Physicians and patients have become increasingly aware that women
with a personal or family history of early-onset breast and/or
ovarian cancer have a significant probability of carrying an altered
breast cancer susceptibility gene. The elegant work of many groups,
nicely summarized in the article by Ms. Cummings and Dr. Olopade, has
begun to provide more specific information for patients and
physicians facing medical decisions, such as those illustrated in the
cases provided in the article.
The American Society of Clinical Oncology (ASCO) has mandated that
medical oncologists be able to recognize inherited cancer syndromes
and discuss with patients the advantages and disadvantages of genetic
testing, based on their individual circumstances. The article
provides much information that should prove useful to oncologists who
want to incorporate inherited breast and ovarian cancer and genetic
testing issues into patient care--whether they provide the testing
and counseling themselves or refer patients to other professionals
for those services.
Genetic testing for cancer susceptibility may help specify cancer
risk assessment for unaffected individuals. Cancer patients and
survivors face a complementary set of issues, which may be more often
encountered by medical oncologists.
Importance of Risk Assessment
The high cost of the resources currently necessary to provide genetic
testing--the actual tests and the hours of counselor/physician
time--have made it reasonable for most programs to offer testing only
to individuals who have a sufficient prior probability of carrying a
mutation, which is often set at about 10%. This probability is
estimated from pedigrees by considering the pattern of breast and
ovarian cancers in a family, ages at diagnosis, and ethnic
derivation. In addition to the approaches described by Cummings and
Olopade, newer models for the personal computer developed at Myriad
Genetics or by Berry and colleagues may further facilitate risk
assessment for complex families by providing more accurate estimates
of their chances of carrying alterations in specific susceptibility genes.[1,2]
Pedigree interpretation and model estimation are the first links in
the chain of probabilistic statements that comprise cancer risk
estimation. Despite the mathematical complexities, all of the
conditional statements in risk estimation--the chance that a
particular cancer or second malignancy will occur by a certain age,
the chance that a deleterious mutation informing that risk will be
found, and, ultimately, the chance that specific interventions will
alter these risks--are not fundamentally different from the
probabilistic information contained in staging algorithms or
treatment trial results. They should, therefore, easily become
familiar territory for oncologists.
Communication of these complex statements and the issues that they
raise for self-image, family communication, and insurance or
employment discrimination is a difficult task. Thus, statements by
official bodies recommend the involvement of a trained genetic
counselor or nurse geneticist as a required component of genetic testing.
As is true for cancer treatment, cancer risk analysis is only as good
as the data on which it is based. Medical documentation of key cancer
diagnoses in relatives permits risk assessments to be as accurate as
possible. Results of genetic tests may assist in cancer risk
estimation. If a genetic test result is not clearly positive,
assessment of the risk of cancer reverts to estimation based on
family history, the accuracy of which may be especially important if
a patient plans prophylactic surgery.
For example, a 35-year-old woman with early-stage breast cancer who
is contemplating prophylactic oophorectomy who reports that her
mother and sister were diagnosed with breast and ovarian cancer,
respectively, by 40 years old has a very high likelihood of carrying
a hereditary predisposition, even if BRCA1 and BRCA2 analyses are
negative. However, if the mother really developed breast cancer at
age 70 and the sister actually had ovarian cysts, the negative test
is much more reassuring and prophylactic oophorectomy would not be
advised or encouraged.
Small families pose a special challenge since individuals may harbor
a germ-line BRCA1 or BRCA2 mutation without a remarkable family
cancer history, as when an altered gene has been transmitted through
the paternal lineage. The chance that a woman with breast cancer
diagnosed before age 30 will have a germ-line BRCA1 or BRCA2 mutation
exceeds 10%, even if she has no other affected relatives, and would
surpass 20% if she were of Ashkenazi Jewish descent.[4,5] Eventually,
rapid inexpensive genetic analysis will replace all of the risk models.
The current availability of genetic testing has not resulted in
uniformly high demand for its use, even among cancer patients. There
have been serious concerns about insurance discrimination, personal
coping, and familial relationships. Ultimately, an individual may
decide to learn her genetic status if the information would influence
medical decisions about cancer treatment, surveillance, or
prevention; provide risk information to other family members; or just
for the sake of knowing about her risk or the "reason" for
her own cancer (see the authors Table 7).
