Metachronous Colorectal Cancer Research Articles

Features of synchronous and metachronous dual primary gastric and colorectal cancer

BACKGROUND Studies evaluating the characteristics of dual primary gastric and colorectal cancer (CRC) (DPGCC) are limited. AIM To analyze the clinicopathologic characteristics and prognosis of synchronous and metachronous cancers in patients with DPGCC. METHODS From October 2010 to August 2021, patients with DPGCC were retrospectively reviewed. The patients with DPGCC were divided into two groups (synchronous and metachronous). We compared the overall survival (OS) between the groups using Kaplan-Meier survival methods. Univariate and multivariate analyses were performed using Cox’s proportional hazards model to identify the independent prognostic factors for OS. RESULTS Of the 76 patients with DPGCC, 46 and 30 had synchronous and metachronous cancers, respectively. The proportion of unresectable CRC in patients with synchronous cancers was higher than that in patients with metachronous cancers (28.3% vs 3.3%, P = 0.015). The majority of the second primary cancers had occurred within 5 years. Kaplan-Meier survival analysis showed that the patients with metachronous cancers had a better prognosis than patients with synchronous cancers (P = 0.010). The patients who had undergone gastrectomy (P < 0.001) or CRC resection (P < 0.001) had a better prognosis than those who had not. In the multivariate analysis, synchronous cancer [hazard ratio (HR) = 6.8, 95% confidence interval (95%CI): 2.0-22.7, P = 0.002)] and stage III-IV gastric cancer (GC) [HR = 10.0, 95%CI: 3.4-29.5, P < 0.001)] were risk prognostic factor for OS, while patients who underwent gastrectomy was a protective prognostic factor for OS [HR = 0.2, 95%CI: 0.1-0.6, P = 0.002]. CONCLUSION Regular surveillance for metachronous cancer is necessary during postoperative follow-up. Surgical resection is the mainstay of therapy to improve the prognosis of DPGCC. The prognosis appears to be influenced by the stage of GC rather than the stage of CRC. Patients with synchronous cancer have a worse prognosis, and its treatment strategy is worth further exploration.

Risk Prediction of Metachronous Colorectal Cancer from Molecular Features of Adenomas: A Nested Case-Control Study.

Identifying new biomarkers may improve prediction of me-CRC for individuals with adenomas and optimize surveillance intervals to reduce risk of colorectal cancer and reduce oversurveillance of patients with low risk of colorectal cancer. Use of DNA CNAs alone does not improve prediction of me-CRC. Further research to improve risk classification is required.

627P Racial disparities in synchronous and metachronous colorectal and prostate cancer: SEER based study 2000-2020

627P Racial disparities in synchronous and metachronous colorectal and prostate cancer: SEER based study 2000-2020

Metachronous colorectal cancer risk according to Lynch syndrome pathogenic variant after extensive versus partial colectomy in the Netherlands: a retrospective cohort study

