Experimental Blood Test for Mesothelioma and Ovarian Cancer

CCR Grand Rounds January 31: Clifton Leaf, Senior Editor at Large, Fortune Magazine. "Cancer Epidemiology, Google, and the Dangerous Legacy of GIGO." February 7: Dr. Ira Pastan, Chief, Laboratory of Molecular Biology, CCR, NCI. "Immunotoxin Therapy of Cancer: Can Success in Treating Hairy Cell Leukemia Be Extended to Other Cancers?" CCR Grand Rounds are held 8:30 to 9:30 a.m. at the NIH campus in Bethesda, Md., in the Clinical Center's Lipsett Amphitheater.

Researchers have developed an experimental blood test that could potentially be used to help diagnose mesothelioma and ovarian cancer if further studies confirm its clinical utility. The test measures levels of a protein called mesothelin that is highly expressed in patients with these cancers.

The researchers used newly developed antibodies to create the test, and they report in the January 15 Clinical Cancer Research that mesothelin is shed into blood and can be accurately measured. They analyzed blood from 56 patients with mesothelioma, 21 patients with ovarian cancer, and more than 100 other control samples. Mesothelin levels were elevated in 71 percent of mesothelioma and 67 percent of ovarian cancer patients.

"Our findings suggest that mesothelin is a good biological marker for mesothelioma and ovarian cancer, but the results need to be validated," says Dr. Raffit Hassan of NCI's Center for Cancer Research (CCR), who led the study. All of the patients in this study were in the late stages of disease.

The researchers also measured mesothelin levels before and after surgery in six patients with peritoneal mesothelioma and found that the levels dropped off rapidly after surgery. If further studies confirm the findings, the test might be used to monitor disease progression, says Dr. Hassan.

Mesothelioma is an aggressive cancer of the lining of the lungs and the abdomen. The disease is difficult to diagnose by conventional imaging studies, and doctors lack routine laboratory tests for monitoring its progression.

Prophylactic Surgery in Women with Lynch Syndrome

A paper published in the January 19 New England Journal of Medicine provides the first evidence that prophylactic surgery can prevent gynecologic cancers in women with Lynch syndrome (hereditary nonpolyposis colorectal cancer).

Women with Lynch syndrome have a 40 to 60 percent lifetime risk of endometrial cancer and a 10 to 12 percent lifetime risk of ovarian cancer. This study analyzed a retrospective cohort of women with germline mutations in the genes that cause Lynch syndrome. Of 315 women, 61 underwent prophylactic removal of the uterus (hysterectomy) and 47 underwent prophylactic removal of the ovaries and fallopian tubes (bilateral salpingo-oophorectomy). Some women underwent both procedures.

None of the women who had a prophylactic hysterectomy had developed endometrial cancer by the end of the study, while 69 women in the control group had. Similarly, compared with women who had a bilateral salpingo-oophorectomy, 47 women who did not have the procedure developed ovarian cancer. Only 1 out of 61 women experienced surgical complications.

The authors acknowledge that their study has several limitations. The data were acquired retrospectively, and the genetic profile of many of the women was not known until after surgery or cancer diagnosis. In addition, it is not yet clear if a decrease in cancer incidence will translate into an increase in overall survival. However, considering the very high risk in this cohort of women, the authors conclude that prophylactic surgery "is an effective strategy for preventing endometrial and ovarian cancer in women with the Lynch syndrome."

Diabetes Risk for Colorectal Cancer Shown in Asian Study

A large prospective cohort study of Singapore Chinese men and women found a significantly increased risk among diabetics for developing colorectal cancer, according to a report in the January 18 Journal of the National Cancer Institute (JNCI).

More than 63,000 participants from the Singapore Chinese Health Study enrolled in the study between 1993 and 1998, report researchers from the University of Singapore and the University of Minnesota Cancer Center. Within the group, 5,469 were diagnosed as diabetic before initial enrollment. By the end of the follow-up period in December 2002, 636 enrollees had been diagnosed with colorectal cancer.

Overall, the risk of colorectal cancer was 50 percent higher among diabetics than among nondiabetics, the researchers found. They also observed statistically significant associations between diabetes and colorectal cancer risk among individuals with higher calorie intake and lower levels of physical activity.

