CONTACT: BECKY SOGLIN
Iowa City IA 52242
(319) 335-6660; fax (319) 384-4638
Release: May 15, 2002
UI study finds inherited genetic factor may not extend ovarian cancer
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,"
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.
University of Iowa Health Care describes the partnership between
the UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and
Clinics and the patient care, medical education and research programs and
services they provide. Visit UI Health Care online at www.uihealthcare.com.