title: Disease evolution and heterogeneity in bilateral breast cancer.
abstract: Bilateral breast cancers (BBC) are currently treated as independent tumors arising in the same patient. Herein, we investigated whether BBC indeed evolve independently at the genomic level. We examined paired targeted next generation sequencing genotypes from 155 paraffin tumors corresponding to 76 BBC patients (75 women and one man; 52 concurrent and 24 metachronous), for coding mutations (amino acid changing, minor allele frequency <0.1%) and single nucleotide polymorphism (SNP) zygosity. Germline genotypes were available for 29 patients. Mutations were present in 80 tumors (54/76 patients; 71%), were mostly tumor-private (90%), more frequent in TP53 (19%), PIK3CA (14%), CDH1, GATA3, MLL3. TP53 mutations were more frequent in metachronous tumors (P<0.001); hormone receptor negative (P<0.001); with higher Ki-67 (P=0.002); and, in younger patients (P=0.01). Hypermutated tumors, all TP53 mutated, were diagnosed as the first incidence in 5 patients; their metachronous counterparts were mutation poor without TP53 involvement. Paired tumors shared common mutations at intratumoral frequency >20% in 10/54 comparable BBC (18.5%), 8/10 concurrent. SNP zygosity status was less preserved in metachronous, compared to concurrent disease. Pathogenic germline mutations were present in 10/29 patients, 9 in BRCA1 and one in TP53 (p.Phe341Val, first report in the germline). BBC demonstrated extensive inter- and intra-patient heterogeneity in the present thus far largest series of corresponding paired genotypes. The majority evolve independently and unpredictably, supporting current clinical practice. A considerable minority though, retains clonal origin and may be regarded as a distinct group for therapeutic interventions among concurrent BBC.
authors.affiliation: Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine Thessaloniki, Greece.
authors.forename: Elena
authors.initials: E
authors.lastname: Fountzilas
authors.affiliation: Department of Pathology, Aristotle University of Thessaloniki School of Health Sciences, Faculty of MedicineThessaloniki, Greece; Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of ThessalonikiThessaloniki, Greece.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Kotoula
authors.affiliation: Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens School of Medicine Athens, Greece.
authors.forename: Flora
authors.initials: F
authors.lastname: Zagouri
authors.affiliation: Victor Chang Cardiac Research InstituteDarlinghurst, NSW, Australia; The University of New South WalesKensington, NSW, Australia.
authors.forename: Eleni
authors.initials: E
authors.lastname: Giannoulatou
authors.affiliation: Health Data Specialists Ltd Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Kouvatseas
authors.affiliation: Department of Medical Oncology, Ioannina University Hospital Ioannina, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Pentheroudakis
authors.affiliation: Department of Pathology, Aristotle University of Thessaloniki School of Health Sciences, Faculty of Medicine Thessaloniki, Greece.
authors.forename: Triantafyllia
authors.initials: T
authors.lastname: Koletsa
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki Thessaloniki, Greece.
authors.forename: Mattheos
authors.initials: M
authors.lastname: Bobos
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki Thessaloniki, Greece.
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Papadopoulou
authors.affiliation: Third Department of Medical Oncology, Agii Anargiri Cancer Hospital Athens, Greece.
authors.forename: Epaminontas
authors.initials: E
authors.lastname: Samantas
authors.affiliation: Department of Plastic Surgery, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medine Thessaloniki, Greece.
authors.forename: Efterpi
authors.initials: E
authors.lastname: Demiri
authors.affiliation: First Department of Surgery, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine Thessaloniki, Greece.
authors.forename: Spyros
authors.initials: S
authors.lastname: Miliaras
authors.affiliation: Second Department of Medical Oncology, Metropolitan Hospital Piraeus, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Christodoulou
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki Thessaloniki, Greece.
authors.forename: Sofia
authors.initials: S
authors.lastname: Chrisafi
authors.affiliation: Third Department of Medical Oncology, Hygeia Hospital Athens, Greece.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Razis
authors.affiliation: Molecular Diagnostics Laboratory, INRaSTES, National Centre for Scientific Research Demokritos Athens, Greece.
authors.forename: Florentia
authors.initials: F
authors.lastname: Fostira
authors.affiliation: Oncology Section, Second Department of Internal Medicine, Hippokration Hospital Athens, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Pectasides
authors.affiliation: Breast Unit, National and Kapodistrian University of Athens School of Medicine Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Zografos
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of ThessalonikiThessaloniki, Greece; Aristotle University of ThessalonikiThessaloniki, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
keywords: Bilateral; breast cancer; clonality; coding mutations; concurrent; contralateral; hypermutation; metachronous; targeted next generation sequencing