Extensive colectomy (subtotal or total colectomy) is often advised for carriers of Lynch syndrome with colorectal cancer. However, the risk of metachronous colorectal cancer might differ by Lynch syndrome variant, meaning that partial colectomy, which has better functional outcomes, might be adequate for some patients with low-risk variants. We aimed to assess the risk of metachronous colorectal cancer after partial colectomy and extensive colectomy in carriers of Lynch syndrome with different pathogenic variants. For this retrospective cohort study, carriers of Lynch syndrome with colorectal cancer in the Netherlands were identified by linkage of the Dutch Foundation for the Detection of Hereditary Tumors (StOET) database and the Dutch Nationwide Network and Registry of Histopathology and Cytopathology (PALGA) database. Data on demographics, Lynch syndrome variants, colorectal cancers, surgery types, mortality, and surveillance colonoscopies were extracted. Data on colorectal cancer and surveillance colonoscopies were updated until Feb 28, 2022. Data on survival status was updated until Feb 7, 2022. MLH1, MSH2, and EPCAM were classified as high-risk variants and MSH6 and PMS2 as low-risk variants. Patients for whom the type of surgery was unknown were excluded. Cox regression time-to-event analyses were done to assess the risk of metachronous colorectal cancer in four subgroups based on pathogenic variant (high-risk vs low-risk variants) and the extent of surgery (extensive colectomy vs partial colectomy). Sex, age at the time of primary colorectal cancer, primary colorectal cancer stage, performance of surveillance colonoscopies, adherence to the surveillance guidelines, and time period of primary colorectal cancer diagnosis were added to the model as possible confounders. Metachronous colorectal cancer was defined as colorectal cancer diagnosed more than 6 months after the primary colorectal cancer. Patients were censored at time of death or assembly of the database. Of 1908 carriers of Lynch syndrome registered in StOET, 532 with a history of colorectal cancer were identified after linkage with PALGA. Five carriers were excluded because of an unknown surgery type, leaving 527 in our sample (mean age at primary colorectal cancer 48·7 years [SD 12·1]; 274 [52%] male and 253 [48%] female). 121 (23%) patients developed metachronous colorectal cancer (median time from primary colorectal cancer to metachronous colorectal cancer 11·0 years [IQR 2·1-17·8]). Metachronous colorectal cancer occurred in 12 (12%) of 97 patients with high-risk variants and extensive colectomy, in 85 (32%) of 267 patients with high-risk variants and partial colectomy, in zero (0%) of 11 patients with low-risk variants and extensive colectomy, and in 24 (16%) of 152 patients with low-risk variants and partial colectomy. Partial colectomy was associated with a higher risk of metachronous colorectal cancer than extensive colectomy in the high-risk variant group (hazard ratio 1·97, 95% CI 1·04-3·73; p=0·039). The risk of metachronous colorectal cancer did not differ between carriers of low-risk variants who had partial colectomy and those of high-risk variants who had extensive colectomy (1·14, 0·55-2·36; p=0·72). The risk of metachronous colorectal cancer after partial colectomy in carriers of low-risk variants is similar to the risk after extensive colectomy in carriers of high-risk variants. This finding suggests that partial colectomy followed by endoscopic surveillance is an appropriate management approach to treat colorectal cancer in carriers of low-risk Lynch syndrome variants. None.

Synchronous and metachronous primary colorectal cancers with concordant and discordant mismatch repair status

Multiple primary colorectal carcinomas (CRCs) synchronous, when detected approximately at the same time, or metachronous, when a significant amount of time has elapsed between diagnoses can show both mismatch repair (MMR) status concordance and discordance between primary tumors. The aim was to evaluate the MMR status of a monoinstitutional, retrospective cohort of synchronous and metachronous CRCs, with a focus on the frequency of cases with discordant MMR status, and explore the MMR status of metastatic nodal deposits. All synchronous and metachronous CRCs diagnosed in our institution between 2011 and 2023 were collected. Clinicopathologic characteristics were evaluated, including MMR status of all CRCs, BRAF mutation, and MLH1 promoter methylation analyses. MMR status discordant cases were further analyzed, and MMR testing was performed on nodal metastases. Of 3671 patients, 107 (2.9%) had multiple CRCs (94 synchronous and 13 metachronous; total number of CRCs 220). Sixty CRCs were MMR deficient (dMMR) (27.3%), and most were right-sided and high-grade and showed special histologic features (P<.00001). Ninety-three patients showed intertumoral MMR concordance: 70 (65.4%) with MMR-proficient (pMMR) CRCs, and 23 (21.5%) were dMMR. Fourteen patients (13.1%) showed intertumoral MMR discordance (at least one dMMR and one pMMR), and in 5 patients, nodal metastases were present: 2 patients harbored metastases only from their pMMR cancer, 2 only from their dMMR cancer, and in 1 patient both pMMR and dMMR metastases were present. In conclusion, all multiple primary CRCs should be analyzed for MMR status as discordant MMR is possible as well as discordant metastatic nodal deposits, and this may be important for patient management.

Clinicopathological features and prognosis of synchronous and metachronous colorectal cancer: a retrospective cohort study.

To investigate the clinicopathological features and prognosis of synchronous and metachronous multiple primary colorectal cancer. Patients who underwent operation for synchronous and metachronous colorectal cancer at the colorectal surgery department of Shanghai Changhai Hospital between January 2000 and December 2021 were included. Perioperative indicators were comprehensively compared and included in the survival analyses. In total, 563 patients with synchronous ( n =372) and metachronous ( n =191) colorectal cancer were included. Patients with synchronous colorectal cancer were more likely to have a long onset time, positive carcinoembryonic antigen, advanced TNM stage, large tumor, perineural invasion, p53 high expression, and mismatch repair proficient. Compared with metachronous colorectal cancer, patients with synchronous colorectal cancer showed worse 5-year overall survival (68.6±3.0% vs 81.9±3.5%, P =0.018) and 5-year disease-free survival (61.2±3.1% vs 71.0±3.9%, P =0.022). In the subgroup analysis, segmental resection was an independent risk factor for the long-term outcomes of bilateral synchronous colorectal cancer. Clinicopathological and molecular features were different between synchronous and metachronous colorectal cancer. Patients with synchronous colorectal cancer showed a worse prognosis than those with metachronous colorectal cancer. Bilateral synchronous colorectal cancer requires extended resection to achieve improved long-term outcomes.