Should Inherited Breast Cancers Be Managed Differently?
Whether the management of inherited cancers should differ from that
of the more common sporadic tumors remains to be determined.
Comparison of the pathologic features of BRCA1- and BRCA2-related
breast cancers with those of sporadic controls have revealed that
high nuclear grade and medullary subtype--features generally more
common in younger women--occur more frequently among BRCA1-related
tumors. Population-based series comparing survival in patients
with hereditary vs sporadic breast cancers have generally shown no
significant differences, stage for stage.[7,8]
The interaction of the BRCA1 and BRCA2 gene products with proteins
involved in the repair of radiation-induced DNA errors have raised
concerns that adjuvant radiation therapy may increase the rates of
local recurrence, radiation-induced second primary cancers, or
treatment-related complications in mutation carriers. Since early
data do not confirm increased radiation-related toxicities in women
with inherited breast cancer, these concerns remain hypothetical at
present.[10,11] Nevertheless, physicians may want to discuss these
issues, as well as the increased rate of contralateral breast cancers
in mutation carriers, when making primary therapy recommendations at
diagnosis. No data regarding differential efficacy of chemotherapy or
tamoxifen (Nolvadex) in inherited vs sporadic breast cancers have yet appeared.
Breast or Ovarian Cancer Survivors
Given the limitations of current analytic technologies, a woman who
has survived breast or ovarian cancer is often the family member
whose genetic test results would be most informative for other
relatives. In our experience, cancer survivors are often less
surprised to learn of positive results and have more difficulty
coping with negative results. The existence of other genes that
confer breast cancer susceptibility leaves open the possibility that
their cancer has an inherited component, and does not completely
eliminate the possibility that the survivor has passed on an
increased risk to her offspring.
Contrary to expectation, women found to carry a predisposing mutation
may find themselves somewhat isolated within their families if,
despite earlier conversations, relatives do not eagerly opt for
testing. Certainly, many families are supportive and open with each
other, but others bring their particular difficulties in
communication to the issues raised by testing. Individuals who
provide psychosocial and emotional support services for patients at
high risk of developing cancer may benefit from some targeted
education about the issues raised by this emerging approach to cancer
1. Frank TS, Manley S, Thomas A, et al: Sequence analysis of BRCA1
and BRCA2: Correlation of mutations with family history and ovarian
cancer risk. J Clin Oncol 61:2417-2425, 1998.
2. Parmigiani G, Berry DA, Aguilar O: Determining carrier
probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2.
Am J Hum Genet 62:145-158, 1998.
3. Statement of the American Societ of Clinical Oncology: Genetic
testing for cancer susceptibility. J Clin Oncol 14(5):1730-1736, 1996.
4. Fitzgerald MG, MacDonald DJ, Krainer M, et al. Germ-line BRCA1
mutations in Jewish and non-Jewish women with early onset breast
cancer. N Engl J Med 334:143-149, 1996.
5. Rao BB, Boyd AA, Volick K, et al: Ashkenazi Jewish population
frequencies for common mutations in BRCA1 and BRCA2. Nat Genet
6. Breast Cancer Linkage Consortium: Pathology of familial breast
cancer: Differences between breast cancers in carriers of BRCA1 or
BRCA2 mutations and sporadic cases. Lancet 349:1505-1510, 1997.
7. Verhoog L, Brekelmans C, Seynaeve C, et al: Survival and tumor
characteristics of breast cancer patients with germline mutations of
BRCA1. Lancet 351:316-321, 1998.
8. Johannasson OT, Ranstam J, Borg A, et al: Survival of BRCA1 breast
and ovarian cancer patients: A population-based study from southern
Sweden. J Clin Oncol 16: 397-404, 1998.
9. Scully R, Chen J, Plug A, et al: Association of BRCA1 with Rad51
in mitotic and meiotic cells. Cell 88:265-275, 1997.
10. Chabner E, Nixon A, Gelman R, et al: Family history and treatment
outcome in young women after breast-conserving surgery and radiation
therapy for early stage breast cancer. J Clin Oncol 16:2045-1051, 1998.
11. Robson ME, Gilewski T, Hass B, et al: BRCA-associated breast
cancer in young Jewish women. J Clin Oncol 61:1642-1649, 1998