Evolutionary history of metastatic breast cancer reveals minimal seeding from axillary lymph nodes

Abstract

Metastatic breast cancers are still incurable. Characterizing the evolutionary landscape of these cancers, including the role of metastatic axillary lymph nodes (ALNs) in seeding distant organ metastasis, can provide a rational basis for effective treatments. Here, we have described the genomic analyses of the primary tumors and metastatic lesions from 99 samples obtained from 20 patients with breast cancer. Our evolutionary analyses revealed diverse spreading and seeding patterns that govern tumor progression. Although linear evolution to successive metastatic sites was common, parallel evolution from the primary tumor to multiple distant sites was also evident. Metastatic spreading was frequently coupled with polyclonal seeding, in which multiple metastatic subclones originated from the primary tumor and/or other distant metastases. Synchronous ALN metastasis, a well-established prognosticator of breast cancer, was not involved in seeding the distant metastasis, suggesting a hematogenous route for cancer dissemination. Clonal evolution coincided frequently with emerging driver alterations and evolving mutational processes, notably an increase in apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like-associated (APOBEC-associated) mutagenesis. Our data provide genomic evidence for a role of ALN metastasis in seeding distant organ metastasis and elucidate the evolving mutational landscape during cancer progression.

Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

“…We performed a literature review to identify cohorts with genomic sequencing data from matched normals, primary tumors (P) and metastases (M) from patients with three common cancer types, namely, colorectal 16,17,[19][20][21][22] , lung 23,24 and breast 23,[25][26][27][28][29] (Table S1, Fig. S1).…”

Is Axillary Sentinel Lymph Node Biopsy Required in Patients Who Undergo Primary Breast Surgery

“…Also, a pre-metastatic niche, which can be formed only from the primary tumor, seems to be necessary [27]. The process of metastasis is complex and starts from the primary tumor, not from positive lymph nodes [7,28,29]. …”

Morphologic and Genomic Heterogeneity in the Evolution and Progression of Breast Cancer

“…Thus, there is a clear clonal ancestry during progression, and the early molecular drivers of behaviour and phenotype (e.g., mutations in TP53, PIK3CA, CDH1, GATA3, amplification of MYC, CCND1, ERRB2/HER2) remain prevalent drivers in metastatic deposits [71][72][73][74][76][77][78][79][80]. Despite this, significant intra-patient heterogeneity develops during progression, even in the absence of systemic therapy; this occurs to a greater extent in progression to distant metastases relative to local lymph nodes and is exacerbated by the selective pressures applied during adjuvant therapy [73,77,[81][82][83][84]. Changes in tumour phenotype or in the intrinsic molecular subtype during progression occurs in around 30% of patients (most often involving the down regulation of PR, but may also involve ER and less frequently a change in HER2 status) and may occur in a non-random manner at specific metastatic sites (e.g., lung, liver and bone metastases) [85][86][87][88].…”

“…Mutational signatures found in the primary tumour are also found in metastases; but as with individual gene mutations, the frequencies of individual mutation signatures may also change, with an enrichment in signatures associated with APOBEC enzymatic activity and homologous recombination deficiency being higher in metastases than in primary tumours [75,78,82]. Evidence suggests the acquisition of APOBEC signature maybe a driver of intra tumour heterogeneity and endocrine resistance [17,84,96,97].…”