Do Not Recommend HER2-Targeted Therapy
If confirmatory HER2 FISH testing is negative for HER2 gene amplification, you must not recommend HER2-targeted therapy, assuming there is no apparent histopathologic discordance. 1
Management Algorithm After Negative FISH
Primary Action: Withhold HER2-Targeted Therapy
- The negative FISH result definitively excludes the patient from HER2-directed treatment 1
- Proceed with treatment planning based on other tumor characteristics (hormone receptor status, grade, stage)
Critical Exception: Assess for Histopathologic Discordance
Before finalizing the negative HER2 status, both the pathologist and oncologist must evaluate whether the clinical and pathologic features are concordant with a HER2-negative result 1:
Red flags suggesting potential discordance include:
- High-grade (grade 3) tumor with aggressive clinical behavior 1
- Clinical presentation suggesting HER2-positive or triple-negative disease biology
- Discordant initial IHC result (if IHC 3+ but FISH negative) 2, 3
If discordance is suspected:
- Discuss the need for additional HER2 testing between pathologist and oncologist 1
- Consider retesting on an alternative specimen (different tumor block or metastatic site if available) 1
- The false-negative rate should be minimized given trastuzumab's curative potential in the adjuvant setting 3
Important Caveats About Testing Accuracy
Interlaboratory Variability
Studies demonstrate that 4-8% of cases show discordance between local and central laboratories 2. Critically, the VIRGO study found that specimens initially deemed HER2-negative locally were found HER2-positive centrally in 4% of cases, potentially denying effective therapy to over 7,000 patients annually in the US alone 2.
Single Test Limitations
Reliance on a single negative test is not advisable 2. Among cases centrally determined to be HER2-positive after initial local negative results, 9 of 17 became positive when the alternative testing methodology (IHC or FISH) was performed 2.
Special Consideration: Metastatic Disease
If the patient previously tested HER2-negative in the primary tumor but now presents with disease recurrence showing clinical behavior suggestive of HER2-positive disease, you must specifically consider retesting HER2 on the metastatic site 1. HER2 status can change between primary and metastatic sites.
Quality Assurance Requirement
The laboratory reporting the negative FISH result must maintain ongoing concordance testing demonstrating ≤5% false-negative rate 3. If your laboratory cannot satisfy this criterion, specimens should be sent to a reference laboratory 3.