Tamoxifen Prevents Breast Cancer, Too

Tamoxifen Prevents Breast Cancer, Too–Or Does It?

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period May- Jun 00	Rank Last Period Mar- Apr 00
1	S. Hulley, et al., "Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women," JAMA-J. Amer. Med. Assoc., 280(7):605-13, 19 August 1998. [U. Calif., San Francisco; Johns Hopkins U., Baltimore, MD; Wake Forest U. Sch. Med., Winston-Salem, NC; Wyeth-Ayerst Res., Radnor, PA] *110ME	51	4
2	L. Hansson, et al., "Effects of intensive blood-pressure- lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial," The Lancet, 351(9118):1755-62, 13 June 1998. [10 institutions worldwide] *ZU444	43	2
3	B. Fisher, et al., "Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study," J. Natl. Cancer Inst., 90(18):1371-88, 16 September 1998. [10 U.S. and Canadian institutions] *120NT	41	1
4	J.G. McHutchinson, et al., "Interferon alpha-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C," New Engl. J. Med., 339(21):1485-92, 19 November 1998. [8 U.S. institutions] *139VT	30	5
5	D.M. Eisenberg, et al., "Trends in alternative medicine use in the United States, 1990-1997: Results of a follow-up national survey," JAMA-J. Amer. Med. Assoc., 280(18):1569-75, 11 November 1998. [Beth Israel Deaconess Med. Ctr., Boston, MA; Harvard Med. Sch., Boston] *136GX	30	†
6	G.L. Davis, et al., "Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis c," New Engl. J. Med., 339(21):1493-9, 19 November 1998. [10 institutions worldwide] *139VT	26	10
7	B. Pitt, et al., "The effect of spironolactone on morbidity and mortality in patients with severe heart failure," New Engl. J. Med., 341(10):709-17, 2 September 1999. [6 institutions worldwide] *231DB	25	†
8	T. Poynard, et al., "Randomised trial of interferon ALPHA2b ribavirin for 48 weeks or for 24 weeks versus interferon ALPHA2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus," The Lancet, 352(9138):1426-32, 31 October 1998. [11 institutions worldwide] *134AJ	23	9
9	L. Zhang, et al., "Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy," New Engl. J. Med., 340(21):1605-13, 27 May 1999. [Aaron Diamond AIDS Res. Ctr., New York, NY; Bernhard Nocht. Inst. Trop. Med., Hamburg, Germany; Los Alamos Natl. Lab, NM] *199QY	20	†
10	M.R. Furtado, et al., "Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy," New Engl. J. Med., 349(21):1614-22, 27 May 1999. [Northwestern U., Chicago, IL; Los Alamos Natl. Lab, NM] *199QY	19	†

SOURCE: ISI's Hot Papers Database. Read the full legend.

amoxifen has been around for over a quarter of a century but it keeps in the news. In June of this year the U.S. Food and Drug Administration licensed it for a condition known as ductal carcinoma-in-situ, and tamoxifen is creeping back into the reckoning again, in Science Watch terms, in a very important context–not the treatment of malignant breast disease, where its place is now recognized, but in prevention.

There were encouraging signs from knowledge of the biology of this antiestrogenic agent and from a reduction in risk of cancer in the contralateral breast when tamoxifen has been given after mastectomy for cancer. However, the solid evidence had to come from randomized clinical trials. The story now gets complicated. Early in 1998 came the first results from U.S. National Surgical Adjuvant Breast Trial P1, coordinated by Bernard Fisher and his colleagues (paper #3). The indications were so encouraging, with a reduction in risk of about a half, that the trial was stopped.

A trial set up by the U.K. Medical Research Council, by contrast, had some difficulty in starting, because of concerns about liver damage from tamoxifen. In July, 1998, the early results appeared, together with those from an Italian study, and they were by no means encouraging (see T. Powles, et al., Lancet, 352[9122]:98-101, 11 July 1998, currently at #12 with 17 citations this period; and U. Veronesi, et al., Lancet, 352[9122]:93-7, 11 July 1998, now ranked at #11 with 18 cites). In the same issue of The Lancet, Canadian commentator Kathleen I. Pritchard tried to make sense of the differences but was forced to conclude that the new evidence "casts doubt on the wisdom of the rush, at least in some places, to prescribe tamoxifen widely for prevention" (pp. 80-81).

So, over two years later, where are we? Science Watch turned to Jack Cuzick, from the Imperial Cancer Research Fund, London. His is the latest overview (see Eur. J. Cancer, 36[10]:1298-302, June 2000). Follow-up of the three older trials continues but we have some positive findings from another trial, with raloxifene rather than tamoxifen. The International Breast Cancer Intervention Study (IBIS) of tamoxifen will not be reporting for another two years. The tamoxifen data (without IBIS) can be combined, in a technique known as metaanalysis, and the odds ratio is 0.5 – 0.6, meaning a reduction in breast-cancer risk of roughly half.

The first generation of preventive trials may not be conclusive but at least we know they can be done. "Getting a clear answer on tamoxifen is still the first priority," Cuzick tells Science Watch. However, there are other approaches, such as blocking estrogen production as opposed to estrogen receptors. "The aromatase inhibitors and new selective estrogen response modifiers are the most attractive choices at the moment," he adds, "but advances in the basic understanding of breast cancer are leading to a plethora of promising new biological agents for future study."

Mr. David W. Sharp, MA (Cambridge) is Deputy Editor of The Lancet, London, U.K.