Hereditary breast and ovarian cancers

June C. Carroll; Carol Cremin; Judith Allanson; Sean M. Blaine; Heather Dorman; Clare A. Gibbons; Jeremy Grimshaw; Christina Honeywell; Wendy S. Meschino; Joanne Permaul; Brenda J. Wilson

Breast cancer is more common in older women, but 1 in every 250 women in their 30s could develop breast cancer over the next 10 years. The causes are not yet known, although a diet high in fat, excess alcohol use, and smoking are contributing factors. Women who carry the BRCA1 or BRCA2 gene mutations are at a much higher risk of developing the disease.

Statistics

Twenty percent of breast cancer is familial (family history of breast cancer). Approximately 5% to 10% of breast cancer is hereditary—a gene mutation has been inherited, which puts the patient at an increased risk of cancer. Two-thirds of these hereditary cancers occur in individuals with BRCA1 or BRCA2 mutations, which are germline mutations. The remaining 10% to 15% is due to some other factor involving the family, such as an environmental factor, chance, or an undiscovered gene mutation. The consequences of having a BRCA mutationare outlined in Table 1.

View this table:

Table 1

Estimated risk of developing cancer by age 70 in BRCA mutation carriers compared with the general population.

BRCA genes

More than 2600 mutations have been found on chromosome 17 in BRCA1 and on chromosome 13 in BRCA2.
These gene mutations have the following characteristics:
- — autosomal dominant transmission and
- — a carrier frequency of approximately
  - -1 per 800 people in the general (White) population and
  - -1 per 40 to 50 people in the Ashkenazic Jewish population (3 common mutations in Ashkenazic Jews).
Both genes are tumour suppressors.
Mutation of these genes leads to the following:
- — an inability to regulate cell death and
- — uncontrolled cell growth leading to cancer.

Who should be offered referral?

Referral for genetic counseling or testing should be offered to patients who meet the following criteria:

multiple cases of breast or ovarian cancer on same side of the family, especially
- — in closely related relatives,
- — in more than 1 generation, and
- — when breast cancer is diagnosed before age 50;
a family member with breast cancer diagnosed before age 35;
a family member with both breast and ovarian cancers;
an Ashkenazic Jewish heritage, particularly with relatives with breast or ovarian cancer;
a family member with primary cancer in both breasts, especially if diagnosed before age 50;
a family member with ovarian cancer;
a family history of male breast cancer; or
a family member with an identified BRCA1 or BRCA2 mutation.

Testing for the faulty genes, BRCA1 and BRCA2, involves a blood test, which is usually available at regional genetic centres and some cancer centres. The test is covered by most provincial health plans if there is a substantial risk. In Ontario, for example, testing eligibility criteria reflect a 10% or higher risk of mutation; affected individuals in a family who are the highest risk are tested first. Genetic testing is generally not offered to unaffected individuals unless a mutation has been identified in the family.

Benefits of genetic testing

Positive test result

Clinical intervention can improve outcomes: risk-reduction mastectomy reduces risk of breast cancer; salpingo-oophorectomy reduces risk of breast and ovarian cancers; and magnetic resonance imaging enhances surveillance for breast cancer.
Family members at risk can be identified.
Positive health behaviour can be reinforced.

Negative test result

Gives reassurance to individuals and their children.

Harms and limitations of genetic testing

There are potential negative aspects to genetic testing for the mutated BRCA genes:

Positive test result

Adverse psychological reaction leading to family issues and distress.
Job or insurance discrimination.
Confidentiality issues, especially among family members.
Incomplete penetrance—having the mutation does not necessarily mean the patient will get the disease.

Negative test result

Adverse psychological reaction, which can include survivor guilt.
Might lead to a complacent attitude toward health.

There are also cases of uninformative test results (variants of unknown significance). In these cases, genetic testing does not detect the gene mutations, even in families with a strong history of breast or ovarian cancer. This underlines our incomplete understanding of inherited susceptibility to cancer.

Bottom line

Increasing age is still the main risk factor for breast cancer. People with “high risk” family histories of breast or ovarian cancer should be offered referral to genetics services, with a discussion of the benefits, harms, and limitations of genetic testing. Risk-reduction mastectomy and oophorectomy can reduce mortality from breast and ovarian cancers in BRCA1 and BRCA2 carriers. Women with “low risk” family histories should be reassured and offered screening, as per general population guidelines.

Additional resources

Predictive Cancer Genetics Steering Committee. Ontario physicians’ guide to referral of patients with family history of cancer to a familial cancer genetics clinic or genetics clinic. Toronto, ON: Ontario Medical Association; 2001. Available from: www.oma.org/pcomm/OMR/nov/01genetics.htm.

Horsman D, Wilson BJ, Avard D, Meschino W, Kim Sing C, Plante M, et al. Clinical management recommendations for surveillance and risk-reduction strategies for hereditary breast and ovarian cancer among individuals carrying a deleterious BRCA1 or BRCA2 mutation. J Obstet Gynaecol Can 2007;29(1):45–60.

Narod SA, Offit K. Prevention and management of hereditary breast cancer. J Clin Oncol 2005;23(8):1656–63.

For a listing of cancer genetics clinics in Canada, along with their respective contact and referral information, visit the Canadian Association of Genetic Counsellors website at www.cagc-accg.ca.