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.