Abstract 7P
Background
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.
Methods
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.
Results
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).
Conclusions
The standardized HER2DX ERBB2 mRNA score predicts the clinical status of HER2 (positive, low and zero) in BC.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
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. Vidal Losada: Financial Interests, Personal, Advisory Board: Novartis/Pfizer, Roche, Pfizer, AstraZeneca/Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Novartis/Pfizer, Roche/Genentech, AstraZeneca/Daiichi Sankyo, Gilead Sciences; Financial Interests, Personal, Other, Travel, Accommodations, expenses: Pfizer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Gilead Sciences. M. Bellet-Ezquerra: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Lilly, Stemline-Menarini; Other, Speaker'sBureau and Travel Expenses: Pfizer; Other, Speaker's Bureau: Novartis, Lilly. J.A. Puig-Butille: Financial Interests, Personal, Invited Speaker: ThermoFisher; Financial Interests, Personal, Funding: CareDX. S. 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. Tolaney: Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Novartis, Gilead, Genentech/Roche, Eisai, Sanofi, Seagen, Daiichi Sankyo, 4D Pharma, ARC Therapeutics; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, Mersana Therapeutics, Ellipses Pharma; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory Board participation: Zentalis, OncXerna, Myovant, Bayer, Zetagen, Infinity Therapeutics, Umoja Biopharma; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline; Financial Interests, Personal, Other, Consulting: Aadi BioPharma; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pfizer, Sanofi, Seagen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Invited Speaker: CytomX. 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.