“ This case underscores the critical role of molecular profiling in tailoring personalized treatment strategies for advanced CRC, providing novel avenues for managing recurrent disease, even in the absence of measurable disease. ”
BUFFALO, NY - October 26, 2026 – A new case report was published in Volume 17 of Oncotarget on October 16, 2026, titled “ WIN-MTB-2024002 – WIN International Molecular Tumor Board: A 52-year-old female with unmeasurable Stage IIIc colon cancer .”
The report describes a 52-year-old woman with stage IIIc colon cancer whose disease remained difficult to monitor despite extensive treatment. Although conventional imaging showed no measurable cancer, repeated blood tests detected circulating tumor DNA (ctDNA), raising concern about possible residual disease. The case highlights how comprehensive molecular profiling and international collaboration may help guide treatment decisions when imaging and molecular findings provide different information.
The report was led by first and corresponding author Oncotarget Editor-in-Chief Dr. Wafik S. El-Deiry , affiliated with the Worldwide Innovative Network (WIN) Consortium and the Legorreta Cancer Center at Brown University . Equal-contributing author Razelle Kurzrock is affiliated with the WIN Consortium and the Medical College of Wisconsin .
Colorectal cancer is a leading cause of cancer-related deaths worldwide. Stage IIIc colon cancer involves extensive regional lymph node involvement and carries a substantial risk of recurrence even after surgery and chemotherapy. Monitoring for residual disease can be challenging when suspicious lymph nodes are too small or show limited activity on conventional imaging.
Molecular profiling can help identify genetic alterations that influence cancer growth and treatment response. Liquid biopsy testing offers additional information by detecting ctDNA released by cancer cells into the bloodstream, potentially identifying molecular evidence of residual disease even when imaging shows no measurable tumor.
The patient initially experienced weight loss, paleness and reduced appetite in June 2021. In February 2022, severe anemia prompted hospitalization and further investigation. Colonoscopy revealed an obstructing mass, and she underwent a right hemicolectomy. Pathological examination confirmed moderately differentiated adenocarcinoma with mucinous features, classified as stage IIIc (pT4bN2bM0). Ten of 25 examined lymph nodes contained cancer.
Following surgery, the patient completed six months of adjuvant FOLFOX chemotherapy. Subsequent imaging identified suspicious retroperitoneal and mesenteric lymph nodes, prompting 11 cycles of FOLFIRI combined with bevacizumab. She later received local radiotherapy targeting suspicious aortocaval lymph nodes in August 2023.
Despite treatment, determining whether cancer remained was difficult. Biopsies of suspicious sites were negative, and PET-CT imaging showed decreasing lymph node activity. By January 2024, previously suspicious areas no longer demonstrated abnormal fluorodeoxyglucose (FDG) uptake, indicating no metabolically detectable disease in those regions.
However, repeated Signatera and Guardant360 liquid biopsy tests detected ctDNA, while additional blood-based testing identified DNA methylation patterns associated with cancer. These findings raised concern about possible molecular residual disease despite the absence of measurable cancer on imaging, creating uncertainty about whether additional treatment or continued surveillance was more appropriate.
Comprehensive genomic profiling identified mutations involving KRAS, TP53, IDH1 and APC, along with other alterations affecting cellular growth and signaling. The tumor was microsatellite stable (MSS), with a relatively low tumor mutational burden, both relevant considerations when evaluating potential immunotherapy options.
Among these alterations, KRAS G12S was associated with abnormal growth signaling, while TP53 mutations affected tumor-suppressor function. APC alterations were linked to dysregulation of the Wnt pathway, an important driver of colorectal cancer, and the uncommon IDH1 R132C mutation provided another potential molecular target for investigation.
Additional analysis classified the tumor as consensus molecular subtype 4 (CMS4), associated with stromal activity and distinct signaling characteristics. The tumor microenvironment showed fibrosis, high PD-L1 expression, elevated VEGFR1 and VEGFR3 levels, and substantial natural killer (NK) cell infiltration. These findings helped inform the discussion of targeted and immune-based treatment strategies.
To evaluate the patient's options, the WIN Consortium International Molecular Tumor Board brought together specialists from 18 institutions across 13 countries. The experts reviewed her clinical history, genomic findings, immune microenvironment and imaging results to discuss potential maintenance therapies and treatments in the event of recurrence.
One proposed maintenance approach combined regorafenib, sulindac and metformin. Regorafenib targets several kinases involved in tumor growth and blood vessel formation, while sulindac was considered for its potential effects on Wnt signaling associated with APC alterations. Metformin was discussed because of its influence on metabolic pathways, including mTOR-related signaling. However, the effectiveness and safety of this specific combination have not been established.
The board also considered fruquintinib, a VEGF receptor inhibitor, combined with sulindac and metformin. Other options included fluorouracil (5-FU), with or without bevacizumab, or a less intensive maintenance strategy involving capecitabine or 5-FU followed by surveillance.
If the cancer recurred, the experts discussed expanding the regorafenib-based combination to include trametinib, a MEK inhibitor, and ivosidenib, an IDH1 inhibitor, to address additional molecular vulnerabilities. However, these combinations remain investigational in this setting, and their safety and effectiveness have not been established. The board also recognized the potential for treatment-related toxicity and the importance of careful monitoring.
