Clinical significance of circulating tumor DNA in neoadjuvant-treated HER2-negative luminal B breast cancer.
Authors: Yunxiang Zhou, Zhiyun Zhang, Ting Ma, Huihui Chen, Lu Shen, Shijie Wu, Xianan Guo, Kexin Liu, Weina Mu, Yuyang Miao, Yiding Chen
Journal: Journal of Clinical Oncology (2024)

e12616 Background: Circulating tumor DNA (ctDNA) holds significant value in the comprehensive management of breast cancer (BC) patients, whereas long-standing questions have been raised concerning the practical utility of ctDNA in HR+/HER2- subtype. Herein, we evaluated the clinical activity of ctDNA in luminal B (HR+/HER2-, with either Ki67≥20% and/or PR&lt;20%) BC patients receiving neoadjuvant therapy. Methods: Patients received neoadjuvant chemotherapy (NCT) or neoadjuvant endocrine therapy combined with CDK4/6 inhibitors (NET) were enrolled. Tumor tissue and plasma samples were collected and subjected to sequencing. Blood was collected for ctDNA analysis before treatment (T0), 2-3 weeks after treatment (T1), at the midpoint of neoadjuvant treatment (T2), prior to surgery (S), and postoperatively (PO). The tumor tissues were biopsied or surgically excised at T0, T1, and S to assess somatic mutation profiling and pathological markers. NGS assays were performed with a custom-designed panel that covered 769 cancer-related genes. Results: As of Jan 7, 2024, 448 tumor tissue and plasma samples from 80 BC patients undergoing NCT (n = 57) or NET (n = 23) were sequenced and analyzed. At T0, positive ctDNA was detected in 62.8% (49/78, another two failed quality control) of the patients. Furthermore, ctDNA detection and the higher concentration had a significant correlation with clinicopathologic characteristics that confer aggressiveness, including larger tumor size, more lymph node metastases, and lower hormone receptor expression. There was also a certain relativity between ctDNA positivity and tumor grading as well as MammaPrint index ( P &lt; 0.1). With the progression of neoadjuvant therapy, the ctDNA positive rate decreased over time (T1: 32/80, 40.0%; T2: 11/61, 18.0%; S: 7/65, 10.8%; and PO: 6/64, 9.4%). Although no correlation was found between pretherapeutic Ki67 expression and T0 ctDNA status ( P = 0.871), the Ki67 expression in early cycles of neoadjuvant therapy (T1) was significantly higher in patients with inter-therapeutic detectable ctDNA. Moreover, the expression and decline of Ki67 after neoadjuvant therapy were significantly correlated with ctDNA positivity at T2, S, and PO. Among the patients who had undergone surgery, 8 patients were classified as RCB 0/1 and the rest 57 as RCB 2/3. All patients who exhibited RCB 0/1 were ctDNA negative at S and PO. Compared to RCB 2/3, patients with RCB 0/1 tumors showed a significant increase in ctDNA concentration at T0 ( P = 0.027). Subgroup analysis revealed similar trends in ctDNA status and concentration changes in the NCT group and NET group. Conclusions: We reported an unprecedented baseline ctDNA positivity in luminal B BC, and the ctDNA levels were closely associated with the clinicopathologic characteristics of patients. As the research progresses, more predictive and prognostic information is expected to be discovered. Clinical trial information: NCT05649475 .