Tamoxifen Or Raloxifene in Postmenopausal Women for Prevention of Breast Cancer: a Tale of Two Choices—Counterpoint

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Point/Counterpoint

Tamoxifen or Raloxifene in Postmenopausal Women for Prevention of Breast Cancer: A Tale of Two Choices—Counterpoint

Carol Fabian

University of Kansas, Kansas City, Kansas

Postmenopausal women 50 years or older with an esti- Marring this otherwise perfect story is the disquiet- mated 5-year Gail model breast cancer risk of >1.66% or ing observation that in the STAR trial the incidence of prior history of lobular carcinoma in situ now have two noninvasive breast cancer was 40% lower for women choices of prevention drug therapy: approved by the randomized to tamoxifen than those randomized to Food and Drug Administration for breast cancer risk raloxifene, and ductal carcinoma in situ comprised 54% reduction tamoxifen and raloxifene. of these in situ cancers (7). The clinical relevance is It has been estimated that f2 million women living in obvious in that >20% of newly diagnosed breast can- the United States would realize a health benefit from cers projected for 2007 will be ductal carcinoma in situ 5 years of tamoxifen given as primary breast cancer pre- (9). Management of ductal carcinoma in situ, which vention therapy (1, 2); yet, only 5% to 30% of risk-eligible often incorporates 5 years of antihormone therapy women choose to take tamoxifen because of potential following surgery F radiation makes this a life-altering side effects and incomplete efficacy (3-5). Serious side event. effects that can occur with tamoxifen, such as deep Although not quite statistically significant at the time venous thrombosis, pulmonary embolism, and uterine of the analysis (P = 0.052), the reduced incidence of cancer, occur primarily in women over 50 years. Treat- in situ cancers in women randomized to tamoxifen ment of elderly, average-risk women with raloxifene in versus raloxifene in STAR is consistent with results in the Multiple Outcomes of Raloxifene Trial was associated prior placebo-controlled trials. In trials in high-risk with fewer breast cancers without the increase in uterine women, tamoxifen has been observed to reduce ductal cancer observed with tamoxifen. However, raloxifene carcinoma in situ by 37% to 49% compared with pla- was associated with a 3-fold increase in thromboembolic cebo (10, 17). Raloxifene has not been compared with a phenomenon, similar to what would be expected with placebo in high-risk women, but in average to low-risk tamoxifen (6). postmenopausal women, raloxifene was not associated Subsequently, the National Surgical Adjuvant Breast with either a significant or numerical reduction in ductal and Bowel Project Study of Tamoxifen and Raloxifene carcinoma in situ compared with placebo (see Fig. 1; (STAR) trial was launched in high-risk postmenopausal refs. 12, 13). The observation that raloxifene is similar to women with the hope that raloxifene would have similar tamoxifen in preventing invasive but less efficacious in efficacy but fewer serious side effects than tamoxifen. preventing in situ cancer seems to counter the existing The initial assessment of the primary end point of the paradigm but that most invasive cancers are derived STAR Trial would seemingly indicate that this hope was from associated in situ lesions. realized. Compared with tamoxifen, women randomized What then might be the explanation for the differences to 5 years of raloxifene in the STAR trial had a similar between raloxifene and tamoxifen with regard to emer- incidence of invasive breast cancer and similar quality of gence of in situ cancer? This seeming paradox could be life but a lower incidence of serious side effects (7, 8). explained if changes in gene expression giving rise to Women randomized to raloxifene had 30% fewer throm- in situ cancer are different than those associated with boembolic events, 25% fewer uterine cancers, and 21% progression from in situ to invasive cancer, and tamo- fewer cataracts compared with those randomized to xifen modulated those genes key to development of tamoxifen. These differences were significant for cata- breast precancer differently than raloxifene. Although racts and the combination of deep venous thrombosis there does not seem to be any gene universally up- and pulmonary emboli (7). regulated or down-regulated in in situ or invasive cancer, several investigators have noted differences in patterns of change in gene expression between normal and in situ cancer and between in situ and invasive cancer (14-16). Further, Frasor et al. (11) have reported that Cancer Epidemiol Biomarkers Prev 2007;16(11):2210 – 2 there is a set of at least 60 genes up-regulated or down- Received 12/18/06; revised 3/12/07; accepted 3/29/07. regulated by tamoxifen but not by raloxifene. If, as Requests for reprints: Carol Fabian, University of Kansas, 3901Rainbow Boulevard, generally thought, hormone receptor–positive invasive Kansas City, KS 66160-7820. Phone: 913-588-7791; Fax: 913-588-3679. in situ E-mail: [email protected] cancer emerges from cancer, the implications Copyright D 2007 American Association for Cancer Research. are that tamoxifen might be more efficacious than ralo- doi:10.1158/1055-9965.EPI-06-1065 xifene in the long run for preventing invasive disease

