Top

Published in:

01-10-2013 | Clinical Trial

Phase I–II study of the farnesyl transferase inhibitor tipifarnib plus sequential weekly paclitaxel and doxorubicin–cyclophosphamide in HER2/neu-negative inflammatory carcinoma and non-inflammatory estrogen receptor-positive breast carcinoma

Authors: Eleni Andreopoulou, Ivette S. Vigoda, Vicente Valero, Dawn L. Hershman, George Raptis, Linda T. Vahdat, Hyo S. Han, John J. Wright, Christine M. Pellegrino, Massimo Cristofanilli, Ricardo H. Alvarez, Karen Fehn, Susan Fineberg, Joseph A. Sparano

Published in: Breast Cancer Research and Treatment | Issue 3/2013

Abstract

Tipifarnib (T) is a farnesyl transferase inhibitor (FTI) that enhances the antineoplastic effects of cytotoxic therapy in vitro, has activity in metastatic breast cancer, and enhances the pathologic complete response (pCR) rate to neoadjuvant doxorubicin–cyclophosphamide (AC) chemotherapy. We, therefore, performed a phase I–II trial of T plus neoadjuvant sequential weekly paclitaxel and 2-week AC chemotherapy in locally advanced breast cancer. Eligible patients with HER2-negative clinical stage IIB–IIIC breast cancer received 12 weekly doses of paclitaxel (80 mg/m²) followed by AC (60/600 mg/m² every 2 weeks and filgrastim), plus T (100 or 200 mg PO on days 1–3 of each P dose, and 200 mg PO on days 2–7 of each AC cycle). The trial was powered to detect an improvement in breast pCR rate from 15 to 35 % (α = 0.10, β = 0.10) in two strata, including ER and/or PR-positive, non-inflammatory (stratum A) and inflammatory carcinoma (stratum B). Of the 60 patients accrued, there were no dose-limiting toxicities among the first six patients treated at the first T dose level (100 mg BID; N = 3) or second T dose level (200 mg BID; N = 3) plus paclitaxel. Breast pCR occurred in 6/33 patients (18 %, 95 % confidence intervals (CI) 7–36 %) and 1/22 patients (4 %, 95 % CI 0–8 %) in stratum B. Combination of the FTI T with weekly paclitaxel–AC is unlikely to be associated with a breast pCR rate of 35 % or higher in patients with locally advanced HER2/neu-negative inflammatory or non-inflammatory ER- and/or PR-positive breast carcinoma.

Rochlitz CF, Scott GK, Dodson JM et al (1989) Incidence of activating ras oncogene mutations associated with primary and metastatic human breast cancer. Cancer Res 49:357–360PubMed

Thor A, Ohuchi N, Hand PH et al (1986) ras gene alterations and enhanced levels of ras p21 expression in a spectrum of benign and malignant human mammary tissues. Lab Invest 55:603–615PubMed

Smith CA, Pollice AA, Gu LP et al (2000) Correlations among p53, Her-2/neu, and ras overexpression and aneuploidy by multiparameter flow cytometry in human breast cancer: evidence for a common phenotypic evolutionary pattern in infiltrating ductal carcinomas. Clin Cancer Res 6:112–126PubMed

Bunone G, Briand PA, Miksicek RJ et al (1996) Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J 15:2174–2183PubMed

Kato S, Masuhiro Y, Watanabe M et al (2000) Molecular mechanism of a cross-talk between oestrogen and growth factor signalling pathways. Genes Cells 5:593–601PubMedCrossRef

Theillet C, Lidereau R, Escot C et al (1986) Loss of a c-H-ras-1 allele and aggressive human primary breast carcinomas. Cancer Res 46:4776–4781PubMed

Kleer CG, van Golen KL, Zhang Y et al (2002) Characterization of RhoC expression in benign and malignant breast disease: a potential new marker for small breast carcinomas with metastatic ability. Am J Pathol 160:579–584PubMedCrossRef

van Golen KL, Bao L, DiVito MM et al (2002) Reversion of RhoC GTPase-induced inflammatory breast cancer phenotype by treatment with a farnesyl transferase inhibitor. Mol Cancer Ther 1:575–583PubMed

Zhu K, Hamilton AD, Sebti SM (2003) Farnesyltransferase inhibitors as anticancer agents: current status. Curr Opin Investig Drugs 4:1428–1435PubMed

10.

