Does Tumor Sidedness Matter After Curative Surgery in Colorectal Cancer? A Retrospective Cohort Study on Recurrence Patterns and Post Recurrence Survival.

BackgroundSeveral studies have demonstrated that right-sided tumors have poorer prognosis than left-sided tumors in patients with unresectable colorectal cancer (CRC). The predictive ability of the tumor sidedness in CRC treated with chemotherapy in each sex is unclear.MethodsSubjects were 964 unresectable recurrent patients treated with chemotherapy with stage II-III CRC after curative resection between 2004 and 2012. Post-recurrence cancer-specific survival (CSS) for each sex was examined.ResultsPatients were 603 males (222 right-side tumors (cecum to transverse colon) and 381 left-sided tumors (descending colon to rectum)), and 361 females (167 right-side tumors and 194 left-sided tumors). Right-sided tumors developed peritoneal recurrences in males and females. Left-sided tumors were associated with locoregional recurrences in males and with lung recurrences in females. Right-sided tumors were associated with shorter post-recurrence CSS in both sexes. In males, multivariate analyses showed that right-sided tumors were associated with shorter post-recurrence CSS (HR: 1.53, P < 0.0001) together with the presence of regional lymph node metastasis histopathological type of other than differentiated adenocarcinoma, the recurrence of liver only, the recurrence of peritoneal dissemination only, and relapse-free interval less than one-year. In females, multivariate analyses showed that right-sided tumors were associated with shorter post-recurrence CSS (HR: 1.50, P = 0.0019) together with advanced depth of invasion, the presence of regional lymph node metastasis, and recurrence of liver only.ConclusionsPrimary tumor sidedness in both sexes in unresectable recurrent CRC patients treated with chemotherapy may have prognostic implications for post-recurrence CSS.

3531 Background: Colorectal cancer (CRC) is a heterogeneous disease with distinct molecular and clinical differences between right- and left-sided tumors. This study analyzes these variations to understand their impact on tumor behavior and treatment strategies. Methods: A total of 445 colonic tumor samples (132 right-sided, 313 left-sided) were profiled to assess mutations, amplifications, and fusions in key cancer-related genes along with targeted transcriptome analysis of 20,802 genes in a subset using semiconductor based next-generation sequencing (NGS) platform at Datar Cancer Genetics. Immunotherapy biomarkers (TMB, MSI, and PD-L1 22C3 TPS) were analyzed in a subset. Results: Right-sided and left-sided colon cancers exhibit substantial molecular heterogeneity, driven by distinct genetic and epigenetic alterations (Table 1). Right-sided tumors were more frequently associated with MSI and had statistically significant higher incidence of BRAF mutations. KRAS mutations were frequently observed in both right-sided and left-sided tumors at equal rates. ERBB2 amplifications were exclusive to left side tumors, whereas oncogenic ERBB2 mutations were equally distributed. Located around ERBB2, PGAP3 gene co‐amplification too was exclusive to left sided tumors. TFE3 alterations were absent from left sided tumors and common on right side. TP53 mutations, though more common in left-sided tumors, the difference was not statistically significant. Gene expression profiling of a subset, including 103 left-sided and 41 right-sided colon tumors, revealed activation of the Wnt / β-catenin signalling pathway, RAS/MAPK pathway, TGF-β signalling pathway, and immune-related pathways, though these differences were not statistically significant, suggesting that while specific drivers may differ—such as the predominance of APC mutations in left-sided tumors (56.8% vs 37.9%) leading to WNT activation and the higher incidence of RSPO2/3 fusions (7.1% vs 1.7%) in right-sided tumors -eventually some pathways are commonly implicated in colorectal cancer biology. Conclusions: Existing therapies like ICIs, HER2 inhibitors, and emerging molecules such as RSPO2/RSPO3 inhibitors could have differing impact based on tumor sidedness. Integrating these distinctions into drug development and clinical trials holds potential to optimize treatment outcomes. Molecular profiles of right- and left-sided colon tumors. Gene Right (%) Left (%) p-Value(Chi-square test) TP53 64.5% 73.2% 0.075644 APC 37.9% 56.8% 0.001354 KRAS 50.0% 43.6% 0.220194 BRAF 18.8% 3.0% 0.00001 TFE3 9.5% 0% 0.109087 ERBB2 mutation 2.3% 2.0% 0.80941 ERBB2 amplification 0% 5.9% 0.023006 PGAP3 amplification 0% 7.1% 0.673427 RSPO2/3 fusion 7.1% 1.7% 0.827207 Immunotherapy Biomarkers TMB 10-14 24.7% 29.3% 0.458066 TMB ³15 15.6% 7.6% 0.059925 MSI-High 8.1% 3.4% 0.066213 PD-L1 Positive 15% 5.6% 0.012571

