TBCRC 001: Randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer

Lisa A. Carey, Hope S. Rugo, P. Kelly Marcom, Erica L. Mayer, Francisco J. Esteva, Cynthia X. Ma, Minetta C. Liu, Anna Maria Storniolo, Mothaffar F. Rimawi, Andres Forero-Torres, Antonio C. Wolff, Timothy J. Hobday, Anastasia Ivanova, Wing Keung Chiu, Madlyn Ferraro, Emily Burrows, Philip S. Bernard, Katherine A. Hoadley, Charles M. Perou, Eric P. Winer

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Abstract

Purpose: Epidermal growth factor receptor (EGFR) is a targetable receptor frequently overexpressed in basal-like breast cancer, which comprises most triple-negative breast cancers (TNBCs), the only subtype without established targeted therapy. Patients and Methods: In this randomized phase II trial, patients with metastatic TNBC received anti-EGFR antibody cetuximab (400 mg/m2 load then 250 mg/m2 per week intravenously [IV]) alone, with carboplatin (area under the curve of 2, once per week IV) added after progression or as concomitant therapy from the beginning. Response rate (RR) was the primary end point; others included time to progression (TTP), overall survival (OS), and toxicity. Embedded correlative studies included molecular subtyping on archival tissue. Fresh tumor tissue before and after 7 to 14 days of therapy was used for microarray analyses exploring EGFR pathway activity and inhibition. Results: In 102 patients with TNBC, RRs were 6% (two of 31) to cetuximab and 16% (four of 25) to cetuximab plus carboplatin after progression. RR to those treated from the beginning with cetuximab plus carboplatin was 17% (12 of 71); 31% of patients responded or had prolonged disease stabilization. The cetuximab plus carboplatin regimen was well tolerated, but both TTP and OS were short at 2.1 months (95% CI, 1.8 to 5.5 months) and 10.4 months (95% CI, 7.7 to 13.1 months), respectively. Of 73 patients with archival tissue for analysis, 74% had basal-like molecular subtype. Sixteen patients had tumor biopsies before and 1 week after therapy; genomic patterns of the EGFR pathway showed activation in 13 and inhibition by therapy in five. Conclusion: Despite strong preclinical data, combination cetuximab plus carboplatin in metastatic TNBC produced responses in fewer than 20% of patients. EGFR pathway analysis showed that most TNBCs involved activation. However, cetuximab blocked expression of the EGFR pathway in only a minority, suggesting that most had alternate mechanisms for pathway activation.

Original languageEnglish
Pages (from-to)2615-2623
Number of pages9
JournalJournal of Clinical Oncology
Volume30
Issue number21
DOIs
StatePublished - Jul 20 2012

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Triple Negative Breast Neoplasms
Carboplatin
Epidermal Growth Factor Receptor
Therapeutics
Survival
Microarray Analysis
Cetuximab
Area Under Curve
Neoplasms
Breast Neoplasms
Biopsy
Antibodies

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Carey, L. A., Rugo, H. S., Marcom, P. K., Mayer, E. L., Esteva, F. J., Ma, C. X., ... Winer, E. P. (2012). TBCRC 001: Randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. Journal of Clinical Oncology, 30(21), 2615-2623. https://doi.org/10.1200/JCO.2010.34.5579

TBCRC 001 : Randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. / Carey, Lisa A.; Rugo, Hope S.; Marcom, P. Kelly; Mayer, Erica L.; Esteva, Francisco J.; Ma, Cynthia X.; Liu, Minetta C.; Storniolo, Anna Maria; Rimawi, Mothaffar F.; Forero-Torres, Andres; Wolff, Antonio C.; Hobday, Timothy J.; Ivanova, Anastasia; Chiu, Wing Keung; Ferraro, Madlyn; Burrows, Emily; Bernard, Philip S.; Hoadley, Katherine A.; Perou, Charles M.; Winer, Eric P.

In: Journal of Clinical Oncology, Vol. 30, No. 21, 20.07.2012, p. 2615-2623.

