Clinical impact of KRAS mutation status on recurrence patterns and the efficacy of local therapy after hepatectomy for colorectal liver metastases

Clinical impact of KRAS mutation status on recurrence patterns and the efficacy of local therapy after hepatectomy for colorectal liver metastases | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical impact of KRAS mutation status on recurrence patterns and the efficacy of local therapy after hepatectomy for colorectal liver metastases Kosuke Kanemitsu, Hiromitsu Hayashi, Yoshiyuki Tagayasu, Takumi Tanizaki, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9008145/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Kirsten rat sarcoma viral oncogene homolog ( KRAS ) is one of the most frequently mutated oncogenes in colorectal cancer. We aimed to clarify the clinical impact of KRAS mutation status on recurrence patterns, surgical management of recurrent lesions, and prognostic outcomes after curative hepatectomy for colorectal liver metastases (CRLM). Methods This retrospective study included 190 CRLM patients who underwent curative (macroscopic R0 resection) hepatectomy and had known KRAS status (wild-type [WT]: 62.1%; mutant [MT]: 37.9%). Results KRAS mutations were identified in 72 patients. Compared to the WT group, the MT group exhibited significantly shorter overall survival (OS) and recurrence-free survival (RFS). The MT group was characterized by more frequent early recurrence (within 1 year), multiple lesions, and multi-organ metastases. Multivariate analysis identified KRAS mutation as an independent predictor of poor OS and RFS, whereas CEA ≥ 5 ng/mL was independently associated with OS but not RFS. Notably, among patients who experienced recurrence, those who underwent local therapy (repeat resection or ablation) showed comparable OS between the MT and WT groups. Conversely, in patients who did not receive local therapy, the MT group had significantly worse OS. Mutation sites (G12, G13, others) did not significantly influence outcomes. Conclusions: KRAS mutations are associated with aggressive recurrence patterns and a poor prognosis in CRLM. However, active local therapy for recurrent lesions may mitigate this adverse impact, achieving survival outcomes comparable to those of WT cases. colorectal cancer liver metastases RAS mutations KRAS12C KRAS12D Figures Figure 1 Figure 2 Figure 3 Introduction Colorectal cancer is the second-most common malignancy worldwide. Colorectal liver metastases (CRLM) are frequent, with approximately 50% of patients diagnosed with hepatic metastases either at initial presentation or upon recurrence[ 1 ]. While surgical resection remains the only potentially curative option, approximately 70% of patients experience recurrence even after radical resection[ 1 – 3 ]. This high recurrence rate suggests that many patients harbor micrometastases despite receiving effective chemotherapy and surgery. The Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutation, detectable in up to 50% of colorectal cancer cases, drives cancer proliferation via epidermal growth factor receptor (EGFR)-independent activation of the MAPK pathway [ 4 – 10 ]. KRAS mutations are established poor prognostic factors for overall survival (OS) and recurrence-free survival (RFS) following CRLM resection [ 11 – 17 ]. However, the underlying biological and clinical features that drive aggressive recurrence patterns in KRAS -mutant CRLM have not been fully elucidated. Furthermore, it remains unclear whether interventional local therapies, such as repeat resection or radiofrequency ablation (RFA), can offset this adverse prognostic impact. While previous meta-analyses have established KRAS as a marker of poor prognosis, the mitigating role of local treatment for recurrence has not been systematically clarified. This study aimed to investigate the clinical impact of KRAS status on recurrence patterns, the management of recurrent lesions, and long-term outcomes. Methods Study Design and Patient Selection This retrospective single-center study included consecutive patients who underwent hepatectomy for CRLM at Kumamoto University Hospital between August 2005 and August 2022. Of the 291 patients who underwent hepatectomy during this period, nine patients who underwent non-curative resection and 92 patients with unknown KRAS mutation status were excluded. The remaining 190 patients who underwent curative hepatectomy (macroscopic R0 resection) and had confirmed KRAS mutation status were included in the analysis. Curative resection was defined as complete macroscopic removal of all detectable metastatic lesions. Pathological margin status was evaluated histologically. The study protocol was approved by the Ethics Review Committee of Kumamoto University (# 1291) and conducted in accordance with the Declaration of Helsinki. Patient follow-up and data collection Patients were followed every 3–4 months after hepatectomy through physical examination, serum carcinoembryonic antigen (CEA) measurement, and contrast-enhanced computed tomography or magnetic resonance imaging. Recurrence was defined as the presence of radiologically detectable metastatic lesions consistent with colorectal cancer recurrence. RFS was defined as the interval from hepatectomy to the first recurrence, death, or last follow-up. OS was defined as the interval from hepatectomy to death or last follow-up. Post-recurrence survival (PRS) was defined as the interval from radiological confirmation of recurrence to death or last follow-up. Postoperative complications were graded according to the Clavien–Dindo classification, and pathological staging was determined using the UICC TNM classification (8th edition). KRAS Mutation Analysis KRAS mutation status was assessed using clinically validated assays as previously described [ 12 ]. In 104 patients, RAS mutation status was determined using the MEBGEN RASKET-B Kit (Medical & Biological Laboratories Co., Ltd., Japan) at certified reference laboratories. In the remaining 86 patients, KRAS and NRAS mutations were analyzed using droplet digital PCR–based multiplex screening kits (Bio-Rad Laboratories, Inc., Hercules, CA, USA). Both methods are widely used in clinical practice for colorectal cancer. One patient with concurrent KRAS and NRAS mutations was included in the analysis as the primary objective of the study was to evaluate the impact of KRAS mutation status. No BRAF mutations were detected in this cohort. Statistical analysis Continuous variables are presented as medians with interquartile ranges (IQR) and were compared using the Mann–Whitney U test. Categorical variables were compared using the chi-squared test or Fisher’s exact test, as appropriate. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. A Cox proportional hazards model was used for univariate and multivariate analyses. Variables with p < 0.05 in univariate analyses were included in multivariate models using backward stepwise selection. Statistical significance was set at p < 0.05. Optimal cutoff values for the multivariate analysis were determined using receiver operating characteristic (ROC) curve analysis. All statistical analyses were performed using JMP Pro, version 16.0.0 (SAS Institute, Cary, NC, USA). Results Of the 190 patients, 118 (62.1%) had KRAS wild-type and 72 (37.9%) had KRAS mutant status. Except for a lower BMI and a higher prevalence of primary tumors located in the descending to sigmoid colon in KRAS -mutant group, no significant differences in clinicopathological characteristics were observed between the two groups. Details of KRAS mutation sites and their frequencies are summarized in Table 1 ; the most common mutations were G12D (30.6%) and G12V (20.8%). Microsatellite instability-high was observed in one case within KRAS wild-type group, and no BRAF mutations were detected in the tested cases. Neoadjuvant chemotherapy was administered to 70.3% of KRAS wild-type group and 56.9% of the mutant group, while adjuvant chemotherapy was provided to 42.4% and 38.9%, respectively (Table 1 ). Regarding molecular targeted agents, anti-EGFR antibodies were administered exclusively to KRAS wild-type patients (39.8% preoperatively and 8.0% postoperatively), whereas no KRAS mutated patients received anti-EGFR therapy. Anti-VEGF antibodies were more frequently used in KRAS -mutant group than in wild-type group, both preoperatively (82.9% vs. 42.2%) and postoperatively (10.7% vs. 6.0%)(Table 1 ). Table 1 Clinical and pathological characteristics in comparison between wild and KRAS mutant status. Characteristic variables † Median (IQR) KRAS status All patients (n = 190) wild (n = 118) mutant (n = 72) P value ‡ Sex (Men) 111 (58.4%) 69 (58.5%) 42 (58.3%) 0.98 Age 64.5 (25–85) 63.5 (25–85) 66.5 (35–85) 0.15 Body mass index (kg/m 2 ) 22.6 (13.5–32.5) 23.1 (13.5–31) 21.6 (14.9–32.5) 0.03 Localization of primary tumor 0.02 Ascending colon 28 (14.7%) 14 (11.9%) 14 (19.4%) Transverse colon 6 (3.2%) 3 (2.5%) 3 (4.2%) Descending - Sigmoid colon 79 (41.6) 59 (50%) 20 (27.8%) Rectum 77 (40.5) 42 (35.6%) 35 (48.6%) Primary AJCC T-category 0.44 T1/2 19 (10.0%) 10 (8.4%) 9 (12.7%) T3/4 171 (90.0%) 109 (91.6%) 62 (87.3%) Primary microvascular invasion 138 (72.6%) 86 (70.5%) 52 (76.5%) 0.82 Primary lymphatic invasion 80 (42.1%) 47 (39.0%) 32 (47.8%) 0.69 Preoperative CEA (ng/mL) 6.6 (0.5–2061) 6.2 (0.5–2061) 7.7 (1.2–866) 0.77 Preoperative CA19-9 19.5 (0.1–2191) 18.8 (0.6–1756) 23.9 (0.1–2191) 0.16 Tumor number 3 (1–25) 3 (1–21) 3 (1–25) 0.57 Tumor size (mm) 23 (2-110) 25.5 (3–95) 20.0 (2-110) 0.08 Timing of liver metastases 0.15 Metachronous 52 (27.4%) 28 (23.7%) 24 (33.3%) Interval between colectomy and liver diagnosis (months) 12.0 (6.9–21.0) 13.3 (10.4–23.1) 9.4 (6.1–20.4) 0.18 Major hepatectomy 33 (17.4%) 21 (17.8%) 12 (16.7%) 0.84 RAS mutation site G12A - - 3 (4.2%) G12C - - 8 (11.1%) G12D - - 22 (30.6%) G12S - - 4 (5.6%) G12V - - 15 (20.8%) G13D - - 9 (12.5%) G13R - - 1 (1.4%) Other - - 10 (13.8%) MSI-H 1 1 (0.8%) 0 0.28 Preoperative Chemotherapy 124 (65.3%) 83 (70.3%) 41 (56.9%) 0.06 Biologic agent Anti-EGFR 33 (26.6%) 33 (39.8%) 0 Anti-VEGF 69 (55.6%) 35 (42.2%) 34 (82.9%) Non 22 (17.8%) 15 (18.0%) 7 (17.1%) Adjuvant Chemotherapy 78 (41.1%) 50 (42.4%) 28 (38.9%) 0.64 Biologic agent Anti-EGFR 4 (5.1%) 4 (8.0%) 0 Anti-VEGF 6 (7.7%) 3 (6.0%) 3 (10.7%) Non 68 (87.2%) 43 (86.0%) 25 (89.3%) CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19 − 9; IQR, interquartile range; MSI-H, Microsatellite Instability-High;*Categorical variables are presented as proportions. Non-normally distributed variables are reported as medians with interquartile ranges. †Categorical data were compared using the chi-square test or Fisher’s exact test. Non-normally distributed data were compared using the Kruskal-Wallis test. Perioperative outcomes and recurrence patterns according to KRAS mutation status Regarding the surgical outcomes, no significant differences were observed in operative time, blood loss, postoperative complications, or postoperative hospital stay between the two groups (Table 2 ). During a median follow-up of 34.3 months (IQR: 0.4–176.7 months), 82 deaths occurred. The median observation period in KRAS wild-type and mutant groups was 39.2 months (IQR: 0.4–176.7 months) and 25.0 months (IQR: 1.3–159.4 months), respectively. Patients with KRAS mutations had significantly shorter OS (p = 0.001) and RFS (p = 0.003) than those with KRAS wild-type status (Fig. 1 A and 1 B). The 1-, 3-, and 5-year OS rates were 94.5%, 79.3%, and 63.9% in the wild-type group compared to 92.2%, 52.3%, and 23.5% in the mutant group. Similarly, 1-, 3-, and 5-year RFS rates were 44.0%, 23.9%, and 15.7% for the wild-type group and 21.1%, 7.1%, and 4.7% for the mutant group (Fig. 1 B). Thus, recurrence within