From the Hepatopancreatobiliary Service, Department of Surgery (Ecker, Court, D'Angelica, Drebin, Jarnagin, Wei), Memorial Sloan Kettering Cancer Center, New York, NY.
Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands (Janssen).
J Am Coll Surg. 2022 Aug 1;235(2):342-349. doi: 10.1097/XCS.0000000000000212. Epub 2022 Apr 5.
There is increased use of neoadjuvant fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the management of localized pancreatic ductal adenocarcinoma (PDAC), yet there are few validated biomarkers of treatment response.
Consecutive patients (n = 196) with resectable, borderline resectable or locally advanced PDAC (2012-2019) receiving FOLFIRINOX as initial treatment and with targeted sequencing of a pretreatment biopsy were identified in a prospective institutional database. Genomic alterations were determined in the 4 driver mutations (KRAS, TP53, CDKN2A, SMAD4), and associations between genomic alterations and clinical outcomes were assessed.
Alterations in KRAS (n = 172, 87.8%) and TP53 (n = 131, 66.8%) were common; alterations in CDKN2A (n = 49, 25.0%) and SMAD4 (n = 36, 18.4%) were less frequently observed. A total of 105 patients (53.6%) were able to undergo resection, of whom 8 (7.6%) had a complete/near-complete pathologic response. There were no somatic alterations associated with major pathologic response. Alterations in SMAD4 were associated with a lower rate of surgical resection (27.8% vs 59.4%, p < 0.001); this was additionally observed in a multivariable regression model accounting for resectability status (OR 0.35, 95% confidence interval [CI] 0.15-0.85). Thirty-three patients (16.8%) developed metastatic disease while on neoadjuvant therapy. SMAD4 alterations were associated with a significant risk of metastatic progression on therapy when controlling for resectability status (OR 3.31, 95% CI 1.44-7.60).
SMAD4 alterations are associated with more frequent development of metastasis during neoadjuvant FOLFIRINOX and lower probability of reaching surgical resection. Evaluation of alternative chemotherapy regimens in patients with SMAD4 alterations will be important to distinguish whether this represents a prognostic or predictive biomarker.
氟尿嘧啶、亚叶酸、伊立替康和奥沙利铂（FOLFIRINOX）在局部胰腺导管腺癌（PDAC）的治疗中的应用越来越多，但治疗反应的有效生物标志物却很少。
连续入选了 196 例接受 FOLFIRINOX 作为初始治疗的可切除、交界可切除或局部晚期 PDAC（2012-2019 年）患者，这些患者在一个前瞻性机构数据库中进行了靶向预处理活检的测序。在 4 个驱动突变（KRAS、TP53、CDKN2A、SMAD4）中确定了基因组改变，并评估了基因组改变与临床结果之间的关系。
KRAS 改变（n=172，87.8%）和 TP53 改变（n=131，66.8%）很常见；CDKN2A 改变（n=49，25.0%）和 SMAD4 改变（n=36，18.4%）则少见。共有 105 例患者（53.6%）能够进行手术切除，其中 8 例（7.6%）有完全/接近完全的病理缓解。没有与主要病理缓解相关的体细胞改变。SMAD4 改变与手术切除率较低相关（27.8%比 59.4%，p<0.001）；在考虑到可切除性的多变量回归模型中也观察到了这种相关性（OR 0.35，95%置信区间 [CI] 0.15-0.85）。33 例患者（16.8%）在新辅助治疗期间发生转移性疾病。控制可切除性状态后，SMAD4 改变与治疗过程中转移进展的显著风险相关（OR 3.31，95%CI 1.44-7.60）。
SMAD4 改变与新辅助 FOLFIRINOX 期间更频繁地发生转移以及更不可能达到手术切除相关。在 SMAD4 改变的患者中评估替代化疗方案将很重要，以区分这是否是预后或预测生物标志物。
