title: Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease.
abstract: The primary aim was to derive evidence for or against the clinical importance of several biologic processes in patients treated with neoadjuvant chemotherapy (NAC) by assessing expression of selected genes with prior implications in prognosis or treatment resistance. The secondary aim was to determine the prognostic impact in residual disease of the genes' expression.
  
  
  
  Expression levels of 24 genes were quantified by NanoString nCounter on formalin-fixed paraffin-embedded residual tumors from 126 patients treated with NAC and 56 paired presurgical biopsies. The paired t test was used for testing changes in gene expression, and Cox regression and penalized elastic-net Cox Regression for estimating HRs.
  
  
  
  After NAC, 12 genes were significantly up- and 8 downregulated. Fourteen genes were significantly associated with time to recurrence in univariable analysis in residual disease. In a multivariable model, ACACB, CD3D, MKI67, and TOP2A added prognostic value independent of clinical ER(-), PgR(-), and HER2(-) status. In ER(+)/HER2(-) patients, ACACB, PAWR, and ERBB2 predicted outcome, whereas CD3D and PAWR were prognostic in ER(-)/HER2(-) patients. By use of elastic-net analysis, a 6-gene signature (ACACB, CD3D, DECORIN, ESR1, MKI67, PLAU) was identified adding prognostic value independent of ER, PgR, and HER2.
  
  
  
  Most of the tested genes were significantly enriched or depleted in response to NAC. Expression levels of genes representing proliferation, stromal activation, metabolism, apoptosis, stemcellness, immunologic response, and Ras-ERK activation predicted outcome in residual disease. The multivariable gene models identified could, if validated, be used to identify patients needing additional post-neoadjuvant treatment to improve prognosis. Clin Cancer Res; 22(10); 2405-16. ©2016 AACR.
authors.affiliation: Academic Department of Biochemistry, Royal Marsden Hospital, London, United Kingdom. Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. marie.klintman@icr.ac.uk.
authors.forename: Marie
authors.initials: M
authors.lastname: Klintman
authors.affiliation: Academic Department of Biochemistry, Royal Marsden Hospital, London, United Kingdom. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Buus
authors.affiliation: Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Maggie Chon U
authors.initials: MC
authors.lastname: Cheang
authors.affiliation: Breast Unit, Royal Marsden Hospital, London, United Kingdom.
authors.forename: Amna
authors.initials: A
authors.lastname: Sheri
authors.affiliation: Breast Unit, Royal Marsden Hospital, London, United Kingdom.
authors.forename: Ian E
authors.initials: IE
authors.lastname: Smith
authors.affiliation: Academic Department of Biochemistry, Royal Marsden Hospital, London, United Kingdom. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom. Breast Unit, Royal Marsden Hospital, London, United Kingdom.
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D018365:Neoplasm, Residual / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone