In the Lab

On Cancer: Large Genetic Study Could Improve Endometrial Cancer Diagnosis and Treatment

By Jim Stallard, MA, Writer/Editor  |  Wednesday, May 1, 2013
Pictured: Douglas Levine Gynecologic oncologist Douglas Levine (left)

A large-scale study of endometrial cancers has identified genetic mutations and molecular pathways that could allow women with aggressive forms of the disease to be more precisely diagnosed. These insights could bring much-needed clarity to existing treatment choices and also guide clinical trials and the development of new drugs.

The research, published in the May 2 issue of the journal Nature, suggests that endometrial tumors could be reclassified into distinct subtypes based partly on their genetic makeup. This would make it possible to better individualize treatments for women whose endometrial cancers carry a high risk of recurrence. 

“The landscape of treatment for endometrial cancer today is quite chaotic,” says Memorial Sloan Kettering gynecologic oncologist Douglas A. Levine, the corresponding author of the Nature study. “My hope is that these new findings will help to provide order to that landscape, especially for more-aggressive endometrial cancers.”

As a result of the findings from the study, patients with endometrial cancer could be tested routinely to determine their particular subtype — and based on test results could possibly enroll in a clinical trial. “The findings have immediate therapeutic application,” Dr. Levine explains. “Even if there is no trial targeting a tumor’s particular mutation or pathway, we at least will have a better idea of which existing treatments to use.”

The genetic study was led by Memorial Sloan Kettering and other centers as part of The Cancer Genome Atlas (TGCA), a national project funded jointly by the National Cancer Institute and the National Human Genome Research Institute, both part of the National Institutes of Health.

Divergent Treatments after Surgery

Endometrial cancer, which forms in the tissues lining the uterus, is the fourth leading type of cancer among women and the eighth leading cause of cancer deaths. The two most common subtypes of this cancer are endometrioid adenocarcinomas, which are usually curable, and serous adenocarcinomas, which are more aggressive.

The standard initial treatment for both these subtypes is surgery to remove the tumor. For most endometrioid adenocarcinomas that are low grade (slow growing) this treatment alone is sufficient, although some women may also receive radiation therapy.

But for high-grade endometrioid tumors and all serous tumors, which have a high risk of recurrence, there has been widespread uncertainty among doctors over the best approach beyond surgery. Questions include whether lymph nodes should be removed to track cancer spread and whether radiation or chemotherapy (or both) should be given.

Among these higher-grade cancers, endometrioid tumors are often treated with radiation therapy, while serous tumors — considered more aggressive and more likely to recur — are usually treated with chemotherapy. But the different types don’t always behave as predicted.

“Traditionally, treatment decisions have relied largely on pathology — how tumor cells look under a microscope,” Dr. Levine says. “If we incorporate this new genetic information, it could be a great leap forward. We want to make certain these additional treatments are used effectively — but only when necessary, since they do have side effects.”

The analysis of 373 endometrial tumors showed that approximately one-fourth of high-grade endometrioid tumors have certain types of genetic alterations that are also found in the serous tumors. This suggests that a significant portion of high-grade endometrioid tumors may need more-aggressive treatment after surgery than they usually receive today. In many cases, this would mean treating the endometrioid tumors with chemotherapy rather than radiation therapy.

Potential Drugs Already Being Tested

Many of the endometrial tumors analyzed had mutations in important cancer-related genes and pathways for which targeted therapies are already being tested in clinical trials for other cancers. For example, 84 percent of the tumors have some alteration in the PI3 kinase gene, which lies in a disease pathway called AKT that is implicated in many cancers.

“Several trials testing agents that target the PI3 kinase –AKT pathway in endometrial and other cancers are in progress here at Memorial Sloan Kettering or have already been completed,” Dr. Levine says. “Companies developing these drugs for other cancers are eager to begin testing more of them in endometrial cancer, and they are coming up with newer, more specific drugs all the time. This is going to be a huge field for years to come, so sorting patients into specific subtypes becomes essential to finding the best therapies.” 

TCGA is one of the most comprehensive national efforts to collect and analyze the largest set of tumor samples using state-of-the-art genomic and molecular techniques. Memorial Sloan Kettering has played a key role in TCGA from its earliest stages and currently houses one of TCGA’s Genomic Data Analysis Centers, led by computational biologist Chris Sander, biocomputing manager Nikolaus Schultz, and molecular pathologist Marc Ladanyi.

For the endometrial cancer study, Memorial Sloan Kettering provided more than 10 percent of tissue samples analyzed. Dr. Levine is principal investigator of Memorial Sloan Kettering’s TCGA Tissue Source Site, and Co-Chair of the TCGA Endometrial Working Group.

