Sequencing paired tumor DNA and white blood cells improves circulating tumor DNA tracking and detects pathogenic germline variants in localized colon cancer.

BACKGROUND: In the setting of localized colon cancer (CC), circulating tumor DNA (ctDNA) monitoring in plasma has shown potential for detecting minimal residual disease (MRD) and predicting a higher risk of recurrence. With the tumor-only sequencing approach, however, germline variants may be misidentified as somatic variations, precluding the possibility of tracking in up to 11% of patients due to a lack of known somatic mutations. In this study, we assess the potential value of adding white blood cells (WBCs) to tumor tissue sequencing to enhance the accuracy of sequencing results. PATIENTS AND METHODS: A total of 148 patients diagnosed with localized CC were prospectively recruited at the Hospital Clínico Universitario in Valencia (Spain). Employing a custom 29-gene panel, sequencing was conducted on tumor tissue, plasma and corresponding WBCs. Droplet digital PCR and amplicon-based NGS were performed on plasma samples post-surgery to track MRD. Oncogenic somatic variants were identified by annotating with COSMIC, OncoKB and an internal repository of pathogenic mutations database. A variant prioritization analysis, mainly characterized by the match of oncogenic mutations with the evidence levels defined in OncoKB, was carried out to select specific targeted therapies. RESULTS: Utilizing paired tumor and WBCs sequencing, we identified somatic mutations in all patients (100%) within our cohort, compared to 89% using only tumor tissue. Consequently, the top 10 most frequently mutated genes for plasma monitoring were altered. The sequencing of WBCs identified 9% of patients with pathogenic mutations in the germline, with APC and TP53 being the most frequently mutated genes. Additionally, mutations in genes related to clonal hematopoiesis of indeterminate potential were detected in 27% of the cohort, with TP53, KRAS, and KMT2C being the most frequently altered genes. There were no observed differences in the sensitivity of monitoring MRD using ddPCR or amplicon-based NGS (p = 1). Ultimately, 41% of the patients harbored potentially targetable alterations at diagnosis. CONCLUSION: The germline testing method not only enhanced sequencing results and raised the proportion of patients eligible for plasma monitoring, but also uncovered the existence of pathogenic germline variations, thereby aiding in the identification of patients at a higher risk of hereditary cancer syndromes.

Propensity score analysis of postoperative and oncological outcomes after surgical treatment for splenic flexure colon cancer.

PURPOSE: The surgical treatment of splenic flexure colon cancer (SFCC) is somehow not yet well standardized. Postoperative and oncological results of the three surgical techniques most commonly used to treat SFCC: extended right colectomy (ERC), egmental left colectomy (SLC), and left colectomy (LC) were evaluated. METHODS: The study included all patients with stage I-III SFCC treated by ERC, SLC, or LC between 2005 and 2016. Postoperative and long-term outcomes after the different surgical techniques were analyzed: Propensity score matching (PSM) was performed to compare the outcomes between these surgical techniques and survival analyses were performed using the Kaplan-Meier method and log-rank tests. RESULTS: A total of 170 SFCC patients were operated; ERC was performed in 71 (41.76%), SLC in 36 (21.18%), and LC in 63 (37.06%). There were no significant differences in the short and long-term postoperative outcomes. Three comparison groups were developed so that PSM could be performed between the surgical technique cases: ERC (n = 59) vs. LC (n = 50); ERC (n = 50) vs. SLC (n = 33); and SLC (n = 32) vs. LC (n = 44). No differences in the short or long-term outcomes of these techniques were observed. CONCLUSION: The short and long-term outcomes between ERC, SLC, and LC are similar. SLC should be considered oncologically as appropiate as the other more extensive resections.