Tumor Sidedness Research Articles

Abstract 6389: An exosome-based liquid biopsy powered by machine learning predicts progression-free and overall survival before commencing first-line EGFR inhibitors for metastatic colorectal cancer: The EXONERATE Study

Abstract Introduction: We developed a liquid biopsy assay based on exosomal and cell-free microRNA (exo- and cf-miRNA, respectively) for patients with chemotherapy-naïve, metastatic, unresectable, RAS and BRAF wild-type colorectal cancer (mCRC), to predict progression-free (PFS) and overall survival (OS) before the commencement of first-line treatment with EGFR inhibitors (EXONERATE). Methods: Patients with mCRC were consecutively enrolled in two open-label, nationwide clinical trials and received first-line cetuximab or panitumumab. Cf- and exo-miRNA expression was quantified using RT-qPCR in plasma samples obtained before exposure to EGFR inhibitors. The prespecified primary endpoint was 12-month PFS, hierarchically tested in left-sided mCRC, right-sided mCRC, and the entire cohort. As secondary endpoints, the EXONERATE status was correlated with PFS and OS hazard ratios (HR). Results: After excluding those with RAS/BRAF mutations and unavailable samples, the complete analysis dataset comprised 120 patients (94 with left-sided and 26 with right-sided mCRC; 87 received cetuximab and 33 panitumumab). As expected, right-sided mCRC patients showed inferior PFS and OS outcomes (HR 1.80 [CI95% = 1.13 - 2.80] and 1.80 [CI95% = 1.00 - 3.27], respectively). Genome-wide small RNA sequencing on 20 patient samples identified 12 cf- and 14 exo-miRNA candidates, then narrowed to 8 and 9 based on best performance. We employed machine learning algorithms to develop two liquid biopsy assays, one based on cf- and the other on exo-miRNAs, predicting 12mPFS with AUC values of 0.84 and 0.81, respectively. These were then combined to establish the EXONERATE assay for left-sided mCRC (AUC = 0.89), successfully validated in right-sided mCRC patients (AUC= 0.84). Among left-sided mCRC patients, 35% were EXONERATE-high, exhibiting shorter median PFS (mPFS = 9.5 vs. 18.5 months, p<.001) and a higher mortality rate (HR 0.21 [CI95% = 0.10 - 0.42]). In the right-sided mCRC cohort, the EXONERATE-high panel robustly identified patients with shorter mPFS (8.6 vs. 23.7 months, p=.0042) and predicted 12mPFS with high accuracy (sensitivity 100%, NPV 81%, PPV 100%). Although in univariate analysis both the EXONERATE panel and sidedness showed associations with PFS and OS, in multivariate analysis only the EXONERATE panel could fully account for the differences in PFS and OS (HR 0.22 and HR 0.19, respectively). Hence, we employed the EXONERATE panel agnostically of tumor sidedness and observed that EXONERATE-high patients demonstrated poorer survival outcomes in mPFS (8.9 vs. 19.6 months, HR 0.27 [CI95% = 0.17 - 0.41]) and mOS (22.6 vs. >60 months, HR 0.18 [CI95% = 0.09 - 0.37]). Conclusion: The EXONERATE panel robustly predicted PFS and OS outcomes in both right- and left-sided mCRC patients before receiving either EGFR inhibitor. Citation Format: Xu Caiming, Alessandro Mannucci, Roy Souvick, Esposito Francis, Oliveres Helena, Alonso-Orduña Vicente, Escudero Pilar, Fernández-Martos Carlos, Salud Antonieta, Gallego Javier, Rodriguez Jose Ramon, Martín-Richard Marta M. Marta, Fernández-Plana Julen, Manzano Hermini, Aparicio Jorge, Feliu Jaime, Maurel Joan, Ajay Goel. An exosome-based liquid biopsy powered by machine learning predicts progression-free and overall survival before commencing first-line EGFR inhibitors for metastatic colorectal cancer: The EXONERATE Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6389.

