KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer

Abstract

BackgroundKRAS mutations, present in over 40% of metastatic colorectal cancer (mCRC), are negative predictive factors for anti-EGFR therapy. Mutations in KRAS-G12C have a cysteine residue for which drugs have been developed. Published data on this specific mutation are conflicting; thus, we studied the frequency and clinical characteristics in a real-world and population-based setting.MethodsPatients from three Nordic population-based cohorts and the real-life RAXO-study were combined. RAS and BRAF tests were performed in routine healthcare, except for one cohort. The dataset consisted of 2,559 patients, of which 1,871 could be accurately classified as KRAS, NRAS, and BRAF-V600E. Demographics, treatments, and outcomes were compared using logistic regression. Overall survival (OS) was estimated with Kaplan–Meier, and differences were compared using Cox regression, adjusted for baseline factors.ResultsThe KRAS-G12C frequency was 2%–4% of all tested in the seven cohorts (mean 3%) and 4%–8% of KRAS mutated tumors in the cohorts (mean 7%). Metastasectomies and ablations were performed more often (38% vs. 28%, p = 0.040), and bevacizumab was added more often (any line 74% vs. 59%, p = 0.007) for patients with KRAS-G12C- vs. other KRAS-mutated tumors, whereas chemotherapy was given to similar proportions. OS did not differ according to KRAS mutation, neither overall (adjusted hazard ratio (HR) 1.03; 95% CI 0.74–1.42, reference KRAS-G12C) nor within treatment groups defined as “systemic chemotherapy, alone or with biologics”, “metastasectomy and/or ablations”, or “best supportive care”, RAS and BRAF wild-type tumors (n = 548) differed similarly to KRAS-G12C, as to other KRAS- or NRAS-mutated (n = 66) tumors.ConclusionsIn these real-life and population-based cohorts, there were no significant differences in patient characteristics and outcomes between patients with KRAS-G12C tumors and those with other KRAS mutations. This contrasts with the results of most previous studies claiming differences in many aspects, often with worse outcomes for those with a KRAS-G12C mutation, although not consistent. When specific drugs are developed, as for this mutation, differences in outcome will hopefully emerge.

Clinical efficacy of sequential treatments in KRASG12C-mutant metastatic colorectal cancer: findings from a real-life multicenter Italian study (CRC-KR GOIM)

“…In line with previous findings, liver (71/111, 64%) and lung (46/111; 41.4%) were the most frequent metastatic sites. 10 , 13 , 15 …”

“… 19 , 20 , 21 , 22 The percentage of KRASG12C -mutant mCRC is low, however, and the prognostic and predictive role of this mutation is still debated and poorly understood. 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 …”

“… 7 , 8 The presence of KRASG12C is rare (2%-4%), however, and so far, merely few and heterogenous retrospective series have evaluated the impact of KRASG12C on the response to chemotherapy and as a prognostic biomarker, with discordant results. 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 KRASG12C tumors were associated with a shorter OS compared with non- KRASG12C tumors. 9 , 10 , 11 , 12 , 13 Other studies reported that KRASG12C mutation conferred resistance with reduced overall response rate (ORR) to first-line chemotherapy doublets plus bevacizumab compared with different KRAS mutations, but did not affect progression-free survival (PFS) or OS.…”

“… 14 Finally, another study reported no difference in terms of response and OS across KRASG12C and other KRAS -mutant mCRC. 15 Furthermore, due to the retrospective nature of those studies, the small number of patients included in the studies and the setting and/or the type of chemotherapy regimens (mono-chemotherapy versus chemotherapy doublets, post-operative chemotherapy versus palliative treatment), the best treatment strategy is still unknown.…”

Health-Related Quality of Life in Metastatic Colorectal Cancer Patients Treated with Curative Resection and/or Local Ablative Therapy or Systemic Therapy in the Finnish RAXO-Study

“…It is also often combined with metastasectomy to obtain a radical procedure when surgery cannot leave a sufficient amount of normal liver behind [ 42 ], constituting the majority of patients with LAT in this study. In the non-curative setting, systemic therapy as the only strategy leads to median OS of 15–21 months in population-based patient series [ 2 , 47 ]. The CLOCC trial compared systemic therapy with or without radiofrequency ablation and demonstrated that adding a local treatment might prolong OS in patients with non-resectable CRC liver metastases [ 48 ]; contrary to the aim of cure with LAT in this study.…”