Atypical hyperplasia: preventing development of breast cancer – pro

Atypical ductal hyperplasia is a condition which raises a risk of cancer but is not in itself cancer. As such, it does not fit the guidelines criteria to approve BRCA testing on the basis of the personal history of breast cacner. In fact, this condition is known to be prophylaxed by the use of tamoxifen, which is also an option for BRCA carriers. However, other BRCA options, such as prophylactic mastectomy and oophorectomy are not routinely performed for atypical ductal hyperplasia. Performing BRCA testing is not idicated for prevention of this condition.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 study reported a nearly a 57% increase in invasive cancer compared to patients without atypical hyperplasia (10.11 events per 1,000 patients vs 6.44 events per 1,000 patients) with a mean follow-up of 47.7 months.

The most extensive evaluation of chemoprevention agents has been with tamoxifen. Tamoxifen, a selective estrogen receptor modulator (SERM), inhibits the binding of estrogen to estrogen receptors and also acts as an agonist on bone, the uterus, and liver. The data from multiple, randomized studies have supported the use of tamoxifen for prevention of breast cancer in high-risk individuals. The largest of these studies, the Breast Cancer Prevention Trial (NSABP P-1), compared tamoxifen to placebo in over 13,000 women with a Gail model score ≥ 1.66%. The study was halted early due to a 49% reduction of invasive breast cancer. More specifically, tamoxifen reduced the risk of breast cancer in LCIS patients by 56% and in atypical hyperplasia patients by 86%. It is interesting that tamoxifen preferentially decreased the incidence of estrogen receptor (ER)-positive tumors, a common finding of atypical hyperplasia and LCIS.[61,62] In addition, there was a 50% reduction in the incidence of noninvasive cancers in the tamoxifen arm. Adverse outcomes due to tamoxifen, such as increased risk of endometrial cancer and thromboembolic events, were reported (risk ratio of 2.53 for endometrial cancer and 3.01 for pulmonary embolism).

A smaller reduction was noted in the International Breast Cancer Intervention Study (IBIS-I) in which a 32% risk reduction was noted after 50 months in patients with a greater than twofold relative risk of breast cancer. Two additional European studies, the Royal Marsden Hospital study and the Italian study, have failed to demonstrate a statistical benefit toward tamoxifen, but many believe that differences in patient selection, poor compliance, and insufficient power account for the differences. A further meta-analysis of these four trials produced a 38% reduction in the incidence of breast cancer and decreased ER-positive tumors by 48%.

Raloxifene, a second-generation SERM, is similar to tamoxifen in its effects on breast, bone, and liver. However, raloxifene is not an estrogen agonist on the uterus. The initial study, the Multiple Outcomes of Raloxifene Evaluation (MORE), primarily evaluated osteoporosis with a secondary endpoint of breast cancer incidence. A 76% decrease in breast cancer incidence was noted in the raloxifene group compared to placebo over 4 years. The Continuing Outcomes Relevant to Evista (CORE) trial further evaluated raloxifene after 4 additional years of use, for a total of 8 years. A 66% reduction was noted in the raloxifene arm of the study. The results of these trials led to the NSABP STAR P-2 trial where 5 years of raloxifene was compared head-to-head with 5 years of tamoxifen in high-risk, postmenopausal individuals. Raloxifene could not be administered to premenopausal women secondary to increased incidence of ovarian cyst. In approximately 20,000 randomized patients, there were no statistical differences in invasive breast cancer incidence between the two groups (P=.83). Compared with tamoxifen, the raloxifene arm had fewer in the number of uterine cancers (P=.07), thromboembolic events (P=.01), and cataracts (P=.002). These results support the use of raloxifene as an alternative to tamoxifen. It is important to note that the incidence of noninvasive cancer was lower in the tamoxifen arm although this was not statistically significant (P=.052).
More recently, it had been realized that there is an associaiton between preinvasive lesions and BRCA positivity(9,10); however, there is no evidence that preventive strategies are useful and guidelines continue to not recommend BRACA tests for women with arypical hyperlasia.
  1. Cuzick J, Forbes J, Edwards R, et al. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet. 2002;360:817-824.
  2. Powles T, Eeles R, Ashley S, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet. 1998;352:98-101.
  3. Veronesi U, Maisonneuve P, Costa A, et al. Prevention of breast cannncer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet. 1998;352:93-97.
  4. Bao T, Prowell T, Stearns V. Chemoprevention of Breast cancer: tamoxifen, raloxifene, and beyond. Am J Ther. 2006;13:337-348.
  5. Cuzick, J, Powles T, Veronesi U, et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet. 2003;361:296-300.
  6. Cummings SR, Eckert S, Krueger KA, et al. The effect on raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Mutiple Outcomes of Raloxifene Evaluation. JAMA. 1999;281:2189-2197. Erratum in: JAMA. 1999 Dec 8;282(22):2124.
  7. Martino S, Cauley JA, Barrett-Conner E, et al. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst. 2004;96: 1751-1761.
  8. 8.Banu Arun et a, High Prevalence of Preinvasive Lesions Adjacent to BRCA1/2-Associated Breast Cancers Cancer Prev Res February 2009 2; 122
  9. Michael J. Hall et al, Prevalence of BRCA1 and BRCA2 Mutations in Women with Breast Carcinoma In Situ and Referred for Genetic Testing Cancer Prev Res December 1, 2010 3:12 1579-1585

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