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CRC Biomarker Testing
Precision Management of Colorectal Cancer With Biomarker Testing: An APP Perspective

Released: June 16, 2026

Ann Marie Siney
Ann Marie Siney, RN, MSN, ANP-BC
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Key Takeaways
  • Universal MMR/MSI testing remains foundational for all newly diagnosed colorectal cancers, while broader molecular profiling becomes especially important once metastatic disease is present or suspected.
  • For metastatic colorectal cancer, information on the status of RAS, BRAF V600E, HER2, MSI/dMMR, KRAS G12C, and rare fusions can meaningfully change treatment options, clinical trial conversations, and patient education.
  • NPs and PAs can reduce biomarker-related testing delays by anticipating tissue needs, clarifying liquid biopsy limitations, tracking results, and translating complex reports into actionable next steps for the care team.

In this ClinicalThought commentary, nurse practitioner Ann Marie Siney discusses the importance of incorporating biomarker testing early in the colorectal cancer (CRC) care pathway to inform treatment selection, identify hereditary cancer syndromes, and support personalized care. She also addresses common barriers to biomarker testing and offers practical strategies for nurse practitioners (NPs) and physician associates (PAs) to improve implementation in routine practice.

Ann Marie Siney, RN, MSN, ANP-BC:
In the United States, CRC remains a common and clinically consequential diagnosis. CRC is the third most commonly diagnosed cancer in both women and men and the second leading cause of cancer-related death in the US. In fact, the American Cancer Society estimates 158,850 new cases and 55,230 deaths in 2026. Incidence has declined in some older populations but continues to rise in younger adults, with rates among people younger than 50 increasing by 3% per year from 2013 to 2022.

For NPs and PAs, these epidemiologic trends matter because CRC care often starts by asking 2 questions: What does this patient need today, and what molecular information could change the next treatment decision? In practice, that means normalizing biomarker testing as part of the diagnostic and treatment planning workflow rather than viewing it as an optional later step.

Germline vs Somatic Testing: A Patient-Friendly Distinction
One of the most common questions patients ask is whether biomarker testing is the same as genetic testing. A useful distinction is that germline testing looks for hereditary cancer syndromes that may affect the patient and their relatives, whereas somatic testing evaluates acquired tumor alterations that may guide treatment selection. Lynch syndrome is the most common inherited CRC syndrome, accounting for approximately 2% to 4% of all CRCs, and familial adenomatous polyposis accounts for less than 1% of CRCs but carries a high lifetime CRC risk without appropriate surveillance or preventive intervention.

This distinction extends beyond terminology and can affect patient care. Loss of mismatch repair (MMR) protein expression or microsatellite instability–high (MSI-H) status supports immunotherapy eligibility in advanced disease. In addition, specific MMR loss patterns may prompt evaluation for Lynch syndrome, often through tumor-based reflex testing such as MLH1 promoter methylation testing when MLH1/PMS2 loss is identified, followed by germline evaluation when appropriate.

Advanced practice providers (APPs) are often the healthcare professionals who translate this into plain language: for example, ‘some results help the oncology team select therapy,’ whereas other results may prompt genetic counseling, cascade testing, or earlier screening for relatives.

What to Test and When
Universal MMR or MSI is recommended in all newly diagnosed patients with colon cancer. The MMR deficient (dMMR)/MSI-H genotype occurs in approximately 10% to 15% of localized CRC but only about 4% to 5% of metastatic CRC, making it both a diagnostic/genetic counseling signal and a treatment-guiding biomarker in advanced disease.

Once metastatic disease is diagnosed or confirmed, broader molecular profiling should be obtained early enough to inform treatment planning. Current guidelines and recent reviews emphasize, at minimum, assessment of RAS and BRAF gene mutations, HER2 amplifications, and dMMR/MSI-H status, with broader profiling encouraged to identify tumor-agnostic treatment options such as those that target NTRK and RET fusions and high tumor mutational burden when relevant.

The practical biomarker list for metastatic CRC includes RAS status, BRAF V600E, HER2 amplification/overexpression, dMMR/MSI-H, and rare NTRK or RET fusions. Prevalence estimates vary by cohort, but the CRC biomarker resource approximates KRAS non-G12C alterations in 40%, KRAS G12C in 3%, NRAS alterations in 4%, BRAF V600E in 8% to 12%, HER2 amplification/overexpression in 3% to 4%, MSI-H/dMMR in 4% to 5%, and PIK3CA mutations in 10% to 25% of metastatic CRCs.

Applying Results Without Over- or Underinterpretation
The clinical value of biomarker testing is clearest when results are tied to a treatment-related question. For example, dMMR/MSI-H unresectable or metastatic CRC may be treated with immune checkpoint inhibitor–based strategies. Pembrolizumab is approved for first-line treatment of unresectable or metastatic dMMR/MSI-H CRC based on the randomized phase III KEYNOTE-177 trial, as is nivolumab plus ipilimumab based on the randomized phase III CheckMate 8HW trial.

