Table 2 Proposed pathology report comments for non-classical HER2 FISH categories

Monosomy

Ratio ≥2.0, HER2 signals/cell<4.0

This invasive cancer has an average CEP17 signal of <2.0 resulting in a HER2/CEP17 ratio≥2.0 by FISH, despite a low average HER2 copy number of<4.0. There is limited data on how these patients respond to HER2-targeted therapy. However, the ASCO/CAP Guideline recommends considering these cases HER2 positive based on limited data from a similar group of patients included in the HERA trials that did not appear to show reduced benefit for trastuzumab. Clinical correlation with other patient factors and the pathologic features of the patient’s cancer (including HER2 by IHC) should be used in this setting when considering treatment with HER2-targeted therapies. Despite uncertainty of benefit, this patient is considered eligible for HER2-targeted therapy based on the eligibility criterion for the first-generation trastuzumab trials and the 2013 ASCO/CAP HER2 Testing Guideline Update.

Low amplified

Ratio ≥2.0, HER2 signals/cell=4.0–5.9

This invasive cancer has a low level of increased HER2 signals (4–6) and a HER2:CEP17 ratio ≥2.0. Although there is limited data to suggest benefit of HER2-targeted therapy in this setting, these patients were considered eligible for the first generation of trastuzumab trials. Clinical correlation with other patient factors and the pathologic features of the patient’s cancer (including HER2 by IHC) should be used in this setting when considering treatment with HER2-targeted therapies. This patient is eligible for HER2-targeted therapy based on the 2013 ASCO/CAP HER2 Testing Guideline Update.

Co-amplified/polysomy

Ratio<2.0, HER2 signals/cell>6.0

This invasive cancer has ≥6.0 mean HER2 signals/cell but also has increased centromere (CEP17) control signals, resulting in a HER2:CEP17 ratio <2.0. Because array-based comparative genomic hybridization (aCGH) studies have shown that true polysomy (duplication of the entire chromosome) is actually rare, whereas gain of the pericentromeric region of chromosome 17 is more commonly observed, the ASCO/CAP Guideline recommends considering these cases HER2 positive. However, there is limited data to indicate if patients receive benefit from HER2-targeted therapy in this setting without overexpression of the HER2 protein by IHC. Clinical correlation with other patient factors and the pathologic features of the patient's cancer (including HER2 by IHC) should be used in this setting when considering treatment with HER2-targeted therapies. This patient is eligible for HER2-targeted therapy based on the 2013 ASCO/CAP HER2 Testing Guideline Update.

Equivocal

Ratio<2.0, HER2 signals/cell=4.0–5.9

This invasive cancer has a negative ratio (<2.0) and an equivocal mean HER2 signals/cell between (≥4 and <6). Common reasons for this include frequent cells with low-level increased HER2 signal cells with coordinate mild increases in the mean CEP17 signals/cell or scattered cells with ≥6 HER2 signals/cell in a non-clustered, scattered distribution.* The 2013 ASCO/CAP HER2 Testing Guideline update recommends reporting these cases as equivocal for HER2 gene amplification. Because of the equivocal results, additional cells were counted by a second independent observer and the results above are an average of the two counts. There is limited data to indicate if patients receive benefit from HER2-targeted therapy in this setting without overexpression of the HER2 protein by IHC. Additional HER2 testing is recommended on additional samples if/when available. Clinical correlation with other patient factors and the pathologic features of the patient's cancer (including HER2 by IHC) should be used in this setting when considering treatment with HER2-targeted therapies.

* Offer an additional comment indicating the pattern seen in the specific case, if any.

Heterogeneous

Clustered amplified population >10%

This invasive cancer has two distinct, clustered subpopulations (heterogeneous) with different HER2 gene status. The ASCO/CAP Guideline recommends reporting heterogeneous cases that have a clustered subpopulation of amplified cells representing>10% of the total as HER2-positive (with results given for both populations present). Because of the presence of clustered heterogeneity, separate counts were performed in the two areas by two independent observers in each cell population. This patient is eligible for HER2-targeted therapy based on the 2013 ASCO/CAP HER2 Testing Guideline update.