C-MYC alterations and association with patient outcome in early-stage HER2-positive breast cancer from the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial

Edith A. Perez, Robert Brian Jenkins, Amylou Dueck, Anne E. Wiktor, Patrick P. Bedroske, S. Keith Anderson, Rhett P. Ketterling, William R. Sukov, Kazunori Kanehira, Beiyun Chen, Xochiquetzal J. Geiger, Cathy A. Andorfer, Ann E. McCullough, Nancy E. Davidson, Silvana Martino, George W. Sledge, Peter A. Kaufman, Leila A. Kutteh, Julie R. Gralow, Lyndsay N. Harris & 3 others James N. Ingle, Wilma L. Lingle, Monica M. Reinholz

Research output: Contribution to journalArticle

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Abstract

Purpose: Findings from the human epidermal growth factor receptor 2 (HER2) -positive National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 trial suggested that MYC/HER2 coamplification (> 5.0 copies/nucleus) was associated with additional benefit from adjuvant trastuzumab in patients with early-stage breast cancer. To further explore this relationship, we investigated associations between MYC amplification and disease-free survival (DFS) in a similar adjuvant trastuzumab HER2-positive breast cancer trial - North Central Cancer Treatment Group (NCCTG) N9831. Patients and Methods: This analysis included 799 patients randomly assigned to receive chemotherapy alone or with concurrent trastuzumab on N9831. Fluorescence in situ hybridization (FISH) was performed by using a dual-probe mixture for MYC and centromere 8 (MYC:CEP8) on tissue microarrays. MYC amplification was prespecified as MYC:CEP8 ratio > 2.2 or average MYC copies/nucleus > 5.0. Exploratory variables included polysomy 8. Results: In comparing DFS (median follow-up, 4.0 years) between treatments, patients with MYC:CEP8 ratio ≤ 2.2 (n = 618; 77%) and > 2.2 (n = 181; 23%) had hazard ratios (HRs) of 0.46 (P < .001) and 0.67 (P = .33), respectively (interaction P = .38). Patients with MYC copies/nucleus ≤ 5.0 (n = 534; 67%) and > 5.0 (n = 265; 33%) had HRs of 0.52 (P = .002) and 0.48 (P = .02), respectively (interaction P = .94). Patients with MYC:CEP8 ratio < 1.3 with normal chromosome 8 copy number (n = 141; 18%) and ≥ 1.3 or < 1.3 with polysomy 8 (n = 658; 82%) had HRs of 0.66 (P = .28) and 0.44 (P < .001), respectively (interaction P = .23). Patients with MYC copies/nucleus < 2.5 (n = 130; 16%) and ≥ 2.5 (n = 669; 84%) had HRs of 1.07 (P = .87) and 0.42 (P < .001), respectively (interaction P = .05). Conclusion: We did not confirm the B31 association between MYC amplification and additional trastuzumab benefit. Exploratory analyses revealed potential associations between alternative MYC/chromosome 8 copy number alterations and differential benefit of adjuvant trastuzumab.

Original languageEnglish (US)
Pages (from-to)651-659
Number of pages9
JournalJournal of Clinical Oncology
Volume29
Issue number6
DOIs
StatePublished - Feb 20 2011

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Breast Neoplasms
Chromosomes, Human, Pair 8
Neoplasms
Disease-Free Survival
Therapeutics
Pyridinolcarbamate
Centromere
Fluorescence In Situ Hybridization
human ERBB2 protein
Trastuzumab
Breast
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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C-MYC alterations and association with patient outcome in early-stage HER2-positive breast cancer from the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial. / Perez, Edith A.; Jenkins, Robert Brian; Dueck, Amylou; Wiktor, Anne E.; Bedroske, Patrick P.; Anderson, S. Keith; Ketterling, Rhett P.; Sukov, William R.; Kanehira, Kazunori; Chen, Beiyun; Geiger, Xochiquetzal J.; Andorfer, Cathy A.; McCullough, Ann E.; Davidson, Nancy E.; Martino, Silvana; Sledge, George W.; Kaufman, Peter A.; Kutteh, Leila A.; Gralow, Julie R.; Harris, Lyndsay N.; Ingle, James N.; Lingle, Wilma L.; Reinholz, Monica M.

In: Journal of Clinical Oncology, Vol. 29, No. 6, 20.02.2011, p. 651-659.

