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

Abstract

Breast cancer (BC) represents the most commonly diagnosed cancer among females worldwide. Although targeted therapy has greatly improved the efficacy of treating BC, a large proportion of BC patients eventually develop recurrence or metastasis. Traditional invasive tumor tissue biopsy is short of comprehensiveness in tumor assessment due to heterogeneity. Liquid biopsy, an attractive non-invasive approach mainly including circulating tumor cell and circulating tumor DNA (ctDNA), has been widely utilized in a variety of cancers with the advances of sequencing technologies in recent years. The ctDNA that is found circulating in body fluids refers to DNA released from tumor cells and has shown clinical utility in metastatic breast cancer (MBC). With the results of genomic variants detection, ctDNA could be used to predict clinical outcomes, monitor disease progression, and guide treatment for patients with MBC. Moreover, the drug resistance problem may be addressed by ctDNA detection. In this review, we summarized the technological developments and clinical applications of ctDNA in MBC.

Detection of ESR1 Mutations Based on Liquid Biopsy in Estrogen Receptor-Positive Metastatic Breast Cancer: Clinical Impacts and Prospects

“…As shown in Table 1 , four studies (BOLERO-2, SoFEA, PALOMA-3, and FERGI) revealed a high prevalence of ESR1 mutations in second and higher treatment line, with a total mutation rate of 32% (684/2136), while one study (MONALEESA-2) evaluated the ESR1 mutations in first-line treatment and reported a low prevalence of ESR1 mutations (4%). Our previous work revealed an ESR1 mutation rate of 24.7% (169/685) in the HR+ MBC patients ( 19 ). And this proportion seemed to be higher (30%–40%) in ER+ HER2- MBC patients who had resistance to ET, especially to AIs ( 31 ).…”

“…The most commonly detected ESR1 point mutations locate in codons 380, 537, and 538 within the LBD ( 19 , 26 ) ( Figure 1B ). Several large-scale clinical trials have investigated the prevalence of ctDNA ESR1 mutations in ER+ MBC patients ( 27 – 30 ).…”

“…ESR1 Y537S mutants required the highest dose to completely block transcriptional activity and cell proliferation compared with other mutants ( 52 ). The selection of ESR1 Y537S was identified as the variant that most likely promoted the resistance to FUL ( 19 , 53 ). Even though the biochemical mechanism of the FUL relative resistance has not been elucidated, patients with mutations in the ESR1 LBD may benefit from higher-dose or more potent SERMs/SERDs ( 6 , 14 , 33 ).…”

“…The ddPCR has long been preferred to detect ESR1 mutations for its higher sensitivity and accuracy ( 57 ). Whereas, NGS can interrogate larger regions such as gene panels without prior knowledge of the mutations ( 19 , 58 , 59 ). Several common commercially available NGS technologies include Guardant360 (Guardant Health), FoundationOne Liquid and FoundationACT (Foundation Medicine Inc).…”

“…All the work mentioned above essentially underline the importance of detecting circulating ESR1 mutations in metastatic settings. In recent years, the sequencing technology has developed rapidly from Polymerase Chain Reaction (PCR) to Next-Generation Sequencing (NGS), which allows efficient and accurate detection of genomic alterations in cancer and accelerates the process of precision medicine ( 18 , 19 ). Herein, we summarized recent progress of detecting ESR1 mutations based on liquid biopsy and different sequencing technologies in ER+ metastatic BC (MBC) and discussed its clinical implications and prospects.…”