Colon Cancer Research Articles

Pattern and predictors of D3 lymph node station positivity in patients undergoing curative surgery for adenocarcinoma of colon.

137 Background: The prognosis and surgical management of colon cancer is intricately related to its lymphatic drainage. The oncological outcome of apical node positivity has been evaluated in different studies with varying results. There is no published regional data on the rate of apical node positivity in colon cancer. An insight into the probability of apical node metastases and the risk factors for the same may help us in prognosticating colon cancer patients better. Methods: This was a prospective observational study conducted at the Regional Cancer Centre Thiruvananthapuram from September 2022 to June 2024. Our primary objective was to determine the prevalence of apical lymph node positivity in patients undergoing surgery for colon cancer with D3 lymphadenectomy. The secondary objectives were to find out the factors associated with the risk of apical node metastasis, the incidence of skip metastases to apical nodes, the adequacy of lymph node harvest and the postoperative complications. Patients undergoing primary surgery for adenocarcinoma of the colon were included. Patients with metastatic disease, synchronous colon or rectal cancers, past history of colonic surgery were excluded. All patients underwent D3 lymphadenectomy along with colectomy depending upon the tumour location. Lymphatic tissue corresponding to the D3 station was retrieved and sent separately after grossing the fresh specimen on the side table in the operating room. Results: A total of 139 patients were included in the study. Fifty two (37.4%) patients had stage III disease, 38.9% had stage II disease and the rest had stage I colon cancer. The mean nodal harvest was 17.86 and mean apical node harvest was 2.04. Node harvest was adequate in 89.21% patients. The apical node positivity rate was 7.19% (10 patients). Skip metastasis to the apical nodes was found in 2 patients. Lymphovascular invasion, number of positive lymph nodes and young age (≤45 years) had a significant correlation with apical node positivity on multivariate analysis. Clavien Dindo grade 3 and above complications were seen in 5.03%. Conclusions: Our study showed an apical node positivity rate of 7.19%, with a skip metastasis rate of 1.4%. This is the first Indian data on apical node positivity rate in colon cancer and its predictors. The prognostic value of apical nodes and the occurrence of skip metastasis to the apical nodes are compelling reasons to advocate D3 dissection, even with relatively low prevalence of apical node positivity.

Predictors of late recurrence of colorectal cancer (CRC) among older long-term survivors using claims-based evidence.

66 Background: There are established features that predict early recurrence of CRC in the first 5 years from diagnosis, but predictors of late recurrence 5-10 years after diagnosis are less well understood. Long-term CRC survivors require multidisciplinary follow-up accounting for both cancer and non-cancer related conditions. Identifying predictors of cancer recurrence after 5 years of disease-free survival may help inform survivorship care. Methods: This was a retrospective cohort study of patients aged ≥66 in the SEER-Medicare database with non-metastatic CRC diagnosed between 2003 and 2011. As SEER does not collect recurrence data, we used a validated algorithm to identify treated recurrence in Medicare claims. Patients with early recurrence or a second primary malignancy in years 0-5 were excluded. Demographic and cancer-specific clinical data were collected at time of cancer diagnosis. Comorbidities were identified between 4 -5 years after cancer diagnosis and recurrence was modeled starting at year 5 using restricted mean survival time (RMST) regression. Estimates from RMST models were converted to RMST ratios (ratio <1 indicates shorter time to event). The Fine-Gray model was used to estimate cumulative incidence of CRC recurrence or mortality between 5 and 10 years after cancer diagnosis. Results: 20,255 patients with non-metastatic CRC were included: 16,158 with colon cancer (33.4% stage I, 41.7% stage II, 25.0% stage III), and 4,097 with rectal cancer (43.1% stage I, 30.1% stage II, 26.7% stage III). Mean age at cancer diagnosis was 77 years. In those who remained disease free five years after initial diagnosis, late recurrence developed in 4.8% (973/20,255) of the combined CRC cohort, 4.2% (679/16,158) of those with colon cancer, and 7.2% (294/4,097) of those with rectal cancer. In colon cancer, stage III disease was associated with a shorter time to recurrence (RMST ratio = 0.97, CI = 0.96-0.98). In both colon (RMST ratio = 0.98, 95% CI 0.96-0.99) and rectal cancer (RMST ratio = 0.97, 95% CI 0.94-0.99) having ≥3 comorbidities was associated with a shorter RMST, consistent across disease stages. For colon cancer, the cumulative incidence of CRC-specific mortality vs. all-cause mortality in years 5-10 from diagnosis was 3% (95% CI 2.8-3.0) vs. 35% (95% CI 34.0-36.0), respectively. For rectal cancer, during the same period, the corresponding rates were 6% (95% CI 5.4-7.0) vs. 30% (95% CI 28.4-31.0). Conclusions: Late CRC recurrence is rare in the SEER-Medicare population. Primary risk factors are advanced stage at diagnosis and multiple co-morbidities. Patients who survive 5 years from their diagnosis have a higher risk of all-cause mortality compared to CRC-specific mortality. Interpretation of data is limited by the validated algorithm used to detect recurrence, as it may underestimate recurrence in patients who did not undergo treatment or workup for recurrent disease.

Survival outcomes for right- versus left-sided colon cancer and rectal cancer in patients receiving regorafenib and/or trifluridine/tipiracil for refractory metastatic colorectal cancer: Findings from the multicenter retrospective ReTrITa study.

