The FDA-Approved Breast Cancer HER2 Evaluation kit (HercepTest; Dako) May Miss Some HER2-Positive Breast Cancers

Frank Schneider, MD; Yulan Jin, MD, PhD; Kevin Van Smaalen, MD; Evin H. Gulbahce, MD; Rachel E. Factor, MD; Xiaoxian Li, MD, PhD

Disclosures

Am J Clin Pathol. 2019;151(5):504-510. 

In This Article

Results

Patient Information and Tumor Characteristics

The information is summarized in Table 1. The median age of the patients was 62.5 years, with a range from 38 to 90 years. The carcinoma diagnoses include invasive ductal carcinoma (24 [46.2%]), lobular carcinoma (five [9.6%]), mixed carcinoma with ductal and lobular features (two [3.8%]), tubular carcinoma (one [1.9%]), and metastatic breast carcinoma (20 [38.5%]). Thirty-three of the 52 cases had metastatic disease either in the axillary lymph node or other organs. Most patients (40 [76.9%]) did not receive chemotherapy before the specimens were collected in this study.

High Discordance Rate Between FISH and the FDA kit in FISH HER2+ Cases

Of the 52 tumors, 22 were HER2+, 29 were negative, and one was equivocal based on FISH results Table 2. Five (22.7%) of the 22 FISH-positive cases were scored as negative (1+) by the FDA kit Image 1. These five cases were reevaluated by another Clinical Laboratory Improvement Amendments–certified reference laboratory using the same FDA kit on sequential unstained slides, and the results were negative in all five cases Table 3. All 22 FISH-positive cases were detected as either positive (3+) or equivocal (2+) by the LDT (Table 2). The characteristics of the five discordant cases are summarized in Table 3. These five cases were still FISH positive by the most current 2018 ASCP/CAP recommendation on HER2 evaluation.[16] All five patients received HER2-targeted therapy and chemotherapy. Three patients had metastatic disease and did not receive surgery; these three patients had a partial or an excellent clinical response. One patient had neoadjuvant therapy and surgery at an outside hospital and reported to have a partial response. The last patient had neoadjuvant therapy, and the tumor showed MD Anderson residual cancer burden III at the time of surgery. All patients were alive during the last follow-up (Table 3).

Image 1.

A representative case that was human epidermal growth factor receptor 2 (HER2) negative by the US Food and Drug Administration (FDA) kit but positive by fluorescent in situ hybridization (FISH) analysis. A representative bone biopsy case that was scored as negative by the FDA approved HercepTest kit, equivocal by the laboratory developed test (LDT), and positive by FISH analysis. A, H&E morphology (x200). B, Immunohistochemistry staining using the HercepTest kit (x200). C, Immunohistochemistry staining using the LDT (x200).

There is a high concordance rate between FISH and the FDA kit in FISH-negative and FISH-equivocal cases. All FISH-negative cases were negative or equivocal by the FDA kit, and the one FISH-equivocal case was equivocal by the FDA kit (Table 2). The overall concordance rate between FISH and the FDA kit was 90.4%.

High Concordance Rate Between FISH and LDT Results

All of the 22 FISH-positive cases were positive or equivocal by the LDT (Table 2). The one FISH-equivocal case was equivocal by LDT. All of the 29 FISH HER2-negative cases were scored as negative or equivocal by the LDT (Table 2). The overall concordance rate between FISH and LDT was 100%, which was above the 95% threshold desired by the ASCO/CAP guidelines.

High Number of LDT-equivocal Cases was Scored as Negative by the FDA kit

There were 38 cases scored as equivocal by the LDT, of which 17 (44.7%) were scored as negative by the FDA kit Table 4. The five HER2 FISH-positive but FDA kit–negative cases were part of the 17 cases. There were 22 cases scored as equivocal by the FDA kit. One of the 22 (4.5%) cases was negative by the LDT; this case was FISH negative with a HER2/CEP17 ratio of 1.1.

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