# HER2 ISH amplified (ERBB2 gene amplification)

Source: https://onco.cc/biomarkers/her2-ish-amplified/  
OnCo record `her2-ish-amplified` (Biomarker). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

ISH counts copies of the HER2 gene in each tumour cell. A ratio of 2 or more against the chromosome 17 control, or 6 or more copies per cell, is amplified and HER2-positive whatever the protein stain showed.

## Summary

In situ hybridisation (fluorescent FISH or chromogenic dual ISH) measures ERBB2 gene copies. Under ASCO/CAP 2018, a HER2/CEP17 ratio >= 2.0 with an average HER2 copy number >= 4.0 per cell is positive (group 1); a ratio < 2.0 with copy number >= 6.0 is positive (group 3); ratio >= 2.0 with copy number < 4.0 (group 2) and ratio < 2.0 with copy number 4.0 to < 6.0 (group 4) need concurrent IHC and are positive only if the IHC is 3+ (or 2+ on recount for group 4 in some readings). Labels for trastuzumab, pertuzumab, trastuzumab emtansine and trastuzumab deruxtecan accept ISH+ as HER2-positive; the FDA list carries the HER2 FISH pharmDx, PathVysion, INFORM HER-2/neu, SPOT-LIGHT CISH and Ventana Dual ISH kits as companion diagnostics.

## Fields

- Kind: Biomarker
- Last checked: 2026-09-23
- Also known as: HER2 ISH+; HER2 FISH positive; ERBB2 amplification; HER2 amplified; HER2/CEP17 ratio >= 2.0; HER2 gene amplification; HER2 Dual ISH
- Tags: biomarker; her2

## Notes

- Colorectal cancer: the HERACLES diagnostic criteria, not the breast or gastric ones, define positivity. A tumour is HER2-positive when intense membranous HER2 staining is present in more than 50% of cells (immunohistochemistry 3+), or immunohistochemistry 2+ with in situ hybridisation confirmation in more than 50% of cells; in the validation, no immunohistochemistry 0 or 1+ case was amplified and silver and fluorescence in situ hybridisation agreed completely (Valtorta 2015). That threshold selects about 5% of RAS wild-type patients (48 of 914 screened for HERACLES) and 2 to 3% of all colorectal cancers. Plasma HER2 copy number, adjusted for tumour fraction, selected patients as well as tissue in TRIUMPH (Nakamura 2021).
- Gallbladder and biliary cancer: ERBB2 amplification confirmed by central ISH was the entry criterion of HERIZON-BTC-01 (Harding 2023). By sequencing, amplification was present in 8% of 260 gallbladder cancer patients alone and 1.5% with a mutation (Mondaca 2024) and in 10.2% of 244 samples in cBioPortal gbc_mskcc_2022. Chromogenic dual ISH found amplification in all IHC 3+ and some 2+ and 1+ tumours (Angerilli 2026).

## Sources

- ASCO/CAP HER2 testing in breast cancer guideline, 2018 focused update (Wolff et al., J Clin Oncol): https://doi.org/10.1200/JCO.2018.77.8738
- FDA: List of FDA-Authorized Companion Diagnostic Devices: https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools

## Connected records

- biomarkers: [HER2 (ERBB2) activating mutation](https://onco.cc/biomarkers/her2-mutation/), [HER2 IHC 2+ (equivocal, reflex to ISH)](https://onco.cc/biomarkers/her2-ihc-2-plus/), [HER2 IHC 3+ (HER2-positive by immunohistochemistry)](https://onco.cc/biomarkers/her2-ihc-3-plus/)
- cancers: [Biliary tract cancer (all types)](https://onco.cc/cancers/biliary-tract-cancer/), [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Early HER2-positive breast cancer](https://onco.cc/cancers/her2-positive-early-breast-cancer/), [Gallbladder cancer](https://onco.cc/cancers/gallbladder/), [HER2-positive breast cancer](https://onco.cc/cancers/breast-her2-positive/), [HER2-positive gastric cancer](https://onco.cc/cancers/gastric-her2-positive/)
- drugs: [HER2 IHC and ISH companion assays (HercepTest, PATHWAY 4B5, HER2 Dual ISH)](https://onco.cc/drugs/her2-testing-assays/), [Pertuzumab](https://onco.cc/drugs/pertuzumab/), [Trastuzumab](https://onco.cc/drugs/trastuzumab/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [Trastuzumab emtansine](https://onco.cc/drugs/trastuzumab-emtansine/)
- terms: [FISH / ISH (in situ hybridisation)](https://onco.cc/terms/fish/), [Gene amplification and copy-number change](https://onco.cc/terms/gene-amplification/), [HER2 testing in biliary tract cancer (IHC, ISH and NGS)](https://onco.cc/terms/her2-testing-in-biliary-cancer/), [HER2-positive (IHC 3+ or ISH-amplified)](https://onco.cc/terms/her2-positive/)
- key papers: [Assessment of a HER2 scoring system for colorectal cancer: results from a validation study](https://onco.cc/key-papers/paper-valtorta-her2-scoring-colorectal-heracles-mod-pathol-2015/), [Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial (TRIUMPH)](https://onco.cc/key-papers/paper-nakamura-triumph-ctdna-pertuzumab-trastuzumab-her2-colorectal-nat-med-2021/), [Clinical and genomic characterization of ERBB2-altered gallbladder cancer: exploring differences between an American and a Chilean cohort](https://onco.cc/key-papers/paper-mondaca-erbb2-gallbladder-us-chile-jco-go-2024/), [Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES)](https://onco.cc/key-papers/paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016/), [HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials](https://onco.cc/key-papers/paper-richman-her2-amplification-quasar-focus-piccolo-j-pathol-2016/), [HER2 status in extrahepatic cholangiocarcinoma and gallbladder carcinoma: concordance between immunohistochemistry and chromogenic in situ hybridization in 140 cases](https://onco.cc/key-papers/paper-angerilli-her2-ihc-cish-biliary-hum-pathol-2026/), [Trastuzumab deruxtecan in patients with HER2-positive advanced colorectal cancer (DESTINY-CRC02): primary results from a multicentre, randomised, phase 2 trial](https://onco.cc/key-papers/paper-destiny-crc02-lancet-oncol-2024/), [Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER)](https://onco.cc/key-papers/paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023/), [Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study](https://onco.cc/key-papers/paper-harding-lancet-oncol/)
- targets: [HER2](https://onco.cc/targets/her2/)

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