PO.CL01.10 · 临床研究
循环肿瘤DNA动态可预测PIK3CA突变型乳腺癌对新辅助化疗的反应，但不能预测长期结局
Circulating tumor DNA dynamics predict the response to neoadjuvant chemotherapy but not long-term outcomes in PIK3CA -mutated breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：循环肿瘤DNA（ctDNA）动态在接受新辅助化疗（NAC）的PIK3CA突变型乳腺癌中的临床意义尚不明确。我们评估了在基线和术前之间定义的ctDNA模式是否与病理完全缓解（pCR）和长期远处结局相关。
方法：本研究前瞻性纳入了122例计划在2016年5月至2017年9月期间接受NAC的I-III期乳腺癌患者。从治疗前福尔马林固定石蜡包埋（FFPE）活检标本中提取肿瘤DNA，使用微滴式数字PCR（ddPCR）分析PIK3CA热点突变（E542K、E545K和H1047R）。在基线（NAC前）、术前和术后采集血液样本。通过ddPCR定量肿瘤匹配的PIK3CA突变型ctDNA。基线和术前之间的ctDNA动态被分为四种模式：持续阴性（-/-）、清除（+/-）、持续阳性（+/+）和NAC后新发（-/+）。pCR定义为乳腺和淋巴结中浸润性癌完全消失。在中位随访96个月（范围9-108）后评估远处转移。
结果：从122例患者中的113个原发肿瘤中提取了肿瘤DNA。在113个肿瘤中的36个（32%）中检测到PIK3CA突变。可从36例PIK3CA突变型肿瘤患者中的34例（94%）获得血浆样本。在这34例患者中，ctDNA模式如下：17例为持续阴性，14例为清除，2例为持续阳性，1例为NAC后新发。所有患者术后ctDNA均为阴性。9例患者（26%）出现pCR，包括17例持续阴性患者中的5例和14例清除患者中的4例，而持续阳性或NAC后新发的患者均未达到pCR。33例患者可进行远处复发的随访。5例患者发生远处转移：持续阴性组3例，清除组1例，持续阳性组1例。尽管持续阳性患者在数值上表现出更高的转移率（2例中的1例），但大多数晚期远处复发源自术前ctDNA阴性的模式。
结论：在接受NAC治疗的PIK3CA突变型乳腺癌中，术前ctDNA阳性提示残留疾病，但不能可靠地预测长期结局。两点式ctDNA评估可能不足以进行预后分层。需要进一步的长期随访和大规模研究来验证这些发现。
查看英文原文 English abstract
Background: The clinical significance of circulating tumor DNA (ctDNA) dynamics in PIK3CA -mutated breast cancer treated with neoadjuvant chemotherapy (NAC) remains unclear. We evaluated whether ctDNA patterns defined between baseline and pre-surgery are associated with pathological complete response (pCR) and long-term distant outcomes.
Methods: A total of 122 patients with stage I-III breast cancer who were scheduled to receive NAC between May 2016 and September 2017 were prospectively enrolled in this study. Tumor DNA extracted from pretreatment formalin-fixed, paraffin-embedded (FFPE) biopsy specimens was analyzed for PIK3CA hotspot mutations (E542K, E545K, and H1047R) using droplet digital PCR (ddPCR). Blood samples were collected at baseline (pre-NAC), pre-surgery, and post-surgery. Tumor-matched PIK3CA -mutated ctDNA was quantified by ddPCR. ctDNA dynamics between baseline and pre-surgery were categorized into four patterns: persistent-negative (-/-), cleared (+/-), persistent-positive (+/+), and post-NAC-emergent (-/+). pCR was defined as the complete disappearance of invasive carcinoma in both the breast and lymph nodes. Distant metastasis was assessed after a median follow-up of 96 months (range, 9-108).
Results: Tumor DNA was extracted from 113 primary tumors in 122 patients. PIK3CA mutations were detected in 36 (32%) of the 113 tumors. Plasma samples were available from 34 (94%) of 36 patients with PIK3CA -mutated tumors. Among these 34 patients, the ctDNA patterns were as follows: 17 were persistent-negative, 14 were cleared, two were persistent-positive, and one was post-NAC-emergent. Post-surgical ctDNA was negative in all patients. pCR occurred in nine patients (26%), including five of 17 persistent-negative patients and four of 14 cleared patients, whereas none of the persistent-positive or post-NAC-emergent patients achieved pCR. Follow-up for distant recurrence was available for 33 patients. Distant metastasis developed in five patients: Three in the persistent-negative group, one in the cleared group, and one in the persistent-positive group. Although persistent-positive patients showed a numerically higher metastatic rate (one of two), most late distant relapses arose from preoperative ctDNA-negative patterns.
Conclusions: In PIK3CA -mutated breast cancer treated with NAC, pre-surgical ctDNA positivity indicated residual disease but did not reliably predict long-term outcomes. A two-point ctDNA assessment may be insufficient for prognostic stratification. Further long-term follow-up and large-scale studies are needed to validate these findings.
利益披露 Disclosure
A. Sato, None..
M. Tanabe, None.