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A case-matched gender comparison transcriptomic screen identifies eIF4E and eIF5 as potential prognostic markers in male breast cancer

Humphries, Matthew P.; Rajan, Sreekumar Sundara; Droop, Alastair; Suleman, Charlotte A.B.; Carbone, Carmine; Nilsson, Cecilia; Honarpisheh, Hedieh; Cserni, Gabor; Dent, Jo and Fulford, Laura, et al. (2017) In Clinical Cancer Research 23(10). p.2575-2583
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... (More)

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.

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@article{5539ab5a-95e9-49fe-9799-4fa3f84716be,
  abstract     = {<p>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.</p>},
  author       = {Humphries, Matthew P. and Rajan, Sreekumar Sundara and Droop, Alastair and Suleman, Charlotte A.B. and Carbone, Carmine and Nilsson, Cecilia and Honarpisheh, Hedieh and Cserni, Gabor and Dent, Jo and Fulford, Laura and Jordan, Lee B. and Jones, J. Louise and Kanthan, Rani and Litwiniuk, Maria and Di Benedetto, Anna and Mottolese, Marcella and Provenzano, Elena and Shousha, Sami and Stephens, Mark and Walker, Rosemary A. and Kulka, Janina and Ellis, Ian O. and Jeffery, Margaret and Thygesen, Helene H. and Cappelletti, Vera and Daidone, Maria G. and Hedenfalk, Ingrid A. and Fjällskog, Marie-Louise and Melisi, Davide and Stead, Lucy F. and Shaaban, Abeer M. and Speirs, Valerie},
  issn         = {1078-0432},
  language     = {eng},
  month        = {05},
  number       = {10},
  pages        = {2575--2583},
  publisher    = {American Association for Cancer Research},
  series       = {Clinical Cancer Research},
  title        = {A case-matched gender comparison transcriptomic screen identifies eIF4E and eIF5 as potential prognostic markers in male breast cancer},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-16-1952},
  volume       = {23},
  year         = {2017},
}