Resected Colorectal Cancer Patients Research Articles

Efficacy of laparoscopic low anterior resection for colorectal cancer patients with 3D-vascular reconstruction for left coronary artery preservation.

Laparoscopic low anterior resection (LLAR) has become a mainstream surgical method for the treatment of colorectal cancer, which has shown many advantages in the aspects of surgical trauma and postoperative rehabilitation. However, the effect of surgery on patients' left coronary artery and its vascular reconstruction have not been deeply discussed. With the development of medical imaging technology, 3D vascular reconstruction has become an effective means to evaluate the curative effect of surgery. To investigate the clinical value of preoperative 3D vascular reconstruction in LLAR of rectal cancer with the left colic artery (LCA) preserved. A retrospective cohort study was performed to analyze the clinical data of 146 patients who underwent LLAR for rectal cancer with LCA preservation from January to December 2023 in our hospital. All patients underwent LLAR of rectal cancer with the LCA preserved, and the intraoperative and postoperative data were complete. The patients were divided into a reconstruction group (72 patients) and a nonreconstruction group (74 patients) according to whether 3D vascular reconstruction was performed before surgery. The clinical features, operation conditions, complications, pathological results and postoperative recovery of the two groups were collected and compared. A total of 146 patients with rectal cancer were included in the study, including 72 patients in the reconstruction group and 74 patients in the nonreconstruction group. There were 47 males and 25 females in the reconstruction group, aged (59.75 ± 6.2) years, with a body mass index (BMI) (24.1 ± 2.2) kg/m2, and 51 males and 23 females in the nonreconstruction group, aged (58.77 ± 6.1) years, with a BMI (23.6 ± 2.7) kg/m2. There was no significant difference in the baseline data between the two groups (P > 0.05). In the submesenteric artery reconstruction group, 35 patients were type I, 25 patients were type II, 11 patients were type III, and 1 patient was type IV. There were 37 type I patients, 24 type II patients, 12 type III patients, and 1 type IV patient in the nonreconstruction group. There was no significant difference in arterial typing between the two groups (P > 0.05). The operation time of the reconstruction group was 162.2 ± 10.8 min, and that of the nonreconstruction group was 197.9 ± 19.1 min. Compared with that of the reconstruction group, the operation time of the two groups was shorter, and the difference was statistically significant (t = 13.840, P < 0.05). The amount of intraoperative blood loss was 30.4 ± 20.0 mL in the reconstruction group and 61.2 ± 26.4 mL in the nonreconstruction group. The amount of blood loss in the reconstruction group was less than that in the control group, and the difference was statistically significant (t = -7.930, P < 0.05). The rates of anastomotic leakage (1.4% vs 1.4%, P = 0.984), anastomotic hemorrhage (2.8% vs 4.1%, P = 0.672), and postoperative hospital stay (6.8 ± 0.7 d vs 7.0 ± 0.7 d, P = 0.141) were not significantly different between the two groups. Preoperative 3D vascular reconstruction technology can shorten the operation time and reduce the amount of intraoperative blood loss. Preoperative 3D vascular reconstruction is recommended to provide an intraoperative reference for laparoscopic low anterior resection with LCA preservation.

Tissue-free liquid biopsies combining genomic and methylation signals for minimal residual disease detection in patients with early colorectal cancer from the UK TRACC Part B study.

Absence of post-operative circulating tumour DNA (ctDNA) identifies resected colorectal cancer (CRC) patients with low recurrence risk for adjuvant chemotherapy (ACT) de-escalation. We present the largest resected CRC cohort to date with tissue-free minimal residual disease (MRD) detection. TRACC included stage I-III resectable CRC patients. Prospective longitudinal plasma collection for ctDNA occurred pre- and post-surgery, post-ACT, every 3m for year 1 and every 6m in years 2 and 3 with imaging annually. The Guardant Reveal assay evaluated genomic and methylation signals. The primary endpoint was 2yr recurrence free survival (RFS) by post-operative ctDNA detection. (NCT04050345) Results: Between December 2016 and August 2022, 1203 were patients enrolled. Plasma samples (n=997) from 214 patients were analysed. 143 patients were evaluable for the primary endpoint; 92 (64.3%) colon, 51 (35.7%) rectal; 2 (1.4%) stage I, 64 (44.8%) stage II, 77 (53.8%) stage III. Median follow-up was 30.3m (95% CI: 29.5-31.3). 2yr RFS was 91.1% in patients with ctDNA not detected post-operatively and 50.4% in those with ctDNA detected (HR 6.5 [2.96-14.5] p<0.0001). Landmark negative predictive value (NPV) was 91.2% (95% CI 83.9-95.9). Longitudinal sensitivity and specificity were 62.1% (95% CI 42.2-79.3) and 85.9% (95% CI 78.9-91.3) respectively. Median lead-time from ctDNA detection to radiological recurrence was 7.3m (IQR 3.3-12.5; n=9). Tissue-free MRD detection with longitudinal sampling predicts recurrence in stage I-III CRC without need for tissue sequencing. NPV is high supporting ACT de-escalation in patients with ctDNA not detected post-operatively, now being investigated in the UK TRACC Part C study.