Abstract 925: Continuing anti-EGFR treatment prolonged survival in mCRC patients receiving conversion liver resection

Abstract Introduction: Anti-EGFR monoclonal antibody plus doublet chemotherapy is the mainstay of first-line treatment of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. Some of these patients might undergo secondary resection. However, there is no standardized suggestion on whether colorectal cancer liver metastasis patients should keep target therapy after secondary resection. NCCN guidelines suggest chemotherapy only in patients receiving primary liver resection. Whether we could spare the use of target therapy after secondary resection is the main aim of our study. Methods: Using Taiwan's National Health Insurance Research Database, we established a cohort of KRAS wild-type mCRC patients treated with first-line anti-EGFR therapy plus doublet chemotherapy between 2013 and 2018. Secondary surgery was defined as either resection of liver metastases or radiofrequency ablation. Results: 5694 stage IV mCRC patients received anti-EGFR MAb plus doublet chemotherapy as a first-line treatment between 2013 and 2018. 174 patients were enrolled in the final analysis, with 153 continuing anti-EGFR MAb after secondary resection and 21 patients without anti-EGFR MAb. Compared with those who without anti-EGFR therapy after secondary resection, patients who continued anti-EGFR MAb exhibited significantly longer overall survival (OS; median, 43.8 vs. 31.9 months, p = 0.031) but not in time to treatment failure (TTF; median, 22.2 vs. 26.6 months, p = 0.841). The OS benefits of continuing anti-EGFR MAb remained regardless of left-sided or right-sided primary tumors (40.9 vs. 43.0 months, p = 0.980). The patient cohort from 2016 to 2018 showed more prolonged survival than from 2012 to 2015 (not reached vs. 40.450, p = 0.0305). TTF has no statistical difference when considering patient cohort or primary tumor location. In multivariate analyses, continuing first-line anti-EGFR MAb therapy after secondary resection remained an independent predictor of longer OS. Conclusion: For mCRC patients who received secondary resection after first-line anti-EGFR and doublet chemotherapy, continuing anti-EGFR MAb after resection was associated with significantly longer OS regardless of primary tumor sidedness. Citation Format: Yao-Yu Hsieh, Chin-Wen Tsai, T-CARE Group, Yi-Hsieh Liang. Continuing anti-EGFR treatment prolonged survival in mCRC patients receiving conversion liver resection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 925.

Fluoropyrimidine type, patient age, tumour sidedness and mutation status as determinants of benefit in patients with metastatic colorectal cancer treated with EGFR monoclonal antibodies: individual patient data pooled analysis of randomised trials from the ARCAD database

BackgroundKRAS mutations in metastatic colorectal cancer (mCRC) are used as predictive biomarkers to select therapy with EGFR monoclonal antibodies (mAbs). Other factors may be significant determinants of benefit.MethodsIndividual patient data from randomised trials with a head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or best supportive care) in mCRC, across all lines of therapy, were pooled. Overall survival (OS) and progression-free survival (PFS) were compared between groups. Treatment effects within the predefined KRAS biomarker subsets were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). EGFR mAb efficacy was measured within the KRAS wild-type subgroup according to BRAF and NRAS mutation status. In both KRAS wild-type and mutant subgroups, additional factors that could impact EGFR mAb efficacy were explored including the type of chemotherapy, line of therapy, age, sex, tumour sidedness and site of metastasis.Results5675 patients from 8 studies were included, all with known mCRC KRAS mutation status. OS (HRadj 0.90, 95% CI 0.84–0.98, p = 0.01) and PFS benefit (HRadj 0.73, 95% CI 0.68–0.79, p < 0.001) from EGFR mAbs was observed in the KRAS wild-type group. PFS benefit was seen in patients treated with fluorouracil (HRadj 0.75, 95% CI 0.68–0.82) but not with capecitabine-containing regimens (HRadj 1.04, 95% CI 0.86–1.26) (pinteraction = 0.002). Sidedness also interacted with EGFR mAb efficacy, with survival benefit restricted to left-sided disease (pinteraction = 0.038). PFS benefits differed according to age, with benefits greater in those under 70 (pinteraction = 0.001). The survival benefit was not demonstrated in those patients with mutations found in the KRAS, NRAS or BRAF genes. The presence of liver metastases interacted with EGFR mAb efficacy in patients with KRAS mutant mCRC (pinteraction = 0.004).ConclusionThe benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases.

Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer.

Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62-0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83-1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795 .

Association of KRAS G12C Status with Age at Onset of Metastatic Colorectal Cancer.

The association of age at the onset of CRC and the prevalence of a KRAS G12C mutation is unclear. A retrospective, multicenter study evaluating metastatic CRC patients from January 2019 to July 2023, treated at the Oncoclinicas units and tested for tissue based KRAS/NRAS and BRAF mutations in a centralized genomics lab. A mismatch repair (MMR) status was retrieved from different labs and electronic medical records, as were patient demographics (age, gender) and tumor sidedness. The chi-square test was used to examine the association between clinical and molecular variables, with p value < 0.05 being statistically significant. A total of 858 cases were included. The median age was 63.7 years (range 22-95) and 17.4% were less than 50 years old at the diagnosis of metastatic CRC. Male patients represented 50.3% of the population. The sidedness distribution was as follows: left side 59.2%, right side 36.8% and not specified 4%. The prevalence of the KRAS mutation was 49.4% and the NRAS mutation was 3.9%. Among KRAS mutated tumors, the most common variants were G12V (27.6%) and G12D (23.5%), while KRAS G12C was less frequent (6.4%), which represented 3.1% of the overall population. The BRAF mutant cases were 7.3% and most commonly V600E. Only five (<1%) non-V600E mutations were detected. MSI-high or dMMR was present in 14 cases (1.6%). In the age-stratified analysis, left-sidedness (p < 0.001) and a KRAS G12C mutation (p = 0.046) were associated with a younger age (<50 years). In the sidedness-stratified analysis, a BRAF mutation (p = 0.001) and MSI-high/dMMR status (p = 0.009) were more common in right-sided tumors. Our data suggest that KRAS G12C mutations are more frequent in early-onset metastatic CRC. To the best of our knowledge, this is the largest cohort in the Latin American population with metastatic CRC reporting RAS, BRAF and MSI/MMR status.

Tumor genomics and sidedness to predict outcomes in metastatic colorectal cancer (mCRC).

207 Background: Tumor sidedness is a prognostic factor and predictive parameter for EGFR monoclonal antibody (mAb) treatment in mCRC. Sidedness is believed to be a surrogate for genomic differences. This study aimed to evaluate genomics vs. tumor sidedness in anticipating outcomes in mCRC. Methods: We included patients (pts) with microsatellite stable mCRC tested by Foundation Medicine tissue comprehensive genomic profiling assay. Patient data was obtained by the US-based de-identified Flatiron Health-Foundation Medicine real-world clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (1/2011–3/2023). Genomic alterations (GA) in 324 genes were compared between right and left side tumors using Fisher’s exact test, adjusted for multiple comparisons. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were compared by Cox proportional hazard models adjusted for prognostic features in pts receiving 1st line chemotherapy (chemo) + EGFR mAb or bevacizumab (bev). Multivariable analyses including prognostic features, sidedness and GA were performed. Comparisons of the explanatory power of genomics vs. sidedness were performed by the likelihood ratio test (LRT). Results: 3845mCRC pts (2584 left and 1261 right) were included. GA in APC, TP53, ARID1A, and FBXW7 were more prevalent in left side, while GA in BRAF, KRAS, AMER1A, PIK3CA, RNF43, BCOR, PTEN, SMAD4, MAP2K1, and BCOR in right side. 2109 pts received chemo + EGFR mAb or bev. Multivariable analyses identified BRAF, KRAS, MAP2K1, and APC as independently associated with outcomes. Pts were classified as having GA in RAS pathway (RASalt: KRAS/NRAS, BRAF, or MAP2K1), APC (APCalt), both RAS pathway and APC (APC/RASalt), and none. RASalt group had less favorable outcomes while APCalt group had more favorable outcomes, regardless of treatment received and sidedness. LRT indicated that when genomics was added to the sidedness evaluation, there was an improvement in outcome prediction (p&lt;0.001), but not when sidedness was added to genomics. Conclusions: Tumor genomics better explains differences in outcomes than sidedness in 1st line treatment in mCRC. [Table: see text]

High-resolution transcriptional signature to predict survival benefit in colorectal cancer (CRC) treated with EGFR inhibitors (EGFRi) independent of RAS/BRAF mutation status or tumor sidedness.