Assessment of Incidence of Metachronous Neoplasms after Surgical Resection of Colorectal Cancer

Abstract Background Cancer colon is the second most common cause of cancer in women and the third most common in men. Globally incidences vary 10-fold with highest rates in Australia, New Zealand, Europe and the US and lowest rates in Africa and South-Central Asia. However, in Egypt, CRC represent 4.2% of all cancers in male and 3.8% in females. Aim of the Work The aim of our study was to assess the incidence of Metachronous neoplasms after curative surgical resection of colorectal cancer and assess different risk factors for metachronous Cancer colon occurrence. Patients and Methods We enrolled 100 patients in this retrospective cohort study to predict incidence and risk factors of metachronous colorectal cancer (CRC) after 6 months of curative surgical resection of colorectal cancer. Results After 6 months of post-operative follow up, 90% of cases had no recurrence of CRC, 5% had polyps and did polypectomy, 5% had mass lesion. So patients were divided into two groups, Group (1) included patients with no recurrent CRC. Group (2) included patients with recurrent CRC. The incidence of metachronous CRC was 5% for mass and 5% for polyps in patients who underwent curative surgical resection of colorectal cancer. In both Univariate and multivariate Logistic regression analysis for the parameters affecting recurrent mass, DM was the only significant risk factor associated with the incidence of metachronous CRC with P values (0.043, 0.049) respectively. Conclusion The incidence of metachronous CRC in this study was 5% for mass and 5% for polyps in patients who underwent curative surgical resection of colorectal cancer. DM is a significant risk factor of metachronous CRC.

Aspirin chemoprevention in colorectal cancer: network meta-analysis of low, moderate, and high doses.

Colorectal cancer is the third most common cancer, with nearly 2 million cases worldwide and just under 1 million deaths in 2020. Several trials have demonstrated that aspirin has the potential to reduce the incidence and/or recurrence of colorectal cancer; however, the optimal aspirin dose is unclear. Relevant studies were identified by searching MEDLINE, Embase and the Cochrane Library from database inception to 2 February 2022. Data from RCTs in which the incidence of colorectal cancer in patients without active colorectal cancer assigned to aspirin versus control were included. Two investigators independently identified studies and abstracted data. Study quality was assessed using Cochrane Collaboration risk-of-bias 2 tool. The study was performed according to PRISMA guidelines. Aspirin dose was stratified into low (50-163 mg/day), mid (164-325 mg/day), and high (500-1200 mg/day). Thirteen articles representing 11 RCTs (92 550 participants) were included, with studies assessing aspirin as primary prophylaxis in general or high-risk populations, and as secondary prophylaxis for metachronous colorectal cancer. There was a statistically significant reduction in colorectal cancer incidence in the high-dose aspirin group compared with the group that received no aspirin or placebo (OR 0.69, 95 per cent credible interval 0.50 to 0.96; surface under the cumulative ranking 0.82). There was no statistically significant difference between mid- and low-dose aspirin versus no aspirin/placebo. In this network meta-analysis of RCTs, high-dose aspirin was associated with a reduction in colorectal cancer incidence. However, this was based on a limited number of trials. This study did not show a statistically significant risk reduction in colorectal cancer incidence with mid- or low-dose aspirin.

Metachronous colorectal cancer metastasis: Who, what, when and what to do about it.

Metachronous colorectal cancer (CRC) metastasis occurs due to micrometastatic disease, in up to 23% of patients who have undergone curative-intent treatment. Metachronous metastasis tends to occur within 2 years of initial treatment. Diagnosis relies on posttreatment surveillance strategies. Care for patients with metachronous CRC metastasis is complex and requires careful multidisciplinary consideration. Those with isolated and technically resectable diseases are recommended to undergo metastasectomy with adjunct chemotherapy, however, survival, even after curative-intent resection, is poor.

