Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are two cancer-derived blood biomarkers that inform on patient prognosis and treatment efficacy in breast cancer. We prospectively evaluated the clinical validity of quantifying both CTCs (CellSearch) and ctDNA (targeted next-generation sequencing). Their combined value as prognostic and early monitoring markers was assessed in 198 HER2-negative metastatic breast cancer patients. All patients were included in the prospective multicenter UCBG study COMET (NCT01745757) and treated by first-line chemotherapy with weekly paclitaxel and bevacizumab. Blood samples were obtained at baseline and before the second cycle of chemotherapy. At baseline, CTCs and ctDNA were respectively detected in 72 and 74% of patients and were moderately correlated (Kendall’s τ = 0.3). Only 26 (13%) patients had neither detectable ctDNA nor CTCs. Variants were most frequently observed in TP53 and PIK3CA genes. KMT2C/MLL3 variants detected in ctDNA were significantly associated with a lower CTC count, while the opposite trend was seen with GATA3 alterations. Both CTC and ctDNA levels at baseline and after four weeks of treatment were correlated with survival. For progression-free and overall survival, the best multivariate prognostic model included tumor subtype (triple negative vs other), grade (grade 3 vs other), ctDNA variant allele frequency (VAF) at baseline (per 10% increase), and CTC count at four weeks (≥5CTC/7.5 mL). Overall, this study demonstrates that CTCs and ctDNA have nonoverlapping detection profiles and complementary prognostic values in metastatic breast cancer patients. A comprehensive liquid-biopsy approach may involve simultaneous detection of ctDNA and CTCs.

循环肿瘤细胞 (CTC) 和循环肿瘤 DNA (ctDNA) 是两种癌症衍生的血液生物标志物，可以为乳腺癌患者的预后和治疗效果提供信息。我们前瞻性地评估了量化 CTC（CellSearch）和 ctDNA（靶向下一代测序）的临床有效性。在 198 名 HER2 阴性转移性乳腺癌患者中评估了它们作为预后和早期监测标志物的综合价值。所有患者均纳入前瞻性多中心 UCBG 研究 COMET (NCT01745757)，并接受每周一次紫杉醇和贝伐单抗的一线化疗。在基线和第二个化疗周期之前采集血样。在基线时，分别在 72% 和 74% 的患者中检测到 CTC 和 ctDNA 并且呈中度相关（Kendall's τ = 0.3）。只有 26 (13%) 名患者既没有可检测的 ctDNA 也没有 CTC。在TP53和PIK3CA基因中最常观察到变体。在 ctDNA 中检测到的KMT2C / MLL3变异与较低的 CTC 计数显着相关，而GATA3则出现相反的趋势改动。基线和治疗 4 周后的 CTC 和 ctDNA 水平都与存活率相关。对于无进展和总生存期，最佳多变量预后模型包括肿瘤亚型（三阴性与其他）、分级（3 级与其他）、基线时的 ctDNA 变异等位基因频率 (VAF)（每增加 10%）和 CTC 计数4 周（≥5CTC/7.5 mL）。总的来说，这项研究表明 CTC 和 ctDNA 在转移性乳腺癌患者中具有不重叠的检测特征和互补的预后价值。综合液体活检方法可能涉及同时检测 ctDNA 和 CTC。