67 Background: Several studies show that patients (pts) with colon cancer, particularly pts with right colon cancer (RCC), have lower survival rates than those with rectal cancer. This argues that colorectal cancer should be divided into three clinical entities: RCC, left colon cancer (LCC) and rectal cancer (RC). In refractory metastatic colorectal cancer (mCRC), regorafenib (R) and trifluridine/piracil (T) were found to improve survival. This real-life subgroup survival analysis focused on treatment with R and T, sequential or not, according to the above three primary tumor sites. Methods: Clinical data of pts diagnosed with mCRC and treated with R and/or T between 2012 and 2023 were retrospectively collected at 17 Italian cancer centers. The purpose of this analysis was to compare the overall survival (OS) and progression-free survival (PFS) of pts who received R and/or T as third line and beyond, according to their primary tumor site. Results: The entire ReTrITA study enrolled 1156 patients. 261 (22.5%) of them received the T/R sequence (T/R), 155 (13.4%) the reverse sequence (R/T), 427 (37%) T, and 313 (27.1%) R. For the purpose of this subgroup analysis we identified 381 RCC pts (32.9%), 531 LCC pts (45.9%) and 244 RC pts (21.2%). When comparing the groups treated with the sequential treatment, we observed a statistically significant OS improvement for pts receiving R prior to T: 17,4 vs. 12,2 months (mos) in RCC pts (HR = 0,67; 95% CI = 0,46-0,99; P = 0,0461); 16,1 vs. 15,1 mos in LCC pts (HR = 0,71; 95% CI = 0,51-1,00; P = 0,0559) and 16,6 vs. 11,4 mos in RC pts (HR = 0,57; 95% CI = 0,36-0,89; P = 0,0153). R/T sequence was also found to provide a considerable PFS benefit: 11,8 vs. 7,8 mos in RCC pts (HR = 0,53; 95% CI = 0,37-0,76; P = 0,0006); 11,7 vs. 8,9 mos in LCC pts (HR = 0,64; 95% CI = 0,47-0,88; P = 0,0071) and 10,7 vs. 8,2 mos in RC pts (HR = 0,63; 95% CI = 0,42-0,96; P = 0,0342). The non-sequential administration of R and T had no statistically significant impact on survival outcomes in the three groups. Conclusions: Our real-world subanalysis suggests that the R/T sequence significantly increases survival for pts with primary colon and rectal cancer, even after third-line treatment. Examining the pts groups treated with R and T as monotherapy based on the primary tumour site, however, did not allow us to make any significant conclusions. Treatment decisions should, however, constantly include the patient's characteristics, such as sex, ECOG PS, and the extent of metastatic disease. However, in order to verify our findings, prospective studies are required.

Disparities in stage of diagnosis of colon cancer: Differences by Hispanic background, race, and ethnicity.

24 Background: Given noted heterogeneity in Hispanic adults, cancer outcomes reported in aggregate may not detect disparities within specific Hispanic subgroups. The objective was to assess whether any potential differences in colon cancer (CC) stage at diagnosis among patients with Hispanic background (HBackground) could be explained by differences in socio-economic determinants of health (SDOH) including income, education and insurance status. Methods: The National Cancer Database was queried for patients diagnosed with CC from 2004 to 2021. Two logistic regression models generated adjusted odds ratios of late-stage (III-IV) vs early-stage (I-II) CC at diagnosis, disaggregated either by HBackground or R&E, compared to non-Hispanic White (NHW) patients. Model 1 controlled for patient/facility characteristics; Model 2 controlled for additional SDOH. Results: Of the 442,742 CC patients identified, 6% were Hispanics. Compared to NH adults, Hispanic patients were more likely (6% higher odds, p<0.0001) to present with late-stage CC. When Hispanic patients were disaggregated by HBackground, some were more likely (Mexicans 16%; Cubans 20% and South/Central Americans 12%) than NHW adults to present with late-stage CC while others (Puerto Ricans and Dominicans) were not. Disaggregation by R&E indicated that only Hispanic-White patients were more likely (12%) to present with late-stage disease than NHW patients. Controlling for SDOH, R&E differences in stage at diagnosis persisted but HBackground differences became insignificant (Table). Conclusions: Disaggregation of Hispanic adults by HBackground identifies specific subgroups at increased risk for late-stage CC at diagnosis. Understanding modifiable SDOH may identify opportunities for improving early detection of CC and outcomes in specific Hispanic subgroups. Odds of presenting with late-stage colon cancer of “Hispanic” patients disaggregated by race and ethnicity or Hispanic background compared to non-Hispanic Whites. Disaggregation based on: Model 1: Adjusted for age, facility type, year of diagnosis, and Charlson-Deyo comorbidity Model 2: Adjusted for age, facility type, year of diagnosis, Charlson-Deyo comorbidity, neighborhood income, neighborhood education, and insurance status aOR (95% CI) p-value aOR (95% CI) p-value Non-Hispanic White (n=418,046) (ref) (ref) Hispanic White (n=24,058) 1.12 (1.09, 1.15) <.0001 1.04 (1.01, 1.07) 0.01 Hispanic Background Mexican (n=3,612) 1.16 (1.08, 1.24) <.0001 1.05 (0.97, 1.13) 0.25 South/Central American (n= 1,734) 1.12 (1.02, 1.24) 0.02 1.01 (0.91, 1.12) 0.83 Cuban (n=937) 1.20 (1.05, 1.36) 0.001 1.11 (0.97, 1.27) 0.13 Puerto Rican (n=1,280) 1.07 (0.95, 1.19) 0.28 1.01 (0.90, 1.14) 0.88 Dominican (n=465) 1.14 (0.94, 1.39) 0.18 1.02 (0.83, 1.25) 0.85 aOR, Adjusted odds ratio; CI, confidence Interval.

Digesting danger: A two-decade study exploring the association between food processing and colon cancer.