one year after surgery was more frequent in KRAS mutant group (79.2% vs. 61.9%). Furthermore, the number of recurrent tumors was significantly higher in KRAS mutant group than that in the wild-type group (p = 0.03) (Table 2 ). Extrahepatic and multi-organ recurrences were also significantly more common in KRAS mutant compared to the wild-type group. Collectively, CRLM patients with KRAS mutations exhibited more aggressive and widespread recurrent patterns, which may result in worse prognostic outcomes than CRLM patients with wild-type KRAS . Table 2 Perioperative outcomes and recurrence pattern according to KRAS status. Characteristic variables * Median (IQR) KRAS status All patients (n = 190) wild (n = 118) mutant (n = 72) P value ‡ Observational period (months) 34.3 (0.43-176.64) 39.2 (0.43–176.6) 25.0 (1.27–159.6) 0.005 Operating time (minutes) 400 (110–986) 400 (140–718) 401 (110–986) 0.75 Intraoperative bleeding (mL) 328 (0-4057) 350 (0-2205) 269.5 (5-4057) 0.89 Postoperative complications (≥ Grade III in Clavien-Dindo classification) 17 (8.9%) 12 (10.2%) 5 (6.9%) 0.44 Length of postoperative hospital stay (day) 13 (5-123) 13 (6-123) 12 (5-104) 0.78 R0/R1 (%) 158/32 (83.2%/16.8%) 98/20 (83.1%/16.9%) 60/12 (83.3%/16.7%) 0.94 Recurrence (Yes) 148 (77.3%) 87 (73.9%) 61 (84.1%) 0.07 Recurrence within 1 year (Yes) 130 (68.4%) 73 (61.9%) 57 (79.2%) 0.009 Number of recurrent tumors 3 (1–14) 3 (1–46) 0.03 Site of recurrence 0.22 Intrahepatic only 72 46 26 Extrahepatic (both) 76 (24) 41 (11) 35 (11) Number of recurrent organs 0.02 Single/Multiple 76 (87.4%)/12 (12.6%) 42 (68.9%)/19 (31.1%) *Categorical variables are presented as proportions. Non-normally distributed variables are reported as medians with interquartile ranges. †Categorical data were compared using the chi-square test or Fisher’s exact test. Non-normally distributed data were compared using the Kruskal-Wallis test. Univariate and multivariate analyses of worse prognostic factors for OS and RFS Next, we examined the prognostic factors of worse OS and RFS in patients with CRLM who underwent curative hepatectomy using Cox proportional hazards regression analyses (Table 3 ). In the univariate analysis for OS, KRAS mutation (HR, 1.91; 95% CI, 1.46–4.06; P = 0.005), multiple tumors (HR, 1.70; 95% CI, 1.02–2.81; P = 0.038), postoperative complications (HR, 2.47; 95% CI, 1.20–4.68; P = 0.006), and CEA level of ≥ 5 ng/mL (HR, 1.96; 95% CI, 1.21–3.19; P = 0.007) were significantly associated with worse OS. In the multivariate analyses, KRAS mutant (HR, 1.96; 95% CI, 1.26–3.05; P = 0.003), postoperative complications (HR, 2.42; 95% CI, 1.29–4.53; P = 0.006), and CEA level of ≥ 5 ng/mL (HR, 1.68; 95% CI, 1.04–2.71; P = 0.034) were independently associated with worse OS. In the univariate analysis of RFS, KRAS mutations (HR, 1.56; 95% CI, 1.12–2.19; P = 0.009), tumor number multiple (HR, 1.49; 95% CI, 1.02–2.17; P = 0.038) and CEA level of ≥ 5 ng/mL (HR, 1.69; 95% CI, 1.20–2.39; P = 0.003) were significantly associated with worse RFS. In the multivariate analyses, KRAS mutations (HR, 1.54; 95% CI, 1.11–2.16; P = 0.011) was significantly and independently associated with worse RFS. Thus, KRAS mutation status was independently associated with poor OS and RFS in patients with CRLM undergoing curative hepatectomy. Additionally, to explore prognostic factors in patients who developed recurrence, we conducted a separate multivariable Cox regression analysis for survival after recurrence (Table 4 ). In this model, early recurrence (< 12 months; HR 3.12, p = 0.0007) was independent unfavorable prognostic factors, whereas receipt of local therapy remained a strong independent favorable factor (HR 0.17, 95% CI 0.10–0.30, p < 0.0001). Table 3 Prognostic impact of the perioperative clinical and pathological characteristics for overall, and recurrence-free survival after resection for CRLM by cox proportional hazards regression analyses. Overall survival Univariable HR (95% CI) P Multivariable HR (95% CI) * P KRAS status Mutant (vs. Wild) 1.91 (1.46–4.06) 0.005 1.96 (1.26–3.05) 0.003 T stage 3–4 (vs.0–2) 0.70 (0.35–1.41) 0.318 N stage 1–2 (vs. 0) 0.92 (0.58–1.45) 0.724 Timing of liver metastases Synchronous (vs. Metachronous) 1.18 (0.72–1.93) 0.508 Interval between colectomy and liver diagnosis (months) 0.59 (0.21–1.63) 0.272 ≥ 30 months (vs. <30 months) Tumor number Multiple (vs. Single) 1.70 (1.02–2.81) 0.038 1.56 (0.90–2.69) 0.111 Tumor size ≥ 30 mm (vs. < 30mm) 1.34 (0.85–2.05) 0.212 Margin status R1 (vs. R0) 1.43 (0.83–2.47) 0.219 Major hepatectomy Yes (vs. No) 1.20 (0.69–2.11) 0.525 Postoperative complications ≥ Grade III in Clavien-Dindo classification (vs. Grade I-II) 2.47 (1.20–4.68) 0.006 2.42 (1.29–4.53) 0.006 CEA ≥ 5 ng/mL (vs. < 5 ng/mL) 1.96 (1.21–3.19) 0.007 1.68 (1.04–2.71) 0.034 Recurrence-free survival KRAS status Mutant (vs. Wild) 1.56 (1.12–2.19) 0.009 1.54 (1.11–2.16) 0.011 Tumor number Multiple (vs. Single) 1.49 (1.02–2.17) 0.038 1.27 (0.88–1.83) 0.196 Postoperative complications ≥Grade III in Clavien-Dindo classification (vs. Grade I-II) 1.41 (0.78–2.55) 0.259 CEA ≥ 5 ng/mL (vs. < 5 ng/mL) 1.69 (1.20–2.39) 0.003 1.34 (0.95–1.83) 0.093 CI, confidence interval; HR, hazard ratio; CEA, carcinoembryonic antigen; *Multivariable Cox proportional hazards regression models included variables showing a univariable association (P < 0.05) with recurrence-free, cancer-specific, and overall survival. †The median amount of intraoperative bleeding was used. Table 4 Prognostic impact of the perioperative clinical and pathological characteristics for survival after recurrence by cox proportional hazards regression analyses. Survival after recurrence Univariable HR (95% CI) P Multivariable HR (95% CI) * P KRAS status Mutant (vs. Wild) 1.94 (1.23–3.04) 0.004 1.53 (0.96–2.44) 0.071 Recurrence within 1 year Yes (vs. No) 2.26 (1.24–4.13) 0.008 3.12 (1.62–6.03) 0.0007 Site of recurrence Intrahepatic (vs. Extrahepatic (extra- and intra-rec)) 0.92 (0.58–1.45) 0.724 Local therapy for recurrence Yes (vs. No) 0.20 (0.12–0.34) < 0.0001 0.17 (0.10–0.30) < 0.0001 CI, confidence interval; HR, hazard ratio; *Multivariable Cox proportional hazards regression models included variables showing a univariable association (P < 0.05) with survival after recurrence. †The median amount of intraoperative bleeding was used. Clinical impact of KRAS mutant sites on the prognostic outcomes in patients with CRLM undergoing curative hepatectomy Among patients with KRAS mutations, the clinical impact of KRAS mutation sites on the OS and RFS in patients with CRLM who underwent curative hepatectomy was investigated (Fig. 2 ). OS and RFS after hepatectomy did not differ significantly among patients with KRAS codon 12, codon 13, and other mutations (Fig. 2 A and 2 B). Furthermore, no significant differences were observed in survival following recurrence between these mutation sites among patients who received local therapy for recurrent lesions; notably, however, no deaths occurred within five years in KRAS codon 13 group (Fig. 2 C). Similarly, in patients who did not receive local therapy for recurrence, the specific mutation site did not significantly affect PRS (Fig. 2 D). Collectively, these findings suggest that KRAS mutation site does not influence the treatment response in CRLM patients with recurrence after curative hepatectomy. Clinical Impact of Local Therapy for Recurrence We further investigated the impact of interventional local therapy (surgical approach or ablation therapy) for recurrent lesions on OS in both KRAS -wild and mutant groups (Table 5 ). Local therapy rates were comparable between groups (55.2% for wild-type vs. 42.6% for mutant, p = 0.15). Intrahepatic recurrences were the most frequent targets for local therapy. Among extrahepatic recurrences, the lungs were the most commonly treated site, followed by lymph nodes and other locations. No significant differences were found in the type or anatomical site of local therapy between KRAS wild-type and mutant groups. The median interval from radiologic confirmation of recurrence to local therapy was 49.5 days (IQR 18.3–154.8), with no significant difference between the groups (wild-type: 56 days [IQR 17–149] vs. mutant: 43 days [IQR 18.5–167] days, p = 0.18;). Table 5 Local therapy for recurrence according to KRAS mutation status Characteristic variables * Median (IQR) KRAS status All patients (n = 148) wild (n = 87) mutant (n = 61) P value ‡ Local therapy for recurrence 0.15 Yes 48 (55.2%) 26 (42.6%) Surgery (combined with chemotherapy) 62 (19) 40 (13) 22 (6) Intrahepatic 40 27 13 Extrahepatic (extra- and intra-rec) 22 (3) 13 (1) 9 (2) Lung 15 9 6 LN 4 3 1 Others 3 2 1 RFA (combined with chemotherapy) 12 (4) 8 (4) 4 (0) Intrahepatic 7 5 2 Extrahepatic (extra- and intra-rec) 5 (0) 3 (0) 2 (0) Lung 5 3 2 Resection margin status at surgery for recurrence 0.21 R0 51(81.3%) 35 (85.7%) 16 (72.7%) R1 11(18.7%) 6 (14.3%) 5(27.3%) Local recurrence after RFA 2 (16.7%) 1 (12.5%) 1 (11.1%) 0.69 Time from recurrence to local therapy (days) 49.5 (18.3-154.8) 56 (17–149) 43 (18.5–167) 0.18 *Categorical variables are presented as proportions. Non-normally distributed variables are reported as medians with interquartile ranges. †Categorical data were compared using the chi-square test or Fisher’s exact test. Non-normally distributed data were compared using the Kruskal-Wallis test. Furthermore, the quality of local treatment was evaluated by comparing surgical margin status and local recurrence rates after RFA. Proportions of R0/R1 resections and RFA local recurrence rates were comparable between groups, suggesting that differences in treatment quality do not account for survival variations. Among patients who underwent local intervention, surgical resection was more commonly performed than RFA in both KRAS wild-type and mutant groups. Crucially, patients who underwent local therapy for recurrence showed comparable OS regardless of KRAS status (p = 0.64; Fig. 3 A). In contrast, among those who did not receive local therapy, KRAS -mutant group had significantly worse OS (p = 0.007; Fig. 3 B). The 5-year OS rates for patients receiving local therapy were 77.9% (wild-type) and 43.1% (mutant), compared to 28.8% and 10.2%, respectively, for those who did not (Fig. 3 C). Additionally, primary tumor location (left vs. right side) did not significantly influence survival outcomes between the two groups (Supplemental Fig. 1). Discussion This study highlights four key findings: (1) KRAS mutations are associated with aggressive and widespread recurrence patterns; (2) KRAS status is an independent predictor of OS and RFS; (3) the specific KRAS mutation site does not significantly influence treatment response or prognosis; and (4) aggressive local therapy for recurrence can achieve survival outcomes in KRAS -mutant patients comparable to those in wild-type patients Our findings align with previous reports that KRAS mutations predict early recurrence and lung metastases [11, 18]. Additionally, Brudvik et al. reported that colorectal cancer patients with KRAS mutations frequently experienced liver metastatic recurrence[11]. In the present cohort, KRAS -mutant CRLM was characterized by recurrence within one year, a higher number of recurrent lesions, and more frequent multi-organ metastases, reflecting a more aggressive tumor biology. These recurrence patterns likely contribute to the inferior OS and RFS observed in patients with KRAS mutations. Comparing recurrence patterns between KRAS wild-type and mutant tumors provides important clinical insights into tumor biology and may help refine postoperative surveillance strategies (e.g., frequency and imaging modalities) and guide decisions on the use of local therapy in recurrent cases. Several mechanisms may