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Characterisation of KRAS, Including KRAS G12C, Mutations in Gastrointestinal and Metastatic Colorectal Cancer

Focusing on the KRAS G12C variant
02 Jul 2021
Gastrointestinal cancers;  Pathology/Molecular biology

Three studies delineating the prevalence of KRAS mutations in gastrointestinal and colorectal cancer, with specific focus on the KRAS G12C mutation, and an evaluation of patient outcomes according to the mutation status were presented at the ESMO World Congress on Gastrointestinal Cancer 2021 (30 June - 3 July).

An analysis of a large patient population was presented by Prof. Mohamed L. Salem of the Levine Cancer Institute in Charlotte, US, which characterised KRAS mutation variants and determined the prevalence of the KRAS G12C variant in gastrointestinal malignancies.

Emerik Österlund, PhD student at the Uppsala University, Department of Immunology, Genetics and Pathology and Helsinki University Hospital and colleagues from Finland, Sweden and Norway evaluated the prevalence of KRAS and KRAS G12C mutations in 1441 patients with metastatic colorectal cancer.

Dr. Yuki Matsubara of the Department of Clinical Oncology, Aichi Cancer Center Hospital in  Nagoya, Japan and a Japan-based team provided evidence in a retrospective study that patients with colorectal cancer and the KRAS G12C mutation had shorter survival following first-line chemotherapy than those with non-G12C mutations.

The prevalence of the KRAS G12C variant differs across gastrointestinal tumour types and subtypes

Prof. Salem noted that sotorasib, a KRAS G12C inhibitor, has shown promising anticancer activity in patients with advanced solid tumours harbouring the KRAS G12C mutation, which underscored the need to define the occurrence of this variant across other types of KRAS-mutated solid tumours.

Since the distribution of KRAS variants has not been well described to date, Prof. Salem and co-investigators determined the prevalence of the different KRAS variants, including G12C and its associated genomic alterations, in gastrointestinal cancers by conducting this retrospective review of 17,009 patients with gastrointestinal cancers that also had Tempus xT or xF next-generation sequencing.

The associations between cancer subtypes and KRAS variants, KRAS variants and immunotherapy biomarkers, and co-mutations between KRAS G12C and other oncogenes was analysed using logistic regression.  False discovery rate-adjusted p-value (FDR-P) was used for multiple testing with FDR-P < 0.05 as the cut-off for statistical significance.

KRAS G12C was most frequently detected in appendiceal, colorectal, small bowel, pancreatic, and biliary cancers

KRAS mutations were detected in 7559 (44.4%) gastrointestinal tumours; 325 (4.3%) of the mutations were G12C. Among KRAS-mutated gastrointestinal tumours the most frequently identified were G12D (35.4%), G12V (23.5%), G12R (8.7%), G13D (8.0%), Q61H (4.6%), and G12C (4.3%).

The distribution of KRAS variants was found to differ according to the type of gastrointestinal tumour (FDR-P < 0.001).  In 3,693 KRAS mutated pancreatic cancers the most common variants were G12D (41.8%), G12V (31.6%), G12R (16.1%), Q61H (4.7%), and G12C (1.8%), whereas the most commonly occurring variants in 2,971 KRAS-mutated colorectal cancers were G12D (29.9%), G12V (20.0%), G13D (15.8%), G12C (7.0%), G12A (4.9%), and Q61H (4.2%). Among 136 KRAS-mutated appendiceal cancers, G12D (50.7%), G12V (25.7%), G12C (7.4%), G13D (7.4%), G12S (2.9%), and Q61H (2.2%) were the most prevalent variants.

Regarding all gastrointestinal cancers with and without KRAS mutations, G12C variants were most often found in 11 of 279 (3.9%) patients with appendiceal, 208 of 6586 (3.2%) patients with colorectal, 9 of 630 (1.4%) patients with small bowel, 66 of 5029 (1.3%) patients with pancreatic, and 18 of 1481 (1.2%) patients with biliary cancers.

