New York, NY, Nov. 2 - Research by an international team of Italian and American scientists could pave the way for a new drug to prevent breast and ovarian cancers.
Led by world-renowned investigator Umberto Veronesi, MD, a clinical trial of women with early stage breast cancer suggests that the vitamin A compound fenretinide helped protect younger women against the formation of a second breast malignancy and prevented them from developing ovarian cancer.
"The effect of fenretinide differed greatly depending on the woman's age or menopausal status," said Dr. Veronesi, Scientific Director of the European Institute of Oncology in Milan, at a press briefing in New York today. "Our primary goal was to prevent breast cancer. While there was a beneficial effect on premenopausal women who were taking fenretinide, the trend was reversed in postmenopausal women who were treated with the vitamin A derivative. We also observed a statistically significant reduction in ovarian cancer in the younger women taking fenretinide."
"This exploratory research suggests that fenretinide, accompanied by circulating estrogens, holds promise as an effective breast and ovarian cancer preventive," he said, noting "this is the first time a single agent has an impact on these two major diseases in women."
Results of the five-year randomized trial of some 3,000 women who had early stage breast cancer (Stage I or 0) will be published tomorrow in the November 3 issue of the Journal of the National Cancer Institute (NCI). The article was co-authored by Dr. Veronesi and 20 research colleagues in Italy and the United States, including Michael B. Sporn, MD, former director of the NCI's chemoprevention program who is now Professor of Pharmacology at the Dartmouth Medical Center in Hanover, NH. The Italian-based trial was funded primarily by the NCI with help from three Italian organizations, the Istituto Tumori of Milan, the National Research Council and the Italian Association for Cancer Research.
Worldwide, breast cancer is the most common cancer in women, accounting for more than 700,000 cases each year. In the United States and Europe, breast cancer is the leading cause of death for women ages 33-54.
"Although patients detected early and treated for breast cancer have a good prognosis, still every year, one in 100 women will develop a second malignancy in the opposite breast and two to three women will have a second cancer in the same breast," said Dr. Veronesi. "We knew if we could reduce the survivors' risk of another cancer with fenretinide, the drug could then be tested in healthy women at increased risk of breast cancer, opening up a new avenue of primary prevention."
In 11 clinical centers throughout Italy, 2972 women aged 30-70 with surgically-removed Stage I breast cancer or ductal carcinoma in situ were randomly assigned to either no treatment, or 200 mg of oral fenretinide daily for five years. Overall, the investigators observed no statistically significant differences between the treatment and control groups. However, a different effect was noted depending on age or menopausal status: a protective effect of fenretinide was apparent in premenopausal women in the fenretinide group (85 vs. 129 cancers in the control group), while a slight, statistically non-significant increase was observed among postmenopausal women in the fenretinide group (80 vs. 63 cancers in the control group).
Dr. Michael Osborne, Director of the Strang-Cornell Breast Cancer Center and Chief of the Breast Service at New York-Presbyterian Hospital, called the findings "a breakthrough discovery which holds great promise for prevention of breast cancer in younger women. This will stimulate further research into identifying new agents free of side effects which may be used in combination to maximize risk reduction."
Importantly, the study also showed a statistically significant reduction of ovarian cancer in women aged 50 or younger who were treated with fenretinide, with six cases in the control group vs. no cases in the fenretinide group during the five-year treatment period.
Ovarian cancer, though much less common than breast, is harder to detect early and therefore more deadly. This year, Europe and the United States each will have an estimated 25-30,000 new ovarian diagnoses and close to 15,000 deaths due to ovarian cancer. "We are excited about the prospect of a therapy to prevent a disease which is responsible for more deaths than any other cancer of the female reproductive system," said Dr. Veronesi.
Observed side effects of the fenretinide regimen included skin or mucosal dryness, diminished adaptation to the dark, which was eased by staying off the capsules three days each month, and some gastrointestinal complaints. As with tamoxifen, fenretinide can cause fetal defects, so premenopausal patients were advised to use contraceptive measures while on treatment and for up to six months after stopping.
This trial is the first of its kind to test the effect of the vitamin A analogue on breast carcinogens in humans; in prior studies, the compound had shown remarkable anti-tumor activities and low toxicity in laboratory animals. The R. W. Johnson Pharmaceutical Research Institute provided the compound.
Stressing the need for further studies, Dr. Veronesi said more information would be coming from two trials currently underway with members of his chemoprevention team. One is a prevention trial testing fenretinide (200 mg) combined daily with low-dose tamoxifen (5 mg) on premenopausal women who are at increased risk of breast cancer according to the Gail model, or because they have had a previous in situ cancer. In animal studies, fenretinide and tamoxifen -- the estrogen-receptor modulator which appears to dramatically block the development of estrogen-receptive tumors -- have been shown to have an enhanced effect against tumor formation.
Addressing the problem of fenretinide needing the presence of estrogen to work as a cancer fighter, a second trial is testing fenretinide combined with hormone replacement therapy (HRT) on healthy postmenopausal women who are candidates for estrogen therapy.
Today's briefing was held with the support of the American-Italian Cancer Foundation, the New York-based nonprofit organization whose mission is to develop and encourage international cooperation among physicians and researchers in the fight against cancer.
Umberto Veronesi,Giuseppe De Palo, Ettore Marubini, Alberto Costa, Franca Formelli, Luigi Mariani, Andrea Decensi, Tiziana Camerini, Marco Rosselli Del Turco, Maria Gaetana Di Mauro, Maria Grazia Muraca, Marcella Del Vecchio, Carmine Pinto, Giuseppe D¹Aiuto, Corrado Boni, Tiziana Campa, Andrea Magni, Rosalba Miceli, Marjorie Perloff, Wilfred F. Malone, Michael B. Sporn. l. Randomized Trial of Fenretinide to Prevent Second Breast Malignancy in Women with Early Breast Cancer, Journal of the National Cancer Institute, Vol. 91, No 21 Nov 3, 1999.
The article may be accessed at http://jnci.oupjournals.org
Journal
JNCI Journal of the National Cancer Institute