A STAR Is Born

The Study of Tamoxifen and Raloxifene (STAR) compared and contrasted the efficacy and side effects of tamoxifen, the established agent, with raloxifene (Evista)-a medicine that is currently used for the prevention of osteoporosis in high-risk postmenopausal women, but also reduces the incidence of breast cancer. Both tamoxifen and raloxifene are selective estrogen-receptor modulators (SERMs), which are antiestrogenic in the breast but have estrogenlike qualities and can preserve bone density.

The STAR trial is published in JAMA, but what does STAR show? The general conclusion is that raloxifene reduces the risk of invasive breast cancer at exactly the same rate as tamoxifen. It is well recognized that tamoxifen reduces the incidence of primary breast cancer by about 50%. In contrast, raloxifene is slightly less effective than tamoxifen at reducing the incidence of noninvasive breast cancer, but fortunately mammography can still be employed as a detection modality. The good news is that raloxifene produced fewer thromboembolic events, fewer cataracts, fewer cataract surgeries, and fewer hysterectomies than tamoxifen. There were fewer cases of uterine cancer (36 cases with tamoxifen, 23 cases with raloxifene). However, osteoporotic fractures were similar in each group, again demonstrating the SERM qualities of both medicines.

What do we make of all of this? The authors (and I am one of them) concluded that raloxifene is the winner based upon equal efficacy when compared to tamoxifen as far as invasive breast cancer is concerned, but with fewer side effects. Raloxifene has clear-cut advantages for postmenopausal women considering the chemoprevention of breast cancer as a health-care option.

About half a million women are already using raloxifene to prevent osteoporosis, but there will also be a 75% reduction in the incidence of breast cancer. There will be tens of thousands fewer breast cancers over the next decade. With the results of STAR, we can now expect (after FDA approval) raloxifene to reduce breast cancer risk in well women with an elevated risk level. But is this the best we can do?

The fact that these agents reduce breast cancer incidence is remarkable, as neither was initially designed to do this task. However, two questions should be asked: (1) Why does raloxifene perform so well at preventing breast cancer by about 75% in women being treated for osteoporosis but only by about 50% in the women in STAR? (2) Why is raloxifene less effective than tamoxifen at controlling noninvasive breast cancer after about 3 years of treatment?

I suggest that it is because the pharmacologies of tamoxifen and raloxifene are very different and compliance is critical. Tamoxifen is converted into active metabolites and is very long-acting. In contrast, raloxifene is the active drug, is poorly absorbed (2%), and is rapidly excreted. Forgetting to take raloxifene now allows estrogen to encourage the growth of any preexisting breast cancers. I would suggest that raloxifene is doing a remarkably good job in the face of the high estrogen levels in the healthy women in the STAR trial. For the future, perhaps we can do much better by using new SERMs that have long biologic half-lives to block endogenous estrogen in a woman's body "all day, every day" (with apologies to the Fox Chase Cancer Center motto).

What about endometrial cancer? There are lower numbers of endometrial cancer in women taking raloxifene, but it can be argued that women taking tamoxifen have higher numbers of hysterectomies (244 for tamoxifen and 111 for raloxifene) and hence the numbers for tamoxifen could be higher than reported. Naturally, the same women have uterine pathology reports so this explanation is easy to check, but the number of hysterectomies should be much higher to increase the number of endometrial cancers with tamoxifen.

Another explanation is that the well-primed estrogenized uterus does harbor endometrial cancer (unlike the uterus of an osteoporotic woman) and raloxifene first blocks but then eventually causes the growth of raloxifene-stimulated endometrial cancer. This has been observed in the laboratory. Patients need to be apprised of the fact that endometrial cancer is a possibility during raloxifene treatment in the general (nonosteoporotic) population. Alternatively, based on STAR there is very little risk for endometrial cancer with tamoxifen (2 per 1,000) compared to 60-year-old controls (1 per 1,000).

So what are the practical advances that we now see following the birth of our new star? Raloxifene reduces the incidence of breast cancer in women at risk and those women being treated for osteoporosis. Nevertheless, tamoxifen remains the agent of choice for premenopausal women as raloxifene has not been tested in premenopausal populations and is not recommended for this application. Women will now benefit based on evidence from well-designed prospective clinical trials. For the future, pharmaceutical companies need to develop better SERMs to provide optimal health care.

-V. Craig Jordan, OBE, PhD, DSc