Landscape of , Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in -Mutated Cancers

Overview

Journal JCO Precis Oncol

Specialty Oncology

Date 2022 Mar 23

PMID 35319967

Authors

Mohamed E Salem

Sherif M El-Refai

Wei Sha

Alberto Puccini

Axel Grothey

Thomas J George

Jimmy J Hwang

Bert ONeil

Alexander S Barrett

Kunal C Kadakia

Laura W Musselwhite

Derek Raghavan

Eric Van Cutsem

Josep Tabernero

Jeanne Tie

Affiliations

Soon will be listed here.

Abstract

Purpose: Promising single-agent activity from sotorasib and adagrasib in -mutant tumors has provided clinical evidence of effective KRAS signaling inhibition. However, comprehensive analysis of -variant prevalence, genomic alterations, and the relationship between and immuno-oncology biomarkers is lacking.

Materials And Methods: Retrospective analysis of deidentified records from 79,004 patients with various cancers who underwent next-generation sequencing was performed. Fisher's exact test evaluated the association between cancer subtypes and variants. Logistic regression assessed comutations with other oncogenes and the association between variants and immuno-oncology biomarkers.

Results: Of the 79,004 samples assessed, 13,758 (17.4%) harbored mutations, with 1,632 (11.9%) harboring and 12,126 (88.1%) harboring other variants (). Compared with across all tumor subtypes, was more prevalent in females (56% 51%, false discovery rate-adjusted value [FDR-] = .0006), current or prior smokers (85% 56%, FDR- < .0001), and patients age > 60 years (73% 63%, FDR- ≤ .0001). The most frequent variants across all subtypes were G12D (29.5%), G12V (23.0%), G12C (11.9%), G13D (6.5%), and G12R (6.2%). was most prevalent in patients with non-small-cell lung cancer (9%), appendiceal (3.9%), colorectal (3.2%), tumor of unknown origin (1.6%), small bowel (1.43%), and pancreatic (1.3%) cancers. Compared with -mutated, -mutated tumors were significantly associated with tumor mutational burden-high status (17.9% 8.4%, odds ratio [OR] = 2.38; FDR- < .0001). -mutated tumors exhibited a distinct comutation profile from -mutated tumors, including higher comutations of (20.59% 5.95%, OR = 4.10; FDR- < .01) and (15.38% 4.61%, OR = 3.76; FDR- < .01).

Conclusion: This study presents the first large-scale, pan-cancer genomic characterization of . The mutation was more prevalent in females and older patients and appeared to be associated with smoking status. tumors exhibited a distinct comutation profile and were associated with tumor mutational burden-high status.

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References

Downward J . Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003; 3(1):11-22. DOI: 10.1038/nrc969. View

Canon J, Rex K, Saiki A, Mohr C, Cooke K, Bagal D . The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019; 575(7781):217-223. DOI: 10.1038/s41586-019-1694-1. View

Arbour K, Rizvi H, Plodkowski A, Hellmann M, Knezevic A, Heller G . Treatment Outcomes and Clinical Characteristics of Patients with KRAS-G12C-Mutant Non-Small Cell Lung Cancer. Clin Cancer Res. 2021; 27(8):2209-2215. PMC: 8771577. DOI: 10.1158/1078-0432.CCR-20-4023. View

Ostrem J, Peters U, Sos M, Wells J, Shokat K . K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013; 503(7477):548-51. PMC: 4274051. DOI: 10.1038/nature12796. View

Ebi H, Faber A, Engelman J, Yano S . Not just gRASping at flaws: finding vulnerabilities to develop novel therapies for treating KRAS mutant cancers. Cancer Sci. 2014; 105(5):499-505. PMC: 4317830. DOI: 10.1111/cas.12383. View

Limsui D, Vierkant R, Tillmans L, Wang A, Weisenberger D, Laird P . Cigarette smoking and colorectal cancer risk by molecularly defined subtypes. J Natl Cancer Inst. 2010; 102(14):1012-22. PMC: 2915616. DOI: 10.1093/jnci/djq201. View

