Treating colorectal cancer in the era of precision medicine
Not all colorectal cancers respond to the same treatments. Here is how molecular profiling is changing what is possible.
Clinical Connections · June 2026 · 10 min read · By Maria Poimenidou
Colorectal cancer is the third most commonly diagnosed cancer worldwide and the second leading cause of cancer-related death. It arises in the colon or rectum and, in its early stages, often presents with no symptoms at all. By the time symptoms appear, including changes in bowel habits, rectal bleeding, abdominal discomfort, or unexplained anaemia, the disease has frequently progressed. This is why screening matters: catching colorectal cancer early, before symptoms develop, dramatically improves the odds of successful treatment.
What makes this cancer particularly challenging is its heterogeneity. No two colorectal tumors are genetically identical, and treatment increasingly depends on understanding the molecular makeup of an individual patient's tumor rather than applying a single standard approach.
Metastatic colorectal cancer: current treatment approaches
For patients with metastatic disease, chemotherapy remains the backbone of treatment, particularly for those whose tumors lack specific molecular targets. Standard first-line regimens are built around oxaliplatin- or irinotecan-based combinations with fluorouracil (5-FU). Unlike some other solid tumors, surgical removal of the primary tumor in metastatic colorectal cancer does not improve overall survival unless there are acute complications such as obstruction, uncontrolled bleeding, or perforation risk.
Tumor location has emerged as a meaningful factor in treatment planning. Left-sided tumors generally carry a better prognosis than right-sided tumors, and patients with RAS wild-type, left-sided disease may benefit from the addition of anti-EGFR therapy to their chemotherapy backbone.
Genetic profiling is now a standard part of the workup. RAS mutations are present in up to 60% of colorectal cancer cases and are an active area of targeted drug development. HER2 amplification, identified in roughly 4% of cases and historically associated with breast and gastric cancers, is increasingly recognised as a relevant and actionable target in metastatic colorectal cancer. The practical upshot for patients is clear: biomarker testing should be part of every conversation with an oncologist at diagnosis.
How research has transformed colorectal cancer treatment
The most significant recent advance in colorectal cancer has been immunotherapy for tumors with high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR). These highly mutated tumors, which account for 10 to 15% of early-stage cases and roughly 5% of advanced cases, respond exceptionally well to immune checkpoint blockade in a way that most colorectal cancers do not.
Two trials in particular have shaped how MSI-H metastatic colorectal cancer is treated today:
KEYNOTE-177: Pembrolizumab is now the established standard of care for MSI-H metastatic colorectal cancer, having outperformed chemotherapy in the phase 3 KEYNOTE-177 trial. Median progression-free survival was 16.5 months with pembrolizumab versus 8.2 months with chemotherapy (HR 0.60; P=0.0002), with a higher response rate and fewer treatment-related adverse events.
SAMCO/PRODIGE-54: This phase 2 trial demonstrated that avelumab significantly improved progression-free survival and disease control duration compared to standard second-line chemotherapy in patients with dMMR/MSI metastatic colorectal cancer, with a more favourable safety profile.
Not all MSI-H patients respond equally, and resistance can emerge over time. Research continues to explore how to sustain durable responses and whether combinations can overcome that resistance.
Perhaps the most exciting emerging approach is neoadjuvant immunotherapy, given before surgery rather than after. The NICHE-2 trial demonstrated that pre-surgical nivolumab plus ipilimumab in locally advanced dMMR colon cancer produced major pathological responses in 95% of patients and complete pathological responses in 68%, with no disease recurrence observed after more than two years of follow-up. The ongoing IMOTHEP trial aims to validate these findings at scale.
Current challenges: the subtypes that remain difficult to treat
Immunotherapy has been transformative for MSI-H disease. For the remaining molecular subtypes, the picture is more complicated.
BRAF-mutant disease: BRAF V600E mutations occur in 8 to 12% of metastatic colorectal cancer cases and carry a poor prognosis. The BEACON trial established that combining encorafenib with cetuximab and binimetinib significantly improved overall survival compared to standard chemotherapy in patients who had progressed on one or two prior regimens. The phase 3 BREAKWATER trial is now testing whether incorporating chemotherapy into this combination can further improve first-line outcomes.