Do resected colorectal cancer patients need early chest imaging? Impact of clinicopathologic characteristics on time to development of pulmonary metastases.

For patients with colorectal cancer (CRC), the lung is the most common extra-abdominal site of distant metastasis. However, practices for chest imaging after colorectal resection vary widely. We aimed to identify characteristics that may indicate a need for early follow-up imaging. We retrospectively reviewed charts of patients who underwent CRC resection, collecting clinicopathologic details and oncologic outcomes. Patients were grouped by timing of pulmonary metastases (PM) development. Analyses were performed to investigate odds ratio (OR) of PM diagnosis within 3 months of CRC resection. Of 1600 patients with resected CRC, 233 (14.6%) developed PM, at a median of 15.4 months following CRC resection. Univariable analyses revealed age, receipt of systemic therapy, lymph node ratio (LNR), lymphovascular and perineural invasion, and KRAS mutation as risk factors for PM. Furthermore, multivariable regression showed neoadjuvant therapy (OR: 2.99, p < 0.001), adjuvant therapy (OR: 6.28, p < 0.001), LNR (OR: 28.91, p < 0.001), and KRAS alteration (OR: 5.19, p < 0.001) to predict PM within 3 months post-resection. We identified clinicopathologic characteristics that predict development of PM within 3 months after primary CRC resection. Early surveillance in such patients should be emphasized to ensure timely identification and treatment of PM.

Venetoclax is a potent hepsin inhibitor that reduces the metastatic and prothrombotic phenotypes of hepsin-expressing colorectal cancer cells.

Introduction: Hepsin is a type II transmembrane serine protease and its expression has been linked to greater tumorigenicity and worse prognosis in different tumors. Recently, our group demonstrated that high hepsin levels from primary tumor were associated with a higher risk of metastasis and thrombosis in localized colorectal cancer patients. This study aims to explore the molecular role of hepsin in colorectal cancer. Methods: Hepsin levels in plasma from resected and metastatic colorectal cancer patients were analyzed by ELISA. The effect of hepsin levels on cell migration, invasion, and proliferation, as well as on the activation of crucial cancer signaling pathways, was performed in vitro using colorectal cancer cells. A thrombin generation assay determined the procoagulant function of hepsin from these cells. A virtual screening of a database containing more than 2000 FDA-approved compounds was performed to screen hepsin inhibitors, and selected compounds were tested in vitro for their ability to suppress hepsin effects in colorectal cancer cells. Xenotransplantation assays were done in zebrafish larvae to study the impact of venetoclax on invasion promoted by hepsin. Results: Our results showed higher plasma hepsin levels in metastatic patients, among which, hepsin was higher in those suffering thrombosis. Hepsin overexpression increased colorectal cancer cell invasion, Erk1/2 and STAT3 phosphorylation, and thrombin generation in plasma. In addition, we identified venetoclax as a potent hepsin inhibitor that reduced the metastatic and prothrombotic phenotypes of hepsin-expressing colorectal cancer cells. Interestingly, pretreatment with Venetoclax of cells overexpressing hepsin reduced their invasiveness in vivo. Discussion: Our results demonstrate that hepsin overexpression correlates with a more aggressive and prothrombotic tumor phenotype. Likewise, they demonstrate the antitumor role of venetoclax as a hepsin inhibitor, laying the groundwork for molecular-targeted therapy for colorectal cancer.

Prognostic scoring system to predict mortality after surgery in resectable colorectal cancer

Link of Video Abstract: https://youtu.be/mYpKu0PcJrM Background: Colorectal cancer remains as the major problem worldwide. Numerous studies have investigated factors associated with mortality and recurrence rates in colorectal cancer. To facilitate the everyday use of mortality predictors, they should be incorporated into a prognostic scoring system. This study aimed to identify factors affecting mortality in resectable colorectal cancer patients after surgery and to develop a prognostic scoring system capable of predicting mortality in these patients. Methods: This retrospective cohort study involved colorectal cancer patients at Cipto Mangunkusumo Hospital, Indonesia, from January 2016 – April 2020 diagnosed with resectable colorectal cancer. Data were collected from medical records, operation reports, histopathology reports, and laboratory test results. Mortality was assessed three years after curative surgery. Result: A total of 214 resectable colorectal cancer patients were included in the study. Tumor size ≥ 5 cm, T3/T4 staging, absence of adjuvant chemotherapy, unachieved free circumferential margin, and CEA levels &gt; 11.4 ng/mL were significantly associated with increased three-year mortality. The constructed three-year mortality prognostic scoring system was able to predict outcomes with a sensitivity of 91.3% and a specificity of 67.6%. Conclusion: The prognostic scoring system, consisting of five variables, is significantly capable of predicting three-year mortality rates with high sensitivity

Primary tumor resection in colorectal cancer patients with unresectable distant metastases: a minireview.

