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Vitamin A analogue protects against breast cancer

Janice Hopkins Tanne New York

A synthetic vitamin A analogue, fenretinide, reduced the rate of second breast cancers in premenopausal women in a study by Dr Umberto Veronesi of the Istituto Nazionale Tumori and the European Institute of Oncology in Milan and colleagues (Journal of the National Cancer Institute 1999;91:1847-56).

In postmenopausal women, however, it seemed to increase the risk of a second breast cancer. The drug also reduced the rate of ovarian cancer in women under 50.

"Chemoprevention is relatively new. The carcinogenic process is multi-step and this substance might interfere with and stop the process," said Dr Veronesi at a press conference in New York last week. "Women who have been treated for breast cancer have a high risk of developing another cancer in the same breast or the other breast."

The trial involved 2972 women aged 30 to 70 years from 10 Italian institutions. All women had had surgery for stage I breast cancer or ductal carcinoma in situ. They were randomised to 200 mg of fenretinide a day or no treatment for five years.

Almost half the women (48%) in the study were premenopausal. The study was stopped in July 1993, when the US National Cancer Institute recommended adjuvant treatment for all patients with breast cancer. Median observation time was 97 months.

Compared with the control group, premenopausal women taking fenretinide had fewer second cancers in the same breast (100 v 121) or in the opposite breast (27 v 42).

No cases of ovarian cancer occurred among women aged 50 or younger in the fenretinide group during treatment, and six cases occurred in the control group. After treatment stopped, three cases of ovarian cancer occurred in women in the fenretinide group.

"Fenretinide is one of many analogues of vitamin A. It has very little toxicity because it does not accumulate in the liver, as vitamin A does. I took it myself for one year; nothing happened. Its second advantage is that it accumulates in the breast," Dr Veronesi said.

The drug reduced second cancers by about 35% in young women, but it was "a great surprise" that it seemed to increase breast cancers in postmenopausal women.

"The drug has a double effect, depending on the presence or absence of circulating oestrogen. This substance might be combined with other drugs, like tamoxifen, that have more efficacy with increasing age.... The combination is synergistic."

Fenretinide might act by affecting levels of insulin-like growth factor I. Dr Veronesi emphasised that fenretinide is quite different from vitamin A and that high doses of vitamin A are dangerous.

Dr Veronesi has begun two large trials of fenretinide as a preventive agent, one involving postmenopausal women who are receiving hormone replacement therapy, and a second in high risk premenopausal women.

Breast surgeon Dr Michael Osborne, president of the Strang Cancer Prevention Center in New York, called the study "very exciting.... We've seen that tamoxifen can reduce breast cancer in women at high risk by 50%." Fenretinide might be combined with tamoxifen for cancer prevention.
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Ron Law
bmj.com, 12 Nov 1999 [Full text]