underlie the poor prognosis observed in KRAS -mutant CRLM. Beyond aggressive recurrence patterns, KRAS -mutant tumors are associated with limited systemic treatment options, most notably the lack of efficacy of anti-epidermal growth factor receptor antibodies. Nevertheless, our results indicate that effective local eradication of recurrent lesions may overcome these biological disadvantages. Indeed, multivariable analysis restricted to patients with recurrence confirmed that receipt of local therapy was a strong independent favorable prognostic factor, even after adjustment for KRAS mutation status and recurrence timing. These findings align with recent reports highlighting the increasing role of surgical and ablative approaches in precision treatment strategies for CRLM [19–21]. Similarly, clinicopathological factors of the primary tumor, such as lateral lymph node metastasis and perineural invasion in colorectal cancer, have been reported as strong prognostic indicators after hepatectomy for CRLM, independent of metastatic tumor burden[22]. This suggests that both the molecular and anatomic characteristics of the primary tumor contribute to recurrence risk and survival outcomes in CRLM. We further evaluated whether the specific KRAS mutation site influenced clinical outcomes. In contrast to some reports suggesting biological heterogeneity among KRAS subtypes, we observed no significant differences in OS, RFS, or PRS among KRAS codon 12, codon 13, and other mutations. Although survival after local therapy appeared favorable in patients with KRAS codon 13 mutations, the limited sample size precludes definitive conclusions. Overall, these results suggest that K RAS mutation site does not substantially affect the efficacy of local treatment for recurrent CRLM. To our knowledge, this is the first study to demonstrate that the adverse prognostic impact of KRAS mutations can be attenuated through active local management. This suggests that treatment decisions for recurrent lesions should be based on the feasibility of local intervention rather than molecular status alone. Therefore, multidisciplinary discussion regarding the feasibility of local therapy is essential for patients with KRAS mutations. This study has several limitations. First, its retrospective, single center design may limit generalizability, and treatment strategies evolved over the long study period. Second, molecular profiling was limited primarily to KRAS status, and other genomic alterations such as TP53 or SMAD4 were not assessed. Third, although potential biases related to access to local therapy were addressed, unmeasured confounding factors cannot be completely excluded. Nevertheless, additional analyses regarding treatment timing, the quality of local therapy, and the treatment era supported the robustness of our findings. In conclusion, KRAS mutations are associated with aggressive recurrence and a poor prognosis in CRLM. However, active local therapy for recurrent lesions can achieve survival outcomes comparable to wild-type cases. A multidisciplinary approach to assess the feasibility of local therapy is essential for optimizing the management of KRAS -mutant CRLM. Declarations Authors’ Contributions K. K. and H. H. conceived and designed the experiments. KK, TT, YT, YA, TT, TO, DO, YS, RI, and YK performed the experiments. KK and HH analyzed the data. HH and KK drafted the manuscript. Collection of clinical samples: KK, TT, YT, YA, TT, TO, DO, YS, RI, YK, SN, and KM. HH and MI organized the manuscript and approved the final version to be published. Acknowledgments This work was supported by a Grant-in-Aid for Scientists (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant no. 24K11915 to H.H.). The authors thank the Core Laboratory for Medical Research and Education, Kumamoto University School of Medicine, for technical support. Funding Information No financial support was provided for the study. Conflict of Interest statement The authors declare no conflicts of interest, financial or otherwise. Data availability statement The data supporting the findings of this study are available from the corresponding author upon reasonable request. Ethics Statement Approval of the research protocol: The protocol of this study was approved by the human ethics review committee of the Graduate School of Medicine, Kumamoto University, and carried out according to the Declaration of Helsinki and Good Clinical Practice Guidelines. Informed Consent: N/A. Registry and the Registration No. of the study/trial: N/A. Animal Studies: N/A. References Nordlinger, B.; Sorbye, H.; Glimelius, B.; Poston, G.J.; Schlag, P.M.; Rougier, P.; Bechstein, W.O.; Primrose, J.N.; Walpole, E.T.; Finch-Jones, M.; et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008, 371, 1007-1016. Adams, R.B.; Aloia, T.A.; Loyer, E.; Pawlik, T.M.; Taouli, B.; Vauthey, J.N.; Americas Hepato-Pancreato-Biliary, A.; Society of Surgical, O.; Society for Surgery of the Alimentary, T. Selection for hepatic resection of colorectal liver metastases: expert consensus statement. HPB (Oxford). 2013, 15, 91-103. Kasai, S.; Ashida, R.; Sugiura, T.; Ohgi, K.; Yamada, M.; Otsuka, S.; Kagawa, H.; Shiomi, A.; Kinugasa, Y.; Uesaka, K. Long-term outcomes of staged liver resection for synchronous liver metastases from colorectal cancer and the clinical impact of early recurrence: A single-center retrospective cohort study. Ann Gastroenterol Surg. 2023, 7, 318-325. 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Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013, 6, pl1. Liu, P.; Wang, Y.; Li, X. Targeting the untargetable KRAS in cancer therapy. Acta Pharm Sin B. 2019, 9, 871-879. Shukla, S.; Allam, U.S.; Ahsan, A.; Chen, G.; Krishnamurthy, P.M.; Marsh, K.; Rumschlag, M.; Shankar, S.; Whitehead, C.; Schipper, M.; et al. KRAS protein stability is regulated through SMURF2: UBCH5 complex-mediated β-TrCP1 degradation. Neoplasia. 2014, 16, 115-128. Brudvik, K.W.; Mise, Y.; Chung, M.H.; Chun, Y.S.; Kopetz, S.E.; Passot, G.; Conrad, C.; Maru, D.M.; Aloia, T.A.; Vauthey, J.N. RAS Mutation Predicts Positive Resection Margins and Narrower Resection Margins in Patients Undergoing Resection of Colorectal Liver Metastases. Ann Surg Oncol. 2016, 23, 2635-2643. Brudvik, K.W.; Kopetz, S.E.; Li, L.; Conrad, C.; Aloia, T.A.; Vauthey, J.N. Meta-analysis of KRAS mutations and survival after resection of colorectal liver metastases. Br J Surg. 2015, 102, 1175-1183. Takematsu, T.; Mima, K.; Hayashi, H.; Kitano, Y.; Nakagawa, S.; Hiyoshi, Y.; Okabe, H.; Imai, K.; Miyamoto, Y.; Baba, H. RAS mutation status in combination with the JSHBPS nomogram may be useful for preoperative identification of colorectal liver metastases with high risk of recurrence and mortality after hepatectomy. J Hepatobiliary Pancreat Sci. 2024, 31, 69-79. Diener, M.K.; Fichtner-Feigl, S. Biomarkers in colorectal liver metastases: Rising complexity and unknown clinical significance? Ann Gastroenterol Surg. 2021, 5, 477-483. Margonis, G.A.; Spolverato, G.; Kim, Y.; Karagkounis, G.; Choti, M.A.; Pawlik, T.M. Effect of KRAS Mutation on Long-Term Outcomes of Patients Undergoing Hepatic Resection for Colorectal Liver Metastases. Ann Surg Oncol. 2015, 22, 4158-4165. Sakai, N.; Furukawa, K.; Takayashiki, T.; Kuboki, S.; Takano, S.; Ohtsuka, M. Differential effects of KRAS mutational status on long-term survival according to the timing of colorectal liver metastases. BMC Cancer. 2021, 21, 412. Rhaiem, R.; Rached, L.; Tashkandi, A.; Bouche, O.; Kianmanesh, R. Implications of RAS Mutations on Oncological Outcomes of Surgical Resection and Thermal Ablation Techniques in the Treatment of Colorectal Liver Metastases. Cancers (Basel). 2022, 14. Tajiri, T.; Mima, K.; Beppu, T.; Hayashi, H.; Horino, T.; Adachi, Y.; Imai, K.; Masuda, T.; Miyamoto, Y.; Iwatsuki, M. RAS-Beppu Classification: A New Recurrence Risk Classification System Incorporating the Beppu Score and RAS Status for Colorectal Liver Metastases. Cancers (Basel). 2025, 17. Tie, J.; Lipton, L.; Desai, J.; Gibbs, P.; Jorissen, R.N.; Christie, M.; Drummond, K.J.; Thomson, B.N.; Usatoff, V.; Evans, P.M.; et al. KRAS mutation is associated with lung metastasis in patients with curatively resected colorectal cancer. Clin Cancer Res. 2011, 17, 1122-1130. Maki, H.; Jain, A.J.; Haddad, A.; Lendoire, M.; Chun, Y.S.; Vauthey, J.N. Locoregional treatment for colorectal liver metastases aiming for precision medicine. Ann Gastroenterol Surg. 2023, 7, 543-552. Masuda, T., Beppu, T., Okabe, H., Imai, K., Hayashi, H. How Can We Improve the Survival of Patients with Colorectal Liver Metastases Using Thermal Ablation? Cancers (Basel). 2025, 17. Issue 2 Rhaiem, R.; Cauchy, F.; Faron, M.; Sa Cunha, A.; Farges, O. Thermal Ablation in the Curative Treatment of Colorectal Liver Metastasis: New Standard of Care? — Lessons Learned from the COLLISION Trial. Hepatobiliary Surg Nutr.2025 Jun 1;14(3):486-489. Uotani, T.; Takamoto, T.; Nara, S.; Ban, D.; Mizui, T.; Moritani, K.; Tsukamoto, S.; Kanemitsu, Y.; Fujii, T.; Esaki, M. Impact of primary tumor clinicopathological factors on prognosis after hepatic resection for rectal liver metastases. Ann Gastroenterol Surg. 2025, 9, 814-821. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9008145","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":599907747,"identity":"508d7c86-4708-41f0-8672-585ac8241ab7","order_by":0,"name":"Kosuke Kanemitsu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCUlEQVRIie3PsUrEMBjA8YYDXSquCQd9hkogIIT2QVwSCr3l3Dt0iBTapQ/QlxDOxTklUJdg14qLWW4+cBUx7SqtdRPMHzIkfD8+4nku1x8M2gOEB4PLDRDyFNLxfidXEIpRVbRtk6XTfQ1J+UF3ifK1ml4XCaqqI2oyhb1hH8qLso/uK2W35PRmjmx9TdBBqwA0lqDyNXnU3JIuvRUzJID7M2RKhTfQkitLiLQECLVAdkdkPhUvR8LL54T0ZplsISPoQaS89jsmpZYRGX7YgmqNr5uOYnheyFZkCSOD3cIW/gKfKvNS5zCIFSjeP8IoJv3OvJ1yOku+xadJtnZ8LP7NsMvlcv2PvgA5DW5N1CtfFwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-7054-2022","institution":"Kumamoto University: Kumamoto Daigaku","correspondingAuthor":true,"prefix":"","firstName":"Kosuke","middleName":"","lastName":"Kanemitsu","suffix":""},{"id":599907748,"identity":"5656e256-26dd-4659-9e00-0c038a7669b6","order_by":1,"name":"Hiromitsu Hayashi","email":"","orcid":"https://orcid.org/0000-0002-1832-4287","institution":"Kumamoto University: Kumamoto Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Hiromitsu","middleName":"","lastName":"Hayashi","suffix":""},{"id":599907749,"identity":"7c2ef50e-d79d-46e0-a5a0-cdb6aa334ff3","order_by":2,"name":"Yoshiyuki Tagayasu","email":"","orcid":"","institution":"Kumamoto University: Kumamoto Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Yoshiyuki","middleName":"","lastName":"Tagayasu","suffix":""},{"id":599907750,"identity":"6f14a7f5-7b1c-43c0-aaee-845c7096e972","order_by":3,"name":"Takumi Tanizaki","email":"","orcid":"","institution":"Kumamoto University: Kumamoto Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Takumi","middleName":"","lastName":"Tanizaki","suffix":""},{"id":599907751,"identity":"8fb62126-1e2b-4c60-922c-8751ec57d5e6","order_by":4,"name":"Yuki Adach","email":"","orcid":"","institution":"Kumamoto University: Kumamoto Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Adach","suffix":""},{"id":599907752,"identity":"69c050f2-d1d1-468e-a332-8b400b2e619d","order_by":5,"name":"Takashi Ofuchi","email":"","orcid":"","institution":"Kumamoto University: Kumamoto Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Ofuchi","suffix":""},{"id":599907753,"identity":"96738f3f-bca9-4e42-b78a-a1e0227544d6","order_by":6,"name":"Takuya Tajiri","email":"","orcid":"","institution":"Kumamoto University: Kumamoto Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Takuya","middleName":"","lastName":"Tajiri","suffix":""},{"id":599907754,"identity":"f47f02ce-963a-444b-8b52-fb54d4ab0801","order_by":7,"name":"Yuki Kitano","email":"","orcid":"","institution":"Kumamoto University: Kumamoto Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Kitano","suffix":""},{"id":599907755,"identity":"4a323747-043f-4f0c-a124-c5b225bd51dc","order_by":8,"name":"Hirohisa Okabe","email":"","orcid":"","institution":"Kumamoto University: Kumamoto Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Hirohisa","middleName":"","lastName":"Okabe","suffix":""},{"id":599907756,"identity":"84498620-fff7-4400-befc-399d972b9ebd","order_by":9,"name":"Masaaki Iwatsuki","email":"","orcid":"","institution":"Kumamoto University: Kumamoto Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Masaaki","middleName":"","lastName":"Iwatsuki","suffix":""}],"badges":[],"createdAt":"2026-03-02 09:20:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9008145/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9008145/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104182667,"identity":"e31d8080-609f-4686-bd95-43a185b1b93a","added_by":"auto","created_at":"2026-03-08 17:38:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":60647,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePrognostic impact of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eKRAS\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e mutation status in patients with colorectal liver metastasis following hepatectomy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall survival (A) and recurrence-free survival (B) after hepatectomy in patients with colorectal liver metastases with \u003cem\u003eKRAS\u003c/em\u003e mutations or \u003cem\u003eKRAS\u003c/em\u003e wild-type status.