This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Robert, N. Articles by Slamon, D. Search for Related Content PubMed PubMed Citation Articles by Robert, N. Articles by Slamon, D. Social Bookmarking                            What's this?

Randomized Phase III Study of Trastuzumab, Paclitaxel, and Carboplatin Compared With Trastuzumab and Paclitaxel in Women With HER-2–Overexpressing Metastatic Breast Cancer

Nicholas Robert, Brian Leyland-Jones, Lina Asmar, Robert Belt, Des Ilegbodu, David Loesch, Robert Raju, Elizabeth Valentine, Robert Sayre, Melody Cobleigh, Kathy Albain, Cecelia McCullough, Lea Fuchs, Dennis Slamon

From US Oncology Research Inc, Houston, TX; Departments of Oncology and Medicine, McGill University, Montreal, Quebec, Canada; Rush-Presbyterian-St Luke's Medical Center, Chicago; Loyola University Medical Center, Maywood, IL; and the University of California, Los Angeles, School of Medicine,Los Angeles, CA

Address reprint requests to Nicholas Robert, MD, 8503 Arlington Blvd, Suite 400, Fairfax, VA 22031; e-mail: nicholas.robert{at}usoncology.com

PURPOSE: This randomized, multicenter, phase III trial evaluated the efficacy and safety of trastuzumab and paclitaxel with or without carboplatin as first-line therapy for women with HER-2–overexpressing metastatic breast cancer (MBC).

PATIENTS AND METHODS: HER-2 overexpression was defined as immunohistochemical staining scores of 2+ or 3+. Between November 1998 and May 2002, 196 women with HER-2–overexpressing MBC were randomly assigned to six cycles of either trastuzumab 4 mg/kg loading dose plus 2 mg/kg weekly thereafter with paclitaxel 175 mg/m² every 3 weeks (TP), or trastuzumab 4 mg/kg loading dose plus 2 mg/kg weekly thereafter with paclitaxel 175 mg/m² and carboplatin area under the time-concentration curve = 6 every 3 weeks (TPC) followed by weekly trastuzumab alone.

RESULTS: Baseline characteristics of the 196 patients were well balanced between study arms. Objective response rate (ORR) was 52% (95% CI, 42% to 62%) for TPC versus 36% (95% CI, 26% to 46%) for TP (P = .04). Median progression-free survival (PFS) was 10.7 months for TPC and 7.1 months for TP (hazard ratio [HR], 0.66; 95% CI, 0.59 to 0.73; P = .03). Improved clinical outcomes with TPC were most evident in HER-2 3+ patients, with an ORR of 57% (95% CI, 45% to 70%) v 36% (95% CI, 25% to 48%; P = .03) and median PFS of 13.8 v 7.6 months (P = .005) for TPC and TP, respectively (HR, 0.55; 95% CI, 0.46 to 0.64). Both regimens were well tolerated, and febrile neutropenia and neurotoxicity occurred infrequently; grade 4 neutropenia occurred more frequently with TPC (P < .01).

CONCLUSION: The addition of carboplatin to paclitaxel and trastuzumab improved ORR and PFS in women with HER-2–overexpressing MBC. This well-tolerated regimen represents a new therapeutic option.

Supported by grants from Bristol-Myers Squibb Co, Princeton, NJ, and Genentech Inc, South San Francisco, CA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				J. S. Ross, E. A. Slodkowska, W. F. Symmans, L. Pusztai, P. M. Ravdin, and G. N. Hortobagyi The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti-HER-2 Therapy and Personalized Medicine Oncologist, April 1, 2009; 14(4): 320 - 368. [Abstract] [Full Text] [PDF]

				S Knopp, C Trope, J M Nesland, and R Holm A review of molecular pathological markers in vulvar carcinoma: lack of application in clinical practice J. Clin. Pathol., March 1, 2009; 62(3): 212 - 218. [Abstract] [Full Text] [PDF]

				S. R. McWhinney, R. M. Goldberg, and H. L. McLeod Platinum neurotoxicity pharmacogenetics Mol. Cancer Ther., January 1, 2009; 8(1): 10 - 16. [Abstract] [Full Text] [PDF]

				J. Cortes, S. Di Cosimo, M. A. Climent, H. Cortes-Funes, A. Lluch, P. Gascon, J. I. Mayordomo, M. Gil, M. Benavides, L. Cirera, et al. Nonpegylated Liposomal Doxorubicin (TLC-D99), Paclitaxel, and Trastuzumab in HER-2-Overexpressing Breast Cancer: A Multicenter Phase I/II Study Clin. Cancer Res., January 1, 2009; 15(1): 307 - 314. [Abstract] [Full Text] [PDF]

				A. Kruschinski, A. Moosmann, I. Poschke, H. Norell, M. Chmielewski, B. Seliger, R. Kiessling, T. Blankenstein, H. Abken, and J. Charo Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas PNAS, November 11, 2008; 105(45): 17481 - 17486. [Abstract] [Full Text] [PDF]