For left-sided metastatic CRC (mCRC) characterized by wild-type RAS/BRAF, anti-EGFR therapy can be an important option, whereas RAS mutations predict lack of benefit from anti-EGFR antibodies. BRAF V600E has become increasingly actionable: in February 2026, the FDA granted traditional approval to encorafenib plus cetuximab and fluorouracil-based chemotherapy for treatment-naive BRAF V600E–mutated mCRC, following earlier accelerated approval with mFOLFOX6.

Other biomarker-directed options include tucatinib plus trastuzumab for previously treated RAS wild-type, HER2-positive unresectable or metastatic CRC; adagrasib plus cetuximab as well as sotorasib plus panitumumab for previously treated KRAS G12C–mutated mCRC; and tissue-agnostic targeted therapies for selected NTRK or RET fusion–positive solid tumors following progression on fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. These examples are useful in patient education because they show why a report that initially looks like a long list of genes may directly affect eligibility for standard therapy, clinical trial enrollment, or both.

2026 Data Updates
Recent updates reinforce the need to identify actionable subgroups early. At the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, updated results from the phase III BREAKWATER trial of encorafenib plus cetuximab and FOLFIRI vs standard therapy in previously untreated BRAF V600E–mutant mCRC showed improved outcomes, with median progression-free survival (PFS) of 15.2 vs 8.3 months and no new safety concerns. These data are built on the evidence base supporting FDA approval of encorafenib-containing first-line combinations in BRAF V600E–mutant mCRC.

We also need to consider that the term “advanced disease” should be defined more clearly, because it is often used in practice to refer to unresectable or metastatic disease rather than resected stage III disease. This distinction is increasingly important as immunotherapy moves into earlier-stage dMMR/MSI-H colorectal cancer. In the phase III ATOMIC trial, adjuvant atezolizumab plus mFOLFOX6 followed by atezolizumab monotherapy significantly improved disease-free survival (DFS) vs mFOLFOX6 alone in patients with resected stage III dMMR colon cancer, with 3-year DFS of 86.3% vs 76.2% and an hazard ratio for recurrence or death of 0.50 (95% CI, 0.35-0.73; P <.001). These results supported FDA acceptance and Priority Review of Roche/Genentech’s supplemental BLA for atezolizumab plus chemotherapy as adjuvant treatment after surgery for stage III dMMR/MSI-H colon cancer. Atezolizumab is also being evaluated in the phase II ANTONIO trial in patients with MSI-H/dMMR high-risk stage II or stage III CRC who are ineligible for oxaliplatin, but efficacy in that setting remains investigational.  

At the 2026 ASCO GI Symposium, the phase III COMMIT study of FOLFOX, bevacizumab, and atezolizumab vs atezolizumab monotherapy in previously untreated dMMR/MSI-H mCRC showed improved PFS, with a reported hazard ratio of 0.439 and 12-month PFS rates of 66.7% vs 35.1%, respectively, highlighting ongoing refinement in dMMR/MSI-H mCRC. Although practice integration depends on guideline updates, availability, patient fitness, and regimen-specific risks, this finding underscores why accurate dMMR/MSI-H status remains clinically consequential.

Where NP and PA Teams Can Remove Barriers
Common barriers to implementing biomarkers in precision medicine include busy clinics, uncertainty about which test(s) to order, insufficient tissue, variable turnaround times, cost concerns, and difficulty interpreting multipage next-generation sequencing (NGS) reports.

Liquid biopsy can shorten time to results and may be especially helpful when tissue is limited or decisions are urgently needed, but a negative plasma result can be noninformative when tumor shedding is low. Confirmation with tissue is important when plasma testing is negative, discordant, or clinically incomplete.

APPs can make the testing process more reliable by building biomarker checkpoints into routine care. At diagnosis, confirm that MMR/MSI testing has been performed. When metastatic disease is present, confirm that comprehensive profiling has been ordered, track specimen status, and communicate with pathology if tissue adequacy is uncertain. If a report is unclear, ask whether the finding is pathogenic and actionable, whether it is a variant of uncertain significance, whether HER2 criteria have been met, and whether the assay used DNA, RNA, IHC, FISH, PCR, or a combination of methods.

Cost conversations should be proactive but handled thoughtfully. Medicare coverage and financial assistance processes may reduce patient burden, but coverage and copays can vary. The safest counseling message is that financial navigation should begin before testing is abandoned. The team can involve laboratory representatives, financial counselors, social workers, and patient financial relief programs via the testing laboratory, patient when patients are worried about affordability.

Practical Takeaway for the Clinic
For NPs and PAs, biomarker testing in CRC is not only about knowing which drug is appropriate for a given mutation—it is about ordering the right test at the right time, preserving tissue, recognizing when a result changes treatment, avoiding overinterpretation of nonactionable findings, and helping patients understand why the oncology team may wait for results before finalizing a plan. When those steps are handled consistently, biomarker testing becomes less of a bottleneck and more of a bridge to individualized care.

Your Thoughts
What part of biomarker testing in CRC creates the greatest challenge in your practice: ordering the right assay, obtaining adequate tissue, interpreting NGS reports, navigating cost and access, or translating results into treatment discussions?

Visit the program page to listen to a podcast or download a PDF resource on this topic. Also, feel free to join the discussion and share the workflow questions you most want to address.

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What is the most common barrier you encounter when trying to integrate CRC biomarker testing into patient care?

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