Despite the introduction of new molecular classifications, advanced colorectal cancer (CRC) is treated with chemotherapy supplemented with anti-EGFR and anti-VEGF targeted therapy. In this study, 552 CRC cases with different primary tumor locations (250 left side, 190 rectum, and 112 right side) were retrospectively analyzed by next generation sequencing for mutations in 50 genes. The most frequently mutated genes were TP53 in left-sided tumors compared to right-sided tumors and BRAF in right-sided tumors compared to left-sided tumors. Mutations in KRAS, NRAS, and BRAF were not detected in 45% of patients with left-sided tumors and in 28.6% of patients with right-sided tumors. Liver metastases were more common in patients with left-sided tumors. Tumors on the right side were larger at diagnosis and had a higher grade (G3) than tumors on the left. Rectal tumors exhibit distinctive biological characteristics when compared to left-sided tumors, including a higher absence rate of KRAS, NRAS, and BRAF mutations (47.4% in rectal versus 42.8% in left-sided tumors). These rectal tumors are also unique in their primary metastasis site, which is predominantly the lungs, and they have varying mutation rates, particularly in genes such as BRAF, FBXW7, and TP53, that distinguish them from tumors found in other locations. Primary tumor location has implications for the potential treatment of CRC with anti-EGFR therapy.

The aim of this study is to evaluate outcomes in patients with peritoneal metastasis of colorectal cancer (pmCRC) who underwent cytoreductive surgery and intraperitoneal chemotherapy (CRS/IPC) in relation to the location of the primary tumor. Regional therapy, including cytoreductive surgery and intraperitoneal chemotherapy, has been associated with improved survival in patients with pmCRC. Location of the primary tumor has been shown to be prognostic in patients with metastasis. A retrospective review was performed for all patients who underwent complete cytoreduction and intraperitoneal chemotherapy from 2010 to 2017, examining patient and tumor characteristics, overall and recurrence-free survival, recurrence patterns, and tumor mutational profiles. Ninety-three patients were included in the study: 49 (53%) with a right-sided and 44 (47%) with a left-sided primary tumor. Patients with a right-sided tumor had significantly shorter recurrence-free survival (median, 6.3months; 95% CI, 4.7-8.1months vs 12.3months; 95% CI, 3.6-21.7months; P = 0.02) and overall survival (median, 36.6months; 95% CI, 26.4-46.9months vs 83.3months; 95% CI 44.2-122.4months; P = 0.03). BRAF and KRAS mutations were more frequent in right-sided tumors, and APC and TP53 mutations were more frequent in left-sided tumors, which were more chromosomally instable. BRAF mutations were associated with early recurrence. Tumor sidedness is a predictor of oncological outcomes after CRS/IPC. Tumor sidedness and molecular characteristics should be considered when counseling patients regarding expected outcomes and when selecting or stratifying pmCRC patients for clinical trials of regional therapy.

