Abstract
This phase II study of liarozole fumarate (R85246, liarozole), a novel imidazole with retinomimetic and aromatase inhibitory effects, was designed to determine the efficacy and tolerability in postmenopausal women with advanced breast cancer in progression, to correlate these effects with hormonal levels, and to evaluate quality of life. Twenty-nine women with ER-positive or unknown metastatic disease who received ≥ 2 prior hormonal therapies were treated with 150–300 mg liarozole twice daily until disease progression. All patients were evaluable for toxicity and 25 for response. Four patients (16.0%, 95% CI 5.3–37.4%) had partial remission (PR) of their disease for a median of 7.4 months (range 1.2–12.9) and 7 (28%) had disease stabilization for a median of 4.8 months (1.6–16.0). Estradiol decreased from pre-treatment levels of 9.2–52 pM (mean 17.1) to below detection (9.2 pM, p=0.0005) after 1 month. Similarly estrone levels fell from 14–307 pM (mean 92.7) to below detection (9.2 pM, p=0.0001). The most common toxicity was dermatological (96.6%) with features compatible with hypervitaminosis A syndrome such as rash, pruritus, dry skin, and brittle nails. The majority of these were mild to moderate in severity. No significant improvement in quality of life scores (FLI-C) were noted. Liarozole is an active new treatment for breast cancer in patients heavily pre-treated with hormone therapies. Further studies are needed to confirm its relative efficacy in both receptor positive and negative postmenopausal breast cancer.
Similar content being viewed by others
References
Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment with illustrative cases. Lancet 3: 104-107, 1986
Henderson IC: Endocrine therapy in metastatic breast cancer. In: Harris JR, Hellman S, Henderson IC, Kinne DW (eds) Breast Diseases. JB Lippincott, Philadelphia, 1987, 421 p
Kostraba N, Kiang D, Frenning D, Theologides A, Kennedy BJ: Multiple endocrine therapy in the management of advanced breast cancer. (Abstract #586) Proc Am Assoc Cancer Res 21: 147, 1980
Buzdar A, Jonat W, Howell A, Jones SE, Blomqvist C, Vogel CL, Eirmann W, Wolter JM, Azab M, Webster A, Plourde PV for the Arimidex Study Group: Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. J Clin Oncol 14: 2000-2011, 1996
Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L, Bellmunt J, Bezwoda W, Gardin G, Gudgeon A, Morgan M, Fornasiero A, Hoffmann W, Michel J, Harschek T, Tjabbes T, Chaudri HA, Homberger U, Trunet PF: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16: 453-461, 1998
Taylor SG, Gelman RS, Falkson G, Cummings FJ: Combination chemotherapy compared to tamoxifen as initial therapy for Stage IV breast cancer in elderly women. Ann Int Med 104: 455-461, 1986
Mahler C, Verhelst J, Denis L: Ketoconazole and liarozole in the treatment of advanced prostatic cancer. Cancer 71: 1068-1073, 1993
Dijkman GA, Fernandez del Moral P, Bruynseels J, De Porre P, Denis L, Debruyne FMJ: Liarozole (R75251) in hormoneresistant prostate cancer patients. Prostate 33: 26-31, 1997
Wouters W, van Dun J, Dillen A, Coene M-C, Cools W, De Coster R: Effects of liarozole, a new antitumoral compound, on retinoic acid-induced inhibition of cell growth and on retinoic acid metabolism in MCF-7 human breast cancer cells. Cancer Res 52: 2841-2846, 1992
Van heusden J, Borgers M, Ramaekers F, Xhonneux B, Wouters W, De Coster R, Smets, G: Liarozole potentiates the all-trans-retinoic acid-induced structural remodelling in human breast carcinoma MCF-7 cells in vitro. Eur J Cell Biol 71: 89-98, 1996
Koymans LMH, Moereels H, Vanden Bossche H: A molecular model for the interaction between vorozole and other nonsteroidal inhibitors and human cytochrome P450 19 (P450 aromatase). J Steroid Biochem Molec Biol 53 (1-6): 191-197, 1995
Bruynseels J, De Coster R, Van Rooy P, Wouters W, Coene M-C, Snoeck E, Raeymaekers A, Freyne E, Sanz G, Vanden Bossche G, Vanden Bossche H, Willemsens G, Janssen, PAJ: R75251, a new inhibitor of steroid biosynthesis. Prostate 16: 345-357, 1990
Van Wauwe JP, Coene M-C, Goossens J, Cools W, Monbaliu J: Effects of cytochrome P450 inhibitors on the in vivo metabolism of all-trans-retinoic acid in rats. J Pharmacol Exp Ther 252: 365-369, 1990
Van Wauwe J, Van Nyen G, Coene M-C, Stoppie P, Cools W, Goossens J, Borghgraef P, Janssen PAJ: Liarozole, an inhibitor of retinoic acid metabolism, exerts retinoid-mimetic effects in vivo. J Pharmacol Exp Ther 261: 773-779, 1992
Van Wauwe J, Coene M-C, Cools W, Goosens J, Lauwers W, Le Jeune L, Van Hove CW, Van Nyen G: Liarozole fumarate inhibits the metabolism of 4-keto-all-trans-retinoic acid. Biochem Pharmacol 47: 737-741, 1994
End D, Wouters W, Garrabrant T, Bowden C, De Coster R, Van Ginckel R: Anti-tumor effects of liarozole in TA3 mammary carcinoma: comparison to retinoic acid. (Abstract #158) Proc Am Assoc Cancer Res 33: 27, 1992
Liarozole Investigator's Brochure, 3rd edition, August, 1994
Fishman B, Pastrnak S, Wallenstein SL, Houde RW, Holland JC, Foley KM: The Memorial Pain Assessment Card: a valid instrument for the measurement of cancer pain. Cancer 60: 1151-1157, 1987
World Health Organization. Cancer Pain Relief, Geneva, 1986
Schipper H, Clinch J, McMurray A, Levitt M: Measuring the quality of life of cancer patients: the Functional Living Index-Cancer: development and validation. J Clin Oncol 2: 472-483, 1984
World Health Organization, 1979. Handbook for reporting results of cancer treatment. Offset Publication No. 48 WHO, Geneva, 1979
De Coster R, Beerens D, Dom J, Willemsens G: Endocrinological effects of single daily ketoconazole therapy in male beagle dogs. Acta Endocrinol 107: 275-281, 1984
De Coster R, Caers I, Coene M-C, Amery W, Beerens D, Haelterman C: Effects of high dose ketoconazole therapy on the main plasma testicular and adrenal steroids in previously untreated prostatic cancer patients. Clin Endocrinol 24: 657-664, 1986
Woestenborghs R, Prinsen P, Embrechts L, Van Rompaey F, Heykants J: HPLC-fluorescence method for the determination of R075251 in plasma and animal tissues. Janssen Research Foundation, September 1989, Preclinical Research Report R061405/3
Iveson TJ, Ahem J, Smith IE: Response to third-line endocrine treatment for advanced breast cancer. Eur J Cancer 29A: 572-574, 1993
Garcia-Giralt E, Ayme Y, Carton M, Daban A, Delozier T, Fargeot P, Fumoleau P, Gorins A, Guerin D, Guerin R, Maillart P, Mauriac L, May-Levin F, Metz R, Namer M, Olivier JP, Pommatau E, Pouillart P, Pujade-Lauraine E, Rouesse J, Serrou B, Vitse M, Zylberait D: Second and third line hormonotherapy in advanced post-menopausal breast cancer: a multicenter randomized trial comparing medroxyprogesterone acetate with aminoglutethimide in patients who have become resistant to tamoxifen. Br Cancer Res Treat 24: 139-145, 1992
Ingle JN, Johnson PA, Suman VJ, Gerstner JB, Mailliard JA, Camoriano JK, Germe DH Jr, Loprinzi CL, Hatfield AK, Hartmann LC: A randomized phase II trial of two dosage levels of letrozole as third-line hormonal therapy for women with metastatic breast carcinoma. Cancer 80(2): 218-224, 1997
