Abstract
BackgroundTrastuzumab 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.MethodsThe 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.ResultsAmong 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.ConclusionsHER2 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.
Highlights
T-DM1 is an antibody–drug conjugate that combines the human epidermal growth factor receptor type 2 (HER2)targeted antitumor properties of trastuzumab with the maytansinoid, DM1, a potent microtubule-disrupting agent, joined by a stable linker [1]
T-DM1 significantly improved progression-free survival (PFS) and overall survival (OS) compared to the combination of capecitabine and lapatinib in the phase III EMILIA study [2], and has become a standard treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) previously treated with trastuzumab and taxanes in accordance
A total of 34 patients with HER2-positive metastatic breast cancer who had been treated with T-DM1 were included in this study
Summary
T-DM1 is an antibody–drug conjugate that combines the human epidermal growth factor receptor type 2 (HER2)targeted antitumor properties of trastuzumab with the maytansinoid, DM1, a potent microtubule-disrupting agent, joined by a stable linker [1]. In the phase III MARIANNE trial, patients with previously untreated HER2-positive locally advanced or metastatic breast cancer were randomized to trastuzumab plus a taxane (docetaxel or paclitaxel), T-DM1 plus placebo, or T-DM1 plus pertuzumab. Both T-DM1-containing regimens showed non-inferiority, but not superiority, in terms of PFS over trastuzumab plus a taxane. The objective response rate was 67.9% with trastuzumab plus a taxane, 59.7% with T-DM1 plus placebo, and 64.2% with T-DM1 plus pertuzumab [4] These results implied that a significant proportion of patients experience disease progression without any signs of tumor regression or stabilization of disease despite early treatment with T-DM1, and the primary resistance rate to T-DM1 is probably as high as 30%. 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
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