‘Genetic heterogeneity' in HER2/neu testing by fluorescence in situ hybridization: a study of 2522 cases
Bibliographic record
Abstract
Amplification for the ERBB2 oncogene encoding the HER2/neu protein (HER2) is of predictive and prognostic importance in breast carcinoma. Fluorescence in situ hybridization (FISH) is a widely accepted method for determining HER2 amplification status. A HER2-amplified tumor is defined as having a ratio of HER2 signals to chromosome 17 centromeric probe signals (HER2/CEP17 ratio) exceeding 2.2. However, the presence of scattered cells demonstrating HER2 amplification is of unclear significance. A 2009 panel guideline defined a tumor with 'genetic heterogeneity' as having at least 5% but fewer than 50% of (non-clustered) tumor nuclei with a ratio >2.2. The study objective was to examine the statistical distribution of breast tumors tested by FISH for HER2 amplification, after implementation of this 2009 guideline. We identified 2522 consecutive breast carcinoma cases (2009-2011) tested for HER2 amplification. All cases were tested by FISH using a standard clinical protocol, adhering to established guidelines. For each case, data on cell counts were retrieved electronically. Each tumor was compared with a theoretical normal distribution by quantile-quantile analysis. Of 2522 FISH tests for HER2, 1900 (75%) were non-amplified, 394 (16%) were amplified, and 228 (9%) were HER2-equivocal. A total of 666 (26%) had 'genetic heterogeneity.' Among these 'genetically heterogeneous' cases, the ratio was non-amplified in 430 (64.5%), amplified in 24 (4%), and equivocal in 212 (31.5%). The amplified subpopulation in 'genetically heterogeneous' tumors was larger if the overall ratio was close to 2.2. However, the percentage of nuclei >2.2 in a 'genetically heterogeneous' tumor was not informative of the underlying tumor-cell distribution. We conclude that the proportion of HER2-amplified nuclei within a tumor does not contribute information independent of the actual HER2/CEP17 ratio. Reassessment of the definition of 'genetic heterogeneity' in HER2 testing is warranted.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".