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Fenretinide Reduces Breast Cancer Recurrence in Premenopausal Patients

Fenretinide Reduces Breast Cancer Recurrence in Premenopausal Patients

NEW YORK—Premenopausal women who are at risk for breast cancer recurrence may benefit from a new chemopreventive agent, according to the lead researcher of a clinical trial of women with early stage breast cancer. And the agent holds promise for use as a primary chemopreventive in healthy high-risk premenopausal women.

At a press briefing, Professor Umberto Veronesi, scientific director of the European Institute of Oncology, Milan, Italy, outlined the significance of the results of the new trial.

The agent is N-(4-hydroxyphenyl) retinamide (fenretinide), a vitamin A analog that has been shown in preclinical studies to inhibit breast carcinogenesis.

The trial, funded primarily by the NCI, enrolled 2,972 women, aged 30 to 70 years, with resected stage I breast cancer or ductal carcinoma in situ (DCIS). Half were randomly assigned to receive 200 mg/day of fenretinide for 5 years; the other half received no treatment.

The primary endpoint was the incidence of contralateral or ipsilateral breast cancer within 7 years of randomization.

Although the two arms showed no statistically significant difference in the occurrence of second breast cancers, a highly significant benefit was seen among premenopausal women in the fenretinide arm. There were 85 second breast cancers in premenopausal women receiving fenretinide, compared with 129 second breast cancers in the control group, a difference of nearly 35%.

Among postmenopausal women, however, fenretinide appeared to slightly increase the risk of developing a second cancer (80 vs 63 cancers in the control group), an increase Professor Veronesi termed not statistically significant, but warranting further investigation.

He explained that there appears to be a relationship between the protective effect of fenretinide and the presence of circulating estrogens. “A new study, supported by the Susan B. Komen Breast Cancer Foundation, is looking at fenretinide in postmenopausal women on hormone replacement therapy,” he said.

NCI-Funded Trial

A second trial, supported by the NCI, will compare fenretinide, tamoxifen [Nolvadex], and the two in combination. Investigators hope to discover whether there is a synergistic effect when the agents are combined, permitting lower doses with less toxicity.

Unlike other retinoids, which accumulate in the liver and thus risk significant hepatotoxicity, fenretinide is absorbed by mammary tissues. Side effects are few and relatively minor. They include skin and mucosal dryness, GI complaints, and diminished visual adaptation to the dark, the last of which can be eliminated with a monthly 3-day drug holiday. The complete report has been recently published in the Journal of the National Cancer Institute (Nov. 3, 1999).

Michael P. Osborne, MD, director of the Strang-Cornell Breast Center, New York, called the findings “a breakthrough discovery that holds great promise for primary prevention of breast cancer in younger high-risk women and could have an important impact on public health.”

Professor Veronesi agreed. “There is a need for effective prevention in women at risk during their reproductive years,” he said. He noted that in the United States, breast cancer is the leading cause of death for women aged 33 to 54.

“Although patients detected and treated early have a good prognosis, every year one in 100 women will develop a second malignancy in the opposite breast, and two to three will have a second cancer in the same breast. If fenretinide can be shown to reduce the risk of another

cancer, it can then be tested in healthy women at increased risk for breast cancer, opening up a new avenue of primary prevention,” Professor Veronesi said.

Although researchers have thus far studied the drug only in women with a history of breast cancer, future studies should focus on the possible preventive benefits for women at risk because of family history, the presence of a genetic defect, or precancerous findings on mammography, he said.

Because tamoxifen is an antiestrogen, “it is not well suited for young women, whereas fenretinide is safe and relatively free of side effects,” Dr. Osborne said. “The next logical step would be a large trial of women—especially young women—who are at increased risk of developing breast cancer.”

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