Colorectal cancer (CRC) is the second most common cause of cancer-related death among both men and women worldwide and the third most common cancer overall. About 20% of patients diagnosed with CRC were discovered to have distant metastatic lesions, the majority of which were located in the liver. For the optimum treatment of CRC patients with hepatic metastases, interventional radiologists, medical oncologists, and surgeons must all collaborate. The surgical excision of the primary tumor is an important part of CRC treatment since it has been found to be curative in cases of CRC with minimal metastases. However, given the evidence to date was gathered from retrospective data, there is still controversy over the effectiveness of primary tumor resection (PTR) in improving the median overall survival (OS) and quality of life. Patients who have hepatic metastases make up a very tiny fraction of those who are candidates for resection. With a focus on the PTR, this minireview attempted to review the current advancements in the treatment options for hepatic colorectal metastatic illness. This evaluation also included information on PTR's risks when performed on individuals with stage IV CRC.

Left hemicolectomy and low anterior resection in colorectal cancer patients: Knight-griffen vs. transanal purse-string suture anastomosis with no-coil placement.

Colorectal cancer (CRC) is considered one of the most frequent neoplasms of the digestive tract with a high mortality rate. Left hemicolectomy (LC) and low anterior resection (LAR) with minimally invasive laparoscopic and robotic approaches or with the open technique are the gold standard curative treatment. Seventy-seven patients diagnosed with CRC were recruited between September 2017 and September 2021. All patients underwent a preoperative staging with a full-body CT scan. The goal of this study was to compare both types of surgeries, LC-LAR LS with Knight-Griffen colorectal anastomosis and LC-LAR open with Trans-Anal Purse-String Suture Anastomosis (the TAPSSA group), by positioning a No-Coil transanal tube (SapiMed Spa, Alessandria, Italy), in terms of postoperative complications such as prolonged postoperative ileus (PPOI), anastomotic leak (AL), postoperative ileus (POI), and hospital stay. The patients were divided into two groups: the first with 39 patients who underwent LC and LAR in LS with Knight-Griffen anastomosis (Knight-Griffen group) and the second with 38 patients who underwent LC and LAR by the open technique with the TAPSSA group. Only one patient who underwent the open technique suffered AL. POI was 3.76 ± 1.7 days in the TAPSSA group and 3.07 ± 1.3 days in the Knight-Griffen group. There were no statistically significant differences in terms of AL and POI between the two different groups. The important point that preliminarily emerged from this retrospective study was that the two different techniques showed similarities in terms of AL and POI, and therefore, all the advantages reported in the previous studies pertaining to No-Coil also hold good in this study regardless of the surgical technique used. However, randomized controlled trials are needed to confirm these findings.

Patient-specific tumor-informed circulating tumor DNA (ctDNA) analysis for molecular residual disease (MRD) detection in surgical patients with stage I-IV colorectal cancer (CRC).

213 Background: Identifying molecular residual disease (MRD) with tailored tumor-informed ctDNA-based next-generation sequencing (NGS) assays after curative surgery could facilitate the individualized management of resected colorectal cancer (CRC) patients. Here, we prospectively evaluated the clinical performance of tumor-informed ctDNA mutation analysis using a novel Burning Rock Patient-specific Prognostic and Potential Therapeutic Marker Tracking (brPROPHET) approach for assessing MRD in resected CRC patients. Methods: The brPROPHET assay was designed to track patient-specific somatic variants based on whole-exome sequencing (WES) of the tumor tissue and matched white blood cells (WBCs). Fixed panel with informed calling (FI) and fixed panel with agnostic calling (FA) assays were performed in a subset of patients with a 168-gene panel spanning 273 kb of the human genome for a head-to-head comparison. Results: A total of 117 patients (stage II/III 53[45.0%]/41[35.0%]) were analyzed. 60 (51.0%) patients were treated with adjuvant therapy after surgery. brPROPHET assay was designed to target up to 55 variants per patient. Only 6% (344/5835) of designed variants were included in the fixed panels. 75% (2908/3886) of genes selected for panel design were private to a specific patient. Preoperative ctDNA was detected in 97% (113/117) of the patients with 88% (14/16), 98% (52/53), 98% (40/41), and 100% (7/7) in stage I, II, III and IV, respectively. The median ctDNA levels were observed to be higher in patients with advanced stages and significantly correlated with tumor volume. MRD status was tested postoperatively on day 7 and day 30 with a positivity rate of 18% (21/117) and 15% (14/93), respectively. Due to a short follow-up period, only two patients had recurred, and ctDNA was detected prior to radiological relapse, with a lead time of 1 and 2 months, respectively. Among 74 patients enrolled for parallel comparing three MRD assays, preoperative ctDNA was detected in 97.3%, 75.7%, and 68.9% of patients with brPROPHET, FI and FA fixed panel assays, respectively. 20.3% (15/74) of patients had baseline ctDNA captured by brPROPHET assay only. The ctDNA levels of these patients (median:0.3 mean tumor molecules [MTM] / milliliter [mL]) were lower than those captured by FI/FA fixed panels (median:3.0 MTM/mL, p&lt;0.05). A total of 135 postoperative blood samples were tested by all three assays, the positive rates with brPROPHET, FI and FA fixed panel assays were 14.8%, 8.1%, and 6.7% respectively. Conclusions: This initial study reported the clinical performance of the patient-specific brPROPHET assay in CRC, demonstrating superior sensitivity in detecting preoperative and postoperative ctDNA than the fixed panel assays. The ongoing study including correlation with clinical outcomes and serial testing will be presented.

