Metastatic progression of breast cancer: insights from 50 years of autopsies.
Bottom Line: 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.
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.Show MeSH
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Mentions: Most copy number alterations (CNAs; deletions, gains and amplifications) were shared between the primary tumour and its metastases, reflecting the close clonal relationship of all tumour foci within a case (Figure 1; see also supplementary material, Figures S3–S7). The majority of CNAs therefore occurred as early events in the major clonal expansion of the primary tumour. However, evidence of clonal diversity was observed between the primary tumour and its corresponding metastases in four cases. For example, in case 7, focal amplification of 2q11.2–q12.1 was detected in the primary tumour but not in the metastases, and amplification of 10q22.2–q22.3 was identified in the metastases but not in the primary tumour. FISH analysis demonstrated that this clonal heterogeneity occurred within the primary tumour (Figure 1; see also supplementary material, Figure S2) and that the clone harbouring the 10q22 amplification had spread. Similarly, in other cases, additional CNAs were detected in all the metastases compared with the corresponding primary tumour (see supplementary material, Figures S5–S7), suggesting (as for case 7) that the clonal diversity most likely occurred prior to dissemination. Of these six cases, only one patient received adjuvant chemotherapy, suggesting that the genomic heterogeneity observed was not treatment-induced.
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.