PURPOSE Liquid biopsies, including circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), can be used to understand disease prognosis, tumor heterogeneity, and dynamic response to treatment in metastatic breast cancer (MBC). We explored a novel, 180-gene ctDNA panel and the association of this platform with CTCs and CTC clusters. METHODS A total of 40 samples from 22 patients with MBC were included in the study. For the primary analysis, all patients had ctDNA sequencing using the PredicinePLUS™ platform. CTCs and CTC clusters were examined using the CellSearch™ System. Clinical and pathological variables were reported using descriptive analyses. Associations between CTC count and specific genomic alterations were tested using the Mann-Whitney U test. RESULTS Of 43 sequenced patients, 40 (93%) had at least one detectable genomic alteration with a median of 6 (range 1-22). Fifty-seven different genes were altered, and the landscape of genomic alterations was representative of MBC, including the commonly encountered alterations TP53, PTEN, PIK3CA, ATM, BRCA1, CCND1, ESR1, and MYC. In patients with predominantly hormone-receptor-positive MBC, the number of CTCs was significantly associated with alterations in ESR1 (P < 0.005), GATA3 (P < 0.05), CDH1 (P < 0.0005), and CCND1 (P < 0.05) (Mann-Whitney U test). Thirty-six percent of patients had CTC clusters, which were associated with alterations in CDH1, CCND1, and BRCA1 (all P < 0.05, Mann-Whitney U test). In an independent validation cohort, CTC enumeration confirmed significant associations with ESR1 and GATA3, while CTC clusters were significantly associated with CDH1. CONCLUSIONS We report on a novel ctDNA platform that detected genomic alterations in the vast majority of tested patients, further indicating potential clinical utility for capturing disease heterogeneity and for disease monitoring. Detection of CTCs and CTC clusters was associated with particular genomic profiles.

中文翻译：

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新型循环肿瘤DNA下一代测序平台与转移性乳腺癌中循环肿瘤细胞（CTC）和CTC簇的关联。

目的液体活检，包括循环肿瘤DNA（ctDNA）和循环肿瘤细胞（CTC），可用于了解疾病的预后，肿瘤异质性以及对转移性乳腺癌（MBC）治疗的动态反应。我们探索了一个新颖的180基因ctDNA面板，并将该平台与CTC和CTC簇相关联。方法本研究共纳入22例MBC患者的40个样本。对于初步分析，所有患者均使用PredicinePLUS™平台进行ctDNA测序。使用CellSearch™系统检查了CTC和CTC簇。使用描述性分析报告了临床和病理变量。使用Mann-Whitney U检验对CTC计数与特定基因组改变之间的关联进行了检验。结果43位测序患者中，40（93％）具有至少一个可检测到的基因组改变，中位值为6（范围1-22）。改变了57个不同的基因，基因组改变的格局代表了MBC，包括常见的TP53，PTEN，PIK3CA，ATM，BRCA1，CCND1，ESR1和MYC。在主要为激素受体阳性MBC的患者中，CTC的数量与ESR1（P <0.005），GATA3（P <0.05），CDH1（P <0.0005）和CCND1（P <0.05）的改变显着相关（ Mann-Whitney U检验）。36％的患者患有CTC簇，这与CDH1，CCND1和BRCA1的改变有关（所有P <0.05，Mann-Whitney U检验）。在独立的验证队列中，CTC枚举确认与ESR1和GATA3有显着关联，而CTC簇与CDH1显着相关。结论我们报告了一个新颖的ctDNA平台，该平台可在绝大多数被测患者中检测到基因组改变，进一步表明了在捕获疾病异质性和疾病监测方面的潜在临床效用。CTC和CTC簇的检测与特定的基因组图谱相关。