Generation of HER2-specific antibody immunity during trastuzumab adjuvant therapy associates with reduced relapse in resected HER2 breast cancer

Nadine Norton, Nicholas Fox, Christie Ann McCarl, Kathleen S. Tenner, Karla Ballman, Courtney L. Erskine, Brian M. Necela, Donald Northfelt, Winston W. Tan, Carmen Calfa, Mark Pegram, Gerardo Colon-Otero, Edith A. Perez, Raphael Clynes, Keith L. Knutson

Research output: Contribution to journalArticle

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Abstract

Background: Resected HER2 breast cancer patients treated with adjuvant trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induce HER2-specific antibodies which correlate with improved survival in HER2 metastatic breast cancer patients. It remains unclear whether the generation of immunity required trastuzumab and whether endogenous antibody immunity is associated with improved disease-free survival in the adjuvant setting. In this study, we addressed this question by analyzing serum anti-HER2 antibodies from a subset of patients enrolled in the NCCTG trial N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. Methods: Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831. Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and compared between arms and with disease-free survival. Results: Prior to therapy, across all three arms, N9831 patients had similar mean anti-HER2 IgG levels. Following treatment, the mean levels of antibodies increased in the trastuzumab arms but not the chemotherapy-only arm. The proportion of patients who demonstrated antibodies increased by 4% in Arm A and by 43% in the Arms B and C combined (p=0.003). Cox modeling demonstrated that larger increases in antibodies were associated with improved disease-free survival in all patients (HR=0.23; p=0.04). Conclusions: These results show that the increased endogenous antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant, in view of its correlation with improved disease-free survival. The findings may have important implications for predicting treatment outcomes in patients treated with trastuzumab in the adjuvant setting.

Original languageEnglish (US)
Article number52
JournalBreast Cancer Research
Volume20
Issue number1
DOIs
StatePublished - Jun 14 2018

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Immunity
Breast Neoplasms
Recurrence
Antibodies
Disease-Free Survival
Drug Therapy
Therapeutics
Trastuzumab
Survival
Adjuvant Chemotherapy
Combination Drug Therapy
Serum
Anti-Idiotypic Antibodies
Immunoglobulin G

Keywords

  • Adaptive immune response
  • Disease-free survival
  • HER2+
  • Trastuzumab

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Generation of HER2-specific antibody immunity during trastuzumab adjuvant therapy associates with reduced relapse in resected HER2 breast cancer. / Norton, Nadine; Fox, Nicholas; McCarl, Christie Ann; Tenner, Kathleen S.; Ballman, Karla; Erskine, Courtney L.; Necela, Brian M.; Northfelt, Donald; Tan, Winston W.; Calfa, Carmen; Pegram, Mark; Colon-Otero, Gerardo; Perez, Edith A.; Clynes, Raphael; Knutson, Keith L.

In: Breast Cancer Research, Vol. 20, No. 1, 52, 14.06.2018.

Research output: Contribution to journalArticle

Norton, N, Fox, N, McCarl, CA, Tenner, KS, Ballman, K, Erskine, CL, Necela, BM, Northfelt, D, Tan, WW, Calfa, C, Pegram, M, Colon-Otero, G, Perez, EA, Clynes, R & Knutson, KL 2018, 'Generation of HER2-specific antibody immunity during trastuzumab adjuvant therapy associates with reduced relapse in resected HER2 breast cancer', Breast Cancer Research, vol. 20, no. 1, 52. https://doi.org/10.1186/s13058-018-0989-8
Norton, Nadine ; Fox, Nicholas ; McCarl, Christie Ann ; Tenner, Kathleen S. ; Ballman, Karla ; Erskine, Courtney L. ; Necela, Brian M. ; Northfelt, Donald ; Tan, Winston W. ; Calfa, Carmen ; Pegram, Mark ; Colon-Otero, Gerardo ; Perez, Edith A. ; Clynes, Raphael ; Knutson, Keith L. / Generation of HER2-specific antibody immunity during trastuzumab adjuvant therapy associates with reduced relapse in resected HER2 breast cancer. In: Breast Cancer Research. 2018 ; Vol. 20, No. 1.
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abstract = "Background: Resected HER2 breast cancer patients treated with adjuvant trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induce HER2-specific antibodies which correlate with improved survival in HER2 metastatic breast cancer patients. It remains unclear whether the generation of immunity required trastuzumab and whether endogenous antibody immunity is associated with improved disease-free survival in the adjuvant setting. In this study, we addressed this question by analyzing serum anti-HER2 antibodies from a subset of patients enrolled in the NCCTG trial N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. Methods: Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831. Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and compared between arms and with disease-free survival. Results: Prior to therapy, across all three arms, N9831 patients had similar mean anti-HER2 IgG levels. Following treatment, the mean levels of antibodies increased in the trastuzumab arms but not the chemotherapy-only arm. The proportion of patients who demonstrated antibodies increased by 4{\%} in Arm A and by 43{\%} in the Arms B and C combined (p=0.003). Cox modeling demonstrated that larger increases in antibodies were associated with improved disease-free survival in all patients (HR=0.23; p=0.04). Conclusions: These results show that the increased endogenous antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant, in view of its correlation with improved disease-free survival. The findings may have important implications for predicting treatment outcomes in patients treated with trastuzumab in the adjuvant setting.",
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T1 - Generation of HER2-specific antibody immunity during trastuzumab adjuvant therapy associates with reduced relapse in resected HER2 breast cancer

