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 Fjallskog, Davide Melisi, Lucy F Stead, Abeer M. Shaaban, Valerie Speirs

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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; 1-9. (c)2016 AACR.
Original languageUndefined/Unknown
JournalClinical Cancer Research
DOIs
Publication statusPublished - Dec 1 2016

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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. (2016). A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer. Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-16-1952