Accuracy of a faecal immunochemical test in patients under colonoscopy surveillance of colorectal adenoma and cancer.

Surveillance of colorectal neoplasia place great strain on colonoscopy resources, and faecal immunochemical tests (FIT) are under-investigated for this purpose. The aim of this study was to report the outcome of FIT among patients scheduled for post-polypectomy and post-resection colorectal cancer (CRC) surveillance. Patients scheduled for colonoscopy surveillance at five endoscopy units in mid-Sweden in 2016-2020 were eligible. They provided a faecal sample from 2 separate days, which were analysed by iFOBT QuikRead go® (Aidian Oy). Both the colonoscopies, and the FIT analyses were conducted by staff blinded to the other. Out of 216 included patients, 157 (73%) underwent both a complete colonoscopy and had at least one FIT analysed prior to the examination. The indication for surveillance was previous adenoma in 69 (44%) and post-resection CRC in 88 (56%) patients. Two (1%) in the CRC surveillance group were diagnosed with a metachronous CRC, whereas 49 (56%) patients in the CRC surveillance, and 17 (25%) in the adenoma group had no pathology identified at colonscopy (P < 0.001). The proportion of patients diagnosed with adenomas requiring surveillance according to European Society of Gastrointestinal Society (ESGE) guidelines 2020 was 6 (7%) in the post-CRC resection versus 7 (10%) in the adenoma surveillance group (P = 0.4). Based on one FIT and at cut-off 10 µg Hb/g, sensitivity for CRC was 100%, specificity 83% (95% confidence interval [CI]: 77-89), Positive Predictive Value (PPV) 7% (-2 to 16) and Negative Predictive Value (NPV) 100%. All patients with an adenoma requiring surveillance had a FIT below this cut-off. Adding a second FIT decreased the specificity. Larger studies to evaluate the accuracy and consequences of using FIT for surveillance of colorectal neoplasia are needed. FIT may be more interesting for post-resection CRC surveillance than follow-up of adenoma.

Comparison of synchronous neoplasms at colonoscopic diagnosis of early-onset versus average-onset colorectal cancer.

3623 Background: Colorectal cancer (CRC) incidence has steadily increased in adults younger than 50 years (EO-CRC) since the 1990s, with a predominance in the left colon and rectum. Precursor lesions of CRCs are adenomas, including advanced adenomas, and sessile serrated polyps. Given that neoplastic development is age-related, we hypothesized that patients with early-onset CRC (EO-CRC) may have fewer adenomas compared to patients with average-onset CRC (AO-CRC) at diagnosis. Methods: We performed a retrospective review of electronic health records at Mayo Clinic or Mayo Health System [2012 to 2021] and randomly selected 150 patients with EO-CRC who met eligibility criteria and matched them with 150 AO-CRC patients based on gender and colonoscopy indication. Known hereditary syndromes or inflammatory bowel disease were excluded. At colonoscopy where CRC was diagnosed, we recorded findings of adenomas, advanced adenomas (&gt; 1 cm, villous histology, or high-grade dysplasia), and sessile serrated polyps (SSP). Results: Median age at diagnosis was 43 years for EO-CRC and 67 years for AO-CRC. No significant differences in BMI, family history of CRC, MMR, BRAFV 600E KRAS status or SSPs were found between groups (all p &gt; 0.05). Among patients with colon cancer, no difference was found for adenoma number yet patients with EO-colon cancer (EO-CC) had larger polyps [median of 10 mm vs 5 mm, p = 0.001] (Table) compared with AO-colon cancer (AO-CC). At least 1 adenoma was found in 56% and 47% of patients with EO-CC and AO-CC, respectively. Moreover, advanced adenomas were significantly more common in the EO-CC group compared with the AO-CC group (42% and 14%, p &lt; 0.001) [ Table]. Among patients with rectal cancer, non-advanced adenomas were less frequent and although advanced adenoma were similar in frequency, they were more commonly located in the rectum in EO-rectal compared to AO-rectal cancers (Table). Conclusions: Patients with EO-colon cancer had a significantly higher likelihood of a synchronous advanced adenoma in the colon compared to those with AO-CRC. Together, these data suggest accelerated carcinogenesis throughout the colorectum in early onset patients, with increased risk for development of synchronous and metachronous CRC. [Table: see text]

Differences in genome, transcriptome, miRNAome, and methylome in synchronous and metachronous liver metastasis of colorectal cancer.