Read more about this study in the New York Times, the Wall Street Journal, and Bloomberg.

This research was supported by the National Cancer Institute of the National Institutes of Health (NIH) under award 5U24CA143840-04.

Comments

My niece Gilya Murlakov age 49, who lives in Israel has been recently diagnosed with serous papillary endometrial uterine adenocarcinoma stage IV. She has received one dose so far of chemo(cisplatinum and Taxol). She has ascites fluid with metastatic invasion of the colon/small intestine interface. This caused a blockage in her elimination. She was operated on yesterday because the intestine perforated and she became septic. Part of the colon and intestine were removed. We would like to know if she would be a suitable candidate for your study or for your treatment strategy. Please contact me at the above email address.

Fannie, if your niece would like to find out about coming to Memorial Sloan-Kettering as an international patient, we suggest she contact our Bobst International Center. You can find the information here: http://www.mskcc.org/cancer-care/international-patients Thank you for your comment.

Thank you for your continued work on this horrible disease. One year out from diagnosis with UPSC and I plan on a very long life. I pray that God guides you in this important work.

I am 20 months from last chemo treatment at UT Southwestern for stage 3 grade 3 carsonma sacorma (MMMT) uterine cancer. Thank you for doing this study. It is the first time that I have really seen something being done for uterine cancer. I pray that more research is done so that a cure or early testing is found so more women do not get this and die from it. My Gyn Onc Dr. also took samples for research when she did my surgery, so I feel that I am contributing to some of the research going on. Thanks for the hard work you and the others are doing.

I had a Grade 3 tumor, Stage 3 with 2 pelvic nodes. Treated with external and internal radiation and 6 rounds of chemo. Many complications: bilateral lymphedema, chronic diarrhea, hematuria, vaginal atrophy, and a new systemic disease, now threatening my sight. To find out that either the radiation or the chemo was not indicated would have saved me from a very diminished "quality of life." Both radiation and chemo are non-specific destroyers. Let's get to nano particle technology sooner than later.

I was recently diagnosed with endometrial serous intraepithelial carcinoma Stage 0, and while further treatment is not recommended for me at this time (treated at Fox Chase and slide review at Hopkins, I would like to be able to help advance the knowledge based. If research is ongoing, and my slides would be of use, I would be happy to have them sent to MSK. Thank you

Thanks for your comment Sandy. We spoke with Dr. Levine, who says,"We appreciate the offer and will keep it in mind as new studies develop.
We encourage you and any other patients to participate in tissue
banking and clinical trials as appropriate." To find out more about our clinical trials, visit: http://www.mskcc.org/cancer-care/clinical-trials.

If an endometrial cancer patient had surgery at MSK in 2012, was tissue from that patient likely included in this study? And if so, can any findings of one's genetic results be shared with these patients?

We spoke with Dr. Levine, who said that the tissue requirements were quite strict for this study. Each patient had to specifically consent for her tissue to be used in this research. The findings from this study are not linked backed to individual patients. Thank you for your comment.

wow, perhaps this is encouraging for future cure. Stage 1 grade 2 Endo carcinoma.Brachytherapy 3 x Da Vinci total Hysterectomy lymph nodes as well.

i had a recent operation at the mayo clinic phoenix az for tubular cancer(high grade aggressive 3) had complete hysteractomy(Dr.Magrina,performed the robotis surgery)so far I have not deceided to take the suggested 3 or 6 times chemo-what do you suggest-

Elfriede, we are not able to provide personal medical advice on our blog. If you'd like to make an appointment to speak with a Memorial Sloan-Kettering doctor, you can call 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment. Thank you for your comment.

Very encouraged by the news of new and improved treatments for endometrial cancer. I was diagnosed in 2006 and thankfully required no further treatment after a full hysterectomy. Cousin diagnosed with the same 3 years ago but was not so lucky. Reoccurance and spread cost Lisa her life in February. Please keep up the hard work and find help for those who need it.

Any kind of breakthrough in the fight against any type of cancer is great news! It's been almost 5 years since my radical hysterectomy, 3 rounds of Cisplatin/ Taxol, 30 days of radiation including High-Dose Internal Radiation, and a final 3 rounds of Cisplatin/Taxol for Stage IIIC Endometrial Cancer. Turns out women my age (38 at the time) don't really get this type of cancer unless very obese. But they do get it if there is a genetic abnormality. In my case - HNPCC. I now have to look out for 6 types of cancer, including colon which I have an 80% chance of getting.
But you know what - I'm alive TODAY! I'm doing great. Still get tired easily - but I ration my energy. I'm in the gym 4 days a week, I don't eat processed foods, don't eat a lot of meat, drink endless water and MOST of all...I have a wonderful relationship with God!
May God bless all the researchers and all the people who have cancer and the angels who take care of them!

