The article by Dr. Srivastava and
colleagues provides a broad
overview of the procedures for assessing the risk of breast and ovarian cancer
in women with a family history of these diseases. Below, we make some additional
comments that may be useful to practitioners in risk-evaluation clinics.
When evaluating patients for possible deleterious BRCA
mutations, determining ancestry may be a critical issue. Founder mutations are
present in ethnically isolated populations and are responsible for a significant
proportion of breast and ovarian cancer cases attributed to an inherited
susceptibility. Founder mutations have been identified in Ashkenazi Jews,[1-3]
French Canadians, Japanese, Italians, Swedes, Finns, Belgians,
In Caucasian individuals, it is estimated that 1 out of 300
individuals carries a mutation in BRCA1 or BRCA2, whereas 1 out of 40
individuals of Ashkenazi Jewish ethnicity harbors such a mutation. Penetrance of
BRCA1/2 may be somewhat lower in Ashkenazi Jews than estimates derived from
studies of the original families; however, other recent studies show a
higher penetrance. Individuals of Dutch ancestry may be advised to pursue a
special test that is designed to detect two founder genomic deletions that have
been observed in this population.
Genes That Predispose
to Breast Cancer
Variants of uncertain significance (VUS) abound in the BRCA
genes. Their significance remains uncertain primarily due to the relatively
scant knowledge regarding their biological impact. Testing additional family
members for the familial VUS can be helpful in establishing, for example, that
the VUS was inherited from a noncancer lineage or that the VUS does not appear
to track with cancer cases seen in the family.
The BRCA genes are examples of tumor-suppressor genes as defined
by Knudson’s two-hit hypothesis. As the authors point out, other
tumor-suppressor genes such as p53 (one of the genes responsible for Li-Fraumeni
syndrome) also predispose to hereditary breast cancer. Li-Fraumeni syndrome (or
SBLA syndrome [sarcomas, breast and brain tumors, leukemia, laryngeal and lung
cancer, and adrenocortical carcinoma]) can also be caused by mutations in the
newly discovered hCHK2 gene, which confers a predisposition to sarcoma, breast
cancer, and brain tumors. It is anticipated that testing for this gene in
certain families may be appropriate when such a test becomes clinically
The Best Model
When assessing empiric risk for breast cancer, it is best to use
the model that shows the fewest limitations for the patient’s personal and
family history. In contrast to the authors’ statement, the Claus model does
provide estimates of breast cancer risk for women with a family history of
ovarian cancer in a first-degree relative. The BRCAPRO model is limited in
that it considers BRCA1/2 to be the only possible predisposing genes, with all
other high-penetrance breast cancers being scored as sporadic. Some scientific
evidence points to other breast cancer susceptibility genes that have yet to be
identified, and therefore, BRCAPRO is likely to overestimate the probability of
a BRCA mutation in a family. This model also fails to incorporate a previous
breast tissue diagnosis that may impact risk. When calculating the risk of
finding a BRCA mutation in a family, the uncertainty is even greater.
The Myriad tables should be used with caution, because the
informed consents used by many clinics may not allow for the dissemination of
family history information to the testing company. All models are meant only as
guides for the counselor and patient, setting the stage for a risk-evaluation
discussion tailored to the patient’s needs.
Although patients considering risk management options are often
referred to practitioners in other disciplines, it is neither time efficient nor
cost effective to have onsite multidisciplinary specialists. The model of a risk
evaluation clinic run by a genetic counselor or nurse geneticist plus a
physician versed in cancer genetics is widely adopted and appears to work quite
Treating Women at High Risk
for Breast Cancer
The earliest steps in breast carcinogenesis due to BRCA1/2
mutations are not completely understood. More information is needed prior to
making any definitive statements on genotype/phenotype correlations. A
preponderance of estrogen receptor-negative tumors may apply to BRCA1-related
disease, but not cancer associated with BRCA2. Regarding the use of selective
estrogen-receptor modulators for chemoprevention, we believe that raloxifene
(Evista) is not yet a risk-reduction alternative for high-risk breast cancer
patients outside of research protocols.
Breast conservation appears to be a reasonable option for most
women who are BRCA carriers. Nevertheless, women who are mutation carriers and
require mastectomy to treat a breast cancer diagnosis may wish to discuss the
risks and benefits of a possible bilateral prophylactic mastectomy, if they
desire reconstruction with autologous tissue after their therapeutic mastectomy,
as this type of reconstruction can, in general, only be performed once with
With or without reconstruction, prophylactic bilateral
mastectomy is an option that many BRCA1/2 carriers wish to discuss. The
usefulness of this risk management option is also controversial. A retrospective
study by Hartmann et al revealed a 90% reduction in breast cancer risk after
prophylactic mastectomy. However, it is not known how many of the women
studied actually had a BRCA1/2 mutation. Inclusion criteria for
"high-risk" women were broad and included variables that may not be
associated with an inherited susceptibility to breast cancer. Therefore, the
women in this cohort who underwent prophylactic mastectomy may not have been at
"high" enough risk. Furthermore, there are almost no data on any
long-term effects, such as quality of life and psychosexual function. These
results must be applied with caution to the BRCA carrier population until
further genetic information becomes available.
Controlling Breast Cancer Risk
We believe that significant scientific evidence supports certain
lifestyle interventions to control breast cancer risk. For example, limiting
alcohol to three to five drinks per week, consumption of more than five
servings of fruits and vegetables per day, and routine exercise[18,19] have
all shown substantial benefits with regard to breast cancer risk. It is
reasonable to consider counseling on these measures as part of a patient’s
breast cancer risk management.
The Health Insurance Portability and Accountability Act is a
major step forward in protecting patients from genetic discrimination. However,
detailed knowledge of its specific limitations is helpful for certain patients.
The protection provided by this law does not extend to life and disability
insurance, and we believe these issues should be discussed with patients,
especially young patients who may not have life and disability insurance.
In practical terms, there is a pressing need to more fully
understand the efficacy of lifestyle changes, as well as chemopreventive and
surgical interventions, as they apply to carriers of specific gene mutations. In
particular, appropriate end points and patient satisfaction should be studied,
in addition to cancer risk and survival. For example, research outcomes that
center on patient desires, satisfaction, and decision-making processes are
largely unknown for these high-risk individuals. Integrating this knowledge into
a more detailed understanding of hormone action on breast tissue will be needed
to design effective and comprehensive cancer risk reduction interventions for
women at high risk.
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