PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline-and taxane-based chemotherapy: Correlative analysis of C9741 (alliance)

Minetta C. Liu; Brandelyn N. Pitcher; Elaine R. Mardis; Sherri R. Davies; Paula N. Friedman; Jacqueline E. Snider; Tammi L. Vickery; Jerry P. Reed; Katherine Deschryver; Baljit Singh; William J. Gradishar; Edith A. Perez; Silvana Martino; Marc L. Citron; Larry Norton; Eric P. Winer; Clifford A. Hudis; Lisa A. Carey; Philip S. Bernard; Torsten O. Nielsen; Charles M. Perou; Matthew J. Ellis; William T. Barry

doi:10.1038/npjbcancer.2015.23

PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline-and taxane-based chemotherapy: Correlative analysis of C9741 (alliance)

Minetta C. Liu, Brandelyn N. Pitcher, Elaine R. Mardis, Sherri R. Davies, Paula N. Friedman, Jacqueline E. Snider, Tammi L. Vickery, Jerry P. Reed, Katherine Deschryver, Baljit Singh, William J. Gradishar, Edith A. Perez, Silvana Martino, Marc L. Citron, Larry Norton, Eric P. Winer, Clifford A. Hudis, Lisa A. Carey, Philip S. Bernard, Torsten O. NielsenCharles M. Perou, Matthew J. Ellis, William T. Barry

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Abstract

PAM50 intrinsic breast cancer subtypes are prognostic independent of standard clinicopathologic factors. CALGB 9741 demonstrated improved recurrence-free (RFS) and overall survival (OS) with 2-weekly dose-dense (DD) versus 3-weekly therapy. A significant interaction between intrinsic subtypes and DD-therapy benefit was hypothesized. Suitable tumor samples were available from 1,471 (73%) of 2,005 subjects. Multiplexed gene-expression profiling generated the PAM50 subtype call, proliferation score, and risk of recurrence score (ROR-PT) for the evaluable subset of 1,311 treated patients. The interaction between DD-therapy benefit and intrinsic subtype was tested in a Cox proportional hazards model using two-sided alpha = 0.05. Additional multivariable Cox models evaluated the proliferation and ROR-PT scores as continuous measures with selected clinical covariates. Improved outcomes for DD therapy in the evaluable subset mirrored results from the complete data set (RFS; hazard ratio = 1.20; 95% confidence interval = 0.99–1.44) with 12.3-year median follow-up. Intrinsic subtypes were prognostic of RFS (P<0.0001) irrespective of treatment assignment. No subtype-specific treatment effect on RFS was identified (interaction P = 0.44). Proliferation and ROR-PT scores were prognostic for RFS (both P<0.0001), but no association with treatment benefit was seen (P = 0.14 and 0.59, respectively). Results were similar for OS. The prognostic value of PAM50 intrinsic subtype was greater than estrogen receptor/HER2 immunohistochemistry classification. PAM50 gene signatures were highly prognostic but did not predict for improved outcomes with DD anthracycline-and taxane-based therapy. Clinical validation studies will assess the ability of PAM50 and other gene signatures to stratify patients and individualize treatment based on expected risks of distant recurrence.

Original language	English (US)
Article number	15023
Journal	npj Breast Cancer
Volume	2
Issue number	1
DOIs	https://doi.org/10.1038/npjbcancer.2015.23
State	Published - Dec 14 2016

ASJC Scopus subject areas

Oncology
Radiology Nuclear Medicine and imaging
Pharmacology (medical)

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10.1038/npjbcancer.2015.23

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Liu, M. C., Pitcher, B. N., Mardis, E. R., Davies, S. R., Friedman, P. N., Snider, J. E., Vickery, T. L., Reed, J. P., Deschryver, K., Singh, B., Gradishar, W. J., Perez, E. A., Martino, S., Citron, M. L., Norton, L., Winer, E. P., Hudis, C. A., Carey, L. A., Bernard, P. S., ... Barry, W. T. (2016). PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline-and taxane-based chemotherapy: Correlative analysis of C9741 (alliance). npj Breast Cancer, 2(1), Article 15023. https://doi.org/10.1038/npjbcancer.2015.23

Liu, MC, Pitcher, BN, Mardis, ER, Davies, SR, Friedman, PN, Snider, JE, Vickery, TL, Reed, JP, Deschryver, K, Singh, B, Gradishar, WJ, Perez, EA, Martino, S, Citron, ML, Norton, L, Winer, EP, Hudis, CA, Carey, LA, Bernard, PS, Nielsen, TO, Perou, CM, Ellis, MJ & Barry, WT 2016, 'PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline-and taxane-based chemotherapy: Correlative analysis of C9741 (alliance)', npj Breast Cancer, vol. 2, no. 1, 15023. https://doi.org/10.1038/npjbcancer.2015.23

