New HER2-negative breast cancer subtype responsive to anti-HER2 therapy identified

Ian A Macneil,Sajjad M Soltani,Lance G Laing,Brian F Sullivan,Samantha Kharbush,Douglas M Hawkins,David J Burns,Jodie R Pietruska,Nicole G Osterhaus,Benjamin E Rich

doi:10.1007/s00432-020-03144-7

Abstract

PurposeHER2 signaling functional activity may be important to measure in addition to HER2 protein quantification when identifying patients eligible for HER2 therapies. A HER2 Signaling Function (CELx HSF) Test for HER2-negative patients uses patient’s live tumor cells on a biosensor to identify patients with abnormally high HER2-related signaling (HSFs+) likely to respond to anti-HER2 therapies.MethodsThe CELx HSF test was employed to: (1) characterize the sensitivity and specificity of the test to detect abnormal levels of HER2 signaling; (2) evaluate the inhibitory effectiveness of five different anti-HER2 therapies; (3) assess the correlation between CELx HSF test detection of abnormal HER2 signaling and response to HER2 therapy using xenograft models; and (4) confirm the prevalence of abnormal HER2 signaling amongst HER2-negative breast cancer patients (HER2−/HSFs+).ResultsHER2−/HSFs+ breast cancer patient samples were identified and showed sensitivity to five approved anti-HER2 therapies. Xenograft studies using both HER2+ and HER2− cell lines confirmed that CELx HER2 signaling status better predicts HER2 inhibitor efficacy than HER2 receptor status. In a study of 114 HER2-negative breast tumor patient samples, 27 (23.7%; 95% CI = 17–32%) had abnormal HER2 signaling (HSFs+). A ROC curve constructed with this dataset projects the CELx HSF Test would have greater than 90% sensitivity and specificity to detect the HER2−/HSFs+ patient population.ConclusionsThe CELx HSF test is a well-characterized functional biomarker assay capable of identifying dynamic HER2-driven signaling dysfunction in tumor cells from HER2-negative breast cancer patients. This test has demonstrated efficacy of various HER2 targeted therapies in live tumor cells from the HSFs+ population and correlated the test result to HER2 drug response in mouse xenograft studies. The proportion of HER2-negative breast cancer patients found to have abnormal HER2 signaling in a 114 patient sample study, 20–25%, is significant. A clinical trial to evaluate the efficacy of anti-HER2 therapies in this patient population is warranted.

Highlights

The human epidermal growth factor receptor 2 (HER2) gene encodes a receptor tyrosine kinase that is amplified or overexpressed in approximately 15% of human breast cancers1 3 Vol.:(0123456789)Journal of Cancer Research and Clinical Oncology (2020) 146:605–619 and is a potent driver of oncogenic transformation and breast tumorigenesis (Akiyama et al 1986; Al-Kuraya et al 2004; Dawood et al 2010; Fiore et al 1987; Muller et al 1988; Slamon et al 1987)
Retrospective analyses of both the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial and the designed North Central Cancer Treatment Group (NCCTG) N9831 trial found that a subset of breast cancer patients classified by in situ hybridization (ISH)/IHC as HER2− unexpectedly benefited from treatment with the anti-HER2 antibody trastuzumab (Paik et al 2008; Perez et al 2010)
The findings of this study suggest that a new sub-type of HER2−/HER2 signaling function (HSF)+ breast cancer identified by the CELx HSF Test may be responsive to HER2 targeted therapies

Summary

Introduction

The human epidermal growth factor receptor 2 (HER2) gene encodes a receptor tyrosine kinase that is amplified or overexpressed in approximately 15% of human breast cancers1 3 Vol.:(0123456789)Journal of Cancer Research and Clinical Oncology (2020) 146:605–619 and is a potent driver of oncogenic transformation and breast tumorigenesis (Akiyama et al 1986; Al-Kuraya et al 2004; Dawood et al 2010; Fiore et al 1987; Muller et al 1988; Slamon et al 1987). Retrospective analyses of both the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial and the designed North Central Cancer Treatment Group (NCCTG) N9831 trial found that a subset of breast cancer patients classified by ISH/IHC as HER2− unexpectedly benefited from treatment with the anti-HER2 antibody trastuzumab (Paik et al 2008; Perez et al 2010). This further uncovered a significant false negative rate for current HER2 biomarkers, i.e. patients that would be excluded from treatment that may respond to HER2-targeted therapy. These results reveal that overexpression or amplification of HER2 is only weakly correlated to the disease mechanism associated with HER2 signaling dysfunction

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Results

Conclusion