Abstract ES7-3: ES7-3 Mechanisms of resistance to Her2 positive disease

Abstract

The epidermal growth factor receptor-2 (HER2) is a member of the HER family, a robust and complex signaling network with multiple redundant inputs (ligands and receptors), central signals, and ample feedback routes. HER2 amplification occurs in about 15% of breast cancers and is a major driver of cell proliferation and survival. Therapies targeting HER2, including the monoclonal antibodies trastuzumab and pertuzumab, the trastuzumab drug conjugate T-DM1, and the HER1/2 tyrosine kinase inhibitor lapatinib, have substantially improved outcome of patients with this subtype of disease. Stemming from preclinical evidence, in recent years the use of combined (dual) anti-HER agents to more completely block the receptor layer (HER1, 2, and 3), has been successfully translated to the clinic, and the latest studies suggest that at least some oncogene-addicted HER2-positive tumors might not require chemotherapy at all if HER2 is effectively blocked. Experimental and clinical findings further propose that blocking estrogen receptor would also be necessary in tumors expressing both receptors.

Yet, despite progress in the care of HER2-positive breast cancer, treatment resistance remains a key problem in many patients. Therefore, establishing molecular determinants of response and resistance and associated biomarkers is essential in order to empower the identification of patients who may benefit from a de-escalation approach of only receptor-targeted therapy without chemotherapy. We also need to identify and perhaps target additional genes, pathways, genomic alterations, and other compensatory mechanisms associated with resistance. Ongoing efforts to identify gene expression signatures, mutation profiles, and pathways associated with response/resistance in the neoadjuvant setting suggest that the expression levels of HER2 itself, the HER2-enriched subtype, and the estrogen receptor gene ESR1, as well as mutations in PIK3CA, are among the most significant predictors of response. These and other studies also suggest a key role for the tumor immune infiltrate in predicting response to anti-HER2 therapy. Importantly, many of these studies have been confounded by co-administration of chemotherapy, rendering their biomarker results somewhat difficult to interpret. Additional clinical and preclinical hypothesis- and discovery-driven studies have revealed a number of additional pathways and novel mechanisms involved in treatment resistance. Among others, there are altered and compensatory signaling interactions within the HER network receptor layer, other membrane and cellular kinase pathways, metabolic pathways, and regulatory components of the cell cycle machinery. These escape pathways may be derived from genetic aberrations and/or epigenetic compensatory signals, and may preexist predominantly in the primary tumor or become enriched by treatment pressure selection. Understanding mechanisms of resistance and associated biomarkers can lead to better and more tailored therapeutic strategies to circumvent resistance and improve patient outcome.

Citation Format: Schiff R. ES7-3 Mechanisms of resistance to Her2 positive disease [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES7-3.