Table 1 Current NCCN predictive markers
From: The current state of molecular profiling in gastrointestinal malignancies
Molecular abnormality | Test | Method | When | Details |
|---|---|---|---|---|
Colon cancers 2.2021 | ||||
MLH1, MSH2, MSH6 or PMS2 mutations | MMR protein expression | IHC | Work-up | Universal testing for MMR or MSI is recommended in all patients newly diagnosed with colorectal cancer. dMMR and MSI-H testing are recommended to predict response to pembrolizumab. Patients with Stage II MSI-H tumors generally have a good prognosis and do not benefit from 5-FU adjuvant therapy. |
MSI | MSI; changes in short repeated DNA sequences | PCR NGS | Work-up | |
KRAS/NRAS | KRAS (exon 2,3,4) gene; NRAS (exon 2,3,4) gene mutations | NGS | Work-up for metastatic disease: primary tumor and/or metastases | Patients with any known KRAS mutation (exon 2,3,4) or NRAS mutation (exon 2,3,4) should not be treated with either cetuximab or panitumumab. A BRAF V600E mutation makes response to panitumumab or cetuximab highly unlikely unless given with a BRAF inhibitor (e.g., vemurafenib or encorafenib). If patient tumors have a known RAS/RAF mutation, HER2 testing is not indicated. Anti-HER2 therapy is indicated only in HER2-amplified tumors that are also RAS and BRAF wild type. |
BRAF | V600E mutation | IHC NGS | ||
HER2 (ERBB2) | Gene amplification | FISH IHC NGS | ||
NTRK1/2/3 | Gene fusion | FISH IHC RT-PCR NGS | Not specified | TRK inhibitors have activity in patients with NTRK fusions (not mutations). Data support limiting testing for NTRK fusions to tumors that are KRAS, NRAS, BRAF, and HER2 wild-type and (arguably) those that are MMR deficient (dMMR)/MSI-H. |
Gastric/esophageal/GEJ Cancers 2/2021 | ||||
HER2 | Amplification | (F)ISH NGS | Work-up any time for suspected or documented inoperable locally advanced, recurrent, or metastatic adenocarcinoma | Particularly if trastuzumab therapy is being considered. |
Protein expression | IHC | |||
PD-L1 (CD274) and HER2 protein | Protein expression | IHC | HER2 negative status corresponds with higher PD-L1 expression rates. Together with MMR, HER2 is a potential biomarker for anti-PD-L1 therapy PD-L1 and MSI testing should be considered on locally advanced, recurrent, or metastatic esophageal or GEJ cancers in patients who are candidates for treatment with PD-1 inhibitors. In gastric cancer, universal testing for MSI/MMR is recommended in all newly diagnosed patients. If sufficient tissue is available, broader NGS may be contemplated. At present, three targeted therapeutic agents have been approved by the FDA for use in esophageal and GEJ cancers: trastuzumab (HER2 positivity), ramucirumab, and pembrolizumab (MSI/MMR, PD-L1 expression, or high tumor mutation burden [TMB; by NGS]). NGS offers the opportunity to assess numerous mutations simultaneously. | |
MSI | MSI; changes in short repeated DNA sequences | PCR NGS | ||
MLH1, MSH2, MSH6 or PMS2 mutations | MMR protein expression | IHC | ||
NTRK1/2/3 | Gene fusion | NGS | Not specified | The FDA approved the use of select TRK inhibitors (entrectinib, larotrectinib) for NTRK gene fusion-positive solid tumors. |
Hepatobiliary cancer 1.2021 | ||||
MSI | MSI; changes in short repeated DNA sequences | PCR | Prior to primary treatment of metastatic or unresectable Gallbladder Cancer or metastatic intrahepatic cholangiocarcinoma | The PD-1 inhibitor, pembrolizumab can be used in patients with MSI-H/dMMR/TMB-H tumors. |
MLH1, MSH2, MSH6 or PMS2 mutations | MMR protein expression | IHC | ||
FGFR2 | Gene fusion | NGS | Evaluate for subsequent lines of therapy for unresectable or metastatic bile duct cancer | FGFR2 inhibitors (pemigatinib, infigratinib) are an option for cholangiocarcinoma with FGFR2 fusions or rearrangement. |
IDH1 | Mutation | NGS | Evaluate for subsequent lines of therapy for unresectable or metastatic bile duct cancer | IDH1 inhibitor (ivosidenib) can be used for cholangiocarcinoma with IDH1 mutations. |
BRAF | V600E mutation | NGS | Evaluate for subsequent lines of therapy for unresectable or metastatic bile duct cancer | Dabrafenib + trametinib can be used for BRAF V600E mutant tumors. |
NTRK1/2/3 | Gene fusion | FISH RT-PCR NGS | Hepatobiliary cancer | TRK inhibitors (entrectinib, larotrectinib) have activity in patients with NTRK fusions. |
Pancreatic 2/2021 | ||||
BRCA1 & BRCA2 BRAF HER2 KRAS PALB2 | Mutation (somatic and germline) | IHC NGS | Initial work-up Tumor and blood | Cell-free DNA testing can be considered if tumor tissue testing is not feasible. 9% of pancreatic cancers harbor a germline or somatic BRCA1 or BRCA2 mutation. Olaparib can be used if patient disease has not progressed on first-line platinum-based chemotherapy. Other DDR enzyme inhibitors may be effective. An EGFR inhibitor (e.g., erlotinib) = chemotherapy may benefit KRASwt patients. A BRAF mutation makes this response unlikely. |
Fusions: inc ALK, NRG1, NTRK, ROS1 | IHC PCR NGS | Fusions are rare but, taking NTRK as an example, TRK inhibitors (e.g., larotrectinib) in these patients very effective. Other fusion inhibitors are experimental in pancreatic cancer but an option. | ||
MLH1, MSH2, MSH6 or PMS2 mutations | MMR protein expression | IHC | Work-up for locally advanced or metastatic disease | Pembrolizumab is an option in first-line and beyond, particularly for patients with MSI-H and dMMR tumors and no other satisfactory treatment options. |
MSI | MSI; changes in short repeated DNA sequences | PCR NGS | ||