HER2 genomic amplification in circulating tumor DNA and estrogen receptor positivity predict primary resistance to trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer
Open Access
- 26 April 2018
- journal article
- research article
- Published by Springer Science and Business Media LLC in Breast Cancer
- Vol. 25 (5), 605-613
- https://doi.org/10.1007/s12282-018-0861-9
Abstract
Background Trastuzumab emtansine (T-DM1) is approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC), and has high efficacy. However, some patients exhibit primary resistance to T-DM1, and thus methods that can predict resistance in clinical practice are needed. Genomic analysis of circulating tumor DNA (ctDNA) in plasma is a non-invasive and reproducible method. This study aimed to predict primary resistance to T-DM1 by combining genomic analysis of ctDNA and other clinicopathological features of patients with HER2-positive ABC. Methods The study population comprised 34 patients with HER2-positive ABC who had been treated with T-DM1. Correlations between clinicopathological characteristics of patients and primary resistance to T-DM1 were examined, and HER2 gene copy number and PIK3CA gene mutations were analyzed using plasma ctDNA samples obtained from 16 patients before T-DM1 administration. Results Among the 34 patients, nine (26.5%) had progressive disease at the first efficacy analysis; these patients were considered to have primary resistance to T-DM1. No significant difference was found in the rate of primary resistance to T-DM1 between groups. Among 16 patients whose ctDNA was analyzed, four showed primary resistance to T-DM1. These four patients showed negative HER2 gene amplification in ctDNA and were ER-positive and/or PR-positive by immunohistochemistry. Conclusions HER2 gene amplification in ctDNA and ER and PR status may predict primary resistance to T-DM1. A liquid biopsy before the initiation of T-DM1 treatment could be a non-invasive way to predict whether a patient would exhibit primary resistance to T-DM1.Keywords
This publication has 36 references indexed in Scilit:
- Investigation of the freely available easy-to-use software ‘EZR’ for medical statisticsBone Marrow Transplantation, 2012
- Clinically Used Breast Cancer Markers Such As Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor 2 Are Unstable Throughout Tumor ProgressionJournal of Clinical Oncology, 2012
- Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell linesAnnals of Oncology, 2010
- New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)European Journal of Cancer, 2009
- Regulation of ERBB2 by oestrogen receptor–PAX2 determines response to tamoxifenNature, 2008
- A Functional Genetic Approach Identifies the PI3K Pathway as a Major Determinant of Trastuzumab Resistance in Breast CancerCancer Cell, 2007
- Expression of p95HER2, a Truncated Form of the HER2 Receptor, and Response to Anti-HER2 Therapies in Breast CancerJNCI Journal of the National Cancer Institute, 2007
- Docetaxel, Cisplatin, and Trastuzumab As Primary Systemic Therapy for Human Epidermal Growth Factor Receptor 2–Positive Locally Advanced Breast CancerJournal of Clinical Oncology, 2006
- Insulin-like Growth Factor-I Receptor/Human Epidermal Growth Factor Receptor 2 Heterodimerization Contributes to Trastuzumab Resistance of Breast Cancer CellsCancer Research, 2005
- PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patientsCancer Cell, 2004