87 Background: Dietary patterns play a significant role in cancer prevention and progression, yet the specific association of food processing with colon cancer remains largely under-investigated. The NOVA classification system categorizes foods by their level of processing, providing a unique way to examine this relationship. Colon cancer remains a leading global health concern, and emerging evidence points to diet as potential contributors. This study explores associations between NOVA-classified foods and colon cancer, offering new insights into the role of food processing in cancer development. Methods: Survey data from the NHANES database (from 1999 to 2018) was probed for demographic and clinically relevant data, and day one food journals were converted into NOVA classifications. Participants aged 20 and older were included for analysis, including those with and without colon cancer (n=339 and 47615, respectively). Independent two-sample t-tests were conducted to compare the mean proportion of daily energy consumption of various NOVA food categories between the two groups, and a Benjamini-Hochberg correction was applied to adjust for multiple comparisons at p<0.05. Sensitivity analyses were performed using total grams and percent total caloric intake as inputs. Subgroup analyses were conducted via a logistic regression model including BMI, age, ethnicity, gender, education, country of birth, and military service. Results: Individuals with colon cancer had higher intake of ham and salted meats (NOVA 3, adjusted p=0.028) compared to those without cancer. Conversely, individuals without cancer consumed more legumes (NOVA 1, adjusted p=0.028), oils (NOVA 2, adjusted p=0.023), and “other processed foods” that did not fall into a specific processed food category (NOVA 3, adjusted p=0.038). Subgroups analyses revealed a greater association with colon cancer for age greater than 50 and non-hispanic White ethnicity. Conclusions: To our knowledge, this is the only study at this scale that evaluates colon cancer prevalence in the context of dietary behaviors stratified by level of industrial processing. The significant associations between ham and salted meats consumption, age greater than 50, and non-Hispanic White ethnicity with increased cancer prevalence highlight the impact of dietary and demographic patterns on colorectal carcinogenesis. Additional studies are needed to confirm these hypotheses in the prospective setting.

Optimal cut-off value for lymph node harvesting in colon cancer based on tumor stage and sidedness: A retrospective analysis of a Japanese nationwide cohort.

149 Background: The presence of fewer than 12 harvested lymph nodes (LN) is currently considered a risk factor in stage II colon cancer (CC). However, this cut-off value does not take into consideration the biological differences associated with tumor sidedness. Moreover, the applicability of this cut-off value to stage III CC is unknown. Methods: Patients with pathological stage II/III CC who underwent curative surgical resection were assessed using data from the Japanese Society for Cancer of the Colon and Rectum database (2001–2015). The optimal cut-off value of harvested LN was evaluated by analyzing all cut-off values (i.e., 3–40), taking into account the point estimate of the hazard ratio (HR) and lower limit of the 95% confidence interval (CI), according to the tumor stage (II/III) and sidedness (right/left). A Cox proportional hazards model was used to investigate the impact of the number of harvested LN on overall survival, adjusting for age, sex, T stage, histology, size of tumor, sidedness, adjuvant chemotherapy and extent of colon resection. Multivariate analysis was also conducted. Results: From the data, 4249 (left/right; 3248/1001) and 3549 (left/right; 2798/751) patients with stage II and III CC, respectively, were identified. The median number of harvested LN was identical between stage II (18, interquartile range [IQR] (12–15)) and III (18, IQR (13–25)). However, this number was higher in right-sided CC (21, IQR (14–31)) versus left-sided CC (17, IQR (12–24)). In stage II, the conventional cut-off value (i.e., 12 LN) was identified as a prognostic factor in the multivariate analysis (HR 1.45; 95% CI: 1.20–1.75; p<0.001). Nevertheless, the prognostic impact of the number of harvested LN was stronger when the optimal cut-off value was set to 7 (HR 1.88; 95% CI: 1.44–2.44; p<0.001). In stage III, the optimal cut-off value was 12 (HR 1.88; 95% CI: 1.44–2.44; p<0.001). When evaluated based on tumor sidedness, the optimal cut-off value differed, especially for stage III. Data are shown in the table. Similar results were obtained following the exclusion of the extent of bowel resection as variable in Multivariate analysis. Conclusions: While the presence of 12 harvested LNs remains a valid prognostic factor, the optimal cut-off value can be further evaluated based on tumor stage and sidedness. Stage II Stage III All Left Right All Left Right Cut-off value 12 12 12 12 12 12 N(>cut-off/<cut-off) 3209/1040 2371/877 838/163 2814/735 2181/617 633/118 HR(>cut-off/<cut-off)(95% CI) 1.45 (1.20-1.75) 1.49 (1.20-1.84) 1.31 (0.85-2.02) 1.30 (1.09-1.55) 1.27 (1.05-1.54) 1.43 (0.97-2.13) P value <0.001 <0.001 0.216 <0.003 0.015 0.073 Cut-off value 7 7 10 20 13 N(>cut-off/<cut off) 3930/319 2977/271 889/112 1200/1598 609/142 HR(>cut-off/<cut-off)(95% CI) 1.88 (1.44-2.44) 2.07 (1.56-2.74) 1.39 (0.84-2.27) 1.35 (1.13-1.60) 1.59 (1.11-2.28) P value <0.001 <0.001 0.198 <0.001 0.011

NRG-GI008: Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-North America).

TPS310 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines v serial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox v more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate v delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox v FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Current accrual (as of 9-20-2024): 500/1,912. Clinical trial information: NCT05174169 .

Risk factors for mortality and financial burdens in patients with colon cancer.

