Tumor Sequencing Test Brings Personalized Treatment Options to More Patients

By Eva Kiesler,

Thursday, June 12, 2014

Pictured: Michael Berger
Summary

A powerful diagnostic test, MSK-IMPACT™ gives our doctors an unparalleled amount of information about individual people’s cancers to guide their treatment.

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 developed MSK-IMPACT in the Department of Pathology. Marc Ladanyi, Chief of the Molecular Diagnostics Service, led the clinical validation of the test together with molecular pathologist Marcia Arcila, and bioinformatician Donovan Cheng.

The bulk of the tests will be done for patients with advanced disease, for whom results can help guide treatment choices. The assay will also be offered on a research basis in the newly launched Marie-Josée and Henry R. Kravis Center for Molecular Oncology.

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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.

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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.

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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.”

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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.

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Comments

I had a large metaplastic carcinoma of the breast, Stage IIa, that had completely surrounded a DCIS. Unfortunately, the entire breast eventually had to be removed (at the advice of the Mayo clinic, which reviewed my core biopsy slides) to obtain a clear diagnosis.

My first oncologist refused to do tumor genome testing, or testing for inherited tendencies, saying that the treatment she would use would be the same dose dense AC-T regimen, regardless, and, "insurance won't usually pay for it anyway".

The hospital where my surgery was done have the whole specimen. (I have heard the slides AND the excised tumor/organ are usually kept for many years; is this true?) The 2nd-opinion oncologist wants tumor genome testing, but the hospital has dragged its feet and committed errors, so that after 5 weeks, there is apparently no specimen available to him to do adequate genome testing. Since without the testing, he can't make better recommendations, I am with the original "no genome testing" MD for now.

So, I have these questions:

Your test/expertise sound better. If I can get to you, are you sure you can get the specimen that was removed about 50 days ago? Do you actually need a specimen from which you can make your own slides?
Secondly, if I have to pay for it out of pocket, what is the current usual charge?
Lastly, as I have had no choice (due to the risk in long delay of treatment), but to start the 8-week AC protocol, is it too late to start something different, based on MSK-IMPACT after it is finished--or even before it's finished?. (I have been told that once you start a protocol, it is important top finish, just as it is when you take antibiotics for a throat infection, due to the risk of creating cancer cell resistance without killing all of the cells.)

If so, I will aim for getting there right after it is completed, instead of moving ahead with the Taxol, unless your physician advises coming at a different time. What is the wait time for new patient to see a MSK provider? Thank You, Penny

Dear Penny, we’re very sorry to hear about your diagnosis. We recommend that you call our Patient Access Service at 800-525-2225. They will be able to answer your questions about arranging an appointment and having your tissue samples and/or pathology slides reviewed. You can go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.

I have neuroendocrine pancreatic cancer and am a patient at MSKCC. The Pancreatic Cancer Action Network Organization has a program called "Know Your Tumor". Is this similar to MSK Impact? They state that part of the program is a Proteomic analysis that analyzes the protein expression of the tumor cells. Is there any additional info obtained from this test as compared to MSK Impact?

Dear Chuck, we're not familiar with the details of the "Know Your Tumor" program, but your MSK medical oncologist probably knows more about it. We recommend that you discuss this with your healthcare team. Thank you for your comment, and best wishes to you.

Can you please send me more medical information by email please. Thanks!!!

Dear Joseph, to find out more about MSK-IMPACT, you may be interested in a few more recent blog posts about it. You can learn more here:

https://www.mskcc.org/blog/reaching-milestone-researchers-report-result…

https://www.mskcc.org/blog/powerful-tumor-dna-test-has-guided-cancer-tr…

https://www.mskcc.org/blog/computational-biologist-explains-how-patient…

Thank you for your comment.

