CSCIENTIFIC BACKGROUND
Colon carcinomas (CRC) account for about 14% of all tumors in adults. Histologically, >95% of colon carcinoma patients present with adenocarcinoma. The prognosis of colon carcinomas depends on the location (colon versus rectum) and stage at diagnosis. While 5-year survival is 85% to 90% in stage I and II, survival rates drop to about 60% in stage III and 5% in stage IV. CRCs are biologically heterogeneous. Primarily, variants in the APC gene and chromosomal instability occur. Another pathway involves the so-called serrated adenomas with epigenetic promoter methylation and high microsatellite instability (MSI), and there are also mixed forms.
While the majority of CRC occur sporadically, familial clustering is seen in approximately 10% of CRC. About 2% to 3% of all CRC are due to Lynch syndrome or hereditary non-polyposis colon cancer (HNPCC) syndrome. Microsatellite instability (MSI) analysis is recommended on tumor material in all patients with CRC to further test for Lynch syndrome to assess response to immunotherapy with checkpoint inhibitors (ICI). The simultaneous presence of a high MSI (MSI-H) and a variant in BRAF strongly suggests the presence of a sporadic tumor. This can be supported by analysis of MLH1 promoter methylation, which also results in MSI-H. Sporadic MSI-H is detectable in approximately 20% of stage II patients, which correlates with localization in the right colon, poor histologic differentiation, and mucinous adenocarcinomas. These patients are associated with a slightly better prognosis but do no benefit from adjuvant therapy with 5-fluorouracil.
GENOMIC ALTERATIONS
Variants in BRAF (8-10% of CRC) are associated with a more aggressive CRC phenotype, chemotherapy resistance, MSI-H, and poorer overall survival. Again, anti-EGFR therapy shows no improvement in overall survival and progression-free survival. For patients with BRAF variants, previously treated with anti-EGFR therapy, therapy with the BRAF inhibitor, vemurafenib, in combination with irinotecan and cetuximab or panitumumab is recommended.
Approximately 10% to 20% of unselected CRC patients show variants in PIK3CA, which are associated with CRC in the right hemicolon, mucinous subtype, and variants in KRAS. Variants in PIK3CA are also associated with resistance to anti-EGFR therapy. However, CRC patients with PIK3CA variants who start aspirin therapy after diagnosis show higher CRC-specific survival and overall survival than patients without PIK3CA variants.
Approximately 2% of CRC patients exhibit overexpression of HER2, which results in >90% from amplification of ERBB2 and rarely from activating variants in ERBB2. This is associated with acquired primary and secondary resistance to anti-EGFR therapy. Currently, HER2-targeted therapies are being tested in HER2-positive metastatic CRC patients in clinical trials and thus may offer a therapeutic option for resistance to anti-EGFR therapy.
Kinase fusions are detected in <1% to 2% of CRC patients, primarily involve RET, NTRK, ALK, and ROS, and are clustered in CRC in the right hemicolon, associated with MSI-H and RAS wild-type, and shortened overall survival. Few studies show that patients with these fusions may benefit from targeted tyrosine kinase inhibitor therapy.
For patients for whom none of the above biomarkers are available for therapy, MSI-H or even mismatch repair deficiency (MMR-D) is a predictive biomarker for ICI. However, this limits this type of therapy to approximately 5% of metastatic CRC. MMR-D leads to an accumulation of somatic variants and thus a high tumor mutation burden (TMB).
However, this can also arise independently of an MMR-D/MSI-H, e.g., due to variants in POLE. Therefore, a high TMB seems to be a more appropriate marker for the response of ICI. Homozygous or hemizygous variants in JAK1 are predictive for resistance to ICI. They are found in approximately 15% of primary CRC, but less frequently in metastatic CRC.
POSSIBLE THERAPIES
All patients with metastatic CRC should be offered analysis of the KRAS, NRAS, and BRAF genes. Variants in KRAS (~ 50% of CRC) and NRAS (~ 5% of CRC) result in loss of the antiproliferative effect of EGFR antibodies. Therefore, anti-EGFR therapy (e.g., cetuximab, panitumumab) is only effective in patients who do not have a variant in KRAS or NRAS. In addition, patients with tumor site in the right hemicolon despite not having a variant in KRAS or NRAS, show no benefit with anti-EGFR therapy. Therefore, first-line therapy with anti-EGFR antibodies and combination chemotherapy is recommended for CRC patients who are KRAS/NRAS-wild-type and have the a left-sided primary tumor, whereas patients with the right-sided primary tumor and/or variants in KRAS or NRAS are advised to receive chemotherapy in combination with bevacizumab, if necessary.
TARGETED PANEL
BRAF, KRAS, NRAS, POLE, Fusion genes: NTRK1/2/3, RET, MSI
References
Sveen et al. 2020, Nat Rev Clin Oncol 17:11 / Taieb et al. 2019, Drugs 79:1375 / Gbolahan and O'Neil 2019, Transl Gastroenterol Hepatol 4:9 / Vacante et al. 2018, World J Clin Cases 6:869 / NCCN Guidelines, Colon Cancer, Version 2.2019 / www.onkopedia.com/de/onkopedia/guidelines/kolonkarzinom, Stand Oktober 2018
