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Breast Cancer Prevention With Fenretinide in Young Women at Genetic and Familil Risk. A Phase III Randomized Clinical Trial

Phase 3
20 Years
46 Years
Open (Enrolling)
High-Risk Cancer

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Trial Information

Breast Cancer Prevention With Fenretinide in Young Women at Genetic and Familil Risk. A Phase III Randomized Clinical Trial

Retinoids have been studied as chemo preventive compounds in clinical trials because of
their acknowledged role in regulating cell growth, differentiation and apoptosis in
preclinical models. Induction of apoptosis is a unique feature of fenretinide
(4-hydroxyphenylretinamide, 4-HPR),(2) the most widely studied retinoid in clinical trials
of breast cancer chemoprevention for its selective accumulation in the breast tissue and its
very low toxicity. The fifteen-year follow up of a randomized phase III trial of fenretinide
to prevent second breast cancer indicates that fenretinide induced a 17%, durable reduction
of second breast cancer incidence. When stratified by menopausal status, the analysis showed
a 38%, statistically significant reduction of second breast cancers in premenopausal women
and this protective effect persisted for up to 15 years, i.e. 10 years after treatment
cessation. Importantly, the younger were the women, the greater was the trend of benefit of
fenretinide, with a remarkable 50% risk reduction in women aged 40 years or younger, whereas
the benefit disappeared after age 55. One explanation for the different effects of
fenretinide according to menopausal status or age is a different modulation of circulating
IGF-I in premenopausal and postmenopausal women, with a reduction of IGF-I levels only in
premenopausal subjects.

When considering the protective activity of fenretinide on second breast cancer in young
women and a similar trend on ovarian cancer (the latter at least during intervention)(4, 5),
it appears that young women at high risk such as those with germ line BRCA-1 and 2 mutations
or those with a high family risk may be ideal candidates for further investigation on this
retinoid. Indeed, fenretinide is highly effective in inhibiting the growth of BRCA-1 mutated
breast cancer cell lines. Since a reduction of second breast cancer might be a surrogate
marker of primary prevention, a favourable effect of fenretinide provides strong rationale
for a primary prevention trial in unaffected women at high-risk for breast cancer.

Importantly, at clinically relevant doses, fenretinide has shown to induce NO-mediated
apoptosis in human and murine BRCA-1 mutated cancer cells, and In this ability fenretinide
was the most potent of the phenylretinamide analogues against BRCA-1 mutated breast cancer

Additionally, recent studies have shown that 4-HPR modulates gene expression in ovarian
cells, with an up-regulation of expression of proapoptotic genes in OVCA433 cells and
down-regulation of mutant BRCA genes in IOSE (premalignant) cells and OVCA433 cells. This
suggests a preventive effect in premalignant cells and a treatment effect in cancer cells.

Increasing evidence sustains a link between the rising prevalence of metabolic syndrome in
the Western world and breast cancer incidence. The retinol-binding protein 4 (RBP4), an
adipocyte-secreted molecule, is the only specific transport protein for retinol in the blood
and correlates with components of the metabolic syndrome, including increased body-mass
index, waist-to-hip ratio, serum triglycerides. Plasma concentrations of RBP4 are known to
decrease proportionally with retinol during fenretinide administration and normalization of
RBP4 by fenretinide in insulin-resistant obese mice has shown to improve insulin action and
glucose tolerance.

Among other molecular biomarker candidates for malignant tumours, cell-free DNA circulating
in serum is very promising. Unlike uniformly truncated DNA released from apoptotic cells,
DNA released from dead cancer cells varies in size. Serum DNA integrity and the ratio of
longer fragments to total DNA may be clinically useful for detecting breast cancer
progression. Since free-circulating DNA is a non-invasive approach and can be detected in
cancer patients and not in disease-free individuals, it will be interesting to study if it
can be used as an early detection biomarker.

