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Invasive lobular carcinoma (ILC) accounts for 10-15% of primary breast cancer and is typically ER+ and ERBB2 non-amplified. There is preclinical evidence that somatic ERBB2 mutation may provide an alternative and tractable mechanism for upregulation of HER2 activity in tumors that do not express HER2 by current clinical criteria. Using large public datasets, we previously demonstrated that targetable ERBB2 mutations are enriched in ILC versus invasive ductal carcinoma (IDC) and are an independent prognostic factor in ILC (HR=3.7, 95% CI 1.2-11.0; p=0.021)*. We next hypothesized that a gene expression signature incorporating HER2 activity due to ERBB2 mutation and / or amplification would validate the prognostic signal we found in ILC. To derive a novel gene expression signature of HER2 activity that accounted for the effect of potentially targetable ERBB2 mutations in ERBB2 non-amplified tumors, we applied a weighted average difference method to gene expression data in cases from the METABRIC 2012 (N=1,980) and TCGA 2015 (N=817) cohorts. To compare our novel gene expression signature with an established signature of HER2 activity, we performed multivariate regression modeling of response to neratinib, a small molecule tyrosine kinase inhibitor of HER1, 2 and 4, using pharmacogenomic data accessed via the CellMinerCDB online portal. We show that our novel HER2 pathway signature score uniquely enriches for ERBB2 mutated tumors. Using a Cox regression model and stratifying gene expression scores into upper versus lower quartiles, we were able to validate the prognostic signal of ERBB2 mutations in ILC tumors (HR for 10-year OS in ILC=2.3, 95% CI 1.04-5.05; p=0.040). In contrast, no relationship was found between ERBB2 mutation status or novel HER2 pathway enrichment score and patient outcome in cases of IDC. We conclude that ERBB2 mutations that are enriched in ILC provide a robust biomarker of HER2 pathway activation and can be detected via gene expression signature. Novel clinical trials of HER2-targeted therapy in ERBB2 non-amplified primary ILC are warranted. *Reference: Kurozumi S et al, Cancer Research 2019, 80(4) suppl: SABCS 2019 Abstract P1-18-06 and medRxiv 2020.01.24.20018622 Citation Format: Mansour Alsaleem, Sasagu Kurozumi, Kartikeya Bhardwaj, Cintia Monteiro, Stacey EP Joosten, Andrew R Green, Takaaki Fujii, Ken Shirabe, Ian O Ellis, Emad A Rakha, Nigel P Mongan, David M Heery, Wilbert Zwart, Steffi Oesterreich, Simon J Johnston. Targetable ERBB2 mutation status is an independent marker of adverse prognosis in estrogen receptor positive, ERBB2 non-amplified primary lobular breast carcinoma: Validation using a novel gene signature of HER2 activation [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-11.