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9008145/v1/db8a7c04294b5d331524d85a.png"},{"id":104182713,"identity":"35f8fbb6-a6c8-44da-a1b2-8f86420d005e","added_by":"auto","created_at":"2026-03-08 17:39:05","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":69180,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePrognostic impact of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eKRAS\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e mutation site in patients with colorectal liver metastasis after hepatectomy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall survival and recurrence-free survival (A, B) after hepatectomy in patients with colorectal liver metastases according to \u003cem\u003eKRAS\u003c/em\u003e mutation sites 12, 13, and others. Survival after recurrence in patientswith local therapy (C) and without local therapy (D) according to \u003cem\u003eKRAS\u003c/em\u003e mutation sites 12, 13, and others.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9008145/v1/95482b92dd08e0a0d983a081.png"},{"id":104182739,"identity":"1dd4275b-3709-467c-8389-8e8599a8d552","added_by":"auto","created_at":"2026-03-08 17:39:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":47593,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImpact of local therapy on survival after recurrence according to \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eKRAS\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e mutation status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSurvival after recurrence in patients treated with local therapy (A) and survival after recurrence in patients without local therapy (B) in patients with colorectal liver metastasis with \u003cem\u003eKRAS\u003c/em\u003e mutations or \u003cem\u003eKRAS\u003c/em\u003ewild-type status. Survival after recurrence, summarizing the four groups of recurrent cases (C). Pairwise comparisons with Bonferroni correction were additionally performed.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9008145/v1/81cb3c097849caa538fd0243.png"},{"id":105564051,"identity":"1706c20a-e807-4bb3-907f-511ce1ae283d","added_by":"auto","created_at":"2026-03-27 12:48:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1587083,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9008145/v1/138f1865-a34f-4b39-a8e6-eb55f7d3faea.pdf"}],"financialInterests":"","formattedTitle":"Clinical impact of KRAS mutation status on recurrence patterns and the efficacy of local therapy after hepatectomy for colorectal liver metastases","fulltext":[{"header":"Introduction","content":"\u003cp\u003eColorectal cancer is the second-most common malignancy worldwide. Colorectal liver metastases (CRLM) are frequent, with approximately 50% of patients diagnosed with hepatic metastases either at initial presentation or upon recurrence[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. While surgical resection remains the only potentially curative option, approximately 70% of patients experience recurrence even after radical resection[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This high recurrence rate suggests that many patients harbor micrometastases despite receiving effective chemotherapy and surgery.\u003c/p\u003e \u003cp\u003eThe Kirsten rat sarcoma viral oncogene homolog (\u003cem\u003eKRAS\u003c/em\u003e) mutation, detectable in up to 50% of colorectal cancer cases, drives cancer proliferation via epidermal growth factor receptor (EGFR)-independent activation of the MAPK pathway [\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. \u003cem\u003eKRAS\u003c/em\u003e mutations are established poor prognostic factors for overall survival (OS) and recurrence-free survival (RFS) following CRLM resection [\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15 CR16\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, the underlying biological and clinical features that drive aggressive recurrence patterns in \u003cem\u003eKRAS\u003c/em\u003e-mutant CRLM have not been fully elucidated. Furthermore, it remains unclear whether interventional local therapies, such as repeat resection or radiofrequency ablation (RFA), can offset this adverse prognostic impact. While previous meta-analyses have established \u003cem\u003eKRAS\u003c/em\u003e as a marker of poor prognosis, the mitigating role of local treatment for recurrence has not been systematically clarified. This study aimed to investigate the clinical impact of \u003cem\u003eKRAS\u003c/em\u003e status on recurrence patterns, the management of recurrent lesions, and long-term outcomes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Patient Selection\u003c/h2\u003e \u003cp\u003eThis retrospective single-center study included consecutive patients who underwent hepatectomy for CRLM at Kumamoto University Hospital between August 2005 and August 2022. Of the 291 patients who underwent hepatectomy during this period, nine patients who underwent non-curative resection and 92 patients with unknown \u003cem\u003eKRAS\u003c/em\u003e mutation status were excluded. The remaining 190 patients who underwent curative hepatectomy (macroscopic R0 resection) and had confirmed \u003cem\u003eKRAS\u003c/em\u003e mutation status were included in the analysis.\u003c/p\u003e \u003cp\u003eCurative resection was defined as complete macroscopic removal of all detectable metastatic lesions. Pathological margin status was evaluated histologically. The study protocol was approved by the Ethics Review Committee of Kumamoto University (# 1291) and conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatient follow-up and data collection\u003c/h3\u003e\n\u003cp\u003ePatients were followed every 3\u0026ndash;4 months after hepatectomy through physical examination, serum carcinoembryonic antigen (CEA) measurement, and contrast-enhanced computed tomography or magnetic resonance imaging. Recurrence was defined as the presence of radiologically detectable metastatic lesions consistent with colorectal cancer recurrence. RFS was defined as the interval from hepatectomy to the first recurrence, death, or last follow-up. OS was defined as the interval from hepatectomy to death or last follow-up. Post-recurrence survival (PRS) was defined as the interval from radiological confirmation of recurrence to death or last follow-up. Postoperative complications were graded according to the Clavien\u0026ndash;Dindo classification, and pathological staging was determined using the UICC TNM classification (8th edition).\u003c/p\u003e\n\u003ch3\u003eKRAS Mutation Analysis\u003c/h3\u003e\n\u003cp\u003e \u003cem\u003eKRAS\u003c/em\u003e mutation status was assessed using clinically validated assays as previously described [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In 104 patients, \u003cem\u003eRAS\u003c/em\u003e mutation status was determined using the MEBGEN RASKET-B Kit (Medical \u0026amp; Biological Laboratories Co., Ltd., Japan) at certified reference laboratories. In the remaining 86 patients, \u003cem\u003eKRAS\u003c/em\u003e and \u003cem\u003eNRAS\u003c/em\u003e mutations were analyzed using droplet digital PCR\u0026ndash;based multiplex screening kits (Bio-Rad Laboratories, Inc., Hercules, CA, USA). Both methods are widely used in clinical practice for colorectal cancer. One patient with concurrent \u003cem\u003eKRAS\u003c/em\u003e and NRAS mutations was included in the analysis as the primary objective of the study was to evaluate the impact of \u003cem\u003eKRAS\u003c/em\u003e mutation status. No \u003cem\u003eBRAF\u003c/em\u003e mutations were detected in this cohort.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eContinuous variables are presented as medians with interquartile ranges (IQR) and were compared using the Mann\u0026ndash;Whitney U test. Categorical variables were compared using the chi-squared test or Fisher\u0026rsquo;s exact test, as appropriate. Survival curves were estimated using the Kaplan\u0026ndash;Meier method and compared using the log-rank test. A Cox proportional hazards model was used for univariate and multivariate analyses. Variables with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in univariate analyses were included in multivariate models using backward stepwise selection. Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Optimal cutoff values for the multivariate analysis were determined using receiver operating characteristic (ROC) curve analysis. All statistical analyses were performed using JMP Pro, version 16.0.0 (SAS Institute, Cary, NC, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eOf the 190 patients, 118 (62.1%) had \u003cem\u003eKRAS\u003c/em\u003e wild-type and 72 (37.9%) had \u003cem\u003eKRAS\u003c/em\u003e mutant status. Except for a lower BMI and a higher prevalence of primary tumors located in the descending to sigmoid colon in \u003cem\u003eKRAS\u003c/em\u003e-mutant group, no significant differences in clinicopathological characteristics were observed between the two groups. Details of \u003cem\u003eKRAS\u003c/em\u003e mutation sites and their frequencies are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; the most common mutations were G12D (30.6%) and G12V (20.8%). Microsatellite instability-high was observed in one case within \u003cem\u003eKRAS\u003c/em\u003e wild-type group, and no BRAF mutations were detected in the tested cases. Neoadjuvant chemotherapy was administered to 70.3% of \u003cem\u003eKRAS\u003c/em\u003e wild-type group and 56.9% of the mutant group, while adjuvant chemotherapy was provided to 42.4% and 38.9%, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Regarding molecular targeted agents, anti-EGFR antibodies were administered exclusively to \u003cem\u003eKRAS\u003c/em\u003e wild-type patients (39.8% preoperatively and 8.0% postoperatively), whereas no \u003cem\u003eKRAS\u003c/em\u003e mutated patients received anti-EGFR therapy. Anti-VEGF antibodies were more frequently used in \u003cem\u003eKRAS\u003c/em\u003e-mutant group than in wild-type group, both preoperatively (82.9% vs. 42.2%) and postoperatively (10.7% vs. 6.0%)(Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical and pathological characteristics in comparison between wild and \u003cem\u003eKRAS\u003c/em\u003e mutant status.