Table 4.
An overview of the potential clinical relevance of the evolving molecular biomarker landscape in mCRC
| Biomarker | Clinical relevancea | Biomarker type | Clinical implications |
|---|---|---|---|
| DPD (DPYD) | I | Predictive | See Table 1 for current guidance. Testing before fluoropyrimidine administration is not routinely recommended. However, some European countries currently recommend genotype-guided individualised dosing and this may become increasingly universally utilised in the clinic |
| UGT1A1 | I | Predictive | See Table 1 for current guidance |
| RAS (KRAS, NRAS) | I | Predictive | See Table 1 for current guidance |
| MSI | I | Predictive and prognostic | See Table 1 for current guidance |
| BRAF | II | Prognostic; predictive value to be confirmed | See Table 1 for current guidance |
| CMS | III | Predictive and prognostic | CMS has been shown to be prognostic for response and survival outcomes and predictive for chemotherapy efficacy |
| CRIS | III | Predictive | CRIS has been shown to predict response to anti-EGFR therapy |
| HER2 | II | Predictive; prognostic value to be confirmed | Alterations in this gene have been associated with poorer survival outcomes. HER2 may become a valuable therapeutic target in mCRC; dual HER2-targeted therapy has demonstrated efficacy |
| EGFR | III | Predictive | See Table 1 for current guidance |
| HER3 | III | Predictive | High HER3 expression is predictive of anti-EGFR therapy benefit |
| microRNA | III | Predictive | A number of microRNAs have been identified as promising predictive biomarkers for anti-EGFR therapy |
| Anti-angiogenic markers | III | Predictive | Many markers have been identified as predictive for response to anti-angiogenic agents; however, their clinical utility needs to be confirmed in large prospective trials |
| Tumour mutational load | III | Predictive; prognostic value to be confirmed | Tumour mutational load may be a predictive biomarker for response to chemotherapy and immunotherapy |
| Gene fusions (RET/ALK/ROS1/NTRK) | III | Predictive and prognostic | Preliminary evidence suggests that rare gene fusions may be negative predictive biomarkers for anti-EGFR therapy. Targeted strategies inhibiting RET, ALK, ROS and TrkA-B-C have demonstrated encouraging results |
| CIMP | III | Predictive and prognostic to be confirmed | Data for the prognostic and predictive role of CIMP status in CRC are currently contradictory |
| HPP1 methylation | IV | Prognostic | Detection of HPP1 methylation before chemotherapy has been associated with poor survival outcomes |
| TS | IV | – | See Table 1 for current guidance |
| ERCC1 | IV | – | See Table 1 for current guidance |
| PIK3CA | IV | – | See Table 1 for current guidance |
| PTEN | IV | _ | See Table 1 for current guidance |
BRAF B-rapidly accelerated fibrosarcoma, CIMP CpG island methylator phenotype, CMS consensus molecular subtypes, CRC colorectal cancer, CRIS colorectal cancer intrinsic subtypes, DPD dihydropyrimidine dehydrogenase, DPYD DPD gene, EGFR epidermal growth factor receptor, ERCC1 excision repair cross-complementation group 1, HER human epidermal growth factor, KRAS Kirsten rat sarcoma viral oncogene, mCRC metastatic colorectal cancer, MSI microsatellite instability, NRAS neuroblastoma RAS, PIK3CA phosphatidylinositol 3-kinase catalytic subunit alpha, PTEN phosphatase and tensin homolog, RAS rat sarcoma, TS thymidylate transferase, UGT1A1 UDP glucuronosyltransferase 1 family, polypeptide A1
aI, currently clinically relevant; II, likely to be clinically relevant soon; III may be clinically relevant in the future; IV, not clinically relevant