Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
David M. Rubenstein Center for Pancreas Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
J Natl Cancer Inst. 2024 Sep 1;116(9):1429-1438. doi: 10.1093/jnci/djae095.
BACKGROUND: Mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogene alteration in pancreatic ductal adenocarcinoma, and KRAS glycine to cystine substitution at codon 12 (G12C) mutations (KRAS G12Cmut) are observed in 1%-2%. Several inhibitors of KRAS G12C have recently demonstrated promise in solid tumors, including pancreatic cancer. Little is known regarding clinical, genomics, and outcome data of this population. METHODS: Patients with pancreatic cancer and KRAS G12Cmut were identified at Memorial Sloan Kettering Cancer Center and via the American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange database. Clinical, treatment, genomic, and outcomes data were analyzed. A cohort of patients at Memorial Sloan Kettering Cancer Center with non-G12C KRAS pancreatic cancer was included for comparison. RESULTS: Among 3571 patients with pancreatic ductal adenocarcinoma, 39 (1.1%) with KRAS G12Cmut were identified. Median age was 67 years, and 56% were female. Median body mass index was 29.2 kg/m2, and 67% had a smoking history. Median overall survival was 13 months (95% CI: 9.4 months, not reached) for stage IV and 26 months (95% CI: 23 months, not reached) for stage I-III. Complete genomic data (via American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange database) was available for 74 patients. 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 pancreatic ductal adenocarcinoma, ARID1A co-mutations were more frequent in KRAS G12Cmut (P < .05). Overall survival did not differ between KRAS G12Cmut and non-G12C KRAS pancreatic ductal adenocarcinoma. Germline pathogenic variants were identified in 17% of patients; 2 patients received KRAS G12C-directed therapy. CONCLUSION: Pancreatic cancer and KRAS G12Cmut may be associated with a distinct clinical phenotype. Genomic features are similar to non-G12C KRAS-mutated pancreatic cancer, although enrichment of ARID1A co-mutations was observed. Targeting of KRAS G12C in pancreatic cancer provides a precedent for broader KRAS targeting in pancreatic cancer.
背景：突变的 Kirsten 大鼠肉瘤病毒致癌基因同源物（KRAS）是胰腺导管腺癌中最常见的致癌基因改变，并且在 1%-2%的病例中观察到 KRAS 甘氨酸到半胱氨酸取代密码子 12（G12C）突变（KRAS G12Cmut）。最近，几种 KRAS G12C 抑制剂在实体瘤中，包括胰腺癌中，显示出了希望。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和美国癌症研究协会项目基因组学、证据、肿瘤、信息、交换数据库中确定了患有胰腺导管腺癌和 KRAS G12Cmut 的患者。分析了临床、治疗、基因组和结果数据。为了进行比较，还纳入了纪念斯隆凯特琳癌症中心的一组患有非 G12C KRAS 胰腺导管腺癌的患者。
结果：在 3571 名胰腺导管腺癌患者中，发现了 39 名（1.1%）患有 KRAS G12Cmut。中位年龄为 67 岁，56%为女性。中位体重指数为 29.2kg/m2，67%有吸烟史。IV 期患者的中位总生存期为 13 个月（95%CI：9.4 个月，未达到），I-III 期患者的中位总生存期为 26 个月（95%CI：23 个月，未达到）。对于 74 名患者，完整的基因组数据（通过美国癌症研究协会项目基因组学、证据、肿瘤、信息、交换数据库）是可用的。最常见的共同改变包括 TP53（73%）、CDKN2A（33%）、SMAD4（28%）和 ARID1A（21%）。与非 G12C KRAS 突变的胰腺导管腺癌的大型队列（n=2931）相比，KRAS G12Cmut 中 ARID1A 共突变更为常见（P<.05）。KRAS G12Cmut 与非 G12C KRAS 胰腺导管腺癌的总生存期无差异。在 17%的患者中发现了种系致病性变异；2 名患者接受了 KRAS G12C 定向治疗。
结论：胰腺导管腺癌和 KRAS G12Cmut 可能与独特的临床表型相关。基因组特征与非 G12C KRAS 突变的胰腺导管腺癌相似，尽管观察到 ARID1A 共突变的富集。KRAS G12C 在胰腺癌中的靶向治疗为胰腺癌中更广泛的 KRAS 靶向治疗提供了先例。
Genet Test Mol Biomarkers. 2020-12
Technol Cancer Res Treat. 2020
Lung Cancer. 2023-10
N Engl J Med. 2023-8-24
J Clin Oncol. 2023-9-1
CA Cancer J Clin. 2023-1
N Engl J Med. 2023-1-5
N Engl J Med. 2023-1-5
Am Soc Clin Oncol Educ Book. 2022-4
Zotero 插件