Tumor-informed or tumor-agnostic circulating tumor DNA as a biomarker for risk of recurrence in resected colorectal cancer patients.

Circulating tumor DNA (ctDNA) has been increasingly recognized as a promising minimally-invasive biomarker that could identify patients with minimal residual disease and a high risk of recurrence after definitive treatment. In this study, we've compared the clinical utility and sensitivity of 2 different approaches to ctDNA analyses: tumor-informed and tumor-agnostic in the management of colorectal (CRC) patients. The clinical benefits of a single timepoint ctDNA analysis compared to serial ctDNA monitoring after definitive treatment were also evaluated to uncover the ideal surveillance protocol. Patient-paired resected tumor tissues, peripheral blood cells, and a total of 127 pre-operative and serial plasma cell-free DNA (cfDNA) samples after definitive treatment from 38 CRC patients that had undergone curative intent surgery were analyzed using a commercial NGS cfDNA panel. Up to 84% (32/38) of the recruited patients were detected with at least 1 genomic alteration from the tumor tissues that could be monitored using the tumor-informed ctDNA approach and none of the detected alterations were clonal hematopoiesis (CH) related. In contrast, 37% (14/38) of patients were detected with at least 1 monitoring alteration after exclusion of CH mutations using the tumor-agnostic approach. Serial plasma samples after definitive therapy were available for 31 patients. In the landmark ctDNA analysis, 24% (7/29) of patients had detectable ctDNA and were more likely to relapse than ctDNA-negative patients (p < 0.05). The landmark analysis sensitivity and specificity for recurrence were 67% and 87%, respectively. The incorporation of longitudinal ctDNA analysis at 6-months intervals improved the sensitivity to 100%. The median variant allele frequency (VAF) of the ctDNA mutations detected during surveillance was 0.028% (range: 0.018-0.783), where up to 80% (8/10) of the mutations were detected at VAF lower than the tumor-agnostic detection limit of 0.1%. Utilizing the tumor-agnostic approach reduced the recurrence detection sensitivity to 67% (4/6). Serial ctDNA analyses predicted disease recurrence at a median of 5 months ahead of radiological imaging. Longitudinal monitoring using tumor-informed ctDNA testing shows high analytical sensitivity, low probability of false-positive results due to CH mutations, and improved sensitivity in detecting recurrence which may modify the clinical management of CRC.

43O Preoperative chemotherapy prior to primary tumor resection for colorectal cancer patients with asymptomatic resectable primary lesion and synchronous unresectable liver-limited metastases (RECUT): A prospective, randomized, controlled, multicenter clinical trial

Primary tumor resection (PTR) was preferably performed for metastatic colorectal cancer (mCRC) with an asymptomatic resectable primary tumor and synchronous unresectable colorectal liver-limited metastases (CRLMs) with conversion therapy intent.

Colorectal cancers with a residual adenoma component: Clinicopathologic features and KRAS mutation.

Background/AimColorectal cancer is well known for its “adenoma-carcinoma” sequential carcinogenesis. Some colorectal cancers demonstrate a residual adenoma component during progression from adenoma to invasive carcinoma. However, the clinicopathological significance of residual adenoma component remains unclear. In this study, we aimed to investigate the clinicopathologic and molecular characteristics including the KRAS mutation in colorectal cancers containing a residual adenoma component.Materials and methodsIn this study, 498 surgically resected colorectal cancer patients were enrolled. Their detailed clinicopathologic features and results of molecular study including KRAS mutation test and microsatellite instability were analyzed.ResultsA residual adenoma component was identified in 42 (8.4%) patients with colorectal cancer. The presence of a residual adenoma component was associated with a high frequency of the KRAS mutation (65%, p = 0.031) as well as indolent clinicopathological features, including polypoid gross type (p < 0.001), well-differentiated histology (p < 0.001), low pT (p < 0.001) and pN stage (p = 0.003), absence of vascular invasion (p = 0.005), and a better progression-free prognosis (p = 0.029). The cases with an adenoma component had a 35.7% discordance rate on the KRAS mutation tests in their adenoma and carcinoma regions.ConclusionIn conclusion, colorectal cancer with a residual adenoma component showed indolent clinicopathologic features and frequent KRAS mutations. Due to the discordance in the incidence of the KRAS mutation between the adenoma and carcinoma components, the adenoma component should be documented in the pathology report, and care should be taken not to include the adenoma component when collecting samples for molecular testing.