Hello,
I am an Italian citizen. Just got diagnosed with intrahepatic cholangiocarcinoma, non resectable.
I am going to start chemo in a week.
I am interested in understanding what will be the benefits if I take the MSK-IMPACT test. Will I get better cure in terms of different chemo mix? Will I be able to substitute or complement chemo with immunotherapy? What concrete steps will follow the outcome of the tests?
Thanks a lot for giving us all more chances to make it.
Ciao ciao
Matteo

Dear Matteo, we're sorry to hear about your diagnosis. MSK-IMPACT is used to determine which mutations are driving patients' tumors, so that the patients can be matched with the best possible therapy for their particular cancer. Often, this may be a clinical trial of a new, experimental treatment. If you are interested in coming to MSK as a patient, you can contact our International Center at international@mskcc.org or go to https://www.mskcc.org/experience/become-patient/international-patients for more information. You may also want to ask your doctor in Italy if there is some kind of genomic testing that can be doing on your tumor there. Although MSK-IMPACT is Memorial Sloan Kettering's proprietary test, there are many other similar genomic tests that are available to patients through commercial labs or other research centers. Thank you for your comment, and best wishes to you.

Is there a way to find out a patient's TMB after MSK-IMPACT has been run? If so, what would be the best way for a patient to get this information?

Thank you!

Dear Christopher, if you already had MSK-IMPACT testing, we recommend that you contact your physician at MSK to discuss this. If you are not already an MSK patient and would like to find out about coming here, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment and best wishes to you.

Does the MSK Impact test report tumor mutation burden (TMB)?

Dear Marjorie, this is part of MSK-IMPACT testing. Thank you for your comment.

Is it possible to make an MSK-IMPACT test not being a patient of your clinic? And does every patient gets such a test during diagnostics/treatment?

Dear Sabrine, at this time MSK-IMPACT is generally only available to MSK's patients, with a few exceptions. This testing is offered to MSK patients with metastatic (stage 4) cancer. Thank you for your comment.

Hi my daughter was diagnosed with tcell lymphoma...chemo has been particularly hard on her. Could this test help direct the types of treatment she should be using?

Dear Abigail, we're very sorry to hear about your daughter's diagnosis. The MSK-IMPACT is used only for solid tumors, but there are other sequencing tests that can be done for blood cancers, both at MSK and at other centers. If you would like your daughter to have a consultation with MSK experts to learn more, you can call 800-525-2225 or go to to https://www.mskcc.org/experience/become-patient/appointment for more information. If she is not able to travel to New York, you can also discuss genetic sequencing of her cancer with her current medical team. Thank you for your comment, and best wishes to you and your family.

My father has a recurrent high grade dedifferentiated liposarcoma. We have done analysis for a target therapy, in details:
Whole exome squencing (WXS) of the DNA from the biopsy of the primary excissed tumor and from normal blood done at Scilifelab Clinical Genomics in Stockholm
DEPTH OF WXS:
200x for the tumor, and of 40x for the germline control
Then the trained physician, have done the analysis with Molecular Health Guide software from Molecular Health GmbH, Kurfürsten-Anlage 21, 69115 Heidelberg. This had shown that two mutations could be interesting for a target therapy.
• BRCA2.V959fs chr13:32911368
therapeutic option with PARP inhibitors, namely olaparib
• NF1.Q589* chr17:29550505
therapeutic option with MEK inhibitors, such as trametinib
PROBLEMS:
• BRCA2 frameshift mutation the number of reads in the tumor, is rather low (20)
• NF1 mutation the number of reads is sufficient (283), but the frequency in the tumor is rather low (3,18%)
Another company in Germany, Centogene, have done the validation of this mutations and found that they were NOT present.
So actually the analysis didn't give us any possible treatment option.
I actually have the output files of the whole exome sequencing and I was wondering if your analysis is more accurate than the one we have done and in case if you can do it from the fasta files of the sequencing.
Moreover my father tomorrow will have the second surgery so a new biopsy will be available. Since he underwent 5 cycles of chemiotherapy in between how likely is it that recurrent tumor will carry new mutations and in case is worthy to extract DNA and do the analysis on those new samples? Thanks

Dear Gianluca, we're sorry to hear about your father's diagnosis. Unfortunately, we are not able to make medical recommendations on our blog. This is something he should discuss with his healthcare team. If your father would like to arrange for consultation with an MSK expert, he can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment. If he is outside the US, which it sounds like he might be, he would need to go through our International Center. You can reach them at international@mskcc.org or go to https://www.mskcc.org/experience/become-patient/international-patients. Thank you for your comment and best wishes to you and your family.