@article{10838c298db84401bea90361f5f62437,

title = "PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline-and taxane-based chemotherapy: Correlative analysis of C9741 (alliance)",

abstract = "PAM50 intrinsic breast cancer subtypes are prognostic independent of standard clinicopathologic factors. CALGB 9741 demonstrated improved recurrence-free (RFS) and overall survival (OS) with 2-weekly dose-dense (DD) versus 3-weekly therapy. A significant interaction between intrinsic subtypes and DD-therapy benefit was hypothesized. Suitable tumor samples were available from 1,471 (73%) of 2,005 subjects. Multiplexed gene-expression profiling generated the PAM50 subtype call, proliferation score, and risk of recurrence score (ROR-PT) for the evaluable subset of 1,311 treated patients. The interaction between DD-therapy benefit and intrinsic subtype was tested in a Cox proportional hazards model using two-sided alpha = 0.05. Additional multivariable Cox models evaluated the proliferation and ROR-PT scores as continuous measures with selected clinical covariates. Improved outcomes for DD therapy in the evaluable subset mirrored results from the complete data set (RFS; hazard ratio = 1.20; 95% confidence interval = 0.99–1.44) with 12.3-year median follow-up. Intrinsic subtypes were prognostic of RFS (P<0.0001) irrespective of treatment assignment. No subtype-specific treatment effect on RFS was identified (interaction P = 0.44). Proliferation and ROR-PT scores were prognostic for RFS (both P<0.0001), but no association with treatment benefit was seen (P = 0.14 and 0.59, respectively). Results were similar for OS. The prognostic value of PAM50 intrinsic subtype was greater than estrogen receptor/HER2 immunohistochemistry classification. PAM50 gene signatures were highly prognostic but did not predict for improved outcomes with DD anthracycline-and taxane-based therapy. Clinical validation studies will assess the ability of PAM50 and other gene signatures to stratify patients and individualize treatment based on expected risks of distant recurrence.",

author = "Liu, {Minetta C.} and Pitcher, {Brandelyn N.} and Mardis, {Elaine R.} and Davies, {Sherri R.} and Friedman, {Paula N.} and Snider, {Jacqueline E.} and Vickery, {Tammi L.} and Reed, {Jerry P.} and Katherine Deschryver and Baljit Singh and Gradishar, {William J.} and Perez, {Edith A.} and Silvana Martino and Citron, {Marc L.} and Larry Norton and Winer, {Eric P.} and Hudis, {Clifford A.} and Carey, {Lisa A.} and Bernard, {Philip S.} and Nielsen, {Torsten O.} and Perou, {Charles M.} and Ellis, {Matthew J.} and Barry, {William T.}",

note = "Funding Information: We are grateful to the patients for generously participating in the related studies. We also thank the CALGB, ECOG, NCCTG, and SWOG investigators and research coordinators for their efforts on behalf of the patients and protocol. This work was supported by grants from the National Cancer Institute for Strategic Partnering to Evaluate Cancer Signatures (SPECS; MJE, CMP, PSB, and TON; CA114722), to the Washington University Pathology Coordinating Office (CA114736), to the Alliance for Clinical Trials in Oncology (Monica M. Bertagnolli; Chair; CA31946), to the Alliance Statistics and Data Center (Daniel J. Sargent; CA33601), and to the NCCTG (CA025224), ECOG (CA21115), and SWOG (CA32102). Additional funding was provided by the Breast Cancer Research Foundation. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE74821 (https://www.ncbi.nlm.nih.gov/geo/query/ acc.cgi?acc=GSE74821). Publisher Copyright: {\textcopyright} 2016 Breast Cancer Research Foundation/Macmillan Publishers Limited.",

year = "2016",

month = dec,

day = "14",

doi = "10.1038/npjbcancer.2015.23",

language = "English (US)",

volume = "2",

journal = "npj Breast Cancer",

issn = "2374-4677",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline-and taxane-based chemotherapy

T2 - Correlative analysis of C9741 (alliance)

AU - Liu, Minetta C.

AU - Pitcher, Brandelyn N.

AU - Mardis, Elaine R.

AU - Davies, Sherri R.

AU - Friedman, Paula N.

AU - Snider, Jacqueline E.

AU - Vickery, Tammi L.

AU - Reed, Jerry P.

AU - Deschryver, Katherine

AU - Singh, Baljit

AU - Gradishar, William J.

AU - Perez, Edith A.

AU - Martino, Silvana

AU - Citron, Marc L.

AU - Norton, Larry

AU - Winer, Eric P.

AU - Hudis, Clifford A.

AU - Carey, Lisa A.

AU - Bernard, Philip S.

AU - Nielsen, Torsten O.

AU - Perou, Charles M.