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristic variables\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e\u003cem\u003eKRAS\u003c/em\u003e status\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll patients\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;190)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ewild\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;118)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003emutant\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;72)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (Men)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e111 (58.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69 (58.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42 (58.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.5 (25\u0026ndash;85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.5 (25\u0026ndash;85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66.5 (35\u0026ndash;85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.6 (13.5\u0026ndash;32.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.1 (13.5\u0026ndash;31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.6 (14.9\u0026ndash;32.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocalization of primary tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAscending colon\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (14.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (11.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (19.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransverse colon\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (3.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (4.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDescending - Sigmoid colon\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79 (41.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (27.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRectum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e77 (40.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (35.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35 (48.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary AJCC T-category\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (10.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (8.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (12.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e171 (90.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e109 (91.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62 (87.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary microvascular invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e138 (72.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86 (70.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52 (76.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary lymphatic invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80 (42.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47 (39.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (47.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreoperative CEA (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.6 (0.5\u0026ndash;2061)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.2 (0.5\u0026ndash;2061)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.7 (1.2\u0026ndash;866)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreoperative CA19-9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19.5 (0.1\u0026ndash;2191)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.8 (0.6\u0026ndash;1756)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23.9 (0.1\u0026ndash;2191)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor number\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (1\u0026ndash;25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (1\u0026ndash;21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (1\u0026ndash;25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (2-110)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.5 (3\u0026ndash;95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20.0 (2-110)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTiming of liver metastases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetachronous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 (27.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (23.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterval between colectomy and liver diagnosis (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.0 (6.9\u0026ndash;21.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.3 (10.4\u0026ndash;23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.4 (6.1\u0026ndash;20.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMajor hepatectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (17.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (17.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eRAS\u003c/em\u003e mutation site\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG12A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (4.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG12C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (11.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG12D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (30.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG12S\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (5.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG12V\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (20.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG13D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG13R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (13.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMSI-H\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreoperative Chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e124 (65.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83 (70.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41 (56.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiologic agent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-EGFR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (26.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (39.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-VEGF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69 (55.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (42.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (82.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (17.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (18.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (17.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdjuvant Chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78 (41.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (42.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 (38.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiologic agent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-EGFR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (5.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (8.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-VEGF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (7.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (6.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (10.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68 (87.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43 (86.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (89.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eCEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9; IQR, interquartile range; MSI-H, Microsatellite Instability-High;*Categorical variables are presented as proportions. Non-normally distributed variables are reported as medians with interquartile ranges. \u0026dagger;Categorical data were compared using the chi-square test or Fisher\u0026rsquo;s exact test. Non-normally distributed data were compared using the Kruskal-Wallis test.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePerioperative outcomes and recurrence patterns according to KRAS mutation status\u003c/h2\u003e \u003cp\u003eRegarding the surgical outcomes, no significant differences were observed in operative time, blood loss, postoperative complications, or postoperative hospital stay between the two groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). During a median follow-up of 34.3 months (IQR: 0.4\u0026ndash;176.7 months), 82 deaths occurred. The median observation period in \u003cem\u003eKRAS\u003c/em\u003e wild-type and mutant groups was 39.2 months (IQR: 0.4\u0026ndash;176.7 months) and 25.0 months (IQR: 1.3\u0026ndash;159.4 months), respectively. Patients with \u003cem\u003eKRAS\u003c/em\u003e mutations had significantly shorter OS (p\u0026thinsp;=\u0026thinsp;0.001) and RFS (p\u0026thinsp;=\u0026thinsp;0.003) than those with \u003cem\u003eKRAS\u003c/em\u003e wild-type status (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). The 1-, 3-, and 5-year OS rates were 94.5%, 79.3%, and 63.9% in the wild-type group compared to 92.2%, 52.3%, and 23.5% in the mutant group. Similarly, 1-, 3-, and 5-year RFS rates were 44.0%, 23.9%, and 15.7% for the wild-type group and 21.1%, 7.1%, and 4.7% for the mutant group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Thus, recurrence within one year after surgery was more frequent in \u003cem\u003eKRAS\u003c/em\u003e mutant group (79.2% vs. 61.9%). Furthermore, the number of recurrent tumors was significantly higher in \u003cem\u003eKRAS\u003c/em\u003e mutant group than that in the wild-type group (p\u0026thinsp;=\u0026thinsp;0.03) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Extrahepatic and multi-organ recurrences were also significantly more common in \u003cem\u003eKRAS\u003c/em\u003e mutant compared to the wild-type group. Collectively, CRLM patients with \u003cem\u003eKRAS\u003c/em\u003e mutations exhibited more aggressive and widespread recurrent patterns, which may result in worse prognostic outcomes than CRLM patients with wild-type \u003cem\u003eKRAS\u003c/em\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePerioperative outcomes and recurrence pattern according to \u003cem\u003eKRAS\u003c/em\u003e status.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristic variables\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e\u003cem\u003eKRAS\u003c/em\u003e status\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll patients\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;190)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ewild\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;118)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003emutant\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;72)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObservational period (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34.3 (0.43-176.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39.2 (0.43\u0026ndash;176.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.0 (1.27\u0026ndash;159.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOperating time (minutes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e400 (110\u0026ndash;986)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e400 (140\u0026ndash;718)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e401 (110\u0026ndash;986)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntraoperative bleeding (mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e328 (0-4057)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e350 (0-2205)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e269.5 (5-4057)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative complications\u003c/p\u003e \u003cp\u003e(\u0026ge;\u0026thinsp;Grade III in Clavien-Dindo classification)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (8.