HER2DX ERBB2 mRNA score captures the dynamic range of ERBB2 expression in both HER2-negative and HER2+ breast cancer (BC). In a previous study (Prat et al. EBiomedicine 2022), ERBB2 mRNA predicted clinical HER2+ status with high performance in the validation dataset (n=353; AUC=0.96). Here, we evaluated the ability of HER2DX ERBB2 mRNA to predict HER2+, HER2-low, and HER2-0 status.
Standardized HER2DX was evaluated centrally on formalin-fixed paraffin-embedded tumors from 1,149 samples with HER2+ (n=1,029) vs. HER2-negative status (n=120). We trained a new ERBB2 cutoff (by means of decision trees) to predict HER2-low (n=73) versus HER2-0 (n=47) status, and tested in an independent validation dataset of 110 HER2-negative tumors with known HER2-low (n=60) and HER2-0 (n=50) status. To quantify the diagnostic performance: area under the ROC curve (ROC AUC), global accuracy, positive (PPV) and negative predictive value (NPV) were calculated.
In the HER2+ and HER2-negative dataset (n=1,149), the ROC AUC of ERBB2 mRNA expression to predict HER2+ status was 0.98. The mean ERBB2 expression (in log base 2) in HER2+ and HER2-negative disease was 1.41 and -2.41, respectively (14.1-fold difference). Of note, 0.8% of HER2-negative cases were identified as ERBB2-positive and 9.9% of HER2+ cases were identified as ERBB2 negative. In the HER2-negative training dataset (n=120), the ROC AUC of ERBB2 mRNA expression to predict HER2-low vs. HER2-0 status was 0.80, and a new cutoff was identified with 77.5% accuracy (68.5% PPV and 84.9% NPV). In the independent validation HER2-negative dataset (n=110), the ROC AUC of ERBB2 mRNA expression was 0.77. With the new ERBB2 cutoff, the overall accuracy to predict HER2-low and HER2-0 cases was 65.5% (66.7% PPV and 64.9% NPV). Finally, the mean ERBB2 mRNA expression (in log base 2) in HER2-low and HER2-0 disease was -1.86 and -2.72, respectively (1.8-fold difference).
The standardized HER2DX ERBB2 mRNA score predicts the clinical status of HER2 (positive, low and zero) in BC.
The authors.
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G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer/ AstraZeneca / Veracyte / Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech. M. Oliveira: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo / AstraZeneca, Gilead, Pierre Fabre, Roche, Seagen, iTEOS, Relay Therapeutics; Financial Interests, Personal, Invited Speaker: Gilead, MSD, Novartis, Pfizer, Roche, Seattle Genetics, AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Boehringer-Ingelheim, GSK, Roche, Seattle Genetics, Zenith Epigenetics, Gilead, Ayala Pharmaceuticals; Financial Interests, Invited Speaker: Roche; Non-Financial Interests, Invited Speaker: SOLTI Breast Cancer Research; Other, Travel Grant: Pierre Fabre, Eisai, Gilead, AstraZeneca. M.J. 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Pernas Simon: Financial Interests, Personal, Advisory Board: Seagen, AstraZeneca- Daiichi Sankyo, Pierre-Fabre, Pfizer; Financial Interests, Personal, Invited Speaker: Lilly, Novartis, Eisai, Roche; Financial Interests, Institutional, Invited Speaker: Astra-Zeneca, Novartis, Daiichi Sankyo; Non-Financial Interests, Invited Speaker: SOLTI. C. Bueno Muiño: Financial Interests, Personal, Invited Speaker: Novartis, Daiichi Sankyo, AstraZeneca, GSK; Financial Interests, Personal, Advisory Board: Pfizer. M. Martin Jimenez: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Roche/Genentech, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Lilly, Novartis, Roche/Genentech; Financial Interests, Institutional, Research Grant: Novartis, Roche, Puma; Non-Financial Interests, Invited Speaker: TRIO; Non-Financial Interests, Leadership Role: GEICAM. P. Tarantino: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Daiichi Sankyo. A.G. Waks: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Genentech, Macrogenics, Merck. E.A. Mittendorf: Financial Interests, Personal, Advisory Board: Merck, BioNTech; Financial Interests, Institutional, Research Grant, I have a grant from SU2C funded by Roche/Genentech that supports the conduct of a clinical trial: Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Gilead provides clinical trial support to my institution for a study that I am the PI on: Gilead; Financial Interests, Personal, Invited Speaker: Roche/Genentech, BMS; Non-Financial Interests, Invited Speaker: American Society of Clinical Oncology; Non-Financial Interests, Advisory Role, I serve in an advisory role as a Komen Scholar: Komen for the Cure. S.M. 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J. Cortés: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp& Dohme, GSK, LEUKO, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp& Dohme, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies; Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma B, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pfizer, Gilead, AstraZeneca. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. F. Brasó-Maristany: Financial Interests, Personal, Invited Speaker: Reveal Genomics. All other authors have declared no conflicts of interest.