Despite distant metastases being the critical factor affecting patients' survival, they remain poorly understood. Our study thus aimed to molecularly characterize colorectal cancer liver metastases (CRCLMs) and explore whether molecular profiles differ between Synchronous (SmCRC) and Metachronous (MmCRC) colorectal cancer. This characterization was performed by whole exome sequencing, whole transcriptome, whole methylome, and miRNAome. The most frequent somatic mutations were in APC, SYNE1, TP53, and TTN genes. Among the differently methylated and expressed genes were those involved in cell adhesion, extracellular matrix organization and degradation, neuroactive ligand-receptor interaction. The top up-regulated microRNAs were hsa-miR-135b-3p and -5p, and the hsa-miR-200-family while the hsa-miR-548-family belonged to the top down-regulated. MmCRC patients evinced higher tumor mutational burden, a wider median of duplications and deletions, and a heterogeneous mutational signature than SmCRC. Regarding chronicity, a significant down-regulation of SMOC2 and PPP1R9A genes in SmCRC compared to MmCRC was observed. Two miRNAs were deregulated between SmCRC and MmCRC, hsa-miR-625-3p and has-miR-1269-3p. The combined data identified the IPO5 gene. Regardless of miRNA expression levels, the combined analysis resulted in 107 deregulated genes related to relaxin, estrogen, PI3K-Akt, WNT signaling pathways, and intracellular second messenger signaling. The intersection between our and validation sets confirmed the validity of our results. We have identified genes and pathways that may be considered as actionable targets in CRCLMs. Our data also provide a valuable resource for understanding molecular distinctions between SmCRC and MmCRC. They have the potential to enhance the diagnosis, prognostication, and management of CRCLMs by a molecularly targeted approach.

Metachronous Colorectal Cancer in Icelandic MSH6 and PMS2 Lynch Syndrome Carriers in 1955–2017: A Population-based Study

Metachronous Colorectal Cancer in Icelandic MSH6 and PMS2 Lynch Syndrome Carriers in 1955–2017: A Population-based Study

Metachronous colorectal cancers in Icelandic MSH6 and PMS2 Lynch syndrome carriers in 1955-2017: A population-based study.

76 Background: The prevalence of Lynch syndrome in Iceland is the highest described so far or 1:226 with three founder mutations, one in MSH6 and two in PMS2, and was first reported in 2017. Lynch syndrome predisposes carriers to colorectal cancer and metachronous primaries. Most data on metachronous colorectal cancer reflects on MLH1 and MSH2 carriers and is not well described in MSH6 and PMS2 carriers. The purpose of this study was to examine the cumulative incidence of metachronous colorectal cancer in Icelandic Lynch syndrome carriers diagnosed with colorectal cancer from 1955-2017. Methods: This retrospective study included all individuals with pathogenic variants in mismatch repair genes identified in a nationwide genotype database and a colorectal cancer diagnosis in the Icelandic Cancer Registry from 1955-2017. DeCODE genetics has collected extensive genotypic information on the Icelandic population sequencing the whole genomes of 49,708 Icelanders and imputing genotypes into 116,573 Icelanders whose DNA had been genotyped with SNP chips. Cancer information was obtained from patient charts and cause of death obtained from the Cause of Death Register. All polyp pathology was accessed in the pathology registry and reassessed by two pathologists. Results: A total of 65 individuals developed colorectal cancer during the study period with 34 (52.3%) PMS2 carriers and 25 (38.5%) MSH6 carriers. The cumulative incidence of metachronous colorectal cancer was low or one case (1.5%) in an MSH2 carrier with a median follow-up time of 58 months (Q1 8.0, Q3 167.0, range 0-365 months) in the cohort. Only two (3.1%) individuals, one with MSH2 and one with MSH6 pathogenic variants, underwent a total colectomy. Median age at first colorectal cancer diagnosis was 63 years (Q1 54.0, Q3 72.5, range 28-94). Thirty-one (47.7%) individuals had polyps resected during the study period with adenomas (67.1%) being the most common. Significantly more MSH6 carriers had a history of advanced adenomas as compared to PMS2 carriers (36.0 % vs 11.8%, p = 0.026). Five-year colorectal cancer survival was 81.4% for PMS2 carriers and 71.5% for MSH6 carriers. Conclusions: The incidence of metachronous colorectal cancer was zero in Lynch syndrome carriers with MSH6 or PMS2 pathogenic variants from 1955-2017 despite these individuals not undergoing rigorous Lynch syndrome screening. This would support performing segmental colectomies and following European screening guidelines for MSH6 and PMS2 carriers in Iceland.