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (10.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (6.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of postoperative hospital stay (day)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (5-123)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (6-123)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (5-104)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR0/R1 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e158/32 (83.2%/16.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e98/20 (83.1%/16.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60/12 (83.3%/16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrence (Yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e148 (77.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87 (73.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61 (84.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrence within 1 year (Yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e130 (68.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73 (61.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57 (79.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of recurrent tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (1\u0026ndash;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (1\u0026ndash;46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSite of recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntrahepatic only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtrahepatic (both)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of recurrent organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle/Multiple\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76 (87.4%)/12 (12.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42 (68.9%)/19 (31.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*Categorical variables are presented as proportions. Non-normally distributed variables are reported as medians with interquartile ranges.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u0026dagger;Categorical data were compared using the chi-square test or Fisher\u0026rsquo;s exact test. Non-normally distributed data were compared using the Kruskal-Wallis test.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eUnivariate and multivariate analyses of worse prognostic factors for OS and RFS\u003c/h3\u003e\n\u003cp\u003eNext, we examined the prognostic factors of worse OS and RFS in patients with CRLM who underwent curative hepatectomy using Cox proportional hazards regression analyses (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In the univariate analysis for OS, \u003cem\u003eKRAS\u003c/em\u003e mutation (HR, 1.91; 95% CI, 1.46\u0026ndash;4.06; P\u0026thinsp;=\u0026thinsp;0.005), multiple tumors (HR, 1.70; 95% CI, 1.02\u0026ndash;2.81; P\u0026thinsp;=\u0026thinsp;0.038), postoperative complications (HR, 2.47; 95% CI, 1.20\u0026ndash;4.68; P\u0026thinsp;=\u0026thinsp;0.006), and CEA level of \u0026ge;\u0026thinsp;5 ng/mL (HR, 1.96; 95% CI, 1.21\u0026ndash;3.19; P\u0026thinsp;=\u0026thinsp;0.007) were significantly associated with worse OS. In the multivariate analyses, \u003cem\u003eKRAS\u003c/em\u003e mutant (HR, 1.96; 95% CI, 1.26\u0026ndash;3.05; P\u0026thinsp;=\u0026thinsp;0.003), postoperative complications (HR, 2.42; 95% CI, 1.29\u0026ndash;4.53; P\u0026thinsp;=\u0026thinsp;0.006), and CEA level of \u0026ge;\u0026thinsp;5 ng/mL (HR, 1.68; 95% CI, 1.04\u0026ndash;2.71; P\u0026thinsp;=\u0026thinsp;0.034) were independently associated with worse OS. In the univariate analysis of RFS, \u003cem\u003eKRAS\u003c/em\u003e mutations (HR, 1.56; 95% CI, 1.12\u0026ndash;2.19; P\u0026thinsp;=\u0026thinsp;0.009), tumor number multiple (HR, 1.49; 95% CI, 1.02\u0026ndash;2.17; P\u0026thinsp;=\u0026thinsp;0.038) and CEA level of \u0026ge;\u0026thinsp;5 ng/mL (HR, 1.69; 95% CI, 1.20\u0026ndash;2.39; P\u0026thinsp;=\u0026thinsp;0.003) were significantly associated with worse RFS. In the multivariate analyses, \u003cem\u003eKRAS\u003c/em\u003e mutations (HR, 1.54; 95% CI, 1.11\u0026ndash;2.16; P\u0026thinsp;=\u0026thinsp;0.011) was significantly and independently associated with worse RFS. Thus, \u003cem\u003eKRAS\u003c/em\u003e mutation status was independently associated with poor OS and RFS in patients with CRLM undergoing curative hepatectomy. Additionally, to explore prognostic factors in patients who developed recurrence, we conducted a separate multivariable Cox regression analysis for survival after recurrence (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). In this model, early recurrence (\u0026lt;\u0026thinsp;12 months; HR 3.12, p\u0026thinsp;=\u0026thinsp;0.0007) was independent unfavorable prognostic factors, whereas receipt of local therapy remained a strong independent favorable factor (HR 0.17, 95% CI 0.10\u0026ndash;0.30, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrognostic impact of the perioperative clinical and pathological characteristics for overall, and recurrence-free survival after resection for CRLM by cox proportional hazards regression analyses.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eOverall survival\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnivariable HR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMultivariable HR (95% CI)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eKRAS\u003c/em\u003e status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMutant (vs. Wild)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.91 (1.46\u0026ndash;4.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.96 (1.26\u0026ndash;3.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u0026ndash;4 (vs.0\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.70 (0.35\u0026ndash;1.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.318\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026ndash;2 (vs. 0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.92 (0.58\u0026ndash;1.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.724\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTiming of liver metastases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSynchronous (vs. Metachronous)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.18 (0.72\u0026ndash;1.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.508\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterval between colectomy and liver\u003c/p\u003e \u003cp\u003ediagnosis (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.59 (0.21\u0026ndash;1.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.272\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; 30 months (vs. \u0026lt;30 months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor number\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple (vs. Single)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.70 (1.02\u0026ndash;2.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.56 (0.90\u0026ndash;2.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.111\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; 30 mm (vs. \u0026lt; 30mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.34 (0.85\u0026ndash;2.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.212\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMargin status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR1 (vs. R0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.43 (0.83\u0026ndash;2.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.219\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMajor hepatectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes (vs. No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.20 (0.69\u0026ndash;2.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.525\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative complications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; Grade III in Clavien-Dindo classification (vs. Grade I-II)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.47 (1.20\u0026ndash;4.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.42 (1.29\u0026ndash;4.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCEA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;5 ng/mL (vs. \u0026lt; 5 ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.96 (1.21\u0026ndash;3.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.68 (1.04\u0026ndash;2.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRecurrence-free survival\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eKRAS\u003c/em\u003e status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMutant (vs. Wild)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.56 (1.12\u0026ndash;2.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.54 (1.11\u0026ndash;2.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor number\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple (vs. Single)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.49 (1.02\u0026ndash;2.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.27 (0.88\u0026ndash;1.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.196\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative complications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;Grade III in Clavien-Dindo classification (vs. Grade I-II)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.41 (0.78\u0026ndash;2.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.259\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCEA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;5 ng/mL (vs. \u0026lt; 5 ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.69 (1.20\u0026ndash;2.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.34 (0.95\u0026ndash;1.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.093\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eCI, confidence interval; HR, hazard ratio; CEA, carcinoembryonic antigen; *Multivariable Cox proportional hazards regression models included variables showing a univariable association (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) with recurrence-free, cancer-specific, and overall survival. \u0026dagger;The median amount of intraoperative bleeding was used.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrognostic impact of the perioperative clinical and pathological characteristics for survival after recurrence by cox proportional hazards regression analyses.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eSurvival after recurrence\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnivariable HR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMultivariable HR (95% CI)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eKRAS\u003c/em\u003e status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMutant (vs. Wild)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.94 (1.23\u0026ndash;3.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.53 (0.96\u0026ndash;2.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.071\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrence within 1 year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes (vs. No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.26 (1.24\u0026ndash;4.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.12 (1.62\u0026ndash;6.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.0007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSite of recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntrahepatic (vs. Extrahepatic (extra- and intra-rec))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.92 (0.58\u0026ndash;1.