300 Background: Colon cancer remains one of the most common cancers of the digestive system and continues to rank high among the leading causes of cancer-related deaths, despite the increased prevalence of screening. In this study, we aimed to investigate risk factors for mortality and health care costs in hospitalized patients diagnosed with colon cancer. Methods: Patients admitted to the hospital in 2019 and 2020 were identified using the Nationwide Inpatient Sample database and categorized into two groups based on the presence of colon cancer (with relevant ICD-10 codes). To account for confounding factors, multivariate regression analysis was applied to calculate mortality. Statistical analyses were conducted to assess mortality rates, length of stay, and hospital charges. Results: A total of 169,805 patients were admitted with a primary diagnosis of colon cancer, with a mean age of 67.6 years. The majority were White (69.9%), and 50.2% were male. Age over 60 (OR: 1.67, p < 0.001) and sepsis (OR: 16.01, p < 0.001) were associated with increased in-hospital mortality among colon cancer patients, while higher household income (76th to 100th percentile, OR: 0.71, p = 0.011) and treatment at an urban teaching facility (OR: 0.54, p < 0.001) were linked to a lower risk of in-hospital mortality. Female gender (OR: 0.88, p = 0.080) and having inflammatory bowel disease (OR: 0.67, p = 0.055) did not significantly affect in-hospital mortality, nor did Black race (OR: 1.1, p = 0.348) or Hispanic race (OR: 1.15, p = 0.287) compared to White patients. Sepsis (+11.8 days, p<0.001; +$192,699, p< 0.001), age over 60 (+0.99 days, p<0.001; +$6,134, p<0.001), and care at urban teaching hospitals (+0.54 days, p< 0.001; +$32,230, p< 0.001) were associated with longer hospital stays and higher total charges. Conversely, female gender (-0.21 days, p=0.001; -$5,529, p<0.001) and higher income (-0.69 days, p<0.001; -$1,565, p=0.466) were linked to shorter hospital stays and lower total charges. Conclusions: Early recognition of sepsis in colon cancer patients could potentially reduce in-hospital mortality rates, as well as significantly decrease costs and length of stay. The higher mortality rates observed in patients with sepsis may be attributed to the immunocompromised state associated with cancer. Implementing targeted interventions to address the higher risks in older patients and those with sepsis could improve outcomes and reduce the overall burden of colon cancer-related hospitalizations. Impact of patient demographics, socioeconomic factors, and clinical conditions on mortality, length of hospital stay, and total hospital charges. Data Mortality Length of Hospital stay Total Charge Age>60 1.67 (p< 0.001) 0.99 days, p<0.001 $6428, p< 0.001 Race (Hispanic compared to White race) 1.15 (p=0.287) 0.38 days, p= 0.004 $14,127, p<0.001 Race (Black compared to White race) 1.1 (p=0.348) 1.4 days, p< 0.001 $5370, p=0.002 Female gender 0.88 (p=0.08) -0.21 days, p= 0.001 -$5529, p< 0.001 High house hold income 0.71 (p= 0.011) -0.69 days, p<0.001 -$1565, p= 0.466 Treatment at urban teaching facility 0.54 (p<0.001 0.54 days, p<0.001 $32230, p< 0.001 Sepsis 16.01 (p<0.001) 11.8 days, p<0.001 $192699, p< 0.001 IBD 1.05 (p=0.888) 0.67 days, p=0.055 $5348, p=0.293

Utility of computed tomography (CT) –based staging of mismatch repair deficient (dMMR) colon cancer.

45 Background: dMMR tumors are characterized by rapid primary tumor growth with reduced likelihood for nodal and distant metastases compared to MMR proficient (pMMR) tumors. Neoadjuvant immune checkpoint inhibitors (ICIs) have demonstrated promising efficacy for localized colon cancer with high pathologic complete response rates and low relapse rates. This raises the question if surgical treatment could be avoided with accurate radiographic staging while avoiding overtreatment of early stage tumors. This study assesses the utility of radiographic staging by CT for dMMR tumors compared to pathologic staging. Methods: Patients with stage I-III colon cancer treated with upfront surgical resection were retrospectively reviewed from a single institution from 2012 to 2023 in two cohorts: 1) dMMR colon cancer and 2) pMMR colon cancer limited to similar sample size as matched controls. Clinical stage was determined based on CT scans prior to surgical resection by 2 independent radiologists blinded to pathologic stage, and the results were correlated to pathologic stage. Clinical characteristics were extracted from the electronic medical record. Statistical analysis was performed using SPSS. Results: We identified 80 patients with dMMR colon cancer and 66 with pMMR tumors. CT clinical tumor staging was discordant from pathologic staging for 68% of dMMR tumors and 61% for pMMR tumors. For T4 dMMR tumors, CT had a 74% sensitivity and 44% specificity. T4 tumors were understaged by radiology to less than T4 for 56% of cases. For dMMR nodal staging, CT had 89% sensitivity and 50% specificity (Table 1). For pathologic node positive tumors, 14% were understaged by radiologist CT read to node negative. For pathologic node negative tumors, 50% of tumors were overstaged to node positive by radiologist CT read. There was poor inter-rater reliability for both T stage and N stage for dMMR and pMMR tumors. The weakest agreement between radiologists was for T stage (dMMR kappa = 0.246, mMMR kappa = 0.145). Conclusions: Radiologic clinical staging of dMMR and pMMR colon cancer does not correlate well with pathologic staging. There were high rates of understaging by CT evaluation for patients who may be candidates for neoadjuvant treatment (T4, N+). Furthermore, there was poor inter-rater reliability between radiologists, indicating that CT staging alone may not be sufficient. Additional diagnostic modalities for nodal detection may be necessary to accurately clinically stage patients before neoadjuvant ICIs in patients with locally advanced disease. Comparing utility of pMMR versus dMMR tumors for T4 and node positive disease. pMMR (n = 66) dMMR (n = 80) T4 versus T3 or less Sensitivity (%) 92 74 Specificity (%) 51 47 PPV (%) 80 77 NPV (%) 82 63 Node positive versus node negative Sensitivity (%) 60 50 Specificity (%) 75 89 PPV (%) 81 89 NPV (%) 53 50 Abbreviations: PPV = positive predictive value; NPV = negative predictive value.

ANKRD22 participates in the proinflammatory activities of macrophages in the colon cancer tumor microenvironment.

Tumor-associated macrophages (TAMs) are among the most common types of immune cells in the colon cancer microenvironment. Reprogramming M2-type TAMs with immunosuppressive functions into M1-type TAMs with proinflammatory functions is a novel strategy for reshaping the tumor microenvironment (TME) and enhancing the efficacy of immunotherapy in colon cancer. However, the key molecules and mechanisms underlying TAM polarization require further clarification. Our previous study suggested that ANKRD22 may play a role in regulating the functional state transition of macrophages. However, the expression levels of ANKRD22 in colon TAMs and its specific effects on tumor proliferation remain unclear. In the present study, we observed elevated ANKRD22 expression in M1-type TAMs. The expression level of ANKRD22 was positively correlated with the survival period of patients with colon cancer and with the infiltration abundance of M1-type TAMs, and ANKRD22 expression was negatively correlated with the infiltration abundance of M2-type TAMs. A significant decrease in ANKRD22 expression in macrophages cocultured with colon cancer cell culture supernatant as well as in macrophages directly derived from colorectal cancer tissues was observed. Single-cell RNA sequencing, spatial transcriptomic studies, and subcutaneous xenograft experiments in mice revealed that Ankrd22 silencing altered the subtype distribution of macrophages, attenuated their proinflammatory activity, and enhanced their protumor activity. Additionally, we identified a small-molecule ANKRD22 upregulator that could aid in the development of novel therapeutics targeting TAM remodeling.

