Phylogenetic reconstruction of breast cancer reveals two routes of metastatic dissemination associated with distinct clinical outcome

Abstract

Background: In breast cancer (BC), axillary lymph node (ALN) involvement is one of the strongest adverse prognostic factors. However, it is unclear whether loco-regional lymph node deposits are effectively the root of secondary metastases or only an indicator of competence of the primary tumour to spread to distant organs. Methods: Here, we investigated the evolutionary trajectories of primary tumour, ALN and distant metastasis samples from 16 estrogen-receptor (ER)-positive lymph node-positive BC patients. Low-pass whole genome sequencing was performed to infer somatic copy number aberrations and the phylogenetic profiles for all patients were obtained. Findings: We show that lymph nodes and distant metastases shared a common origin in only 25% of the cases highlighting that the predominant route of metastatic dissemination is the direct seeding of tumour cells from the primary tumour to distant organs, independently of lymph node metastasis. Noticeably, patients sharing a common origin significantly have worse prognosis. Interpretation: Our results shed light on the routes on which tumour cells metastasize and their role in disease progression in ER-positive BC. Funding: This work has received financial support from Les Amis de l'Institut Bordet, MEDIC, the Breast Cancer Research Foundation (BCRF),

The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early Metastasis to Lymph Nodes

“…In addition, lymph nodes formed an independent clade with a few mutations shared between the primary treatment-naïve tumor and other lesions, suggesting that spreading may occur early in these tissues. This same pattern has been reported in other molecular studies [13,32,47]. Clinical and molecular analyses in TNBC and breast cancer have also shown dissemination to lymph nodes from small T1 tumors (<2 cm), and the occurrence of metastatic spread in the early stages of tumor growth [48][49][50].…”

Insights Into Unveiling a Potential Role of Tertiary Lymphoid Structures in Metastasis

“…In 213 samples from 17 patients with colorectal cancer only 35 percent of distant metastases shared a common sub-clonal origin as the LN metastases, which is expected for a cancer that particularly favors hepatic metastasis via the portal vein (Naxerova et al, 2017). However, what is surprising are the findings of Venet et al, who showed that in estrogen receptor positive breast cancer, 75 percent of the distant metastasis did not share a common clonal origin with the axillary LN (Venet et al, 2020).…”

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“…35 Accordingly, clinical evidence of self-seeding 36 whereby a metastatic cell re-infiltrates its primary tumour-and of metastasis-to-metastasis spread 37,38 has been documented, with one such study in HR + breast cancer patients reporting a common origin between lymph node and distant metastases in up to 25% of cases. 39 When do tumour cells disseminate? Early versus late dissemination The first step of the metastatic cascade refers to the ability of cancer cells to escape from the primary tumour.…”