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

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.

<p>Advances in the Detection Technologies and Clinical Applications of Circulating Tumor DNA in Metastatic Breast Cancer</p>

“…[98][99][100] HER2 gene amplification in ctDNA and ER/ PR status may predict primary resistance to T-DM1 (trastuzumab emtansine), which is an antibody-drug conjugate with high efficacy approved for the treatment of patients with HER2+ ABC. 101 In a phase I study by Li et al, HER2 bypass signaling pathway along with PI3K/AKT/mTOR pathway and TP53 was shown to be significantly associated with poorer PFS in patients with HER2+ MBC treated with the combination of pyrotinib and capecitabine (median, 16.8 vs. 29.9 months, P = 0.006). 102 Theoretically, HER2-(nonamplified) BC patients do not benefit from HER2-directed drugs.…”

Circulating Tumor Cells in Metastatic Breast Cancer: From Genome Instability to Metastasis

“…Another example of diagnostic and prognostic potential of ctDNA is in the acquired resistance to anti-HER2 therapy which is characterized mainly by the following molecular mechanisms: downstream activation of PI3K signaling pathway (e.g., activating mutations in PI3K catalytic subunit, loss of functional tumor suppressor PTEN) and expression of constitutively active truncated p95-HER2 receptor lacking trastuzumab binding site (Gajria and Chandarlapaty, 2011 ). This results in an increased compensatory reliance on other facilitators of growth signaling such as ER, progesterone receptor (PR), and insulin receptor (IR), and, finally, loss of ERBB2 (Gajria and Chandarlapaty, 2011 ; Sakai et al, 2018 ; Branco et al, 2019 ). The latter is especially common in hormone receptor positive tumors (Sakai et al, 2018 ; Branco et al, 2019 ).…”

“…This results in an increased compensatory reliance on other facilitators of growth signaling such as ER, progesterone receptor (PR), and insulin receptor (IR), and, finally, loss of ERBB2 (Gajria and Chandarlapaty, 2011 ; Sakai et al, 2018 ; Branco et al, 2019 ). The latter is especially common in hormone receptor positive tumors (Sakai et al, 2018 ; Branco et al, 2019 ). Loss of ERBB2 amplification was successfully diagnosed in patient ctDNA obtained prior to treatment with trastuzumab emtansine (T-DM1)—an antibody-drug (maytansinoid) conjugate, and was associated with primary resistance to HER2-targeted therapy (Sakai et al, 2018 ).…”

“…The latter is especially common in hormone receptor positive tumors (Sakai et al, 2018 ; Branco et al, 2019 ). Loss of ERBB2 amplification was successfully diagnosed in patient ctDNA obtained prior to treatment with trastuzumab emtansine (T-DM1)—an antibody-drug (maytansinoid) conjugate, and was associated with primary resistance to HER2-targeted therapy (Sakai et al, 2018 ). Likewise, monitoring the temporal dynamics in the presence of ERBB2 amplification in circulating DNA was reported to be predictive not only of resistance to anti-HER2 therapy, but also of disease dormancy and progression (Ma et al, 2016 ).…”

“…Mutations in PIK3CA and other members of PI3K downstream signaling such as PTEN and mTOR, are some of the most frequently reported aberrations in breast cancer (Zardavas et al, 2014 ). Hence, it is not suprising that mutated PIK3CA and MTOR were identified in ctDNA and associated with resistance (Murtaza et al, 2013 ; Ma et al, 2016 , 2017 ; Kodahl et al, 2018 ; Sakai et al, 2018 ). Importantly the ratio of mutated PIK3CA along with TP53 can be used as a laboratory biomarker to differentiate ctDNA from cfDNA that is not tumor derived, therefore reducing the potential for false positives (Cristofanilli et al, 2013 ; Diaz and Bardelli, 2014 ; Schiavon et al, 2015 ).…”