title: Discordant assessment of tumor biomarkers by histopathological and molecular assays in the EORTC randomized controlled 10041/BIG 03-04 MINDACT trial breast cancer : Intratumoral heterogeneity and DCIS or normal tissue components are unlikely to be the cause of discordance.
abstract: Accurate identification of breast cancer patients most likely to benefit from adjuvant systemic therapies is crucial. Better understanding of differences between methods can lead to an improved ER, PgR, and HER-2 assessment. The purpose of this preplanned translational research is to investigate the correlation of central IHC/FISH assessments with microarray mRNA readouts of ER, PgR, and HER-2 status in the MINDACT trial and to determine if any discordance could be attributed to intratumoral heterogeneity or the DCIS and normal tissue components in the specimens. MINDACT is an international, prospective, randomized, phase III trial investigating the clinical utility of MammaPrint in selecting patients with early breast cancer for adjuvant chemotherapy (n = 6694 patients). Gene-expression data were obtained by TargetPrint; IHC and/or FISH were assessed centrally (n = 5788; 86 %). Macroscopic and microscopic evaluation of centrally submitted FFPE blocks identified 1427 cases for which the very same sample was submitted for gene-expression analysis. TargetPrint ER had a positive agreement of 98 %, and a negative agreement of 95 % with central pathology. Corresponding figures for PgR were 85 and 94 % and for HER-2 72 and 99 %. Agreement of mRNA versus central protein was not different when the same or a different portion of the tumor tissue was analyzed or when DCIS and/or normal tissue was included in the sample subjected to mRNA assays. This is the first large analysis to assess the discordance rate between protein and mRNA analysis of breast cancer markers, and to look into intratumoral heterogeneity, DCIS, or normal tissue components as a potential cause of discordance. The observed difference between mRNA and protein assessment for PgR and HER-2 needs further research; the present analysis does not support intratumoral heterogeneity or the DCIS and normal tissue components being likely causes of the discordance.
authors.affiliation: Department of Pathology, European Institute of Oncology and University of Milan, Via Ripamonti 435, 20141, Milan, Italy. giuseppe.viale@ieo.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.affiliation: Department of Statistics, European Organization for Research and Treatment of Cancer, Brussels, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Slaets
authors.affiliation: Medical Affairs, Agendia, Amsterdam, The Netherlands.
authors.forename: Femke A
authors.initials: FA
authors.lastname: de Snoo
authors.affiliation: Department of Statistics, European Organization for Research and Treatment of Cancer, Brussels, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Bogaerts
authors.affiliation: Department of Pathology, European Institute of Oncology and University of Milan, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Leila
authors.initials: L
authors.lastname: Russo
authors.affiliation: Medical Affairs, Agendia, Amsterdam, The Netherlands.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: van't Veer
authors.affiliation: Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Emiel J T
authors.initials: EJ
authors.lastname: Rutgers
authors.affiliation: Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Piccart-Gebhart
authors.affiliation: Medical Affairs, Agendia, Amsterdam, The Netherlands.
authors.forename: Lisette
authors.initials: L
authors.lastname: Stork-Sloots
authors.affiliation: Department of Pathology, European Institute of Oncology and University of Milan, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dell'Orto
authors.affiliation: Medical Affairs, Agendia, Amsterdam, The Netherlands.
authors.forename: Annuska M
authors.initials: AM
authors.lastname: Glas
authors.affiliation: Breast Unit, Champalimaud Cancer Center, Lisbon, Portugal.
authors.forename: Fatima
authors.initials: F
authors.lastname: Cardoso
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011960:Receptors, Estrogen / Q000096:biosynthesis* / Q000235:genetics; D011980:Receptors, Progesterone / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human
keywords: Breast cancer; Concordance; ER; Gene expression; HER2; Hormone receptor; IHC/FISH; PgR; TargetPrint; Tumor heterogeneity
references.citation: J Clin Oncol. 2006 Oct 1;24(28):4611-9
references.pmid: 17008703
references.citation: J Clin Oncol. 2007 Nov 20;25(33):5287-312
references.pmid: 17954709
references.citation: J Clin Oncol. 2008 May 20;26(15):2473-81
references.pmid: 18487567
references.citation: Clin Cancer Res. 2009 Nov 15;15(22):7003-11
references.pmid: 19887485
references.citation: J Clin Oncol. 2010 Jun 1;28(16):2784-95
references.pmid: 20404251
references.citation: J Clin Oncol. 2010 Oct 1;28(28):4300-6
references.pmid: 20697093
references.citation: Breast Cancer Res. 2015;17(1):133
references.pmid: 26429296
references.citation: J Clin Oncol. 2011 Nov 10;29(32):4279-85
references.pmid: 21990395
references.citation: Eur J Cancer. 2011 Dec;47(18):2742-9
references.pmid: 22051734
references.citation: J Clin Oncol. 2012 Mar 1;30(7):729-34
references.pmid: 22291085
references.citation: Mod Pathol. 2012 Jun;25(6):869-76
references.pmid: 22301704
references.citation: J Clin Oncol. 2013 Nov 1;31(31):3997-4013
references.pmid: 24101045
references.citation: Ann Oncol. 2014 Apr;25(4):816-23
references.pmid: 24667714
references.citation: Clin Cancer Res. 2010 Nov 1;16(21):5222-32
references.pmid: 20837693