Top

Published in:

Open Access 01-01-2020 | Breast Cancer | Preclinical study

Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy

Authors: Suzanne E. Wardell, Alexander P. Yllanes, Christina A. Chao, Yeeun Bae, Kaitlyn J. Andreano, Taylor K. Desautels, Kendall A. Heetderks, Jeremy T. Blitzer, John D. Norris, Donald P. McDonnell

Published in: Breast Cancer Research and Treatment | Issue 1/2020

Abstract

Purpose

Fulvestrant is a selective estrogen receptor downregulator (SERD) that is approved for first- or second-line use as a single agent or in combination with cyclin dependent kinase or phosphatidylinositol 3-kinase inhibitors for the treatment of metastatic breast cancer. Fulvestrant exhibits exceptionally effective antitumor activity in preclinical models of breast cancer, a success that has been attributed to its robust SERD activity despite modest receptor downregulation in patient tumors. By modeling human exposures in animal models we probe the absolute need for SERD activity.

Methods

Three xenograft models of endocrine therapy-resistant breast cancer were used to evaluate the efficacy of fulvestrant administered in doses historically used in preclinical studies in the field or by using a dose regimen intended to model clinical exposure levels. Pharmacokinetic and pharmacodynamic analyses were conducted to evaluate plasma exposure and intratumoral ER downregulation.

Results

A clinically relevant 25 mg/kg dose of fulvestrant exhibited antitumor efficacy comparable to the historically used 200 mg/kg dose, but at this lower dose it did not result in robust ER downregulation. Further, the antitumor efficacy of the lower dose of fulvestrant was comparable to that observed for other oral SERDs currently in development.

Conclusion

The use of clinically unachievable exposure levels of fulvestrant as a benchmark in preclinical development of SERDs may negatively impact the selection of those molecules that are advanced for clinical development. Further, these studies suggest that antagonist efficacy, as opposed to SERD activity, is likely to be the primary driver of clinical response.

Available only for authorised users

Burstein HJ, Lacchetti C, Anderson H, Buchholz TA, Davidson NE, Gelmon KA, Giordano SH, Hudis CA, Solky AJ, Stearns V, Winer EP, Griggs JJ (2019) Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: ASCO clinical practice guideline focused update. J Clin Oncol 37(5):423–438. https://doi.org/10.1200/JCO.18.01160 CrossRef

Rugo HS, Rumble RB, Macrae E, Barton DL, Connolly HK, Dickler MN, Fallowfield L, Fowble B, Ingle JN, Jahanzeb M, Johnston SR, Korde LA, Khatcheressian JL, Mehta RS, Muss HB, Burstein HJ (2016) Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology Guideline. J Clin Oncol 34(25):3069–3103. https://doi.org/10.1200/JCO.2016.67.1487 CrossRefPubMed

Robertson JF, Lindemann JP, Llombart-Cussac A, Rolski J, Feltl D, Dewar J, Emerson L, Dean A, Ellis MJ (2012) Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized ‘FIRST’ study. Breast Cancer Res Treat 136(2):503–511. https://doi.org/10.1007/s10549-012-2192-4 CrossRefPubMed

Perey L, Paridaens R, Hawle H, Zaman K, Nole F, Wildiers H, Fiche M, Dietrich D, Clement P, Koberle D, Goldhirsch A, Thurlimann B (2007) Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00). Ann Oncol 18:64–69CrossRef

Ingle JN, Suman VJ, Rowland KM, Mirchandani D, Bernath AM, Camoriano JK, Fishkin PAS, Nikcevich DA, Perez EA (2006) Fulvestrant in women with advanced breast cancer after progression on prior aromatase inhibitor therapy: North Central Cancer Treatment Group Trial N0032. J Clin Oncol 24:1052–1056CrossRef

