早期检测对于转移性乳腺癌发病前的治疗计划至关重要。循环肿瘤细胞是易于获取的生物标志，对于既往内分泌治疗失败的雌激素受体阳性转移性乳腺癌患者，可以更好地进行监测和个体化管理。
2017年10月15日，美国癌症研究学会《临床癌症研究》正式发表托马斯·杰斐逊大学、圣心天主教大学、西北大学、罗马大学的研究报告，证实了转移性乳腺癌单个循环肿瘤细胞（CTC）水平雌激素受体1（ESR1）基因突变检测和监测的可行性。
该研究使用循环肿瘤细胞分子定性方法，分析ESR1基因14个热点突变的异质性及其与内分泌耐药的相关性。结合CellSearch和DEPArray技术，可以从3例雌激素受体阳性转移性乳腺癌患者，回收71个循环肿瘤细胞和12个白细胞。利用多次退火环状循环扩增和链终止法测序，对40个循环肿瘤细胞和12个白细胞进行全基因组扩增。
结果发现，上述3例患者其中2例有ESR1突变（Y537），1例单个循环肿瘤细胞有2种不同的ESR1突变，另1例杂合性丢失。配对细胞游离DNA检出所有突变。
此外，1例分析了2份连续血液标本，细胞游离DNA和循环肿瘤细胞均出现既往研究尚未报道的ESR1突变（Y537S和T570I）。
因此，该研究表明，单个循环肿瘤细胞分析即可得出关于克隆异质性的重要信息，并且可以成为发现潜在致病新突变的来源。最后，该研究还验证了液体活检的工作流程，这将有助于ESR1突变和内分泌耐药发生的早期检测以及进一步靶向疗法的选择。
Clin Cancer Res. 2017 Oct 15;23(20):6086-6093.
Detection of Activating Estrogen Receptor Gene (ESR1) Mutations in Single Circulating Tumor Cells.
Paolillo C, Mu Z, Rossi G, Schiewer MJ, Nguyen T, Austin L, Capoluongo E, Knudsen K, Cristofanilli M, Fortina P.
Thomas Jefferson University, Philadelphia, Pennsylvania; Catholic University of the Sacred Heart, Rome, Italy; Northwestern University, Chicago, Illinois; Sapienza University, Rome, Italy.
PURPOSE: Early detection is essential for treatment plans before onset of metastatic disease. Our purpose was to demonstrate feasibility to detect and monitor estrogen receptor 1 (ESR1) gene mutations at the single circulating tumor cell (CTC) level in metastatic breast cancer (MBC).
EXPERIMENTAL DESIGN: We used a CTC molecular characterization approach to investigate heterogeneity of 14 hotspot mutations in ESR1 and their correlation with endocrine resistance. Combining the CellSearch and DEPArray technologies allowed recovery of 71 single CTCs and 12 WBC from 3 ER-positive MBC patients. Forty CTCs and 12 WBC were subjected to whole genome amplification by MALBAC and Sanger sequencing.
RESULTS: Among 3 selected patients, 2 had an ESR1 mutation (Y537). One showed two different ESR1 variants in a single CTC and another showed loss of heterozygosity. All mutations were detected in matched cell-free DNA (cfDNA). Furthermore, one had 2 serial blood samples analyzed and showed changes in both cfDNA and CTCs with emergence of mutations in ESR1 (Y537S and T570I), which has not been reported previously.
CONCLUSIONS: CTCs are easily accessible biomarkers to monitor and better personalize management of patients with previously demonstrated ER-MBC who are progressing on endocrine therapy. We showed that single CTC analysis can yield important information on clonal heterogeneity and can be a source of discovery of novel and potential driver mutations. Finally, we also validate a workflow for liquid biopsy that will facilitate early detection of ESR1 mutations, the emergence of endocrine resistance and the choice of further target therapy.
PMID: 28679775
DOI: 10.1158/1078-0432.CCR-17-1173
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