The CRC Map Is Complete. How to Use It?

WASHINGTON, DC — In the mapping of colorectal cancer for much of the past three decades the dominant question has been “which molecular features of this tumor matter?” Now, the question shifts to “how can veterans benefit?”

The broad outlines of the molecular map of colorectal cancer (CRC)—from MSI and mismatch repair status, to RAS and BRAF mutation profile and HER2 amplification, onto PIK3CA and PI3K pathway alterations and to KRAS G12C—provide sufficient detail to guide most major clinical decision from adjuvant therapy in stage II disease through third-line options in refractory metastatic CRC.

CheckMate 8HW established that molecular subtype and not tumor location, stage or performance status, determines whether chemotherapy is the right treatment at all.¹ KRAS mutations were considered undruggable for decades, but CodeBreak 300 changed that narrative, converting a dead-end mutation class into an actionable target.² ALASCCA proved utility of molecular testing in nonmetastatic disease,³ while the ARCAD analysis demonstrated the value through treatment.⁴ Biomarkers guide the entire treatment journey.

The Veteran Difference

But, there are caveats. The molecular map in CRC was drawn largely from civilian populations. The trial cohorts that established the predictive value of MSI status, RAS wild-type classification and PI3K pathway alterations enrolled patients from academic cancer centers and cooperative group networks that skew toward nonveteran, predominantly white, urban-dwelling adults. The biomarker thresholds, mutation prevalences and treatment effect sizes from those trials are unlikely to translate without modification to a veteran population with different exposure histories, different biological aging trajectories and different comorbidity profiles.

Burn pit and radiation exposure both have plausible pathways for contributing to gastrointestinal malignancy. Whether they leave molecular fingerprints in CRC tumors such as altered mutational signatures, pathway activation patterns or epigenetic modifications that affect prognosis or treatment response is not yet known, because the tumor biorepository infrastructure needed to answer it is just now being built by the VA.

While expanding knowledge of CRC in veterans, the VA’s NPOP can also contribute to refinement of genomic alteration frequencies in the broader population by utilizing its equal access system to expand the data available for understanding metastatic CRC in younger and more diverse populations than most clinical trials enroll. A study of NGS results from 5,015 veterans, for instance, recently found that 9 of the top 10 most commonly altered genes in metastatic prostate cancer were the same in non-Hispanic Black and non-Hispanic white veterans. The frequencies of specific alterations, however, varied substantially by race and ethnicity.⁵

Emerging Therapies Continue to Refine CRC Treatment

In addition, the science continues to evolve in CRC, with multiple new or prospective therapies in testing today, some of which the VA will likely be incorporating into care pathways soon. Others would benefit from access to the VA’s clinical trial program.

The phase 3 COMMIT trial presented at the ASCO Gastrointestinal Cancers Symposium in January evaluated one emerging therapy. The researchers found that a combination of chemotherapy with bevacizumab and atezolizumab extended progression-free survival to 2 years, up from 5 months for atezolizumab alone, for patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer.⁶

The combination “could be a game-changer for the first-line treatment of deficient mismatch repair or microsatellite instability-high metastatic colorectal cancer,” said Vishwanath Sathyanarayanan, MD, of Apollo Hospitals in Bangalore, India.

In February, the combination of encorafenib with cetuximab and fluorouracil-based chemotherapy (either mFOLFOX6 or FOLFIRI) received FDA approval for treatment of mCRC patients with a BRAF V600E mutation based on the phase 3 BREAKWATER trial.⁷

A study published in December looks likely to unearth some of the differences between early and late onset CRC. Yale researchers identified key metabolic and genetic patterns that differed by age group. “The tumors from early-onset patients seem to have a different biology,” said Dr. Oladimeji Aladelokun, PhD, a post-doctoral assistant at YSPH and contributing author of the study.⁸

Other studies are looking at ways to restore sensitivity to previous therapies in patients. Among those is one studying the effectiveness of using an anti-EGFR agent such as cetuximab or panitumumab in the first and third lines of therapy in patients with metastatic CRC with wild-type RAS genes. The study also examined the use of liquid biopsies to monitor tumor evolution.⁹

Beyond liquid biopsy, circulating tumor DNA (ctDNA) analysis could add a further dimension to CRC care. Post-surgical ctDNA clearance is establishing itself as a tool for risk-stratifying stage II and III patients after resection, helping to identify patients whose treatment-resistant residual disease warrants more intensive adjuvant therapy and those who may safely receive lower doses or stop therapy. Serial ctDNA monitoring in the metastatic setting provides real-time molecular surveillance of treatment response, resistance emergence, and tumor evolution in ways that restaging CT imaging alone cannot.

