NCCN updates Colorectal Cancer Testing and Treatment Guidelines

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 145,600 new cases of CRC will be diagnosed in the United States in 2019 and about 51,020 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23. Even though colon cancer localized to the bowel is potentially curable with surgery and adjuvant chemotherapy, advanced colon cancer is often incurable with a 5-year survival rate of 11%.

The 2019 NCCN guideline update for colon cancer has expanded the scope of personalized medicine and clinical diagnostics by incorporating biomarker testing to guide treatment. With the identification of new biomarkers and expansion of biomarker testing to guide treatment among patients with colorectal cancer, studies are underway to classify colorectal cancer (CRC) based on comprehensive gene expression profiles. The Consensus Molecular Subtypes (CMS) is one of the most robust transcriptome-based classification of colorectal cancer (CRC). The CMS subtype may influence the efficacy of chemotherapy and CMS might be a new predictive factor for the efficacy of chemotherapy against mCRCs. The CRC Subtyping Consortium (CRCSC) initiated by 15 institutions analyzed more than 30 different gene expression sets across multiple platforms and sample preparation methods and identified four different molecular subtypes, CMS1, CMS2, CMS3 and CMS4. This covers approximately 87% of all CRC cases, thus leaving approximately 13% of cases molecularly uncharacterized.

CMS1: Approximately 14 percent of all CRC are considered CMS1, of which approximately 12 percent are sporadic (non-inherited), while the remaining patients have inherited disease (Lynch Syndrome). Tumors are located in the proximal colon, have a high BRAF V600E mutation rate and are associated with impaired DNA mismatch repair (MMR). Patients in this group tend to have a lower rate of relapse and if relapse does occur, they are associated with poor outcomes (about 9 months). The 5-year survival rate for this group is about 73%.

CMS2: This is the most common CRC subtype with approximately 39% of the CRC patients belonging to this group. Majority of the tumors are located in the left colon and tumors are characterized by the initial loss of APC, a tumor suppressor gene, followed by an activating mutation in KRAS and loss of TP53. Patients in this group have higher survival rates (35 months) after relapse. The 5-year survival rate for this group is 77%, the best among the four different CRC subtypes.

CMS3: Approximately 13 percent of CRC patients belong to this group. KRAS mutations are most frequently found in this patient group (68%) and approximately 3% of patients in this group overexpress HER2. Patients in this group have the second highest survival rates, with a 5-year survival rate of 75%.

CMS4: These tumors are characterized by MSS (MicroSatellite Stable) with frequent mutation of genes such as APC, KRAS, PIK3CA, and TP53. Patients in this group often have poor prognosis as they are diagnosed at advanced stages. They have little or no benefit from systemic adjuvant therapy and those with metastatic disease are often resistant to EGFR inhibitors, independent of KRAS mutation status. They have the worst 5-year Overall Survival (62%) of any molecular subtype.

The following are the key 2019 NCCN guideline updates 

KRAS, NRAS and BRAF Mutation Testing

All patients with metastatic colorectal cancer should have tumor tissue genotyped for KRAS, NRAS and BRAF mutations individually or as a part of Next Generation Sequencing (NGS) panel

MicroSatellite Instability (MSI) or MisMatch Repair (MMR) Testing

1) The presence of BRAF V600E mutation in the setting of absence of MLH1 would preclude the diagnosis of Lynch Syndrome in a majority of cases. However, approximately 1% of cancers with BRAF V600E mutation and loss of MLH-1 are Lynch Syndrome and therefore, caution should be exercised, in excluding patients with a strong family history from germline screening in the case of BRAF V600E mutations

2) ImmunoHistoChemistry (IHC) refers to staining of tumor tissue for protein expression of the four mismatch repair MMR genes, MLH1, MSH2, MSH6, and PMS2, known to be mutated in Lynch Syndrome. A normal IHC test implies that all 4 MMR proteins are normally expressed or retained. An abnormal or positive IHC test implies loss or absence of expression of one or more of the 4 MMR proteins. When IHC is reported as positive, caution should be exercised to ensure that positive IHC refers to absence of mismatch expression and not presence of expression. Loss of expression by IHC in any of the MMR genes should then be followed up with genetic testing. Abnormal MLH1 on IHC should be followed by tumor testing for BRAF V600E mutation. The presence of BRAF V600 E mutation is consistent with sporadic cancer.


mFOLFOXIRI with EGFR inhibitor VECTIBIX® (Panitumumab) or ERBITUX® (Cetuximab) was added as a treatment option for unresectable stage IV mCRC that are left-sided and are KRAS/NRAS/BRAF wild-type.


The combination regimen FOLFOX + VECTIBIX® or ERBITUX® was added for KRAS/NRAS/BRAF wild-type tumors.


Patients with advanced or metastatic CRC who are not appropriate candidates for intensive therapy may be offered OPDIVO® (Nivolumab) or KEYTRUDA® (Pembrolizumab), as a single agent or a combination of OPDIVO® and YERVOY® (Ipilimumab), only for tumors that are MMR deficient and MSI High (Category 2B). These same immunotherapy options are also listed in the guidelines as second and third-line options for MMR deficient and MSI High patients.

NTRK Gene Fusion

Tumors should be tested for Neurotrophic Receptor Tyrosine Kinase (NTRK) gene fusion, and VITRAKVI® (Larotrectinib) is now a second-line treatment option for patients with metastatic CRC that is NTRK gene fusion positive.


BRAF wild-type was added as an indication for treatment, where KRAS and NRAS wild-type are noted. Combination therapies added to the guidelines as second-line options include

1) TAFINLAR® (Dabrafenib) targeting BRAF plus MEKINIST® (Trametinib) targeting MEK along with ERBITUX® or VECTIBIX® which are EGFR targeted monoclonal antibodies

2) BRAFTOVI® (Encorafenib) targeting BRAF plus MEKTOVI® (Binimetinib) targeting MEK along with ERBITUX® or VECTIBIX®.

NCCN Guidelines Updates: Management of Metastatic Colorectal Cancer. Messersmith WA. Presented at 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.