Distinct role of tumor-infiltrating lymphocytes between synchronous and metachronous colorectal cancer.

Tumor-infiltrating lymphocytes (TILs) may influence the prognosis of colorectal liver metastasis (CRLM). We assessed the prognostic value of evaluating TILs in the primary and metastatic sites of synchronous CRLM as well as metachronous CRLM. We examined 90 patients who underwent curative primary and liver metastasis resection for colorectal cancer. CD8+ TILs (cytotoxic T cells) or CD45RO+ TILs (memory T cells) in both primary and metastatic sites were simultaneously evaluated by immunohistochemistry. Fifty-one patients had synchronous CRLM, and 39 patients had metachronous CRLM. In synchronous cases, the overall survival (OS) was significantly worse in patients with low CD8+ or CD45RO+ TILs in a metastatic site than in those with high CD8+ or CD45RO+ TILs (P = 0.017 and P = 0.005, respectively). Multivariate analysis showed that age ≥ 65years (P = 0.043), maximum tumor size ≥ 30mm (P = 0.003), primary N2-3 (P = 0.019), and low CD8+ TILs in metastatic site (P = 0.046) were independent poor prognostic factors. In contrast, in metachronous cases, OS was significantly worse in patients with low CD45RO+ TILs in a primary site than in those with high CD45RO+ TILs (P = 0.021). CD45RO+ TILs in a primary site (P = 0.044) were determined to be independent prognostic factor on multivariate analysis. The immune microenvironment between synchronous and metachronous CRLM might be different, and these differences may affect its prognosis.

Second-line bevacizumab plus FOLFOX in patients with metastatic colorectal cancer previously treated with adjuvant oxaliplatin-based chemotherapy.

157 Background: There is a rarity of evidence for retreatment with oxaliplatin for metastatic colorectal cancer (mCRC), especially in combination with bevacizumab. This is a retrospective study of second line bevacizumab (Bev) plus FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin) in patients with metastatic colorectal cancer previously treated with adjuvant oxaliplatin-containing chemotherapy. Methods: Patients with age older than 18 and histologically confirmed metastatic colorectal cancer treated with second line bevacizumab plus FOLFOX in a single institute between 2015 and 2020 were enrolled. History of previous adjuvant chemotherapy regimens in patients with metachronous metastatic colorectal cancer was analyzed. Progression-free survival (PFS) and overall survival (OS) of the second line treatment were calculated using Kaplan-Meier method and compared between patients pretreated with adjuvant oxaliplatin (ReOx) and oxaliplatin-naive patients (control) with the log rank test. Results: A total of 72 patients were included. 23 patients (ReOx) were pretreated with adjuvant oxaliplatin and 49 patients (control) were oxaliplatin-naive before the second line treatment. There was a tendency of younger age in the ReOx group, but not statistically significant. Liver metastasis was significantly more frequent in the control group. The median PFS and OS in the ReOx group and the control group were 4.3 months (95% confidence interval [CI], 3.67–21.50) versus 5.5 months (95% CI, 4.23–8.20, hazard ratio [HR] = 0.84), and 10.5 months (95% CI, 5.40–30.37) versus 9.4 months (95% CI, 6.00–14.9, HR = 1.01) respectively. There was no significant difference of PFS ( p= 0.523) and OS ( p= 0.9745) between two groups. Conclusions: This study suggests a potential survival benefit of bevacizumab plus FOLFOX for mCRC patients previously treated with adjuvant oxaliplatin-containing treatment comparable to oxaliplatin-naive patients. [Table: see text]

Association of wnt signalling with metachronous colonic polyp risk.

