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

My husband recently had is parotid gland removed due to acinic cell carcinoma, which has since metastasized to the lungs. Next week we will undergo a second biopsy for purposes of dna sequencing through Univeristy of Michigan MI-ONCOSEQ. Is the sequencing data tied into a common repository with MSK-IMPACT? If not, how do we join forces and make use of the biopsy tissue in both catalogues? Thanks for any info.

Laura, we sent your questions to Dr. Berger, who replied, "Because clinical sequencing for precision medicine is so new, there are not yet common repositories or even common standards for sharing patients' clinical sequencing data across institutions. At this point, MI-ONCOSEQ data and MSK-IMPACT data are maintained in separate databases. However, we are working closely with colleagues at other institutions to establish mechanisms for sharing data and results, and we are participating in large-scale international initiatives sponsored by research and philanthropic funds to do just this." Thank you for your comment.

Is this test used on melanoma patients? My husband has mets on his liver, spleen, lungs and brain. We live in NW PA and could make the trip if it would be helpful for him.

My son is a patient at MSKCC and we just got a copy of his MSK-IMPACT test results. Do you have any literature that will help us interpret/understand the results? Thanks so much for all you do!

Dear Tracie,

This link to the National Cancer Institute has some helpful, but basic, information about the genetics of cells might be included in a pathology report:
http://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/patholog…

And here's some information on understanding lab tests (again, not exactly what Impact tests for, but some of the language may be useful):
http://www.cancer.gov/about-cancer/diagnosis-staging/understanding-lab-…

Hopefully this is somewhat useful, but it's best to ask his doctor to interpret the specific results as they pertain to his circumstances and explain their implications.

Thank you for reaching out to us.

Sirs,
I am interested to learn whether you provide germline information off of the blood results genetic studies at this time.

Bonnie Liebers MS LCGC
Director of Clinical and Client Services and Remote Consultation

Thank you for your question. This is an emerging area of work and the kinds of detailed genetic analyses you mention are offered only to a very limited number of patients at this time.

My husband had a salvage radical prostatectomy at MSK 2/2014 (post-rad tx 1999). His PSa returned later in 2014. He is under medical treatment now for that. Would the MSK-iMPACT test be able to be performed using his prostatectomy specimen(s), now held by MSK? (PCa was found in the prostate & seminal vesicles but not in lymph nodes removed.)
Thank you.

Dear Gabrielle, we're sorry to hear about your husband's diagnosis. Please follow up with his oncologist to discuss whether MSK-IMPACT would be useful for him. Thanks for reaching out to us.

I am a patient at MSK and I had the MSK-IMPACT test. I was found with 4 mutations of ERBB2, H3F3A, PPP2R1A, and SMARCA4. I have a rare cancer of Extramammary Paget's Disease. I just completed a clinical trial with Neratinib to address the ERBB2 mutation. Are there any other clinical trials for the remaining three mutations? In addition, have those remaining mutations been clinically validated?

Jerome, this is something you should discuss with your MSK team. Thank you for your comment.

Are there plans to make the MSK-IMPACT test available for patients outside of the MSK system? Thank you.

Damon, thank you for reaching out. There are no current plans to offer MSK-IMPACT to non-MSK patients. However, a similar test is available from the commercial laboratory Foundation Medicine.

Hello,
My husband was diagnosed with esophageal cancer metastasized to distal lymph nodes. We have been seen by an oncologist who uses a lab to test if the chemo treatment is effective or not. Here is what they do: They use filters to trap cancer cells from which they extract DNA and do a gene profile. From that, they look for mutation ratios (normal/mutations). If the radio is high, then the chemotherapy meds are not working, if the ratio is low, then the chemotherapy medications work effectively. He also sends urine to a lab to look for mutations, a biomarker to evaluate what is happening. Lastly, he also sends blood to a lab to do a in-vitro chemo sensitivity to evaluate the pathway in which CA replicates. Based on that, they prioritize 10 meds to see which is helping. Based on this he decides which medication combination is good. Is this a valid way to look at the treatment options

Kristina, we sent your question to Yelena Janjigian, who is an expert in treating esophageal cancer. Dr. Janjigian explained that in general these kinds of research tests are interesting but not ready for prime time for routine clinical practice. She noted that there are several FDA approved regiments in the armamentarium of esophageal cancer treatment, and that these kinds of research test can't show definitively that a tumor is not going to respond to a particular treatment. We recommend that you discuss this further with your husband's healthcare team, since we are not able to comment on his particular case.