The prevalence of KRAS G12C did not significantly differ between colon (3.2%), rectal (3.1%), and rectosigmoid (3.5%) tumours (p = 0.95). KRAS G12C mutations occurred infrequently in gastric cancers (9 of 1401; 0.6%), oesophageal adenocarcinomas (3 of 686; 0.004%), and hepatocellular carcinoma (1 of 467; 0.2%), and were not detected in 205 squamous cell carcinomas (SCCs) of the oesophagus or in 195 SCCs of the anal canal.

Significant differences among all gastrointestinal cancers in co-occurring genomic mutations with KRAS G12C compared to non-G12C were observed in the following genes: APC (67.1% versus 39.6%), CDKN2A (9.2% versus 26.6%), CTNNB1 (8.6% versus 4.0%), KEAP1 (4.0% versus 1.2%), and KMT2D (8.0% versus 3.8%) respectively (FDR-P < 0.05). No significant differences in co-occurring mutations between KRAS G12C and non-G12C tumours were observed in colorectal cancer.

Regarding microsatellite instable (MSI) status, gastrointestinal cancers with the KRAS G12C variant were less likely to be associated with MSI-high status than those without G12C (odds ratio [OR] 0.63; 0.23-1.72), and in KRAS-wild-type (OR 0.32; 0.12-0.87) tumours (FDR-P < 0.0001).

Patient characteristics did not differ significantly between patients with KRAS G12C mutation and those with other KRAS mutations in a Nordic cohort of patients with metastatic colorectal cancer

Emerik Österlund and colleagues from Scandinavia performed the biomarker study to determine the prognostic and possibly predictive value of KRAS G12C mutations in metastatic colorectal cancer. They explained that current data regarding the KRAS G12C mutation is limited and conflicting, although drugs have been developed targeting the cysteine residue of the G12C variant, making it of special interest to determine the prevalence of this mutation.

This analysis used combined data from patients in the prospective real-life Finnish RAXO study, its population-based data collection sub-study, and the population-based Scandinavian SP/PRCRC cohorts, but excluded patients with incomplete RAS and BRAF testing. Logistic and Cox regression models were used to compare demographics, treatments, and outcomes.

A total of 91 patients with KRAS G12C mutations were identified and characterised.

Among the respective cohorts listed above, the KRAS G12C mutation frequency in patients overall was 4%, 4% and 2%, and the KRAS G12C mutation frequency was 7%, 8%, and 4% among all patients with KRAS mutation across the respective cohorts.

No differences between the 91 patients with KRAS G12C mutation and 658 patients with other KRAS mutations were observed according to age, sex, performance status, synchronous/metachronous presentation, number of metastatic sites, blood counts, alkaline phosphatase, carcinoembryonic antigen (CEA) status, or median overall survival (OS).

Patient characteristics were similar between patients with KRAS G12C and those with other KRAS mutations

Regarding patient demographics in those with KRAS G12C mutation compared to patients with other KRAS mutations, the primary tumour site was right colon in 29% versus 34%, left colon in 37% versus 33%, and rectal in 34% versus 33% of the respective patients. Liver metastases were present in 65% versus 71%, lung in 40% versus 34%, peritoneal in 14% versus 18% and distant lymph node in 26% versus 22% of patients with the KRAS G12C variant versus those with other KRAS mutations. Systemic therapy was given to 90% of patients harbouring KRAS G12C and to 86% of patients with other KRAS mutations; no differences in number of lines of therapy, drug exposures, responses, and median OS was observed between these cohorts.

Metastasectomy and/or local ablations were performed in 38% of KRAS G12C patients versus 28% of patients with other KRAS mutations cases. Best supportive care was administered in 9% versus 13% of the respective groups, which affected OS non-significantly; median OS was 31.5 versus 22.8 months (hazard ratio [HR] 0.83; 95% sonfidence interval 0.64-1.08), respectively. However, median OS was unaffected within each treatment group, including metastasectomy, systemic therapy and best supportive care alone.

Differences regarding 456 RAS and BRAF wild-type tumours showed the same associations for KRAS G12C as for other KRAS or NRAS (n=54) mutations. Poorer survival was observed in patients with BRAF mutations.

Patients with the KRAS G12C mutation had shorter survival following first-line chemotherapy

Dr. Matsubara and a research team from Japan aimed to define the prognostic impact of the KRAS G12C mutation in patients with metastatic colorectal cancer in a real-world setting. They retrospectively reviewed the medical records of patients with metastatic colorectal cancer receiving first-line chemotherapy from January 2005 to December 2017 at four large oncology facilities in Japan. 

