Diagnostic Evaluation of HER-2 as a Molecular Target: An Assessment of Accuracy and Reproducibility of Laboratory Testing in Large, Prospective, Randomized Clinical Trials

Abstract

Purpose: To critically assess the accuracy and reproducibility of human epidermal growth factor receptor type 2 (HER-2) testing in outside/local community-based hospitals versus two centralized reference laboratories and its effect on selection of women for trastuzumab (Herceptin)b ased clinical trials. Experimental Design: Breast cancer specimens from 2,600 women were prospectively evaluated by fluorescence in situ hybridization (FISH) for entry into Breast Cancer International Research Group (BCIRG) clinical trials for HER-2-directed therapies. Results: HER-2 gene amplification by FISH was observed in 657 of the 2,502 (26%) breast cancers successfully analyzed. Among 2,243 breast cancers with central laboratory immunohistochemistry (10H8-IHC) analysis, 504 (22.54%) showed overexpression (2+ or 3+). Outside/ local laboratories assessed HER-2 status by immunohistochemistry in 1,536 of these cases and by FISH in 131cases. Overall, the HER-2 alteration status determined by outside/local immunohistochemistry showed a 79% agreement rate [j statistic, 0.56; 95% confidence interval (95% CI), 0.52-0.60], with FISH done by the central laboratories. The agreement rate comparing BCIRG central laboratory 10H8-IHC and outside/local laboratory immunohistochemistry was 77.5% (j statistic, 0.51; 95% CI, 0.46-0.55). Finally, HER-2 status, determined by unspecified FISH assay methods at outside/local laboratories, showed a 92% agreement rate (j statistic, 0.83; 95% CI, 0.73-0.93), with FISH done at the BCIRG central laboratories. Conclusions: Compared with the HER-2 status determined at centralized BCIRG reference laboratories, these results indicate superiority of FISH to accurately and reproducibly assess tumors for the HER-2 alteration at outside/local laboratories for entry to clinical trials.

The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast Cancers

“…Internalization was performed as detailed previously (11). Cells (2,000,000 cells/tube) were incubated for 1 hour at 4 C with 2 mL of 3 mg/mL Alexa Fluor 488 (AF488)-labeled SYD985 or 2 mL of 3 mg/mL Alexa Fluor 488-labeled T-DM1.…”

“…According to these criteria, approximately 20% to 25% of all metastatic breast cancer patients are currently eligible for T-DM1 therapy (9,10). A HER2-targeting drug that has a clinical benefit in patients whose tumor is FISH-negative but has detectable IHC HER2 expression (2þ and 1þ) would at least double that population (10,11).…”

Intraepithelial CD8-positive T lymphocytes predict survival for patients with serous stage III ovarian carcinomas: relevance of clonal selection of T lymphocytes

“…This scenario has been proposed and experimentally supported in the case of HER2/neuexpressing tumour cells in breast carcinomas (Peoples et al, 1995;Wiech et al, 2008, Goodell et al, 2008. Evidence of such a mechanism for TILs in ovarian carcinoma is still sparse (Raspollini et al, 2005;Yang et al, 2007), especially as the rate of HER2/neuexpressing tumour cells varies from 1.9 to 35% (Press et al, 2005). Nevertheless, the identification of clonally restricted TILs represents an important basis for further exploitation and development of immune-based therapies (Sabbatini and Odunsi, 2007), also targeting Her2/neu (Disis et al, 2002).…”

Bispecific Antibodies and Antibody–Drug Conjugates (ADCs) Bridging HER2 and Prolactin Receptor Improve Efficacy of HER2 ADCs

“…The efficacy of T-DM1 has been demonstrated only in patients with HER2 overexpression defined as IHC3 þ (7) or FISH amplification ratio ! 2, which is only about half of metastatic breast cancer patients with detectable IHC HER2 expression (8,9). Thus, there is a need for HER2-directed ADCs that are more effective in patients expressing low/moderate levels of HER2.…”