AU - Norton, Nadine

AU - Fox, Nicholas

AU - McCarl, Christie Ann

AU - Tenner, Kathleen S.

AU - Ballman, Karla

AU - Erskine, Courtney L.

AU - Necela, Brian M.

AU - Northfelt, Donald

AU - Tan, Winston W.

AU - Calfa, Carmen

AU - Pegram, Mark

AU - Colon-Otero, Gerardo

AU - Perez, Edith A.

AU - Clynes, Raphael

AU - Knutson, Keith L.

PY - 2018/6/14

Y1 - 2018/6/14

N2 - Background: Resected HER2 breast cancer patients treated with adjuvant trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induce HER2-specific antibodies which correlate with improved survival in HER2 metastatic breast cancer patients. It remains unclear whether the generation of immunity required trastuzumab and whether endogenous antibody immunity is associated with improved disease-free survival in the adjuvant setting. In this study, we addressed this question by analyzing serum anti-HER2 antibodies from a subset of patients enrolled in the NCCTG trial N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. Methods: Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831. Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and compared between arms and with disease-free survival. Results: Prior to therapy, across all three arms, N9831 patients had similar mean anti-HER2 IgG levels. Following treatment, the mean levels of antibodies increased in the trastuzumab arms but not the chemotherapy-only arm. The proportion of patients who demonstrated antibodies increased by 4% in Arm A and by 43% in the Arms B and C combined (p=0.003). Cox modeling demonstrated that larger increases in antibodies were associated with improved disease-free survival in all patients (HR=0.23; p=0.04). Conclusions: These results show that the increased endogenous antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant, in view of its correlation with improved disease-free survival. The findings may have important implications for predicting treatment outcomes in patients treated with trastuzumab in the adjuvant setting.

AB - Background: Resected HER2 breast cancer patients treated with adjuvant trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induce HER2-specific antibodies which correlate with improved survival in HER2 metastatic breast cancer patients. It remains unclear whether the generation of immunity required trastuzumab and whether endogenous antibody immunity is associated with improved disease-free survival in the adjuvant setting. In this study, we addressed this question by analyzing serum anti-HER2 antibodies from a subset of patients enrolled in the NCCTG trial N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. Methods: Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831. Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and compared between arms and with disease-free survival. Results: Prior to therapy, across all three arms, N9831 patients had similar mean anti-HER2 IgG levels. Following treatment, the mean levels of antibodies increased in the trastuzumab arms but not the chemotherapy-only arm. The proportion of patients who demonstrated antibodies increased by 4% in Arm A and by 43% in the Arms B and C combined (p=0.003). Cox modeling demonstrated that larger increases in antibodies were associated with improved disease-free survival in all patients (HR=0.23; p=0.04). Conclusions: These results show that the increased endogenous antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant, in view of its correlation with improved disease-free survival. The findings may have important implications for predicting treatment outcomes in patients treated with trastuzumab in the adjuvant setting.

KW - Adaptive immune response

KW - Disease-free survival

KW - HER2+

KW - Trastuzumab

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