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

• Published in: Breast cancer (Tokyo, Japan) Vol. 25; no. 5; pp. 605 - 613
• Main Authors: Sakai, Hitomi, Tsurutani, Junji, Iwasa, Tsutomu, Komoike, Yoshifumi, Sakai, Kazuko, Nishio, Kazuto, Nakagawa, Kazuhiko
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 01.09.2018; Springer
• Subjects: Analysis; Breast cancer; Cancer Research; DNA; Epidermal growth factor; Estrogen; Gene mutations; Genes; Genetic research; Immunohistochemistry; Medical research; Medicine; Medicine & Public Health; Medicine, Experimental; Metastasis; Oncology; Original; Original Article; Pertuzumab; Phenols; Surgery; Surgical Oncology; Trastuzumab emtansine (T-DM1); Circulating tumor DNA (ctDNA); HER2; Primary resistance
• ISSN: 1340-6868; 1880-4233
• DOI: 10.1007/s12282-018-0861-9

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.