Genetic Predisposition and Chemoprevention: What Have We Learned?
Kathleen I. Pritchard, MD and Pamela Goodwin, MD, MSc, FRCP
The role of genetics in breast cancer risk has been a hot topic of discussion over the past few years. One session, chaired by Dr. Judy Garber, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and Dr. Monica Morrow, of the Northwestern University Medical School in Chicago, Illinois, offered an update on the roles of BRCA1 and BRCA2 in hereditary breast cancer.
A complementary session, chaired by Dr. Trevor Powles, of the Royal Marsden Hospital in Surrey, United Kingdom, discussed the most recent chemoprevention strategies.
BRCA1, BRCA2, and Beyond
The 2 major breast cancer predisposition genes, known as BRCA1 and BRCA2, have been implicated in up to 40% of hereditary breast cancers. However, between 35% and 70% of women who appear to have a hereditary predisposition to breast cancer do not have identifiable mutations in either BRCA1 or BRCA2, suggesting that there are as yet undiscovered genes contributing to hereditary breast cancer risk.Clinical testing for mutations in 1 of these 2 genes is complicated by the fact that a broad range of protein-truncating mutations have been identified in both genes. Additional missense mutations, particularly these mutations, which are believed to be associated with cancer risk, have an uncertain effect on disease risk.
The identification of founder mutations in some populations (Ashkenazi -- 185delAG or 5382insC in BRCA1 and 6174delT in BRCA2; Icelandic -- 999delT in BRCA2) facilitates targeted testing in selected populations. However, in most families, mutation analysis should begin with an affected individual who has the greatest likelihood of carrying a mutation. Once a mutation has been identified, informative testing can then be offered to other family members.
Breast cancer risk in carriers of mutations has been reported to range from 85% in members of high-risk families to 50% or lower in unselected Ashkenazi individuals and/or lower risk families. It is not clear what determines these differences in penetrance. Nevertheless, testing for mutations can be crucial, since, in addition to widely recognized increases in breast and ovarian cancer risk, carriers of mutations in these genes, particularly BRCA2, may also be at increased risk for pancreatic carcinoma, prostate cancer, and melanoma.
Management of breast cancer risk in carriers of mutations was also discussed. Although data from randomized trials are not available, observational data indicate that prophylactic mastectomy reduces the risk of subsequent breast cancer by 90% or more in high-risk individuals. Similar data are not available regarding carriers of mutations, but it appears that the greatest benefit may be seen when prophylactic mastectomy is done at an earlier age and in high-penetrance families.
The benefits of hormonal intervention is unclear. Prophylactic oophorectomy has been reported to reduce breast cancer risk by up to 50% in mutation carriers,[6-9] and 1 case-control study suggests that tamoxifen lowers breast cancer risk in the same group of women. However, most breast cancers in BRCA1 carriers are estrogen-receptor-negative, which would therefore likely be unaffected by such hormonal interventions.[11-13] Furthermore, data from a UK trial of tamoxifen vs placebo in women with a strong family history of breast cancer suggest that tamoxifen is ineffective in lowering breast cancer risk in this population.
Thus, the benefits of hormonal intervention in carriers of mutations are unclear.Given these data, additional research clearly needs to be done to better understand the function of BRCA1 and BRCA2, the factors that influence penetrance in different families, and the optimal approaches to cancer risk management.
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