Short-term efficacy, safety and survival of laparoscopic radical resection for colorectal cancer patients with bowel obstruction.

To investigate the short-term efficacy of laparoscopic radical resection for colorectal cancer with bowel obstruction and the effects of the surgery on inflammatory factors for improving the clinical treatment of the condition. The data of colorectal cancer patients presenting bowel obstruction (n=167) treated at our hospital from January 2019 to December 2020 were assessed. The patients were divided into a laparoscopic radical resection of colorectal cancer group (LRRCC, n=90) and open surgery group (OP, n=77). Before treatment and on the 1st, 3rd, 5th, 7th and 15th day after treatment, their serum levels of pain factors, neuropeptide Y, prostaglandin E2 and nerve growth factor were measured by a serum biochemistry analyzer, their levels of inflammatory factors including C-reactive protein, interleukin 6 (IL-6), IL-8 and tumor necrosis factor-α by ELISA, and their amount of CD3+, CD4+ and CD8+ T cell subsets were measure by flow cytometry. Anorectal motility was assessed before and 4 and 8 weeks after treatment. Survival rates were assessed using the Kaplan-Meier method. On the 1st, 3rd, 5th, 7th and 15th day after treatment, compared with the OP group, the LRRCC group had lower levels of serum pain factors, inflammatory factors and CD8+T lymphocytes, while their numbers of CD3+ and CD4+ T lymphocytes subsets were significantly increased. Further, the LRRCC group had fewer complications and significantly higher survival rates, demonstrating better efficacy than the OP group. Laparoscopic radical resection was effective and achieved superior outcomes than open surgery in treating colorectal cancer patients with bowel obstruction.

Efficacy and safety of triplet chemotherapy plus anti-EGFR agents in metastatic colorectal cancer: a systematic review and meta-analysis

BackgroundTo date, the optimal treatment for potentially resectable metastatic colorectal cancer (mCRC) patients has yet to be determined. Encouraging results have been reported in studies exploring the efficacy of triplet chemotherapy plus anti-epidermal growth factor receptor (anti-EGFR) target agents. Thus, we conducted a meta-analysis to evaluate the efficacy and safety of triplet chemotherapy plus anti-EGFR target agents.MethodsWe systematically searched the PubMed, Embase, and Web of Science databases from December 2004 to October 2021 for studies examining the efficacy of triplet chemotherapy plus anti-EGFR target agents in mCRC patients. The primary outcomes were the objective response rate (ORR) and R0 resection rate (R0RR), and the secondary outcomes were median progression-free survival (mPFS), median overall survival (mOS), and toxicity. Data were analyzed with R software 4.1.2.ResultsFourteen studies comprising 762 patients with mCRC were included in this meta-analysis. Analysis with a random effects model revealed that after treatment with triplet chemotherapy plus anti-EGFR target agents, the pooled ORR was 82% (95% CI= 76–88%, I2= 76%), and the pooled R0RR of colorectal liver metastasis (CLM) was 59% (95% CI= 49–68%, I2= 60%). The mPFS ranged from 9.5 to 17.8 months, and the mOS ranged from 24.7 to 62.5 months. A total of 648 grade 3 or 4 adverse events were reported; the most commonly reported events were diarrhea (174/648), neutropenia (157/648), and skin toxicity (95/648), which had pooled prevalence rates of 29% (95% CI= 20–39%, I2= 84%), 28% (95% CI= 20–37%, I2= 77%), and 17% (95% CI= 11–24%, I2= 66%), respectively.ConclusionsTriplet chemotherapy plus anti-EGFR agents therapy seems to be capable of increasing the ORR of mCRC patients and the R0RR of CLM patients. The toxicity of this treatment is manageable. High-quality randomized controlled trial (RCT) studies are required for further validation.

The relation of blood cell division control protein 42 level with disease risk, comorbidity, tumor features/markers, and prognosis in colorectal cancer patients.

BackgroundCell division control protein 42 (CDC42) is involved in colorectal cancer (CRC) progression by modulating CD8+ T cell activation, immune escape, and direct oncogenetic biological processes. This study aimed to explore the correlation of blood CDC42 with disease risk, comorbidities, disease features, tumor markers, and prognosis among CRC patients.MethodsCDC42 in peripheral blood mononuclear cells was detected by reverse transcription‐quantitative polymerase chain reaction from 250 resectable CRC patients and 50 healthy controls (HCs). CDC42 was divided by quartiles, as well as high and low expressions in CRC patients for correlation and survival analysis.ResultsCDC42 was elevated in CRC patients vs. HCs (p < 0.001), which had a good ability to distinguish CRC patients from HCs with the area under the curve (95% confidence interval) of 0.889 (0.841–0.937). In CRC patients, CDC42 was not associated with demographics or comorbidities (all p > 0.05), while its higher quartile was linked to increased T stage (p < 0.001), N stage (p = 0.009), TNM stage (p < 0.001), abnormal carcinoembryonic antigen (p = 0.043), and adjuvant chemotherapy administration (p = 0.002). Higher CDC42 quartile (p = 0.002) and CDC42 high (vs. low) (p < 0.001) were related to worse disease‐free survival (DFS); meanwhile, elevated CDC42 quartile (p = 0.002) and CDC42 high (vs. low) (p = 0.001) were also linked to poor overall survival (OS). Multivariate Cox's regression analysis presented that CDC42 quartile 3 and 4 (vs. quartile 1) independently predicted declined DFS and OS (all p < 0.05).ConclusionCirculating CDC42 relates to higher disease risk, T, N, and TNM stage, abnormal tumor marker, and poor prognosis among CRC patients.

