Genomics to reshape endometrial cancer treatment

May 1, 2013
Scientists at Washington University's Genome Institute have shown that adding genomics-based testing to the standard diagnostic workup for endometrial cancer could change the recommended treatment for some women. Credit: Robert Boston, Washington University in St. Louis

The most in-depth look yet at endometrial cancer shows that adding genomics-based testing to the standard diagnostic workup could change the recommended course of treatment for some women.

The new research, involving nearly 400 women with endometrial , is published May 2 in the journal Nature. The endeavor is part of The Cancer Genome Atlas project, funded by the National Institutes of Health (NIH).

The study also indicates that some endometrial tumors are genetically similar to subtypes of ovarian cancer and deadly basal-like breast cancer. Future clinical trials should evaluate whether some endometrial cancers could be treated with drugs typically used for the other cancers, says project co-leader Elaine Mardis, PhD, co-director of The Genome Institute at Washington University School of Medicine in St. Louis. The other co-leader is Douglas A. Levine, MD, of the Memorial Sloan-Kettering Cancer Center.

A second Cancer Genome Atlas paper will be published May 1 in the New England Journal of Medicine. That research, also led by Washington University, describes finding virtually all the major mutations involved in .

While gynecologic oncologists have long recognized two subtypes of endometrial cancer, one more aggressive than the other, the new data reveal four novel subtypes and also suggest that the frequency of mutations in a tumor could be used to help guide treatment decisions.

"We are entering an era when tumors can be evaluated from a genomics standpoint, not just by looking at under a microscope," Mardis says. "This more comprehensive approach provides a clearer picture of the way particular endometrial cancers will behave and will be important to gynecological oncologists who treat this disease."

As part of the new research, a consortium of researchers analyzed tumors from 373 women with endometrial cancer using different technologies to look for defects in DNA, RNA (a close chemical cousin of DNA) and proteins.

Their analysis indicates that about 25 percent of women with endometrial cancer who are thought to have a favorable prognosis based on pathology reports instead have a more formidable form of the disease, based on underlying genetic changes, and should be treated aggressively.

Clinically, endometrial cancers fall into two categories: endometrioid and serous. Endometrioid cancers generally are associated with excess estrogen, obesity and a favorable prognosis. In contrast, serous endometrial cancers are more common in older women and generally have poorer outcomes.

After surgery to remove endometrial cancer, women with the endometrioid subtype typically are treated with radiation therapy to kill remaining cancer cells, while those with serous tumors receive a more aggressive treatment – chemotherapy.

Doctors distinguish between the two tumor subtypes by evaluating cancer cells under a microscope. But categorizing some tumors is difficult, and pathologists don't always agree.

Looking closely at endometrioid tumors classified as high-grade, meaning they are more likely to grow quickly and spread, the investigators showed that many share genetic features with serous tumors. These include frequent mutations in TP53, a tumor suppressor gene, as well as extensive copy number alterations, which refer to a cell having too many or too few copies of a gene.

"This highlights the benefit of digging deeper to find the genetic drivers of cancer growth," Mardis says. "Even though high-grade endometrioid and serous endometrial cancer are different from a pathological standpoint, they are genetically very similar and may require a similar course of treatment."

With a complete analysis of the tumor samples, the investigators identified four novel genomic-based subtypes of endometrial cancer, which set the stage for developing new ways to diagnose and treat the disease. The subtypes are based, in part, on the frequency of mutations in the tumors.

"The Cancer Genome Atlas' multidimensional approach to collecting genomic data, including clinical and pathology information, have made these findings possible," says Harold Varmus, MD, director on the National Cancer Institute. "Without the integrated characterization of so many tumor samples, correlations between histology and genomic data may not have been observed or potential clinical outcomes identified."

Interestingly, one subtype features an exceedingly high mutation rate in the POLE gene and, in this respect, is similar to an "ultramutated" subtype of colorectal cancer. But, surprisingly, patients with these kinds of tumors generally have good outcomes.

