Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Surgery, MedStar Health, Baltimore, Maryland.
JAMA Surg. 2022 Jul 1;157(7):e221362. doi: 10.1001/jamasurg.2022.1362. Epub 2022 Jul 13.
The use of neoadjuvant therapy (NAT) in resectable pancreatic ductal adenocarcinoma (PDAC) remains controversial. A favorable pathologic response (complete or marked tumor regression) to NAT is associated with better outcomes in patients with resected PDAC. The role of NAT for early systemic control compared with immediate surgical resection for PDAC is under investigation. In the era of precision medicine, biomarkers for patient selection and prediction of therapy response are crucial.
To evaluate the use of assessment for protein expression on fine-needle aspiration (FNA) biopsy specimens in predicting pathologic response to NAT in treatment-naive patients.
DESIGN, SETTING, AND PARTICIPANTS: This was a single-institution prognostic study from a high-volume center for pancreatic cancer. All specimens were obtained between January 1, 2009, and December 31, 2018, with a median (SE) follow-up of 20.2 (1.4) months. Analysis of the data was performed from October 1, 2019, to April 30, 2021. Targeted RNA sequencing of frozen FNA biopsy specimens from a discovery cohort of 23 patients was performed to identify genes with aberrant expression that was associated with patients' pathologic response to NAT. Immunohistochemical staining was performed on an additional 80 FNA biopsy specimens to assess expression of matrix metalloproteinase 7 (MMP-7) and its association with pathologic response. Receiver operating characteristic curves for prediction of favorable pathologic response were determined.
In the discovery cohort (12 [52.1%] male; 3 [13.0%] Black and 20 [86.9%] White), RNA sequencing showed that lower MMP-7 expression was associated with favorable pathologic response (College of American Pathologists system scores of 0 [complete response] and 1 [marked response]). In the validation cohort (40 [50.0%] female; 9 [11.3%] Black and 71 [88.7%] White), patients with negative MMP-7 expression were significantly more likely to have a favorable pathologic response (odds ratio, 21.25; 95% CI, 6.19-72.95; P = .001). Receiver operating characteristic curves for prediction of favorable pathologic response from multivariable Cox proportional hazards regression modeling showed that MMP-7 expression increased the area under the curve from 0.726 to 0.906 (P < .001) even after stratifying by resectability status. The positive predictive value and negative predictive value of MMP-7 protein expression on FNA biopsy specimens in predicting unfavorable pathologic response (scores of 2 [partial response] or 3 [poor or no response]) were 88.2% and 73.9%, respectively.
Assessment of MMP-7 expression on FNA biopsy specimens at the time of diagnosis may help identify patients who would benefit the most from NAT.
重要性：新辅助治疗（NAT）在可切除胰腺导管腺癌（PDAC）中的应用仍存在争议。NAT 后病理完全缓解或显著缓解与接受 PDAC 切除术患者的更好结局相关。与立即进行手术切除相比，NAT 用于早期全身控制的作用正在研究中。在精准医学时代，患者选择和治疗反应预测的生物标志物至关重要。
目的：评估细针抽吸（FNA）活检标本中蛋白表达评估预测治疗初治患者对 NAT 的病理反应。
设计、地点和参与者：这是一项来自高容量胰腺癌中心的单机构预后研究。所有标本均于 2009 年 1 月 1 日至 2018 年 12 月 31 日获得，中位（SE）随访时间为 20.2（1.4）个月。数据分析于 2019 年 10 月 1 日至 2021 年 4 月 30 日进行。对 23 例患者的发现队列的冷冻 FNA 活检标本进行靶向 RNA 测序，以鉴定与患者对 NAT 的病理反应相关的异常表达基因。对另外 80 份 FNA 活检标本进行免疫组织化学染色，以评估基质金属蛋白酶 7（MMP-7）的表达及其与病理反应的关系。确定预测有利病理反应的受试者工作特征曲线。
结果：在发现队列（12 例 [52.1%] 男性；3 例 [13.0%] 黑人，20 例 [86.9%] 白人）中，RNA 测序显示 MMP-7 表达较低与有利的病理反应相关（美国病理学家协会系统评分 0 [完全缓解] 和 1 [显著缓解]）。在验证队列（40 例 [50.0%] 女性；9 例 [11.3%] 黑人，71 例 [88.7%] 白人）中，MMP-7 表达阴性的患者发生有利病理反应的可能性显著更高（比值比，21.25；95%CI，6.19-72.95；P = .001）。多变量 Cox 比例风险回归模型预测有利病理反应的受试者工作特征曲线显示，即使在分层考虑可切除性状态后，MMP-7 表达也将曲线下面积从 0.726 增加到 0.906（P < .001）。MMP-7 蛋白在 FNA 活检标本中的表达预测不良病理反应（评分 2 [部分缓解] 或 3 [差或无反应]）的阳性预测值和阴性预测值分别为 88.2%和 73.9%。
结论和相关性：在诊断时评估 MMP-7 在 FNA 活检标本中的表达可能有助于识别最受益于 NAT 的患者。
