Inherited Genetic Factor May Not Extend Ovarian Cancer Survival

A University of Iowa Health Care investigation has found that, contrary to some reports, women with inherited ovarian cancer may not have a better survival prognosis than women with ovarian cancer due to other mechanisms.

At least 10 percent of ovarian cancers are inherited, and many of these cases are due to women inheriting a BRCA1 gene that doesn't function properly. Some researchers have suggested that women with ovarian cancer who have a faulty BRCA1 gene are more likely to live longer than women who also have ovarian cancer but whose BRCA1 gene functions normally. Other investigators have suggested no such survival difference exists.

The UI study controlled for more outcome predictors than any of the previous studies and could not find a measurable difference in survival due to hereditary BRCA1 dysfunction. The findings are published in the May issue of Clinical Cancer Research.

"Our study could not validate previous conclusions that women with inherited ovarian cancer have a better overall prognosis than those who have sporadic or random ovarian cancer," said Richard Buller, M.D., Ph.D., UI professor of obstetrics and gynecology and the study's principal investigator. "It still might be the case that hereditary ovarian cancer offers some increased survival over other ovarian cancers but we can't prove it with this study. Apparent survival differences are probably due to other factors."

Buller said the findings have implications for giving patients more accurate prognostic information. "Based on what we've learned, I can no longer tell women that having inherited ovarian cancer makes their prognosis better," he said. "The studies that would have allowed me to give that prognosis didn't have the appropriate controls that our study does."

Previous studies had shown an average 80 percent survival advantage for women who had hereditary BRCA1 gene dysfunction. Buller said the recent UI investigation included enough cases to have detected that 80 percent rate if it indeed existed. "Our next step will be to try to analyze more ovarian cancer cases. An even larger number of cases will increase our ability to detect a smaller difference in survival, such as 30 percent, if it exists," he said.

The UI study focused on 59 cases of ovarian cancer that showed BRCA1 dysfunction due to one of three causes -- inheriting a defective gene; a gene mutation in the cancer but not inherited; or a loss of gene function in the cancer (known as gene silencing) -- and 59 cases of ovarian cases in which the women's BRCA1 genes were not faulty. No previous study had controlled for the non-inherited forms of BRCA1 dysfunction or for a mutated p53 gene (a tumor suppressor). All the cases had been diagnosed and/or treated at the Holden Comprehensive Cancer Center at the UI.

Instead of comparing the survival rates among the groups with the three different types of BRA1 dysfunction, the study compared each BRCA1 group to a carefully matched control group that did not have any BRCA1 dysfunction. For example, the team compared women with the first type of BRCA1 dysfunction --hereditary -- to women who were alike in every other way, such as age at which diagnosed and post-treatment condition, except that their BRCA1 genes were normal. The two groups had virtually identical survival rates of 4.5 years (hereditary BRCA1 defect) and 4.6 years (no BRCA1 gene defect).

"We controlled for the common outcome predicators in ovarian cancer so that we were very careful to compare apples to apples instead of apples to oranges," Buller said. "You can't just take a general population of ovarian cancer patients to study their survival. You need to consider whether they have any BRCA1 dysfunction plus other variables that could explain differences between groups, such as age of diagnosis, disease stage and the amount of disease left after surgical treatment.

He pointed out that women with cancers in which the BRCA1 gene is silenced (completely shut off) have more tumor left after surgery than women whose BRCA1 gene has mutated, yet this residual tumor problem apparently has nothing to do with the gene dysfunction.

"If differences in survival were caused by just a problem with the gene, then you would expect women with mutated and silenced BRCA1 genes to have the same amount of disease left after surgery. After all, in both cases, that gene doesn't work," Buller said. "However, since the amount of tumor remaining differs, some factor other than the gene may have an influence."

Buller said that care needs to be taken in interpreting studies, whether they support or reject possible causes and effects. "When you interpret a study that shows a link, such as between a genetic condition and an increased survival rate, you need to be sure you have controlled for all the important variables," he explained. "Likewise, when interpreting studies that indicate a link does not exist, as with our investigation, you must be sure that you studied enough cases not to have overlooked any differences."

Last January, Buller and colleagues showed that BRCA1 gene dysfunction in women with ovarian cancer is more common than previously thought and frequently occurs through ways other than inheritance. That study indicated that up to one in four women with ovarian cancer have some type of BRCA1 dysfunction. When it functions normally, BRCA1 helps to keep tumors from developing. However, its exact function is not known.

According to the American Cancer Society, approximately 23,300 new cases of ovarian cancer will be diagnosed in the United States this year, and about 13,900 women will die from the disease. Among women whose ovarian cancer is diagnosed before it spreads from the ovaries, 95 percent will survive at least five years. Overall, approximately three of four women with ovarian cancer live at least one year after their diagnosis, and more than half live five years or longer.

In addition to Buller, the study team included Mark Shahin, M.D., a former UI fellow in gynecologic oncology; John Geisler, M.D., a UI fellow in gynecologic oncology; Melanie Zogg, UI research assistant in gynecologic oncology; Barry De Young, M.D., UI associate professor in pathology; and Charles Davis, Ph.D., a former UI professor in biostatistics.

The study was supported in part by National Institutes of Health grants awarded to Buller and Geisler, and by the Florence and Marshall Schwid Award given to Buller from the Gynecologic Cancer Foundation.

The Holden Comprehensive Cancer Center is Iowa's only National Cancer Institute-designated comprehensive cancer center. NCI-designated comprehensive cancer centers are recognized as the leaders in developing new approaches to cancer prevention and cancer care, conducting leading edge research and educating the public about cancer. Visit the center online at http://www.uihealthcare.com/depts/cancercenter.