I couldn’t access your link but here is the abstract--please note that
fenretinide was actually contraindicated in postmenopausal breast cancer patients as it was associated with an INCREASED incidence of second breast cancers. Seems to effectively decrease the development of second breast cancers in premenopausal patients. I added another abstract as well as 20(recent) of 545 articles on fenretinide. You have got a lot of homework!
A 15-year follow-up of women in a breast cancer trial has found that fenretinide[1] - a drug related to vitamin A - significantly cuts the risk of a second breast cancer among younger patients.
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).
Abstract:
Purpose: The synthetic retinoid fenretinide administered for 5 years for prevention of second breast cancer showed
no difference after a median of 8 years, but a possible reduction in premenopausal women. We conducted a long-term
analysis in a subgroup of women who were regularly followed up in a single center.
Patients and methods: We analyzed data after a median follow-up of 14.6 years (IQ range, 12.3–16.3 years) from
1739 women aged 30–70 (872 in the fenretinide arm and 867 in the observation arm), representing 60% of the initial
cohort of 2867 women. The main efficacy endpoint was second primary breast cancer (contralateral or ipsilateral).
Results: The number of second breast cancers was 168 in the fenretinide arm and 190 in the control arm (hazard
ratio = 0.83, 95% CI, 0.67–1.03). There were 83 events in the fenretinide arm and 126 in the observation arm in
premenopausal women (HR = 0.62, 95% CI, 0.46–0.83), and 85 and 64 events in postmenopausal women
(HR = 1.23, 95% CI, 0.63–2.40). The younger were the women, the greater was the risk reduction associated with
fenretinide, which attained 50% in women aged 40 years or younger and disappeared after age 55 (P-age*treatment
interaction = 0.023). There was no difference in cancers in other organs, distant metastases or survival.
Conclusions: Fenretinide induces a significant risk reduction of second breast cancer in premenopausal
women, which is remarkable at younger ages, and persists several years after treatment cessation.
Since adverse events are limited, a trial in young women at high-risk is warranted.
another recent related Italian abstract:
1: Endocr Relat Cancer. 2006 Mar;13(1):51-68.
Related Articles, Links
*
Clinical trials with retinoids for breast cancer chemoprevention.
Zanardi S, Serrano D, Argusti A, Barile M, Puntoni M, Decensi A.
Department of Medical and Preventive Oncology, E.O. Ospedali Galliera, Mura delle Cappuccine 14, 16128 Genoa, Italy.
Retinoids have been studied as chemopreventive agents in clinical trials due to their established role in regulating cell growth, differentiation and apoptosis in preclinical models. Experimental evidence suggests that retinoids affect gene expression both directly, by activating and/or repressing specific genes, and indirectly, by interfering with different signal transduction pathways. Induction of apoptosis is a unique feature of fenretinide, the most widely studied retinoid in clinical trials on breast cancer chemoprevention due to its selective accumulation in breast tissue and to its favourable toxicological profile. In a phase III breast cancer prevention trial, fenretinide showed a durable trend to a reduction of second breast malignancies in premenopausal women. This pattern was associated with a favourable modulation of circulating IGF-I and its main binding protein (IGF-binding protein-3, IGFBP-3), which have been associated with breast cancer risk in premenopausal women in different prospective studies. In a subsequent biomarker study on premenopausal women who had participated in the phase III trial, high IGF-I and low IGFBP-3 baseline levels were found to predict second breast cancer risk, although the magnitude of their changes during treatment did not fulfil the requirements for suitable surrogate end-point biomarkers. In postmenopausal women, fenretinide did not reduce second breast cancer incidence, nor did it induce significant modulation of the IGF system. Similarly, fenretinide was not found to affect risk biomarkers significantly in early postmenopausal women on hormone replacement therapy, who are at increased risk of developing breast cancer. Biomarker studies of fenretinide alone or in combination with different nuclear receptor ligands are being conducted. In particular, clinical trials of fenretinide and tamoxifen have proved to be feasible, and this combination appears to be safe and well tolerated in high-risk women, especially when low-dose tamoxifen is employed. Novel retinoid X receptor-selective retinoids, or rexinoids, have been shown to suppress the development of breast cancer in several animal models with minimal toxicity, and are being intensively studied either alone or in combination with selective oestrogen receptor modulators, both in vitro and in vivo. The rexinoid, bexarotene, has recently been approved for the treatment of patients with cutaneous T-cell lymphoma, and a biomarker trial with bexarotene in women with high breast cancer risk is currently underway.
Twenty of 545 articles on fenretinide:
2:
Ates-Alagoz Z, Coban T, Buyukbingol E.
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Synthesis and antioxidant activity of new tetrahydro-naphthalene-indole derivatives as retinoid and melatonin analogs.
Arch Pharm (Weinheim). 2006 Apr;339(4):193-200.
PMID: 16572477 [PubMed - in process]
3:
Villani MG, Appierto V, Cavadini E, Bettiga A, Prinetti A, Clagett-Dame M, Curley RW, Formelli F.
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4-oxo-fenretinide, a recently identified fenretinide metabolite, induces marked G2-M cell cycle arrest and apoptosis in fenretinide-sensitive and fenretinide-resistant cell lines.
Cancer Res. 2006 Mar 15;66(6):3238-47.
PMID: 16540676 [PubMed - indexed for MEDLINE]
4:
Yang B, Fan L, Fang L, He Q.
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Hypoxia-mediated fenretinide (4-HPR) resistance in childhood acute lymphoblastic leukemia cells.