RAS-mutant disease: RAS-mutant colorectal cancer does not respond to anti-EGFR therapy, anti-BRAF agents, or immunotherapy. KRAS inhibitors including sotorasib, adagrasib, and divarasib have shown early promise, particularly when combined with EGFR inhibition. The phase 3 CodeBreaK 300 trial demonstrated that sotorasib plus panitumumab significantly prolonged progression-free survival compared to standard treatment in patients with chemotherapy-refractory KRAS G12C-mutated metastatic colorectal cancer.
KRAS G12D and G12V mutations: These subtypes are more prevalent in colorectal cancer than the G12C variant and are an active focus of drug development, with several programmes now in early-phase trials.
The future of colorectal cancer research
The direction of travel in colorectal cancer research is clear: move effective therapies earlier, reduce treatment burden, and make decisions based on biology rather than convention. Several areas are particularly active:
Neoadjuvant and adjuvant use of targeted therapies, deploying the most effective agents before or after surgery rather than reserving them for advanced disease.
Circulating tumor DNA (ctDNA) as a tool to identify which patients genuinely need adjuvant chemotherapy after surgery and which can safely avoid it, sparing many from toxicity that provides no benefit.
Expanded precision oncology, ensuring that every patient with metastatic colorectal cancer undergoes comprehensive biomarker testing and that treatment choices are matched to the specific molecular driver of their disease.
The goal is less toxic, more effective treatment for more patients.
Why clinical trials matter
Every treatment used in oncology today reached patients through clinical trials. Trials are not a last resort. They are the mechanism by which the field moves forward, and for many patients they represent access to therapies that are not yet available through standard care. Clinical trials can offer:
Access to new treatments before they become widely available, often at no cost to the patient.
The opportunity to contribute to research that will improve outcomes for future patients.
Close monitoring by a dedicated clinical research team throughout the study period.
When to consider a clinical trial
When standard treatments are not producing adequate responses or have stopped working.
When a patient's tumor has a specific genetic profile that makes them a candidate for a targeted experimental therapy.
When a patient is seeking a treatment with a better tolerability profile than current options.
Every patient enrolled in a trial is assigned a clinical research coordinator who ensures they receive appropriate care and monitoring. Most oncology trials are not placebo-controlled: participants typically receive either the current standard of care or the investigational therapy being tested. Seeking a second opinion is always reasonable and can open doors to trial opportunities not offered at the primary institution.
FOOD FOR THOUGHT
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RAS status, BRAF status, MSI/MMR status, and HER2 amplification all have direct implications for treatment choice in colorectal cancer, yet access to and awareness of full biomarker profiling at diagnosis remains inconsistent. For patients and families, the most important question to ask is not just what is the treatment plan, but what testing has been done to make sure it is the right one.
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The NICHE-2 results, which showed 95% major pathological response rates after just four weeks of pre-surgical immunotherapy, raise a possibility that would have seemed radical not long ago: that some patients with dMMR colon cancer might achieve such complete responses that surgery becomes unnecessary. Data from rectal cancer trials with dostarlimab are already pointing in this direction, with some patients avoiding surgery entirely. This is not yet standard practice, but the trajectory is clear.
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For decades, a RAS mutation in colorectal cancer was effectively a closed door. Anti-EGFR therapies did not work, immunotherapy did not work, and chemotherapy was the only option for the majority of metastatic colorectal cancer cases. CodeBreaK 300 is the first phase 3 trial to demonstrate a progression-free survival benefit from KRAS inhibition in colorectal cancer. It covers only the G12C variant, which is a minority of RAS-mutant cases, but the principle is established and the pipeline is expanding rapidly to G12D, G12V, and other variants.
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After surgery, the standard approach for high-risk colorectal cancer patients has been adjuvant chemotherapy on the assumption that microscopic residual disease may be present. Circulating tumor DNA offers the possibility of detecting whether residual disease actually exists, identifying who genuinely needs treatment and who does not. For patients and families weighing the side effects and quality of life costs of chemotherapy, that is one of the more consequential questions this field is now in a position to answer.
