Vitamin A-like Drug Cuts The Risk Of Second Breast Cancers In Young Women

The Italian research team reporting the findings on-line (Thursday 4 May) in Annals of Oncology[2], are sufficiently convinced of the drug's protective potential to call for a trial to test its use as a preventive in pre-menopausal healthy women at high risk of the disease. They are now seeking international partners and funding for such a trial.

The women in the long-term follow-up comprised a sub-group of 1,700 --- 60% of the patients in a 10-centre trial lead by Professor Umberto Veronesi and co-ordinated by Milan's Istituto Nazionale Tumori when he was its director. The study, which began in 1987, randomised more than 2,800 women to receive 200 mg fenretinide daily for five years or no extra treatment after surgery for early-stage breast cancer.

The new analysis, also lead by Professor Veronesi, who is now Director of the European Institute of Oncology in Milan, followed the 1,739 patients who had been recruited by the Istituto Nazionale Tumori centre, investigating whether these patients developed a second cancer either in the treated breast or the other breast.

Co-author Dr Andrea Decensi, Director of the Department of Medical Oncology at the Galliera Hospital in Genoa, said: "We followed these patients for between 12 and 16 years and we found 168 second breast cancers in the fenretinide arm and 190 in the control arm. In post-menopausal women there were actually more cancers in the fenretinide arm than among the controls (85 as against 64). But, among pre-menopausal women there were only 83 second cancers in the fenretinide group compared with 126 in the control group.

Dr Decensi said that overall, this meant a 17% reduction in second cancers among the fenretinide group, which was of borderline statistical significance. But, there were four really strong messages within that overall finding:

• fenretinide had different effects on post-menopausal and pre-menopausal women and the increase in second breast cancers among post-menopausal women in the fenretinide arm meant it should not be given to that age group;
• it produced a statistically significant 38% reduction in second breast cancers in pre-menopausal women and halved the risk in women under 40;
• the protection in pre-menopausal women still persisted at 15 years follow-up even though the drug was given for only five years;
• the drug was effective in pre-menopausal women against both oestrogen receptor positive and oestrogen receptor negative breast cancer

Professor Veronesi said that fenretinide appeared to work by re-imposing order on breast cells that were in the process of becoming disorganised and growing out of control and also by forcing those that were in danger of becoming immortal to undergo normal cell death (apoptosis).

He said that the study had the limitation of being a retrospective sub-group analysis, so it needed to be updated and confirmed by results for the other 40% of patients, which they planned to do if funds became available.

"This sub-group analysis had not been foreseen when the original study was planned, so our findings are therefore hypothesis generating. It means that we are not in a position to make clinical recommendations from these data alone, but that this evidence provides a rationale for a new trial in young women at high risk of breast cancer. However, the magnitude of the effect, and the finding that the younger the woman the greater was the benefit, is so striking that we believe it is likely to be real."

The researchers also want studies to discover exactly how the drug works because the biological mechanisms are still unclear, especially the reasons why it works differently in younger or older women. They suggest that fenretinide may enhance the protective or damaging effects of hormones in different ways according to the stage of breast gland development in women.

Said Dr Decensi: "Its differential effect recalls the effect of first full term pregnancy on breast cancer risk, which is protective at a young age and deleterious at an older age."

He said the team wanted to initiate a prevention trial in young high-risk women, which would also look at the drug's potential for preventing ovarian cancer where there was some existing evidence that it may also be effective. They hoped that it might be possible to undertake it as a multi-centre international Europe/USA collaboration.

Professor Guiseppe De Palo from the Istituto Nazionale, who co-ordinated the study, explained that women carrying the BRCA-1 and 2 'breast cancer' genes, which also confer a higher risk of ovarian cancer, would be ideal candidates for a prevention trial. The drug had few side effects although there were still concerns that it could be harmful to unborn babies, which meant young women taking part must use reliable contraception.

"Fenretinide is something of a Cinderella drug," he said. "Like other retinoids it is tricky to manufacture because it is difficult to maintain the stability of the formulation and there are problems of pharmacological interactions. So, the pharmaceutical industry was reluctant to risk investing in its long-term clinical research, especially given that the patent would run out and tamoxifen was already on the market for treatment and had more efficacy data from large international trials."

Dr Decensi added that a preventive trial of fenretinide would be a clear example of the importance of health-care provider and community support for not-for-profit academic clinical research with older compounds. These were often safer than new agents for which long-term safety --- a crucial issue in prevention --- was still unknown.

[1] Fenretinide: A synthetic retinoid --- analogue of retinol (vitamin A), which binds to and activates retinoic acid receptors, inducing cell differentiation and cell death in some tumour types. It also inhibits tumour growth by modulating the growth factors associated with blood vessel development.
[2] Fifteen-year results of a randomized phase III trial of fenretinide to prevent second breast cancer. Annals of Oncology. doi"10.1093/annonc/mdl047.