Lianne Koens1, Peter M van de Ven2, Nathalie J Hijmering3, Marie J Kersten4, Arjan Diepstra5, Martine Chamuleau6, Daphne de Jong3. 1. Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands. 2. Department of Epidemiology and Biostatistics, VU Medical Center, Amsterdam, the Netherlands. 3. Department of Pathology, VU Medical Center, Amsterdam, the Netherlands. 4. Department of Hematology, Academic Medical Center, Amsterdam, the Netherlands. 5. Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. 6. Department of Hematology, VU Medical Center, Amsterdam, the Netherlands.
Abstract
AIMS: CD30 immunohistochemistry (IHC) in malignant lymphoma is used for selection of patients in clinical trials using brentuximab vedotin, an antibody drug-conjugate targeting the CD30 molecule. For reliable implementation in daily practice and meaningful selection of patients for clinical trials, information on technical variation and interobserver reproducibility of CD30 immunohistochemistry (IHC) staining is required. METHODS AND RESULTS: We conducted a three-round reproducibility assessment of CD30 scoring for categorised frequency and intensity, including a technical validation, a 'live polling' pre- and post-instruction scoring round and a web-based round including individual scoring with additional IHC information to mimic daily diagnostic practice. Agreement in all three scoring rounds was poor to fair (κ = 0.12-0.35 for CD30-positive tumour cell percentage and κ = 0.16-0.41 for staining intensity), even when allowing for one category of freedom in percentage of tumour cell positivity (κ = 0.30-0.61). The first round with CD30 staining performed in five independent laboratories showed objective differences in staining intensity. In the second round, approximately half the pathologists changed their opinion on CD30 frequency after a discussion on potential pitfalls, highlighting hesitancy in decision-making. Using fictional cut-off points for percentage of tumour cell positivity, agreement was still suboptimal (κ = 0.35-0.60). CONCLUSIONS: Lack of agreement in cases with heterogeneous expression is shown to influence patient eligibility for treatment with brentuximab vedotin, both in clinical practice and within the context of clinical trials, and limits the potential predictive value of the relative frequency of CD30-positive neoplastic cells for clinical response.
AIMS: CD30 immunohistochemistry (IHC) in malignant lymphoma is used for selection of patients in clinical trials using brentuximab vedotin, an antibody drug-conjugate targeting the CD30 molecule. For reliable implementation in daily practice and meaningful selection of patients for clinical trials, information on technical variation and interobserver reproducibility of CD30 immunohistochemistry (IHC) staining is required. METHODS AND RESULTS: We conducted a three-round reproducibility assessment of CD30 scoring for categorised frequency and intensity, including a technical validation, a 'live polling' pre- and post-instruction scoring round and a web-based round including individual scoring with additional IHC information to mimic daily diagnostic practice. Agreement in all three scoring rounds was poor to fair (κ = 0.12-0.35 for CD30-positive tumour cell percentage and κ = 0.16-0.41 for staining intensity), even when allowing for one category of freedom in percentage of tumour cell positivity (κ = 0.30-0.61). The first round with CD30 staining performed in five independent laboratories showed objective differences in staining intensity. In the second round, approximately half the pathologists changed their opinion on CD30 frequency after a discussion on potential pitfalls, highlighting hesitancy in decision-making. Using fictional cut-off points for percentage of tumour cell positivity, agreement was still suboptimal (κ = 0.35-0.60). CONCLUSIONS: Lack of agreement in cases with heterogeneous expression is shown to influence patient eligibility for treatment with brentuximab vedotin, both in clinical practice and within the context of clinical trials, and limits the potential predictive value of the relative frequency of CD30-positive neoplastic cells for clinical response.
Authors: Angeles Alvarez Secord; Kirsten Bell Burdett; Kouros Owzar; David Tritchler; Alexander B Sibley; Yingmiao Liu; Mark D Starr; J Chris Brady; Heather A Lankes; Herbert I Hurwitz; Robert S Mannel; Krishnansu S Tewari; David M O'Malley; Heidi Gray; Jamie N Bakkum-Gamez; Keiichi Fujiwara; Matthew Boente; Wei Deng; Robert A Burger; Michael J Birrer; Andrew B Nixon Journal: Clin Cancer Res Date: 2020-01-09 Impact factor: 12.531