Is there a place to see my wife's results online?

Dear Mike, you should discuss this with your wife's healthcare team. Thank you for your comment.

I have stage IV colon cancer that has spread to the liver and the lungs. The biopsy report is the kras cancer type. If you believe it would be worthwhile to investigate I would be happy to send all findings to date. Not really interested in chemo,to many side effects. I am still working full time. Oncologist says 6 months to live without chemo.

Congrats, on your latest FDA approval !!
Do you have any plans of offering your MSK-IMPACT in other clinical labs across US ? If so, please email me details.

Dear Krishna, thank you for your comment. At this time the MSK-IMPACT test is only performed in MSK labs.

I am currently a Stage IIIB Melanoma patient at MD Anderson. My tumor was tested for genetic mutations and I'm pretty sure it was only the "hotspot" testing that was performed. As such it was determined that I do not have any of the standard genetic mutations. I would very much like to know what genetic mutations I do have with the hope that it may provide some guidance to a better targeted therapy for me. Do you accept outside tumor samples for testing in this wide range gene testing?

Thank you.

Dear Ken, we're very sorry to hear about your diagnosis. We do not accept tumor tissue from outside MSK at this time. We recommend that you discuss your options for treatment with your doctors at MD Anderson. If you would like to speak with someone at MSK about arranging a consultation, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information. Thank you for your comment, and best wishes to you.

I have an ovarian cancer patient whose only tumor sample is from original diagnosis 6 years ago. Are you able to sequence from a sample this old? if so, how do we refer her for an appointment? Thx

Dear Dorry, according to Dr. Berger, the success rate for sequencing older tumors with MSK-IMPACT has been quite high, even for tumor samples as old as 10 years. If your patient would like to come to MSK for a consultation and to learn more, she can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment.

Would you accept orders for this test from other Hospitals?

Dear Paul, the MSK-IMPACT test is currently available only to MSK patients. If you are interested in making an appointment for a consultation with one of our doctors, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.

Whether the surgical resection of tumor is performed elsewhere, and the patient wants to continue the therapy at MSK :
Is it possible to run MSK-IMPACT on tumor samples from their paraffin blocks (pathology blocks) ?

Dear Pooya, it is possible to run MSK-IMPACT on paraffin-embedded specimens. If you would like to make an appointment for a consultation to learn more about becoming an MSK patient, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.

In regards to my first question & considering high rate of chromosomal changes in salivary gland tumours;

1. should we run a karyotyping of tumoural cells ahead of MSK-IMPACT or your test would be just enough to demonstrate such a changes ?

2. considering the possibility of mosaicism in a tumour would MSK-IMPACT be accurate enough to detect changes in smaller number of cells ?

Thank you for your answer

Dear Pooya, if you make an appointment at MSK, you can discuss what is needed to submit tumor samples. Thank you for your comment.

That I am not in NYC/USA may I know how long would it take to have the results after submission of paraffin blocks ?

Dear Pooya, MSK-IMPACT testing is available only to MSK patients, so the first step to getting your tumor sample tested is to become a patient. If you are outside the United States, you can contact our International Center at international@mskcc.org. You can go to https://www.mskcc.org/experience/become-patient/international-patients for more information. Thank you for your comment, and best wishes to you.

what's the time frame on the MSK-Impact test? My dad has his blood work done on Wednesday, just curious how long before the results are resulted?

Dear Amy, the results usually take a few weeks. Your dad's doctor can discuss this with you when he gets the tests. Thank you for your comment and best wishes to both of you.

I have stage iv metastic breast cancer (to bones). I was informed today on the need for a lung biopsy. If I have the biopsy where I live, can I still take advantage of the MSK-Impact testing? If so, what should I do? I understand a certain amount of tissue is needed to to the testing. The test is scheduled for 4/24.

Dear Joan, we're very sorry to hear about your diagnosis. At this time MSK-IMPACT testing is available only to people who are patients at MSK. However, many other hospitals are able to offer similar genomic testing, either through their own tests or by sending biopsies to commercial labs. We recommend that you discuss this with the doctor who is doing your biopsy next week.

Thank you for your comment and best wishes to you.

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