"Our results are consistent with the growing body of epidemiologic evidence that links a history of diabetes mellitus (primarily type 2) with colorectal cancer risk," the investigators comment.

They also note there was "no trend suggesting increasing risk of colorectal cancer among diabetics in the higher Body Mass Index (BMI) categories." That finding is similar to a large Korean study published a year ago, which found that the diabetes and cancer risk link was not tied to obesity (NCI Cancer Bulletin, Jan. 18, 2005). "Both Asian populations (i.e., Koreans and Singapore Chinese) are generally lean," compared with U.S. and European populations, they state. "Therefore, our data suggest that high BMI per se does not drive the diabetes-colorectal cancer association."

Breast Cancer Risk Increased in BRCA2 Carriers in Iceland

Following the identification of inherited mutations in the tumor suppressor genes BRCA1 and BRCA2, studies have shown that women with mutations in these genes are at significantly higher risk for breast and ovarian cancers than other women. Results of a retrospective population-based study suggest that at least one specific BRCA2 mutation (999del5 on exon 9) was four times more likely to appear in breast cancer patients in 2002 (71.9 percent) than it was in 1920 (18.6 percent).

Other trends were also evident when Dr. Laufey Tryggvadóttir from the Icelandic Cancer Registry and colleagues looked at 847 women diagnosed with breast cancer and their close relatives during that period. The risk of death before age 70 doubled in those who had the mutation. Also, their cancers were nearly four times more likely to appear between ages 20-39 than after age 59.

The authors note that the marked increase in risk for the BRCA2 carriers was similar to the risk for the overall Icelandic population, as well as that of relatives of those with another wild-type BRCA2 mutation. They suggest that the increase in breast cancer risk is likely the result of "dramatic changes in lifestyle that occurred during the 20th century," such as greater overall life expectancy, women maturing biologically at younger ages, and having fewer children at later ages.

The study, published in the January 18 JNCI, used data and tissue samples collected from all women in Iceland diagnosed with cancer since 1911.

Study Examines Adjuvant Radiation for Endometrial Cancer

Results of a retrospective analysis of more than 21,000 women with early-stage endometrial cancer demonstrate a significant survival benefit with adjuvant radiation therapy (RT) in subsets of women with high-risk disease. Overall and relative survival were significantly improved in women with stage IC disease with tumor grades 1, 3, and 4, compared with women who did not receive adjuvant therapy. The study appears in the January 25 Journal of the American Medical Association.

As opposed to stage IA, in which the tumor is within the inner lining of the uterus, stage IC endometrial cancer has spread into the outer portion of the myometrium, the layer of muscle around the uterus. The higher the grade of the tumor, the more malignant it is considered to be. However, early-stage endometrial cancer is considered to be highly curable with surgery and recurrence risk is generally low.

To conduct the study, Dr. David Gaffney of the Huntsman Cancer Institute and University of Utah Medical Center, analyzed data from NCI's Surveillance, Epidemiology, and End Results program on women with stage IA through IC node-negative endometrial adenocarcinoma. Approximately 19 percent of patients were treated with adjuvant RT.

Previous studies have shown variable results in women with early-stage disease at intermediate and high risk, according to Dr. Gaffney and his colleagues, demonstrating improvements in local control and/or disease-free survival, but not in overall survival. This may be because the prior randomized trials have had "poor accrual and insufficient patient numbers at the time of analysis," they commented.

"To our knowledge, as the largest reported population analysis of the use of adjuvant radiation therapy in early-stage endometrial adenocarcinoma to date, it is significant that our study reveals an association in both overall survival and relative survival for adjuvant RT in stage IC disease (grades 1 and 3-4 cohorts)," they wrote.

Dr. Ted Trimble of NCI's Division of Cancer Treatment and Diagnosis, called the study results "provocative," but cautioned that more information is still needed to determine which early-stage patients are at highest risk for recurrence after surgery and how best to treat them. NCI is planning an endometrial cancer state-of-the-science meeting for late 2006, he said, to help plan future treatment studies.