SCIENTIFIC BACKGROUND

AKT1, ALK, ALK, ATM, BRAF, ERBB2, JAK1, KRAS, MET, NRAS, NTRK1, NTRK2, NTRK3, PIK3CA, RET, ROS1

SCIENTIFIC BACKGROUND

Colon carcinomas (colorectal cancer, CRC) account for about 14% of all tumors in adults. Every year in Germany, about 27,000 men and 30,000 women develop colon cancer. Histologically, >95% of patients have adenocarcinoma while neuroendocrine tumors, lymphomas, sarcomas or squamous cell carcinomas occur less frequently. The prognosis depends on the localization (colon versus rectum) and the stage at diagnosis. While the 5-year survival rate in stage I and II is 85% to 90%, the survival rate in stage III drops to about 60% and in stage IV to 5%. CRCs are biologically heterogeneous. Primarily, variants in the APC gene and chromosomal instability occur. Another developmental pathway is via serrated adenomas with epigenetic promoter (CpG) methylations and high microsatellite instability (MSI), but there are also mixed forms.

 

While the majority of CRC occurs sporadically, familial clustering is observed in about 10% of CRC. About 2-3% of all CRC are due to Lynch syndrome or hereditary non-polyposis colon cancer (HNPCC). Experts of the National Comprehensive Cancer Network (NCCN) recommend microsatellite instability (MSI) analysis on tumor material from all patients with CRC, in order to carry out further testing for Lynch syndrome if certain criteria are met or to assess the response to immunotherapy with immune checkpoint inhibitors (ICI). The simultaneous presence of a high MSI (MSI-H) and a BRAF variant strongly suggests the presence of a sporadic tumor. This can be supported by the analysis of MLH1 promoter methylation, which also leads to MSI-H. Sporadic MSI-H is detectable in about 20% of stage II patients, which correlates with a localization in the right colon, poor histological differentiation and mucinous adenocarcinomas. These patients are considered to have a slightly better prognosis, but receive no benefit from adjuvant therapy with 5-fluorouracil (5-FU).

 

All patients with metastatic CRC should be offered an analysis of the genes KRAS, NRAS and BRAF. Variants in KRAS (about 50% of CRC) and NRAS (about 5% of CRC) lead to ligand‑independent, constitutive activation of the MAPK signalling pathway, so that the antiproliferative effect of EGFR antibodies is lost. Therefore, anti-EGFR therapy (e.g., cetuximab, panitumumab) is only effective in patients who do not have any variant in KRAS or NRAS. In addition, patients with a tumor site in the right hemicolon and KRAS/NRAS wild-type do not benefit from anti-EGFR therapy in terms of progression-free and overall survival. Therefore, first-line therapy with anti‑EGFR antibodies and combination chemotherapy is currently recommended for CRC patients with KRAS/NRAS wild-type and a left-sided primary tumor, while patients with a primary tumor in the right-side of the colon and/or variants in KRAS or NRAS are advised to undergo chemotherapy, possibly in combination with bevacizumab.

 

Variants in BRAF (8-10% of CRC) are associated with a more aggressive CRC phenotype, chemotherapy resistance, MSI-H and poor overall survival. Again, anti-EGFR therapy shows no improvement in overall survival and progression-free survival. For patients with a BRAF variant previously treated with anti-EGFR therapy, therapy with the BRAF inhibitor vemurafenib in combination with irinotecan and cetuximab or panitumumab is recommended.

 

About 10-20% of unselected CRC patients show variants in PIK3CA 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 begin aspirin therapy after diagnosis show higher CRC-specific survival and overall survival than patients without PIK3CA variants.

 

About 2% of CRC patients show overexpression of HER2, which in >90% is caused by amplification of ERBB2 and in rare cases by 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 clinical trials in HER2-positive metastatic CRC patients and may offer a therapeutic option where there is resistance to anti-EGFR therapy.

 

Kinase fusion is detected in <1-2% of CRC patients, primarily affecting RET, NTRK, ALK and ROS; it is more common in right hemicolon CRC, associated with MSI-H and RAS wild-type as well as shortened overall survival. Several studies show that patients with these fusions can benefit from targeted tyrosine kinase inhibitor therapy.

 

For patients without one of the above-mentioned biomarkers for therapy, a high MSI (MSI-H) or a mismatch repair deficiency (MMR-D) is a predictive biomarker for immunotherapy with immune checkpoint-inhibitors (ICI). However, this limits this type of therapy to about 5% of metastatic CRC. MMR-D leads to an accumulation of somatic variants and thus to a high tumor mutation burden (TMB). However, this can also occur independently of an MMR-D/MSI-H, such as through variants in POLE. Therefore, a high TMB seems to be a more appropriate marker for the response of immunotherapy with ICI. Homozygous or hemizygous variants in JAK1 are predictive of resistance to immunotherapy with ICI. They are found in about 15% of primary CRC, but less frequently in metastatic CRC.

 

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

GENES
AKT1, ALK, ALK, ATM, BRAF, ERBB2, JAK1, KRAS, MET, NRAS, NTRK1, NTRK2, NTRK3, PIK3CA, RET, ROS1
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