Crespo NC, Ohkanda J, Yen TJ et al (2001) The farnesyltransferase inhibitor, FTI-2153, blocks bipolar spindle formation and chromosome alignment and causes prometaphase accumulation during mitosis of human lung cancer cells. J Biol Chem 276:16161–16167PubMedCrossRef

11.

Crespo NC, Delarue F, Ohkanda J et al (2002) The farnesyltransferase inhibitor, FTI-2153, inhibits bipolar spindle formation during mitosis independently of transformation and Ras and p53 mutation status. Cell Death Differ 9:702–709PubMedCrossRef

12.

Ashar HR, James L, Gray K et al (2001) The farnesyl transferase inhibitor SCH 66336 induces a G(2) → M or G(1) pause in sensitive human tumor cell lines. Exp Cell Res 262:17–27PubMedCrossRef

13.

Sepp-Lorenzino L, Rosen N (1998) A farnesyl-protein transferase inhibitor induces p21 expression and G1 block in p53 wild type tumor cells. J Biol Chem 273:20243–20251PubMedCrossRef

14.

Le Gouill S, Pellat-Deceunynck C, Harousseau JL et al (2002) Farnesyl transferase inhibitor R115777 induces apoptosis of human myeloma cells. Leukemia 16:1664–1667PubMedCrossRef

15.

Han JY, Oh SH, Morgillo F et al (2005) Hypoxia-inducible factor 1alpha and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer. J Natl Cancer Inst 97:1272–1286PubMedCrossRef

16.

Kelland LR, Smith V, Valenti M et al (2001) Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer. Clin Cancer Res 7:3544–3550PubMed

17.

Sun J, Ohkanda J, Coppola D et al (2003) Geranylgeranyltransferase I inhibitor GGTI-2154 induces breast carcinoma apoptosis and tumor regression in H-Ras transgenic mice. Cancer Res 63:8922–8929PubMed

18.

Kohl NE, Omer CA, Conner MW et al (1995) Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat Med 1:792–797PubMedCrossRef

19.

Marcus AI, Zhou J, O’Brate A et al (2005) The synergistic combination of the farnesyl transferase inhibitor lonafarnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase. Cancer Res 65:3883–3893PubMedCrossRef

20.

Loprevite M, Favoni RE, De Cupis A et al (2004) In vitro study of farnesyltransferase inhibitor SCH 66336, in combination with chemotherapy and radiation, in non-small cell lung cancer cell lines. Oncol Rep 11:407–414PubMed

21.

Wang EJ, Johnson WW (2003) The farnesyl protein transferase inhibitor lonafarnib (SCH66336) is an inhibitor of multidrug resistance proteins 1 and 2. Chemotherapy 49:303–308PubMedCrossRef

22.

Jin W, Wu L, Liang K et al (2003) Roles of the PI-3K and MEK pathways in Ras-mediated chemoresistance in breast cancer cells. Br J Cancer 89:185–191PubMedCrossRef

23.

Weinstein-Oppenheimer CR, Henriquez-Roldan CF, Davis JM et al (2001) Role of the Raf signal transduction cascade in the in vitro resistance to the anticancer drug doxorubicin. Clin Cancer Res 7:2898–2907PubMed

24.

Rasouli-Nia A, Liu D, Perdue S et al (1998) High Raf-1 kinase activity protects human tumor cells against paclitaxel-induced cytotoxicity. Clin Cancer Res 4:1111–1116PubMed

25.

