PURPOSE 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. EXPERIMENTAL DESIGN 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. RESULTS 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. CONCLUSIONS 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.

中文翻译：

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胰腺癌经典和基础转录亚型的临床和基因组特征。


目的 胰腺癌的转录分析定义了两种主要的转录亚型：经典亚型和基础亚型。初步数据表明，基底肿瘤患者的生存期较短，并且不同转录亚型对 FOLFIRINOX 和吉西他滨加白蛋白结合型紫杉醇的治疗敏感性不同。实验设计 我们检查了 8,743 名在 Caris Life Sciences 进行的胰腺癌 RNA 测序患者。在 RNA 测序上使用纯度无关亚型算法鉴定经典亚型和基础亚型，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 = 7,250） 和 （ii） 结果队列包括具有可用生存结果的转移性疾病患者 （n = 5,335）。两个队列共有 3,842 名患者。采用 Kaplan-Meier 曲线和 Cox 比例风险回归评估患者生存率。结果 在生物标志物队列中，3,063 例肿瘤 （42.2%） 为强经典 （SC），2,015 例肿瘤 （27.8%） 为强基底 （SB）。SC 和 SB 肿瘤与组织学表型和活检部位具有很强的相关性。SB 肿瘤的 KRAS 、 TP53 和 ARID1A 突变率较高，SMAD4 突变率较低，上皮-间质转化的转录证据较好。77 例病例中有 60 例 （78%） 在时间和/或空间不同的病灶之间保持其转录亚型。在结果队列中，SB 亚型与较短的总生存时间相关，无论他们是接受 FOLFIRINOX 还是吉西他滨加白蛋白结合型紫杉醇作为一线化疗。 突变的 KRAS 等位基因类型预后良好;然而，这种影响仅限于 SC 肿瘤，而所有突变的 KRAS 等位基因在 SB 肿瘤中的预后同样较差。结论 SB 亚型是较差结果的强独立预测因子，无论使用何种前期化疗方案。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。