Department of Digestive Surgery, Rouen University Hospital, Rouen, France.
Department of Genomic and Personalized Medicine in Cancer and Neurological Disorders, Normandie University, UNIROUEN, Rouen University Hospital, Rouen, France.
Ann Surg. 2024 Nov 1;280(5):734-744. doi: 10.1097/SLA.0000000000006468. Epub 2024 Aug 5.
To investigate in patients treated for a resectable pancreatic ductal adenocarcinoma [pancreatic adenocarcinoma (PA)], the prognostic value of baseline carbohydrate antigen 19.9 (CA19-9) and circulating tumor DNA (ctDNA) for overall survival (OS), to improve death risk stratification, based on a planned ancillary study from PANACHE01-PRODIGE 48 trial.
Biological borderline situation that was first used by the MD Anderson, became a standard practice following the international consensus conference in 2016 to manage PA. Regarding the risk of systemic disease, especially in the setting of "markedly elevated" CA19-9, neoadjuvant therapy is advised to avoid unnecessary surgery, with a risk of early recurrence. To best define biological borderline situations, new biomarkers are needed.
Characteristics at diagnosis and OS were compared between patients with or without ctDNA status available. OS was estimated with the Kaplan-Meier method and compared with a log-rank test. The restricted cubic spline approach was used to identify the optimal threshold for biological parameters for death risk stratification. Univariate and multivariate Cox proportional hazard models were estimated to assess the association of ctDNA status and other parameters with OS.
Among the 132 patients from the primary population for analysis in the PANACHE01 -PRODIGE 48 trial, 92(71%) were available for ctDNA status at diagnosis. No selection bias was identified between patients with or without ctDNA status. Fourteen patients (15%) were ctDNA+ and exhibited a higher risk for death [ P = 0.0188; hazard ratio (95% CI): 2.28 (1.12-4.63)]. In the 92 patients with ctDNA status available among the other parameters analyzed, only CA19-9 was statically associated with OS in univariate analysis. Patients with a log of CA19-9 equal or superior to 4.4 that corresponds to a CA19-9 of 80 UI/mL were identified at higher risk for death [ P = 0.0143; hazard ratio (95% CI): 2.2 (1.15-4.19)]. In multivariate analysis, CA19-19 remained independently associated with OS ( P = 0.0323). When combining the 2 biomarkers, the median OS was 19.4 [IC 95%: 3.8-not reached (NR)] months, 30.2 (IC 95%: 17.1-NR) months and NR (IC 95%: 39.3-NR) for "CA19-9 high and ctDNA+ group," "CA19-9 high or ctDNA+ group," and "CA19-9 low and ctDNA- group," respectively (log-rank P = 0.0069).
Progress in the management of potentially operable PA remains limited, relying solely on strategies to optimize the sequence of complete treatment, based on modern multidrug chemotherapy (FOLFIRINOX, GemNabPaclitaxel) and surgical resection. The identification of risk criteria, such as the existence of systemic disease, is an important issue, currently referred to as "biological borderline disease." Few data, particularly from prospective studies, allow us to identify biomarkers other than CA19-9. Combining ctDNA with CA19-9 could be of interest to best define biological borderline situations in PA.
在接受可切除胰腺导管腺癌（PA）治疗的患者中，研究基线糖抗原 19.9（CA19-9）和循环肿瘤 DNA（ctDNA）对总生存期（OS）的预后价值，以改善死亡风险分层，这是基于 PANACHE01-PRODIGE 48 试验的辅助研究。
首先由 MD Anderson 使用的生物学边界情况，在 2016 年国际共识会议后成为管理 PA 的标准做法。关于全身疾病的风险，特别是在“明显升高”的 CA19-9 情况下，建议进行新辅助治疗以避免不必要的手术，因为存在早期复发的风险。为了最好地定义生物学边界情况，需要新的生物标志物。
比较了具有或不具有 ctDNA 状态的患者在诊断时的特征和 OS。使用 Kaplan-Meier 方法估计 OS，并与对数秩检验进行比较。使用受限立方样条方法确定用于死亡风险分层的生物参数的最佳阈值。使用单变量和多变量 Cox 比例风险模型评估 ctDNA 状态和其他参数与 OS 的关联。
在 PANACHE01-PRODIGE 48 试验的主要人群中，有 132 名患者进行了分析，其中 92 名（71%）在诊断时可获得 ctDNA 状态。在具有或不具有 ctDNA 状态的患者之间未发现选择偏倚。14 名患者（15%）为 ctDNA+，死亡风险更高[P=0.0188；风险比（95%CI）：2.28（1.12-4.63）]。在其他分析的 92 名具有 ctDNA 状态的患者中，只有 CA19-9 在单变量分析中与 OS 具有统计学相关性。CA19-9 对数等于或高于 4.4（相当于 CA19-9 为 80 UI/mL）的患者死亡风险更高[P=0.0143；风险比（95%CI）：2.2（1.15-4.19）]。在多变量分析中，CA19-19 仍然与 OS 独立相关（P=0.0323）。当结合这两种生物标志物时，中位 OS 分别为 19.4[IC 95%：3.8-NR]个月、30.2[IC 95%：17.1-NR]个月和 NR（IC 95%：39.3-NR）为“CA19-9 高且 ctDNA+组”、“CA19-9 高或 ctDNA+组”和“CA19-9 低且 ctDNA-组”（对数秩 P=0.0069）。
潜在可手术 PA 的治疗进展仍然有限，仅依赖于优化基于现代多药化疗（FOLFIRINOX、GemNabPaclitaxel）和手术切除的完整治疗序列的策略。识别风险标准（如全身疾病的存在）是一个重要问题，目前被称为“生物学边界疾病”。很少有数据，特别是来自前瞻性研究的数据，允许我们确定除 CA19-9 之外的其他生物标志物。将 ctDNA 与 CA19-9 结合起来可能有助于更好地定义 PA 中的生物学边界情况。