Lundgren S, Kvinnsland S, Utaaker E: Oral high-dose progestins as treatment for advanced breast cancer. Acta Oncol 28: 811-816, 1989
Conte CC, Nemoto T, Rosner D, Dao TL: Therapeutic oophorectomy in metastatic breast cancer. Cancer 64: 150-153, 1989
Donkx P, Deree J, Degreef H: Inhibition of the metabolism of endogenous retinoic acid as treatment for severe psoriasis: an open study with oral liarozole. Br J Dermatol 133: 426-432, 1995
Lucker GPH, Heremans AMC, Boegheim PJ, Van de Kerkhof PCM, Steijlen PM: Oral treatment of ichthyosis by the cytochrome P-450 inhibitor liarozole. Br J Dermatol 136: 71-75, 1997
De Coster R, Wouters W, Bruynseels J: P450-dependent enzymes as targets for prostate cancer therapy. J Steroid Biochem 56: 133-143, 1996
Alexieva-Figusch J, Blankenstein MA, Hop WCJ, Klijn JGM, Lamberts SWJ, De Jong FH, Docter R, Adlercreutz H, Van Gilse HA: Treatment of metastatic breast cancer patients with different dosages of megestrol acetate; dose relations, metabolic and endocrine effects. Eur J Cancer Clin Oncol 20: 33-40, 1984
Santen RJ, Wells SA, Cohn N, Demers LM, Misbin RI, Foltz EL: Compensatory increase in TSH secretion without effects on prolactin secretion in patients treated with aminoglutethimide. J Clin Endocrinol Metab 45: 739-746, 1977
Rallison ML, Kumagai LF, Tyler FH: Goitrous hypothyroidism induced by aminoglutethimide, anticonvusant drug. J Clin Endocr 27: 265-272, 1967
Lippman ME, Dickson RB: Mitogenic regulation of normal and malignant breast epithelium. Yale J Biol Med 62: 459-480, 1989
Pollak MN, Huynh HT, Lefebvre SP: Tamoxifen reduces serum insulin-like growth factor I (IGF-I). Br Cancer Res Treat 22: 91-100, 1992
Helle SI, Holly JMP, Tally M, Hall K, Vander Stappen J, Lonning PE: Influence of treatment with tamoxifen and change in tumor burden on the IGF-system in breast cancer patients. Int J Cancer 69: 335-339, 1996
Bentel JM, Lebwohl DE, Cullen KJ, Rubin MS. Rosen N, Mendelsohn J, Miller WH Jr: Insulin-like growth factors modulate the growth inhibitory effects of retinoic acid on MCF-7 breast cancer cells. J Cell Physiol 165: 212-221, 1995
Iwase H, Kobayashi S, Itoh Y, Fukuoka H, Kuzushima T, Iwata H, Yamashita T, Naitoh A, Itoh K, Masaoka A: Evaluation of serum tumor markers in patients with advanced or recurrent breast cancer. Br Cancer Res Treat 33: 83-88, 1994
Aydiner A, Topuz E, Disci R, Yasasever V, Dincer M, Dincol K, Bilge N: Serum tumor markers for detection of bone metastasis in breast cancer patients. Acta Oncol 33: 181-186, 1994
Seidmon EJ, Trump DL, Kreis W, Hall SW, Kurman MR, Ouyang SP, Wu J, Kremer AB: Phase I/Il dose-escalationstudy of liarozole in patients with stage D2 hormonerefractory carcinoma of the prostate. Ann Surg Oncol 2:550-556, 1995
Zhao J, Tan BK, Marcelis S, Verstuyf A, Bouillon R: Enhancement of antiproliferative activity of 1α,25-dihydroxyvitamin D3 (analogs) by cytochrome P450 enzyme inhibitors is compound-and cell-type specific. J Steroid Biochem Molec Biol 57: 197-202, 1996
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Goss, P.E., Oza, A., Goel, R. et al. Liarozole fumarate (R85246): a novel imidazole in the treatment of receptor positive postmenopausal metastatic breast cancer. Breast Cancer Res Treat 59, 55–68 (2000). https://doi.org/10.1023/A:1006320122711
Issue Date:
DOI: https://doi.org/10.1023/A:1006320122711