Research output: Contribution to journalArticle

Carey, LA, Rugo, HS, Marcom, PK, Mayer, EL, Esteva, FJ, Ma, CX, Liu, MC, Storniolo, AM, Rimawi, MF, Forero-Torres, A, Wolff, AC, Hobday, TJ, Ivanova, A, Chiu, WK, Ferraro, M, Burrows, E, Bernard, PS, Hoadley, KA, Perou, CM & Winer, EP 2012, 'TBCRC 001: Randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer', Journal of Clinical Oncology, vol. 30, no. 21, pp. 2615-2623. https://doi.org/10.1200/JCO.2010.34.5579
Carey, Lisa A. ; Rugo, Hope S. ; Marcom, P. Kelly ; Mayer, Erica L. ; Esteva, Francisco J. ; Ma, Cynthia X. ; Liu, Minetta C. ; Storniolo, Anna Maria ; Rimawi, Mothaffar F. ; Forero-Torres, Andres ; Wolff, Antonio C. ; Hobday, Timothy J. ; Ivanova, Anastasia ; Chiu, Wing Keung ; Ferraro, Madlyn ; Burrows, Emily ; Bernard, Philip S. ; Hoadley, Katherine A. ; Perou, Charles M. ; Winer, Eric P. / TBCRC 001 : Randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. In: Journal of Clinical Oncology. 2012 ; Vol. 30, No. 21. pp. 2615-2623.
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abstract = "Purpose: Epidermal growth factor receptor (EGFR) is a targetable receptor frequently overexpressed in basal-like breast cancer, which comprises most triple-negative breast cancers (TNBCs), the only subtype without established targeted therapy. Patients and Methods: In this randomized phase II trial, patients with metastatic TNBC received anti-EGFR antibody cetuximab (400 mg/m2 load then 250 mg/m2 per week intravenously [IV]) alone, with carboplatin (area under the curve of 2, once per week IV) added after progression or as concomitant therapy from the beginning. Response rate (RR) was the primary end point; others included time to progression (TTP), overall survival (OS), and toxicity. Embedded correlative studies included molecular subtyping on archival tissue. Fresh tumor tissue before and after 7 to 14 days of therapy was used for microarray analyses exploring EGFR pathway activity and inhibition. Results: In 102 patients with TNBC, RRs were 6{\%} (two of 31) to cetuximab and 16{\%} (four of 25) to cetuximab plus carboplatin after progression. RR to those treated from the beginning with cetuximab plus carboplatin was 17{\%} (12 of 71); 31{\%} of patients responded or had prolonged disease stabilization. The cetuximab plus carboplatin regimen was well tolerated, but both TTP and OS were short at 2.1 months (95{\%} CI, 1.8 to 5.5 months) and 10.4 months (95{\%} CI, 7.7 to 13.1 months), respectively. Of 73 patients with archival tissue for analysis, 74{\%} had basal-like molecular subtype. Sixteen patients had tumor biopsies before and 1 week after therapy; genomic patterns of the EGFR pathway showed activation in 13 and inhibition by therapy in five. Conclusion: Despite strong preclinical data, combination cetuximab plus carboplatin in metastatic TNBC produced responses in fewer than 20{\%} of patients. EGFR pathway analysis showed that most TNBCs involved activation. However, cetuximab blocked expression of the EGFR pathway in only a minority, suggesting that most had alternate mechanisms for pathway activation.",
author = "Carey, {Lisa A.} and Rugo, {Hope S.} and Marcom, {P. Kelly} and Mayer, {Erica L.} and Esteva, {Francisco J.} and Ma, {Cynthia X.} and Liu, {Minetta C.} and Storniolo, {Anna Maria} and Rimawi, {Mothaffar F.} and Andres Forero-Torres and Wolff, {Antonio C.} and Hobday, {Timothy J.} and Anastasia Ivanova and Chiu, {Wing Keung} and Madlyn Ferraro and Emily Burrows and Bernard, {Philip S.} and Hoadley, {Katherine A.} and Perou, {Charles M.} and Winer, {Eric P.}",
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T2 - Randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer

AU - Carey, Lisa A.

AU - Rugo, Hope S.

AU - Marcom, P. Kelly

AU - Mayer, Erica L.

AU - Esteva, Francisco J.

AU - Ma, Cynthia X.

AU - Liu, Minetta C.

AU - Storniolo, Anna Maria

AU - Rimawi, Mothaffar F.