				C. L. Arteaga, A. O'Neill, S. L. Moulder, M. Pins, J. A. Sparano, G. W. Sledge, and N. E. Davidson A Phase I-II Study of Combined Blockade of the ErbB Receptor Network with Trastuzumab and Gefitinib in Patients with HER2 (ErbB2)-Overexpressing Metastatic Breast Cancer Clin. Cancer Res., October 1, 2008; 14(19): 6277 - 6283. [Abstract] [Full Text] [PDF]

				K. Bullock and K. Blackwell Clinical Efficacy of Taxane-Trastuzumab Combination Regimens for HER-2-Positive Metastatic Breast Cancer Oncologist, May 1, 2008; 13(5): 515 - 525. [Abstract] [Full Text] [PDF]

				J. M. Park, M. Terabe, J. C. Steel, G. Forni, Y. Sakai, J. C. Morris, and J. A. Berzofsky Therapy of Advanced Established Murine Breast Cancer with a Recombinant Adenoviral ErbB-2/neu Vaccine Cancer Res., March 15, 2008; 68(6): 1979 - 1987. [Abstract] [Full Text] [PDF]

				E. Azambuja, V. Durbecq, D. D. Rosa, M. Colozza, D. Larsimont, M. Piccart-Gebhart, and F. Cardoso HER-2 overexpression/amplification and its interaction with taxane-based therapy in breast cancer Ann. Onc., February 1, 2008; 19(2): 223 - 232. [Abstract] [Full Text] [PDF]

				N. Eckstein, K. Servan, L. Girard, D. Cai, G. von Jonquieres, U. Jaehde, M. U. Kassack, A. F. Gazdar, J. D. Minna, and H.-D. Royer Epidermal Growth Factor Receptor Pathway Analysis Identifies Amphiregulin as a Key Factor for Cisplatin Resistance of Human Breast Cancer Cells J. Biol. Chem., January 11, 2008; 283(2): 739 - 750. [Abstract] [Full Text] [PDF]

				A. Chan and R. de Boer Use of Trastuzumab for Metastatic Breast Cancer in Australia: Inaccurate Results and Alternative Interpretation of Findings J. Clin. Oncol., December 10, 2007; 25(35): 5662 - 5663. [Full Text] [PDF]

				S.-A. Pearson, C. L. Ringland, and R. L. Ward Use of Trastuzumab for Metastatic Breast Cancer in Australia: Interpreting Findings From a Cohort of 1,469 Women on a National Access Program Versus 41 Women Treated by Two Medical Oncologists J. Clin. Oncol., December 10, 2007; 25(35): 5663 - 5664. [Full Text] [PDF]

				J. C. Liu, T. Deng, R. S. Lehal, J. Kim, and E. Zacksenhaus Identification of Tumorsphere- and Tumor-Initiating Cells in HER2/Neu-Induced Mammary Tumors Cancer Res., September 15, 2007; 67(18): 8671 - 8681. [Abstract] [Full Text] [PDF]

				C. A. Ritter, M. Perez-Torres, C. Rinehart, M. Guix, T. Dugger, J. A. Engelman, and C. L. Arteaga Human Breast Cancer Cells Selected for Resistance to Trastuzumab In vivo Overexpress Epidermal Growth Factor Receptor and ErbB Ligands and Remain Dependent on the ErbB Receptor Network Clin. Cancer Res., August 15, 2007; 13(16): 4909 - 4919. [Abstract] [Full Text] [PDF]

				C. A. Hudis Trastuzumab -- Mechanism of Action and Use in Clinical Practice N. Engl. J. Med., July 5, 2007; 357(1): 39 - 51. [Full Text] [PDF]

				S. A. Perez, M. V. Karamouzis, D. V. Skarlos, A. Ardavanis, N. N. Sotiriadou, E. G. Iliopoulou, M. L. Salagianni, G. Orphanos, C. N. Baxevanis, G. Rigatos, et al. CD4+CD25+ Regulatory T-Cell Frequency in HER-2/neu (HER)-Positive and HER-Negative Advanced-Stage Breast Cancer Patients Clin. Cancer Res., May 1, 2007; 13(9): 2714 - 2721. [Abstract] [Full Text] [PDF]

				M. Colozza, E. de Azambuja, N. Personeni, F. Lebrun, M. J. Piccart, and F. Cardoso Achievements in Systemic Therapies in the Pregenomic Era in Metastatic Breast Cancer Oncologist, March 1, 2007; 12(3): 253 - 270. [Abstract] [Full Text] [PDF]

				C. L. Arteaga Will Single-Time Tumor Profiling and a "Guilt by Association" Approach Allow Us to Outsmart HER2-Positive Breast Cancer? Clin. Cancer Res., February 15, 2007; 13(4): 1071 - 1073. [Full Text] [PDF]

				F. Meric-Bernstam and M.-C. Hung Advances in targeting human epidermal growth factor receptor-2 signaling for cancer therapy. Clin. Cancer Res., November 1, 2006; 12(21): 6326 - 6330. [Abstract] [Full Text] [PDF]