Preoperative botensilimab (BOT) with or without balstilimab (BAL) for patients with resectable locally advanced pMMR or dMMR colon cancer: Results from the UNICORN trial by GONO.

158 Background: Standard treatment for patients (pts) with localized colon cancer (CC) is surgery and adjuvant chemotherapy where indicated. Neoadjuvant strategies allow for earlier exposure to systemic therapy, potentially leading to tumor downstaging, micro-metastases eradication, improved survival, and may pave the way for non-operative management (NOM). BOT, a novel Fc-enhanced multifunctional anti-CTLA-4 antibody plus BAL, an anti-PD-1 antibody, have demonstrated activity in proficient mismatch repair (pMMR) CC pts with durable responses in metastatic CC and unprecedented rates of pathological complete response (pCR) in the localized setting. Methods: UNICORN is a window-of-opportunity, multicohort, umbrella platform phase II trial enrolling non-metastatic, radiologically staged rT3-4 N0-2, resectable CC pts to be treated with a short course preoperative targeted treatment according to a prespecified molecular profile assessed by immunohistochemistry and next-generation sequencing on tumor biopsy. Pts with pMMR or deficient (dMMR) tumors received intravenous (IV) BOT at 1 mg/kg on day 1 (cohorts 4 or 6) or IV BOT 1 mg/kg on day 1 and BAL 3 mg/kg on days 1 and 15 (cohorts 5 or 7, enrolled after 4 and 6) and underwent radical surgery on day 35 ± 5. Pathological response (pR), major response (pMR) and pCR rates were defined as ≤ 50%, ≤10% and 0% residual viable tumor. The primary endpoint was centrally assessed pMR rate in each cohort. According to a Fleming 1-stage design, choosing β=80% and α=5%, 14 pts were enrolled in each cohort and the treatment was judged promising if ≥5/14 pMRs were observed. Results: All 56 enrolled pts completed preoperative treatment and underwent surgery. Timely surgery was performed in most pts (98%), except 1 who underwent surgery with a delay < 4 weeks due to treatment-related hyperthyroidism. Among pts with pMMR disease, activity was limited for BOT monotherapy (pMR 0%, pR 43%). With BOT + BAL, pCR was 29%, pMR 36% and pR 71%. Among those with dMMR status, BOT led to pCR, pMR and pR in 29%, 36% and 64% pts, respectively. Notably, BOT + BAL led to pCR and pMR in 93% and 100% pts. Adverse events (AEs) of any grade occurred in 28/56 pts (50%), and 22 (39%) were deemed immune-related. Serious AEs occurred in 9 pts (16%) and were treatment-related in 3 pts (5%). Conclusions: The primary endpoint was met in all cohorts except for BOT monotherapy in pts with pMMR status. Despite limited sample size, the activity of 1 neoadjuvant cycle with BOT + BAL favorably compares to ipilimumab/nivolumab in both pMMR and dMMR subgroups. pCR rate was remarkable in pMMR and the highest ever reported in dMMR pts, paving the way to NOM studies irrespective of MMR status. Clinical trial information: EU-CT 2022-501308-90-00 . Molecular status n° Treatment pCR, n (%) pMR, n (%) pR, n (%) pMMR 14 BOT 0 (0) 0 (0) 6 (43) 14 BOT/BAL 4 (29) 5 (36) 10 (71) dMMR 14 BOT 4 (29) 5 (36) 9 (64) 14 BOT/BAL 13 (93) 14 (100) 14 (100)

Association between muscle mass, visceral adiposity, and histologic tumor stromal features in colon cancer.

Sarcopenia and obesity are indicators for poor outcomes in colon cancer. Additionally, aggressive histopathologic tumor stromal features, such as a low tumor-stroma ratio (TSR) and low tumor-infiltrating lymphocytes (TILs) predict survival and treatment response. As their relationship remains underexplored, we studied the association between skeletal muscle mass, visceral adipose tissue (VAT), TSR, and TILs in patients with colon cancer. We studied 194 stage II/III colon carcinoma patients who underwent elective surgery. Preoperative computed tomography (CT) scans classified patients into four groups based on skeletal muscle index (normal/low) and visceral adipose tissue index (normal/high). Tumor tissues were assessed for TSR and TILs, and five-year disease recurrence and relative hazard were evaluated. Among the patients, 56 (28.9%) were classified as Normal Muscle, Normal VAT, 26 (13.4%) as Normal Muscle, High VAT, 75 (38.7%) as Low Muscle, Normal VAT, and 37 (19.1%) as Low Muscle, High VAT. Patients with low skeletal muscle mass were more often male (62.5% vs. 39%, P=0.005). Stroma-high tumors were less common in Low Muscle, Normal VAT patients (24%) compared to Normal Muscle, High VAT (50%), Low Muscle, High VAT (48.6%), and Normal Muscle, Normal VAT (41.1%) patients (P=0.020). Tumors with low TILs were similarly distributed across groups (P=0.679). Low Muscle, Normal VAT patients had a lower recurrence hazard compared to both Low Muscle, High VAT (hazard ratio [HR] 0.34, 95% CI 0.12-0.98, P=0.048) and Normal Muscle, Normal VAT (HR 0.31, 95% CI 0.11-0.87, P=0.027) patients. Low Muscle, Normal VAT colon cancer patients exhibited fewer aggressive tumor features and a lower recurrence risk compared to Low Muscle, High VAT patients. These findings highlight the importance of body composition in tumor biology and prognosis.