Cancer Epidemiol Biomarkers Prev 2007;16(11). November 2007

particularly after treatment has been stopped (carryover Table 1.Factors considered when making the choice effect). In fact, a beneficial carryover effect is beginning between tamoxifen and raloxifene for primary pre- to emerge in the initial primary prevention trials of vention in postmenopausal women tamoxifen versus placebo such that reduction in risk for Factor Drug favored breast cancer seems to continue after treatment with tamoxifen is completed, but risk for most side effects is Efficacy concern greatest Tamoxifen reduced (2, 17, 18). This means the long-term benefit to Safety concern greatest Raloxifene risk ratio with tamoxifen may be higher than originally Dyspareunia/reduced libido Tamoxifen Benign uterine conditions Raloxifene anticipated. No comparable data on the carryover effect Cataracts Raloxifene exist for raloxifene. Low-activity CYP2D6 alleles Raloxifene What about other differences between raloxifene and Increased risk for thromboembolism Neither tamoxifen that might affect the choice of one drug over another? In the STAR trial, both drugs were associated with similar effects on quality of life but raloxifene was associated with a higher incidence of dyspareunia, women considering tamoxifen were to have CYD2D6 musculoskeletal complaints, and weight gain, whereas alleles tested before initiating drug, cost differential in tamoxifen was associated with a higher incidence of hot favor of tamoxifen might disappear. Currently, testing flashes, vaginal discharge, bladder control problems, and for CYP2D6 activity before tamoxifen use is uncommon. leg cramps but better overall sexual function (8). Women In the end, the high-risk postmenopausal patient and already troubled by loss of libido and dyspareunia might her physician are likely to make the choice between then chose tamoxifen over raloxifene. tamoxifen and raloxifene based on the relative impor- Pharmacokinetics of these drugs are different. Due to tance of efficacy versus safety and factors in her personal better bioavailability and longer terminal half-life of health history (see Table 1). The decision-making process tamoxifen, systemic drug levels are not as likely to be is likely to be complex. The risk-eligible woman who affected as much by missed doses of tamoxifen as by already has cataracts, evidence of benign uterine con- missed doses of raloxifene, a consideration for women ditions, or low CYP2D6 activity might be better served with average or worse compliance with chronic medica- with raloxifene. Conversely, the risk-eligible postmeno- tion intake (19-22). On the other hand, raloxifene is likely pausal woman who has no uterus, is already bothered by to be the better choice for the 5% to 10% of individuals dyspareunia, and/or whose greatest concern is efficacy homozygous for low-activity CYP2D6 alleles or those might opt for tamoxifen, which is associated with re- on potent CYP2D6 inhibitors. CYP2D6 mediated genera- duced risk for both noninvasive and invasive cancer. A tion of the potent tamoxifen metabolites 4-OH-tamoxifen quantitative method for weighing the relative risks and and endoxifen is thought to be responsible for much of benefits of tamoxifen versus raloxifene based on personal the antitumor activity of tamoxifen (23). health history and preferences would be helpful in this Cost differential for the two drugs may be important decision-making process. Although expanding the num- for women with no or limited prescription benefits. In ber of alternatives increases the complexity of decision our Medical Center Retail Pharmacy, the cost of 30 days making, it may also increase the proportion of women of generic tamoxifen is $16.60 compared with $95.70 for willing to consider prevention therapy. Two choices are 30 days of raloxifene. Retail prices for the two drugs better than one. at a national pharmacy chain outlet in town were $61.59 for tamoxifen and $96.99 for raloxifene. If, however, all References 1. Freedman AN, Graubard BI, Rao SR, McCaskill-Stevens W, Ballard- Barbash R, Gail MH. Estimates of the number of US women who could benefit from tamoxifen for breast cancer chemoprevention. J Natl Cancer Inst 2003;95:526 – 32. 2. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1study. J Natl Cancer Inst 2005; 97:1652 – 62. 3. Bober SL, Hoke LA, Duda RB, Regan MM, Tung NM. 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Carol Fabian

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