THERAPY

MORE not yet enough for raloxifene and breast cancer prevention

-Roben Carlson-

Interim data from the ongoing MORE (Multiple Outcomes of Ralomene Evaluation) study show that postmenopausal women with osteoporosis receiving raloxifene had a 70% reduced risk of developing newly diagnosed breast cancer, compared with placebo recipients. However, data from the MORE study cannot be compared head-ro-head with that from the Breast Cancer Prevention Trial (BCPT) which examined the effect of prophylactic tamoxifen therapy in women at high risk of developing breast cancer. The implications of these recent study findings were discussed at the 34th Annual Meeting of the American Society of Clinical Oncology [Los Angeles, US; May 1998].

The BCPT was prematurely terminated after about 4 years of therapy when results showed that. compared with placebo. tamoxifen reduced the rate of invasive and noninvasive breast cancers by 45%.*

Currently. the selective estrogen-receptor modulator (SERM) raloxifene is only approved by the US FDA for the prevention of osteoporosis in post­menopausal women. The MORE trial was designed to examine the ability of raloxifene to treat postmeno­pausal women with osteoporosis and to prevent fractures in these women. However. secondary study end points highlighted at the meeting included monitoring the incidence of breast and endometrial cancer.

Favourable profile Other studies in postmenopausal women have

shown that raloxifene has protective effects on bone. and may reduce markers of cardiovascular risk (total and LDL-cholesterol and fibrinogen levels). With this promising therapeutic profile, it appears that some raloxifene proponents are positioning the agent as the 'do-all' drug of the future for postmenopausal women. However. it is still too early to recommend this approach. as the clinical trials conducted to date have been designed to primarily evaluate effects on fracture risk and not breast cancer prevention.

MORE infonnation In the MORE trial, 7705 postmenopausal women

with osteoporosis (mean age 66.5 years) and no history of breast or endometrial cancer were randomised to receive placebo or raloxifene 60 or 120mglday. Details of the interim results from the study were presented by Dr Stephen Cummings from the University of California at San Francisco, US.

As expected, raloxifene therapy significantly decreased the fracture rate compared with placebo. said Dr Cummings. In addition, after a median follow-up period of 33 months, there was a 70% reduction in the incidence of newly diagnosed invasive breast cancers in raloxifene, compared with placebo. recipients.

At this time. 35 cases of invasive breast cancer have been confirmed: 13 among raloxifene recipients and 22 among placebo recipients. even though there were twice as many raloxifene recipients. This translates to a relative risk for raloxifene. compared with placebo. recipients of 0.3 (p < 0.001). Interest­ingly, raloxifene 60 and 120 mg/day produced similar risk reductions.

* See Inphanna 1132: 17.11 Apr 1998; lnJ631977

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Only a few cases of endometrial cancer have been diagnosed in the MORE study cohort and there are no significant differences in incidence at this stage between the 3 treatment groups (4 cases in each group). This finding has helped fuel the debate over whether raloxifene would be a preferable agent to tamoxifen for breast cancer prevention.

Raloxifene and tamoxifen have different estrogenic effects in the uterus. Tamoxifen stimulates the endometrium and is associated with a small but statistically significant risk of endometrial cancer. On the other hand. it is considered that raloxifene has no adverse endometrial effects.

Some hypothesise that raloxifene may therefore offer better overall prevention for women than tamoxifen when the risks of endometrial cancer. fracture. and breast cancer are all taken into account.

Not surprisingly. raloxifene increased the risk of venous thrombosis and pulmonary embolism to a similar degree as has been reported for estrogen replacement therapy and tamoxifen. However. precise data on these adverse events from the MORE trial are not yet available.

Where are we now? 'Our major conclusion at this point is that

approximately two and a half years of treatment with raloxifene reduces the risk of breast cancer in postmenopausal women who have osteoporosis and no history of breast or endometrial cancer' • commented Dr Cummings. The trial is continuing so that the long-term effects of raloxifene on prevention of breast cancer can be better characterised. However, caution is needed in interpreting these results as all women in the study have osteoporosis. which itself is associated with a reduced risk of developing breast cancer. he added.

Support from meta-analysis Additional information supporting the fact that

raloxifene i:; a:;~ociated \\'ith a reduction in incidence of breast cancer was presented by Dr Craig Jordan from the Robert Lurie Cancer Center at Northwestern University, Chicago. US.

The meta-analysis data were pooled from over 10 000 patients enrolled in 9 separate placebo-controlled. double-blind, randomised studies (including the MORE study) examining the effects of raloxifene on the prevention and treatment of osteoporosis. Women in these studies underwent baseline and regular mamograms.

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Reduced cancer risk A total of 58 cancers were found in 10 553 women;

these included 1.7 breast cancersll000 women receiving raloxifene and 3.7 breast cancers/lOOO women receiving placebo. The incidences of invasive breast cancer were 1.3/1000 and 3.0/1000 women, respectively.

Raloxifene therapy reduced the incidence of all new breast cancers (invasive and non-invasive) by 54% compared with placebo at a median follow-up of 33 months.

Interestingly, raloxifene reduced the incidence of estrogen receptor(ER)-positive breast cancers by 70%, compared with placebo. There was no difference in the incidence of ER-negative tumours between raloxifene and placebo recipients. Raloxifene was also associated with a 55% reduction in the risk for developing invasive breast cancer.

From the meta-analysis data, the adverse events noted most frequently in raloxifene and placebo recipients included hot flashes (25 and 18% of patients, respectively) and leg cramps (6 and 2%, respectively). According to Dr Jordan, most women did not find these events serious enough to discontinue treatment.

STAR on the horizon A definitive answer to the question of whether

raloxifene is a real contender for tamoxifen's crown may have to wait another 5 years. STAR (Study of TAmoxifen and Raloxifene) is a head-to-head study comparing the efficacy of these 2 agents in the prevention of breast cancer in postmenopausal women at increased risk of breast cancer. The study will recruit ~ 20 000 postmenopausal women and is due to start later this year.

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Inpharma-13 Jun 1II1II No. 1141

THERAPY

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