What does a FISH (Fluorescence In Situ Hybridization) negative result mean for breast cancer (CA)?

FISH Negative Breast Cancer: Definition and Clinical Implications

FISH negative breast cancer refers to breast tumors that do not show amplification of the HER2 gene when tested by Fluorescence In Situ Hybridization (FISH), indicating these tumors are HER2-negative and will not benefit from HER2-targeted therapies such as trastuzumab or lapatinib. 1

Definition and Diagnostic Criteria

FISH is considered the gold standard method for determining HER2 status in breast cancer due to its accuracy and reliability. According to established guidelines:

• FISH negative breast cancer is defined as having a HER2/CEP17 ratio of less than 1.8 or an average of fewer than 4 copies of HER2 gene per nucleus 1
• This contrasts with FISH positive results (HER2/CEP17 ratio > 2.2 or > 6 HER2 gene copies per nucleus) 1
• An equivocal range exists for FISH results with ratios between 1.8-2.2 or average gene copy numbers between 4.0-6.0 1

Clinical Significance

FISH negative status has important therapeutic implications:

• Patients with FISH negative metastatic breast cancer show lack of responsiveness to HER2-targeted therapies including trastuzumab and lapatinib 1
• Only patients with FISH positive breast cancers demonstrate significant improvement in outcomes when receiving HER2-targeted therapies 1
• FISH negative status helps avoid unnecessary treatment with expensive targeted therapies that would provide no benefit 1

Comparison with IHC Testing

While both FISH and Immunohistochemistry (IHC) are used to determine HER2 status, FISH is considered more reliable:

• DNA is less affected by tissue processing artifacts than proteins, resulting in fewer experimental errors with FISH testing 1
• IHC is associated with both false-negative and false-positive results due to factors including:
  • Preanalytic tissue processing issues
  • Inconsistent antibody performance
  • Antigen retrieval techniques
  • Subjective interpretation 1
• FISH shows higher concordance with clinical outcomes in predicting response to HER2-targeted therapies 1

Testing Algorithm and Interpretation

Current guidelines recommend the following approach:

• IHC is often used as initial screening, with FISH performed for equivocal (IHC 2+) cases 1
• FISH negative results (ratio < 1.8) in combination with IHC 0 or 1+ confirm HER2-negative status 1
• A small percentage (1.5-6.9%) of IHC negative cases may actually be FISH positive, representing potentially missed opportunities for HER2-targeted therapy 2, 3
• When IHC and FISH results are discordant, FISH is generally considered more reliable for determining treatment decisions 1, 3

Importance of Accurate Testing

Accurate HER2 status determination is critical for appropriate treatment selection:

• False negative results may deprive patients of potentially beneficial HER2-targeted therapy 1, 2
• False positive results may expose patients to unnecessary toxicity and costs of ineffective treatment 1
• Laboratories should implement rigorous quality control measures to ensure testing accuracy 1
• Proper tissue handling is essential, with specimens fixed in 10% neutral buffered formalin for 6-48 hours 1

Recent Developments

• Next-generation sequencing (NGS) is emerging as an alternative method for detecting HER2 amplification 2, 4
• NGS can simultaneously detect somatic mutations and HER2 amplification, providing comprehensive genetic profiling 2
• Some studies have shown high concordance between NGS and FISH for determining HER2 status 2

In summary, FISH negative breast cancer represents tumors without HER2 gene amplification that will not benefit from HER2-targeted therapies. Accurate determination of HER2 status through reliable testing methods is crucial for appropriate treatment selection and optimal patient outcomes.