Brave New World: Analysis of Early Clinical Experience with Molecular Sequencing in the Treatment of Rectal Cancer.

Background: Advances in genetic sequencing technologies, including somatic next-generation sequencing and circulating tumor DNA assays, have significantly impacted rectal cancer management. However, the clinical implications of these technologies remain incompletely understood.

Objective: To evaluate patterns and clinical utility of genetic sequencing among patients with rectal cancer.

Design: Retrospective cohort analysis from a prospectively maintained institutional registry.

Setting: Single National Cancer Institute-designated cancer center.

Patients: A total of 251 patients diagnosed with rectal cancer between January 2017 and April 2024, who underwent genetic testing.

Interventions: Somatic tumor sequencing and circulating tumor DNA analysis.

Main outcome measures: Response to total neoadjuvant therapy, local recurrence, and distant metastasis.

Results: Genetic testing utilization increased substantially from 2017 to 2024, with somatic next generation sequencing testing rising from 3% to 33% and circulating tumor DNA from 2% to over 45%. Tumor mutational burden did not correlate significantly with response to total neoadjuvant therapy, recurrence, or metastasis. Mutation profiles across carcinogenesis pathways showed no significant differences between complete responders and those with residual disease after adjustment (p = 0.145). After total neoadjuvant therapy, circulating tumor DNA positivity strongly correlated with residual disease (sensitivity: 76.5%, specificity: 82.4%; p = 0.0016), with tumor-agnostic circulating tumor DNA assays demonstrating significantly higher sensitivity than tumor-informed tests (100% vs. 50%, p = 0.03).

Limitations: Retrospective design, potential selection bias, single-center data.

Conclusions: Despite increasing adoption, somatic next generation sequencing alone lacks clear prognostic or predictive utility for rectal cancer management. In contrast, circulating tumor DNA testing demonstrated substantial promise for assessing response to total neoadjuvant therapy, particularly using tumor-agnostic platforms. Further prospective studies are needed to refine clinical guidelines and fully integrate these genetic technologies into rectal cancer care. See Video Abstract.