Nationwide evaluation of mutation-tailored anti-EGFR therapy selection in patients with colorectal cancer in daily clinical practice

Abstract

For a nationwide real-word data study on the application of predictive mutation testing of patients with colorectal cancer (CRC) for anti-epidermal growth factor receptor (EGFR) therapy stratification, pathology data were collected from the Dutch Pathology Registry from October 2017 until June 2019 (N=4060) and linked with the Netherlands Cancer Registry. Mutation testing rates increased from 24% at diagnosis of stage IV disease to 60% after 20-23 months of follow-up (p<0.001). Application of anti-EGFR therapy in KRAS/NRAS wild-type patients was mainly observed from the third treatment line onwards (65% vs 17% in first/second treatment line (p<0.001)). The national average KRAS/NRAS/BRAF mutation rate was 63.9%, being similar for next-generation sequencing (NGS)-based approaches and single gene tests (64.4% vs 61.2%, p=ns). NGS-based approaches detected more additional potential biomarkers, for example, ERBB2 amplifications (p<0.05). Therefore, single gene tests are suitable to stratify patients with mCRC for anti-EGFR therapy, but NGS is superior enabling upfront identification of therapy resistance or facilitate enrolment into clinical trials.

Keywords: colorectal neoplasms; diagnostic techniques and procedures; molecular; pathology.

Figure 1

Molecular characterisation of patients with colorectal cancer (CRC). (A) Timeline and flow chart showing the search strategy to obtain all nationwide pathology reports of mutation analysis of patients with CRC performed between 1 October 2017 until 30 June 2019. A large proportion of reports was excluded as no mutation analyses were present (ie, the queries ‘molecular biology’, ‘MSI’ (microsatellite instability) and ‘MLH1’ obtained high amount of reports with immunohistochemistry of mismatch repair proteins). Manual curation of obtained pathology reports showed 4060 patients with CRC undergoing predictive mutation analyses in this 21-month study period. (B) Frequency of reported KRAS, NRAS and BRAF mutations obtained from the pathology reports depicted in panel A. (C) Funnel plot showing the reported diagnostic yield (ie, percentage of KRAS, NRAS and BRAF mutations) per pathology department. Nationwide percentage and 95% CI are shown. (D) Frequency of reported KRAS, NRAS and BRAF mutations by multigene panel next-generation sequencing (NGS) and non-NGS analysis. (E)Mutational landscapes of CRC cases concerning KRAS, NRAS, BRAF, PIK3CA and ERBB2 alterations. Results of multigene panel NGS approaches are shown left and non-NGS approaches right. Each column represents a tumour sample. Each row represents a gene. A coloured bar represents a variant (see legend), a white bar represents no alteration and a grey bar represents not analysed (ie, not present in NGS panel or single gene analysis).

Figure 2

Mutation testing rates of patients with metastatic colorectal cancer (CRC). (A) Timeline and flow chart showing the data collection of the pathology reports of all patients with CRC diagnosed with synchronous metastasis between 1 October and 31 December 2017. These patients were obtained from the Netherlands Cancer Registry and linked to the Dutch Pathology Registry (PALGA) by a trusted third party in September 2019. This linked dataset was used to study the mutation testing rates. Unlinked patients with CRC were mainly caused by absence of a pathological diagnosis. (B)The uptake of mutation analysis for patients with stage IV CRC after different periods of follow-up: 1–3 months, 6–9 months, 12–15 months and 20–23 months of follow-up. Data are shown for the whole cohort (N=620) and corrected for patients alive 1 month after initial diagnosis (N=571), 6 months after diagnosis (N=436), 12 months after diagnosis (N=321) and after 21 months (N=227). The McNemar test was applied to study significance. ^**P <0.001.

Figure 3

Uptake of anti-epidermal growth factor receptor (EGFR) therapy in patients with metastatic colorectal cancer (mCRC). (A) Time line and flow chart showing the data collection of both synchronous and metachronous mCRC that underwent mutation analysis between October and December 2017. These patients were linked to the Netherlands Cancer Registry by a trusted third party, enabling therapy registration of these patients. Twenty-five of the patients were excluded for further analysis, as they were diagnosed with stage I–III CRC in 2017 and hence were no candidates for anti-EGFR therapy. Patient records were fully updated including specification of all treatment lines for patients with diagnosis of the primary tumour from 2015 onwards (N=402). For patients with a primary tumour before 2015 (N=84), registration was limited to whether anti-EGFR therapy was applied or not. Unlinked cases were caused by limitations in the linkage procedures. (B) Uptake of anti-EGFR therapy in patients without a KRAS or NRAS mutation merged over all treatment lines (left). In the right panel of the graph uptake for patients that received one or two treatment lines is compared with patients receiving three or more treatment lines. NB: for 35 patients without a KRAS or NRAS mutation it was only registered whether anti-EGFR therapy was applied or not. The Fisher’s exact test was applied to study differences in molecular testing rates. **P<0.001. (C) Overview of the proportions of patients that were treated with anti-EGFR therapy per treatment line. The number of patients present in each line is depicted on top of each bar.