KRAS 野生型胰腺腺癌细胞的精准医疗。

Precision medicine for KRAS wild-type pancreatic adenocarcinomas.

机构信息

Gustave Roussy, Département de Médecine, 94800 Villejuif, France; Sorbonne Université, Faculté de Médecine, 75005 Paris, France.

Gustave Roussy, Département de Médecine, 94800 Villejuif, France; Oncostat INSERM U1018, Gustave Roussy, Ligue Contre le Cancer, Université Paris-Saclay, Villejuif, France; Gustave Roussy, Département de Biostatistiques et D'épidémiologie, Université Paris-Saclay, Villejuif, France.

出版信息

Eur J Cancer. 2024 Jan;197:113497. doi: 10.1016/j.ejca.2023.113497. Epub 2023 Dec 15.

DOI:10.1016/j.ejca.2023.113497

PMID:38134480

Abstract

BACKGROUND

KRAS mutation is the most common molecular alteration in pancreatic adenocarcinoma (PDAC), and around 10% of patients harbor KRAS wild-type tumors (KRAS).

METHODS

A retrospective chart review of clinical/molecular data was performed including all PDAC patients with a determined KRAS status (tumor molecular profiling on tissue or liquid biopsy).

RESULTS

342 patients were included with 54 KRAS PDAC (16%) compared to 288 patients with KRAS PDAC. Median age was 61 years [IQR:54.0;67.0] and 164 pts (48%) were female. At diagnosis, KRAS patients (63%) were more frequently diagnosed at a non-metastatic stage compared to KRAS patients (41%) (p = 0.003). Regarding metastatic sites, liver was less frequent in KRAS (39%, p < 0.0001). Median overall survival (mOS) from initial diagnosis was significantly higher in the KRAS group compared to KRAS (50.8 months, CI95% [32.0-NR] vs 21.1 months, CI95% [18.9-23.4] (p < 0.004 after adjustment on age, ECOG and stage at diagnosis). In first-line systemic treatment, (mostly FOLFIRINOX) progression-free survival (PFS) was also higher in KRAS. Based on ESCAT classification, a putative actionable alteration (ESCAT I-III) was identified in 19 (36%) KRAS pts and 46 (16%) KRAS patients (p < 0.0001) with more alterations in FGFR2, BRAF(V600E), NRTK and more MSI tumors. KRAS harbored also fewer alterations in TP53, CDKN2A, and SMAD4. 12 KRAS patients received a molecularly-matched treatment with clinical benefit and improved outcomes compared to KRAS patients.

CONCLUSIONS

KRAS patients display distinct disease characteristics and outcomes with prolonged overall survival. KRAS patients also harbor more actionable molecular alterations, leading to higher survival rates after receiving molecularly matched treatments.

摘要

背景

KRAS 突变是胰腺导管腺癌（PDAC）中最常见的分子改变，约 10%的患者存在 KRAS 野生型肿瘤（KRAS）。

方法

对所有 KRAS 状态确定的 PDAC 患者（组织或液体活检的肿瘤分子分析）进行临床/分子数据的回顾性图表审查。

结果

共纳入 342 例患者，其中 54 例为 KRAS PDAC（16%），288 例为 KRAS PDAC。中位年龄为 61 岁[IQR：54.0；67.0]，164 例（48%）为女性。在诊断时，与 KRAS 患者（41%）相比，KRAS 患者（63%）更常被诊断为非转移性阶段（p=0.003）。关于转移部位，KRAS 患者的肝脏转移较少（39%，p<0.0001）。与 KRAS 患者相比，KRAS 患者的初始诊断后的中位总生存期（mOS）明显更高（50.8 个月，CI95%[32.0-NR] vs 21.1 个月，CI95%[18.9-23.4]（调整年龄、ECOG 和诊断时的分期后，p<0.004）。在一线系统治疗中，KRAS 患者的无进展生存期（PFS）也更高（主要为 FOLFIRINOX）。根据 ESCAT 分类，在 19 例（36%）KRAS 患者和 46 例（16%）KRAS 患者中发现了潜在的可治疗改变（ESCAT I-III）（p<0.0001），其中 FGFR2、BRAF(V600E)、NRTK 改变更多，且更多为微卫星不稳定肿瘤。KRAS 还携带较少的 TP53、CDKN2A 和 SMAD4 改变。与 KRAS 患者相比，12 例 KRAS 患者接受了分子匹配治疗，具有临床获益，并改善了预后。