With Aromatase Inhibitors Now in Hand, Where Stands Tamoxifen?

With Aromatase Inhibitors Now in Hand, Where Stands Tamoxifen?

by David W. Sharp

WHAT'S HOT IN MEDICINE
Rank	Paper	Citations This Period (Jul-Aug 05)	Rank Last Period (May-Jun 05)
1	T.J. Lynch, et al., "Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib," New Engl. J. Med., 350(21): 2129-39, 20 May 2004. [Harvard Med. Sch., Boston, MA; Harvard Sch. Public Health, Boston, MA] *821XM	89	1
2	J.G. Paez, et al., *"EGFR* mutations in lung cancer: Correlation with clinical response to gefitinib therapy,"** Science, 304(5676): 1497-1500, 4 June 2004. [7 U.S. and Japanese institutions] *825YR	86	2
3	H.H. Hurwitz, et al., "Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer," New Engl. J. Med., 350(23): 2335-42, 3 June 2004. [9 U.S. institutions] *825JY	73	7
4	G.L. Anderson, et al. (Women’s Health Initiative Steering Comm.), "Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women’s Health Initiative randomized controlled trial," JAMA-J. Amer. Med. Assoc., 291(14): 1701-12, 14 April 2004. [Program office: NHLBI, Bethesda, MD] *811RJ	45	3
5	C.P. Cannon, et al., "Intensive versus moderate lipid lowering with statins after acute coronary syndromes," New Engl. J. Med., 350(15): 1495-504, 8 April 2004. [5 institutions worldwide] *810CI	44	4
6	M.G. Kris, et al., "Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer. A randomized trial, " JAMA-J. Am. Med. Assoc., 290(16): 2149-58, 22/29 October 2003. [Correspond. author: Memorial Sloan-Kettering Cancer Ctr., New York, NY] *734CB	43	†
7	D. Cunningham, et al., "Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer," New Engl. J. Med., 351(4): 337-45, 22 July 2004. [9 institutions worldwide] *839RC	42	†
8	J.W. Moses, "Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery," New Engl. J. Med., 349(14): 1315-23, 2 October 2003. [10 U.S. institutions] *727EM	38	5
9	W. Pao, et al., "EGF receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib," Proc. Natl. Acad. Sci. USA, 101(36): 13306-11, 7 September 2004. [Mem. Sloan-Kettering Cancer Ctr., New York, NY; Washington U. Sch. Med., St. Louis, MO] *853AT	38	†
10	A.A. Hedley, et al., "Prevalence of overweight and obesity among US children, adolescents, and adults, 1999-2002," JAMA-J. Am. Med. Assoc., 291(23): 2847-50, 16 June 2004. [Ctrs. Dis. Control & Prevent., Atlanta, GA and Hyattsville, MD; U. Calif., Berkeley] *828GT	37	†
SOURCE: ISI’s Hot Papers Database. the Legend.

ex-hormone dependency is common in certain forms of cancer, notably prostate in men and female breast cancer. For several years now tamoxifen has been standard therapy after surgery for many women with cancer of the breast. The hormone of dependency here is estrogen, and tamoxifen antagonizes the estrogen receptor. However, it is not a pure antagonist. Also, longer-term studies suggest that the drug’s effect lasts not longer than five years, though there is uncertainty on this point, and two trials likely to throw more light on this finished recruitment only a year ago. In women who have reached menopause the source of estrogen is via conversion of androgens to estrogen by aromatase, predominantly in peripheral fat, but found ubiquitously in many tissues. Interest has thus focussed on new a class of drug referred to as aromatase inhibitors. There are three potent and specific aromatase inhibitors in clinical use: letrozole, anastrozole, and exemestane, but it is the first of these that attracts attention this time because, at #13, lies the main report on trial MA.17, a randomized study of letrozole compared with placebo in postmenopausal women with early-stage breast cancer (P.E. Goss, et al., New Engl. J. Med., 349[19]: 1793-802, 2003; latest citation count 30, total cites 156).

"The chronic relapsing nature of hormone-dependent breast cancer was not previously well understood," says Dr. Paul E. Goss, director of breast cancer research at Boston’s Massachusetts General Hospital, "but is now recognized that the majority of recurrences and deaths occur beyond the initial five years from diagnosis." Thus trial MA.17 addressed a "large unmet medical need and in a very novel timeframe," Dr Goss tells Science Watch. "Dramatic" is a word that journal editors permit sparingly, but that is how Goss describes the main result of MA.17 (#13) because recurrences were halved in women on the active drug. Estimated four-year disease-free survival rates were 93% in the letrozole group and 87% in those on placebo. In fact the study was stopped early because of this result, a decision mandated on a priori criteria for trial cessation but causing some concern to the journal’s editorialists (J. Bryant, N. Wolmark, New Engl. J. Med., 349[19]: 1855-57, 2003) and to a U.K. critic, Prof. Michael Baum (Cancer Control, 11[4]: 217-21, 2004, and Eur. J. Cancer, 41[12]: 1667-77).

Stopping a trial early may well lose the opportunity to acquire further safety data but that does not mean that the need to monitor potential adverse effects such as those on bone or the cardiovascular system has been neglected by the MA.17 trialists, who remain busy with various substudies and reports. For example, lipid levels do not seem to be adversely affected by taking letrozole (K.M. Wasan, et al., Ann. Oncol., 16[5]: 707-15, 2005); nor has there been an adverse effect on quality of life (T.J. Whelan, et al., J. Clin. Oncol., 23(28): 6931-40, 2005). A 2004 review on aromatase inhibitors (P. Morandi, et al., Cancer, 101[7]: 1482-89, 2004) noted that adverse effects on bone were a concern in three major trials of exemestane, anastrozole and letrozole (MA.17). Tabulated differences in paper #13 were not significant for this particular unwanted effect, but Goss and colleagues reported a separate bone substudy at the December, 2004, San Antonio Breast Cancer Symposium. This showed an increase in bone resorption in women on letrozole and "a significant difference in ‘newly diagnosed’ osteoporosis" but no significant increase in clinical fractures.

For this year’s San Antonio gathering, which took place just after the deadline for this column, there were no fewer than 33 abstracts mentioning letrozole, among them evaluations of the Breast International Group’s study suggesting that this aromatase inhibitor is as cost-effective as tamoxifen in women with hormone receptor positive early breast cancer. Goss et al. reported an ongoing dramatic and increasing reduction of breast-cancer recurrences in women in continued follow-up from the MA. 17 trial. Furthermore, he reports on a substantial benefit to women from the trial who had been taking placebo before switching to letrozole, further justification in the trialists’ minds that early stopping was justified. Anastrozole had 23 abstracts and exemestane 15 in the same San Antonio meeting. By December 11, 2005, when the 28^th San Antonio symposium ended, attendees will have acquired a clearer idea of the relative merits of these three drugs vis-à-vis each other and the long-established adjuvant agent tamoxifen and of what issues remain to be clarified.

David W. Sharp, M.A. (Cambridge), is a contributing editor to The Lancet, London, U.K.


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Science Watch^®, January/February 2006, Vol. 17, No. 1
Citing URL: http://www.sciencewatch.com/jan-feb2006/sw_jan-feb2006_page5.htm