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 James 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 (US)
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 James; 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 James ; 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.",
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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 James

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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