# Genomic characterization of metastatic breast cancers

Source: https://onco.cc/key-papers/paper-bertucci-metastatic-breast-genomics-nature-2019/  
OnCo record `paper-bertucci-metastatic-breast-genomics-nature-2019` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Sequencing 617 metastatic breast cancers showed they carry more mutations and more clonal diversity than early tumours, and that metastatic triple-negative cancers have somatic loss of both copies of a homologous recombination gene in 7% against 2% of early ones.

## Summary

The landscape of somatic alterations was investigated in 617 metastatic breast cancers. Nine driver genes (TP53, ESR1, GATA3, KMT2C, NCOR1, AKT1, NF1, RIC8A, RB1) were more frequently mutated in hormone receptor-positive, HER2-negative metastatic cancers (381) than in early cancers from TCGA, with 18 enriched amplicons and increased mutational signatures S2, S3, S10, S13 and S17; TP53, RB1 and NF1 mutations and S10, S13 and S17 marked poor outcome. Metastatic TNBCs showed an increased frequency of somatic biallelic loss-of-function mutations in homologous recombination DNA repair genes compared with early TNBC (7% versus 2%). Metastatic cancers showed increased mutational burden and clonal diversity.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Nature
- Year: 2019
- DOI: 10.1038/s41586-019-1056-z
- Authors: Bertucci F, Ng CKY, Patsouris A, et al.
- Findings: Metastatic TNBC: somatic biallelic homologous recombination gene loss 7% versus 2% in early TNBC.; Metastatic tumours carry higher mutational burden and clonal diversity than early tumours.; TP53, RB1 and NF1 mutations and signatures S10, S13, S17 mark poor outcome in HR-positive metastatic disease.
- What it means: Re-biopsy and re-sequencing at relapse can find repair defects and a higher mutation burden that the primary did not show, which matters for PARP inhibitor and immunotherapy eligibility in metastatic TNBC.
- Caveats: French SAFIR and MOSCATO programmes; patients heavily pretreated.; The TNBC subset was small relative to the hormone receptor-positive group.

## Sources

- Bertucci et al., Nature 2019: genomic characterisation of 617 metastatic breast cancers: https://doi.org/10.1038/s41586-019-1056-z
- PubMed: https://pubmed.ncbi.nlm.nih.gov/31118521/

## Connected records

- cancers: [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/), [Metastatic triple-negative breast cancer](https://onco.cc/cancers/tnbc-metastatic/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- targets: [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [NF1 (neurofibromin)](https://onco.cc/targets/nf1/), [RB1](https://onco.cc/targets/rb1/), [TP53](https://onco.cc/targets/tp53/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [Double-strand break repair: HR versus end joining](https://onco.cc/pathways/homologous-recombination-repair/)
- terms: [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/)
- people: [Fabrice André](https://onco.cc/people/fabrice-andre/)
- journals: [Nature](https://onco.cc/journals/nature/)
- biomarkers: [Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations](https://onco.cc/biomarkers/brca-somatic/)

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