203 Background: Cetuximab (CTX) and Panitumumab (PMB) therapies directed at EGFR have been restricted to left-sided CRC harboring wild-type KRAS ( KRASWT), limiting their utility. Approximately 50% of mCRC fail to respond to EGFRi, thus identification of predictive biomarkers is an unmet need. Here we evaluate a CTX sensitivity score (CTX-S) that we previously reported (Yang M. et al., 2019), in a large, real-world population of RAS/BRAF mutant vs wild-type and in right- vs left-sided tumors. Methods: CTX/PMB-treated CRC specimens (n=1124) with clinical outcomes, NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) were tested at Caris Life Sciences (Phoenix, AZ). 1097 specimens were MSS as determined by IHC of MMR proteins and/or NGS. Association of CTX-S with RAS/BRAF mutation and tumor sidedness was performed in MSS tumors. Tumors with likely pathogenic mutations in KRAS, NRAS or BRAF were considered as RASMUT /BRAFMUT, or RASWT /BRAFWT if no mutation was detected for each gene. Samples were stratified based on CTX-S quintiles. Survival on EGFRi was calculated from the initiation of EGFRi to last contact using Kaplan-Meir method. Results: Higher CTX-S quintiles were significantly associated with longer survival on EGFRi in RAS/BRAF wild-type as well as -mutant subpopulations. Similar results were seen in left- vs. right-sided tumors (Table). Higher CTX-S quintiles were associated with a survival benefit in all CMS classes but CMS2; however, the vast majority of CMS2 tumors (460/467) were among the top 3 CTX-S quintiles. As the median survival among the top 3 quintiles was ~2-fold higher than the bottom 2 quintiles, we used stratification by the 40th percentile for the genomic analysis. CTX-S &gt;40th percentile was associated with an increased prevalence in APC (91 vs 47%) and TP53 (93 vs 76%) mutations and decreased prevalence in BRAF (6 vs 32%), SMAD4 (8 vs 19%), RNF43 (1 vs 12%) and ATM (2 vs 5%) mutations (all q&lt;0.05). Conclusions: Our data suggest that CTX-S may predict longer survival on EGFRi, surprisingly independent of RAS/BRAF mutation status as well as tumor sidedness. Patients with high CTX-S had increased prevalence of CMS2 and harbored more APC and TP53 mutations. A strong EGFRi biomarker would likely expand the utility of EGFRi to right-sided tumors and possibly to RASMUT tumors. Further validation of these biomarkers in a prospective clinical trial is warranted and could change our current standard of care for CRC.[Table: see text]

Impact of acquired RAS, BRAF and PIK3CA mutation at 8 weeks on the efficacy of anti-EGFR monoclonal antibodies in metastatic colorectal cancer.

193 Background: Recent studies indicate that the emergence of RAS/BRAF mutation sometimes occurs during initial anti-EGFR monoclonal antibody (mAb)-based treatment in metastatic colorectal cancer (mCRC). However, limited data was available regarding the timing and frequency of the emergence of RAS/BRAF mutation, and its impact on the efficacy of anti-EGFR mAb. With this background, we conducted an observational study to monitor RAS, BRAF, and PIK3CA mutation status by ctDNA in RAS/BRAF wt mCRC. Methods: RAS-trace is a pilot study to monitor RAS, BRAF, and PIK3CA mutation status by ctDNA, using NGS-based Plasma-Safe-SeqS technology for RAS/BRAF wt (diagnosed from tissue samples) mCRC treated with anti-EGFR mAb as a first-line chemotherapy. ctDNA- RAS/BRAF/PIK3CA status evaluated at baseline, 8, 12, 16, 20, 24, 36, 48 weeks and disease progression. The primary endpoint was the time to the acquired RAS mutations. The results of ctDNA at baseline and 8 weeks are presented. Results: Forty-two patients were enrolled, and 40 and 39 were used in the analysis of ctDNA at baseline and 8 weeks, respectively. All patients received mFOLFOX6 plus cetuximab (N=32) or panitumumab (N=8). At baseline, RAS, BRAF, and PIK3CA mutations were detected in 3, 3, and 1 of the 40 patients, respectively. One patient had both KRAS and BRAF mutations. Baseline ctDNA mutations were not associated with the presence of liver metastases, tumor sidedness, early tumor shrinkage, depth of response or skin rash ≥Grade 2. At 8 weeks, RAS, BRAF, and PIK3CA mutations were detected in 3, 2, and 0 among the 39 patients, respectively. One patient had both KRAS and BRAF mutations. ctDNA mutations at 8 weeks were not associated with the presence of liver metastases, tumor sidedness, or early tumor shrinkage, however, they were associated with depth of response and had a tendency of skin rashes ≥ Grade 2 (Table). Conclusions: Emergence of RAS/BRAF/PIK3CA mutations at 8 weeks may be related to the response of anti-EGFR mAb. The association of ctDNA status with survival outcomes will be presented in 2025. Clinical trial information: jRCT1050210160 . [Table: see text]

