Double-blind phase III trial of adjuvant chemotherapy withand without bevacizumab in patients with lymph node-positiveand high-risk lymph node-negative breast cancer (E5103)

Kathy D. Miller, Anne O'Neill, William Gradishar, Timothy J. Hobday, Lori J. Goldstein, Ingrid A. Mayer, Stuart Bloom, Adam M. Brufsky, Amye J. Tevaarwerk, Joseph A. Sparano, Nguyet Anh Le-Lindqwister, Carolyn B. Hendricks, Donald W. Northfelt, Chau T. Dang, George W. Sledge

Research output: Contribution to journalArticle

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Abstract

Purpose Bevacizumab improves progression-free survival but not overall survival in patients with metastatic breast cancer. E5103 tested the effect of bevacizumab in the adjuvant setting in patients with human epidermal growth factor receptor 2-negative disease. Patients and Methods Patients were assigned 1:2:2 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A), bevacizumab only during AC and paclitaxel (arm B), or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C). Random assignment was stratified and bevacizumab dose adjusted for choice of AC schedule. Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C. The primary end point was invasive disease-free survival (IDFS). Results Four thousand nine hundred ninety-four patients were enrolled. Median age was 52 years; 64% of patients were estrogen receptor positive, 27% were lymph node negative, and 78% received dose-dense AC. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across all arms. Grade $ 3 hypertension was more common in bevacizumab-treated patients, but thrombosis, proteinuria, and hemorrhage were not. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0% in arms A, B, and C, respectively. Bevacizumab exposure was less than anticipated, with approximately 24% of patients in arm B and approximately 55% of patients in arm C discontinuing bevacizumab before completing planned therapy. Five-year IDFS was 77% (95% CI, 71% to 81%) in arm A, 76% (95% CI, 72% to 80%) in arm B, and 80% (95% CI, 77% to 83%) in arm C. Conclusion Incorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer. Longer duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation.

Original languageEnglish (US)
Pages (from-to)2621-2629
Number of pages9
JournalJournal of Clinical Oncology
Volume36
Issue number25
DOIs
StatePublished - Sep 1 2018
Externally publishedYes

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Adjuvant Chemotherapy
Lymph Nodes
Breast Neoplasms
Cyclophosphamide
Disease-Free Survival
Paclitaxel
Bevacizumab
Survival
Anthracyclines
Proteinuria
Estrogen Receptors
Doxorubicin
Appointments and Schedules
Thrombosis
Radiotherapy
Therapeutics
Heart Failure
Placebos
Hemorrhage
Hypertension

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Double-blind phase III trial of adjuvant chemotherapy withand without bevacizumab in patients with lymph node-positiveand high-risk lymph node-negative breast cancer (E5103). / Miller, Kathy D.; O'Neill, Anne; Gradishar, William; Hobday, Timothy J.; Goldstein, Lori J.; Mayer, Ingrid A.; Bloom, Stuart; Brufsky, Adam M.; Tevaarwerk, Amye J.; Sparano, Joseph A.; Le-Lindqwister, Nguyet Anh; Hendricks, Carolyn B.; Northfelt, Donald W.; Dang, Chau T.; Sledge, George W.

In: Journal of Clinical Oncology, Vol. 36, No. 25, 01.09.2018, p. 2621-2629.

