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© Oxford University Press 2007.
IN THIS ISSUE
Long-Term Preventive Effect of Tamoxifen on Breast Cancer RiskTamoxifen is not only an effective treatment for estrogen receptor (ER)-positive breast cancer, but it also reduces the risk of breast cancer in high-risk women. Reports from randomized trials show that both of these effects appear to persist beyond the active treatment period. However, tamoxifen also causes a range of side effects, including thromboembolic events and endometrial cancer. In this issue, Cuzick et al. (p. 272) report the results of an extended follow-up of the IBIS-I trial, which randomly assigned more than 7,000 high-risk women to take daily tamoxifen or a placebo for 5 years. After a median follow-up of 8 years, women in the tamoxifen group had a statistically significantly lower risk of breast cancer than those in the placebo group. The risk of side effects was higher in the tamoxifen group than the placebo group during active treatment, but those differences largely disappeared after active treatment ended. This finding indicates a more favorable benefit–risk ratio with longer follow-up than previously calculated.
A second study, the Royal Marsden trial, compared tamoxifen and placebo in a randomized, double-blinded breast cancer prevention trial. Patients were treated for 8 years, and afterward follow-up of the nearly 2,500 participants continued. Powles et al. (p. 283) report the results of the blinded 20-year follow-up. The risk of overall invasive breast cancer in the tamoxifen group was lower than that in the placebo group, but the difference was not statistically significant. During the 8-year treatment period, the risk of ER-positive breast cancer was approximately the same in both groups. However, in the post-treatment period, the risk was statistically significantly lower in the tamoxifen group than in the placebo group. The authors conclude that tamoxifen appears to have long-term effects in the prevention of ER-positive breast cancer.
In an editorial, Veronesi et al. (p. 258) note that the long-term results of both trials, together with data from several U.S. trials, demonstrate that the cost–benefit ratio of tamoxifen is favorable in certain groups of women. They contend that, collectively, these data move tamoxifen beyond the proof-of-principle stage and suggest that it should be considered as an option for chemoprevention of ER-positive breast cancer in high-risk women.
Test of New Selection Protocol for Lynch Syndrome Screening
Patients with Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), have a high risk of developing colorectal cancer at a young age. Members of families suspected of having HNPCC are offered counseling and prevention programs with regular colonoscopy to reduce disease morbidity and mortality. To more accurately diagnose HNPCC, Lagerstedt Robinson et al. (p. 291) tested a new protocol to select patients for genetic screening of mismatch repair genes using family members who had previously undergone counseling. (Germline mutations in these genes are found in many families with HNPCC.) More than half of the 112 patients from the 285 families selected for mutation screening had germline mutations in mismatch repair genes. The authors conclude that the new protocol substantially increases the detection of HNPCC.
In a related editorial, Lynch et al. (p. 261) discuss the progress that has been made in diagnosing HNPCC and the existing issues, complexities, and limitations of current diagnostic protocols.
Risk of Secondary Sarcoma In Childhood Cancer Survivors
Childhood cancer survivors have an increased risk of developing secondary sarcomas. To determine the true incidence of secondary sarcomas and associated risk factors, Henderson et al. (p. 300) analyzed data from more than 14,000 childhood cancer survivors. The risk of a sarcoma was more than ninefold higher among childhood cancer survivors than the general population. Increased risks of secondary sarcomas were associated with radiation therapy, a primary sarcoma diagnosis, a history of other secondary neoplasms, and treatment with higher doses of anthracyclines or alkylating agents.
KISS1 Secretion and Processing and Metastasis Suppression
The KISS1 metastasis suppressor gene encodes a secreted protein that is processed into a series of smaller peptides known as kisspeptins. To investigate the role of KISS1 secretion and processing in the suppression of metastasis, Nash et al. (p. 309) engineered epitope-tagged versions of intact KISS1 and of a nonsecretable form of KISS1. They then introduced these to human melanoma cells by transfection. Only cells transfected with the intact form secreted kisspeptins to the medium, and such cells developed fewer metastases in vivo than cells transfected with the nonsecretable form. Although kisspeptin activity in an entirely different context—regulation of sexual maturation—is mediated by binding to the GPR54 G protein–coupled receptor, the authors note that the low expression of GPR54 on the melanoma cells used in this study suggests that kisspeptins may act through a different receptor or a paracrine mechanism in the suppression of metastasis. Whatever the mechanism, they suggest, exogenous kisspeptins may have the capacity to modify metastasis in vivo.
Bisphosphonate Dosing Regimens in a Metastasis Model
Bisphosphonates exhibit antitumor activity in animal models, but only at high doses that are incompatible with the clinical dosing regimens approved for treating cancer patients with skeletal metastases. Daubiné et al. (p. 322) compared the antitumor effects of clinical dosing regimens for the bisphosphonates zoledronic acid and clodronate in a mouse model of bone metastasis. When given after intravenous injection with human breast cancer cells, daily clodronate was less effective at decreasing skeletal tumor burden than daily or weekly zoledronic acid. When given before breast cancer cell injection, daily clodronate and daily or weekly zoledronic acid were more effective at decreasing the tumor burden than the control (water alone). A single dose of zoledronic acid given before or after breast cancer cell injection was ineffective. The authors conclude that daily or repeated intermittent therapy with clinical doses of bisphosphonates inhibits skeletal tumor growth in this mouse model.
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Del.icio.us What's this?
J Natl Cancer Inst 2007 99: 258-260.
J Natl Cancer Inst 2007 99: 261-263.
J Natl Cancer Inst 2007 99: 272-282.
J Natl Cancer Inst 2007 99: 283-290.
J Natl Cancer Inst 2007 99: 291-299.
J Natl Cancer Inst 2007 99: 300-308.
J Natl Cancer Inst 2007 99: 309-321.
J Natl Cancer Inst 2007 99: 322-330.
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