Novel antibody-drug conjugates against HER2 are showing high activity in clinically HER2-negative (cHER2-) breast cancer (BC) with low HER2 expression. However, the clinical and molecular features of cHER2-/HER2-low BC are yet to be elucidated.
We collected retrospective data from 8 multicenter cHER2- BC datasets, including 4 clinical trials. HER2 status in each study was determined using standard FDA-approved antibodies and ISH-techniques and classified according to the ASCO/CAP guidelines. For this study, tumors were regrouped in HER2 0 (0 score) and HER2-low (1+ or 2+ with ISH-negativity). The following variables were compared between the 2 groups in all patients and according to hormone receptor (HR) status: age, grade, ki67, histotype, tumor size, HR, HER2 and nodal status. nCounter-based PAM50 subtypes distribution and the expression of the 50 PAM50 genes, including ERBB2, were also compared.
A total of 3,136 patients with cHER2- disease (57.4% HER2-low and 42.6% HER2 0) were evaluated. Overall, 888 (28.3%) tumor samples came from metastatic sites. No statistically significant differences were found regarding clinicopathological variables between HER2-low and HER2 0. Within HR-positive (+) disease (n=2,497), 63.2% and 36.8% of tumors were HER2-low and HER2 0, respectively. Subtype distribution was similar across HR+/HER2-low and HR+/HER2 0. A total of 45/50 PAM50 genes were found differentially expressed between HR+/HER2-low and HR+/HER2 0 (False Discovery Rate [FDR]<5%). High expression of luminal (e.g. ESR1 and FOXA1) and ERBB2, and low expression of proliferation-related genes (e.g. MKI67) was found in HER2-low compared to HER2 0. Within triple negative BC (TNBC) (n=622), 34.2% were HER2-low and 65.8% were HER2 0. Subtype distribution was similar across TNBC/HER2-low and TNBC/HER2 0. No PAM50 gene was found differentially expressed between TNBC/HER2-low and TNBC/HER2 0 (FDR≥5%). Finally, ERBB2 mRNA levels were higher in HER2-low/HR+ tumors than HER2-low/TNBC (p<0.001).
HER2-low disease within clinically HER2- BC is frequent. However, significant differences exist according to HR status. Compared to HER2-low/TNBC, HER2-low/HR+ disease is a more distinct biological entity and has higher ERBB2 expression.
Clinical trial identification
Legal entity responsible for the study
Instituto de Salud Carlos III - PI16/00904, Pas a Pas, Save the Mama, Breast Cancer Now - 2018NOVPCC1294. Fundación Científica Asociación Española Contra el Cáncer - Ayuda Postdoctoral AECC 2017. Fundación SEOM, Becas FSEOM para Formación en Investigación en Centros de Referencia en el Extranjero 2016 and 2018.
C.H. Barrios: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): AstraZeneca, Novartis, Roche, GSK, Pfizer, Libbs, Daiichi Sankyo and MSD. A. Lluch: Research grant/Funding (self): Amgen, AstraZeneca, Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Celgene, Pierre Fabre; Advisory/Consultancy: Novartis, Pfizer, Roche/Genentech, Eisai, Celgene. M. Martin Jimenez: Research grant/Funding (self): Roche, PUMA and Novartis; Advisory/Consultancy: AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly, PUMA, Taiho Oncology, Daiichi Sankyo and Pfizer; Speaker Bureau/Expert testimony: AstraZeneca, Amgen, Roche/Genentech, Novartis and Pfizer. A. Prat: Honoraria (self): Pfizer, Novartis, Roche, MSD Oncology, Lilly and Daiichi Sankyo; Research grant/Funding (self): Novartis and Roche; Travel/Accommodation/Expenses: Daiichi Sankyo; Advisory/Consultancy: NanoString Technologies, Amgen, Roche, Novartis, Pfizer and Bristol-Myers Squibb; Licensing/Royalties: patent PCT/EP2016/080056. All other authors have declared no conflicts of interest.