Lundy Joanne, Harris Marion, Zalcberg John, Zimet Allan, Goldstein David, Gebski Val, Borsaru Adina, Desmond Christopher, Swan Michael, Jenkins Brendan J, Croagh Daniel
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.
Front Oncol. 2021 Dec 9;11:770022. doi: 10.3389/fonc.2021.770022. eCollection 2021.
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death and lacks effective treatment options. Diagnostic endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsies represent an appealing source of material for molecular analysis to inform targeted therapy, as they are often the only available tissue for patients presenting with PDAC irrespective of disease stage. However, EUS-FNA biopsies are typically not used to screen for precision medicine studies due to concerns about low tissue yield and quality. Epidermal growth factor receptor (EGFR) inhibition has shown promise in clinical trials of unselected patients with advanced pancreatic cancer, but has not been prospectively tested in wild-type patients. Here, we examine the clinical utility of EUS-FNA biopsies for molecular screening of wild-type PDAC patients for targeted anti-EGFR therapy to assess the feasibility of this approach.
Fresh frozen EUS-FNA or surgical biopsies from PDAC patient tumours were used to screen for mutations. Eligible patients with recurrent, locally advanced, or metastatic wild-type status who had received at least one prior line of chemotherapy were enrolled in a pilot study (ACTRN12617000540314) and treated with panitumumab at 6mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was 4-month progression-free survival (PFS).
275 patient biopsies were screened for mutations, which were detected in 88.3% of patient samples. 8 eligible wild-type patients were enrolled onto the interventional study between November 2017 and December 2020 and treated with panitumumab. 4-month PFS was 14.3% with no objective tumour responses observed. The only grade 3/4 treatment related toxicity observed was hypomagnesaemia.
This study demonstrates proof-of-principle feasibility to molecularly screen patients with pancreatic cancer for targeted therapies, and confirms diagnostic EUS-FNA biopsies as a reliable source of tumour material for molecular analysis. Single agent panitumumab was safe and tolerable but led to no objective tumour responses in this population.
胰腺导管腺癌（PDAC）是癌症死亡的主要原因，且缺乏有效的治疗选择。诊断性内镜超声引导下细针穿刺活检（EUS-FNA）是一种有吸引力的分子分析材料来源，可为靶向治疗提供依据，因为对于无论疾病处于何阶段的PDAC患者，EUS-FNA活检往往是唯一可获得的组织。然而，由于担心组织获取量少和质量问题，EUS-FNA活检通常不用于精准医学研究的筛查。表皮生长因子受体（EGFR）抑制在未选择的晚期胰腺癌患者临床试验中已显示出前景，但尚未在野生型患者中进行前瞻性测试。在此，我们研究EUS-FNA活检在野生型PDAC患者分子筛查以进行靶向抗EGFR治疗中的临床实用性，以评估该方法的可行性。
使用来自PDAC患者肿瘤的新鲜冷冻EUS-FNA活检或手术活检来筛查突变。符合条件的复发、局部晚期或转移性野生型患者，且之前至少接受过一线化疗，被纳入一项试点研究（ACTRN12617000540314），并接受帕尼单抗治疗，剂量为6mg/kg静脉注射，每2周一次，直至疾病进展或出现不可接受的毒性。主要终点是4个月无进展生存期（PFS）。
对275份患者活检样本进行了突变筛查，在88.3%的患者样本中检测到了突变。2017年11月至2020年12月期间，8名符合条件的野生型患者被纳入干预性研究，并接受帕尼单抗治疗。4个月PFS为14.3%，未观察到客观肿瘤反应。观察到的唯一3/4级治疗相关毒性是低镁血症。
本研究证明了对胰腺癌患者进行分子筛查以进行靶向治疗的原理性可行性，并确认诊断性EUS-FNA活检是用于分子分析的可靠肿瘤材料来源。单药帕尼单抗安全且可耐受，但在该人群中未导致客观肿瘤反应。
