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Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831
Patrick C Roche1, Vera J Suman, Robert B Jenkins
1Mayo Clinic and Mayo Foundation, Rochester, MN, USA.
Abstract:
The efficacy of trastuzumab for metastases coupled with the relatively poor prognosis of patients with node-positive, HER2-positive breast cancer has led to the evaluation of trastuzumab as an adjuvant therapy. A prospective, randomized, three-arm, phase III trial is being conducted by the Breast Intergroup (N9831) for women with primary, operable, histologically confirmed, node-positive breast carcinoma that strongly overexpresses (3+) HER2 protein and/or displays HER2/neu gene amplification, as determined by local laboratory testing. The protocol requires confirmatory central testing of HER2 status using the HercepTest immunohistochemistry and the Vysis PathVysion fluorescence in situ hybridization (FISH) assays. Tumor specimens from the first 119 patients enrolled in N9831 were centrally tested; 74% were found to be HercepTest 3+ and 66% were found to have HER2 gene amplification. Only six of nine (67%) of the specimens submitted by local laboratories as FISH positive could be confirmed by central assays. The concordance for central HercepTest and central FISH assays was 92%. The poor concordance (74%) between local and central testing for HER2 status has led to modifications in the eligibility criteria for N9831.
Insights
Trastuzumab shows promise as adjuvant therapy for HER2-positive breast cancer. However, discrepancies in HER2 testing between local and central labs necessitate revised eligibility criteria for clinical trials.
Area of Science:
- Oncology
- Clinical Trials
- Molecular Diagnostics
Background:
- Trastuzumab is effective for HER2-positive metastatic breast cancer.
- Patients with node-positive, HER2-positive breast cancer have a poor prognosis.
- Adjuvant trastuzumab is being evaluated to improve outcomes.
Purpose of the Study:
- To evaluate trastuzumab as adjuvant therapy in a phase III trial (N9831).
- To assess HER2 status using central immunohistochemistry (HercepTest) and fluorescence in situ hybridization (FISH).
- To identify discrepancies in local versus central HER2 testing.
Main Methods:
- Prospective, randomized, three-arm, phase III trial (N9831).
- Inclusion criteria: primary, operable, node-positive, HER2-positive (3+ or gene amplification) breast carcinoma.
- Central confirmation of HER2 status via HercepTest and Vysis PathVysion FISH assays.
Main Results:
- Of 119 centrally tested patients, 74% were HercepTest 3+ and 66% had HER2 gene amplification.
- Only 67% of locally FISH-positive specimens were confirmed centrally.
- Central HercepTest and FISH concordance was 92%.
Conclusions:
- Significant discordance (74%) exists between local and central HER2 testing.
- This variability impacts patient eligibility for adjuvant trastuzumab trials.
- Trial eligibility criteria were modified due to testing discrepancies.