Weijenberg M, Aardening P, de Kok T, De Goeij A, van den Brandt P . Cigarette smoking and KRAS oncogene mutations in sporadic colorectal cancer: results from the Netherlands Cohort Study. Mutat Res. 2008; 652(1):54-64. DOI: 10.1016/j.mrgentox.2007.12.008. View

Dong Z, Zhong W, Zhang X, Su J, Xie Z, Liu S . Potential Predictive Value of and Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma. Clin Cancer Res. 2017; 23(12):3012-3024. DOI: 10.1158/1078-0432.CCR-16-2554. View

Sun L, Hsu M, Cohen R, Langer C, Mamtani R, Aggarwal C . Association Between KRAS Variant Status and Outcomes With First-line Immune Checkpoint Inhibitor-Based Therapy in Patients With Advanced Non-Small-Cell Lung Cancer. JAMA Oncol. 2021; 7(6):937-939. PMC: 8050787. DOI: 10.1001/jamaoncol.2021.0546. View

10.

Tsoi K, Pau C, Wu W, Chan F, Griffiths S, Sung J . Cigarette smoking and the risk of colorectal cancer: a meta-analysis of prospective cohort studies. Clin Gastroenterol Hepatol. 2009; 7(6):682-688.e1-5. DOI: 10.1016/j.cgh.2009.02.016. View

11.

Jones S, Lambert S, Williams G, Best J, Sampson J, Cheadle J . Increased frequency of the k-ras G12C mutation in MYH polyposis colorectal adenomas. Br J Cancer. 2004; 90(8):1591-3. PMC: 2410274. DOI: 10.1038/sj.bjc.6601747. View

12.

Samowitz W, Albertsen H, Sweeney C, Herrick J, Caan B, Anderson K . Association of smoking, CpG island methylator phenotype, and V600E BRAF mutations in colon cancer. J Natl Cancer Inst. 2006; 98(23):1731-8. DOI: 10.1093/jnci/djj468. View

13.

Botteri E, Iodice S, Bagnardi V, Raimondi S, Lowenfels A, Maisonneuve P . Smoking and colorectal cancer: a meta-analysis. JAMA. 2008; 300(23):2765-78. DOI: 10.1001/jama.2008.839. View

14.

Beaubier N, Bontrager M, Huether R, Igartua C, Lau D, Tell R . Integrated genomic profiling expands clinical options for patients with cancer. Nat Biotechnol. 2019; 37(11):1351-1360. DOI: 10.1038/s41587-019-0259-z. View

15.

Beaubier N, Tell R, Lau D, Parsons J, Bush S, Perera J . Clinical validation of the tempus xT next-generation targeted oncology sequencing assay. Oncotarget. 2019; 10(24):2384-2396. PMC: 6481324. DOI: 10.18632/oncotarget.26797. View

16.

Ostrem J, Shokat K . Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov. 2016; 15(11):771-785. DOI: 10.1038/nrd.2016.139. View

17.

Fernandes L, Epstein C, Bobe A, Bell J, Stumpe M, Salazar M . Real-world Evidence of Diagnostic Testing and Treatment Patterns in US Patients With Breast Cancer With Implications for Treatment Biomarkers From RNA Sequencing Data. Clin Breast Cancer. 2021; 21(4):e340-e361. DOI: 10.1016/j.clbc.2020.11.012. View

18.

Andre T, Shiu K, Kim T, Jensen B, Jensen L, Punt C . Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020; 383(23):2207-2218. DOI: 10.1056/NEJMoa2017699. View

19.

Hong D, Fakih M, Strickler J, Desai J, Durm G, Shapiro G . KRAS Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med. 2020; 383(13):1207-1217. PMC: 7571518. DOI: 10.1056/NEJMoa1917239. View

20.

Araujo L, Souza B, Leite L, Parma S, Lopes N, Malta F . Molecular profile of KRAS G12C-mutant colorectal and non-small-cell lung cancer. BMC Cancer. 2021; 21(1):193. PMC: 7905642. DOI: 10.1186/s12885-021-07884-8. View