Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Department of Internal Medicine, Breast Cancer Center South Holland South, Ikazia Hospital, Rotterdam, The Netherlands.
Breast Cancer Res Treat. 2024 May;205(1):87-95. doi: 10.1007/s10549-023-07231-4. Epub 2024 Jan 31.
HER2 overexpressing circulating tumor cells (CTCs) are observed in up to 25% of HER2-negative metastatic breast cancer patients. Since targeted anti-HER2 therapy has drastically improved clinical outcomes of patients with HER2-positive breast cancer, we hypothesized that patients with HER2 overexpressing CTCs might benefit from the addition of trastuzumab to chemotherapy.
In this single-arm, phase II trial, patients with HER2-positive CTCs received trastuzumab as addition to first-line treatment with taxane chemotherapy. Patients with detectable CTCs but without HER2 overexpression that received taxane chemotherapy only, were used as control group. The primary outcome measure was progression-free rate at 6 months (PFR6), with a target of 80%. In November 2022, the study was terminated early due to slow patient accrual.
63 patients were screened, of which eight patients had HER2-positive CTCs and were treated with trastuzumab. The median number of CTCs was 15 per 7.5 ml of blood (range 1-131) in patients with HER2-positive CTCs, compared to median 5 (range 1-1047) in the control group. PFR6 was 50% in the trastuzumab group and 54% in the taxane monotherapy group, with no significant difference in median PFS (8 versus 9 months, p = 0.51).
No clinical benefit of trastuzumab was observed, although this study was performed in a limited number of patients. Additionally, we observed a strong correlation between the number of evaluable CTCs and the presence of HER2-positive CTCs. We argue that randomized studies investigating agents that are proven to be solely effective in the HER2-positive patient group in patients with HER2-positive CTCs and HER2-negative tissue are currently infeasible. Several factors contribute to this impracticality, including the need for more stringent thresholds, and the rapidly evolving landscape of cancer treatments.
在多达 25%的 HER2 阴性转移性乳腺癌患者中观察到 HER2 过表达循环肿瘤细胞（CTC）。由于针对 HER2 的靶向治疗极大地改善了 HER2 阳性乳腺癌患者的临床结局，我们假设 HER2 过表达 CTC 患者可能受益于曲妥珠单抗联合化疗。
在这项单臂、II 期试验中，HER2 阳性 CTC 患者在接受紫杉烷化疗一线治疗的基础上加用曲妥珠单抗。仅接受紫杉烷化疗且可检测到 CTC 但无 HER2 过表达的患者作为对照组。主要观察指标为 6 个月无进展率（PFR6），目标为 80%。2022 年 11 月，由于患者入组缓慢，该研究提前终止。
筛选了 63 例患者，其中 8 例患者的 HER2 阳性 CTC 接受了曲妥珠单抗治疗。HER2 阳性 CTC 患者的中位 CTC 数为每 7.5ml 血液 15 个（范围 1-131），而对照组为每 7.5ml 血液 5 个（范围 1-1047）。曲妥珠单抗组的 PFR6 为 50%，紫杉烷单药组为 54%，中位无进展生存期（PFS）无显著差异（8 个月与 9 个月，p=0.51）。
尽管本研究纳入的患者数量有限，但并未观察到曲妥珠单抗的临床获益。此外，我们观察到可评估的 CTC 数量与 HER2 阳性 CTC 的存在之间存在很强的相关性。我们认为，目前在 HER2 阳性 CTC 且组织学为 HER2 阴性的患者中，针对仅对 HER2 阳性患者群体有效的药物进行随机研究是不可行的。这一不切实际的情况有几个因素导致，包括需要更严格的阈值以及癌症治疗领域的快速发展。