Hu XF, Veroni M, Deluise M, Wakeling A, Sutherland R, Watts CKW, Zalcberg JR (1993) Circumvention of tamoxifen resistance by the pure antiestrogen Ici-182,780. Int J Cancer 55(5):873–876. https://doi.org/10.1002/ijc.2910550529 CrossRefPubMed

Osborne CK, Coronadoheinsohn EB, Hilsenbeck SG, Mccue BL, Wakeling AE, Mcclelland RA, Manning DL, Nicholson RI (1995) Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast-cancer. J Natl Cancer Inst 87(10):746–750. https://doi.org/10.1093/jnci/87.10.746 CrossRefPubMed

Howell A, Osborne CK, Morris C, Wakeling AE (2000) ICI 182,780 (Faslodex): development of a novel, “pure” antiestrogen. Cancer 89:817–825CrossRef

Nair AB, Jacob S (2016) A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 7(2):27–31. https://doi.org/10.4103/0976-0105.177703 CrossRefPubMedPubMedCentral

10.

Western blot quantitation. http://lukemiller.org/index.php/2010/11/analyzing-gels-and-western-blots-with-image-j/. Accessed 1 Sept 2019

11.

Livak K, Schmittgen T (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(DDC(T)) method. Methods 25:402–408CrossRef

12.

Prescribing information for faslodex. http://www.azpicentral.com/pi.html?product=faslodex. Accessed 1 Sept 2019

13.

Agrawal A, Robertson JF, Cheung KL, Gutteridge E, Ellis IO, Nicholson RI, Gee JM (2016) Biological effects of fulvestrant on estrogen receptor positive human breast cancer: short, medium and long-term effects based on sequential biopsies. Int J Cancer 138(1):146–159. https://doi.org/10.1002/ijc.29682 CrossRefPubMed

14.

Wright TM, Wardell SE, Jasper JS, Stice JP, Safi R, Nelson ER, McDonnell DP (2014) Delineation of a FOXA1/ERalpha/AGR2 regulatory loop that is dysregulated in endocrine therapy-resistant breast cancer. Mol Cancer Res 12(12):1829–1839. https://doi.org/10.1158/1541-7786.MCR-14-0195 CrossRefPubMedPubMedCentral

15.

Wardell SE, Ellis MJ, Alley HM, Eisele K, VanArsdale T, Dann SG, Arndt KT, Primeau T, Griffin E, Shao J, Crowder R, Lai JP, Norris JD, McDonnell DP, Li S (2015) Efficacy of SERD/SERM hybrid-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant breast cancer. Clin Cancer Res 21(22):5121–5130. https://doi.org/10.1158/1078-0432.CCR-15-0360 CrossRefPubMedPubMedCentral

16.

Joseph JD, Darimont B, Zhou W, Arrazate A, Young A, Ingalla E, Walter K, Blake RA, Nonomiya J, Guan Z, Kategaya L, Govek SP, Lai AG, Kahraman M, Brigham D, Sensintaffar J, Lu N, Shao G, Qian J, Grillot K, Moon M, Prudente R, Bischoff E, Lee KJ, Bonnefous C, Douglas KL, Julien JD, Nagasawa JY, Aparicio A, Kaufman J, Haley B, Giltnane JM, Wertz IE, Lackner MR, Nannini MA, Sampath D, Schwarz L, Manning HC, Tantawy MN, Arteaga CL, Heyman RA, Rix PJ, Friedman L, Smith ND, Metcalfe C, Hager JH (2016) The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER + breast cancer. Elife. https://doi.org/10.7554/eLife.15828 CrossRefPubMedPubMedCentral

17.

Weir HM, Bradbury RH, Lawson M, Rabow AA, Buttar D, Callis RJ, Curwen JO, de Almeida C, Ballard P, Hulse M, Donald CS, Feron LJ, Karoutchi G, MacFaul P, Moss T, Norman RA, Pearson SE, Tonge M, Davies G, Walker GE, Wilson Z, Rowlinson R, Powell S, Sadler C, Richmond G, Ladd B, Pazolli E, Mazzola AM, D’Cruz C, De Savi C (2016) AZD9496: an oral estrogen receptor inhibitor that blocks the growth of ER-positive and ESR1-mutant breast tumors in preclinical models. Cancer Res 76(11):3307–3318. https://doi.org/10.1158/0008-5472.CAN-15-2357 CrossRefPubMed

18.