AU - Forero-Torres, Andres

AU - Wolff, Antonio C.

AU - Hobday, Timothy J.

AU - Ivanova, Anastasia

AU - Chiu, Wing Keung

AU - Ferraro, Madlyn

AU - Burrows, Emily

AU - Bernard, Philip S.

AU - Hoadley, Katherine A.

AU - Perou, Charles M.

AU - Winer, Eric P.

PY - 2012/7/20

Y1 - 2012/7/20

N2 - Purpose: Epidermal growth factor receptor (EGFR) is a targetable receptor frequently overexpressed in basal-like breast cancer, which comprises most triple-negative breast cancers (TNBCs), the only subtype without established targeted therapy. Patients and Methods: In this randomized phase II trial, patients with metastatic TNBC received anti-EGFR antibody cetuximab (400 mg/m2 load then 250 mg/m2 per week intravenously [IV]) alone, with carboplatin (area under the curve of 2, once per week IV) added after progression or as concomitant therapy from the beginning. Response rate (RR) was the primary end point; others included time to progression (TTP), overall survival (OS), and toxicity. Embedded correlative studies included molecular subtyping on archival tissue. Fresh tumor tissue before and after 7 to 14 days of therapy was used for microarray analyses exploring EGFR pathway activity and inhibition. Results: In 102 patients with TNBC, RRs were 6% (two of 31) to cetuximab and 16% (four of 25) to cetuximab plus carboplatin after progression. RR to those treated from the beginning with cetuximab plus carboplatin was 17% (12 of 71); 31% of patients responded or had prolonged disease stabilization. The cetuximab plus carboplatin regimen was well tolerated, but both TTP and OS were short at 2.1 months (95% CI, 1.8 to 5.5 months) and 10.4 months (95% CI, 7.7 to 13.1 months), respectively. Of 73 patients with archival tissue for analysis, 74% had basal-like molecular subtype. Sixteen patients had tumor biopsies before and 1 week after therapy; genomic patterns of the EGFR pathway showed activation in 13 and inhibition by therapy in five. Conclusion: Despite strong preclinical data, combination cetuximab plus carboplatin in metastatic TNBC produced responses in fewer than 20% of patients. EGFR pathway analysis showed that most TNBCs involved activation. However, cetuximab blocked expression of the EGFR pathway in only a minority, suggesting that most had alternate mechanisms for pathway activation.

AB - Purpose: Epidermal growth factor receptor (EGFR) is a targetable receptor frequently overexpressed in basal-like breast cancer, which comprises most triple-negative breast cancers (TNBCs), the only subtype without established targeted therapy. Patients and Methods: In this randomized phase II trial, patients with metastatic TNBC received anti-EGFR antibody cetuximab (400 mg/m2 load then 250 mg/m2 per week intravenously [IV]) alone, with carboplatin (area under the curve of 2, once per week IV) added after progression or as concomitant therapy from the beginning. Response rate (RR) was the primary end point; others included time to progression (TTP), overall survival (OS), and toxicity. Embedded correlative studies included molecular subtyping on archival tissue. Fresh tumor tissue before and after 7 to 14 days of therapy was used for microarray analyses exploring EGFR pathway activity and inhibition. Results: In 102 patients with TNBC, RRs were 6% (two of 31) to cetuximab and 16% (four of 25) to cetuximab plus carboplatin after progression. RR to those treated from the beginning with cetuximab plus carboplatin was 17% (12 of 71); 31% of patients responded or had prolonged disease stabilization. The cetuximab plus carboplatin regimen was well tolerated, but both TTP and OS were short at 2.1 months (95% CI, 1.8 to 5.5 months) and 10.4 months (95% CI, 7.7 to 13.1 months), respectively. Of 73 patients with archival tissue for analysis, 74% had basal-like molecular subtype. Sixteen patients had tumor biopsies before and 1 week after therapy; genomic patterns of the EGFR pathway showed activation in 13 and inhibition by therapy in five. Conclusion: Despite strong preclinical data, combination cetuximab plus carboplatin in metastatic TNBC produced responses in fewer than 20% of patients. EGFR pathway analysis showed that most TNBCs involved activation. However, cetuximab blocked expression of the EGFR pathway in only a minority, suggesting that most had alternate mechanisms for pathway activation.

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