Effect of changes in body composition and sociodemographic factors on colon cancer survival.

296 Background: Muscle mass, muscle quality, and adipose tissue volumes have been shown to affect colon cancer survival. Further research is required to understand how change in body composition during treatment impacts colon cancer outcomes, and how covariables such mental health and socioeconomic status affect this relationship. The aim of this project was to examine how changes in body composition during chemotherapy for colon cancer impact the duration of disease-free survival (DFS) and how sociodemographic covariables (age, sex, social isolation, depression, anxiety, income, community size) influence this relationship. Methods: Computed tomography (CT) scans from the time of diagnosis and the end of chemotherapy were obtained from individuals treated for stage III colon cancer with oxaliplatin at BC Cancer between 2012 and 2016. Whole body tissue volumes were estimated based on CT images at the level of the third lumbar vertebra, analysed using DAFS Express (Voronoi Health Analytics Inc., Vancouver BC). Muscle quantity was measured as skeletal muscle index (SMI), and muscle quality was measured as skeletal muscle density (SMD) and skeletal muscle gauge (SMG). Quantity of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intermuscular adipose tissue (IMAT), and total adipose tissue (TAT) were also measured. Social isolation, anxiety, and depression symptoms were measured using the validated Psychosocial Screen for Cancer–Revised. Neighbourhood income and community population were estimated using postal codes. Cox proportional hazard models were calculated for the effect of body composition variables on DFS, and interactions with sociodemographic variables. Results: Significant reductions in SMI, SMD, SMG, VAT, IMAT and TAT were observed between diagnosis and post-chemotherapy (n=282). Improved survival was associated with higher SMD and lower IMAT at diagnosis and post-chemotherapy, lower VAT at diagnosis, and an increase in VAT or TAT during chemotherapy. Body composition had a more significant effect on survival in individuals who were older, female, or lived in smaller communities. Conclusions: Significant reductions in SMI, SMD, SMG, VAT, IMAT and TAT were observed between diagnosis and post-chemotherapy (n=282). Improved survival was associated with higher SMD and lower IMAT at diagnosis and post-chemotherapy, lower VAT at diagnosis, and an increase in VAT or TAT during chemotherapy. Body composition had a more significant effect on survival in individuals who were older, female, or lived in smaller communities.

Impact of COVID-19 pandemic on critically ill patients with colon cancer: A population-level study.

297 Background: The COVID-19 pandemic strained healthcare systems and disrupted pre-pandemic levels and trends in the short-term mortality of colon cancer hospitalizations. Colon cancer is the fourth most diagnosed cancer in the US and Texas. The impact on short term mortality in Texas in the years since the COVID-19 pandemic have not been explored. Methods: We used publicly available, deidentified, and state-wide data to conduct a population-base cohort study of hospitalizations aged ≥ 18 years admitted to intensive care units at acute care hospitals in Texas during 2016-2022 with a diagnosis of colon cancer. Hospitalizations transferred to another acute care hospital were excluded from the study. Colon cancer was identified using ICD-10-CM codes C18x and C20 selected from Clinical Classification Software Refined category NEO015: Gastrointestinal cancers - colorectal. Short-term mortality was defined as in-hospital mortality or discharge to a hospice. The response variables are pre-pandemic time trend, level change, change in time trend, and final time trend. The primary analysis method was interrupted time series analysis (ITSA) based on multilevel-multivariable logistic regression with results reported as average marginal effects per quarter (AME) and 95% confidence intervals (95% CI) in changes to the absolute probability of mortality. The matched pairs t-test was applied to ITSA and counterfactual predicted probabilities to further elucidate the impact of the COVID-19 pandemic. Sensitivity analyses was performed for hospitalizations aged ≥ 65 years and for hospitalizations without a diagnosis of COVID-19. Results: A total of 49,007 hospitalizations were included in the study of which 21,995 (44.9%) occurred after the beginning of the pandemic. Unadjusted short-term mortality was lower in the pre-pandemic period compared to the post-pandemic period (18.1% vs 20.1%). On adjusted analysis, the post-pandemic period remained associated with higher mortality rates. The pre-pandemic short-term mortality time trend was negative (AME -0.19%/quarter, 95% CI [-0.28% to -0.10%], p = 0.0001). The change in time trend was positive (AME 0.39%/quarter, 95% CI [0.23% to 0.55%], p < 0.0001) and the change in level was also positive (AME 1.25%, 95% CI [0.0.04% to 2.47%], p = 0.0436). The final time trend was significant and positive (AME 0.20%/quarter, 95% CI [0.07% to 0.33%], p = 0.0023). The point estimate and 95% CI for the difference between ITSA predicted and counterfactual predicted probabilities of mortality was 3.45% (3.41% to 3.48%). Similar results were observed on sensitivity analyses. Conclusions: Since the onset of the pandemic there was a 2% increase in the absolute probability of short-term mortality and a change from negative to positive time trend in short-term mortality. The average impact of the COVID-19 pandemic on the absolute probability of short-term mortality is estimated at over 3%.

Impact of unplanned readmission to the same facility within 30 days following robot-assisted and laparoscopic hemicolectomy for early-onset non-metastatic colon cancer.