Research output: Contribution to journalArticle

Perez, EA, Jenkins, RB, Dueck, A, Wiktor, AE, Bedroske, PP, Anderson, SK, Ketterling, RP, Sukov, WR, Kanehira, K, Chen, B, Geiger, XJ, Andorfer, CA, McCullough, AE, Davidson, NE, Martino, S, Sledge, GW, Kaufman, PA, Kutteh, LA, Gralow, JR, Harris, LN, Ingle, JN, Lingle, WL & Reinholz, MM 2011, 'C-MYC alterations and association with patient outcome in early-stage HER2-positive breast cancer from the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial', Journal of Clinical Oncology, vol. 29, no. 6, pp. 651-659. https://doi.org/10.1200/JCO.2010.30.2125
Perez, Edith A. ; Jenkins, Robert Brian ; Dueck, Amylou ; Wiktor, Anne E. ; Bedroske, Patrick P. ; Anderson, S. Keith ; Ketterling, Rhett P. ; Sukov, William R. ; Kanehira, Kazunori ; Chen, Beiyun ; Geiger, Xochiquetzal J. ; Andorfer, Cathy A. ; McCullough, Ann E. ; Davidson, Nancy E. ; Martino, Silvana ; Sledge, George W. ; Kaufman, Peter A. ; Kutteh, Leila A. ; Gralow, Julie R. ; Harris, Lyndsay N. ; Ingle, James N. ; Lingle, Wilma L. ; Reinholz, Monica M. / C-MYC alterations and association with patient outcome in early-stage HER2-positive breast cancer from the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial. In: Journal of Clinical Oncology. 2011 ; Vol. 29, No. 6. pp. 651-659.
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title = "C-MYC alterations and association with patient outcome in early-stage HER2-positive breast cancer from the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial",
abstract = "Purpose: Findings from the human epidermal growth factor receptor 2 (HER2) -positive National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 trial suggested that MYC/HER2 coamplification (> 5.0 copies/nucleus) was associated with additional benefit from adjuvant trastuzumab in patients with early-stage breast cancer. To further explore this relationship, we investigated associations between MYC amplification and disease-free survival (DFS) in a similar adjuvant trastuzumab HER2-positive breast cancer trial - North Central Cancer Treatment Group (NCCTG) N9831. Patients and Methods: This analysis included 799 patients randomly assigned to receive chemotherapy alone or with concurrent trastuzumab on N9831. Fluorescence in situ hybridization (FISH) was performed by using a dual-probe mixture for MYC and centromere 8 (MYC:CEP8) on tissue microarrays. MYC amplification was prespecified as MYC:CEP8 ratio > 2.2 or average MYC copies/nucleus > 5.0. Exploratory variables included polysomy 8. Results: In comparing DFS (median follow-up, 4.0 years) between treatments, patients with MYC:CEP8 ratio ≤ 2.2 (n = 618; 77{\%}) and > 2.2 (n = 181; 23{\%}) had hazard ratios (HRs) of 0.46 (P < .001) and 0.67 (P = .33), respectively (interaction P = .38). Patients with MYC copies/nucleus ≤ 5.0 (n = 534; 67{\%}) and > 5.0 (n = 265; 33{\%}) had HRs of 0.52 (P = .002) and 0.48 (P = .02), respectively (interaction P = .94). Patients with MYC:CEP8 ratio < 1.3 with normal chromosome 8 copy number (n = 141; 18{\%}) and ≥ 1.3 or < 1.3 with polysomy 8 (n = 658; 82{\%}) had HRs of 0.66 (P = .28) and 0.44 (P < .001), respectively (interaction P = .23). Patients with MYC copies/nucleus < 2.5 (n = 130; 16{\%}) and ≥ 2.5 (n = 669; 84{\%}) had HRs of 1.07 (P = .87) and 0.42 (P < .001), respectively (interaction P = .05). Conclusion: We did not confirm the B31 association between MYC amplification and additional trastuzumab benefit. Exploratory analyses revealed potential associations between alternative MYC/chromosome 8 copy number alterations and differential benefit of adjuvant trastuzumab.",
author = "Perez, {Edith A.} and Jenkins, {Robert Brian} and Amylou Dueck and Wiktor, {Anne E.} and Bedroske, {Patrick P.} and Anderson, {S. Keith} and Ketterling, {Rhett P.} and Sukov, {William R.} and Kazunori Kanehira and Beiyun Chen and Geiger, {Xochiquetzal J.} and Andorfer, {Cathy A.} and McCullough, {Ann E.} and Davidson, {Nancy E.} and Silvana Martino and Sledge, {George W.} and Kaufman, {Peter A.} and Kutteh, {Leila A.} and Gralow, {Julie R.} and Harris, {Lyndsay N.} and Ingle, {James N.} and Lingle, {Wilma L.} and Reinholz, {Monica M.}",
year = "2011",
month = "2",
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doi = "10.1200/JCO.2010.30.2125",
language = "English (US)",
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pages = "651--659",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
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TY - JOUR

T1 - C-MYC alterations and association with patient outcome in early-stage HER2-positive breast cancer from the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial

AU - Perez, Edith A.

AU - Jenkins, Robert Brian

AU - Dueck, Amylou

AU - Wiktor, Anne E.

AU - Bedroske, Patrick P.

AU - Anderson, S. Keith

AU - Ketterling, Rhett P.

AU - Sukov, William R.

AU - Kanehira, Kazunori

AU - Chen, Beiyun

AU - Geiger, Xochiquetzal J.

AU - Andorfer, Cathy A.