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.724\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal therapy for recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes (vs. No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.20 (0.12\u0026ndash;0.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.17 (0.10\u0026ndash;0.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eCI, confidence interval; HR, hazard ratio; *Multivariable Cox proportional hazards regression models included variables showing a univariable association (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) with survival after recurrence. \u0026dagger;The median amount of intraoperative bleeding was used.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eClinical impact of KRAS mutant sites on the prognostic outcomes in patients with CRLM undergoing curative hepatectomy\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAmong patients with \u003cem\u003eKRAS\u003c/em\u003e mutations, the clinical impact of \u003cem\u003eKRAS\u003c/em\u003e mutation sites on the OS and RFS in patients with CRLM who underwent curative hepatectomy was investigated (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). OS and RFS after hepatectomy did not differ significantly among patients with \u003cem\u003eKRAS\u003c/em\u003e codon 12, codon 13, and other mutations (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Furthermore, no significant differences were observed in survival following recurrence between these mutation sites among patients who received local therapy for recurrent lesions; notably, however, no deaths occurred within five years in \u003cem\u003eKRAS\u003c/em\u003e codon 13 group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). Similarly, in patients who did not receive local therapy for recurrence, the specific mutation site did not significantly affect PRS (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). Collectively, these findings suggest that \u003cem\u003eKRAS\u003c/em\u003e mutation site does not influence the treatment response in CRLM patients with recurrence after curative hepatectomy.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eClinical Impact of Local Therapy for Recurrence\u003c/h3\u003e\n\u003cp\u003eWe further investigated the impact of interventional local therapy (surgical approach or ablation therapy) for recurrent lesions on OS in both \u003cem\u003eKRAS\u003c/em\u003e-wild and mutant groups (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Local therapy rates were comparable between groups (55.2% for wild-type vs. 42.6% for mutant, p\u0026thinsp;=\u0026thinsp;0.15). Intrahepatic recurrences were the most frequent targets for local therapy. Among extrahepatic recurrences, the lungs were the most commonly treated site, followed by lymph nodes and other locations. No significant differences were found in the type or anatomical site of local therapy between \u003cem\u003eKRAS\u003c/em\u003e wild-type and mutant groups. The median interval from radiologic confirmation of recurrence to local therapy was 49.5 days (IQR 18.3\u0026ndash;154.8), with no significant difference between the groups (wild-type: 56 days [IQR 17\u0026ndash;149] vs. mutant: 43 days [IQR 18.5\u0026ndash;167] days, p\u0026thinsp;=\u0026thinsp;0.18;).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLocal therapy for recurrence according to \u003cem\u003eKRAS\u003c/em\u003e mutation status\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristic variables\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e\u003cem\u003eKRAS\u003c/em\u003e status\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll patients\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;148)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ewild\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;87)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003emutant\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;61)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal therapy for recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (55.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (42.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgery (combined with chemotherapy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntrahepatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtrahepatic (extra- and intra-rec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRFA (combined with chemotherapy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntrahepatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtrahepatic (extra- and intra-rec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResection margin status at surgery for recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51(81.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (85.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (72.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11(18.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (14.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5(27.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal recurrence after RFA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (11.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from recurrence to local therapy (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49.5 (18.3-154.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (17\u0026ndash;149)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43 (18.5\u0026ndash;167)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*Categorical variables are presented as proportions. Non-normally distributed variables are reported as medians with interquartile ranges. \u0026dagger;Categorical data were compared using the chi-square test or Fisher\u0026rsquo;s exact test. Non-normally distributed data were compared using the Kruskal-Wallis test.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFurthermore, the quality of local treatment was evaluated by comparing surgical margin status and local recurrence rates after RFA. Proportions of R0/R1 resections and RFA local recurrence rates were comparable between groups, suggesting that differences in treatment quality do not account for survival variations. Among patients who underwent local intervention, surgical resection was more commonly performed than RFA in both \u003cem\u003eKRAS\u003c/em\u003e wild-type and mutant groups.\u003c/p\u003e \u003cp\u003eCrucially, patients who underwent local therapy for recurrence showed comparable OS regardless of \u003cem\u003eKRAS\u003c/em\u003e status (p\u0026thinsp;=\u0026thinsp;0.64; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). In contrast, among those who did not receive local therapy, \u003cem\u003eKRAS\u003c/em\u003e-mutant group had significantly worse OS (p\u0026thinsp;=\u0026thinsp;0.007; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). The 5-year OS rates for patients receiving local therapy were 77.9% (wild-type) and 43.1% (mutant), compared to 28.8% and 10.2%, respectively, for those who did not (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). Additionally, primary tumor location (left vs. right side) did not significantly influence survival outcomes between the two groups (Supplemental Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study highlights four key findings: (1) \u003cem\u003eKRAS\u003c/em\u003e mutations are associated with aggressive and widespread recurrence patterns; (2) \u003cem\u003eKRAS\u003c/em\u003e status is an independent predictor of OS and RFS; (3) the specific \u003cem\u003eKRAS\u003c/em\u003e mutation site does not significantly influence treatment response or prognosis; and (4) aggressive local therapy for recurrence can achieve survival outcomes in \u003cem\u003eKRAS\u003c/em\u003e-mutant patients comparable to those in wild-type patients\u003c/p\u003e\n\u003cp\u003eOur findings align with previous reports that \u003cem\u003eKRAS\u003c/em\u003e mutations predict early recurrence and lung metastases [11, 18]. Additionally, Brudvik et al. reported that colorectal cancer patients with \u003cem\u003eKRAS\u003c/em\u003e mutations frequently experienced liver metastatic recurrence[11]. In the present cohort, \u003cem\u003eKRAS\u003c/em\u003e-mutant CRLM was characterized by recurrence within one year, a higher number of recurrent lesions, and more frequent multi-organ metastases, reflecting a more aggressive tumor biology. These recurrence patterns likely contribute to the inferior OS and RFS observed in patients with \u003cem\u003eKRAS\u003c/em\u003e mutations. Comparing recurrence patterns between \u003cem\u003eKRAS\u003c/em\u003e wild-type and mutant tumors provides important clinical insights into tumor biology and may help refine postoperative surveillance strategies (e.g., frequency and imaging modalities) and guide decisions on the use of local therapy in recurrent cases.\u003c/p\u003e\n\u003cp\u003eSeveral mechanisms may underlie the poor prognosis observed in \u003cem\u003eKRAS\u003c/em\u003e-mutant CRLM. Beyond aggressive recurrence patterns, \u003cem\u003eKRAS\u003c/em\u003e-mutant tumors are associated with limited systemic treatment options, most notably the lack of efficacy of anti-epidermal growth factor receptor antibodies. Nevertheless, our results indicate that effective local eradication of recurrent lesions may overcome these biological disadvantages. Indeed, multivariable analysis restricted to patients with recurrence confirmed that receipt of local therapy was a strong independent favorable prognostic factor, even after adjustment for \u003cem\u003eKRAS\u003c/em\u003e mutation status and recurrence timing. These findings align with recent reports highlighting the increasing role of surgical and ablative approaches in precision treatment strategies for CRLM [19\u0026ndash;21]. Similarly, clinicopathological factors of the primary tumor, such as lateral lymph node metastasis and perineural invasion in colorectal cancer, have been reported as strong prognostic indicators after hepatectomy for CRLM, independent of metastatic tumor burden[22]. This suggests that both the molecular and anatomic characteristics of the primary tumor contribute to recurrence risk and survival outcomes in CRLM.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe further evaluated whether the specific \u003cem\u003eKRAS\u003c/em\u003e mutation site influenced clinical outcomes. In contrast to some reports suggesting biological heterogeneity among \u003cem\u003eKRAS\u003c/em\u003e subtypes, we observed no significant differences in OS, RFS, or PRS among \u003cem\u003eKRAS\u003c/em\u003e codon 12, codon 13, and other mutations. Although survival after local therapy appeared favorable in patients with \u003cem\u003eKRAS\u003c/em\u003e codon 13 mutations, the limited sample size precludes definitive conclusions. Overall, these results suggest that \u003cem\u003eK\u003c/em\u003e\u003cem\u003eRAS\u003c/em\u003e mutation site does not substantially affect the efficacy of local treatment for recurrent CRLM.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo our knowledge, this is the first study to demonstrate that the adverse prognostic impact of \u003cem\u003eKRAS\u003c/em\u003e mutations can be attenuated through active local management. This suggests that treatment decisions for recurrent lesions\u0026nbsp;should be based on the feasibility of local intervention rather than molecular status alone. Therefore, multidisciplinary discussion regarding the feasibility of local therapy is essential for patients with \u003cem\u003eKRAS\u003c/em\u003e mutations.