Studies have shown that the prevalence of RAS and BRAF mutations may differ by tumor sidedness among metastatic colorectal cancer (mCRC) patients. Both mutation status and tumor sidedness may impact survival and disease progression and RAS mutation status has been shown to predict response to anti‐epidermal growth factor receptor (EGFR) therapy. A systematic literature review and meta‐analysis were conducted to estimate the pooled prevalence of RAS and BRAF mutations by tumor sidedness in studies of mCRC patients. Forty‐four studies comprising 15 981 mCRC patients tested for RAS and/or BRAF mutations were included in the meta‐analyses. The prevalence of RAS mutations differed significantly by tumor side (32.4% among left‐sided tumors, 41.3% among right‐sided tumors; P = .017), as did the prevalence of KRAS mutations (35.8% among left‐sided tumors, 46.3% among right‐sided tumors; P < .0001) and BRAF mutations (4.3% among left‐sided tumors, 16.3% among right‐sided tumors; P < .0001). Among right‐sided tumors, the prevalence of RAS and KRAS mutations varied significantly by study design, with higher prevalence among observational studies than clinical trials, and there was significant variation by study location for the prevalence of KRAS mutations in left‐sided tumors and the prevalence of BRAF mutations in right‐sided tumors. These results help to better characterize the mCRC population to better inform clinicians and researchers. Few of the included studies reported overall or progression‐free survival (PFS) by both tumor sidedness and mutation status. As both of these factors may have prognostic impact, future studies should consider evaluating survival by these variables.

When treated with molecular targeted agents, patients with unresectable colorectal cancer with right-sided tumors have poorer prognoses than those with left-sided tumors. While primary tumor sidedness may have prognostic value, the prognostic value of tumor sidedness in chemotherapy regimens without targeted therapy is unclear. Our study population comprised 678 consecutive patients with unresectable stage IV colorectal cancer who received systemic chemotherapy at the National Cancer Center Hospital in Japan from 1999 to 2015. Patients were stratified by treatment subgroup (with or without molecular targeted agents and with or without palliative primary tumor resection), and relationships between overall survival (OS) and primary tumor sidedness were evaluated. Multivariate analyses were also performed. Overall, 193 (28%) tumors were right-sided (cecum to transverse colon) and 485 (72%) were left-sided (splenic flexure to rectum). In the overall population, median survival time was 16.4months for those with right-sided tumors and 23.4months for those with left-sided tumors (p < 0.01). Regardless of the use or non-use of targeted agents and performance or non-performance of palliative resection of the primary tumor, those with right-sided tumors showed significantly poorer prognosis than those with left-sided tumors, in all categories. Multivariate analyses showed right-sided tumors to be associated with shorter OS compared with left-sided tumors (hazard ratio 1.26, 95% confidence interval 1.03-1.53; p =0.024). Unresectable stage IV right-sided colorectal tumors were associated with shorter OS compared with left-sided tumors, regardless of treatment strategy. Primary tumor sidedness may be an independent prognostic factor.

The impact of KRAS mutation, microsatellite instability, and tumor laterality on the prognosis of nonmetastatic colon cancer

Tumor location and KRAS mutational status have emerged as prognostic factors of colorectal cancer. We aimed to define the prognostic impact of primary tumor location and KRAS mutational status among synchronous colorectal liver metastases (CRLM) patients who underwent simultaneous curative-intent surgery (SCIS). We compared the clinicopathologic characteristics and long-term outcomes of 227 patients who underwent SCIS for synchronous CRLM, according to tumor location and KRAS mutational status. We cross-classified tumor location and KRAS mutational status and compared survival outcomes between the four resulting patient groups. Forty-one patients (18.1%) had right-sided (RS) tumors and 186 (81.9%) had left-sided (LS) tumors. One-third of tumors (78/227) harbored KRAS mutations. The KRAS mutant-type (KRAS-mt) was more commonly observed among RS tumors than among LS tumors [21/41 (51.2%) vs. 57/186 (30.6%), p = 0.012]. Median follow-up time was 43.4months. Patients with RS tumors had shorter survival times than those with LS tumors [median disease-free survival (DFS): RS, 9.9months vs. LS, 12.1months, p = 0.003; median overall survival (OS): RS, 49.7months vs. LS, 88.8months, p = 0.039]. RS tumors were a negative prognostic factor for DFS [hazard ratio (HR) 1.878, p = 0.001] and OS (HR 1.660, p = 0.060). RS KRAS-mt and LS KRAS wild-type (KRAS-wt) tumors had the worst and best oncological outcomes, respectively. Tumor location has a prognostic impact in patients who underwent SCIS for CRLM, and RS KRAS-mt tumors yielded the worst oncological outcome. These results may allow for more tailored multimodality treatments.

Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer: results from two randomized first-line panitumumab studies

Tumor Location Is Associated With the Prevalence of Braf And Pik3ca Mutations in Patients with Wild-Type Ras Colorectal Cancer: A Prospective Multi-Center Cohort Study in Japan

711 Background: Left- and right-sided colon cancers are significantly different in epidemiologic, clinicopathological and molecular characteristics. However, the impact of primary tumor location in mCRC treated biological targeted agent in combination with chemotherapy is unclear. We therefore investigated the prognostic and predictive impact of primary tumor location in mCRC. Methods: Single-institution, retrospective, case-control study was reviewed. A total of 96 patients with mCRC were enrolled between January 2011 and December 2015. We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy plus cetuximab or bevacizumab. The impact of primary tumor location for cetuximab and bevacizumab groups was analyzed, respectively. Left-sided primary tumors were defined as tumors from rectum to splenic flexure, while right-sided primary tumors were defined as tumors from cecum to the distal part of the transverse colon. Results: 68 patients presented left-sided tumors and 28 patients right-sided primary tumors. In the cetuximab group, left-sided tumors were significantly superior to right-sided tumors in terms of the progression-free survival (PFS) and Overall survival (OS) (PFS, left vs right, 18.3 vs 6.8 M, p = 0.0415; OS, 50.6 vs10.5 M, p = 0.0004). Likewise, in the bevacizumab group, OS showed differences between the left- and right-sided tumors (PFS, left vs right, 11.6 vs 7.3 M, p = 0.1904; OS, 25.7 vs 16.2 M, p = 0.0389). In left-sided tumors, cetuximab group were significantly superior to bevacizumab group in terms of the OS (PFS, cetuximab vs bevacizumab, 18.0 vs 11.6 M, p = 0.1088; OS, 50.6 vs 25.7 m p = 0.0354). Conversely, in right-sided, the survival times showed no differences between cetuximab- and bevacizumab group (PFS, cetuximab vs bevacizumab, 6.8 vs 7.3 M, p = 0.7816; OS, 10.5 vs 16.2 M, p = 0.1088). Conclusions: Our study demonstrates that primary tumor location is an important prognostic factor in previously untreated mCRC. Furthermore, left-sided primary tumor location might be a strong predictor of PFS and OS in cetuximab therapy.

BackgroundPrevious studies have demonstrated that left-sided tumors have better prognoses than right-sided tumors in RAS wild-type mCRC (metastatic colorectal cancer) patients, while anti-EGFR mAbs appear to have no advantage compared with bevacizumab for right-sided tumors in these patients. Nevertheless, it remains unclear whether primary tumor location affects patients’ options for potentially curative resection.MethodsPubMed, the Cochrane Library, Embase, ASCO, and ESMO conference abstracts were searched. The inclusion criteria were RCT (randomized controlled trials) studies that evaluated the efficacy of anti-EGFR mAbs based on primary tumor location. The outcomes included ORR, ETS, and DpR. ORs for ORR were calculated with 95% confidence intervals by Comprehensive Meta-Analysis, version 2.0.ResultNine studies including nine RCTs were analyzed. Regardless of left- or right-sided tumors, the ORRs for anti-EGFR mAb (left-sided: 80.2%, 95% CI, 47–95%; I2 = 76.9%; right-sided: 46.1%, 95% CI, 39.4–53.0%; I2 = 18.9%) were both higher than the control arm including chemotherapy with or without bevacizumab. The ORs for anti-EGFR mAbs have a significant benefit compared with chemotherapy with or without bevacizumab in left-sided tumors (OR = 2.19, 95% CI, 1.41–3.38; P < 0.001). For right-sided tumors, anti-EGFR mAbs still significantly improved the ORR compared with chemotherapy alone (OR = 1.75, 95% CI, 1.05–2.90; P = 0.03), and the OR numerically favored the anti-EGFR mAbs compared with bevacizumab (OR = 1.281, 95% CI, 0.77–2.12; P = 0.335). The data of ETS and DpR from three RCTs also favored the EGFR antibody irrespective of tumor location. Resection data on differentiating tumor locations is inconclusive. For right-sided tumors, it should be noted that median PFS and OS were comparable for patients who achieved ETS in both treatment arms.ConclusionsAnti-EGFR mAbs have advantages in the tumor shrinkage regardless of left- or right-sided tumors, which is important for conversion therapy. For right-sided tumors, anti-EGFR mAbs should remain the first choice for potentially curative resection in RAS wild-type mCRC patients. ETS may represent a subgroup of patients with right-sided tumors who might benefit from the anti-EGFR mAb.

