Background Mutated KRAS is the most common oncogene alteration in pancreatic cancer (PDAC), and KRAS G12C mutations (KRAS G12Cmut) are observed in 1-2%. Several inhibitors of KRAS G12C have recently demonstrated promise in solid tumors, including PDAC. Little is known regarding clinical, genomics and outcome data of this population. Methods Patients with PDAC and KRAS G12Cmut were identified at Memorial Sloan Kettering Cancer Center (MSK), and via the AACR Project GENIE database. Clinical, treatment, genomic and outcomes data were analysed. A cohort of patients at MSK with non-G12C KRAS PDAC was included for comparison. Results Among 3,571 patients with PDAC, 39 with KRAS G12Cmut were identified (1.1%). Median age was 67 years, 56% were female. Median BMI was 29.2 kg/m2, 67% had a smoking history. Median OS 13 months (9.4, not reached (NR)) for stage IV, and 26 months (23, NR) for stage I-III. Complete genomic data (via AACR GENIE) was available for N = 74. Most common co-alterations included: TP53 (73%), CDKN2A (33%), SMAD4 (28%), and ARID1A (21%). Compared with a large cohort (N = 2931) of non-G12C KRAS-mutated PDAC, ARID1A co-mutations were more frequent in KRAS G12Cmut (P < .05). OS did not differ between KRAS G12Cmut and non-G12C KRAS PDAC. Germline pathogenic variants were identified in 17%. N = 2 received KRAS G12C-directed therapy. Conclusion PDAC and KRAS G12Cmut may be associated with a distinct clinical phenotype. Genomic features are similar to non-G12C KRAS-mutated PDAC, although enrichment of ARID1A co-mutations was observed. Targeting of KRAS G12C in PDAC provides a precedent for broader KRAS targeting in PDAC.

中文翻译：

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胰腺癌精准医学：表征 KRAS G12C 突变疾病的临床基因组景观和结果

背景 KRAS 突变是胰腺癌 (PDAC) 中最常见的癌基因改变，KRAS G12C 突变 (KRAS G12Cmut) 的发生率为 1-2%。 KRAS G12C 的几种抑制剂最近在实体瘤（包括 PDAC）中显示出良好的前景。关于该人群的临床、基因组学和结果数据知之甚少。方法 在纪念斯隆凯特琳癌症中心 (MSK) 并通过 AACR Project GENIE 数据库识别患有 PDAC 和 KRAS G12Cmut 的患者。分析了临床、治疗、基因组和结果数据。 MSK 的一组患有非 G12C KRAS PDAC 的患者被纳入比较。结果 在 3,571 名 PDAC 患者中，发现 39 名患者患有 KRAS G12Cmut（1.1%）。中位年龄为 67 岁，其中 56% 为女性。 BMI 中位数为 29.2 kg/m2，67% 有吸烟史。 IV 期的中位 OS 为 13 个月（9.4，未达到 (NR)），I-III 期为 26 个月（23，NR）。 N = 74 的完整基因组数据（通过 AACR GENIE）可用。最常见的共同改变包括：TP53 (73%)、CDKN2A (33%)、SMAD4 (28%) 和 ARID1A (21%)。与大量非 G12C KRAS 突变 PDAC 队列 (N = 2931) 相比，ARID1A 共突变在 KRAS G12Cmut 中更为频繁 (P < .05)。 KRAS G12Cmut 和非 G12C KRAS PDAC 之间的操作系统没有差异。 17% 的人发现了种系致病变异。 N = 2 接受 KRAS G12C 定向治疗。结论 PDAC 和 KRAS G12Cmut 可能与不同的临床表型相关。尽管观察到 ARID1A 共突变的富集，但基因组特征与非 G12C KRAS 突变的 PDAC 相似。 PDAC 中 KRAS G12C 的靶向为 PDAC 中更广泛的 KRAS 靶向提供了先例。