The following  study indicates that the BRCA genes may not be as predictive of
subsequent breast cancer as previous studies showed.  Someone had asked about
this.  I'm sorry if it's a repeat, but I just saw it & thought it very
pertinent to the list.

Medscape Medical News
BRCA Penetrance Overestimated in Studies of High-Risk Patients


Laurie Barclay, MD
Medscape Medical News 2002. c 2002 Medscape


Aug. 21, 2002 - The penetrance of BRCA1 and BRCA2 mutations has been
overestimated because the original studies looked at high-risk families,
according to an article in the Aug. 21 issue of the Journal of the National
Cancer Institute. Less biased population studies suggest a penetrance of only
about 45% to 68% rather than 90%, suggesting that we should temper our
expectations for predictive genetic tests while clarifying the role of other
causative factors.

"Substantial heterogeneity exists in the risk for cancer among individuals in
the population," writes Colin B. Begg, PhD, from the Memorial Sloan-Kettering
Cancer Center in New York, NY. "Penetrance estimates from case proband studies
must be inflated if other factors influence breast cancer risk in addition to
the specific genetic abnormality."

Early studies examined families with multiple cases of breast cancer, leading
to very high penetrance estimates of 71% to 85% by 70 years of age. Although
more recent studies of women with breast cancer who do not necessarily have a
strong family history of the disease have yielded considerably lower
estimates, these also may be biased and tend to overestimate penetrance.

In Begg's review of eight published studies using population-based methods,
all but one used case probands, which tends to inflate penetrance estimates.
The current strategy for estimating risk is unbiased only if all carriers
share an identical risk of developing the disease.

Begg argues that all risk factors for breast cancer are overrepresented in
incident cases of breast cancer, so that a sample of women who have been
diagnosed with breast cancer and who are identified as mutation carriers are
more likely to have other breast cancer risk factors than similar mutation
carriers who are disease-free. Ideally, these risk modifiers which are still
unknown could be used by genetic counselors to predict risk.

"Methodologic techniques to improve the prediction of cancer risk are needed,"
he writes.

In an accompanying editorial, Wylie Burke, MD, PhD, and Melissa A. Austin,
PhD, from the University of Washington in Seattle, address the complexity of
disease risk and its implications for disease prevention. Nongenetic risk
factors may modify the outcome of genetic risk in other settings, such as
smoking, diet, and exercise, which can modify the effect of genetic risk for
heart disease.

"The most important implication of penetrance studies, however, should perhaps
be to temper our expectations for predictive genetic tests," they write.
"Without a healthy respect for the many factors that may influence penetrance,
we will continue to overestimate the risk conferred by BRCA1 and BRCA2
mutations alone and, thus, miss opportunities to develop truly effective
prevention strategies for women who are genetically susceptible to breast
cancer that are based on a broad understanding of causative factors."

J Natl Cancer Inst. 2002;94(16):1185-1187, 1221-1226


P.D. Gordon, RN, BSN, IBCLC
Delaware Division of Public Health--WIC Program
Breastfeeding Coordinator
(302) 739-4614
1-800-222-2189

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