# Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis

Source: https://onco.cc/key-papers/paper-bareche-tnbc-multiomic-heterogeneity-ann-oncol-2018/  
OnCo record `paper-bareche-tnbc-multiomic-heterogeneity-ann-oncol-2018` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Applying the Lehmann subtypes to 550 triple-negative tumours from the two biggest breast cancer genome projects showed each subtype has its own mutations: BL1 is TP53-mutant and unstable, LAR carries PIK3CA in more than half, the immunomodulatory type does best and LAR worst.

## Summary

Copy-number, somatic mutation and gene expression data from METABRIC (355) and TCGA (195) gave 550 TNBC samples classified with the TNBCtype tool; 485 were stably classified (BL1 25%, IM 25%, M 21%, LAR 16%, MSL 13%) and 447 had sequencing. TP53 (81%), MUC16 (21%) and PIK3CA (20%) were the most mutated genes. IM was associated with better prognosis (HR 0.68, 95% CI 0.46 to 0.99) and LAR with worse (HR 1.47, 1.0 to 2.14). BL1 was the most genomically unstable subtype with TP53 mutation in 92% and copy-number deletion of BRCA2, MDM2, PTEN, RB1 and TP53. LAR carried a higher mutational burden with PIK3CA (55%), KMT2C (19%), CDH1 (13%), NF1 (13%) and AKT1 (13%) mutations and was 75% HER2-enriched by PAM50. MYC (64%), PIK3CA (51%) and CDK6 (39%) were the most gained or amplified genes. IM showed high expression of PD1, PDL1 and CTLA4. By PAM50, 76% of TNBCs were basal-like, 15% HER2-enriched, 5% normal-like and 2% luminal.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Annals of Oncology
- Year: 2018
- DOI: 10.1093/annonc/mdy024
- Authors: Bareche Y, Venet D, Ignatiadis M, et al.
- Findings: Stable subtypes among 485: BL1 25%, IM 25%, M 21%, LAR 16%, MSL 13%; BL2 did not reproduce.; TP53 81%, MUC16 21%, PIK3CA 20% overall; TP53 92% in BL1; PIK3CA 55%, AKT1 13%, CDH1 13%, KMT2C 19%, NF1 13% in LAR.; IM better (HR 0.68) and LAR worse (HR 1.47) prognosis; MYC gained or amplified in 64%; PAM50 basal-like 76%.
- What it means: This is the sourced bridge between expression subtype and mutation: it tells a clinician that a LAR tumour is the one to sequence for PIK3CA and AKT1, and that immunomodulatory biology is a favourable prognostic group before any immunotherapy.
- Caveats: Retrospective re-analysis of METABRIC (173-gene panel) and TCGA; sequencing depth and gene coverage differ.; Subtype assignment used the online TNBCtype tool; 65 samples were unclassifiable.

## Sources

- Bareche et al., Ann Oncol 2018: integrative multiomic analysis of 550 TNBCs from METABRIC and TCGA: https://doi.org/10.1093/annonc/mdy024
- PubMed: https://pubmed.ncbi.nlm.nih.gov/29365031/
- cBioPortal study brca_metabric (METABRIC, Nature 2012 and Nat Commun 2016; 320 triple-negative samples, 299 on the 173-gene panel): https://www.cbioportal.org/study/summary?id=brca_metabric
- cBioPortal study brca_tcga_pub (TCGA, Nature 2012; 825 samples, 123 recorded ER-, PR- and HER2-negative, 84 of them exome-sequenced): https://www.cbioportal.org/study/summary?id=brca_tcga_pub

## Connected records

- cancers: [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- targets: [AKT](https://onco.cc/targets/akt/), [Androgen receptor](https://onco.cc/targets/androgen-receptor/), [KMT2C](https://onco.cc/targets/kmt2c/), [NF1 (neurofibromin)](https://onco.cc/targets/nf1/), [PIK3CA / PI3K-alpha](https://onco.cc/targets/pik3ca/), [PTEN](https://onco.cc/targets/pten/), [RB1](https://onco.cc/targets/rb1/), [TP53](https://onco.cc/targets/tp53/)
- institutions: [Institut Jules Bordet](https://onco.cc/institutions/institut-jules-bordet/)
- pathways: [MYC](https://onco.cc/pathways/myc/), [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/)
- terms: [PAM50 / intrinsic subtypes](https://onco.cc/terms/pam50/)
- people: [Martine Piccart](https://onco.cc/people/martine-piccart/)
- journals: [Annals of Oncology](https://onco.cc/journals/annals-of-oncology/)
- biomarkers: [AKT1 E17K mutation](https://onco.cc/biomarkers/akt1-e17k/), [PIK3CA mutation](https://onco.cc/biomarkers/pik3ca-hotspot-mutation/)

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