Q. Are there known major mutations which lead to breast cancer or is there a familial tendency without identifiable mutations?

A. Both are true. First degree relatives of breast cancer patients and dizygotic twins have about 1.7 times the usual risk of developing breast cancer, while monozygotic twins have about 4.4 times the predicted risk, probably from multiple identical inherited alleles.

According to the National Cancer Institute, the syndromes most associated thus far with an autosomal dominant inheritance of breast cancer risk are hereditary breast and ovarian cancer arising from BRCA1 or BRCA2 mutations, Li-Fraumeni syndrome from p53 mutations and Cowden syndrome resulting from PTEN mutations.

Q. For which mutations should she be screened?

A. Thousands of mutations have already been identified. An Open Access On-Line Breast Cancer Mutation Data Base is available at the National Human Genome Research Institute web site.

In this patient, an inquiry should be made as to which mutation was identified in her aunt in order to make screening much easier. Her aunt's mutation was identified as being BRCA2-6174delT. The patient underwent mutation specific sequence analysis for the familial mutation (BRCA2- 6174delT) and, unfortunately, she was found to have the same BRCA2 gene mutation as her maternal aunt. This mutation and a specific BRCA1 mutation (185delAG) have been reported to be common among Ashkenazi Jews (those tracing their roots to Central and Eastern Europe.) More information here.

Carrier frequencies for these mutations have been determined in the general Jewish population, 1.1 percent (95 percent CI 0.7 percent-1.3 percent) for the 185delAG mutation and 1.5 percent (95 percent CI) for the BRCA2, 6174delT mutation. The combined frequency of these two mutations approximates 1 in 50 among Ashkenazi Jews, accounting for 25 percent of early-onset breast cancer and up to 90 percent of families with multiple cases of both breast and ovarian cancer among Ashkenazi Jews.

Q. What are the BRCA genes and what do they encode?

A. BRCA1 and BRCA2 are tumor suppressor genes and mutations of these genes lead to chromosomal instability and cancer susceptibility. Yang et al.(8) have described how BRCA2 functions in DNA binding and repair.

There are at least 13 known mutations and some long rearrangements that are responsible for breast and ovarian cancer. The BRCA1 and BRCA2 genes encode proteins involved in the cellular response to DNA damage. Inactivating mutations in these genes heighten susceptibility to breast and ovarian cancers. The susceptibility to cancer results from inheritance of one mutant allele of either BRCA1 or BRCA2 (autosomal dominant transmission), followed by the loss of the second allele in breast or ovarian epithelial cells (loss of heterozygosity), leading to complete inactivation of the gene. The prevalence of germ-line (inherited) BRCA1 and BRCA2 mutation in general population is 0.1 to 0.2 percent. These mutations contribute to approximately 10 percent of all breast cancer. However, in women younger than 40 years of age with breast cancer and familial cases approximately 75 percent carry these mutations.

Carriers of mutation in BRCA1 are thought to have a 50 to 85 percent lifetime risk of breast cancer and a 20 to 40 percent lifetime risk of ovarian cancer. Women with mutation of BRCA2 appear to have similar risk of breast cancer and a 10 to 20 percent risk of ovarian cancer. Familial cancer tends to occur at a younger age than the sporadic cancer. However, the increased risk in carriers of these mutations is lifelong and in some carriers bilateral breast cancer or both breast and ovarian cancer develop:(1)

Q. How can genetic counseling help in this case?

A. Genetic testing by DNA mutation analysis can help to provide an estimate of risks and provide information for decision-making. Before testing, a patient must be informed about and have a clear understanding of the risks and benefits of genetic testing. Genetic counseling should be offered before testing as well as after the results are received. For more discussion of the ethical issues, please look at an earlier Cyberounds^®, The Privacy of Genetic Information.

Q. What is the patient's risk for developing breast cancer?

A. Although her precise increased risk for developing breast cancer cannot be quantified, studies of this type of mutation in high-risk families indicate that deleterious mutations in BRCA2 may confer as much as an 84 percent risk of breast cancer.(2)

Q. Does she also have an increased risk of developing ovarian cancer or other cancers?

A. Yes, deleterious mutations in BRCA2 may confer as much as a 27 percent risk of ovarian cancer by age 70 in women.(2) Mutations in BRCA2 have also been reported to confer a 12 percent risk of a second breast cancer within five years of the first incidence,(3) as well as a 16 percent risk of subsequent ovarian cancer.(4)

Q. What is the risk for the men in the family?

A. This mutation is not sex-linked, so men also carry it. This mutation may also confer up to a 6 percent risk of male breast cancer and 8 percent risk of prostate cancer by age 70, as well as increased (albeit low) risks for some other cancers.(4) If the individual is of Ashkenazi Jewish ancestry, it is recommended that follow up testing of relatives of this individual include analysis for the mutations 187delAG, 5385insC and 6174delT because of reports of coexistence of two high frequency germ line mutations in some Ashkenazi families.(5) Men who carry this mutation may also pass it on to their sons and daughters and they should also be screened. Breast cancer information is sometimes only shared among the female family members and getting the information to the males may require special effort.

Q. What are the implications for this woman's children?

A. Each of the patient's children has a 50 percent chance for having the mutation. Males with BRCA2 mutations have a increased risk for male breast cancer and prostate, colon and larynx cancer. It would be of value for the patient's sons to be informed about the mutation so that their daughters can have appropriate testing. The patient's brother should also be tested to determine if he and/or any of his children have an increased risk.

Q. What intervention(s) should now be considered for this patient?

A. Continued monthly breast self-examinations, clinical breast examination every six months and frequent periodic breast imaging, including mammography, are indicated for the patient. Total bilateral mastectomy is an alternative option, which although it does not eliminate the risk would reduce residual risk to approximately 3-5 percent.

The patient's approximate risk for getting ovarian cancer is 27 percent.(2) The options for dealing with her possible increased risk for ovarian cancer include removal of the ovaries (oophorectomy), with or without hysterectomy, because once ovarian cancer is detected it is usually too late to successfully treat it. Oophorectomy reduces, but does not totally eliminate, the risk for ovarian cancer, as there remains a residual risk of approximately 3-5 percent (fallopian tube and primary peritoneal cancer).

Finally, there is also an increased incidence of pancreatic cancer associated with BRCA1 and BRCA2 mutations but close surveillance is difficult.

Q. If oophorectomy is carried out, what are the implications with respect to the resultant menopause?

A. Menopause resulting from the removal of the ovaries in premenopausal women will increase the risk for osteoporosis, cardiovascular disease, hot flashes and sexual dysfunction. Hormone replacement therapy is not an option because of the associated increased risk for breast cancer and endometrial cancer.

If tamoxifen were under consideration for chemoprophylaxis against breast cancer, hysterectomy plus oophorectomy would remove the risk of endometrial cancer caused by this medication, although it increases the complexity of the surgical procedure.

Conclusion

In conclusion, bilateral salpingo-oophorectomy in carriers of BRCA mutations can decrease the risk of breast cancer and BRCA related gynecologic cancer.(6),(7) Continued surveillance for papillary serous carcinoma of the peritoneum after oophorectomy is warranted, and salpingo-oophorectomy should be considered, given reports of tumors arising from the fallopian tubes in carriers of BRCA mutation. Prophylactic oophorectomy should not be recommended to women with high risk of breast cancer who do not have documented mutations in BRCA1 or BRCA2, since these cases may be linked to mutations in unidentified genes that do not increase the risk of ovarian cancer. The effectiveness of prophylactic oophorectomy in carriers of BRCA mutations provides a compelling rationale for genetic testing in women with a strong family history of breast cancer.