A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

Matthew P Humphries; Sreekumar Sundara Rajan; Alastair Droop; Charlotte A B Suleman; Carmine Carbone; Cecilia Nilsson; Hedieh Honarpisheh; Gabor Cserni; Jo Dent; Laura Fulford; Lee B Jordan; J Louise Jones; Rani Kanthan; Maria Litwiniuk; Anna Di Benedetto; Marcella Mottolese; Elena Provenzano; Sami Shousha; Mark Stephens; Rosemary A Walker; Janina Kulka; Ian O Ellis; Margaret Jeffery; Helene H Thygesen; Vera Cappelletti; Maria G Daidone; Ingrid A Hedenfalk; Marie-Louise Fjällskog; Davide Melisi; Lucy F Stead; Abeer M Shaaban; Valerie Speirs

doi:10.1158/1078-0432.CCR-16-1952

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

Matthew P Humphries, Sreekumar Sundara Rajan, Alastair Droop, Charlotte A B Suleman, Carmine Carbone, Cecilia Nilsson, Hedieh Honarpisheh, Gabor Cserni, Jo Dent, Laura Fulford, Lee B Jordan, J Louise Jones, Rani Kanthan, Maria Litwiniuk, Anna Di Benedetto, Marcella Mottolese, Elena Provenzano, Sami Shousha, Mark Stephens, Rosemary A WalkerJanina Kulka, Ian O Ellis, Margaret Jeffery, Helene H Thygesen, Vera Cappelletti, Maria G Daidone, Ingrid A Hedenfalk, Marie-Louise Fjällskog, Davide Melisi, Lucy F Stead, Abeer M Shaaban, Valerie Speirs

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

Abstract

Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar.Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico Biomarkers were immunohistochemically assessed in 697 MBCs (n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor.Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed (P = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival.Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required. Clin Cancer Res; 23(10); 2575-83. ©2016 AACR.

Original language	English
Pages (from-to)	2575-2583
Number of pages	9
Journal	Clinical Cancer Research
Volume	23
Issue number	10
Early online date	16 Dec 2016
DOIs	https://doi.org/10.1158/1078-0432.CCR-16-1952
Publication status	Published - May 2017
Externally published	Yes

Bibliographical note

This study was funded by Yorkshire Cancer Research (grant L278). Breast Cancer Now (formerly Breast Cancer Campaign, grant 2007MayPR02) provided funding for the accrual and construction of the MBC TMAs. The Breast Cancer Research Trust contributed toward costs of genomic analysis. This work was partially supported by grants from the Italian Association for Cancer Research and the Swedish Cancer Society.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Keywords

Adult
Aged
Aged, 80 and over
Biomarkers, Tumor
Breast Neoplasms
Breast Neoplasms, Male
Disease-Free Survival
Eukaryotic Initiation Factor-4E
Everolimus
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Imidazoles
Male
Middle Aged
Peptide Initiation Factors
Prognosis
Quinolines
RNA-Binding Proteins
Sex Characteristics
Transcriptome
Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1158/1078-0432.CCR-16-1952Licence: Unspecified

http://clincancerres.aacrjournals.org/Licence: Unspecified

Cite this

Humphries, M. P., Sundara Rajan, S., Droop, A., Suleman, C. A. B., Carbone, C., Nilsson, C., Honarpisheh, H., Cserni, G., Dent, J., Fulford, L., Jordan, L. B., Jones, J. L., Kanthan, R., Litwiniuk, M., Di Benedetto, A., Mottolese, M., Provenzano, E., Shousha, S., Stephens, M., ... Speirs, V. (2017). A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer. Clinical Cancer Research, 23(10), 2575-2583. https://doi.org/10.1158/1078-0432.CCR-16-1952

Humphries, MP, Sundara Rajan, S, Droop, A, Suleman, CAB, Carbone, C, Nilsson, C, Honarpisheh, H, Cserni, G, Dent, J, Fulford, L, Jordan, LB, Jones, JL, Kanthan, R, Litwiniuk, M, Di Benedetto, A, Mottolese, M, Provenzano, E, Shousha, S, Stephens, M, Walker, RA, Kulka, J, Ellis, IO, Jeffery, M, Thygesen, HH, Cappelletti, V, Daidone, MG, Hedenfalk, IA, Fjällskog, M-L, Melisi, D, Stead, LF, Shaaban, AM & Speirs, V 2017, 'A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer', Clinical Cancer Research, vol. 23, no. 10, pp. 2575-2583. https://doi.org/10.1158/1078-0432.CCR-16-1952

