222 Background: Colorectal cancer is the second leading cause of cancer death in the US, with the incidence rising, especially in patients < 50 years of age. In locally advanced rectal cancer (LARC), preoperative chemoradiotherapy (CRT) prior to radical resection achieves significant rates of tumor downstaging, sphincter preservation, and decreased local recurrence. However, biomarkers to predict local recurrence remain lacking. Methods: We identified 46 LARC patients with biopsy-proven local recurrence after CRT plus surgery in the Danish national cancer registry between 2014-2017 as well as 92 matched control cases without local recurrence. The majority of the patients were treated with 50.4 Gy in 28 fractions with concomitant capecitabine. We performed targeted DNA and whole coding transcriptome RNA sequencing on FFPE tumors and germline DNA sequencing on adjacent normal tissue. Results: RNA profiles of local recurrence cases showed enrichment of DNA repair, cell cycle, and oxidative phosphorylation pathways, while profiles of controls were enriched for inflammatory and apoptotic signatures. FBXW7 mutations were significantly associated with local recurrence (Fisher exact test, p = 0.033), and no other mutations showed a similar association. Specifically, TP53 (p = 0.297), KRAS (p = 0.099) or concurrent TP53+KRAS (p= 0.208) mutations were not associated with local recurrence. Conclusions: LARC cases with local recurrence after CRT plus surgery are molecularly distinct from cases without recurrence. Transcriptomic analyses revealed distinct biology, with local recurrence tumors enriched for pathways related to intrinsic CRT resistance, whereas controls showed an immune response. Our analyses nominate FBXW7 mutations as a potential predictive biomarker of local recurrence after CRT plus surgery in LARC and warrant prospective validation.
erve et al. (2026) studied this question.