SAN FRANCISCOOvarian cancers associated with mutations
in the BRCA gene have a different underlying biology than
nonhereditary cancers and may respond better to treatments not
routinely applied in ovarian cancer, according to a study reported at
the 30th Annual Meeting of the Society of Gynecologic Oncologists.
The study showed that women with certain types of hereditary ovarian
cancer survive longer and are typically diagnosed at younger ages
than is the case with sporadic (nonhereditary) ovarian cancer.
Jeff Boyd, PhD, and his associates at Memorial Sloan-Kettering Cancer
Center reported that:
Ovarian cancer patients with BRCA gene mutations were diagnosed at a
mean age of 56, compared to age 61 for similar patients with
The median survival of patients with a mutation was 47 months vs 27
months for controls (P = .004).
Tumors of patients with a mutation appeared to be more responsive to
certain types of chemotherapy not typically thought of as first-line
treatment in ovarian cancer.
In an interview, Dr. Boyd said that progression-free survival was
significantly longer for patients with the BRCA-related
cancers than for control subjects.
About 10% of epithelial ovarian carcinomas are thought to be linked
to inherited mutations in the BRCA1 or BRCA2 genes. These genes
normally function as tumor suppressors. Mutations that impede DNA
repair and gene expressions may lead to malignancies with distinct
molecular, genetic, pathologic, and clinical features.
Study Limited to Jewish Women
Dr. Boyd explained that in order to attain greater genetic
homogeneity, the researchers limited their study to Jewish women with
ovarian cancer. Jewish women who have ovarian cancer and test
negative for the three founder mutations, we can be confident truly
do not have hereditary cancers, Dr. Boyd explained. In
the non-Jewish population, there is a relatively high prevalence of
false-negative genetic tests.
Archival tissue specimens from a consecutive series of 933 cases of
epithelial ovarian carcinoma were analyzed for the presence of one of
the common founder mutations in BRCA1 (185delAG or 5382insC) or BRCA2
All those positive for such a mutation were the subject
group (n = 88), while 101 matched patients negative for BRCA
mutations were the controls. Of the 88 cases, 67 were
linked to BRCA1 and 21 were linked to BRCA2.
In BRCA-linked hereditary ovarian cancers, the mean age at diagnosis
was 54 (range, 31 to 79) for BRCA1 and 62 (range, 44 to 77) for
BRCA2. The BRCA1 mutations are seen at diagnosis in
significantly younger women, but that is not true for BRCA2,
Dr. Boyd said.
The majority of hereditary cancers were of advanced stage, all were
moderately to poorly differentiated, and papillary serous tumors
A survival difference for BRCA1-linked cases correlated with the
extent of primary surgical cytoreduction. The ratio of optimally
debulked to suboptimally debulked cases in these women was 65 to 35;
this ratio was reversed (35 to 65) in controls and BRCA2-linked
Dr. Boyd said that his data suggest that proteins from BRCA mutations
are responding differently and more completely to chemotherapy than
is the case with tumors of patients without the mutation, since the
cases and controls were matched closely for all other prognostic
factors known to affect survival.
He suspects that this means that these mutations alter proteins
involved in DNA repair and that cancers caused by BRCA mutations may
respond best to treatments that cause double-stranded DNA breaks,
such as etoposide (VePesid) or radiation therapy, since the mutated
BRCA proteins cannot repair the damage.
We may want to consider treating hereditary ovarian cancer with
radiation or with etoposide, which are not typical front-line
treatments, he said.
Dr. Boyds group is currently studying the function of BRCA
mutations in cancer cells by putting BRCA back into mutant cells and
testing response to chemotherapy. A future step might be clinical
trials in women who have these mutations based on the regimens found
most effective in these laboratory studies.
This is a good example of translational research in
action, Dr. Boyd said. We take a clinical observation,
use it to lay the foundation for and then prove a scientific
hypothesis in the lab (ie, the biologic function of these proteins),
then return to the clinic with trials that can alter clinical
applications and affect patient survival.
For a lab guy, he said, it is exciting to be able
to take a clinical observation and laboratory data and then go back
to the clinic with something that has an immediate impact on human