In:
Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 3, No. 12_Supplement ( 2010-12-01), p. A71-A71
Abstract:
Retinoids have been studied as chemopreventive compounds because of their role in regulating cell growth, differentiation and apoptosis in preclinical models. Induction of apoptosis is a unique feature of fenretinide (4-hydroxyphenylretinamide, 4-HPR) the most studied retinoid in clinical trials of breast cancer (BC) prevention for its selective accumulation in the breast tissue and its low toxicity. Fenretinide is effective in inhibiting the growth of BRCA1 mutated BC cell lines. Recent studies showed that it modulates gene expression in ovarian cells, with an up-regulation of expression of proapoptotic genes in OVCA433 cells. The fifteen-year follow up of a randomized phase III trial of fenretinide to prevent second BC indicates that it induced a 17% reduction of second BC incidence. More importantly, when stratified by menopausal status, the analysis showed a 38%, statistically significant reduction of second BC in premenopausal women and this effect persisted for up to 15 years. Interestingly, the younger were the women (≤ 40 years), the greater was the trend of benefit by fenretinide. When considering the protective activity of fenretinide on second BC and a similar trend on ovarian cancer (OC) it appears that young women at high risk for both diseases such as carriers of germline BRCA1 and BRCA2 mutations or those with a high family risk may be ideal candidates for further investigation on this retinoid. Since a reduction of second BC might be a surrogate marker of primary prevention, a favorable effect of fenretinide provides strong rationale for a primary prevention trial in unaffected women at high-risk for BC. The European Institute of Oncology (IEO, Milan, Italy) has promoted a multi-centric (15 centres nationwide), randomized phase III placebo-controlled study with fenretinide in healthy young women: 758 healthy women, 25-44 years old, at increased BC risk (BRCA1/2 mutation carriers or subjects with mutation probability ≥20% acc. to BRCAPRO), will be randomized to 4-HPR 200 mg/day vs placebo for 5 years followed by a 10 years follow up period. We will perform a clinical examination every 6 months, and annual breast ultrasound and breast MRI. For subjects ≥ 35 years old also an annual mammography is requested. All subjects will undergo a transvaginal ultrasound at least once a year. At each visit, safety tests (β-HCG, AST, ALT, blood count, creatinine, glycemia, lipid profile, CA-125), and blood samples for biomarkers evaluation at baseline, 12, 36, and 60 months. Enrollment started at the IEO in December 2009. The other centers are expected to start within early 2011. The primary endpoint of the trial is to assess the efficacy of fenretinide in reducing the incidence of invasive BC and ductal intraepithelial neoplasia (DIN). Secondary endpoints are the incidence of non-invasive breast disorders, OC, other cancers and the study of various risk biomarkers. In particular, we will evaluate the change in circulating biomarkers of the IGF system, androgens, retinol binding protein (RBP-4), insulin, blood glucose and VEGF. Genotyping of single nucleotide polymorphisms (SNPs) linked to BC risk (MTHFR, COMT, GH, IGFBP-3, AR, TGF-β genes), degree of methylation of RASSAF1 and RARβ and circulating progranulin will be assessed. The results will be correlated with mammographic instrumental measurements, plasma and tissue biomarkers after 1 year treatment. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A71.
Type of Medium:
Online Resource
ISSN:
1940-6207
,
1940-6215
DOI:
10.1158/1940-6207.PREV-10-A71
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2422346-3
Bookmarklink