Cancer Chemother Pharmacol. 2006 Mar 7; [Epub ahead of print]
PMID: 16520989 [PubMed - as supplied by publisher]
5:
Serrano D, Mariani L, Mora S, Guerrieri-Gonzaga A, Cazzaniga M, Daldoss C, Ramazzotto F, Feroce I, Decensi A, Bonanni B.
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Quality of life assessment in a chemoprevention trial: Fenretinide and oral or transdermal HRT.
Maturitas. 2006 Feb 22; [Epub ahead of print]
PMID: 16500052 [PubMed - as supplied by publisher]
6:
Xu H, Cheepala S, McCauley E, Coombes K, Xiao L, Fischer SM, Clifford JL.
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Chemoprevention of skin carcinogenesis by phenylretinamides: retinoid receptor-independent tumor suppression.
Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):969-79.
PMID: 16467112 [PubMed - in process]
7:
Xiao DK, Du YZ, Fan HY, Chen YL, Chen Z, Zhang J, Wang KK.
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[Mechanisms of fenretinide-triggered apoptosis in leukemic cells]
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2005 Dec;13(6):975-8. Chinese.
PMID: 16403262 [PubMed - in process]
8:
Damodar Reddy C, Guttapalli A, Adamson PC, Vemuri MC, O'Rourke D, Sutton LN, Phillips PC.
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Anticancer effects of fenretinide in human medulloblastoma.
Cancer Lett. 2006 Jan 18;231(2):262-9.
PMID: 16399227 [PubMed - indexed for MEDLINE]
9:
Guerrieri-Gonzaga A, Robertson C, Bonanni B, Serrano D, Cazzaniga M, Mora S, Gulisano M, Johansson H, Intra M, Latronico A, Franchi D, Pelosi G, Johnson K, Decensi A.
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Preliminary results on safety and activity of a randomized, double-blind, 2 x 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in premenopausal women.
J Clin Oncol. 2006 Jan 1;24(1):129-35.
PMID: 16382122 [PubMed - indexed for MEDLINE]
10:
Finnegan CM, Blumenthal R.
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Fenretinide inhibits HIV infection by promoting viral endocytosis.
Antiviral Res. 2006 Feb;69(2):116-23. Epub 2005 Dec 9.
PMID: 16375981 [PubMed - in process]
11:
Goranov BB, Campbell Hewson QD, Pearson AD, Redfern CP.
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Overexpression of RARgamma increases death of SH-SY5Y neuroblastoma cells in response to retinoic acid but not fenretinide.
Cell Death Differ. 2006 Apr;13(4):676-9. No abstract available.
PMID: 16341128 [PubMed - in process]
12:
Barna G, Sebestyen A, Weischede S, Petak I, Mihalik R, Formelli F, Kopper L.
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Different ways to induce apoptosis by fenretinide and all-trans-retinoic acid in human B lymphoma cells.
Anticancer Res. 2005 Nov-Dec;25(6B):4179-85.
PMID: 16309214 [PubMed - indexed for MEDLINE]
13:
Radu RA, Han Y, Bui TV, Nusinowitz S, Bok D, Lichter J, Widder K, Travis GH, Mata NL.
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Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases.
Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4393-401.
PMID: 16303925 [PubMed - indexed for MEDLINE]
14:
Alarcon-Vargas D, Zhang Z, Agarwal B, Challagulla K, Mani S, Kalpana GV.
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Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors.
Oncogene. 2006 Feb 2;25(5):722-34.
PMID: 16302003 [PubMed - indexed for MEDLINE]
15:
Harris G, Ghazallah RA, Nascene D, Wuertz B, Ondrey FG.
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PPAR activation and decreased proliferation in oral carcinoma cells with 4-HPR.
Otolaryngol Head Neck Surg. 2005 Nov;133(5):695-701.
PMID: 16274795 [PubMed - indexed for MEDLINE]
16:
Wu XZ, Zhang L, Shi BZ, Hu P.
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Inhibitory effects of N-(4-hydrophenyl) retinamide on liver cancer and malignant melanoma cells.
World J Gastroenterol. 2005 Oct 7;11(37):5763-9.
PMID: 16270382 [PubMed - indexed for MEDLINE]
17:
Bayes M, Rabasseda X, Prous JR.
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Gateways to clinical trials.
Methods Find Exp Clin Pharmacol. 2005 Sep;27(7):505-22.
PMID: 16258596 [PubMed - indexed for MEDLINE]
18:
Shishodia S, Gutierrez AM, Lotan R, Aggarwal BB.
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N-(4-hydroxyphenyl)retinamide inhibits invasion, suppresses osteoclastogenesis, and potentiates apoptosis through down-regulation of I(kappa)B(alpha) kinase and nuclear factor-kappaB-regulated gene products.
Cancer Res. 2005 Oct 15;65(20):9555-65.
PMID: 16230421 [PubMed - indexed for MEDLINE]
19:
Takahashi N, Honda T, Ohba T.
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Anticancer and superoxide scavenging activities of p-alkylaminophenols having various length alkyl chains.
Bioorg Med Chem. 2006 Jan 15;14(2):409-17. Epub 2005 Oct 3.
PMID: 16203149 [PubMed - indexed for MEDLINE]
20:
Simeone AM, Colella S, Krahe R, Johnson MM, Mora E, Tari AM.
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N-(4-Hydroxyphenyl)retinamide and nitric oxide pro-drugs exhibit apoptotic and anti-invasive effects against bone metastatic breast cancer cells.
Carcinogenesis. 2006 Mar;27(3):568-77. Epub 2005 Sep 30.
PMID: 16199439 [PubMed - indexed for MEDLINE]
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