Dardes RC, O’Regan RM, Gajdos C, Robinson SP, Bentrem D, De Los Reyes A, Jordan VC (2002) Effects of a new clinically relevant antiestrogen (GW5638) related to tamoxifen on breast and endometrial cancer growth in vivo. Clin Cancer Res 8(6):1995–2001PubMed

19.

Connor CE, Norris JD, Broadwater G, Willson TM, Gottardis MM, Dewhirst MW, McDonnell DP (2001) Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational changes in the estrogen receptor. Cancer Res 61(7):2917–2922PubMed

20.

Fanning SW, Mayne CG, Dharmarajan V, Carlson KE, Martin TA, Novick SJ, Toy W, Green B, Panchamukhi S, Katzenellenbogen BS, Tajkhorshid E, Griffin PR, Shen Y, Chandarlapaty S, Katzenellenbogen JA, Greene GL (2016) Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation. Elife. https://doi.org/10.7554/eLife.12792 CrossRefPubMedPubMedCentral

21.

Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, Li Z, Gala K, Fanning S, King TA, Hudis C, Chen D, Taran T, Hortobagyi G, Greene G, Berger M, Baselga J, Chandarlapaty S (2013) ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet 45(12):1439–1445. https://doi.org/10.1038/ng.2822 CrossRefPubMedPubMedCentral

22.

Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ, Cao X, Kalyana-Sundaram S, Wang R, Ning Y, Hodges L, Gursky A, Siddiqui J, Tomlins SA, Roychowdhury S, Pienta KJ, Kim SY, Roberts JS, Rae JM, Van Poznak CH, Hayes DF, Chugh R, Kunju LP, Talpaz M, Schott AF, Chinnaiyan AM (2013) Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet 45(12):1446–1451. https://doi.org/10.1038/ng.2823 CrossRefPubMedPubMedCentral

23.

Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, Fein L, Romieu G, Buzdar A, Robertson J, Brufsky A, Possinger K, Rennie P, Sapunar F, Lowe E, Piccart M (2008) Double-blind, randomized placebo controlled trial of Fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol 26(10):1664–1670CrossRef

24.

Robertson JFR (2007) Fulvestrant (Faslodex)-how to make a good drug better. Oncologist 12:774–784CrossRef

25.

Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Garnett S, Lindemann JP, Sapunar F, Martin M (2010) Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol 28(30):4594–4600. https://doi.org/10.1200/JCO.2010.28.8415 CrossRefPubMed

26.

Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Malorni L, Garnett S, Rukazenkov Y, Martin M (2014) Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst 106(1):djt337. https://doi.org/10.1093/jnci/djt337 CrossRefPubMed

27.

Leo AD, Jerusalem G, Petruzelka L, Torres R, Bondarenko I, Khasanov R, Verhoeven D, Pedrini J, Lichinitser M, Pendergrass K, Garnett S, Lindermann J, Sapunar F, Martin M (2009) CONFIRM: a Phase III, randomized, parallel-group trial comparing fulvestrant 250 mg vs fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. Cancer Res 69(24 Suppl):25

28.

van Kruchten M, de Vries EG, Glaudemans AW, van Lanschot MC, van Faassen M, Kema IP, Brown M, Schroder CP, de Vries EF, Hospers GA (2015) Measuring residual estrogen receptor availability during fulvestrant therapy in patients with metastatic breast cancer. Cancer Discov 5(1):72–81. https://doi.org/10.1158/2159-8290.CD-14-0697 CrossRefPubMed

29.

