# Discovery of biomarkers predictive of GSI response in triple-negative breast cancer and adenoid cystic carcinoma

Source: https://onco.cc/key-papers/paper-stoeck-notch-rearrangements-tnbc-cancer-discov-2014/  
OnCo record `paper-stoeck-notch-rearrangements-tnbc-cancer-discov-2014` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Rearrangements that lock the NOTCH1 or NOTCH2 receptor on were found in 6 of 66 triple-negative breast cancers and no other solid tumour, and only the NOTCH1-rearranged models responded to a gamma-secretase inhibitor.

## Summary

Next-generation sequencing of a large collection of solid tumours identified NOTCH1 and NOTCH2 rearrangements leading to constitutive activation confined to TNBC (6 of 66). TNBC cell lines with NOTCH1 rearrangements and high activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor MRK-003 alone and with paclitaxel in vitro and in vivo; NOTCH2-rearranged lines were resistant. N1-ICD staining in xenografts correlated with response and HES4 expression with patient outcome. Activating NOTCH1 point mutations were also found in adenoid cystic carcinoma.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Cancer Discovery
- Year: 2014
- DOI: 10.1158/2159-8290.CD-13-0830
- Authors: Stoeck A, Lejnine S, Truong A, et al.
- Findings: NOTCH1/2 activating rearrangements in 6 of 66 TNBCs (9%), confined to TNBC.; NOTCH1-rearranged models sensitive to gamma-secretase inhibition; NOTCH2-rearranged resistant.
- What it means: NOTCH is a real but small driver segment in TNBC with a receptor-specific drug response, which is why NOTCH-directed trials require rearrangement or N1-ICD testing rather than treating all TNBC.
- Caveats: Small TNBC series; clinical gamma-secretase inhibitor trials have not delivered an approval.; Rearrangements need RNA or whole-genome methods that DNA panels can miss.

## Sources

- Stoeck et al., Cancer Discov 2014: NOTCH1 and NOTCH2 rearrangements in 6 of 66 TNBCs: https://doi.org/10.1158/2159-8290.CD-13-0830
- PubMed: https://pubmed.ncbi.nlm.nih.gov/25104330/

## Connected records

- cancers: [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- targets: [Gamma-secretase (PSEN1)](https://onco.cc/targets/gamma-secretase/), [NOTCH1](https://onco.cc/targets/notch1/)
- pathways: [Notch signalling](https://onco.cc/pathways/notch/)
- journals: [Cancer Discovery](https://onco.cc/journals/cancer-discovery/)

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