"Having many, many mutations sounds like a bad thing," Mardis explains. "But these patients can't fix the mistakes in their tumor DNA, so their cancer cells mutate themselves into oblivion before they have the opportunity to spread to other locations in the body. The good news for these patients is that their outcomes are excellent, and they don't need aggressive treatment."

Women with serous tumors frequently had mutations in one of two genes that potentially could be targeted with existing targeted therapies. Those with ERBB2 alterations, for example, may be effectively treated with Herceptin, a drug typically used in women with breast cancer who have the same mutation. Additionally, women whose endometrial tumors have PIK3CA mutations may benefit from drugs that inhibit the gene. Those drugs are now in phase II clinical trials.

According to the authors, the new findings provide a roadmap for future clinical trials for endometrial cancer.

"Each tumor subtype may warrant separate clinical trials because of marked genomic differences, which are indicative of different drivers of endometrial cancer," Mardis says. "Developing therapies for each subtype may improve outcomes for many women with endometrial cancer and parallel what has been accomplished in breast cancer."

Endometrial cancer is the fourth most commonly diagnosed cancer among U.S. women. About 50,000 cases will be diagnosed in 2013, and an estimated 8,000 women will die from the disease. For a majority of patients diagnosed with aggressive, high-grade tumors that have spread, the five-year survival rate is about 16 percent, though chemotherapy has been associated with improved survival, and new targeted agents are being tested.

Explore further: Researchers identify novel genes that may drive rare, aggressive form of uterine cancer

More information: Levine DA, Mardis ER and The Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. May 2, 2013.

Related Stories

Researchers identify novel genes that may drive rare, aggressive form of uterine cancer

October 28, 2012
Researchers have identified several genes that are linked to one of the most lethal forms of uterine cancer, serous endometrial cancer. The researchers describe how three of the genes found in the study are frequently altered ...

Genes behind aggressive endometrial cancer found

January 28, 2013
In a major breakthrough for uterine serous carcinoma (USC)—a chemo-resistant, aggressive form of endometrial cancer, Yale researchers have defined the genetic landscape of USC tumors, findings that point to new treatment ...

Scientists decode DNA to find breast tumor signatures that predict treatment response

June 10, 2012
Decoding the DNA of patients with advanced breast cancer has allowed scientists to identify distinct cancer "signatures" that could help predict which women are most likely to benefit from estrogen-lowering therapy, while ...

Low bone density medications may have protective effect on endometrial cancer

March 21, 2012
Low bone density medications, such as Fosamax, Boniva and Actonel, may have a protective effect for endometrial cancer, according to a study at Henry Ford Hospital.

Recommended for you

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Molecular changes with age in normal breast tissue are linked to cancer-related changes

July 20, 2017
Several known factors are associated with a higher risk of breast cancer including increasing age, being overweight after menopause, alcohol intake, and family history. However, the underlying biologic mechanisms through ...

Immune-cell numbers predict response to combination immunotherapy in melanoma

July 20, 2017
Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco ...

Discovery could lead to better results for patients undergoing radiation

July 19, 2017
More than half of cancer patients undergo radiotherapy, in which high doses of radiation are aimed at diseased tissue to kill cancer cells. But due to a phenomenon known as radiation-induced bystander effect (RIBE), in which ...

Definitive genomic study reveals alterations driving most medulloblastoma brain tumors

July 19, 2017
The most comprehensive analysis yet of medulloblastoma has identified genomic changes responsible for more than 75 percent of the brain tumors, including two new suspected cancer genes that were found exclusively in the least ...

Novel CRISPR-Cas9 screening enables discovery of new targets to aid cancer immunotherapy

July 19, 2017
A novel screening method developed by a team at Dana-Farber/Boston Children's Cancer and Blood Disorders Center—using CRISPR-Cas9 genome editing technology to test the function of thousands of tumor genes in mice—has ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.