What Fully Realized Precision Oncology Looks Like for Veterans

The current options and decision points already warrant every veteran with colorectal cancer receiving a complete molecular profile at or shortly after diagnosis, so that it is available before any major treatment decision is finalized, and no branch point in the algorithm is reached without the information needed to navigate it correctly.

The VA’s existing NPOP infrastructure is the most powerful platform for veteran enrollment in precision oncology clinical trials in the country, with 131 sites, centralized next-generation sequencing (NGS), centralized testing coverage, academic partnerships, TeleOncology, and annotated molecular results.

The connection between an NGS result flagging a rare actionable mutation and an open clinical trial slot at a VA-affiliated academic center is the kind of systematic linkage that most community oncology networks cannot offer. The challenge facing the VA today is refining NPOP to maintain and build on that linkage and ensure that a molecular result in a rural CBOC in Alabama generates the same trial access conversation as in large academic-affiliated VAMCs in Atlanta or Chicago.

 

1. André T, Elez E, Lenz HJ, et al. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Lancet. 2025 Feb 1;405(10476):383-395. doi: 10.1016/S0140-6736(24)02848-4. Epub 2025 Jan 25. Erratum in: Lancet. 2025 Mar 1;405(10480):700. doi: 10.1016/S0140-6736(25)00352-6. PMID: 39874977.
2. Pietrantonio F, Salvatore L, Esaki T, et al. Overall Survival Analysis of the Phase III CodeBreaK 300 Study of Sotorasib Plus Panitumumab Versus Investigator’s Choice in Chemorefractory KRAS G12C Colorectal Cancer. J Clin Oncol. 2025 Jul;43(19):2147-2154. doi: 10.1200/JCO-24-02026. Epub 2025 Apr 11. PMID: 40215429; PMCID: PMC12199804.
3. Martling A, Hed Myrberg I, Nilbert M, et al; ALASCCA Study Group. Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer. N Engl J Med. 2025 Sep 18;393(11):1051-1064. doi: 10.1056/NEJMoa2504650. PMID: 40961426.
4. Bando H, Takeda Y, Misumi T, et al. Associations between early tumor shrinkage/depth of response and survival from the ARCAD database. JNCI Cancer Spectr. 2025 Apr 30;9(3):pkaf042. doi: 10.1093/jncics/pkaf042. PMID: 40280867; PMCID: PMC12159729.
5. Ozay ZI, Agarwal N. Race, Ethnicity, and Tumor Genomic Testing in Prostate Cancer. JAMA Netw Open. 2025 May 1;8(5):e259128. doi: 10.1001/jamanetworkopen.2025.9128. PMID: 40354059.
6. Lima CMR. Colorectal Cancer Metastatic dMMR Immunotherapy (COMMIT) study: A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo (FFX/bev) in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC)— NRG-GI004/SWOG-S1610. J Clin Oncol. 44 (2:14). Jan 2026.
7. Elez E, Yoshino T, Shen L, et al; BREAKWATER Trial Investigators. Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. N Engl J Med. 2025 Jun 26;392(24):2425-2437. doi: 10.1056/NEJMoa2501912. Epub 2025 May 30. PMID: 40444708; PMCID: PMC12197837.
8. Janak A, Jain A, Garcia-Milian R, et al. Distinct metabolic and genetic alterations in tumors from early-onset versus late-onset colorectal cancer. Free Radic Biol Med. 2025 Dec 1;240:773-782. doi: 10.1016/j.freeradbiomed.2025.08.052. Epub 2025 Aug 25. PMID: 40865779.
9. Sgouros J, Eliades A, Papadopoulou K, et al. Anti-EGFR re-challenge with chemotherapy in RAS wild-type advanced colorectal cancer (A-REPEAT study): efficacy and correlations with tissue and plasma genotyping. ESMO Gastrointest Oncol. 2025 Jan 8;7:100120. doi: 10.1016/j.esmogo.2024.100120. PMID: 41646483; PMCID: PMC12836756.