Robertson JF, Llombart-Cussac A, Rolski J, Feltl D, Dewar J, Macpherson E, Lindemann J, Ellis MJ (2009) Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study. J Clin Oncol 27(27):4530–4535CrossRef

30.

Ellis MJ, Llombart-Cussac A, Feltl D, Dewar JA, Jasiowka M, Hewson N, Rukazenkov Y, Robertson JF (2015) Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: overall survival analysis from the phase II FIRST study. J Clin Oncol 33(32):3781–3787. https://doi.org/10.1200/JCO.2015.61.5831 CrossRefPubMedPubMedCentral

31.

Wijayaratne A, McDonnell D (2001) The human estrogen receptor-a is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators. J Biol Chem 276(38):35684–35692CrossRef

32.

Wijayaratne A, Nagel S, Paige L, Christensen D, Norris J, Fowlkes D, McDonnell D (1999) Comparative analysis of mechanistic difference among antiestrogens. Endocrinology 140(12):5828–5840CrossRef

33.

Willson TM, Norris JD, Wagner BL, Asplin I, Baer P, Brown HR, Jones SA, Henke B, Sauls H, Wolfe S, Morris DC, McDonnell DP (1997) Dissection of the molecular mechanism of action of GW5638, a novel estrogen receptor ligand, provides insights into the role of ER in bone. Endocrinology 138:3901–3911CrossRef

34.

Burks HE, Abrams T, Kirby CA, Baird J, Fekete A, Hamann LG, Kim S, Lombardo F, Loo A, Lubicka D, Macchi K, McDonnell DP, Mishina Y, Norris JD, Nunez J, Saran C, Sun Y, Thomsen NM, Wang C, Wang J, Peukert S (2017) Discovery of an acrylic acid based tetrahydroisoquinoline as an orally bioavailable selective estrogen receptor degrader for ERalpha + breast cancer. J Med Chem 60(7):2790–2818. https://doi.org/10.1021/acs.jmedchem.6b01468 CrossRefPubMed

35.

Nagasawa J, Govek S, Kahraman M, Lai A, Bonnefous C, Douglas K, Sensintaffar J, Lu N, Lee K, Aparicio A, Kaufman J, Qian J, Shao G, Prudente R, Joseph JD, Darimont B, Brigham D, Maheu K, Heyman R, Rix PJ, Hager JH, Smith ND (2018) Identification of an orally bioavailable chromene-based selective estrogen receptor degrader (SERD) that demonstrates robust activity in a model of tamoxifen-resistant breast cancer. J Med Chem 61(17):7917–7928. https://doi.org/10.1021/acs.jmedchem.8b00921 CrossRefPubMed

36.

Nardone A, Weir H, Delpuech O, Brown H, De Angelis C, Cataldo ML, Fu X, Shea MJ, Mitchell T, Veeraraghavan J, Nagi C, Pilling M, Rimawi MF, Trivedi M, Hilsenbeck SG, Chamness GC, Jeselsohn R, Osborne CK, Schiff R (2019) The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistance. Br J Cancer 120(3):331–339. https://doi.org/10.1038/s41416-018-0354-9 CrossRefPubMed

37.

Tria GS, Abrams T, Baird J, Burks HE, Firestone B, Gaither LA, Hamann LG, He G, Kirby CA, Kim S, Lombardo F, Macchi KJ, McDonnell DP, Mishina Y, Norris JD, Nunez J, Springer C, Sun Y, Thomsen NM, Wang C, Wang J, Yu B, Tiong-Yip CL, Peukert S (2018) Discovery of LSZ102, a potent, orally bioavailable selective estrogen receptor degrader (SERD) for the treatment of estrogen receptor positive breast cancer. J Med Chem 61(7):2837–2864. https://doi.org/10.1021/acs.jmedchem.7b01682 CrossRefPubMed

38.

