimental drug that may be the best treatment option for his or her disease, but that would not have been considered if the mutation had not been found. Other times doctors may spare a patient intensive treatment with standard drugs such as chemotherapy, if test results show that the therapy is likely not to be beneficial.

But Dr. Klimstra emphasizes that many gene changes detected by the test will not be immediately actionable. “If a mutation has rarely been observed in a disease and has not been studied, we may suspect it’s important, but we don’t know what would happen if we were to target it,” he says. “That’s why an important aspect of MSK-IMPACT is to gather data for research to help future patients.”  

Basket Trials

Patients with an actionable mutation that has not yet been studied in their tumor type may be eligible for treatment in a new type of clinical study called a basket trial. Traditional clinical trials focus on a particular cancer type, which is typically defined based on where in the body the cancer originated. Basket trials, however, focus on specific gene changes and may enroll patients with many different types of cancer whose tumors carry similar mutations.

Memorial Sloan Kettering investigators are currently undertaking an intensive research effort to learn what kinds of mutations different tumors have, and how these mutations impact patients’ responses to various kinds of treatment. Dr. Berger and his colleagues are working to develop genomic tests for research on banked tumor samples, as well as other clinical tests to detect mutations MSK-IMPACT might miss.

Comments

any target yet for stage 4 adenocarcinoma nclc KRAS 12D non wild; nothing has helped so no treatment for three years now....I will be in Manhattan month of July staying on E 66 St and First Ave; should I make an appointment?

Carole, we are looking into this and hope to provide a response to you before long. Thank you for your comment.

Carole, we consulted with our physician who suggest that you call the Physician Referral Service for this cancer type at 646-497-9163 to speak with them about this information and determine if a visit is in order. Thanks for your comment.

alimpta and carbo did nothing

I mant to type nsclc stage 4

Are these tests any different to the tests offered by Caris Molecular Intelligence in the USA? Any chance that biopsy samples can be sent from the UK for testing?

Steve, we consulted with Dr. Berger, who responds:

"Caris is a diagnostic company that runs tests to molecularly characterize tumors from patients. I believe they provide a number of services. They have a panel to identify mutations in important cancer genes using next-generation DNA sequencing technology like MSK-IMPACT. MSK-IMPACT examines more genes and is capable of identifying additional types of mutations, but both tests include all genes where there are widely accepted guidelines for altering treatment based on the presence or absence of mutations. Caris also offers other tests that measure the abundance of particular proteins important for cancer diagnosis and treatment."

If you are interested in learning about having a biopsy sample examined, we suggest you contact our International Center at (1-212-639-4900) or go to http://www.mskcc.org/cancer-care/international-patients

How do I order the MSK-IMPACT test?

Dear AJRen, in order to take advantage of this type of molecular testing at Memorial Sloan Kettering you need to make an appointment with one of our specialists. To do so, please call our Physician Referral Service at 800-525-2225.

Thank you for your comment.

Excellent development in the management of malignancy .Can you send the information in the form of article so that I , as an editor , of " BIHAR AND JHARKHAND JOURNAL OF OTOLARYNGOLOGY ' can publish in the journal . Thanks . Dr.Chandra Shekhar , Editor .

Dr. Shekhar, we sent an email about this to the email address that you provided. Thank you for your comment.

Is it possible to have more information on this test? It does not seem to take tumor heterogeneity into account, i.e., you could take 10 biopsies from the same solid tumor and see different mutations in each. Deciding which 'clone' is then most clinically relevant is difficult.

Regards,
Kevin Blighe, Ph.D.
Europe

Hello Kevin, thanks for bringing up the important question about tumor heterogeneity. We forwarded your comment to Dr. Berger and here’s what he says:

“Tumor heterogeneity does indeed complicate both the sensitivity of the test and the interpretation of the results. Knowing that important mutations may only be present in a fraction of tumor cells in a given biopsy, we have designed our test to be as sensitive as possible. We sequence each tumor to very 'deep' coverage, meaning that each gene is captured and sequenced several hundred times. This allows us to confidently detect mutations that are present in as few as 5-10% of cells.

"However, some mutations may not be present at all in one biopsy but present at high levels in a different biopsy. Rather than subjecting patients to multiple biopsies, we are exploring the potential of less invasive technologies involving tumor cells and DNA found in blood to see if they may more accurately represent the heterogeneity of a patient's cancer.”

Also, you can read more about tumor heterogeneity in a recent post on this blog: http://www.mskcc.org/blog/what-tumor-heterogeneity

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