What is the treatment approach for a patient with a TERT promoter mutation, microsatellite stable (MSS) status, and low tumor mutational burden (TMB)?

Understanding Your Genomic Test Results

What These Results Mean

Your genomic testing shows a TERT promoter mutation (C228T), microsatellite stable (MSS) status, and low tumor mutational burden (TMB of 4.7 mutations/Mb), which means standard immunotherapy with checkpoint inhibitors is NOT recommended for your treatment, and you should pursue conventional cancer therapies specific to your tumor type instead. 1, 2

Key Findings Explained

TERT Promoter Mutation (C228T)

• TERT promoter mutations regulate telomerase activity and are associated with cancer development and progression 2, 3
• The C228T mutation specifically has been linked to increased risk of tumor recurrence and death in head and neck cancers, with significantly decreased disease-free survival (20.0% vs 63.0%) and overall survival (16.7% vs 45.1%) compared to patients without this mutation 3
• Currently, there are NO FDA-approved targeted therapies specifically for TERT mutations 2
• This mutation serves primarily as a prognostic marker rather than a therapeutic target at present 3

Microsatellite Stable (MSS) Status

• MSS tumors typically do NOT respond to immune checkpoint inhibitors like pembrolizumab or nivolumab 1, 2
• The NCCN guidelines explicitly state that combination immunotherapy (nivolumab plus ipilimumab) does not have sufficient clinical activity in MSS tumors, even when TMB is high 1
• Only 2.9% of MSS colorectal cancers have high TMB (≥10 mutations/Mb), and your TMB of 4.7 is well below this threshold 4

Low Tumor Mutational Burden (TMB: 4.7 Mutations/Mb)

• The FDA-approved threshold for TMB-high is ≥10 mutations/Mb for pembrolizumab eligibility, and your result of 4.7 is less than half this cutoff 1, 2
• In the KEYNOTE-158 trial, patients with TMB-high tumors (≥10 mut/Mb) had a 29% response rate to pembrolizumab, while those with low TMB had only a 6% response rate 1
• Your low TMB predicts poor response to immunotherapy regardless of cancer type 2, 5

Absence of Other Driver Mutations

• Your testing confirmed NO mutations in BRAF, NF1, or NRAS, which means these are not available as therapeutic targets 1
• This negative finding is important because it rules out specific targeted therapy options that would be available if these mutations were present 1

Treatment Approach

What You Should NOT Receive

• Do NOT pursue treatment with PD-1/PD-L1 checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab) as monotherapy based on your MSS status and low TMB 1, 2
• The NCCN Panel does not recommend TMB biomarker testing for treatment decisions in MSS colorectal cancer specifically because of insufficient clinical activity 1

What You SHOULD Receive

• Focus on conventional therapies appropriate for your specific cancer type: surgery, chemotherapy, and/or radiation therapy 2
• For colorectal cancer specifically, platinum-based chemotherapy with fluoropyrimidines remains the standard approach for MSS tumors 1
• If you have metastatic disease, consider testing for additional actionable targets including NTRK fusions, RET fusions, MET amplifications, or FGFR alterations that may have FDA-approved targeted therapies 1

Special Considerations

• One case report showed responses in MSS/low TMB cholangiocarcinoma patients treated with stereotactic body radiotherapy (SBRT) combined with PD-1 blockade, achieving partial or complete responses despite TMB values of 0.98-3.8 mutations/Mb 6
• However, this represents experimental therapy in a different cancer type and should only be considered within a clinical trial setting 6

Next Steps

Additional Testing to Consider

• Request expanded molecular profiling to identify other potentially actionable alterations including NTRK fusions (present in <1% of cancers but highly responsive to larotrectinib or entrectinib), RET fusions, MET amplifications, or ALK rearrangements 1
• NTRK fusions are mutually exclusive with KRAS, NRAS, and BRAF mutations, and since your testing shows these are wild-type, NTRK testing may be particularly relevant 1

Clinical Trial Opportunities

• Seek enrollment in clinical trials investigating novel therapies for tumors with TERT mutations or MSS/low TMB tumors 2
• Consider trials combining radiation therapy with immunotherapy, as this approach showed promise in case reports despite unfavorable biomarker profiles 6
• Request review by a molecular tumor board if available at your institution, as complex genomic profiles benefit from multidisciplinary expertise 2

Prognostic Implications

• The presence of TERT C228T mutation may indicate higher risk of recurrence and should prompt more aggressive surveillance strategies 3
• Discuss with your oncologist whether more frequent imaging or closer monitoring is appropriate given this prognostic marker 3

Important Caveats

• If your tissue sample is more than 5 years old, TMB results may be artificially elevated due to formalin fixation artifacts, though this is not a concern in your case with low TMB 1
• Cell-free DNA (liquid biopsy) TMB testing has lower precision than tissue-based testing and should not be used alone to direct treatment decisions 1
• Some genomic alterations may represent clonal hematopoiesis (CHIP) rather than tumor mutations, particularly in patients over 50 years old, though this typically affects genes like DNMT3A, TET2, and TP53 rather than TERT 1