Colon Cancer Genomics

(BRAF, ERBB2, KRAS, NRAS, RET)

  1. KRAS G12C mutation (found in 3% of mCRC) Sotorasib (AMG 510)
  2. (HER2) amplifications is a negative predictive biomarker for anti-EGFR therapies.
    Found in ~3%-4% of patients with mCRC and in 6%-8% of patients with KRAS-wild-type mCRC.
  3. BRAF V600E mutations occur in up to 12% of mCRCs and are nearly always mutually exclusive with KRAS This mutation is associated with worse prognosis and predicts a poorer response to anti-EGFR treatment.
  4. Based on the similar OS rates for doublet and triplet combinations, Encorafenib/ Cetuximab is currently recommended in the chemotherapy- refractory setting of BRAF V600E-mutated
  5. HER2-positive mCRC; Number of Trastuzmab based treatments have been (ie: T-DM1, Trastuzumab/Pertuzumab, Trastuzumab/ Lapatinib etc)
  6. Trastuzumab Deruxtecan in HER2-positive mCRC, showed a meaningful improvement in terms of ORR, PFS and OS; 30% of these patients had previously received anti-HER2
  7. MSI is found in 5% of mCRC and is a biomarker of response to immunotherapy in the metastatic The anti-programmed cell death protein 1 (PD-1) agent Pembrolizumab has been tested in mCRC in several clinical trials. Across studies, the ORR was 40%.
  8. NTRK fusions have been reported in 5% of mCRC patients. In mCRC, rearrangements in NTRK genes are more commonly detected in MSI-H tumours and wild-type BRAF/ KRAS/NRAS. Larotrectinib and Entrectinib have produced dramatic and prolonged responses in gastrointestinal malignancies with NTRK fusions.
  9. Blockade of EGFR Over Expression with the monoclonal antibodies (mAbs) Cetuximab or Panitumumab is effective in RAS wild-type CRC.
  10. At relapse, the majority of patients develop RAS mutations, while a subset of patients acquires EGFR extracellular domain Overcoming RAS Mutations in mCRC (40%) Predicts a Negative response to EGFR inhibitors.