title: Male breast cancer precursor lesions: analysis of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program.
abstract: In men, data regarding breast cancer carcinogenesis are limited. The aim of our study was to describe the presence of precursor lesions adjacent to invasive male breast cancer, in order to increase our understanding of carcinogenesis in these patients. Central pathology review was performed for 1328 male breast cancer patients, registered in the retrospective joint analysis of the International Male Breast Cancer Program, which included the presence and type of breast cancer precursor lesions. In a subset, invasive breast cancer was compared with the adjacent precursor lesion by immunohistochemistry (n=83) or targeted next generation sequencing (n=7). Additionally, we correlated the presence of ductal carcinoma in situ with outcome. A substantial proportion (46.2%) of patients with invasive breast cancer also had an adjacent precursor lesion, mainly ductal carcinoma in situ (97.9%). The presence of lobular carcinoma in situ and columnar cell-like lesions were very low (<1%). In the subset of invasive breast cancer cases with adjacent ductal carcinoma in situ (n=83), a complete concordance was observed between the estrogen receptor, progesterone receptor, and HER2 status of both components. Next generation sequencing on a subset of cases with invasive breast cancer and adjacent ductal carcinoma in situ (n=4) showed identical genomic aberrations, including PIK3CA, GATA3, TP53, and MAP2K4 mutations. Next generation sequencing on a subset of cases with invasive breast cancer and an adjacent columnar cell-like lesion showed genomic concordance in two out of three patients. A multivariate Cox model for survival showed a trend that the presence of ductal carcinoma in situ was associated with a better overall survival, in particular in the Luminal B HER2+ subgroup. In conclusion, ductal carcinoma in situ is the most commonly observed precursor lesion in male breast cancer and its presence seems to be associated with a better outcome, in particular in Luminal B HER2+ cases. The rate of lobular carcinoma in situ and columnar cell-like lesions adjacent to male breast cancer is very low, but our findings support the role of columnar cell-like lesions as a precursor of male breast cancer.
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Shusma C
authors.initials: SC
authors.lastname: Doebar
authors.affiliation: The European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Slaets
authors.affiliation: Breast Unit, Champalimaud Clinical Center/Champalimaud Foundation, Lisbon, Portugal.
authors.forename: Fatima
authors.initials: F
authors.lastname: Cardoso
authors.affiliation: Departments of Health Services Research and Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sharon H
authors.initials: SH
authors.lastname: Giordano
authors.affiliation: Transformative Pathology, Ontario Institute for Cancer Research, Toronto, Canada & University of Edinburgh, Scotland, UK.
authors.forename: John Ms
authors.initials: JM
authors.lastname: Bartlett
authors.affiliation: The European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Tryfonidis
authors.affiliation: BOOG Study Center/Dutch Breast Cancer Research Group, Amsterdam, The Netherlands.
authors.forename: Nizet H
authors.initials: NH
authors.lastname: Dijkstra
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands.|BOOG Study Center/Dutch Breast Cancer Research Group, Amsterdam, The Netherlands.
authors.forename: Caroline P
authors.initials: CP
authors.lastname: Schröder
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.|BOOG Study Center/Dutch Breast Cancer Research Group, Amsterdam, The Netherlands.
authors.forename: Christi J
authors.initials: CJ
authors.lastname: van Asperen
authors.affiliation: Department of Oncology, Swedish Association of Breast Oncologists (SABO), Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Barbro
authors.initials: B
authors.lastname: Linderholm
authors.affiliation: Department of Oncology, Cheltenham General Hospital, Gloucestershire, UK.
authors.forename: Kim
authors.initials: K
authors.lastname: Benstead
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Winan Nm
authors.initials: WN
authors.lastname: Dinjens
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: van Marion
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.|BOOG Study Center/Dutch Breast Cancer Research Group, Amsterdam, The Netherlands.
authors.forename: John Wm
authors.initials: JW
authors.lastname: Martens
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.|BOOG Study Center/Dutch Breast Cancer Research Group, Amsterdam, The Netherlands.
authors.forename: Carolien Hm
authors.initials: CH
authors.lastname: van Deurzen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018567:Breast Neoplasms, Male / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism / Q000473:pathology*; D018275:Carcinoma, Lobular / Q000378:metabolism / Q000473:pathology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human