Prevalence and characteristics of KRAS-G12D mutations in patients with solid malignancies.

Abstract

e15027 Background: The KRAS mutations are among the most common genetic mutations found in cancer. Novel KRAS-G12D inhibitors have recently shown potent antitumor activity in KRAS-G12D-bearing tumor cells. Here, we investigate the features of solid tumors harboring the KRAS-G12D mutation. Methods: Patients with KRAS-G12D mutations were identified from the AACR Project GENIE registry v16.1 public. Each tumor type patients were divided into group A (KRAS-wild), group B (KRAS-mutant non G12D) and group C (KRAS-G12D mutant) then clinical data, tumor details, and genomic data were analyzed. Results: Among 221164 samples from 191239 patients, we identified 5% (n = 9529 samples from 9078 patients) positive for KRAS-G12D mutations. These mutations represented 33.26% of Pancreatic cancer (n = 3048), 24.56% of appendicular cancer (n = 225), 23.94% of ampullary cancer (n = 107), 15.37% of small bowel cancer (n = 91) and 13% of colorectal cancer (n = 2751), etc. Regarding pancreatic cancer, the age at Which Sequencing was Reported (Years) was 63 (26-88), 67 (41.5-88), and 66 (38-88) in groups A, B, and C, respectively (P- < 10-10, q- < 10-10). Males represented 56.63%, 50.83%, and 52.82% in groups A, B, and C, respectively (p-4.662e-4, q-5.245e-4). The median mutation count was 4 (1-7), 5 (1-8), and 5 (1-8) in groups A, B, and C, respectively (P- < 10-10, q- < 10-10). The fraction of genome altered was 0.16 (0-1), 0.05 (0-0.52), and 0.06 (0-0.51) in groups A, B, and C, respectively (P- < 10-10, q- < 10-10). BRAF, PTEN, TP53, TSC2, NRAS, TSC1, IDH1 and SMARCB1 mutations were significantly different among the three groups. Regarding appendicular cancer, the Goblet Cell Carcinoid of the Appendix represented 41.4%, 1.96%, and 0.44% while the Mucinous Adenocarcinoma represented 21.63%, 49.8%, and 52.44% in groups A, B, and C, respectively (P- < 10-10, q- < 10-10). In addition, the median mutation count, fraction Genome Altered and TP53 mutation were significantly different between the three groups. Among colorectal cancer patients, the median age was 59 (17-88), 59 (18-88), and 58 (19-88) in groups A, B, and C, respectively (P- 1.760e-3, q- 0.0262). Males represented 55.94%, 50.62%, and 51.95% in groups A, B, and C, respectively (p- < 10-10, q- 9.87e-10). The median mutation count was 7(1-680), 8 (1-644), and 8 (1-532) in groups A, B, and C, respectively (P- < 10-10, q- < 10-10). The fraction of genome altered was 0.18 (0-1), 0.16 (0-1), and 0.14 (0-1) in groups A, B, and C, respectively (P- 1.65e-7, q- 3.683e-6). APC, BRAF, FBXW7, NRAS, PIK3CA, TP53, NOTCH3, ARID1A and other mutations were significantly different among the three groups. Conclusions: KRAS-G12D mutations are widely distributed among solid malignancies and have different clinical and genomic landscapes. Clinical trials evaluating KRAS-G12D inhibitors are ongoing.