(1) Background: There is an abundance of literature available on predictors of survival for patients with colorectal liver metastases (CRLM) but minimal information available on the relationship between the primary tumor location and CRLM survival. The studies that focus on the primary tumor location and CRLM survival exhibit a great deal of controversy and inconsistency with regard to their results (some studies show statistically significant connections between the primary tumor location and prognosis versus other studies that find no significant relationship between these two factors). Furthermore, the majority of these studies have been conducted in the West and have studied more diverse and heterogenous populations, which may be a contributing factor to the conflicting results. (2) Methods: We included patients who underwent liver resection for CRLM between December 2004 and January 2019 at two university-affiliated medical centers in Israel: Carmel Medical Center (Haifa) and Rabin Medical Center (Petach Tikvah). Primary tumors located from the cecum up to and including the splenic flexure were labeled as right-sided primary tumors, whereas tumors located from the splenic flexure down to the anal verge were labeled as left-sided primary tumors. (3) Results: We identified a total of 501 patients. Of these patients, 225 had right-sided primary tumors and 276 had left-sided primary tumors. Patients with right-sided tumors were significantly older at the time of liver surgery compared to those with left-sided tumors (66.1 + 12.7 vs. 62 + 13.1, p = 0.002). Patients with left-sided tumors had slightly better overall survival rates than those with right-sided tumors. However, the differences were not statistically significant (57 vs. 50 months, p = 0.37 after liver surgery). (4) Conclusions: The primary tumor location does not significantly affect patient survival after liver resection for colorectal liver metastasis in the Mediterranean population.

Tumor Sidedness, Recurrence, and Survival After Curative Resection of Localized Colon Cancer

523 Background: Recent evidence indicate that the anatomic location of primary tumors across the colon correlate with survival in the metastatic setting, whereas left-sided tumors may exhibit superior survival compared with right-sided. The Oncotype DX, a 12-gene colon cancer assay, is a clinically validated predictor of recurrence risk in stage II colorectal cancer (CRC) patients. Previous studies had indicated that CDX2-negative colorectal tumors are often associated with several adverse prognostic variables. Recently, it has been shown that without adjuvant chemotherapy, CDX2-negative stage II CRC tumors were associated with a lower rate of disease-free survival than CDX2-positive stage II CRC tumors. We aimed to evaluate whether these validated two prognostic biomarkers may correlate with primary tumor location, and whether tumor location may reflect differential prognosis in stage II CRC. Methods: We retrospectively analyzed a cohort of patients with T3 mismatch repair proficient (MMR-P) stage II CRC for whom 12-gene assay was performed (between 1/2011-2/2016). Pathological report was reviewed for exact primary tumor location and CDX2 immunostaining. Recurrence score (RS) and CDX2 expression were correlated with primary tumor location. Results: The analysis included 1087 patients with MMR-P stage II CRC (median age 69 years (range 29-93)). Tumor distribution across the colon was as follows: 46% (n = 500) were right-sided (cecum, ascending colon, transverse colon) and 54% (n = 587) were left-sided (splenic flexure, descending colon, sigmoid colon and rectum). Recurrence score was higher in right-sided tumors compared with left-sided tumors (p = 0.01). The RS gradually decreased across the colon (cecum - highest score, sigmoid-lowest score, p = 0.04). Right-sided tumors exhibited more CDX2-negative tumors compared with left-sided tumors (p = 0.07). Conclusions: Our study indicate that right-sided colorectal tumors may display worse prognosis compared with left-sided tumors in MMR-P stage II CRC. Primary tumor location may serve as a prognostic factor that should be accounted for recurrence risk assessment and consideration of adjuvant treatment.