Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Clin Cancer Res. 2024 Nov 1;30(21):4932-4942. doi: 10.1158/1078-0432.CCR-24-1164.
Transcriptional profiling of pancreatic cancers has defined two main transcriptional subtypes: classical and basal. Initial data suggest shorter survival for patients with basal tumors and differing treatment sensitivity to FOLFIRINOX and gemcitabine plus nab-paclitaxel by transcriptional subtype.
We examined 8,743 patients with RNA sequencing from pancreatic cancers performed at Caris Life Sciences. Classical and basal subtypes were identified using purity independent subtyping algorithm on RNA sequencing, and two cohorts were analyzed: (i) the biomarker cohort included patients with complete molecular profiling data (n = 7,250) and (ii) the outcome cohort included patients with metastatic disease with available survival outcomes (n = 5,335). A total of 3,842 patients were shared between the two cohorts. Kaplan-Meier curves and Cox proportional hazards regression were used to assess patient survival.
In the biomarker cohort, 3,063 tumors (42.2%) were strongly classical (SC) and 2,015 tumors (27.8%) were strongly basal (SB). SC and SB tumors showed strong associations with histologic phenotypes and biopsy sites. SB tumors had higher rates of KRAS, TP53, and ARID1A mutations, lower rates of SMAD4 mutation, and transcriptional evidence of epithelial-mesenchymal transition. Sixty of 77 cases (78%) maintained their transcriptional subtype between temporally and/or spatially disparate lesions. In the outcome cohort, the SB subtype was associated with shorter overall survival time, regardless of whether they received FOLFIRINOX or gemcitabine plus nab-paclitaxel as first-line chemotherapy. The mutant KRAS allele type was prognostic of outcomes; however, this impact was restricted to SC tumors, whereas all mutant KRAS alleles had similarly poor outcomes in SB tumors.
The SB subtype is a strong independent predictor of worse outcomes, regardless of the up-front chemotherapy regimen used. Clinical trials should further investigate pancreatic cancer transcriptional subtypes as a prognostic and predictive biomarker.
对胰腺癌进行转录组分析，定义了两种主要的转录亚型：经典型和基底型。初步数据表明，基底型肿瘤患者的生存时间更短，并且根据转录亚型对 FOLFIRINOX 和吉西他滨联合 nab-紫杉醇的治疗敏感性不同。
我们检查了来自 Caris Life Sciences 的 8743 名接受 RNA 测序的胰腺癌患者。使用 RNA 测序的纯度独立亚分类算法鉴定经典型和基底型亚型，并分析了两个队列：（i）生物标志物队列，包括具有完整分子分析数据的患者（n = 7250），（ii）结果队列，包括具有可用生存结果的转移性疾病患者（n = 5335）。共有 3842 名患者在两个队列之间共享。使用 Kaplan-Meier 曲线和 Cox 比例风险回归评估患者的生存情况。
在生物标志物队列中，3063 个肿瘤（42.2%）为强经典型（SC），2015 个肿瘤（27.8%）为强基底型（SB）。SC 和 SB 肿瘤与组织表型和活检部位密切相关。SB 肿瘤的 KRAS、TP53 和 ARID1A 突变率较高，SMAD4 突变率较低，并且具有上皮-间充质转化的转录证据。60 例（78%）时空分离病变的肿瘤保持其转录亚型。在结果队列中，SB 亚型与总体生存时间较短相关，无论其一线化疗是否使用 FOLFIRINOX 或吉西他滨联合 nab-紫杉醇。突变型 KRAS 等位基因类型是预后的预测因素；然而，这种影响仅限于 SC 肿瘤，而在 SB 肿瘤中，所有突变型 KRAS 等位基因的预后均较差。
无论使用何种一线化疗方案，SB 亚型都是预后不良的独立强预测因素。临床试验应进一步研究胰腺癌转录亚型作为预后和预测生物标志物。