I was diagnosed with uterine cancer in December 2012. Surgery on January 8 th and learned I would need chemo and radiation. My life turned upside down. Last chemo on 5/28. I am very grateful to both clinicians and researchers at Sloan for their leadership in making sense out of the "chaotic" landscape that currently exists as it pertains to treatment.
Nancy janus

I was diagnosed in Feb 2009 with Stage IIIc endometrial cancer serous adenocarcinoma high grade agressive but is an ovarian type cell which even though I am being treated the same as ovarian cancer does not allow me to participate in clinical trials for ovarian cancer. I had a hysterectomy, 6 rounds of Carbo/Taxol then a recurrence in my aortic node treated with Carbo/Doxil and have been on Doxil for 2 years straight every 4 weeks with clear CT scans. I feel really upset that I do not fit into a clinical trial for ovarian when that is what I am being treated for. Where are we in moving forward with patients like myself? It appears there are only a limited amount of effective chemo drugs for this type of cancer. I appreciate your input Thank you

Jane, unfortunately we are not able to answer personal medical questions on our blog. If you'd like to make an appointment with a Memorial Sloan-Kettering physician to discuss treatment options, please call 800-525-2225. Thank you for your comment.

I am 75. I recently had an endometrial biopsy: a small amount of endometrial hyperplasia with a small non-malignant polyp. I was treated for 10+ years with megestral('94-'05) with no recurrence, followed by dx of bleeding with minimal hyperplasia and non-malignant polyps in '08, '12, and 5-13. I need help to know what are my options.

Grace, unfortunately we are not able to respond to personal medical questions on our blog. If you would like to speak with a Memorial Sloan-Kettering doctor, please call 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment. Thank you for your comment.

4/201(47yrs old) Active, not overweight, not diabetic. A large, fast growing gelatinous tumor was found in my abdomen preventing bowel and bladder functions. Occurred through metastasis from the endometrium. Tumor type Adenocarcinoma of Endometrium, stage 3A. The tumor ruptured a few days before the abdominal hysterectomy which caused a rectocele. Chemo - Taxotere & Carboplatin -6 treatments. It has now been 1 year since my last treatment. I just had a colonoscopy and they found a Tubulovillous Adenoma. These have a high rate of becoming cancer. I'm such a health nut, it is hard to believe. I'm thinking a gene test may be a good idea. What do you think MSK?

Kim, thank you for your comment. We suggest you contact our Clinical Genetics Service. You can find information at:

http://www.mskcc.org/cancer-care/hereditary-genetics

Or call 646-888-4050 for an appointment.

My Mom (81 and in good health) has Stage 4 metastatic uterine serous paipllary adenocarcinoma. She has had 2 rounds of chemo and radiation. The 2nd round of chemo had no reaction. I would like to know if there are any suitable clinical trials or other avenues we should be investigating.

Thank you.

Debbie

Debbie, we are unable to answer specific medical questions on our blog. If you would like to make an appointment with a Memorial Sloan-Kettering physician, please call our Physician Referral Service at 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment. You also can see the list of active clinical trials at Memorial Sloan-Kettering at:

http://www.mskcc.org/cancer-care/clinical-trials/clinical-trial

You can learn about all clinical trials in the U.S. at:

http://clinicaltrials.gov/

Thanks for your comment.

Two part question. What effective treatments have come as a result of this study? My mother has stage IV endometrioid adenocarcinoma type 2 and is being treating at MSK. There doesn't seem to be any effective treatments and we have been pressing our MSK oncologist for more aggressive therapies. She has been very bad in communicating what other therapies are out there besides the "standard" radiation and chemo so we have asked for another MSK oncologist as a result. Apparently, it's MSK policy to not allow patients to switch oncologists unless the one we are assigned to request the change. So we are stuck. Would be able to see another MSK oncologist that is more innovative and knows of more aggressive treatments such as Dr. Levine?

Laila, the research by Dr. Levine that's described in this story is still at an early stage and has not yet led to changes in clinical practice. At Memorial Sloan Kettering, all of our doctors work together as part of a disease management team, which means that your mother will get the benefit of the collective knowledge of all of our doctors no matter who her primary physician is. We do have some clinical trials for patients with endometrial cancer who meet certain qualifications, so this is something that your mother might want to discuss with her current doctor. If you'd like to discuss our policies with someone, you can call our Office of Patient Representative at 212-639-7202. Thank you for your comment.

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