A Challenge to Tamoxifen
Laura Shea, R.N.
Early this past December, AstraZeneca, makers of tamoxifen, held simultaneous press conferences across North America (including here in Montreal) to announce the preliminary findings of their ATAC (Arimidex® tamoxifen, alone or in combination) study. Although Arimidex had been approved for treatment of estrogen-sensitive (ER+) advanced breast cancer in postmenopausal women in 1996, this study was designed to determine the effectiveness/safety of Arimidex compared to tamoxifen as an adjuvant (additional) treatment in early stage breast cancer.
“Landmark study shows Arimidex to be superior to tamoxifen in the treatment of early breast cancer,” blared the headline of the AstraZeneca press release, ”... Arimidex is significantly more effective and has several important safety benefits over the current ‘gold standard’—tamoxifen—in the adjuvant treatment of early stage breast cancer in postmenopausal women.”¹
Is Arimidex really superior to tamoxifen, or is this another instance of pharmaceutical self-promotion?
What is Arimidex?
Arimidex is one of several oral aromatase inhibitors (AI’s), a type of hormone therapy developed to treat women with ER+ breast cancer.² Aromatase is an enzyme found in the adrenal glands, fat and muscle that converts androgens (so-called male hormones) into estrogen. It is responsible for much of the estrogen produced by postmenopausal women. In two out of three postmenopausal women with breast cancer, aromatase is also found in the breast tissue “giving the breast its own supply of estrogen.”³ By inhibiting aromatase, AI’s block the production of estrogen and suppress levels of circulating estrogen. In premenopausal women, who derive most of their estrogen from the ovaries, AI’s are overall considered ineffective.4 Tamoxifen (Nolvadex®), a selective estrogen receptor modulator (SERM) is also a kind of hormone therapy, but works differently. Tamoxifen works by blocking estrogen from binding to breast cancer cells that are ER+. Tamoxifen is thus effective in both pre- and postmenopausal women.5
The ATAC Study
A multi-centred, randomized, double-blind trial, this study involved 9,366 postmenopausal primary breast cancer patients from 380 centers in 21 countries recruited between 1996 and 2000. There were three groups in the study: one group took Arimidex (1 mg daily) and a placebo; another took tamoxifen (20 mg daily) and a placebo; and the third took one pill combining the two drugs and a placebo. Initially, patients were to be followed for five years, but the press conference reported findings based on data analyzed after an average of only 30 months.
Arimidex prolonged disease-free survival better than tamoxifen. Of the 3,125 women taking Arimidex only, 317 (about 10%) suffered a breast cancer recurrence or died, as compared to 379 (12%) of the 3,116 women taking tamoxifen only. A significantly lower incidence of recurrence was experienced by the women on Arimidex-only whose previous tumours had been hormone sensitive. The incidence of contralateral breast cancer (a new primary cancer in the previously unaffected breast) was also significantly lower in the women taking Arimidex. The group taking both Arimidex and tamoxifen did as well but no better than the tamoxifen only group.6
There were slight differences in the side effects experienced by the groups. Those taking Arimidex were less likely to report weight gain (9.2% vs. 11%), vaginal bleeding (4.5% vs. 8.1%), endometrial cancer (0.1% vs. 0.5%), hot flashes (34.3% vs. 39.7%), or strokes (1% vs. 2.1%).7 However, Arimidex users reported an increase in musculoskeletal problems including bone fractures in places particularly susceptible to osteoporotic fracture.7,8 Dr. Michael Baum, who reported these findings at the San Antonio Breast Cancer Symposium, is one of several oncologists who are not about to change their treatment practices: “Longer follow-up and long-term data on bone mineral density and cognitive function are required to allow a complete benefit/risk assessment to be made.... I emphasize the modest difference and it’s in disease-free survival, not overall survival. There are no differences in overall survival at the moment in the two treatment arms.”9
Getting Past the Hype
Media hype around medical studies related to breast cancer (and other diseases) can be misleading. Pharmaceutical companies organize elaborate press conferences which influence the reporting of medical stories in the media. Sensationalized headlines can mislead readers into believing a “medical breakthrough” has occurred, or a “miracle drug” has been discovered, while it is more likely that small steps (albeit important ones) have been made towards finding more effective therapies. The stories are always more complex than they appear. This is a good example. Generally, the media were quick to report that Arimidex might replace tamoxifen as the new gold standard in treatment for early stage breast cancer. But the picture is not so simple.
First, the reports were based on very preliminary findings from a study with an endpoint of five years or recurrence. It is imperative that the researchers continue to monitor the side effects of these drugs. Let’s hope that the short-term results continue over the long term. Secondly, the preliminary results are applicable only to postmenopausal women since the estrogen-suppressing action of Arimidex could have repercussions for women still menstruating. Arimidex is not indicated for premenopausal women. Thirdly, there are serious concerns about ‘cross-resistance’ to the drugs since Arimidex appears not to benefit women who have been on tamoxifen. Fourthly, the results were presented at a scientific meeting and have yet to be published in a respected peer-reviewed medical journal. Finally, any critical evaluation of a scientific study involves knowing who the sponsor is. Both Arimidex and tamoxifen are manufactured by AstraZeneca: the patent on tamoxifen expires this year and Arimidex is roughly ten times more expensive than tamoxifen. Generic forms of tamoxifen cost between 35 to 50 cents per pill. Arimidex costs $4.95 per pill. Like many ‘breakthroughs’, this one should be taken with a grain of salt.
- AstraZeneca press release, December 10, 2001
- There are three oral AI’s approved for the clinical treatment of breast cancer: Arimidex® (anastrozole) and Femara® (letrozole)—both nonsteroidal—and Aromasin® (exemestane) which is steroidal. See footnotes 3 and 4.
- Susan Love, M.D., with Karen Lindsey. Dr. Susan Love’s Breast Book, 3rd ed. Cambridge, MA: Perseus Publishing, 2000:390
- Medscape’s Hematology-Oncology eJournal, 5(1), 2002 www.medscapte.com/viewarticle/424077
- Susan Love, op. cit., p. 391
- Musa Mayer. “Changes to Come in Adjuvant Therapy?” Breast Cancer Action (San Francisco) Newsletter #70, March/April, 2002:1
- ibid., p. 6
- Medscape’s eJournal, op. cit.
- Musa Mayer, op. cit., p. 6