Real-world data of TAS-102 therapy in refractory metastatic colorectal cancer (mCRC): The experience of the University Hospital of Montreal (CHUM).

137 Background: Colorectal cancer poses a substantial healthcare burden due to its elevated rates of diagnosis and mortality. Managing refractory metastatic cases remains a challenge in our practice due to the paucity of therapeutic options. Treatment with Trifluridine-Tipiracil (TAS-102) prolonged overall survival among patients (pts) with mCRC. This study investigates the efficacy of TAS-102 therapy in this patient population and explores various prognostic factors influencing clinical outcomes. Methods: We retrospectively reviewed the data of 53 patients with refractory mCRC treated with at least 1 cycle of TAS-102 at CHUM between March 2018 and January 2023. Multivariate and univariate analyses were employed to evaluate the impact of age, number of prior treatments, presence of KRAS mutation, gender, tumor origin, and Eastern Cooperative Oncology Group (ECOG) performance status on progression-free survival (PFS) and overall survival (OS). Survival analysis was conducted using the Kaplan-Meier method, and Cox regression analysis assessed prognostic factors. Results: The median age was 61 years (23-82), and 27 pts (50.9%) were females. Twenty-two pts (41.5%) had their primary tumor located in the left colon, 17 pts (32.1%) had right-sided tumors, and 14 pts (26.4%) with rectal tumors. 52% of pts received TAS-102 after 2 lines of therapy and 43% beyond third line. The performance status was: ECOG 0/1 in 46 pts (86.8%), and ECOG 2 in 7 pts (13.2%). In our refractory mCRC pts, median PFS was 3 months and median OS 7 months. Univariate analysis demonstrated no significant differences in PFS or OS based on patient sex, KRAS mutation status, tumor sidedness, or the number of prior treatments. In univariate and multivariate analysis ECOG 0/1 pts compared to ECOG 2 pts had a significant improvement in both PFS (HR = 0.33; p = 0.0511) and OS (HR = 0.21; p = 0.0086). Conclusions: In our real-world experience, clinical outcomes were comparable to the findings from the RECOURSE trial, suggesting improved PFS and OS with TAS-102 in heavily pre-treated mCRC patients. ECOG performance status remains a significant prognostic factor and underscores its importance in treatment decisions for this patient population.

APC as a high-utility mutational biomarker that may identify subpopulations of patients with mutant RAS/BRAF and right-sided colorectal cancer (CRC) who derive benefit from EGFR inhibitors (EGFRi).