232 Background: Following colorectal polypectomy, 20-50% of patients develop metachronous polyps, and a proportion have increased colorectal cancer (CRC) risk. However, there are currently no molecular biomarkers for predicting metachronous polyp risk. Constitutive activation of the Wnt signalling cascade is a hallmark of polyp development and carcinogenesis, therefore biomarkers from this pathway were investigated for association with detection of metachronous polyps. Methods: A retrospective study was performed on a tissue microarray (TMA) of left sided colonic polyps from 279 patients undergoing screening polypectomy (May’09-Dec’16) followed by surveillance colonoscopy (up to 6 years). Mutational analysis was performed using the GPOL cancer plus panel, protein expression by Immunohistochemistry and RNA-sequencing by TempO-Seq (BioClavis). Log rank statistics determined associations with time to detection of metachronous polyp. Index polyp number, histology and size were compared to metachronous lesion outcome using χ2/ANOVA and multivariate polynomial regression identified independent predictors of advanced future lesions. Results: APC (91%), KRAS (30%) and SOX9 (23%) were the most frequently mutated genes and APC and SOX9 are both implicated in Wnt signalling. Mutations in APC and co-mutations in SOX9 with ARID1 were associated with a shorter time to detection of metachronous polyps. Neither variant classification nor location of mutations were associated with metachronous polyp detection. Luminal epithelial cells with high expression of E-Cadherin or SOX9 were significantly associated with earlier detection of metachronous polyps or CRC (HR 2.3, 95%CI 1.6-3.3: p&lt;0.001 and: HR 2.0, 95%CI 1.3-3.0; p=0.001 respectively). By χ2/ANOVA analysis, E-Cadherin and SOX9 expression was associated with detection of metachronous polyp (p&gt;0.001, p=0.037 respectively). On multivariate regression, number of polyps (HR 1.2, 95%CI 1.1-1.3; p&lt;0.001), and E-Cadherin expression (HR 2.1, 95%CI 1.5-3; p&lt;0.001), independently predicted metachronous lesions. Gene set enrichment analysis (GSEA) was used to explore differential biology between high and low E-Cadherin or SOX9 expression. For E-Cadherin, all seven immune-annotated MSigDB hallmarks had negative enrichment, however Wnt--catenin signaling was positively enriched (NES=1.50, p-adj&lt;0.1). The top signature enriched for SOX9 was ‘NFB signaling via TNF (NES=1.70, p-adj&lt;0.001). The LGR5 stemness signature was enriched in both high E-Cadherin (NES=1.97 p-adj&lt;0.0001) and high SOX9 (NES=1.48, p-adj&lt;0.0001) groups. Conclusions: Wnt signalling-associated protein expression within index polyp tissue is valuable for predicting metachronous polyp risk. In addition, expression of E-Cadherin and SOX9 in colonic polyps are linked to immune and stemness signatures, suggesting immune and stemness biology may be an underlying driver of metachronous polyp development.

Korean Guidelines for Postpolypectomy Colonoscopic Surveillance: 2022 revised edition.

Colonoscopic polypectomy is effective in decreasing the incidence and mortality of colorectal cancer (CRC). Premalignant polyps discovered during colonoscopy are associated with the risk of metachronous advanced neoplasia. Postpolypectomy surveillance is the most important method for managing advanced metachronous neoplasia. A more efficient and evidence-based guideline for postpolypectomy surveillance is required because of the limited medical resources and concerns regarding colonoscopy complications. In these consensus guidelines, an analytic approach was used to address all reliable evidence to interpret the predictors of CRC or advanced neoplasia during surveillance colonoscopy. The key recommendations state that the high-risk findings for metachronous CRC following polypectomy are as follows: adenoma ≥10 mm in size; 3 to 5 (or more) adenomas; tubulovillous or villous adenoma; adenoma containing high-grade dysplasia; traditional serrated adenoma; sessile serrated lesion containing any grade of dysplasia; serrated polyp of at least 10 mm in size; and 3 to 5 (or more) sessile serrated lesions. More studies are needed to fully comprehend the patients who are most likely to benefit from surveillance colonoscopy and the ideal surveillance interval to prevent metachronous CRC.

P143 Outcomes of ulcerative colitis-associated dysplasia patients treated with endoscopic submucosal dissection: An extended analysis of a single center cohort