I have metastatic breast cancer and my oncologist has been using the "this drug has worked for others, maybe it will work for you" approach. Do you work with oncologists that are not part of the MSK clinic after performing this test to guide their choice of drugs?

Hi, Carol, we are sorry to hear about your diagnosis. The tumor sequencing test we use is currently only available for patients being treated by our physicians here at MSK. If you would like to make an appointment for a consultation with one of our specialists about your treatment options, please call our Physician Referral Service at 800-225-2225. Thank you for reaching out to us.

Hi! My husband had proton therapy in 2009 for his Stage 1T, Gleason 6 prostate cancer. We were told the cancer was low risk and that the rate of cure was about 97%.

Well, his PSA has been increasing slowly over the past 4 years. It still has not reach 2.0, however, which is good but the doctors at our facility are worried about bone metastases.

He has had an F18 bone PET scan and there were some areas of concern that have all been eliminated except for one on the eighth left rib and another on the right scapula.

To zero in on these two areas my husband must undergo a regular bone scan this Tuesday.

We know something is going on to increase his PSA and, if possible, we would like to get a head start in determining what that is.

I did a search online and found your site. Would MSK-IMPACT be useful for someone in my husband's situation?

We would travel to New York to consult with your physicians, if necessary.

Right now, our doctors are thinking that if the worst has happened and these two spots ARE bone mets, that they will spot treat them with targeted proton radiation in the hopes that some of the cells will break off and provide a sort of natural immune cell reaction (or vaccination). Of course, if they are bone mets he will also have to undergo hormone therapy, which he does NOT want, and probably chemo.

Would it be worth our while to investigate further with your group? It sounds like you are doing wonderful, worthwhile work.

Dear Kathy, we are sorry to hear about your husband's diagnosis. If you would like to make an appointment with one of our specialists for a consultation about your husband's condition and possible treatment options, please call our Physician Referral Service (Monday through Friday between 8:30 AM and 5:30 PM Eastern Time) at 800-225-2225. To learn more, please visit https://www.mskcc.org/experience/become-patient/appointment. Thank you for reaching out to us.

My husband has been diagnosed with Stage 4 small cell lung cancer. He is now being treated with topotecan. Would he benefit from this testing? Would it help your research?

Karen, if your husband is found to have a mutation that makes him eligible for a clinical trial, he may be able to benefit from this testing. If you'd like to make an appointment, 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.

I have the results from the impact study, is there any material we can read regarding the somatic alterations details and what they mean? Especially any which would be relevant to treatment alternatives?

Hi Bruce, the best option is for you to discuss your IMPACT results with your doctor. Thank you for your comment.

Hi!
There is a company in Europe utilizing patient blood samples and collecting circulating cancer cells from those samples. They further concentrate on a subset of circulating cancer stem cells. Of those they test conventional cancer drugs and other substances (e.g. vitamins, minerals, herbs and traditional remedies).

What are the differences concerning result applicability between MSK-IMPACT and RGCC test? Does MSK-IMPACT test a wider variety of the drugs in the development pipeline?

Pia, thank you for your question. MSK-IMPACT is a DNA sequencing test. It provides oncologists with genetic information about a patient’s tumor, which can be used to guide the selection of therapies or clinical trials. MSK-IMPACT itself does involve the isolation of cells or exposure to drugs and other compounds. Yet MSK-IMPACT results are often used as a basis for enrolling patients on clinical trials.

Does MSK- IMPACT testing include DNA repair genes, BRCA or ATM?
Is it a panel that is completed in a standard manner or are targets of interest in current clinical trials for the tumor in question done first?
How long does it take to obtain results, once tissue or slides are received by MSKCC?

RK, thank you for reaching out. Yes, MSK-IMPACT includes many DNA repair genes, including BRCA1, BRCA2, and ATM. Altogether we are currently sequencing 468 genes linked to cancer. All genes are sequenced at the same time. On average, we are able to issue reports within three weeks of when both tumor tissue and normal blood are received in the Molecular Diagnostics Service.

My husband had a Whipple porcedure a year ago followed by Gemzar chemotherapy with intolerable side effects, stopped after 4 cycles instead of 6.
Now the cancer is back in the bed of surgery.
The sample has been sent for genetic testing to Foundation one. Is it possible to schedule an appointment to a doctor in S-K to determine the best treatment possible?
Thank yo
Sofia

Dear Sofia, we are sorry to hear about your husband's diagnosis. If he would like to make an appointment with one of our specialists to discuss possible next steps in his care, please contact our Physician Referral Service at 800-525-2225. Thank you for reaching out to us.

