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Background

Survival in patients with metastatic colorectal cancer (mCRC) has markedly improved in patients included in clinical trials. In population-based materials, improvements were seen until about a decade ago, but it is unclear if survival has continued to improve. It is also unclear if regional or gender differences exist.

Material and methods

All patients with mCRC (N = 19,566) in Sweden between 2007 and 2016 were identified from the national quality register, SCRCR, with almost complete coverage. Overall survival (OS) from diagnosis of metastatic disease was calculated in two calendar periods, 2007–2011 and 2012–2016. Differences between groups were compared using Cox regression.

Results

Median age was 72 years, 55% were males, synchronous presentation was seen in 13,630 patients and metachronous in 5936. In synchronous disease, the primary tumour was removed more often during the first than the second period (51% vs 41%, p < 0.001). Median OS (mOS) was 14.0 months. It was longer in those with metachronous than synchronous disease (17.6 vs 13.1 months, p < 0.001) and in males (15.0 vs 12.8 months, p < 0.001), and markedly influenced by age and primary location. It was longer in patients diagnosed during the second period than during the first (14.9 vs 13.1 months, HR 0.89 (95% CI 0.86–0.92), p < 0.001). This difference was seen in all subgroups according to sex, age, presentation, and sidedness. mOS was about one month shorter in 1/6 healthcare regions, most pronounced during the first period. Differences in median of up to 5 months were seen between the region with the shortest and longest mOS.

Conclusions

Overall survival in Swedish patients with mCRC has improved during the past decade but is still substantially worse than reported from clinical trials/hospital-based series, reflecting the selection of patients to trials. Regional differences were seen, but they decreased with time. Women did not have a poorer prognosis in multivariable analyses.

Background

KRAS 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.

Methods

Patients 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.

Results

The 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.

Conclusions

In 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.

BRAF-V600E mutation (mt) is a strong negative prognostic and predictive biomarker in metastatic colorectal cancer (mCRC). Non-V600Emt, designated atypical BRAFmt (aBRAFmt) are rare, and little is known about their frequency, co-mutations and prognostic and predictive role. These were compared between mutational groups of mCRC patients collected from three Nordic population-based or real-world cohorts. Pathology of aBRAFmt was studied. The study included 1449 mCRC patients with 51 (3%) aBRAFmt, 182 (13%) BRAF-V600Emt, 456 (31%) RAS&BRAF wild-type (wt) and 760 (52%) RASmt tumours. aBRAFmt were seen in 2% of real-world and 4% of population-based cohorts. Twenty-six different aBRAFmt were detected, 11 (22%) class 2 (serrated adenocarcinoma in 2/9 tested), 32 (64%) class 3 (serrated in 15/25) and 4 (8%) unclassified. aBRAFmt patients were predominantly male, had more rectal primaries, less peritoneal metastases, deficient mismatch repair in one (2%), and better survival after metastasectomy (89% 5-year overall survival [OS]-rate) compared with BRAF-V600Emt. aBRAFmt and BRAF-V600Emt had poorer performance status and received fewer treatment lines than RAS&BRAFwt and RASmt. OS among aBRAFmt (median 14.4 months) was longer than for BRAF-V600Emt (11.2 months), but shorter than for RAS&BRAFwt (30.5 months) and RASmt (23.4 months). Addition of bevacizumab trended for better OS for the aBRAFmt. Nine patients with aBRAFmt received cetuximab/panitumumab without response. aBRAFmt represents a distinct subgroup differing from other RAS/BRAF groups, with serrated adenocarcinoma in only half. OS for patients with aBRAFmt tumours was slightly better than for BRAF-V600Emt, but worse than for RASmt and RAS&BRAFwt. aBRAFmt should not be a contraindication for metastasectomy.