HER2/HER3 heterodimers and p21 expression are capable of predicting adjuvant trastuzumab response in HER2+ breast cancer

• Published in: Breast cancer research and treatment Vol. 145; no. 1; pp. 33 - 44
• Main Authors: Green, Andrew R., Barros, Fabrício F. T., Abdel-Fatah, Tarek M. A., Moseley, Paul, Nolan, Christopher C., Durham, Alice C., Rakha, Emad A., Chan, Stephen, Ellis, Ian O.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.05.2014; Springer; Springer Nature B.V
• Subjects: Analysis; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Agents - therapeutic use; Biomarkers; Biomarkers, Tumor - analysis; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Cancer research; Cancer therapies; Chemotherapy, Adjuvant; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Drug Resistance, Neoplasm - physiology; Drug therapy; Epidermal growth factor; Female; Humans; Immunohistochemistry; In Situ Hybridization; Kaplan-Meier Estimate; Medicine; Medicine & Public Health; Middle Aged; Monoclonal antibodies; Oncology; Preclinical Study; Protein Multimerization; Receptor, ErbB-2 - metabolism; Receptor, ErbB-3 - metabolism; Trastuzumab; Treatment Outcome; Tumor proteins; HER2/HER3 heterodimers; Breast cancer; Trastuzumab; p21
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-014-2925-7

Human epidermal growth factor receptor 2 (HER2) plays an important role in breast cancer progression and provides predictive information for response to targeted therapy including trastuzumab although this is limited. Downstream pathways, such as PI3K/Akt, are associated with HER2/HER3 heterodimerization promoting survival and proliferation amongst cancer cells. Thus, patient outcome and trastuzumab therapy effectiveness might be further characterised by HER2/HER3 dimerisation and its signalling pathways. HER2/HER3 dimerisation status was assessed, using chromogenic in situ Proximity Ligation Assay, in two breast cancer series: early stage primary breast cancer, including 224 HER2+ patients that were not submitted to trastuzumab, and HER2+ breast cancer where patients were treated with adjuvant trastuzumab ( n  = 143). Levels of biomarkers including PI3K, pAKT, ER, PgR, HER3, BCL2, p53, PTEN and p21 were measured using immunohistochemistry. Levels of HER2/HER3 heterodimers were compared with biomarker expression and patient outcome. An association between high levels of HER2/HER3 dimerisation and absence of hormone receptors, ER and PgR, was observed. We further show for the first time the presence of HER2/HER3 heterodimers and the loss of p21 expression in HER2+ breast cancer predicts a significantly poorer outcome when submitted to adjuvant trastuzumab. Breast cancer patients that reveal high levels of HER2/HER3 dimerisation and loss of p21 are associated with poor survival prognosis in patients with HER2+ breast cancer treated with adjuvant trastuzumab. Further quantification analysis of HER dimer/ligand complexes and downstream signalling pathways will begin to unravel the complex associations with patient outcome and its relationship with sensitivity to targeted treatment.