111 Background: Colon cancer in younger populations has risen in recent years, prompting changes in screening guidelines. Hemicolectomy remains integral for standard treatment for non-metastatic early-onset colon cancer, and many institutions have adopted robot-assisted approaches for this procedure. However, high costs associated with this technology along with mixed data regarding survival benefits and post-surgical complications warrant further investigations on the specific advantages of robot-assisted surgery. This study aims to examine the impact of unplanned readmission to the same facility within 30 days following surgery for patients receiving robot-assisted and laparoscopic hemicolectomy on long-term survival for early-onset non-metastatic colon cancer to see how current paradigms of colon cancer treatment extend to early-onset patients. Methods: The National Cancer Database was used to identify patients under the age of 50 receiving a minimally invasive hemicolectomy for primary non-metastatic colon cancer diagnosed between 2016-2020. Patients were stratified based on surgical approach and whether they underwent an unplanned readmission to the same facility within 30 days following surgery, and survival differences were calculated log-rank test and Cox regression analysis that included co-variates related to tumor characteristics, patient demographics, and facility characteristics. Results: 5,076 patients were identified, with 577 receiving a robot-assisted approach and 4,499 receiving a laparoscopic approach. Multivariate analysis found no significant difference in long-term survival between patients receiving a laparoscopic versus robot-assisted approach (HR: 0.893, 95% CI: 0.687-1.161, p=0.398). Additionally, multivariate analysis found that unplanned readmission within 30 days did not have a significant impact on long-term survival outcomes for patients receiving a robot-assisted approach (HR: 0.856, 95% CI: 0.257-2.848, p=0.800), but it did find worsened survival outcomes for the laparoscopic approach (HR: 1.535, 95% CI: 1.070-2.203, p=0.020). Conclusions: Patients receiving laparoscopic hemicolectomy for early-onset non-metastatic colon cancer appear to have worsened overall long-term survival outcomes when undergoing an unplanned readmission to the same facility within 30 days of surgery when compared to patients receiving a robot-assisted surgical approach. However, it also appears that overall, both surgical approaches have similar overall long-term survival. Further research on how robot-assisted surgery impacts survival and post-surgical complications in patients with early-onset non-metastatic colon cancer is warranted to examine how this advancing technology could improve cancer care.

Shedding Light on the Prognostic and Predictive Value of Circulating Tumor DNA for Management of Patients with Early-Stage Colon Cancer.

The management of early-stage colon cancer involves surgical resection of the primary tumor with or without chemotherapy, depending on pathological staging. The benefit of adjuvant chemotherapy for stage II and III colon cancer is approximately 5% and 15%, indicating the need for optimization for risk stratification and patient selection. Several studies have revealed that current clinicopathological factors lack precision. Circulating tumor DNA (ctDNA) is cell-free DNA originating from cancer cells and can be detected even in the absence of radiologically detectable disease among patients with colon cancer. Recent cohort studies revealed that ctDNA is one of the most significant prognostic factors for patients with early-stage colon cancer, surpassing pathological and clinical risk factors. Prospective cohort studies also suggest there may be a predictive role for ctDNA on the decision for consideration of adjuvant therapy. Currently, randomized clinical trials are enrolling to better define this role. In this review article, we review recent literature on ctDNA and its role in patients with colon cancer. We also elaborate on the future clinical utility of ctDNA in clinical practice and the unmet need for research to optimize currently available ctDNA assays.

Seven-year efficacy and safety in a randomized phase III trial investigating duration of adjuvant oxaliplatin-based therapy (3 vs. 6 months) for patients with high-risk stage II colon cancer: ACHIEVE-2 trial.

169 Background: ACHIEVE-2 was conducted as one of four phase III trials for patients with high-risk stage II colon cancer (CC) investigating the duration of adjuvant (adj) oxaliplatin-based therapy in a prospective pooled analysis, IDEA collaboration. The results of the 7-year follow-up are presented here. Methods: From Feb 2014 to Jan 2017, 525 Asian patients with high-risk stage II CC (T4, inadequate nodal harvest, poorly differentiated, obstruction, perforation, or vascular invasion) were randomly assigned to 3- or 6-month mFOLFOX6/CAPOX treatment after curative surgery. The cutoff date for the data was Jan 2024. Results: Of the 525 randomized patients, 11 were not treated. Among the 514 participants (255 in the 3-month arm; 259 in the 6-montharm), 432 (84%) received CAPOX and 184 (36%) presented with T4 as a high-risk factor for recurrence. The baseline characteristics of the patients in each arm were well balanced between the treatment arms and two therapy regimens. The 7-year disease-free survival (DFS) rates were 83.4% and 81.8% in the 3- and 6-month arms, respectively (hazard ratio [HR]= 1.00 [95% CI, 0.66-1.53]). The 7-year overall survival (OS) rates were 88.4% and 88.8% in the 3- and 6-month arms, respectively (HR= 1.16 [95% CI, 0.70-1.93]). With CAPOX, the HR for DFS and OS of the 3-month arm compared with the 6-month arm were 0.97 (95% CI, 0.61-1.52) and 1.09 (95% CI, 0.64-1.89), respectively. Multivariate analysis of the six high-risk factors for recurrence showed that T4 and inadequate nodal harvest were independent risk factors for both DFS and OS. The rates of any grade of peripheral sensory neuropathy (PSN) lasting up to 96 months in the 3- vs. 6-month arms were 7.9% vs. 25.0% ( P= 0.0189 ). With CAPOX, the incidence of PSN lasting up to 96 months in the 3- vs. 6-month arms were 9.4% vs. 27.5%. Conclusions: The incidence of long-lasting PSN was significantly lower at 3 months than at 6 months of therapy. Three months of CAPOX therapy may be appropriate for high-risk stage II CC, as shorter treatment did not worsen the outcome, even after a long follow-up. Clinical trial information: UMIN000013036 .

The TAB-EOAO study: Trends in use and benefit of adjuvant chemotherapy between early onset and average onset locally advanced colon cancer.