Immunotherapy was another consideration. Given the tumor's high PD-L1 expression, the board discussed a combination of regorafenib, ipilimumab and nivolumab, known as RIN. Potential approaches targeting both PD-1 and TGFβ signaling were also explored, particularly in relation to the CMS4 subtype.
However, the tumor's microsatellite-stable status complicated these possibilities because conventional immune checkpoint inhibitors generally provide limited benefit in most MSS colorectal cancers. High PD-L1 expression alone does not establish sensitivity to immunotherapy, and the proposed combinations require further clinical evaluation.
Additional possibilities included clinical trials investigating pan-RAF inhibitors and NK cell-directed immunotherapies, as well as TAS-102 combined with bevacizumab. The experts also emphasized that further molecular testing could help refine treatment selection if recurrence occurred.
“ This case highlights the role of international MTBs in supporting complex therapeutic decision-making when conventional imaging, tissue biopsy, and molecular profiling provide incomplete or partially discordant information .”
A central challenge was the difference between imaging and molecular testing. Although PET-CT scans and biopsies did not identify measurable active disease at the time of review, persistent ctDNA positivity raised concern about residual cancer below the detection limits of conventional imaging. This uncertainty complicated decisions about whether additional systemic treatment might offer more benefit than continued surveillance.
The report has important limitations. As a single-patient case report, it cannot establish the effectiveness of the proposed therapies or identify the best approach for patients with detectable ctDNA but no measurable disease. Importantly, the report does not document implementation of a specific molecular tumor board recommendation or subsequent clinical outcomes.
Further studies will be needed to determine how ctDNA monitoring should influence treatment decisions and whether molecularly guided maintenance strategies improve outcomes in colorectal cancer. The safety and effectiveness of the proposed combinations will also require prospective evaluation.
Overall, the case illustrates how international molecular tumor boards can integrate genomic findings, liquid biopsy results, imaging and clinical expertise to explore personalized treatment opportunities. Although the proposed strategies remain unvalidated for this patient, the report highlights the potential value of multidisciplinary precision oncology when residual disease is suspected but cannot be measured through conventional imaging.
DOI: https://doi.org/10.18632/oncotarget.28921
Correspondence to: Wafik S. El-Deiry - wafik@brown.edu
Keywords : cancer, precision oncology, molecular tumor board, colon cancer
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WIN-MTB-2024002 – WIN International Molecular Tumor Board: A 52-year-old female with unmeasurable Stage IIIc colon cancer
16-Oct-2026
W.S.E-D. is Chair of the Worldwide Innovative Network (WIN) Association – WIN Consortium and the Scientific Founder of Oncoceutics, Inc. (acquired by Chimerix, Inc.), SMURF-Therapeutics, and p53-Therapeutics. He was also a founder and shareholder of Resurrect Therapeutics. He receives or has received recent funding from NIH/NCI, American Cancer Society, The Warren Alpert Foundation, AACR-Novocure, D&D Pharmatech, Chimerix, AstraZeneca, and Actuate Therapeutics. W.S.E-D. serves as a co-chair and on the Executive Committee of the Caris Life Sciences Precision Oncology Alliance. He serves on the Scientific Advisory Board (uncompensated) of Ocean Biomedicals and American Cancer Society BrightEdge, hold stocks in Jazz Pharmaceuticals and RVMD, and holds equity in Global Cancer Technology. He also serves as co-Editor-in-Chief of Oncotarget, the journal that invited this manuscript in a Collection of articles on Precision Oncology.”. W.S.E-D. was not involved in the peer review of this manuscript or the decision to accept it. C.B. and F.W. are full-time employees of Worldwide Innovative Network (WIN) Association – WIN Consortium. S.M. receives consultancy from Worldwide Innovative Network (WIN) Association – WIN Consortium. R.K. is Chief Medical Officer of the Worldwide Innovative Network (WIN) Association – WIN Consortium and has received research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, OmniSeq, Pfizer, Sequenom, Sysmex, Takeda, and TopAlliance and from the NCI; as well as consultant and/or speaker fees and/or advisory board/consultant for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Inc., Biological Dynamics, Caris, Daiichi, Datar Cancer Genetics, EISAI, EMD Serono, EOM Pharmaceuticals, Iylon, Jackson Laboratories, LabCorp, Lanauria Therapeutics, Merck, NeoGenomics, Neomed, Pfizer, Precirix, Prosperdtx, Quanta Therapeutics, Recordati, Regeneron, Roche, TD2/Volastra, Turning Point Therapeutics, X-Biotech; has an equity interest in CureMatch Inc.; serves on the Board of CureMatch and CureMetrix and XZOM, and is a co-founder of CureMatch. AH-C declares consultant or advisory roles in the following companies, Boehringer Ingelheim, Slingshot Insights, and Karger Publishers (personal), research funding from Bicara therapeutics, GSK, Bayer, Boehringer Ingelheim, CDR-life, Novartis, Vividion therapeutics and NEC Bio (all institution), grant support from Gilead (institution) and financial interest from CDDF and Fundación SEOM.