NEW YORKPremenopausal 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.
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 womenespecially young womenwho are at
increased risk of developing breast cancer.