Lin Po-Han, Wang Ming-Yang, Lo Chiao, Tsai Li-Wei, Yen Tzu-Chun, Huang Thomas Yoyan, Huang Wei-Chih, Yang Karen, Chen Chih-Kai, Fan Sheng-Chih, Kuo Sung-Hsin, Huang Chiun-Sheng
Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan.
Front Oncol. 2021 Nov 12;11:736769. doi: 10.3389/fonc.2021.736769. eCollection 2021.
Patients with stage II to III breast cancer have a high recurrence rate. The early detection of recurrent breast cancer remains a major unmet need. Circulating tumor DNA (ctDNA) has been proven to be a marker of disease progression in metastatic breast cancer. We aimed to evaluate the prognostic value of ctDNA in the setting of neoadjuvant therapy (NAT).
Plasma was sampled at the initial diagnosis (defined as before NAT) and after breast surgery and neoadjuvant therapy(defined as after NAT). We extracted ctDNA from the plasma and performed deep sequencing of a target gene panel. ctDNA positivity was marked by the detection of alterations, such as mutations and copy number variations.
A total of 95 patients were enrolled in this study; 60 patients exhibited ctDNA positivity before NAT, and 31 patients exhibited ctDNA positivity after NAT. A pathologic complete response (pCR) was observed in 13 patients, including one ER(+)Her2(-) patient, six Her2(+) patients and six triple-negative breast cancer (TNBC) patients. Among the entire cohort, multivariate analysis showed that N3 classification and ctDNA positivity after NAT were independent risk factors that predicted recurrence (N3, hazard ratio (HR) 3.34, 95% confidence interval (CI) 1.26 - 8.87, p = 0.016; ctDNA, HR 4.29, 95% CI 2.06 - 8.92, p < 0.0001). The presence of ctDNA before NAT did not affect the rate of recurrence-free survival. For patients with Her2(+) or TNBC, patients who did not achieve pCR were associated with a trend of higher recurrence (p = 0.105). Advanced nodal status and ctDNA positivity after NAT were significant risk factors for recurrence (N2 - 3, HR 3.753, 95% CI 1.146 - 12.297, p = 0.029; ctDNA, HR 3.123, 95% CI 1.139 - 8.564, p = 0.027). Two patients who achieved pCR had ctDNA positivity after NAT; one TNBC patient had hepatic metastases six months after surgery, and one Her2(+) breast cancer patient had brain metastasis 13 months after surgery.
This study suggested that the presence of ctDNA after NAT is a robust marker for predicting relapse in stage II to III breast cancer patients.
II至III期乳腺癌患者复发率较高。复发性乳腺癌的早期检测仍是一项尚未满足的重大需求。循环肿瘤DNA（ctDNA）已被证明是转移性乳腺癌疾病进展的标志物。我们旨在评估ctDNA在新辅助治疗（NAT）背景下的预后价值。
在初始诊断时（定义为NAT之前）以及乳房手术和新辅助治疗后（定义为NAT之后）采集血浆样本。我们从血浆中提取ctDNA，并对目标基因panel进行深度测序。ctDNA阳性通过检测突变和拷贝数变异等改变来标记。
本研究共纳入95例患者；60例患者在NAT之前表现为ctDNA阳性，31例患者在NAT之后表现为ctDNA阳性。13例患者观察到病理完全缓解（pCR），包括1例ER(+)Her2(-)患者、6例Her2(+)患者和6例三阴性乳腺癌（TNBC）患者。在整个队列中，多因素分析显示N3分类和NAT后ctDNA阳性是预测复发的独立危险因素（N3，风险比（HR）3.34，95%置信区间（CI）1.26 - 8.87，p = 0.016；ctDNA，HR 4.29，95%CI 2.06 - 8.92，p < 0.0001）。NAT之前ctDNA的存在不影响无复发生存率。对于Her2(+)或TNBC患者，未达到pCR的患者复发趋势更高（p = 0.105）。晚期淋巴结状态和NAT后ctDNA阳性是复发的重要危险因素（N2 - 3，HR 3.753，95%CI 1.146 - 12.297，p = 0.029；ctDNA，HR 3.123，95%CI 1.139 - 8.564，p = 0.027）。2例达到pCR的患者在NAT后ctDNA阳性；1例TNBC患者术后6个月出现肝转移，1例Her2(+)乳腺癌患者术后13个月出现脑转移。
本研究表明，NAT后ctDNA的存在是预测II至III期乳腺癌患者复发的有力标志物。