Hattersley G, David F, Harris A, Clarkin M, Banks K, Williams G, Glaudemans A, Doorduin J, Koole M, de Vries E, Lyttle R (2014) RAD1901, a novel tissue-selective estrogen receptor degrader (SERD) demonstrates estrogen receptor engagement in a phase 1 clinical study. Paper presented at the San Antonio Breast Cancer Meeting, San Antonio, Texas, United States of America, December 9-13, 2014

39.

Lai A, Kahraman M, Govek S, Nagasawa J, Bonnefous C, Julien J, Douglas K, Sensintaffar J, Lu N, Lee KJ, Aparicio A, Kaufman J, Qian J, Shao G, Prudente R, Moon MJ, Joseph JD, Darimont B, Brigham D, Grillot K, Heyman R, Rix PJ, Hager JH, Smith ND (2015) Identification of GDC-0810 (ARN-810), an orally bioavailable selective estrogen receptor degrader (SERD) that demonstrates robust activity in tamoxifen-resistant breast cancer xenografts. J Med Chem 58(12):4888–4904. https://doi.org/10.1021/acs.jmedchem.5b00054 CrossRefPubMed

40.

Kahraman M, Govek SP, Nagasawa JY, Lai A, Bonnefous C, Douglas K, Sensintaffar J, Liu N, Lee K, Aparicio A, Kaufman J, Qian J, Shao G, Prudente R, Joseph JD, Darimont B, Brigham D, Heyman R, Rix PJ, Hager JH, Smith ND (2019) Maximizing ER-alpha degradation maximizes activity in a tamoxifen-resistant breast cancer model: identification of GDC-0927. ACS Med Chem Lett 10(1):50–55. https://doi.org/10.1021/acsmedchemlett.8b00414 CrossRefPubMed

41.

Wardell SE, Marks JR, McDonnell DP (2011) The turnover of estrogen receptor alpha by the selective estrogen receptor degrader (SERD) fulvestrant is a saturable process that is not required for antagonist efficacy. Biochem Pharmacol 82(2):122–130. https://doi.org/10.1016/j.bcp.2011.03.031 CrossRefPubMedPubMedCentral

42.

Guan J, Zhou W, Hafner M, Blake RA, Chalouni C, Chen IP, De Bruyn T, Giltnane JM, Hartman SJ, Heidersbach A, Houtman R, Ingalla E, Kategaya L, Kleinheinz T, Li J, Martin SE, Modrusan Z, Nannini M, Oeh J, Ubhayakar S, Wang X, Wertz IE, Young A, Yu M, Sampath D, Hager JH, Friedman LS, Daemen A, Metcalfe C (2019) therapeutic ligands antagonize estrogen receptor function by impairing its mobility. Cell 178(4):949–963. https://doi.org/10.1016/j.cell.2019.06.026 CrossRefPubMed

Title: Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy
Authors: Suzanne E. Wardell
Alexander P. Yllanes
Christina A. Chao
Yeeun Bae
Kaitlyn J. Andreano
Taylor K. Desautels
Kendall A. Heetderks
Jeremy T. Blitzer
John D. Norris
Donald P. McDonnell
Publication date: 01-01-2020
Publisher: Springer US
Keywords: Breast Cancer
Breast Cancer
Fulvestrant
Estrogens
Tamoxifen
Published in: Breast Cancer Research and Treatment / Issue 1/2020
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-019-05454-y

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2020

Effect of progressive resistance training on persistent pain after axillary dissection in breast cancer: a randomized controlled trial

Sixty spontaneous vertebral fractures after denosumab discontinuation in 15 women with early-stage breast cancer under aromatase inhibitors

A phase II study of cabozantinib alone or in combination with trastuzumab in breast cancer patients with brain metastases

Residual cancer burden index and tumor-infiltrating lymphocyte subtypes in triple-negative breast cancer after neoadjuvant chemotherapy

A pooled analysis of the cardiac events in the trastuzumab adjuvant trials

COTI-2 reactivates mutant p53 and inhibits growth of triple-negative breast cancer cells

Keynote webinar | Spotlight on antibody–drug conjugates in cancer