@article{2cff343790c24e27a6dfe7c793ada246,

title = "A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer",

abstract = "Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar.Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico Biomarkers were immunohistochemically assessed in 697 MBCs (n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor.Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed (P = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival.Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required. Clin Cancer Res; 23(10); 2575-83. {\textcopyright}2016 AACR.",

keywords = "Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Breast Neoplasms, Breast Neoplasms, Male, Disease-Free Survival, Eukaryotic Initiation Factor-4E, Everolimus, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Imidazoles, Male, Middle Aged, Peptide Initiation Factors, Prognosis, Quinolines, RNA-Binding Proteins, Sex Characteristics, Transcriptome, Journal Article",

author = "Humphries, {Matthew P} and {Sundara Rajan}, Sreekumar and Alastair Droop and Suleman, {Charlotte A B} and Carmine Carbone and Cecilia Nilsson and Hedieh Honarpisheh and Gabor Cserni and Jo Dent and Laura Fulford and Jordan, {Lee B} and Jones, {J Louise} and Rani Kanthan and Maria Litwiniuk and {Di Benedetto}, Anna and Marcella Mottolese and Elena Provenzano and Sami Shousha and Mark Stephens and Walker, {Rosemary A} and Janina Kulka and Ellis, {Ian O} and Margaret Jeffery and Thygesen, {Helene H} and Vera Cappelletti and Daidone, {Maria G} and Hedenfalk, {Ingrid A} and Marie-Louise Fj{\"a}llskog and Davide Melisi and Stead, {Lucy F} and Shaaban, {Abeer M} and Valerie Speirs",

note = "This study was funded by Yorkshire Cancer Research (grant L278). Breast Cancer Now (formerly Breast Cancer Campaign, grant 2007MayPR02) provided funding for the accrual and construction of the MBC TMAs. The Breast Cancer Research Trust contributed toward costs of genomic analysis. This work was partially supported by grants from the Italian Association for Cancer Research and the Swedish Cancer Society. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.",

year = "2017",

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T1 - A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

AU - Humphries, Matthew P

AU - Sundara Rajan, Sreekumar

AU - Droop, Alastair

AU - Suleman, Charlotte A B

AU - Carbone, Carmine

AU - Nilsson, Cecilia

AU - Honarpisheh, Hedieh

AU - Cserni, Gabor

AU - Dent, Jo

AU - Fulford, Laura

AU - Jordan, Lee B

AU - Jones, J Louise

AU - Kanthan, Rani

AU - Litwiniuk, Maria

AU - Di Benedetto, Anna

AU - Mottolese, Marcella

AU - Provenzano, Elena

AU - Shousha, Sami

AU - Stephens, Mark

AU - Walker, Rosemary A

AU - Kulka, Janina

AU - Ellis, Ian O

AU - Jeffery, Margaret

AU - Thygesen, Helene H

AU - Cappelletti, Vera

AU - Daidone, Maria G

AU - Hedenfalk, Ingrid A

AU - Fjällskog, Marie-Louise

AU - Melisi, Davide

AU - Stead, Lucy F

AU - Shaaban, Abeer M

AU - Speirs, Valerie

N1 - This study was funded by Yorkshire Cancer Research (grant L278). Breast Cancer Now (formerly Breast Cancer Campaign, grant 2007MayPR02) provided funding for the accrual and construction of the MBC TMAs. The Breast Cancer Research Trust contributed toward costs of genomic analysis. This work was partially supported by grants from the Italian Association for Cancer Research and the Swedish Cancer Society. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

PY - 2017/5

Y1 - 2017/5

N2 - Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar.Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico Biomarkers were immunohistochemically assessed in 697 MBCs (n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor.Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed (P = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival.Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required. Clin Cancer Res; 23(10); 2575-83. ©2016 AACR.

AB - Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar.Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico Biomarkers were immunohistochemically assessed in 697 MBCs (n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor.Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed (P = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival.Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required. Clin Cancer Res; 23(10); 2575-83. ©2016 AACR.

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KW - Aged

KW - Aged, 80 and over

KW - Biomarkers, Tumor

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KW - Breast Neoplasms, Male

KW - Disease-Free Survival

KW - Eukaryotic Initiation Factor-4E

KW - Everolimus

KW - Female

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Imidazoles

KW - Male

KW - Middle Aged

KW - Peptide Initiation Factors

KW - Prognosis

KW - Quinolines

KW - RNA-Binding Proteins

KW - Sex Characteristics

KW - Transcriptome

KW - Journal Article

UR - http://eprints.whiterose.ac.uk/109588/

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DO - 10.1158/1078-0432.CCR-16-1952

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C2 - 27986751

SN - 1078-0432

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ER -

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

Abstract

Bibliographical note

Keywords

UN SDGs

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Valerie Speirs

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A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Profiles

Valerie Speirs

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