IGF1R protein expression is not associated with differential benefit to concurrent trastuzumab in early-stage HER2+ breast cancer from the North Central Cancer Treatment Group (Alliance) adjuvant trastuzumab trial N9831

Monica M. Reinholz, Beiyun Chen, Amylou Dueck, Kathleen Tenner, Karla Ballman, Darren Riehle, Robert Brian Jenkins, Xochiquetzal J. Geiger, Ann E. McCullough, Edith A. Perez

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Abstract

Background: Preclinical evidence indicates that increased insulin-like growth factor receptor-1 (IGF1R) signaling interferes with the action of trastuzumab suggesting a possible mechanism of trastuzumab resistance. Thus, we evaluated IGF1R prevalence, relationship with demographic data, and association with disease-free survival (DFS) of patients randomized to chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the prospective phase III HER2+ adjuvant N9831 trial. Experimental Design: IGF1R protein expression was determined in tissue microarray sections (three cores per block; N = 1,197) or in whole tissue sections (WS; N = 537) using IHC (rabbit polyclonal antibody against IGF1R β-subunit). A tumor was considered positive (IGF1R+) if any core or WS had ≥1+ membrane staining in >0% invasive cells. Median follow-up was 8.5 years. Results: Of 1,734 patients, 708 (41%) had IGF1R+ breast tumors. IGF1R+ was associated with younger age (median 48 vs 51, P = 0.007), estrogen receptor/progesterone receptor positivit (78% vs. 35%, P < 0.001), nodal positivity (89% vs. 83%, P < 0.001), well/intermediate grade (34% vs. 24%, P < 0.001), tumors ≥2 cm (72% vs. 67%, P = 0.02) but not associated with race or tumor histology. IGF1R did not affect DFS within arms. Between Arms A and C, patients with IGF1R+ and IGF1R tumors had DFS HRs of 0.48 (P ≤ 0.001) and 0.68 (P = 0.009), respectively (Pinteraction = 0.17). Between Arms A and B, patients with IGF1R+ and IGF1R tumors had DFS HRs of 0.83 (P = 0.25) and 0.69 (P = 0.01), respectively (Pinteraction = 0.42). Conclusions: In contrast to preclinical studies that suggest a decrease in trastuzumab sensitivity in IGF1R+ tumors, our adjuvant data show benefit of adding trastuzumab for patients with either IGF1R+ and IGF1R breast tumors.

Original languageEnglish (US)
Pages (from-to)4203-4211
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number15
DOIs
StatePublished - Aug 1 2017

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Breast Neoplasms
Disease-Free Survival
Neoplasms
Proteins
Therapeutics
Somatomedin Receptors
Drug Therapy
Progesterone Receptors
Estrogen Receptors
Trastuzumab
Histology
Research Design
Demography
Staining and Labeling
Rabbits
Membranes
Antibodies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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IGF1R protein expression is not associated with differential benefit to concurrent trastuzumab in early-stage HER2+ breast cancer from the North Central Cancer Treatment Group (Alliance) adjuvant trastuzumab trial N9831. / Reinholz, Monica M.; Chen, Beiyun; Dueck, Amylou; Tenner, Kathleen; Ballman, Karla; Riehle, Darren; Jenkins, Robert Brian; Geiger, Xochiquetzal J.; McCullough, Ann E.; Perez, Edith A.

In: Clinical Cancer Research, Vol. 23, No. 15, 01.08.2017, p. 4203-4211.

Research output: Contribution to journalArticle

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title = "IGF1R protein expression is not associated with differential benefit to concurrent trastuzumab in early-stage HER2+ breast cancer from the North Central Cancer Treatment Group (Alliance) adjuvant trastuzumab trial N9831",
abstract = "Background: Preclinical evidence indicates that increased insulin-like growth factor receptor-1 (IGF1R) signaling interferes with the action of trastuzumab suggesting a possible mechanism of trastuzumab resistance. Thus, we evaluated IGF1R prevalence, relationship with demographic data, and association with disease-free survival (DFS) of patients randomized to chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the prospective phase III HER2+ adjuvant N9831 trial. Experimental Design: IGF1R protein expression was determined in tissue microarray sections (three cores per block; N = 1,197) or in whole tissue sections (WS; N = 537) using IHC (rabbit polyclonal antibody against IGF1R β-subunit). A tumor was considered positive (IGF1R+) if any core or WS had ≥1+ membrane staining in >0{\%} invasive cells. Median follow-up was 8.5 years. Results: Of 1,734 patients, 708 (41{\%}) had IGF1R+ breast tumors. IGF1R+ was associated with younger age (median 48 vs 51, P = 0.007), estrogen receptor/progesterone receptor positivit (78{\%} vs. 35{\%}, P < 0.001), nodal positivity (89{\%} vs. 83{\%}, P < 0.001), well/intermediate grade (34{\%} vs. 24{\%}, P < 0.001), tumors ≥2 cm (72{\%} vs. 67{\%}, P = 0.02) but not associated with race or tumor histology. IGF1R did not affect DFS within arms. Between Arms A and C, patients with IGF1R+ and IGF1R− tumors had DFS HRs of 0.48 (P ≤ 0.001) and 0.68 (P = 0.009), respectively (Pinteraction = 0.17). Between Arms A and B, patients with IGF1R+ and IGF1R− tumors had DFS HRs of 0.83 (P = 0.25) and 0.69 (P = 0.01), respectively (Pinteraction = 0.42). Conclusions: In contrast to preclinical studies that suggest a decrease in trastuzumab sensitivity in IGF1R+ tumors, our adjuvant data show benefit of adding trastuzumab for patients with either IGF1R+ and IGF1R− breast tumors.",
author = "Reinholz, {Monica M.} and Beiyun Chen and Amylou Dueck and Kathleen Tenner and Karla Ballman and Darren Riehle and Jenkins, {Robert Brian} and Geiger, {Xochiquetzal J.} and McCullough, {Ann E.} and Perez, {Edith A.}",
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T1 - IGF1R protein expression is not associated with differential benefit to concurrent trastuzumab in early-stage HER2+ breast cancer from the North Central Cancer Treatment Group (Alliance) adjuvant trastuzumab trial N9831