Abstract 5917: Patient-specific tumor-informed circulating tumor DNA (ctDNA) analysis for postoperative monitoring of patients with stages I-III colorectal cancer (CRC)

Abstract Background: Identifying molecular residual disease (MRD) with tailored tumor-informed ctDNA based next-generation sequencing (NGS) assays after curative surgery could facilitate the individualized management of resected CRC patients. Here, we investigated the clinical utility of tumor-informed ctDNA mutation analysis using a novel Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (PROPHET) approach for accessing MRD in resected CRC patients. Using the same set of baseline and post-operative blood samples, we compared the performance of PROPHET assay with tumor-naïve fixed panel for detecting MRD and predicting recurrence in resected CRC patients. Methods: The prospective study recruited 42 patients diagnosed with stage I-III CRC from May 2019 to Jun 2020 at the First Affiliated Hospital of Soochow University. Tumor tissue samples were collected at surgery. Blood samples collected before surgery (baseline), 8-day post-operative time point before any adjuvant therapy were analyzed. The detection and quantification of ctDNA for MRD assessment was investigated using PROPHET, a personalized, tumor-informed ctDNA assay designed to track up to 50 top-ranked patient-specific somatic variants based on whole-exome sequencing (WES) of the tumor tissue and matched white blood cells (WBCs). Tumor- naïve fixed assay was performed using targeted NGS panel, containing 41 gastrointestinal cancer-related genes. Results: Baseline ctDNA status was detected in 95.23% (40/42) of the patients with PROPHET assay, and 69.05% (29/42) of the patients with fixed panel. Of 42 patients included in the analysis, 1, 25, and 16 patients had pathological stages I, II, and III CRC with baseline ctDNA detected in 100% (1/1), 92% (23/25), 100% (16/16) patients with PROPHET assay, and 100% (1/1), 64% (16/25), 75% (12/16) patients with fixed panel. Post-operative ctDNA-positive status with PROPHET assay was associated with 3-year DFS, compared with ctDNA-negative group (hazard ratio [HR], 16.57, 95% confidence interval [CI]:3.01-91.36, p=0.014). 15% (6/40) patients were identified to be MRD- positive and 83.33% (5/6) patients eventually relapsed at 3-years follow-up. Although fixed panel also showed high performance in predicting relapse HR, 4.48, 95% CI:1.9-10.9; p&amp;lt; 0.001, 27.5% (11/40) patients were identified to be MRD-positive and only 45.45% (5/11) patients eventually relapsed. 3-year prognostication with PROPHET assay at 8-day post-operation yielded higher positive predictive value (83.33% vs 45.45%), negative predictive value (91.18% vs 89.66%), and specificity (96.88% vs 81.25%) as compared with tumor-naïve fixed panel. Conclusion: Patient-specific PROPHET assay based on unique somatic mutation profiles detects patients with high-risk of recurrence, which achieved higher specificity than tumor-naïve fixed panel. Citation Format: Jian Zhou, Jian Yang, Zixiang Zhang, Ye Li, Bin Yi, Yuchen Tang, Dechun Li, Xiaozhe Li, Di Peng, XI Li, Yang Wang, Haiyan Li, Bing Li, Chenyang Wang, Pengfei Zhu, Longfei Chen, Shuailai Wu, Shuai Fang, Chenxi Li, Fujun Qiu, Shannon Chuai, Zhihong Zhang. Patient-specific tumor-informed circulating tumor DNA (ctDNA) analysis for postoperative monitoring of patients with stages I-III colorectal cancer (CRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5917.

Abstract 5133: Genetic characteristics &amp; clonal evolution of Chinese resectable colorectal cancer patients with lung metastases

