Human epidermal growth factor receptor 2 (HER2) status is a crucial predictive factor for prognostic assessment and targeted therapy selection, which may be influenced by intratumor heterogeneity and molecular divergence between the primary site and different metastases. Therefore, we performed a prospective study to confirm the concordance of HER2 amplification in circulating tumor DNA (ctDNA) with primary tumor tissue and verified its clinical implications.
A total of 105 breast cancer patients were enrolled, and dynamic monitoring of HER2 copy numbers in ctDNA was conducted in 31 participants during the treatment. In total, 186 plasma samples were prospectively obtained and blinded to test HER2 copy numbers in ctDNA based on low-coverage whole genome sequencing (WGS) by next-generation sequencing (NGS).
Comparing HER2 copy numbers in ctDNA collected before the initiation of the next line of anticancer treatment with primary tumor tissue, the concordant rate of HER2 amplification was 86.5% (χ2= 52.901, p < 0.001), with a positive and negative predictive value of 94.9% and 80.7%, respectively. Histopathologically positive, high-level amplification of HER2 copy numbers in the baseline was significantly correlated with the best objective response during the anticancer therapy (p = 0.010). Moreover, HER2 copy numbers fluctuated with HER2-targeted therapeutic response, and the patients with a constantly positive level after 6 weeks of treatment appeared to suffer from significantly reduced progression free survival (p < 0.001).
HER2 amplification in ctDNA, with a concordance rate of over 80% with primary tumors, may be a predictive index for prognostic evaluation and therapeutic response monitoring in a noninvasive, repeatable and practical method for breast cancer patients.
National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.
National Natural Science Foundation of China (81472453, 81874122), and the CAMS Initiative for Innovative Medicine (2017-I2M-3-004).
Y. Niu, S. Lu: Employee: Yikon Genomics Co. Ltd.