56 Background: Although, EGFRi including Cetuximab (CTX) and Panitumumab (PMB) is restricted to KRAS wild-type ( KRASWT) tumors, ~50% of patients still fail to respond to therapy. Using a transcriptional signature as a surrogate for cetuximab response, we previously reported that mutations in APC ( APCMUT) and TP53( TP53MUT) might predict cetuximab sensitivity, particularly in RASWT tumors (Yang M. et al., 2019). The current study aimed to use real world EGFRi treatment and survival data to independently validate these mutations as predictive, high-utility biomarkers of benefit to specific subpopulations of CRC. Methods: CTX/PMB-treated CRC specimens (n=1846) with clinical outcomes and NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) were tested at Caris Life Sciences (Phoenix, AZ). All analyses were performed in MSS tumors, determined by immunohistochemistry of MMR proteins and/or NGS. Tumors with likely pathogenic mutations in KRAS, NRAS or BRAF were considered as RASMUT /BRAFMUT, or RASWT /BRAFWT if no mutation was detected for each gene. Survival on EGFRi was calculated from the initiation of EGFRi to last contact (E-OS) or last dose of EGFRi (E-TOT) using Kaplan-Meir method. Results: While concurrent TP53MUT/ APCMUT were associated with improved E-OS compared to TP53MUT alone (hazard ratio [HR]=0.565, p&lt;0.00001), APCMUT tumors were associated with improved E-OS independent of TP53 mutation status. Compared to APCWT, APCMUT were associated with longer E-OS in RAS/BRAF mutant as well as wild-type subpopulations and in left- and right- sided tumors. Furthermore, APCMUT were associated with improved E-TOT in PMB treated tumors independent of RAS/BRAF mutation status and tumor sidedness (HR range:0.59-0.75, all p&lt;0.05). Conclusions: Our data suggests that the simple application of a high-utility mutational biomarker ( APC), may increase the eligibility for successful EGFRi therapy in a substantial subpopulation of RAS/BRAF mt patients as well as right-sided CRC, potentially altering the standard of care. Further validation of this biomarker in a prospective clinical trial is warranted. [Table: see text]

Refining first-line treatment decision in RAS wildtype (RAS-WT) metastatic colorectal cancer (mCRC) by combining clinical biomarkers: Results of the randomized phase 3 trial FIRE-3 (AIO KRK0306).

13 Background: Optimal patient selection for first-line treatment targeting epithelial growth factor receptor (EGFR) in RAS-WT mCRC is based on primary tumor sidedness (PTS) with anti-EGFR being the preferred option for patients with left-sided mCRC (LC). Right-sided mCRCs (RC) are preferentially treated in combination with bevacizumab targeting vascular endothelial growth factor (VEGF). Here, improvement in patient selection was evaluated by combining clinical biomarkers beyond PTS using the randomized phase III trial FIRE-3. Methods: FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in patients with RAS-WT mCRC. Besides PTS, further clinical biomarkers were evaluated in pairwise combinations using Cox regression models and model-based recursive partitioning with Weibull models to predict treatment benefit of either treatment arm regarding overall survival (OS): age, sex, liver-limited disease status (LLD) and baseline carcinoembryonic antigen serum level (CEA). The resulting P-values of second-order interactions were adjusted using Holm-Bonferroni correction. The model with the best test statistics and P-value was chosen for further evaluations. Results: In 400 patients with RAS-WT mCRC, a model combining PTS and LLD status best predicted treatment outcome of either treatment arm (c-index = 0.603, p=0.005). Here, a significant survival benefit of FOLFIRI/Cet over FOLFIRI/Bev was evident in patients with LC/non-LLD (HR 0.62, p=0.02) compared to LC/LLD (HR 0.83, p=0.40). In patients with RC, FOLFIRI/Bev was significantly associated with increased OS compared to FOLFIRI/Cet when patients suffered from non-LLD (HR 2.09, p=0.010). However, patients with RC/LLD rather had a benefit from FOLFIRI/Cet compared to FOLFIRI/Bev (HR 0.59, p=0.218). Conclusions: Combining clinical biomarkers PTS and LLD status might improve optimal patient selection for targeted first-line treatment in RAS-WT mCRC. Validation in further data sets is warranted. Clinical trial information: NCT00433927 .

The Impact of adverse histopathological factors and genetic markers with tumour sidedness on the outcome of standardized surgical management of Colon Cancer: A single centre experience-KSA.

The Impact of adverse histopathological factors and genetic markers with tumour sidedness on the outcome of standardized surgical management of Colon Cancer: A single centre experience-KSA.

Primary tumor sidedness is not prognostic factor in resectable colorectal cancer liver metastasis: a retrospective observational cohort study.

