New anticancer drugs are usually developed specially for the job, but occasionally they are borrowed from another field of medicine, and applied speculatively in cancer. Tamoxifen was designed as an anti-oestrogen, based on the observation that at least a third of breast cancers depend on female sex hormones such as oestrogen for survival. Tamoxifen has shown to be an exceptionally effective molecule in cancer treatment; It was never planned to be a preventive agent, but so it has proved to be! It is now licensed to be used to prevent breast cancer in certain women at high risk of the disease.
Contrast this with raloxifene, a drug first developed to treat osteoporosis in women. A selective benzothiophene oestrogen receptor modulator (SERM), raloxifene binds to oestrogen receptors as a mixed oestrogen and anti-oestrogen effect. It functions as an oestrogen sometimes (in bones and on lipid metabolism) and as an anti-oestrogen in other target tissues (endometrium and breast). So, it has the potential for producing some of oestrogen's beneficial effects without producing its adverse effects. In a trial of its use in osteoporosis, it appeared to have another completely different effect, namely prevention of new hormone dependant breast cancers.
Results from the MORE (The Multiple Outcomes of Raloxifene Evaluation) study of 7,705 women that were randomised to raloxifene or placebo demonstrated that among postmenopausal women with osteoporosis, the risk of invasive breast cancer was decreased by 76% during three years of treatment with raloxifene.
Stronger evidence on the safety and efficacy of raloxifene is awaited from the STAR Trial. This trial includes almost 20,000 postmenopausal women in the US who are at increased risk of breast cancer to determine whether raloxifene is as effective in reducing the chance of developing breast cancer as tamoxifen. Women taking raloxifene demonstrated some side effects and in clinical trials have about three times the chance of developing a deep vein thrombosis or pulmonary embolism as women on a placebo, however there is less risk of cancer of the uterus (a serious side effect of tamoxifen).
An example of a molecule causing much interest in breast cancer treatment is lapatinib, which administered orally. It was designed to hit a subset of the popular Epidermal Growth Factor Receptors (EGFR), which are targeted by other successful agents such as trastuzamab (Herceptin), cetuximab (Erbitux) and gefitinib (Iressa). The first two are monoclonal antibodies, against ErbB2 and ErbB1 respectively, the third is a 'designer' drug. Trials of the combination of antibodies have been promising, so the development of lapatinib to block both receptors via their tyrosine kinase portions is giving rise to optimism. It is a small molecule, like gefitinib, and may have pharmacological advantages over the antibody formulations, such as penetrating the blood-brain barrier.
Early clinical trials with lapatinib suggest that it may hit cancer cells, resistant to other commonly used breast cancer drugs, and to the other EGFR targeting agents, including trastuzamab. Its activity as a single agent is modest, but combination trials already underway are looking promising enough to start randomised comparative large scale investigation. Side effects reported so far suggest a good safety profile, though skin rash, lung and heart effects seen with other members of the drug class will be monitored carefully in the next generation of trials. And, following the example of tamoxifen, it is being tested as a chemo-preventive too.
Dr F. Cardoso from the Jules Bordet Institute, Brussels, who is involved in the drug research comments, "Raloxifene and lapatinib are exciting new drugs which will be of interest in prevention and treatment of breast cancer patients in the future."
Notes: For more information on the MORE trail see JAMA. 1999;281:2189-2197 The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women.
For further information please contact:
Stéphanie Makin, Tonic Life Communications, stephanie.makin@toniclc.com
EBCC5 press office: Tuesday 21st March – Friday 24th March 2006
Tel: +33 4 93 92 84 02
Fax: +33 4 93 92 84 04
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SS3 Prevention strategies
The NSABP's second breast cancer prevention study, the STAR trial
L. Wickerham, V. Fourchotte
NSABP, East Commons Professional Building 5th F1, Pittsburgh, USA
The Study of Tamoxifen and Raloxifene (STAR), the NSABP's second breast cancer prevention study, is designed to determine if raloxifene is as good as or better than tamoxifen in the prevention of primary breast cancer.
Between July 1999 and November 2004, 19,747 postmenopausal women at increased risk for breast cancer were randomly assigned to receive either tamoxifen (20 mg) or raloxifene (60 mg) daily for 5 years. Breast cancer risk was estimated using a modified Gail model. Factors incorporated into the model include, age, race, reproductive history, previous benign breast biopsies, and number of first-degree female relatives who have had breast cancer. Ten percent of the women in the STAR trial were between 35 and 49 years of age, 50% were 50-59, and 40% were 60 +. Their estimated risk of developing breast cancer over the next 5 years varied from 1.67% to over 5%. Seventy-one percent of the women had one or more first-degree female relatives with breast cancer; 9.1% of the women entered had a history of LCIS, and 19.8% had a previous breast biopsy documenting atypical hyperplasia. 51.7% of the participants had undergone a hysterectomy prior to entry. Final analysis of the trial will begin when a previously determined number of invasive breast cancers has occurred, which is expected in late spring 2006.