AU - McCullough, Ann E.

AU - Davidson, Nancy E.

AU - Martino, Silvana

AU - Sledge, George W.

AU - Kaufman, Peter A.

AU - Kutteh, Leila A.

AU - Gralow, Julie R.

AU - Harris, Lyndsay N.

AU - Ingle, James N.

AU - Lingle, Wilma L.

AU - Reinholz, Monica M.

PY - 2011/2/20

Y1 - 2011/2/20

N2 - Purpose: Findings from the human epidermal growth factor receptor 2 (HER2) -positive National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 trial suggested that MYC/HER2 coamplification (> 5.0 copies/nucleus) was associated with additional benefit from adjuvant trastuzumab in patients with early-stage breast cancer. To further explore this relationship, we investigated associations between MYC amplification and disease-free survival (DFS) in a similar adjuvant trastuzumab HER2-positive breast cancer trial - North Central Cancer Treatment Group (NCCTG) N9831. Patients and Methods: This analysis included 799 patients randomly assigned to receive chemotherapy alone or with concurrent trastuzumab on N9831. Fluorescence in situ hybridization (FISH) was performed by using a dual-probe mixture for MYC and centromere 8 (MYC:CEP8) on tissue microarrays. MYC amplification was prespecified as MYC:CEP8 ratio > 2.2 or average MYC copies/nucleus > 5.0. Exploratory variables included polysomy 8. Results: In comparing DFS (median follow-up, 4.0 years) between treatments, patients with MYC:CEP8 ratio ≤ 2.2 (n = 618; 77%) and > 2.2 (n = 181; 23%) had hazard ratios (HRs) of 0.46 (P < .001) and 0.67 (P = .33), respectively (interaction P = .38). Patients with MYC copies/nucleus ≤ 5.0 (n = 534; 67%) and > 5.0 (n = 265; 33%) had HRs of 0.52 (P = .002) and 0.48 (P = .02), respectively (interaction P = .94). Patients with MYC:CEP8 ratio < 1.3 with normal chromosome 8 copy number (n = 141; 18%) and ≥ 1.3 or < 1.3 with polysomy 8 (n = 658; 82%) had HRs of 0.66 (P = .28) and 0.44 (P < .001), respectively (interaction P = .23). Patients with MYC copies/nucleus < 2.5 (n = 130; 16%) and ≥ 2.5 (n = 669; 84%) had HRs of 1.07 (P = .87) and 0.42 (P < .001), respectively (interaction P = .05). Conclusion: We did not confirm the B31 association between MYC amplification and additional trastuzumab benefit. Exploratory analyses revealed potential associations between alternative MYC/chromosome 8 copy number alterations and differential benefit of adjuvant trastuzumab.

AB - Purpose: Findings from the human epidermal growth factor receptor 2 (HER2) -positive National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 trial suggested that MYC/HER2 coamplification (> 5.0 copies/nucleus) was associated with additional benefit from adjuvant trastuzumab in patients with early-stage breast cancer. To further explore this relationship, we investigated associations between MYC amplification and disease-free survival (DFS) in a similar adjuvant trastuzumab HER2-positive breast cancer trial - North Central Cancer Treatment Group (NCCTG) N9831. Patients and Methods: This analysis included 799 patients randomly assigned to receive chemotherapy alone or with concurrent trastuzumab on N9831. Fluorescence in situ hybridization (FISH) was performed by using a dual-probe mixture for MYC and centromere 8 (MYC:CEP8) on tissue microarrays. MYC amplification was prespecified as MYC:CEP8 ratio > 2.2 or average MYC copies/nucleus > 5.0. Exploratory variables included polysomy 8. Results: In comparing DFS (median follow-up, 4.0 years) between treatments, patients with MYC:CEP8 ratio ≤ 2.2 (n = 618; 77%) and > 2.2 (n = 181; 23%) had hazard ratios (HRs) of 0.46 (P < .001) and 0.67 (P = .33), respectively (interaction P = .38). Patients with MYC copies/nucleus ≤ 5.0 (n = 534; 67%) and > 5.0 (n = 265; 33%) had HRs of 0.52 (P = .002) and 0.48 (P = .02), respectively (interaction P = .94). Patients with MYC:CEP8 ratio < 1.3 with normal chromosome 8 copy number (n = 141; 18%) and ≥ 1.3 or < 1.3 with polysomy 8 (n = 658; 82%) had HRs of 0.66 (P = .28) and 0.44 (P < .001), respectively (interaction P = .23). Patients with MYC copies/nucleus < 2.5 (n = 130; 16%) and ≥ 2.5 (n = 669; 84%) had HRs of 1.07 (P = .87) and 0.42 (P < .001), respectively (interaction P = .05). Conclusion: We did not confirm the B31 association between MYC amplification and additional trastuzumab benefit. Exploratory analyses revealed potential associations between alternative MYC/chromosome 8 copy number alterations and differential benefit of adjuvant trastuzumab.

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