Of the 2,457 patients with metastatic colorectal cancer identified, selection criteria was met in 1,632 patients; KRAS exon 2 mutations were detected in 696 patients. In the overall population of 1,632 patients, the KRAS exon 2 mutations were as follows: 261 (16.0%) patients had KRAS G12D, 160 (9.8%) had G13D, 151 (9.3%) had G12V, 45 (2.8%) had G12C, 36 (2.2%) had G12S, and G12A was detected in 31 (1.9%) patients.

Patient characteristics were not significantly different between patients with the KRAS G12C and non-G12C mutations.

With median follow-up of 64.8 months, median progression-free survival (PFS) was 9.4 in patients with the KRAS G12C compared to 10.8 months in patients with non-G12C mutations (HR 1.47; 95% CI 1.08-2.01; p = 0.015); median OS was 21.1 versus 27.3 months, respectively (HR 1.50; 95% CI 1.08-2.08, p = 0.015).

By multivariate analysis, the KRAS G12C mutation was significantly associated with shorter first-line PFS (adjusted HR 1.43; 95% CI 1.04–1.96, p = 0.030) and OS (adjusted HR 1.42; 95% CI 1.01–2.00; p = 0.044).

Conclusions

Prof. Salem and colleagues commented the retrospective nature of their analysis. Treatment and outcome data were not available for the entirety of the dataset. Missing information on patient age and race may limit the power to detect any statistical difference in these variables between KRAS G12C and KRAS non-G12C cancers. They used a TMB cut-off of 10 mut/Mb to define TMB-high versus -low across all tumour types, but the optimal threshold, if any, to identify a cancer as TMB-high for immune checkpoint inhibitor selection remains the subject of debate. Prof. Salem concluded that their data suggest that KRAS G12D and G12V are the most common KRAS variants across the subtypes of gastrointestinal malignancies study; however, the distribution of KRAS variants significantly differed according to the cancer type. They found that KRAS G12C was most frequently observed in patients with appendiceal, colorectal, small bowel, biliary, and pancreatic cancers, but was not detected in small cell carcinoma of the oesophagus or anal canal. They observed significant differences in co-occuring genomic mutations with KRAS G12C, and tumours harbouring KRAS G12C were more likely to be associated with high TMB.  

Dr. Österlund and co-investigators found that left colon cancer is more common in KRAS G12C compared with other KRAS mutations. Peritoneal metastases are less common and lung metastases are more common in KRAS G12C compared with other KRAS mutations. KRAS G12C mutations have little effect on OS and PFS compared with other KRAS mutations. Patients with KRAS G12C-mutated tumours benefit from metastasectomy.

Dr. Matsubara and colleagues concluded that their retrospective study demonstrated that KRAS G12C mutation, as compared to non-G12C mutations, was significantly associated with shorter PFS and OS following first-line chemotherapy, which indicated the importance of a stratified treatment targeting KRAS G12C mutation in metastatic colorectal cancer.

Prof. Pierre Laurent-Puig of the University Paris Descartes in Paris, France who discussed the findings said that KRAS G12C mutations do not seem to have an impact on prognosis in non-metastatic colorectal cancer. KRAS G12C mutation seems to be an adverse prognostic factor in metastatic colorectal cancer, but many other confounding factors can explain this (smoking status, tumour location, type of metastatic spread, other genetic alterations and treatment) than the impact of mutation itself.

Disclosures

In Nordic study, Dr Österlund disclosed grants from the Finska Läkaresällskapet, the Finnish Cancer Foundation, the Competitive State Research Financing of the Expert Responsibility Area of Tampere, Turku, Helsinki, Oulu and Kuopio University Hospitals, Tampere and Helsinki University hospital research funds, and the Swedish Cancer Society. The infrastructure of the RAXO-study, with blood sampling, database and study nurses, was supported by pharmaceutical companies, including Amgen (unrestricted grant), Lilly, Merck KGaA, Roche Finland, Sanofi, and Servier (unrestricted grant).

No external funding was disclosed for other two studies.

References

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