Abstract Background Colorectal cancer (CRC) has a high incidence and mortality. In CRC, the lung is the most common extra-abdominal site of metastasis. Understanding the genetic characteristics and clonal evolution of primary tumor and lung metastases (LM) will help oncologists better outline treatments. To date, few studies for CRC with LM exist. As such, revealing the genetic characteristics and clonal evolution of resectable CRC with LM was the goal of this study. Methods From January 2012 to July 2019, clinical data and formalin-fixed, paraffin-embedded samples were collected from 33 Chinese CRC patients. Nineteen (19) primary tumors and 10 matched LM samples were examined using a 450 cancer gene next-generation sequencing assay. Genomic alterations, including single base substitutions, indels, copy number variations (CNVs), and gene fusion and rearrangement, were assessed. A phylogenetic reconstruction of sequencing data using LICHeE was also performed for each patient. Results Median patient age was 60 years old (48-67 years), with most having right lung metastasis. A significant difference existed between single (21/33, 63.6%) and multiple LM (12/33, 36.4%) (P &amp;lt; 0.01). Median disease-free survival was 20 months (95% CI, 0-84), from primary CRC to LM. The most frequently mutated genes were TP53 (90%), APC (90%), KRAS (53%), MUC16 (26%), ARID1A (21%). A comparison of mutational profiles for primary and matched LM samples revealed that 65.70% of alterations were consistent and that the most frequently mutated genes, including APC, TP53, and KRAS, of the primary tumor were completely consistent with LM. However, some differences between metastatic and primary samples were determined. More CNVs were found in primary samples (11.4% vs. 4.6%), indicating that CNVs are early molecular events for tumorigenesis and disease progression. SMAD4 was only present in two primary samples, while LRP1B was only present in two LM samples. Clonal evolution for eight patients indicated that phylogenetic structure was similar across patients. All patients had at least seven mutations on trunks. In trunks, TP53 (87.5%), APC (87.5%), KRAS (50%), and LRP2 (37.5%) were frequently identified. A new actionable gene (BRCA2) emerged in LM sample was identified in one patient. The mean value of TMB for the primary was almost the same as that for the LM site (5.3 vs. 5 muts/Mb, P &amp;gt; 0.05). Conclusions Our data indicated that the genetic characteristics and clonal evolution of LM are highly consistent with those of the primary tumor, suggesting that suitable treatments can be selected based on the genetic characteristics of primary tumor in CRC patients with LM that cannot be surgically treated. Citation Format: Yong Cheng, Ming-Jian Ge, Peng Dong, Yan-Yu Qiu, Xin-Peng Shu, Jin-Dou Li, Jun-Wei Wang, Xiao-Fang Qi. Genetic characteristics &amp; clonal evolution of Chinese resectable colorectal cancer patients with lung metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5133.

A randomized, double-blind, phase III study comparing trifluridine/tipiracil hydrochloride therapy versus placebo in resected colorectal cancer patients who are positive for blood circulating tumor DNA after standard adjuvant therapy (EPOC 1905): ALTAIR trial in CIRCULATE-Japan (trial in progress).

TPS215 Background: Circulating tumor DNA (ctDNA) can be used to predict the risk of recurrence by detecting molecular residual disease (MRD) in patients with colorectal cancer (CRC). Although patients with MRD positive status have extremely high risk of relapse, no standard treatment has been established for these patients after adjuvant chemotherapy. Trifluridine/tipiracil hydrochloride (FTD/TPI) is an oral anti-tumor agent combining thymidine-based nucleoside analogue with a thymidine phosphorylase inhibitor, which presents improved survival in patients with metastatic CRC refractory to fluoropyrimidines. Methods: The ALTAIR trial is a randomized, double-blind, phase III study designed to establish the superiority of FTD/TPI as compared with placebo in patients with resected CRC who show MRD positive status at any time after curative resection. ctDNA testing for screening patients with MRD positive is performed in the observational GALAXY study (UMIN000039205) that is a prospectively conducted large-scale nationwide registry designed to monitor ctDNA status for patient who can undergo curative resection. A personalized tumor-informed assay (Signatera bespoke multiplex-PCR NGS assay) is used for the detection and quantification of ctDNA-based postsurgical MRD. Key eligibility criteria are (a) having undergone radical resection of primary and/or metastatic tumors, (b) a history of standard adjuvant chemotherapy, (c) positive ctDNA status within the previous 3 months at any time postoperatively, and (d) no obvious relapse confirmed by chest, abdominal, and pelvic CT scans. Patients will be randomly assigned in a 1:1 ratio to receive either 6 months of oral FTD/TPI or a matching course of placebo. Randomization is stratified by age (&lt;70 vs. ≥70 years), stage (stage II or lower vs stage III vs. stage IV or M1), primary tumor location (right-sided vs left-sided colon vs rectum), ctDNA status at 1 month (positive vs negative or unmeasurable), and institution. The primary endpoint is disease free survival (DFS). Key secondary endpoints include rate of conversion from positive to negative ctDNA status, overall survival, adverse events, and quality of life. Assuming that the median DFS in the placebo group is approximately 8 months, a total of 240 patients (120 per arm) will provide 80% power to detect an expected DFS hazard ratio of 0.667 at two-sided significance level of 0.05, with an enrollment period of 2 years and a follow-up period of 1 year. This trial is actively accruing across 39 institutions in Japan and Taiwan and opened to recruitment in August 2018. By October 2021, a total of 67 patients have been enrolled. Clinical trial information: JapicCTI-205363/NCT04457297.

Serum biomarkers predict adjuvant chemotherapy-associated symptom clusters in radical resected colorectal cancer patients.

