title: A functional signal profiling test for identifying a subset of HER2-negative breast cancers with abnormally amplified HER2 signaling activity.
abstract: The results of clinical trials evaluating the efficacy of HER2 inhibitors in patients with breast cancer indicate that the correlation between HER2 receptor levels and patient outcomes is as low as 50%. The relatively weak correlation between HER2 status and response to HER2-targeting drugs suggests that measurement of HER2 signaling activity, rather than absolute HER2 levels, may more accurately diagnose HER2-driven breast cancer. A new diagnostic test, the CELx HER2 Signaling Profile (CELx HSP) test, is demonstrated to measure real-time HER2 signaling function in live primary cells. In the present study, epithelial cells extracted fresh from breast cancer patient tumors classified as HER2 negative (HER2-, n = 34 of which 33 were estrogen receptor positive) and healthy subjects (n = 16) were evaluated along with reference breast cancer cell lines (n = 19). Live cell response to specific HER2 agonists (NRG1b and EGF) and antagonist (pertuzumab) was measured. Of the HER2- breast tumor cell samples tested, 7 of 34 patients (20.5%; 95% CI = 10%-37%) had HER2 signaling activity that was characterized as abnormally high. Amongst the tumor samples there was no correlation between HER2 protein status (by cell cytometry) and HER2 signaling activity (hyperactive or normal) (Regression analysis P = 0.144, R2 = 0.068). One conclusion is that measurement of HER2 signaling activity can identify a subset of breast cancers with normal HER2 receptor levels with abnormally high levels of HER2 signaling. This result constitutes a new subtype of breast cancer that should be considered for treatment with HER2 pathway inhibitors.
authors.affiliation: Celcuity LLC, Minneapolis, MN 55446, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Celcuity LLC, Minneapolis, MN 55446, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Burns
authors.affiliation: Celcuity LLC, Minneapolis, MN 55446, USA.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Rich
authors.affiliation: Celcuity LLC, Minneapolis, MN 55446, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: MacNeil
authors.affiliation: Celcuity LLC, Minneapolis, MN 55446, USA.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Dandapat
authors.affiliation: Celcuity LLC, Minneapolis, MN 55446, USA.
authors.forename: Sajjad M
authors.initials: SM
authors.lastname: Soltani
authors.affiliation: Celcuity LLC, Minneapolis, MN 55446, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Myhre
authors.affiliation: Celcuity LLC, Minneapolis, MN 55446, USA.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Sullivan
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Leo T
authors.initials: LT
authors.lastname: Furcht
authors.affiliation: Division of Hematology, Oncology and Transplantation, Departments of Medicine and Pharmacology and The Masonic Cancer Center, Minneapolis, MN 55455, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Lange
authors.affiliation: Division of Hematology/Oncology and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Hurvitz
authors.affiliation: Celcuity LLC, Minneapolis, MN 55446, USA.
authors.forename: Lance G
authors.initials: LG
authors.lastname: Laing
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology; D015374:Biosensing Techniques; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D006801:Humans; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000819:agonists / Q000037:antagonists & inhibitors / Q000172:deficiency*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D004815:Epidermal Growth Factor; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human; C485206:pertuzumab
keywords: CELx HSP test; HER2 negative; HER2 signaling; targeted therapy; tumor primary cells