Gene mutation marks aggressive endometrial cancer

Targeted therapies for endometrial cancer, the fourth most common cancer of U.S. women, have lagged behind that of many other cancers, say researchers at Washington University School of Medicine in St. Louis.

But the researchers have taken an important step toward changing that by identifying a genetic marker for high-risk endometrial cancer, opening the door for more directed and risk-appropriate treatments.

In the May 26 advance online issue of the Journal of Clinical Oncology, the scientists report that genetic mutation of the ATR gene in tumors raises the risk of cancer recurrence and death in patients with the most prevalent kind of endometrial cancer, endometrioid endometrial cancer.

The ATR (ataxia-telangiectasia mutated and rad3-related kinase) gene, orchestrates cellular responses to DNA damage.

“Women whose endometrial cancers have an ATR mutation have more than four times the risk of having their cancer return,” says the study’s lead author Israel Zighelboim, M.D., a Washington University gynecologic oncologist at the Siteman Cancer Center and Barnes-Jewish Hospital. “This and similar tumor biomarkers could potentially identify those patients most in danger of recurrence and guide the development of treatments aimed at these more aggressive tumors.”

The standard of care for endometrial cancer has historically been a one-size-fits-all approach, says Zighelboim, assistant professor of obstetrics and gynecology. He explains that most women with endometrial cancer typically undergo removal of the uterus, ovaries and local and regional lymph nodes.

“Now we are starting to move away from such very extensive surgery because we realize many women were being overtreated,” Zighelboim says. “That makes molecular markers such as the ATR mutations even more relevant and raises the possibility that we could avoid extensive surgery and its complications in women who don’t have such markers.”

Most of the 40,000 U.S. women found to have endometrial cancer each year are diagnosed in the early stage of the disease, and about 80 percent of these patients will survive long term. But for the minority, the disease will recur and most likely cause death. In the past, oncologists had no reliable way to know who is likely to have a recurrence and thus benefit most from comprehensive surgery and postoperative treatments such as radiation or chemotherapy.

The researchers found ATR mutations in about 5 percent of the 248 endometrioid endometrial tumor samples they analyzed. The samples were obtained from patients treated at the School of Medicine and followed for at least three years. The patients whose tumors had ATR mutations were 4.29 times more likely to have had a recurrence after treatment and 3.88 times more likely to have died.

“Washington University is a national leader in endometrial cancer treatment and research,” says senior author Paul Goodfellow, Ph.D., co-director of the Hereditary Cancer Core at the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital. “We believe endometrial cancer does not receive as much interest or research as it should. We want to change that and help bring about improvements in how doctors manage endometrial cancer patients.”

Next the researchers will work to confirm the prognostic value of ATR mutations in a larger group of endometrial cancer patients using data obtained through the Gynecologic Oncology Group, the National Cancer Institute-funded cooperative research group focused solely on gynecologic malignancies. They will also investigate whether the presence of ATR mutations corresponds to treatment response after recurrence.

Zighelboim I, Schmidt AP, Gao F, Thaker PH, Powell MA, Rader JS, Gibb RK, Mutch DG, Goodfellow PJ. ATR mutation in endometrioid endometrial cancer is associated with poor clinical outcomes. Journal of Clinical Oncology. May 26, 2009 (advance online publication).

Funding from the National Institutes of Health and the Barnes-Jewish Hospital Foundation supported this research.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Siteman Cancer Center is the only federally designated Comprehensive Cancer Center within a 240-mile radius of St. Louis. Siteman Cancer Center is composed of the combined cancer research and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine. Siteman has satellite locations in West County and St. Peters, in addition to its full-service facility at Washington University Medical Center on South Kingshighway.