Breast cancer chemoprevention is rapidly evolving, and there is strong evidence that primary
chemoprevention is possible. The more established preventive agents so far are SERMs
(selective estrogen receptor modulators), while AIs (aromatase inhibitors) are currently
under investigation in postmenopausal populations. All these drugs involve directly the
hormonal pathway of the pathogenesis of the disease, and their target is most likely limited
to hormone responsive tumours. Tamoxifen has great effect as a chemo preventive agent but it
may have serious side effects, while raloxifene may have a better toxicity profile,
especially as concerns the risk of endometrial cancer, but it has been tested only in post
menopause. Fenretinide has shown to possess several good properties both in preclinical
models and clinical trials. In particular, the prolonged effect demonstrated in the phase
III trial chemopreventive trial in breast cancer subjects, together with a trend of
protective effect on the ovaries, has been accompanied by a very low toxicity profile
(mainly reversible skin dryness and rashes and dark adaptation difficulties, often overcome
by a monthly weekend suspension of the drug).

All these characteristics make fenretinide an excellent candidate for chemoprevention in a
cohort of young healthy women with a high susceptibility to early onset breast and ovarian
cancer, such as those who carry a BRCA 1/2 mutation or have a significant family risk. Since
the drug activities are probably not strictly influenced by hormonal responsiveness, it is
possible that it may have effect also on hormone non-responsive cancers, and this may be
very useful particularly in case of BRCA1 mutation carriers.

Side effects and toxicity: visual symptoms (diminished dark adaptability, dryness and
lacrimation) have been reported in approximately 20% of subjects. These symptoms may occur
more frequently at the start of intervention and they tend to recover with time often
without the need for treatment discontinuation. A regular three-days/month drug suspension
has been adopted for a long time in clinical studies to minimize visual impairment.
Although this side effect is in many women manageable (especially following the regular
three day suspension) and reversible, it must be remembered that the dark adaptability
impairment might be potentially dangerous in certain situations such as driving from the
bright sun into a dark tunnel or night driving.

Dermatological disorders, such as skin and mucosal dryness, pruritus and urticaria can be
detected in about 18% of subjects. Mild gastrointestinal symptoms are reported in around 13%
of patients. Interestingly, with the exception of ocular surface disorders, the incidence of
the other adverse effects seems to decrease with time and is significantly more frequent in
postmenopausal women.

Liver toxicity and increase in blood lipid levels, especially triglycerides, are reported
but not consistently in the literature.

Like other retinoids, fenretinide may be potentially teratogenic, although available
studies show no genotoxic effects in vitro and in vivo, and a lack of storage in the human

Thus, appropriate measures of contraception should be adopted when treating potentially
fertile women.

Inclusion Criteria:

1. 20-46 years old women with a known BRCA ½ mutation or with a risk of being a mutation
carrier ≥20%.

2. Performance status =0

3. Willingness to avoid pregnancy during treatment and 12 months after drug cessation

4. No clinical and radiological evidence of breast cancer and ovarian disease

5. Signed informed consent

Exclusion Criteria:

1. History of breast cancer or any other malignancy with the exclusion of CIN and
non-melanoma skin cancer

2. Child bearing or breast feeding

3. Genetic test result (BRCA)=true negative

4. Blood test alterations (grade ≥2 based on the NCI Common Toxicity Criteria)

5. Previous or concurrent use of SERMs, e.g. tamoxifen (for more than 12 months; if
less, a two-months wash-out is required before entering the study)

6. Severe psychiatric disorders or inability to comply to the protocol procedures

7. Any other factor that, at the investigator's discretion, contraindicates the use of

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Outcome Measure:

Breast cancer incidence

Outcome Description:

The aim of the proposed trial is to assess the efficacy of fenretinide, (4 hydroxyphenilretinamide, 4-HPR), a vitamin A derivative, in reducing the incidence of breast cancer (BC) in healthy young premenopausal women at increased familial/genetic risk for BC (i.e. BRCA1 or BRCA2 mutation carriers or subjects at high risk of being carriers). The primary endpoint is the incidence of invasive BC and ductal intraepithelial neoplasia (DIN), histologically diagnosed.

Outcome Time Frame:

every 6 months for 15 years

Safety Issue:


Principal Investigator

Umberto Veronesi

Investigator Role:

Study Chair

Investigator Affiliation:

European Institute of Oncology


Italy: The Italian Medicines Agency

Study ID:

IEO S462/109



Start Date:

December 2009

Completion Date:

December 2024

Related Keywords:

  • High-Risk Cancer
  • breast
  • cancer
  • prevention
  • fenretinide