Impact of PTEN protein expression on benefit from adjuvant trastuzumab in early-stage human epidermal growth factor receptor 2-positive breast cancer in the North Central Cancer Treatment Group N9831 trial.

Edith A. Perez, Amylou Dueck, Ann E. McCullough, Beiyun Chen, Xochiquetzal J. Geiger, Robert Brian Jenkins, Wilma L. Lingle, Nancy E. Davidson, Silvana Martino, Peter A. Kaufman, Leila A. Kutteh, George W. Sledge, Lyndsay N. Harris, Julie R. Gralow, Monica M. Reinholz

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Abstract

It has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) -positive trial-North Central Cancer Treatment Group (NCCTG) N9831. The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with ≥ 1+ staining. Median follow-up was 6.0 years. Of 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74%) had PTEN-positive tumors. PTEN positivity was associated with hormone receptor negativity (χ(2) P < .001) and nodal positivity (χ(2) P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47). In contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status.

Original languageEnglish (US)
Pages (from-to)2115-2122
Number of pages8
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume31
Issue number17
StatePublished - Jun 10 2013

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PTEN Phosphohydrolase
Breast Neoplasms
Neoplasms
Disease-Free Survival
Therapeutics
Staining and Labeling
human ERBB2 protein
Trastuzumab
Drug Therapy
Phosphatidylinositol 3-Kinases
Immunohistochemistry
Monoclonal Antibodies
Hormones

ASJC Scopus subject areas

  • Medicine(all)

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Impact of PTEN protein expression on benefit from adjuvant trastuzumab in early-stage human epidermal growth factor receptor 2-positive breast cancer in the North Central Cancer Treatment Group N9831 trial. / Perez, Edith A.; Dueck, Amylou; McCullough, Ann E.; Chen, Beiyun; Geiger, Xochiquetzal J.; Jenkins, Robert Brian; Lingle, Wilma L.; Davidson, Nancy E.; Martino, Silvana; Kaufman, Peter A.; Kutteh, Leila A.; Sledge, George W.; Harris, Lyndsay N.; Gralow, Julie R.; Reinholz, Monica M.

In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Vol. 31, No. 17, 10.06.2013, p. 2115-2122.

Research output: Contribution to journalArticle

Perez, Edith A. ; Dueck, Amylou ; McCullough, Ann E. ; Chen, Beiyun ; Geiger, Xochiquetzal J. ; Jenkins, Robert Brian ; Lingle, Wilma L. ; Davidson, Nancy E. ; Martino, Silvana ; Kaufman, Peter A. ; Kutteh, Leila A. ; Sledge, George W. ; Harris, Lyndsay N. ; Gralow, Julie R. ; Reinholz, Monica M. / Impact of PTEN protein expression on benefit from adjuvant trastuzumab in early-stage human epidermal growth factor receptor 2-positive breast cancer in the North Central Cancer Treatment Group N9831 trial. In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013 ; Vol. 31, No. 17. pp. 2115-2122.
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abstract = "It has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) -positive trial-North Central Cancer Treatment Group (NCCTG) N9831. The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with ≥ 1+ staining. Median follow-up was 6.0 years. Of 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74{\%}) had PTEN-positive tumors. PTEN positivity was associated with hormone receptor negativity (χ(2) P < .001) and nodal positivity (χ(2) P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47). In contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status.",
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AU - Perez, Edith A.

AU - Dueck, Amylou

AU - McCullough, Ann E.

AU - Chen, Beiyun

AU - Geiger, Xochiquetzal J.

AU - Jenkins, Robert Brian

AU - Lingle, Wilma L.

AU - Davidson, Nancy E.

AU - Martino, Silvana

AU - Kaufman, Peter A.

AU - Kutteh, Leila A.

AU - Sledge, George W.

AU - Harris, Lyndsay N.

AU - Gralow, Julie R.

AU - Reinholz, Monica M.

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N2 - It has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) -positive trial-North Central Cancer Treatment Group (NCCTG) N9831. The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with ≥ 1+ staining. Median follow-up was 6.0 years. Of 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74%) had PTEN-positive tumors. PTEN positivity was associated with hormone receptor negativity (χ(2) P < .001) and nodal positivity (χ(2) P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47). In contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status.

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