AU - Reinholz, Monica M.

AU - Chen, Beiyun

AU - Dueck, Amylou

AU - Tenner, Kathleen

AU - Ballman, Karla

AU - Riehle, Darren

AU - Jenkins, Robert Brian

AU - Geiger, Xochiquetzal J.

AU - McCullough, Ann E.

AU - Perez, Edith A.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Background: Preclinical evidence indicates that increased insulin-like growth factor receptor-1 (IGF1R) signaling interferes with the action of trastuzumab suggesting a possible mechanism of trastuzumab resistance. Thus, we evaluated IGF1R prevalence, relationship with demographic data, and association with disease-free survival (DFS) of patients randomized to chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the prospective phase III HER2+ adjuvant N9831 trial. Experimental Design: IGF1R protein expression was determined in tissue microarray sections (three cores per block; N = 1,197) or in whole tissue sections (WS; N = 537) using IHC (rabbit polyclonal antibody against IGF1R β-subunit). A tumor was considered positive (IGF1R+) if any core or WS had ≥1+ membrane staining in >0% invasive cells. Median follow-up was 8.5 years. Results: Of 1,734 patients, 708 (41%) had IGF1R+ breast tumors. IGF1R+ was associated with younger age (median 48 vs 51, P = 0.007), estrogen receptor/progesterone receptor positivit (78% vs. 35%, P < 0.001), nodal positivity (89% vs. 83%, P < 0.001), well/intermediate grade (34% vs. 24%, P < 0.001), tumors ≥2 cm (72% vs. 67%, P = 0.02) but not associated with race or tumor histology. IGF1R did not affect DFS within arms. Between Arms A and C, patients with IGF1R+ and IGF1R− tumors had DFS HRs of 0.48 (P ≤ 0.001) and 0.68 (P = 0.009), respectively (Pinteraction = 0.17). Between Arms A and B, patients with IGF1R+ and IGF1R− tumors had DFS HRs of 0.83 (P = 0.25) and 0.69 (P = 0.01), respectively (Pinteraction = 0.42). Conclusions: In contrast to preclinical studies that suggest a decrease in trastuzumab sensitivity in IGF1R+ tumors, our adjuvant data show benefit of adding trastuzumab for patients with either IGF1R+ and IGF1R− breast tumors.

AB - Background: Preclinical evidence indicates that increased insulin-like growth factor receptor-1 (IGF1R) signaling interferes with the action of trastuzumab suggesting a possible mechanism of trastuzumab resistance. Thus, we evaluated IGF1R prevalence, relationship with demographic data, and association with disease-free survival (DFS) of patients randomized to chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the prospective phase III HER2+ adjuvant N9831 trial. Experimental Design: IGF1R protein expression was determined in tissue microarray sections (three cores per block; N = 1,197) or in whole tissue sections (WS; N = 537) using IHC (rabbit polyclonal antibody against IGF1R β-subunit). A tumor was considered positive (IGF1R+) if any core or WS had ≥1+ membrane staining in >0% invasive cells. Median follow-up was 8.5 years. Results: Of 1,734 patients, 708 (41%) had IGF1R+ breast tumors. IGF1R+ was associated with younger age (median 48 vs 51, P = 0.007), estrogen receptor/progesterone receptor positivit (78% vs. 35%, P < 0.001), nodal positivity (89% vs. 83%, P < 0.001), well/intermediate grade (34% vs. 24%, P < 0.001), tumors ≥2 cm (72% vs. 67%, P = 0.02) but not associated with race or tumor histology. IGF1R did not affect DFS within arms. Between Arms A and C, patients with IGF1R+ and IGF1R− tumors had DFS HRs of 0.48 (P ≤ 0.001) and 0.68 (P = 0.009), respectively (Pinteraction = 0.17). Between Arms A and B, patients with IGF1R+ and IGF1R− tumors had DFS HRs of 0.83 (P = 0.25) and 0.69 (P = 0.01), respectively (Pinteraction = 0.42). Conclusions: In contrast to preclinical studies that suggest a decrease in trastuzumab sensitivity in IGF1R+ tumors, our adjuvant data show benefit of adding trastuzumab for patients with either IGF1R+ and IGF1R− breast tumors.

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JO - Clinical Cancer Research

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SN - 1078-0432

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