Molecular profiling in colorectal cancer

See ((Right vs left-sided colorectal cancers)).
To identify tumor subtypes for which targeted therapy may be available, all metastatic colon rectal cancer tumors should undergo molecular profiling.
All CRC tumors should undergo molecular testing for mismatch repair deficiency (MMR-D) via immunohistochemistry or microsatellite instability-high MSI-H) via PCR screening for the Lynch syndrome.

The most common mutations in colorectal cancer TP53 and PI3K, but they have no clinical implications.

Among clinically relevant mutations the most common are those in NRAS or KRAS, which occurs in approximately 55% of patients with colorectal cancer.

Patients with a RAS mutation do not benefit from treatment with an anti-epidermal growth factor receptor (EGFR) agent either cetuximab or a panitumumab, which means that the most common actionable mutation is a negative protective factor.

KRAS mutated colorectal tumors or less likely to be mismatch repair deficient.

Approximately 8% of patients with CRC have a BRAF V600E mutation which has a negative associated prognosis.

The median survival for patients with CRC and a BRAF mutation is approximately 18 months, compared with three years for those who have CRC without a BRAF mutation.

Most BRAF-mutated tumors are on the right side of the colon.

Patient with BRAF mutation on the right side of the colon have a worse prognosis than others with right sided lesions negative for BRAF.

CRC BRAF mutated tumors require aggressive combination chemotherapy as first line treatment.

HER2 amplification is present in approximately 4% of patients with CRC.

HER2 amplification occurs almost exclusively in those without RAS mutations, and it occurs in 8% of patients with RAS wild-type CRC.

Patients with HER2 amplification have a worse prognosis than those without the amplification, and do worse than other patients with RAS wild-type CRC.

The mismatch repair (MMR) enzyme deficiency affects approximately 4-5% of patients with metastatic CRC.

Defects in MMR occur in families that have the Lynch syndrome and to a lesser degree in people with endometrial cancer.

The rate of MMR deficiency is higher among patients with stage III CRC affecting approximately 8% of such patients, and among those with stage II disease, affecting approximately 15%.

5% of metastatic CRC tumors are MMR-D or MSI-H, either due to Lynch syndrome or sporadic mutations, and may respond to immunotherapy.

MMR deficiency patients are sensitive to immunotherapy with anti-PD-1 agents.

Patients with MMR deficiency respond fairly well to chemo therapy because they lack DNA repair, so first line treatment may involve chemotherapy, and anti-PD-1 agent, or a combination.

The prognosis for a patient with stage 2 MMR-deficient CRC has a cure rate of greater than 90% with surgery and adjuvant chemo therapy is not required.

NTRK1-3 mutations affect approximately 2-3% of patients with CRC and can be targeted with anti-neurotrophic tyrosine receptor kinase agents.

Newly diagnosed patients should undergo immunohistochemical testing for the presence of MMR enzymes in biopsy specimens, to identify high microsatellite instability CRC.

With left-sided metastatic disease determining whether a patient has a RAS mutation is important to decide whether to use an anti–EGFR agent or bevacizumab.

There are responses to chemotherapy plus anti–EGFR therapy in patients with left-sided BRAF/RAS wild type tumors.
Approximately 8-10% of metastatic colorectal cancers contain a mutation in BRAF, a gene that encodes a signal transduction protein that is involved in the MAPK pathway.
In metastatic colorectal cancer, vemuraafenib mono therapy is really effective due to incomplete inhibition of MAPK signaling.
The combination of BRAF inhibitors and chemotherapy may be more effective in BRAF positive patients with metastatic colorectal cancer.

 In patients  with right-sided tumors there is adverse outcomes to anti-EGFR therapy but benefits from chemotherapy plus VEGF inhibition.

Patients who have early-stage tumors do not need next generation sequencing or testing for RAS mutations.

Patients with stage 2 or 3CRC should be evaluated for MMR deficiency.

Mutations in any of 3RAS oncogenes KRAS, NRAS, and HRAS have been found to lead to autonomous growth in differentiation of cells driving cancer progression.
KRAS or NRAS  mutations correlate with worse outcomes and resistance to anti-EGFR therapy with or without chemotherapy.
KRAS mutations occur in about 52% of specimens, with NRAS and HRAS  mutations occurring at  lower rates in CRC.
KRAS mutated colorectal cancer are less likely to be mismatch repair deficient.
Patient with BRAF mutated metastatic Colorectal Cancer do not respond to anti-EGFR mono therapy with panitumumab or cetuximab and have shorter progressive free survival and overall survival compared with patients wilh zBrAF wild type tumors.
Right-sided compared with left-sided colorectal tumors were found to have higher BRAF Mutation frequency and more likely to be MSI-high (MSI-H).
Approximately 8-10% of metastatic colorectal cancer is contained a mutation in BRAF.
The BRAF gene encodes a signal transduction protein  that is involved in the MAPK pathway.

The BRAF mutation is associated with poor prognosis and BRAF inhibition alone has limited efficacy in treatments of patients with metastatic colorectal cancer.

Vemurafenib, A tyrosine kinase inhibitor that targets BRAF as mono therapy is rarely effective due to incomplete inhibition of the MAPK signaling and reflexive activation of EGFR.
The combination  Vemurafenib with irinote an and cetuximab showed improvement in progression free survival, increased response rate and disease control, and is it option for patients with BRAF positive disease.
Germline sequence variations are present in  up to 10% of patients with metastatic CRC.
Patient with MSI-H  or MMR-D tumors age younger than 50 years or suggestive family history should undergo genetic testing.

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