AU - Ellis, Matthew J.

AU - Barry, William T.

N1 - Funding Information: We are grateful to the patients for generously participating in the related studies. We also thank the CALGB, ECOG, NCCTG, and SWOG investigators and research coordinators for their efforts on behalf of the patients and protocol. This work was supported by grants from the National Cancer Institute for Strategic Partnering to Evaluate Cancer Signatures (SPECS; MJE, CMP, PSB, and TON; CA114722), to the Washington University Pathology Coordinating Office (CA114736), to the Alliance for Clinical Trials in Oncology (Monica M. Bertagnolli; Chair; CA31946), to the Alliance Statistics and Data Center (Daniel J. Sargent; CA33601), and to the NCCTG (CA025224), ECOG (CA21115), and SWOG (CA32102). Additional funding was provided by the Breast Cancer Research Foundation. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE74821 (https://www.ncbi.nlm.nih.gov/geo/query/ acc.cgi?acc=GSE74821). Publisher Copyright: © 2016 Breast Cancer Research Foundation/Macmillan Publishers Limited.

PY - 2016/12/14

Y1 - 2016/12/14

N2 - PAM50 intrinsic breast cancer subtypes are prognostic independent of standard clinicopathologic factors. CALGB 9741 demonstrated improved recurrence-free (RFS) and overall survival (OS) with 2-weekly dose-dense (DD) versus 3-weekly therapy. A significant interaction between intrinsic subtypes and DD-therapy benefit was hypothesized. Suitable tumor samples were available from 1,471 (73%) of 2,005 subjects. Multiplexed gene-expression profiling generated the PAM50 subtype call, proliferation score, and risk of recurrence score (ROR-PT) for the evaluable subset of 1,311 treated patients. The interaction between DD-therapy benefit and intrinsic subtype was tested in a Cox proportional hazards model using two-sided alpha = 0.05. Additional multivariable Cox models evaluated the proliferation and ROR-PT scores as continuous measures with selected clinical covariates. Improved outcomes for DD therapy in the evaluable subset mirrored results from the complete data set (RFS; hazard ratio = 1.20; 95% confidence interval = 0.99–1.44) with 12.3-year median follow-up. Intrinsic subtypes were prognostic of RFS (P<0.0001) irrespective of treatment assignment. No subtype-specific treatment effect on RFS was identified (interaction P = 0.44). Proliferation and ROR-PT scores were prognostic for RFS (both P<0.0001), but no association with treatment benefit was seen (P = 0.14 and 0.59, respectively). Results were similar for OS. The prognostic value of PAM50 intrinsic subtype was greater than estrogen receptor/HER2 immunohistochemistry classification. PAM50 gene signatures were highly prognostic but did not predict for improved outcomes with DD anthracycline-and taxane-based therapy. Clinical validation studies will assess the ability of PAM50 and other gene signatures to stratify patients and individualize treatment based on expected risks of distant recurrence.

AB - PAM50 intrinsic breast cancer subtypes are prognostic independent of standard clinicopathologic factors. CALGB 9741 demonstrated improved recurrence-free (RFS) and overall survival (OS) with 2-weekly dose-dense (DD) versus 3-weekly therapy. A significant interaction between intrinsic subtypes and DD-therapy benefit was hypothesized. Suitable tumor samples were available from 1,471 (73%) of 2,005 subjects. Multiplexed gene-expression profiling generated the PAM50 subtype call, proliferation score, and risk of recurrence score (ROR-PT) for the evaluable subset of 1,311 treated patients. The interaction between DD-therapy benefit and intrinsic subtype was tested in a Cox proportional hazards model using two-sided alpha = 0.05. Additional multivariable Cox models evaluated the proliferation and ROR-PT scores as continuous measures with selected clinical covariates. Improved outcomes for DD therapy in the evaluable subset mirrored results from the complete data set (RFS; hazard ratio = 1.20; 95% confidence interval = 0.99–1.44) with 12.3-year median follow-up. Intrinsic subtypes were prognostic of RFS (P<0.0001) irrespective of treatment assignment. No subtype-specific treatment effect on RFS was identified (interaction P = 0.44). Proliferation and ROR-PT scores were prognostic for RFS (both P<0.0001), but no association with treatment benefit was seen (P = 0.14 and 0.59, respectively). Results were similar for OS. The prognostic value of PAM50 intrinsic subtype was greater than estrogen receptor/HER2 immunohistochemistry classification. PAM50 gene signatures were highly prognostic but did not predict for improved outcomes with DD anthracycline-and taxane-based therapy. Clinical validation studies will assess the ability of PAM50 and other gene signatures to stratify patients and individualize treatment based on expected risks of distant recurrence.

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ER -

PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline-and taxane-based chemotherapy: Correlative analysis of C9741 (alliance)

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