Research output: Contribution to journalArticle

Miller, KD, O'Neill, A, Gradishar, W, Hobday, TJ, Goldstein, LJ, Mayer, IA, Bloom, S, Brufsky, AM, Tevaarwerk, AJ, Sparano, JA, Le-Lindqwister, NA, Hendricks, CB, Northfelt, DW, Dang, CT & Sledge, GW 2018, 'Double-blind phase III trial of adjuvant chemotherapy withand without bevacizumab in patients with lymph node-positiveand high-risk lymph node-negative breast cancer (E5103)', Journal of Clinical Oncology, vol. 36, no. 25, pp. 2621-2629. https://doi.org/10.1200/JCO.2018.79.2028
Miller, Kathy D. ; O'Neill, Anne ; Gradishar, William ; Hobday, Timothy J. ; Goldstein, Lori J. ; Mayer, Ingrid A. ; Bloom, Stuart ; Brufsky, Adam M. ; Tevaarwerk, Amye J. ; Sparano, Joseph A. ; Le-Lindqwister, Nguyet Anh ; Hendricks, Carolyn B. ; Northfelt, Donald W. ; Dang, Chau T. ; Sledge, George W. / Double-blind phase III trial of adjuvant chemotherapy withand without bevacizumab in patients with lymph node-positiveand high-risk lymph node-negative breast cancer (E5103). In: Journal of Clinical Oncology. 2018 ; Vol. 36, No. 25. pp. 2621-2629.
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title = "Double-blind phase III trial of adjuvant chemotherapy withand without bevacizumab in patients with lymph node-positiveand high-risk lymph node-negative breast cancer (E5103)",
abstract = "Purpose Bevacizumab improves progression-free survival but not overall survival in patients with metastatic breast cancer. E5103 tested the effect of bevacizumab in the adjuvant setting in patients with human epidermal growth factor receptor 2-negative disease. Patients and Methods Patients were assigned 1:2:2 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A), bevacizumab only during AC and paclitaxel (arm B), or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C). Random assignment was stratified and bevacizumab dose adjusted for choice of AC schedule. Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C. The primary end point was invasive disease-free survival (IDFS). Results Four thousand nine hundred ninety-four patients were enrolled. Median age was 52 years; 64{\%} of patients were estrogen receptor positive, 27{\%} were lymph node negative, and 78{\%} received dose-dense AC. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across all arms. Grade $ 3 hypertension was more common in bevacizumab-treated patients, but thrombosis, proteinuria, and hemorrhage were not. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0{\%}, 1.9{\%}, and 3.0{\%} in arms A, B, and C, respectively. Bevacizumab exposure was less than anticipated, with approximately 24{\%} of patients in arm B and approximately 55{\%} of patients in arm C discontinuing bevacizumab before completing planned therapy. Five-year IDFS was 77{\%} (95{\%} CI, 71{\%} to 81{\%}) in arm A, 76{\%} (95{\%} CI, 72{\%} to 80{\%}) in arm B, and 80{\%} (95{\%} CI, 77{\%} to 83{\%}) in arm C. Conclusion Incorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer. Longer duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation.",
author = "Miller, {Kathy D.} and Anne O'Neill and William Gradishar and Hobday, {Timothy J.} and Goldstein, {Lori J.} and Mayer, {Ingrid A.} and Stuart Bloom and Brufsky, {Adam M.} and Tevaarwerk, {Amye J.} and Sparano, {Joseph A.} and Le-Lindqwister, {Nguyet Anh} and Hendricks, {Carolyn B.} and Northfelt, {Donald W.} and Dang, {Chau T.} and Sledge, {George W.}",
year = "2018",
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doi = "10.1200/JCO.2018.79.2028",
language = "English (US)",
volume = "36",
pages = "2621--2629",
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T1 - Double-blind phase III trial of adjuvant chemotherapy withand without bevacizumab in patients with lymph node-positiveand high-risk lymph node-negative breast cancer (E5103)

AU - Miller, Kathy D.

AU - O'Neill, Anne

AU - Gradishar, William

AU - Hobday, Timothy J.

AU - Goldstein, Lori J.

AU - Mayer, Ingrid A.

AU - Bloom, Stuart

AU - Brufsky, Adam M.

AU - Tevaarwerk, Amye J.

AU - Sparano, Joseph A.

AU - Le-Lindqwister, Nguyet Anh

AU - Hendricks, Carolyn B.

AU - Northfelt, Donald W.

AU - Dang, Chau T.

AU - Sledge, George W.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Purpose Bevacizumab improves progression-free survival but not overall survival in patients with metastatic breast cancer. E5103 tested the effect of bevacizumab in the adjuvant setting in patients with human epidermal growth factor receptor 2-negative disease. Patients and Methods Patients were assigned 1:2:2 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A), bevacizumab only during AC and paclitaxel (arm B), or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C). Random assignment was stratified and bevacizumab dose adjusted for choice of AC schedule. Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C. The primary end point was invasive disease-free survival (IDFS). Results Four thousand nine hundred ninety-four patients were enrolled. Median age was 52 years; 64% of patients were estrogen receptor positive, 27% were lymph node negative, and 78% received dose-dense AC. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across all arms. Grade $ 3 hypertension was more common in bevacizumab-treated patients, but thrombosis, proteinuria, and hemorrhage were not. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0% in arms A, B, and C, respectively. Bevacizumab exposure was less than anticipated, with approximately 24% of patients in arm B and approximately 55% of patients in arm C discontinuing bevacizumab before completing planned therapy. Five-year IDFS was 77% (95% CI, 71% to 81%) in arm A, 76% (95% CI, 72% to 80%) in arm B, and 80% (95% CI, 77% to 83%) in arm C. Conclusion Incorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer. Longer duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation.

AB - Purpose Bevacizumab improves progression-free survival but not overall survival in patients with metastatic breast cancer. E5103 tested the effect of bevacizumab in the adjuvant setting in patients with human epidermal growth factor receptor 2-negative disease. Patients and Methods Patients were assigned 1:2:2 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A), bevacizumab only during AC and paclitaxel (arm B), or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C). Random assignment was stratified and bevacizumab dose adjusted for choice of AC schedule. Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C. The primary end point was invasive disease-free survival (IDFS). Results Four thousand nine hundred ninety-four patients were enrolled. Median age was 52 years; 64% of patients were estrogen receptor positive, 27% were lymph node negative, and 78% received dose-dense AC. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across all arms. Grade $ 3 hypertension was more common in bevacizumab-treated patients, but thrombosis, proteinuria, and hemorrhage were not. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0% in arms A, B, and C, respectively. Bevacizumab exposure was less than anticipated, with approximately 24% of patients in arm B and approximately 55% of patients in arm C discontinuing bevacizumab before completing planned therapy. Five-year IDFS was 77% (95% CI, 71% to 81%) in arm A, 76% (95% CI, 72% to 80%) in arm B, and 80% (95% CI, 77% to 83%) in arm C. Conclusion Incorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer. Longer duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation.

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