\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. First, its retrospective, single center design may limit generalizability, and treatment strategies evolved over the long study period. Second, molecular profiling was limited primarily to \u003cem\u003eKRAS\u003c/em\u003e status, and other genomic alterations such as \u003cem\u003eTP53\u003c/em\u003e or \u003cem\u003eSMAD4\u003c/em\u003e were not assessed. Third, although potential biases related to access to local therapy were addressed, unmeasured confounding factors cannot be completely excluded. Nevertheless, additional analyses regarding treatment timing, the quality of local therapy, and the treatment era supported the robustness of our findings.\u003c/p\u003e\n\u003cp\u003eIn conclusion, \u003cem\u003eKRAS\u003c/em\u003e mutations are associated with aggressive recurrence and a poor prognosis in CRLM. However, active local therapy for recurrent lesions can achieve survival outcomes comparable to wild-type cases. A multidisciplinary approach to assess the feasibility of local therapy is essential for optimizing the management of \u003cem\u003eKRAS\u003c/em\u003e-mutant CRLM.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors’ Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eK. K. and H. H. conceived and designed the experiments. KK, TT, YT, YA, TT, TO, DO, YS, RI, and YK performed the experiments. KK and HH analyzed the data. HH and KK drafted the manuscript. Collection of clinical samples: KK, TT, YT, YA, TT, TO, DO, YS, RI, YK, SN, and KM. HH and MI organized the manuscript and approved the final version to be published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by a Grant-in-Aid for Scientists (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant no. 24K11915 to H.H.). The authors thank the Core Laboratory for Medical Research and Education, Kumamoto University School of Medicine, for technical support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo financial support was provided for the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The authors declare no conflicts of interest, financial or otherwise.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApproval of the research protocol: The protocol of this study was approved by the human ethics review committee of the Graduate School of Medicine, Kumamoto University, and carried out according to the Declaration of Helsinki and Good Clinical Practice Guidelines.\u003c/p\u003e\n\u003cp\u003eInformed Consent: N/A.\u003c/p\u003e\n\u003cp\u003eRegistry and the Registration No. of the study/trial: N/A.\u003c/p\u003e\n\u003cp\u003eAnimal Studies: N/A.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eNordlinger, B.; Sorbye, H.; Glimelius, B.; Poston, G.J.; Schlag, P.M.; Rougier, P.; Bechstein, W.O.; Primrose, J.N.; Walpole, E.T.; Finch-Jones, M.; et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008, 371, 1007-1016.\u003c/li\u003e\n \u003cli\u003eAdams, R.B.; Aloia, T.A.; Loyer, E.; Pawlik, T.M.; Taouli, B.; Vauthey, J.N.; Americas Hepato-Pancreato-Biliary, A.; Society of Surgical, O.; Society for Surgery of the Alimentary, T. Selection for hepatic resection of colorectal liver metastases: expert consensus statement. HPB (Oxford). 2013, 15, 91-103.\u003c/li\u003e\n \u003cli\u003eKasai, S.; Ashida, R.; Sugiura, T.; Ohgi, K.; Yamada, M.; Otsuka, S.; Kagawa, H.; Shiomi, A.; Kinugasa, Y.; Uesaka, K. Long-term outcomes of staged liver resection for synchronous liver metastases from colorectal cancer and the clinical impact of early recurrence: A single-center retrospective cohort study. Ann Gastroenterol Surg. 2023, 7, 318-325.\u003c/li\u003e\n \u003cli\u003eYaeger R, Chatila WK, Lipsyc MD, Hechtman JF, Cercek A, Sanchez-Vega F, Jayakumaran G, Middha S, Zehir A, Donoghue MTA, et al. Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell. 2018;33(1):125\u0026ndash;136.e3.\u003c/li\u003e\n \u003cli\u003eModest, D.P.; Ricard, I.; Heinemann, V.; Hegewisch-Becker, S.; Schmiegel, W.; Porschen, R.; Stintzing, S.; Graeven, U.; Arnold, D.; von Weikersthal, L.F.; et al. Outcome according to \u003cem\u003eKRAS\u003c/em\u003e-, NRAS- and BRAF-mutation as well as \u003cem\u003eKRAS\u003c/em\u003e mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group. Ann Oncol. 2016, 27, 1746-1753.\u003c/li\u003e\n \u003cli\u003eVaughn CP, Zobell SD, Furtado LV, Baker CL, Samowitz WS. Frequency of \u003cem\u003eKRAS\u003c/em\u003e, BRAF, and NRAS mutations in colorectal cancer. Genes Chromosomes Cancer 2011;50(5):307\u0026ndash;312.\u003c/li\u003e\n \u003cli\u003eGao, J.; Aksoy, B.A.; Dogrusoz, U.; Dresdner, G.; Gross, B.; Sumer, S.O.; Sun, Y.; Jacobsen, A.; Sinha, R.; Larsson, E.; et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013, 6, pl1.\u003c/li\u003e\n \u003cli\u003eLiu, P.; Wang, Y.; Li, X. Targeting the untargetable \u003cem\u003eKRAS\u003c/em\u003e in cancer therapy. Acta Pharm Sin B. 2019, 9, 871-879.\u003c/li\u003e\n \u003cli\u003eShukla, S.; Allam, U.S.; Ahsan, A.; Chen, G.; Krishnamurthy, P.M.; Marsh, K.; Rumschlag, M.; Shankar, S.; Whitehead, C.; Schipper, M.; et al. \u003cem\u003eKRAS\u003c/em\u003e protein stability is regulated through SMURF2: UBCH5 complex-mediated \u0026beta;-TrCP1 degradation. Neoplasia. 2014, 16, 115-128.\u003c/li\u003e\n \u003cli\u003eBrudvik, K.W.; Mise, Y.; Chung, M.H.; Chun, Y.S.; Kopetz, S.E.; Passot, G.; Conrad, C.; Maru, D.M.; Aloia, T.A.; Vauthey, J.N. RAS Mutation Predicts Positive Resection Margins and Narrower Resection Margins in Patients Undergoing Resection of Colorectal Liver Metastases. Ann Surg Oncol. 2016, 23, 2635-2643.\u003c/li\u003e\n \u003cli\u003eBrudvik, K.W.; Kopetz, S.E.; Li, L.; Conrad, C.; Aloia, T.A.; Vauthey, J.N. Meta-analysis of \u003cem\u003eKRAS\u003c/em\u003e mutations and survival after resection of colorectal liver metastases. Br J Surg. 2015, 102, 1175-1183.\u003c/li\u003e\n \u003cli\u003eTakematsu, T.; Mima, K.; Hayashi, H.; Kitano, Y.; Nakagawa, S.; Hiyoshi, Y.; Okabe, H.; Imai, K.; Miyamoto, Y.; Baba, H. RAS mutation status in combination with the JSHBPS nomogram may be useful for preoperative identification of colorectal liver metastases with high risk of recurrence and mortality after hepatectomy. J Hepatobiliary Pancreat Sci. 2024, 31, 69-79.\u003c/li\u003e\n \u003cli\u003eDiener, M.K.; Fichtner-Feigl, S. Biomarkers in colorectal liver metastases: Rising complexity and unknown clinical significance? Ann Gastroenterol Surg. 2021, 5, 477-483.\u003c/li\u003e\n \u003cli\u003eMargonis, G.A.; Spolverato, G.; Kim, Y.; Karagkounis, G.; Choti, M.A.; Pawlik, T.M. Effect of \u003cem\u003eKRAS\u003c/em\u003e Mutation on Long-Term Outcomes of Patients Undergoing Hepatic Resection for Colorectal Liver Metastases. Ann Surg Oncol. 2015, 22, 4158-4165.\u003c/li\u003e\n \u003cli\u003eSakai, N.; Furukawa, K.; Takayashiki, T.; Kuboki, S.; Takano, S.; Ohtsuka, M. Differential effects of \u003cem\u003eKRAS\u003c/em\u003e mutational status on long-term survival according to the timing of colorectal liver metastases. BMC Cancer. 2021, 21, 412.\u003c/li\u003e\n \u003cli\u003eRhaiem, R.; Rached, L.; Tashkandi, A.; Bouche, O.; Kianmanesh, R. Implications of RAS Mutations on Oncological Outcomes of Surgical Resection and Thermal Ablation Techniques in the Treatment of Colorectal Liver Metastases. Cancers (Basel). 2022, 14.\u003c/li\u003e\n \u003cli\u003eTajiri, T.; Mima, K.; Beppu, T.; Hayashi, H.; Horino, T.; Adachi, Y.; Imai, K.; Masuda, T.; Miyamoto, Y.; Iwatsuki, M. RAS-Beppu Classification: A New Recurrence Risk Classification System Incorporating the Beppu Score and RAS Status for Colorectal Liver Metastases. Cancers (Basel). 2025, 17.\u003c/li\u003e\n \u003cli\u003eTie, J.; Lipton, L.; Desai, J.; Gibbs, P.; Jorissen, R.N.; Christie, M.; Drummond, K.J.; Thomson, B.N.; Usatoff, V.; Evans, P.M.; et al. \u003cem\u003eKRAS\u003c/em\u003e mutation is associated with lung metastasis in patients with curatively resected colorectal cancer. Clin Cancer Res. 2011, 17, 1122-1130.\u003c/li\u003e\n \u003cli\u003eMaki, H.; Jain, A.J.; Haddad, A.; Lendoire, M.; Chun, Y.S.; Vauthey, J.N. Locoregional treatment for colorectal liver metastases aiming for precision medicine. Ann Gastroenterol Surg. 2023, 7, 543-552.\u003c/li\u003e\n \u003cli\u003eMasuda, T., Beppu, T., Okabe, H., Imai, K., Hayashi, H. How Can We Improve the Survival of Patients with Colorectal Liver Metastases Using Thermal Ablation? Cancers (Basel). 2025, 17. Issue 2\u003c/li\u003e\n \u003cli\u003eRhaiem, R.; Cauchy, F.; Faron, M.; Sa Cunha, A.; Farges, O. Thermal Ablation in the Curative Treatment of Colorectal Liver Metastasis: New Standard of Care? \u0026mdash; Lessons Learned from the COLLISION Trial. Hepatobiliary Surg Nutr.2025 Jun 1;14(3):486-489.\u003c/li\u003e\n \u003cli\u003eUotani, T.; Takamoto, T.; Nara, S.; Ban, D.; Mizui, T.; Moritani, K.; Tsukamoto, S.; Kanemitsu, Y.; Fujii, T.; Esaki, M. Impact of primary tumor clinicopathological factors on prognosis after hepatic resection for rectal liver metastases. Ann Gastroenterol Surg. 2025, 9, 814-821.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"colorectal cancer, liver metastases, RAS mutations, KRAS12C, KRAS12D","lastPublishedDoi":"10.21203/rs.3.rs-9008145/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9008145/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eKirsten rat sarcoma viral oncogene homolog (\u003cem\u003eKRAS\u003c/em\u003e) is one of the most frequently mutated oncogenes in colorectal cancer. We aimed to clarify the clinical impact of \u003cem\u003eKRAS\u003c/em\u003e mutation status on recurrence patterns, surgical management of recurrent lesions, and prognostic outcomes after curative hepatectomy for colorectal liver metastases (CRLM).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study included 190 CRLM patients who underwent curative (macroscopic R0 resection) hepatectomy and had known \u003cem\u003eKRAS\u003c/em\u003e status (wild-type [WT]: 62.1%; mutant [MT]: 37.9%).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e \u003cem\u003eKRAS\u003c/em\u003e mutations were identified in 72 patients. Compared to the WT group, the MT group exhibited significantly shorter overall survival (OS) and recurrence-free survival (RFS). The MT group was characterized by more frequent early recurrence (within 1 year), multiple lesions, and multi-organ metastases. Multivariate analysis identified \u003cem\u003eKRAS\u003c/em\u003e mutation as an independent predictor of poor OS and RFS, whereas CEA\u0026thinsp;\u0026ge;\u0026thinsp;5 ng/mL was independently associated with OS but not RFS. Notably, among patients who experienced recurrence, those who underwent local therapy (repeat resection or ablation) showed comparable OS between the MT and WT groups. Conversely, in patients who did not receive local therapy, the MT group had significantly worse OS. Mutation sites (G12, G13, others) did not significantly influence outcomes. Conclusions: \u003cem\u003eKRAS\u003c/em\u003e mutations are associated with aggressive recurrence patterns and a poor prognosis in CRLM. However, active local therapy for recurrent lesions may mitigate this adverse impact, achieving survival outcomes comparable to those of WT cases.\u003c/p\u003e","manuscriptTitle":"Clinical impact of KRAS mutation status on recurrence patterns and the efficacy of local therapy after hepatectomy for colorectal liver metastases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-08 17:38:12","doi":"10.21203/rs.3.rs-9008145/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5bddcb05-1587-4bbc-9802-9f955c757e30","owner":[],"postedDate":"March 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-23T05:52:06+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-08 17:38:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9008145","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9008145","identity":"rs-9008145","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}