title: Metastatic progression of breast cancer: insights from 50 years of autopsies.
abstract: There remain no clear guidelines for the optimal management of patients with metastatic breast cancer. To better understand its natural history, we undertook a detailed examination of 197 autopsies performed on women who died of breast cancer. We reviewed clinical, treatment and pathological aspects of all cases and, additionally, pathological features and biomarker expression (ER, PgR, HER2, EGFR, p53, Ki67, c-Kit, CK AE1/AE3) were assessed in detail for the primary tumour and matched metastases for 55 of the cases. Genomes of the primary tumour and multiple metastases were analysed by array-based comparative genomic hybridization for six cases(##) . 945 metastatic deposits were identified, with a median of four/patient. The most common organs involved were lung/pleura (80%), bone (74%), liver (71%) and non-axillary lymph nodes (55%). Major findings included: (a) patients with CNS metastases were more likely to have bone metastases (p < 0.013); (b) younger age was associated with metastasis to the liver (≤ 49 years; p < 0.001) and to gynaecological organs (≤ 49 years; p = 0.001); (c) surgical excision of the primary tumour was associated with metastasis to the liver (p = 0.002); and (d) ER and PgR showed down-regulation during progression in a non-random manner, particularly in lung/pleura (ER; p < 0.001), liver and bone metastases. Genomic analysis revealed DNA copy number variation between the primary tumour and metastases (e.g. amplification of 2q11.2-q12.1 and 10q22.2-q22.3) but little variation between metastases from the same patient. In summary, the association of CNS and bone metastases, liver and gynaecological metastases in young women and the risk of liver metastases following surgery have important implications for the management of patients with breast cancer. Clonal heterogeneity of the primary tumour is important in developing metastatic propensity and the change in tumour phenotype during progression/colonization highlights the importance of sampling metastatic disease for optimal treatment strategies.
authors.affiliation: The University of Queensland, UQ Centre for Clinical Research, Herston, Brisbane, QLD, Australia; Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; The University of Queensland, School of Medicine, Herston, Brisbane, QLD, Australia.
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Cummings
authors.forename: Peter T
authors.initials: PT
authors.lastname: Simpson
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Reid
authors.forename: Janani
authors.initials: J
authors.lastname: Jayanthan
authors.forename: Joanna
authors.initials: J
authors.lastname: Skerman
authors.forename: Sarah
authors.initials: S
authors.lastname: Song
authors.forename: Amy E
authors.initials: AE
authors.lastname: McCart Reed
authors.forename: Jamie R
authors.initials: JR
authors.lastname: Kutasovic
authors.forename: Adrienne L
authors.initials: AL
authors.lastname: Morey
authors.forename: Louise
authors.initials: L
authors.lastname: Marquart
authors.forename: Peter
authors.initials: P
authors.lastname: O'Rourke
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Lakhani
mesh_terms: D000367:Age Factors; D001344:Autopsy; D014408:Biomarkers, Tumor / Q000378:metabolism; D001859:Bone Neoplasms / Q000235:genetics / Q000401:mortality / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D016543:Central Nervous System Neoplasms / Q000235:genetics / Q000401:mortality / Q000556:secondary*; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005833:Genital Neoplasms, Female / Q000235:genetics / Q000401:mortality / Q000556:secondary*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000401:mortality / Q000556:secondary*; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality / Q000556:secondary*; D008207:Lymphatic Metastasis; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011793:Queensland / Q000453:epidemiology; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor
keywords: autopsy; breast cancer; intratumour heterogeneity; metastasis; pathology; treatment