Precision medicine for pancreatic cancer: Characterizing the clinicogenomic landscape and outcomes of KRAS G12C-mutated disease Journal Article
| Authors: | Keane, F.; Chou, J. F.; Walch, H.; Schoenfeld, J.; Singhal, A.; Cowzer, D.; Harrold, E.; O'Connor, C. A.; Park, W.; Varghese, A.; El Dika, I.; Balogun, F.; Yu, K. H.; Capanu, M.; Schultz, N.; Yaeger, R.; O'Reilly, E. M. |
| Article Title: | Precision medicine for pancreatic cancer: Characterizing the clinicogenomic landscape and outcomes of KRAS G12C-mutated disease |
| Abstract: | 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. © 2024 The Author(s). Published by Oxford University Press. All rights reserved. |
| Keywords: | adult; cancer survival; clinical article; controlled study; aged; aged, 80 and over; middle aged; unclassified drug; dna binding protein; overall survival; somatic mutation; genetics; mutation; dna-binding proteins; clinical feature; mortality; cisplatin; fluorouracil; gemcitabine; paclitaxel; cancer patient; comparative study; pancreatic neoplasms; cancer staging; nuclear protein; etoposide; carcinoma, pancreatic ductal; protein; cohort analysis; smoking; transcription factor; protein p53; tumor marker; transcription factors; nuclear proteins; irinotecan; body mass; folinic acid; pancreas tumor; tumor suppressor protein p53; genomics; cyclin dependent kinase inhibitor 2a; cyclin-dependent kinase inhibitor p16; oncogene k ras; codon; drug therapy; oxaliplatin; tp53 protein, human; protein p21; proto-oncogene proteins p21(ras); glycine; kras protein, human; personalized medicine; medical history; smad4 protein; clinical outcome; pancreatic ductal carcinoma; germline mutation; cystine; very elderly; humans; human; male; female; article; precision medicine; smad4 protein, human; biomarkers, tumor; oncogenomics; personalized cancer therapy; arid1a protein, human; cdkn2a protein, human; protein arid1a |
| Journal Title: | JNCI: Journal of the National Cancer Institute |
| Volume: | 116 |
| Issue: | 9 |
| ISSN: | 0027-8874 |
| Publisher: | Oxford University Press |
| Date Published: | 2024-09-01 |
| Start Page: | 1429 |
| End Page: | 1438 |
| Language: | English |
| DOI: | 10.1093/jnci/djae095 |
| PUBMED: | 38702822 |
| PROVIDER: | scopus |
| PMCID: | PMC11378314 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Eileen M. O’Reilly -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work