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.

Keywords: autopsy; breast cancer; intratumour heterogeneity; metastasis; pathology; treatment.

Figure 1

Clonal nature of metastatic progression. The primary breast tumour and metastases from lymph nodes (axilla and non-axillary), lung, liver and adrenal gland from autopsy case 7 were studied by aCGH. (A) Whole-genome copy number profiles were strikingly similar, indicating a close clonal relationship between tumours during progression. Individual plots for chromosomes 2 (B), 10 (C) and 17 (D) are shown for the primary breast tumour and the lung metastases, which are representative of all metastases, and DNA copy number alterations along chromosome 17 emphasize this clonal relatedness of tumours; arrow in (D) marks the amplification of HER2/ERBB2 and all tumour deposits were HER2 3+ positive (not shown). Array CGH also detected an amplification of 2q11.2–q12.1 in the primary tumour only [arrow in (B)] and an amplification of 10q22.2–q22.3 in all metastases, but not in the primary tumour [arrow in (C)]. FISH analysis indicated that this clonal diversity occurred in the primary tumour: the 2q amplification (green) was restricted to the primary tumour (E, F), but the 10q22 amplification (red) was found in a different subclone (in a different tissue block) of the primary tumour (G, H) and was identified in all metastases (I, J) (see also supplementary material, Figure S2).