Abstract 2O
Background
Recently, HER3 has received attention as new anti-HER3 antibody-drug conjugates (e.g. U3-1402) are showing activity in BC. The most common method to determine HER3 expression is immunohistochemistry (IHC)-based assays. However, technical limitations exist when using IHC, such as different sensitivities of the antibodies and its subjectivity in scoring and cut-off determination. To overcome those limitations, we developed an mRNA-based ERBB3 expression assay using FFPE BC tissues and the Nanostring nCounter platform.
Methods
1,580 FFPE primary BC samples representing all IHC-based subtypes, nCounter-based PAM50 subtypes, and ERBB3 expression were analyzed. Results were compared to an independent cohort, METABRIC dataset, which includes 1,943 BC samples analyzed by the Illumina HT 12 IDATS platform.
Results
Among 1,580 samples, 65% were hormonal receptor positive (HR+) and 18% were HER2+. IHC subtype distribution was as follows: 52% HR+/HER2-, 14% HER2+/HR+, 5% HER2+/HR- and 29% triple-negative (TNBC). PAM50 distribution was: 28% Luminal A, 20% Luminal B, 14% HER2-enriched, 29% Basal-like and 9% Normal-like. The range of ERBB3 mRNA expression had an 18.6-fold difference (i.e. from the lowest to the highest ERBB3 value) and the inter-quartile range was 1.5 (in log2), which equals to a difference in expression of 2.9-fold. Overall, HR+/HER2- or PAM50 Luminal A/B subtypes showed the highest expression compared to the other subtypes. The table shows the proportion in our dataset and METABRIC using quartiles and correlation coefficients (CC). Interestingly, the CC of the proportions between the 2 datasets were very similar. Table: 2O
Comparison of the distribution of tumor samples according to ERBB3 mRNA expression in our in-house (IH) nCounter-based dataset versus METABRIC (MB) dataset. Proportions (%) of tumor samples within each quartile (Q) based on IHC subtype and correlation coefficients between both datasets.
| 1st Q IH/MB | 2nd Q IH/MB | 3rd Q IH/MB | 4st Q IH/MB | Correlation coefficients | |
| HR+/HER2- | 14.3/11.6 | 24.4/22.3 | 28.9/29.5 | 32.4/36.6 | 0.99 |
| HR+/HER2+ | 46.3/28.4 | 28.8/31.1 | 21.6/28.9 | 3.3/10.8 | 0.78 |
| HR-/HER2+ | 17.0/21.1 | 31.2/25.8 | 25.7/24.9 | 26.1/28.8 | 0.72 |
| TNBC | 65.2/48.4 | 19.5/28.8 | 9.8/17.5 | 5.6/5.3 | 0.94 |
Conclusions
High ERBB3 mRNA gene expression is observed across all subtypes of BC, although it predominates in HR+/HER2- disease. The assay using FFPE tissues is feasible and reliable. The predictive value of this biomarker will be prospectively tested in the upcoming SOLTI-1805 TOT-HER3 window trial using the U3-1402 anti-HER3 antibody-drug conjugate.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
SOLTI Breast Cancer Group.
Funding
Pas a Pas (AP), Save the Mama (AP). Becas FSEOM para Formación en Investigación en Centros de Referencia en el Extranjero 2018 (TP).
Disclosure
M. Oliveira: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Philips Healthcare; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech/Roche; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Research grant/Funding (institution): Immunomedics; Honoraria (self), Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy, Research grant/Funding (institution): GSK; Research grant/Funding (institution): Boehringer-Ingelheim; Advisory/Consultancy, Research grant/Funding (institution): Puma Biotechnology; Research grant/Funding (institution): Zenith Epigenetics; Travel/Accommodation/Expenses: Pierre-Fabre; Travel/Accommodation/Expenses: GP Pharma; Travel/Accommodation/Expenses: Grünenthal; Travel/Accommodation/Expenses: Eisai. E.M. Ciruelos: Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer. M. Bellet Ezquerra: Honoraria (institution), Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Celgene; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Pfizer. J. Gavila Gregori: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: MSD Oncology. S. Pernas Simon: Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Polyphor; Advisory/Consultancy: TFS. M.J. Vidal: Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self): Daiichi Sankyo. M. Margeli Vila: Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Kern; Research grant/Funding (self): Celgene; Research grant/Funding (self): Kern. P. Villagrasa: Speaker Bureau/Expert testimony: NanoString Technologies. A. Prat: Honoraria (self), Travel/Accommodation/Expenses: Daiichi Sankyo; Advisory/Consultancy: NanoString Technologies; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self): MSD Oncology; Honoraria (self): Lilly; Advisory/Consultancy: Amgen; Advisory/Consultancy: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.