April 13, 2004 Access past issues

Reviewed by: Carol Smigal Rollins School of Public Health Emory University

The Health Outcome

Breast cancer is the most common form of cancer among women. According to the American Cancer Society, in 2003, approximately 267,000 women will be diagnosed with breast cancer in the US (1). Many breast cancer tumors contain estrogen receptors. Estrogens have been found to play a major role in the etiology of breast cancer (2). Tamoxifen is a chemopreventive agent that works by blocking the effect of estrogen on breast tissue. In the National Surgical Adjuvant Breast and Bowel Project P-1 Study (3), tamoxifen has been shown to reduce the risk of estrogen receptor (ER)-positive tumors, but not ER-negative tumors. There have been a multitude of studies that have examined variants of genes involved in estrogen metabolism in association with breast cancer, but none had specifically considered the estrogen receptor status of the tumors.

The Finding

Myoshi et al. investigated the association of polymorphisms in genes CYP19 and CYP1A1 and breast cancer (4). Their goal was to determine if the association would provide useful information for women considering chemoprevention with tamoxifen.

They conducted a case-control study of 257 Japanese women with histologically confirmed breast cancer and 191 controls selected from women who attended a breast cancer screening program in Osaka , Japan . All participants were genotyped for CYP19 and CYP1A1 polymorphisms.

The prevalence of the polymorphisms can be estimated in the population by examining the prevalence in the controls. Coincidentally, the prevalence of both CYP19 and CYP1A1 polymorphisms individually was 38.7% in the controls. 13% of the controls were carriers of both high-risk genotypes.

The authors then examined the association of each of these genotypes with breast cancer. The presence of the
CYP19 (TTTA) _7(-3bp) variant was found to be associated with an increased risk of ER-positive, but not ER-negative breast cancer. Though CYP1A1 was not in itself associated with increased risk, the combination of the two high risk genotypes was associated with an increased risk of ER-positive breast cancer. The resulting odds ratio (adjusted for age, parity, family history, and body mass index) was found to be 3.00 (1.56 -5.74) in all women and 5.37 (1.74 -16.63) in post-menopausal women.

In addition, the authors hypothesized that these polymorphisms might be related to breast cancer via their effect on estrogen metabolism. In order to test this hypothesis, they compared the serum estrogen level in controls with high and low risk genotypes. They did not find a significant difference in the estrogen levels of these groups. This finding failed to support their hypothesis.

Public Health Implications

In an effort to accurately identify candidates for whom tamoxifen would be beneficial, the authors attempt to identify genetic risk factors for the ER-positive form of breast cancer. Based on the results of this study, 22% of ER-positive breast cancer can be attributed to the presence of the CYP19 repeat. The attributable fraction (AF) due to the presence of both high-risk genotypes with ER+ breast cancer is 20.1% in all women, 10.0% in premenopausal women, and 36.2% in post-menopausal women. It is important to note that the finding for post-menopausal women was based on only 20 cases and 13 controls. In fact, in the analysis that stratified on number of high-risk alleles and menopausal status, none of the OR's were statistically significant.

Though this information may not be relevant to the general population, it does appear that these findings may be a significant source of information for women debating the use of tamoxifen. Currently, this prophylaxis is recommended only for high-risk women. Therefore, the prediction of ER-positive breast cancer is relevant to chemoprophylaxis only in a high-risk population. No results are presented stratified on family history or age at diagnosis. It would be beneficial for further studies to examine the predictive value of CYP19 (TTTA) _7(-3bp) or CYP1A1 ⁶²³⁵C) in high-risk populations.

References

1. American Cancer Society. Cancer facts and figures 2003-2004. Atlanta : The American Cancer Society; 2003 .
2. Kristensen V, et al. Molecular epidemiology of breast cancer: genetic variation in steroid hormone metabolism. Mutation Research. 2000 Apr;462(2-3):323-33.
3. Fisher B, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. Journal of the National Cancer Institute. 1998 Sep;90(18):1371-88.
4. Miyoshi Y, et al. Association of genetic polymorphisms in CYP19 and CYP1A1 with the oestrogen receptor-positive breast cancer risk. European Journal of Cancer. 2003 March;39(17):2531-2537.