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

Matthew P Humphries, Sree Sundara Rajan, Alastair Droop, Charlotte Suleman, Carmine Carbone, Cecilia Nilsson, Hedieh Honarpisheh, Gábor Cserni, Jo Dent, Laura Fulford, Lee B Jordan, J Louise Jones, Rani Kanthan, Maria Litwiniuk, Anna Di Benedetto, Maria 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 Stead, Abeer Shaaban, Valerie Speirs

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    Abstract

    Purpose: Breast cancer (BC) affects both genders, but is understudied in men. Although still rare, male BC 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 BC 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 post-treatment samples from a male BC patient receiving Everolimus and PI3K/mTOR inhibitor.

    Results: Gender-specific gene expression patterns were identified. eIF transcripts were up-regulated 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 co-expressed (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); co-expression 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 male BC patients overexpressing eIF4E and eIF5. With mTOR inhibitors which target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required.

    Original languageEnglish
    Pages (from-to)2575-2583
    Number of pages14
    JournalClinical Cancer Research
    Volume23
    Issue number10
    Early online date16 Dec 2016
    DOIs
    Publication statusPublished - May 2017

    Keywords

    • breast cancer
    • genomics
    • eIF
    • survival
    • mTOR inhibitor

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