105 Background: Despite the declining incidence rates (IR) in average onset colon cancer (AO-CC), IR for early onset colon cancer (EO-CC), defined as patients (pts) younger than 50-years-old at diagnosis, has been increasing. Treatment for high risk locally advanced colon cancer (CC) is surgical resection followed by adjuvant chemotherapy (AC). Data indicates a more permissive chemotherapy use in EO-CC. There is limited data about treatment and survival trends in EO-CC. Thus, we aimed to assess the use and benefit of AC between in EO vs AO CC in locally advanced disease. Methods: CC diagnosed between 2000-2020 were identified in the Surveillance, Epidemiology, and End Results Program (SEER) Database. Eligible pts were adults (≥18), Stage II or III at diagnosis. Stage II disease was further stratified as low risk (pT1-3) and high risk (pT4). Logistic regression methods were used to assess Odds Ratio (OR) of AC between EO-CC and AO-CC; Cox models were used to compare overall survival (OS) and Cancer-specific survival (CSS) between both groups during 2000-2010 and 2011-2020. Results: Our study included 136,676 pts (AO-CC= 121,606; EO-CC =15,070). The median age for EO-CC was 44 years versus 71 years for AO-CC population. The use of AC increased over time for both the EO-CC (63% vs 66%) and AO-CC (33% vs 40%). Moreover, pts with AO-CC received less AC than EO-CC in the entire study time (see table). In pts with AO-CC, AC improved CSS (HR=0.69 for 2000-2010, HR=0.50 2011-2020). However, among those with EO-CC, AC improved CSS in 2011-2020 (HR=0.76) but did not improve CSS in 2000-2010 (HR=1.02). Conclusions: Over the past 20 years EO-CC has been managed aggressively, especially for stage II low risk patients where current guidelines do not support the use of AC. In this real world data set we show that for EO-CC AC did not improve CSS in the decade 2000- 2010 but did improve CSS in the 2011- 2020 period. Further analysis may clarify stage specific benefits of AC. There clearly remains a need for better risk stratification, including the use of ctDNA, to identify the subpopulations of EO-CC patients that will best benefit from AC. Multivariable logistic regression model of chemotherapy by timeframe with interaction term: Age* stage. 2000-2010 2011-2020 AO-CC vs EO-CC OR 95% CI OR 95% CI Stage II low risk 0.23 (0.21, 0.26) 0.28 (0.24, 0.32) Stage II high risk 0.28 (0.22, 0.36) 0.28 (0.21, 0.36) Stage III 0.36 (0.32, 0.4) 0.30 (0.26, 0.34)

Clinical and genetic drivers of oligo-metastatic disease in colon cancer.

Oligo-metastatic disease (OMD) in colon cancer patients exhibits distinct clinical behavior compared to poly-metastatic disease (PMD), with a more responsive and indolent course. This study aims to identify clinical and biological factors uniquely associated with oligo-metastatic behavior. Metastatic colon cancer patients from an academic center underwent genetic characterization. OMD was defined as ≤3 lesions per organ, each with a total diameter <70 mm and none exceeding 25 mm. Tumor DNA sequencing by NGS utilized the TruSight Oncology 500 kit. Overall survival (OS) was determined from metastasis diagnosis until death using Kaplan-Meier analysis. Multivariate Cox regression examined prognostic links between clinicopathological and genetic factors. Associations with metastatic patterns were evaluated using Chi-square. The analysis involved 104 patients (44 with OMD, 60 with PMD). OMD was more prevalent in males (P = 0.0299) and with single organ involvement (P = 0.0226). Multivariate analysis adjusted for age (>70 vs. <70 years), gender (male vs. female), tumor side (right vs. left), metastatic involvement (more than one site vs. one site), response to first-line therapy (disease control vs. no disease control), and RAS/BRAF variants (wild-type vs. mutated) identified OMD vs. PMD as the strongest independent predictor of survival (HR: 0.14; 95 % CI: 0.06-0.33; P<0.0001). OMD patients exhibited distinct molecular characteristics, including lower frequencies of BRAF p.V600E (P=0.0315) and KRAS mutations (P=0.0456), as well as a higher frequency of high tumor mutational burden (P=0.0127). Additionally, by integrating data from public datasets and our case study, we hypothesize that some gene alterations (i.e.: BRAF, SMAD4, RAF1, and mTOR) may prevent OMD occurrence. OMD, characterized by male predominance, single-site involvement, and distinct molecular features in colon cancer, suggests the need for tailored management strategies.

BTN1A1 expression in colon cancer: Implications for immunotherapy and patient stratification.

249 Background: Butyrophilin 1A1 (BTN1A1) is a promising immune checkpoint protein offering a novel option for immunotherapy. We discovered that BTN1A1 and PD-L1 expression are mutually exclusive through the JAK/STAT pathway in various tumors. Recently, Nelmastobart, an antibody targeting BTN1A1, successfully completed a Phase 1 clinical trial at three sites in the United States and two in the Republic of Korea, spanning 98 weeks. This abstract focuses on the results from the Phase 1 trial in patients with colorectal cancer (CRC), emphasizing biomarker diagnostics and therapeutics derived from translational research. Methods: We conducted a first-in-human, multicenter, open-label Phase I clinical trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of hSTC810 monotherapy in CRC patients. Extensive analyses of BTN1A1 expression were performed using patient specimens through immunohistochemistry and multi-immunofluorescence techniques to identify critical biomarkers and accurately assess nelmastobart's anticancer activity. We then analyzed progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety alongside translational research findings using patient tissue samples. Results: A total of 47 patients were enrolled in the study. The median PFS across all cohorts was 1.9 months, while the median Kaplan-Meier estimate for OS was 12.8 months. Among the 16 CRC patients enrolled, tissue samples were obtained and analyzed using IHC in 12 patients and OPAL staining in 7 patients. The objective response rate (ORR) for CRC was 2.3%. The median progression-free survival (PFS) and overall survival (OS) were 3.6 months and 11 months, respectively. Notably, PFS, OS, and ORR strongly correlated with BTN1A1 expression levels in CRC patients. High levels of BTN1A1 expression in colorectal tumor tissues correlated with clinical outcomes, identifying BTN1A1 as a potential biomarker for predicting patient responses to targeted therapies. The mutual exclusivity of BTN1A1 and PD-L1 expression suggests that BTN1A1 could serve as a diagnostic marker to identify patients who may be unresponsive to PD-1/PD-L1 blockade therapy and might benefit from BTN1A1 blockade therapy. Conclusions: This Phase 1 clinical trial demonstrated that antibody-mediated BTN1A1 blockade effectively suppresses tumor growth in patients with BTN1A1-positive CRC. These findings suggest that BTN1A1-targeted therapies could provide a viable treatment option for patients with colon cancers that are refractory or resistant to anti-PD-1/PD-L1 therapies. Clinical trial information: NCT05231746 .