Cornwell MM, Smith DE (1993) A signal transduction pathway for activation of the mdr1 promoter involves the proto-oncogene c-raf kinase. J Biol Chem 268:15347–15350PubMed

26.

Johnston SR, Hickish T, Ellis P et al (2003) Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer. J Clin Oncol 21:2492–2499PubMedCrossRef

27.

Sparano JA, Moulder S, Kazi A et al (2006) Targeted inhibition of farnesyltransferase in locally advanced breast cancer: a phase I and II trial of tipifarnib plus dose-dense doxorubicin and cyclophosphamide. J Clin Oncol 24:3013–3018PubMedCrossRef

28.

Sparano JA, Moulder S, Kazi A et al (2009) Phase II trial of tipifarnib plus neoadjuvant doxorubicin–cyclophosphamide in patients with clinical stage IIB–IIIC breast cancer. Clin Cancer Res 15:2942–2948PubMedCrossRef

29.

Bear HD, Anderson S, Brown A et al (2003) The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 21:4165–4174PubMedCrossRef

30.

Green MC, Buzdar AU, Smith T et al (2005) Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol 23:5983–5992PubMedCrossRef

31.

Sparano JA, Wang M, Martino S et al (2008) Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358:1663–1671PubMedCrossRef

32.

Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRef

33.

Symmans WF, Peintinger F, Hatzis C et al (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414–4422PubMedCrossRef

34.

Guarneri V, Broglio K, Kau SW et al (2006) Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors. J Clin Oncol 24:1037–1044PubMedCrossRef

35.

Kuerer HM, Newman LA, Smith TL et al (1999) Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17:460–469PubMed

36.

Prowell TM, Pazdur R (2012) Pathological complete response and accelerated drug approval in early breast cancer. N Engl J Med 366:2438–2441PubMedCrossRef

37.

Prowell TM, Pazdur R (2012) Pathological complete response and accelerated drug approval in early breast cancer. N Engl J Med 366:2438–2441PubMedCrossRef

38.

Barker AD, Sigman CC, Kelloff GJ et al (2009) I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther 86:97–100PubMedCrossRef

39.

Cortazar P, Zhang L, Untch M et al (2012) Meta-Analysis results from the collaborative trials in neoadjuvant breast cancer (CTNeoBC). Breast Cancer Res Treat 72:S1–11, 2012

40.

Esserman LJ, Berry DA, Cheang MC et al (2012) Chemotherapy response and recurrence-free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). Breast Cancer Res Treat 132:1049–1062PubMedCrossRef

41.

Houssami N, Macaskill P, von Minckwitz G et al (2012) Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy. Eur J Cancer 48:3342–3354PubMedCrossRef

Title: Phase I–II study of the farnesyl transferase inhibitor tipifarnib plus sequential weekly paclitaxel and doxorubicin–cyclophosphamide in HER2/neu-negative inflammatory carcinoma and non-inflammatory estrogen receptor-positive breast carcinoma
Authors: Eleni Andreopoulou
Ivette S. Vigoda
Vicente Valero
Dawn L. Hershman
George Raptis
Linda T. Vahdat
Hyo S. Han
John J. Wright
Christine M. Pellegrino
Massimo Cristofanilli
Ricardo H. Alvarez
Karen Fehn
Susan Fineberg
Joseph A. Sparano
Publication date: 01-10-2013
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2013
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-013-2704-x

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

Please log in to get access to this content

Other articles of this Issue 3/2013

Racial disparities in treatment patterns and clinical outcomes in patients with HER2-positive metastatic breast cancer

A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy

The expression of redox proteins in phyllodes tumor

Genetic variants in microRNAs and breast cancer risk in African American and European American women

Multivitamin and mineral use and breast cancer mortality in older women with invasive breast cancer in the women’s health initiative

The molecular diversity of Luminal A breast tumors

Keynote webinar | Spotlight on antibody–drug conjugates in cancer