Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial

Edith A. Perez, E Aubrey Thompson, Karla V. Ballman, S. Keith Anderson, Yan Asmann, Krishna R Kalari, Jeanette E Eckel-Passow, Amylou Dueck, Kathleen S. Tenner, Jin Jen, Jian Bing Fan, Xochiquetzal J. Geiger, Ann E. McCullough, Beiyun Chen, Robert Brian Jenkins, George W. Sledge, Eric P. Winer, Julie R. Gralow, Monica M. Reinholz

Research output: Contribution to journalArticle

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Abstract

Purpose: To develop a genomic signature that predicts benefit from trastuzumab in human epidermal growth factor receptor 2-positive breast cancer. Patients and Methods: DASL technology was used to quantify mRNA in samples from 1,282 patients enrolled onto the Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer (North Central Cancer Treatment Group N9831 [NCCTG-N9831]) adjuvant trastuzumab trial. Cox proportional hazard ratios (HRs), adjusted for significant clinicopathologic risk factors, were used to determine the association of each gene with relapse-free survival (RFS) for 433 patients who received chemotherapy alone (arm A) and 849 patients who received chemotherapy plus trastuzumab (arms B and C). Network and pathway analyses were used to identify key biologic processes linked to RFS. The signature was built by using a voting scheme. Results: Network and functional ontology analyses suggested that increased RFS was linked to a subset of immune function genes. A voting scheme model was used to define immune gene enrichment based on the expression of any nine or more of 14 immune function genes at or above the 0.40 quantile for the population. This model was used to identify immune gene-enriched tumors in arm A and arms B and C. Immune gene enrichment was linked to increased RFS in arms B and C (HR, 0.35; 95% CI, 0.22 to 0.55; P <.001), whereas arm B and C patients who did not exhibit immune gene enrichment did not benefit from trastuzumab (HR, 0.89; 95% CI, 0.62 to 1.28; P =.53). Enriched immune function gene expression as defined by our predictive signature was not associated with increased RFS in arm A (HR, 0.90; 95% CI, 0.60 to 1.37; P =.64). Conclusion: Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzumab.

Original languageEnglish (US)
Pages (from-to)701-708
Number of pages8
JournalJournal of Clinical Oncology
Volume33
Issue number7
DOIs
StatePublished - Mar 1 2015

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Genes
Neoplasms
Recurrence
Survival
Politics
Therapeutics
Breast Neoplasms
Drug Therapy
Trastuzumab
Combination Drug Therapy
Technology
Gene Expression
Messenger RNA
Population

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial. / Perez, Edith A.; Thompson, E Aubrey; Ballman, Karla V.; Anderson, S. Keith; Asmann, Yan; Kalari, Krishna R; Eckel-Passow, Jeanette E; Dueck, Amylou; Tenner, Kathleen S.; Jen, Jin; Fan, Jian Bing; Geiger, Xochiquetzal J.; McCullough, Ann E.; Chen, Beiyun; Jenkins, Robert Brian; Sledge, George W.; Winer, Eric P.; Gralow, Julie R.; Reinholz, Monica M.

In: Journal of Clinical Oncology, Vol. 33, No. 7, 01.03.2015, p. 701-708.

Research output: Contribution to journalArticle

Perez, Edith A. ; Thompson, E Aubrey ; Ballman, Karla V. ; Anderson, S. Keith ; Asmann, Yan ; Kalari, Krishna R ; Eckel-Passow, Jeanette E ; Dueck, Amylou ; Tenner, Kathleen S. ; Jen, Jin ; Fan, Jian Bing ; Geiger, Xochiquetzal J. ; McCullough, Ann E. ; Chen, Beiyun ; Jenkins, Robert Brian ; Sledge, George W. ; Winer, Eric P. ; Gralow, Julie R. ; Reinholz, Monica M. / Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial. In: Journal of Clinical Oncology. 2015 ; Vol. 33, No. 7. pp. 701-708.
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abstract = "Purpose: To develop a genomic signature that predicts benefit from trastuzumab in human epidermal growth factor receptor 2-positive breast cancer. Patients and Methods: DASL technology was used to quantify mRNA in samples from 1,282 patients enrolled onto the Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer (North Central Cancer Treatment Group N9831 [NCCTG-N9831]) adjuvant trastuzumab trial. Cox proportional hazard ratios (HRs), adjusted for significant clinicopathologic risk factors, were used to determine the association of each gene with relapse-free survival (RFS) for 433 patients who received chemotherapy alone (arm A) and 849 patients who received chemotherapy plus trastuzumab (arms B and C). Network and pathway analyses were used to identify key biologic processes linked to RFS. The signature was built by using a voting scheme. Results: Network and functional ontology analyses suggested that increased RFS was linked to a subset of immune function genes. A voting scheme model was used to define immune gene enrichment based on the expression of any nine or more of 14 immune function genes at or above the 0.40 quantile for the population. This model was used to identify immune gene-enriched tumors in arm A and arms B and C. Immune gene enrichment was linked to increased RFS in arms B and C (HR, 0.35; 95{\%} CI, 0.22 to 0.55; P <.001), whereas arm B and C patients who did not exhibit immune gene enrichment did not benefit from trastuzumab (HR, 0.89; 95{\%} CI, 0.62 to 1.28; P =.53). Enriched immune function gene expression as defined by our predictive signature was not associated with increased RFS in arm A (HR, 0.90; 95{\%} CI, 0.60 to 1.37; P =.64). Conclusion: Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzumab.",
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T1 - Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial

AU - Perez, Edith A.

AU - Thompson, E Aubrey

AU - Ballman, Karla V.

AU - Anderson, S. Keith

AU - Asmann, Yan

AU - Kalari, Krishna R

AU - Eckel-Passow, Jeanette E

AU - Dueck, Amylou

AU - Tenner, Kathleen S.

AU - Jen, Jin

AU - Fan, Jian Bing

AU - Geiger, Xochiquetzal J.

AU - McCullough, Ann E.

AU - Chen, Beiyun

AU - Jenkins, Robert Brian

AU - Sledge, George W.

AU - Winer, Eric P.

AU - Gralow, Julie R.

AU - Reinholz, Monica M.

PY - 2015/3/1

Y1 - 2015/3/1

N2 - Purpose: To develop a genomic signature that predicts benefit from trastuzumab in human epidermal growth factor receptor 2-positive breast cancer. Patients and Methods: DASL technology was used to quantify mRNA in samples from 1,282 patients enrolled onto the Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer (North Central Cancer Treatment Group N9831 [NCCTG-N9831]) adjuvant trastuzumab trial. Cox proportional hazard ratios (HRs), adjusted for significant clinicopathologic risk factors, were used to determine the association of each gene with relapse-free survival (RFS) for 433 patients who received chemotherapy alone (arm A) and 849 patients who received chemotherapy plus trastuzumab (arms B and C). Network and pathway analyses were used to identify key biologic processes linked to RFS. The signature was built by using a voting scheme. Results: Network and functional ontology analyses suggested that increased RFS was linked to a subset of immune function genes. A voting scheme model was used to define immune gene enrichment based on the expression of any nine or more of 14 immune function genes at or above the 0.40 quantile for the population. This model was used to identify immune gene-enriched tumors in arm A and arms B and C. Immune gene enrichment was linked to increased RFS in arms B and C (HR, 0.35; 95% CI, 0.22 to 0.55; P <.001), whereas arm B and C patients who did not exhibit immune gene enrichment did not benefit from trastuzumab (HR, 0.89; 95% CI, 0.62 to 1.28; P =.53). Enriched immune function gene expression as defined by our predictive signature was not associated with increased RFS in arm A (HR, 0.90; 95% CI, 0.60 to 1.37; P =.64). Conclusion: Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzumab.

AB - Purpose: To develop a genomic signature that predicts benefit from trastuzumab in human epidermal growth factor receptor 2-positive breast cancer. Patients and Methods: DASL technology was used to quantify mRNA in samples from 1,282 patients enrolled onto the Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer (North Central Cancer Treatment Group N9831 [NCCTG-N9831]) adjuvant trastuzumab trial. Cox proportional hazard ratios (HRs), adjusted for significant clinicopathologic risk factors, were used to determine the association of each gene with relapse-free survival (RFS) for 433 patients who received chemotherapy alone (arm A) and 849 patients who received chemotherapy plus trastuzumab (arms B and C). Network and pathway analyses were used to identify key biologic processes linked to RFS. The signature was built by using a voting scheme. Results: Network and functional ontology analyses suggested that increased RFS was linked to a subset of immune function genes. A voting scheme model was used to define immune gene enrichment based on the expression of any nine or more of 14 immune function genes at or above the 0.40 quantile for the population. This model was used to identify immune gene-enriched tumors in arm A and arms B and C. Immune gene enrichment was linked to increased RFS in arms B and C (HR, 0.35; 95% CI, 0.22 to 0.55; P <.001), whereas arm B and C patients who did not exhibit immune gene enrichment did not benefit from trastuzumab (HR, 0.89; 95% CI, 0.62 to 1.28; P =.53). Enriched immune function gene expression as defined by our predictive signature was not associated with increased RFS in arm A (HR, 0.90; 95% CI, 0.60 to 1.37; P =.64). Conclusion: Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzumab.

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