As I am in the process of becoming an international patient at MSK in the new year (at least a second opinion to start with), I want to make sure that I can benefit from your IMPACT sequencing. I have a bad case of acral nodular melanoma that no clinical trials are targeting. I know that certain recognized genes will be key for my treatment and you are my last beacon of hope. Will you be able to sequence my tumour? Can you really help?

Dear Marc, we are sorry to hear about your diagnosis. Your MSK physician will be best equipped to answer the questions you have about the specifics of your case and determine whether this type of sequencing is appropriate for you. We wish you well as you make the necessary arrangements to come to MSK and begin treatment. Thank you for reaching out to us.

My thirteen year old son was diagnosed in March of this year with pleomorphic liposarcoma. He has lung mets because of the cancer. He was given doxorubicin and ifosfamide which helped with his lung mets but didn't totally get rid of them. The doctors recently tried Halaven, but it didn't stop the growth of the lung mets and new nodules appeared. Would this testing benefit my son?

Hi Holly, we are so very sorry to hear about your son's diagnosis. Molecular testing allows doctors to match patients with clinical trials of targeted therapies, so depending on what mutations exist in your son's cancer, it's possible that he may benefit from testing. If you'd like to make an appointment to learn more, 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 and your family.

How does the MSK impact blood test compare to guardant health's liquid biopsy blood test?

Dear Maureen, the Guardant Health test looks for cancer genes in the bloodstream. MSK-IMPACT is a comprehensive genetic sequencing that is done on solid tumor material after it has been biopsied or surgically removed. Thank you for your question.

Dear team at MSKCC - my 43 yr old wife has recently been diagnosed with breast cancer mets (remission was 5 yrs while on Tomoxafin). She has 3 pelvic area lesions areas with one on the sacrum which is creating some discomfort and occasional leg sensations. Currently she's on the textbook standard for estrogen positive breast cancer - Ibrance + Letrozol and Zometa every 3 months. She had the ovaries out a few months ago. We've discussed the gene sequencing with her oncology team but they don't believe it's effective for bone mets vs the drug therapies and other treatments. We certainly would be interested to come to meet with your team and consider the sequencing strategy. Has MSKCC seen any progress with the estrogen positive breast cancer patients treated there?
Thank you for your reply.

Dear Mike, we're sorry to hear about your wife's diagnosis. MSK has a number of treatment options for metastatic breast cancer, including clinical trials. If your wife would like to come for a consultation, 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.

Hello!
Does this test evaluates more genes than Foundation One's test?
Thank you!
Florencia

Florencia, thank you for reaching out. MSK-IMPACT and Foundation One look at a similar number of genes, are equally sensitive, and yield comparable information about the genomic alterations that are most important for diagnosing and treating cancer.

I had the impact testing done in November and just read re the MET gene - was that gene included in the 468 that were tested for me? It is not mentioned in the report and the cite given for the full 468 genes is an intranet mskcc site that my internet cannot access. This is for lung cancer

Dear Suze, we recommend that you talk with your doctor or someone else from your healthcare team about which genes were included in the panel when you received your MSK-IMPACT testing. Thank you for your comment, and best wishes to you.

Hello,

My Mother has been diagnosed with bladder cancer grade T1 with an aggressive form of cancer and has been scheduled to receive oral chemo (Cisplatin and Gemcitabine).

Her recent biopsy was performed at USC with a blue light cystoscopy and biopsy was performed at 5 locations.

It revealed High-grade papillary urothelial carcinoma and micropapillary and focal palmacytoid features with carcinoma in situ.

Does your center provide any alternative routes to addressing this form of cancer (including tests, treatment, etc.)?

Thank you.
Pete

Dear Pete, we're sorry to hear about your mother's diagnosis. We offer a number of treatments for bladder cancer, including clinical trials. If your mother would like to make a consultation to learn more about what options may be available to her, she 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 and your family.

Hi, my name is Antonio; has the MSK-IMPACT panel been utilized to screen for mutations derived from blood (ctDNA)? is somebody working on it? Thanks

Dear Antonio, at this time the MSK-IMPACT assay is focusing on solid tumors. We are researching ways to analyze tumor DNA in the blood. Thank you for your comment.

I have advanced squamous lung cancer and am being treated at MSKCC. I've had surgery and would think there is pleanty of tissue to test. Just started chemo. The cancer spread rapidly after surgery... I am thinking ahead in case the chemo doesn't work...

Dear Paul, we recommend that you discuss this with your MSK healthcare team. Thank you for your comment, and best wishes to you.

Is it possible to share the design of the MSK-IMPACT panel for other scientific studies?

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