Due to individual heterogeneity, patients at the same stage of colorectal cancer (CRC) who receive the same chemotherapy may experience different symptom clusters. Identifying the precise factors that predict symptom clusters is of great clinical significance for precision care and for improving the quality of life of patients. The present study investigated the relationship between serum biomarkers and adjuvant chemotherapy-related symptom clusters in radically resected CRC patients. Serum biomarkers and clinical/pathological characteristics of the radical resected CRC patients were collected before the first cycle of adjuvant chemotherapy. A demographic questionnaire and M.D. Anderson Gastrointestinal Cancer Symptom Scale (MDASI-GI) were performed on the third day after chemotherapy and exploratory factor analysis was performed to determine the symptoms clusters. Multiple linear regression and correlation analysis were also performed to evaluate the correlation between serum biomarkers and chemotherapy-related symptom clusters. A total of 4 chemotherapy-related symptom clusters were determined in the enrolled radical resected CRC patients, including a fatigue-psychological symptom cluster, gastrointestinal symptom cluster, neurotoxic symptom cluster, and constipation-abdominal distension symptom cluster. Further analysis showed that the gastrointestinal symptom cluster was significantly associated with age, gender, weight change status, neutrophil to lymphocyte ratio (NLR), and body mass index (BMI). Additionally, the fatigue-psychological symptom cluster was found to be significantly associated with high NLR. The neurotoxic symptom cluster was found to be significantly associated with low hemoglobin level. Serum biomarkers and clinical characteristics of the radical resected CRC patients could be used to predict chemotherapy-related symptoms clusters.

N-Acylethanolamine acid amidase (NAAA) is dysregulated in colorectal cancer patients and its inhibition reduces experimental cancer growth.

Background and Purpose N‐Acylethanolamine acid amidase (NAAA) is a lysosomal enzyme accountable for the breakdown of N‐acylethanolamines (NAEs) and its pharmacological inhibition has beneficial effects in inflammatory conditions. The knowledge of NAAA in cancer is fragmentary with an unclarified mechanism, whereas its contribution to colorectal cancer (CRC) is unknown to date.Experimental ApproachCRC xenograft and azoxymethane models were used to assess the in vivo effect of NAAA inhibition. Further, the tumour secretome was evaluated by an oncogenic array, CRC cell lines were used for in vitro studies, cell cycle was analysed by cytofluorimetry, NAAA was knocked down with siRNA, human biopsies were obtained from surgically resected CRC patients, gene expression was measured by RT‐PCR and NAEs were measured by LC–MS.Key ResultsThe NAAA inhibitor AM9053 reduced CRC xenograft tumour growth and counteracted tumour development in the azoxymethane model. NAAA inhibition affected the composition of the tumour secretome inhibiting the expression of EGF family members. In CRC cells, AM9053 reduced proliferation with a mechanism mediated by PPAR‐α and TRPV1. AM9053 induced cell cycle arrest in the S phase associated with cyclin A2/CDK2 down‐regulation. NAAA knock‐down mirrored the effects of NAAA inhibition with AM9053. NAAA expression was down‐regulated in human CRC tissues, with a consequential augmentation of NAE levels and dysregulation of some of their targets.Conclusion and ImplicationsOur results show novel data on the functional importance of NAAA in CRC progression and the mechanism involved. We propose that this enzyme is a valid drug target for the treatment of CRC growth and development.

Snapshots of lymphatic pathways in colorectal cancer surgery using near-infrared fluorescence, in vivo and ex vivo

IntroductionIndocyanine green (ICG) fluorescence imaging has been used for blood flow assessment in anastomoses in the field of colorectal cancer surgery. However, whether ICG fluorescence is related to the presence of cancer cells in the lymph nodes is unclear. We explored the utilization of ICG fluorescence in colorectal cancer surgery. Materials and methodsICG was injected into the submucosa around the tumor before radical resection in colorectal cancer patients. Intraoperatively, near-infrared (NIR) fluorescence was used for lymphatic flow visualization. After specimen removal, harvested lymph nodes were classified as positive or negative based on the detection of fluorescence, followed by pathological examination. ICG distribution on a section of each lymph node was examined by fluorescence microscopy. ResultsOverall, 155 patients underwent real-time NIR fluorescence imaging-guided surgery. Altogether, 1,017 lymph nodes were retrieved from these patients. Metastatic lymph nodes were present in 36 (5.8%) of 622 fluorescence-negative lymph nodes, which was significantly higher than 11 (2.8%) of 395 fluorescence-positive lymph nodes (odds ratio: 2.15, P = 0.03). Fluorescence microscopy of metastatic lymph nodes showed that ICG fluorescence was present in the normal structural region but not in the cancerous region of the lymph nodes. Furthermore, ICG fluorescence was observed in all metastatic lymph nodes, except those with cancer cells occupying >90% of the total area. ConclusionsICG fluorescence detected only the normal parts of the lymph node draining from the peritumoral area and not the cancer tissues. This finding is important for developing appropriate strategies for navigation surgery using NIR fluorescence.