Abstract Background Total proctocolectomy has been recommended for patients with ulcerative colitis (UC)-associated dysplasia due to the risk of its progression to colorectal cancer or metachronous recurrence. Recently, endoscopic resection has been considered as a therapeutic option for dysplasia in UC, and endoscopic submucosal dissection (ESD) has been recommended for lesions where endoscopic mucosal resection is unsuitable. We aimed to investigate the long-term outcomes of UC patients who underwent ESD for dysplasia or early colorectal cancer Methods We retrospectively reviewed 47 patients with UC-associated dysplasia/cancer referred for potential ESD to treat non-polypoid or sessile dysplasia between August 2009 and August 2022 at Asan Medical Center, a tertiary hospital in Seoul. Indications for ESD were determined according to the criteria applied for sporadic colorectal neoplasms based on magnifying endoscopy. Results The median age at UC diagnosis was 45 years, and 24 patients (51%) were male. The median duration of UC was 13 years. Colectomy was recommended for 11 patients, and the remaining 36 patients underwent ESD. The en bloc resection rate was 88.9% (32/36), and the histologic complete resection rate was 77.8% (28/36). Five patients underwent colectomy after ESD due to missed adenocarcinoma, deep submucosal cancer, and multiple dysplasia. A total of 31 patients were followed-up after ESD. Their mean (standard deviation) follow-up period was 45.9 (±30.6) months, and the mean number of post-ESD surveillance endoscopies was 3 (±2). Local recurrence of dysplasia occurred in 3 (3/31, 9.6%) patients; metachronous recurrence occurred in 7 patients (7/31, 22.6%). There were no cases of metachronous colorectal cancer. Conclusion ESD for discrete dysplastic lesions in UC patients is feasible and shows favorable outcomes in terms of colorectal cancer prevention. However, surveillance colonoscopy with short intervals is warranted due to the high metachronous recurrence rate.

Abstract A003: Clinico-molecular real world data demonstrates prognostic significance of a three-gene biomarker for colorectal liver oligometastases

Abstract Background: Colorectal liver oligometastases (CLO) represents a subset of metastatic colorectal cancer (mCRC) patients who may be eligible to undergo curative intent resection which can improve survival. However, given the heterogeneity of this population, prognostic stratification of CLO patients is poorly understood, with a highly variable 5 year survival rate of 25-58%. A three-gene prognostic biomarker based on pathogenic mutations in RAS (KRAS or NRAS), SMAD4, and TP53 was previously described. Here, we validate the prognostication of this three-gene biomarker in a CLO real world data (RWD) cohort. Methods: We leveraged clinico-molecular real world data to develop a retrospective, de-identified cohort of CLO patients for the assessment and development of prognostic biomarkers. Inclusion criteria include curative intent liver resections with negative or unknown surgical margins, tumor samples collected from the colon or liver, metastasis to only the liver at time of sample collection, and minimum 30 days follow up following resection. All samples were profiled with the Tempus xT assay (DNA-seq of 595-648 genes at 500x coverage). Real-world time to progression (rwTTP) was used to assess the prognostic value of the three-gene biomarker using a Cox proportional hazard model, treating gene mutations as both a continuous variable (the total number of genes mutated 0-3) and as categorical variables, while also controlling for neoadjuvant therapy, adjuvant therapy, and metachronous vs. synchronous colorectal cancer. Results: We identified 276 patients that met the inclusion criteria for this study. Of these patients, 27 had three genes with mutations, 85 with two, 155 with one, and 9 with zero mutations. The three-gene biomarker represented as a continuous variable had a rwTTP hazard ratio (HR) of 1.42 (95% confidence interval 1.15-1.77, p=0.001). Comparing three mutations to zero mutations resulted in a HR of 10.60 (95% CI 2.2-50.8, p=0.003, n=36), HR=2.55 (95% CI 1.54-4.22, p=0.0003, n=182) compared to one mutation, and HR=2.47 (95% CI 1.44-4.22, p=0.001, n=112) compared to two mutations. Median rwTTP for patients with mutations in all three genes was 3.7 months compared to 31.0 months for patients with zero mutations from the three-gene biomarker, and 10.0 months for all patients in the cohort. Conclusions: A novel clinico-molecular RWD cohort allowed independent rwTTP validation of a three-gene biomarker in the CLO setting. Although future prospective studies are warranted, the significance of the three-gene biomarker as a prognostic factor suggests that mutation status of RAS, SMAD4, and TP53 may be helpful to guide treatment decisions surrounding curative surgery. Citation Format: Alia Zander, Caroline Epstein, Kabir Manghnani, Ben Terdich, Sun Hae Hong, Justin Guinney, Halla Nimeiri, Martin Stumpe, Timothy Taxter, Kyle A. Beauchamp. Clinico-molecular real world data demonstrates prognostic significance of a three-gene biomarker for colorectal liver oligometastases [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A003.