Allele-specific KRAS mutations as prognostic biomarkers in mucinous adenocarcinoma of the appendix and colorectal cancer.

Abstract

3628 Background: Kristen rat sarcoma virus ( KRAS) mutations (MT) are reported in 40-45% of colorectal cancer (CRC), and they are associated with poor prognosis. In mucinous adenocarcinoma of the appendix (MAAP), which is often treated as CRC due to its rarity, KRAS MT are reported in >50% of tumors, and they are associated with favorable prognosis. We explored whether allele-specific KRAS MT are associated with overall survival (OS) in stage IV MAAP and CRC. Methods: The cBioCancer Genomics Portal was used to obtain genomic data. The prevalence of KRAS MT and the OS associated with allele-specific KRAS MT were explored in stage IV CRC (MSK, Cancer Cell 2018 cohort) and MAAP (MSK, J Clin Oncol 2022 cohort) patients. Survival analysis was performed using the Kaplan-Meier method with log-rank test comparisons. Results: The prevalence of KRASMT in stage IV MAAP (N=149) and CRC (N=1099) was 79.8% and 44.2% respectively. The prevalence of allele-specific KRAS MT (G12D, G12V, G13D and G12C) in MAAP/CRC was 42.3% / 12.4%, 18.8% / 9%, 6.7% / 7.7% and 6% / 2.8% respectively. All other KRAS MT in MAAP/CRC were seen in 6% and 12.2% respectively. In MAAP, the median OS (mOS) in KRAS MT vs. KRAS wild-type (WT) was 147m vs. 50m (p=0.003). Compared to the mOS in KRAS WT, the mOS was 147m (p=0.004) in G12D, 74m (p=0.140) in G12V, not reached (NR) (p=0.049) in G13D and 34m (p=0.589) in G12C. In CRC, the mOS in KRAS MT vs. KRAS WT was 60m vs. 79m (p=0.012). Compared to the mOS in KRAS WT, the mOS was 58m (p=0.249) in G12D, 58m (p=0.015) in G12V, 49m (p=0.002) in G13D and 65m (p=0.437) in G12C. The mOS in MAAP vs. CRC was 50m vs. 79m (p=0.022) in KRAS WT, 147m vs. 58m (p=0.02) in G12D, 74m vs. 58m (p=0.34) in G12V, NR vs. 49m (p=0.044) in G13D and 34m vs. 65m (p=0.13) in G12C. The favorable mOS associated with G12D in MAAP remained significant after adjusting for age, grade and TP53 (p=0.028) Conclusions: KRAS MT are more common in MAAP (79.8%) than in CRC (44.2%). In contrast to CRC, KRAS MT in MAAP are associated with favorable prognosis. Allele-specific KRAS MT are associated with different mOS in MAAP and CRC. The mOS in MAAP with KRAS G12D was exceptionally favorable (147m). To our knowledge, this is the first study to explore allele-specific KRAS mutations as prognostic biomarkers in MAAP, and adds additional data to support the distinct differences between MAAP and CRC at the molecular level. [Table: see text]