Right-sided tumors have been reported to have a poorer survival rate than left-sided tumors; however, there remains debate regarding whether sidedness is an independent prognostic factor in colorectal cancer liver metastasis (CRLM). This study aimed to assess the impact of sidedness on prognosis in resectable CRLM and to identify prognostic factors. Patients who underwent liver resection for CRLM at Samsung Medical Center from January 2008 to December 2021 were included in the investigation. Overall survival (OS) and progression-free survival (PFS) were analyzed, and prognostic factors were identified. A total of 497 patients were included in the study, with 106 on the right side and 391 on the left side. The right-sided group had a higher percentage of synchronous tumors (90.6% vs. 80.3%, P = 0.020). In survival analysis, the right side showed lower 5-year OS (49.7% vs. 54.2, P = 0.305) and 5-year PFS (57.1% vs. 60.2%, P = 0.271), but the differences were not statistically significant. In the analysis of prognostic factors, synchronous tumor (odds ratio [OR], 5.01; P < 0.001), CEA (OR, 1.46; P = 0.016), and maximum tumor size of hepatic metastasis (OR, 1.09; P = 0.026) were associated with OS. In resectable CRLM, there was no difference in prognosis based on sidedness. CEA level, synchronous tumor, and maximum tumor size of hepatic metastasis were identified as prognostic factors.

Unraveling the role of tumor sidedness in prognosis of stage II colon cancer.

Stage II colon cancer has varying risks for metastasis, and treatment strategies depend on molecular and clinicopathological features. While tumor-sidedness is a well-accepted prognostic factor for stage III/IV colon cancer, its role in stage II is controversial. Understanding its effect in stage II is crucial for improving treatment strategies. We analyzed clinical and follow-up data of colon cancer from the Surveillance, Epidemiology, and End Results database (2004-2017). Patients were divided into a primary study cohort (2010-2017) and a validation cohort (2004-2009). The baseline characteristics between right-sided colon cancer (RCC) and left-sided colon cancer (LCC) groups were compared. Moreover, the effect of tumor size on cancer-specific survival (CSS) was evaluated using Kaplan-Meier analysis. The study involved 87,355 patients in the study cohort and 65,858 in the validation cohort. Of the study cohort, 52.3% were diagnosed with RCC. The median age was 64 years old, with 48.5% females and 76.8% of white people. In addition, stage II RCC showed better CSS compared with LCC (5-year CSS 88.0% vs 85.5%, P < 0.001), while stage III/IV RCC demonstrated poorer outcomes. Multivariate Cox regression analysis identified that the right-sidedness was a positive prognostic factor in stages I/II but negative in stages III (HR 1.10, P < 0.001) and IV (HR 1.26, P < 0.001). Chemotherapy rates decreased in RCC, particularly in stage II (RCC vs LCC: 16.2% vs 28.5%, P < 0.001). Subgroup analysis, stratified by T3/T4 stages and chemotherapy status, further highlighted better survival outcomes in RCC. RCC is associated with a significantly better prognosis in stage II. The importance of considering tumor-sidedness in clinical decision-making and the design of future clinical trials should be emphasized.

Sustained Disease Control in Immune Checkpoint Blockade Responders with Microsatellite Instability-high Colorectal Cancer after Treatment Termination.

Outcomes for patients with MSI-H colorectal cancer stopping immunotherapy after disease control remain unknown. Sixty-four patients with MSI-H colorectal cancer from our institution stopping treatment for sustained benefit or toxicity were retrospectively assessed. After median follow up of 22 months and median immunotherapy exposure of 18 months, 88% patients remained without progression. All patients who recurred or progressed and were rechallenged with immunotherapy have continued to experience disease control.

Prognostic Impact of Primary Tumor Sidedness in Stage III Colorectal Cancer: Real-World Evidence from a Brazilian Cohort

BackgroundPrimary tumor sidedness (PTS) is an independent prognostic factor in patients with metastatic colorectal cancer (CRC), with a worse prognosis for right-sided tumors. There are limited data on the prognostic impact of PTS in stage III CRC. The main objective of this study was to analyze the prognostic impact of PTS in stage III CRC. Patients and MethodsA retrospective and uni-institutional cohort study was performed in an oncology reference center. Patients with stage III CRC treated with a 5-fluorouracil and oxaliplatin-based chemotherapy regimen (mFLOX regimen) from October 2007 to February 2013 were included. The primary outcome was the probability of overall survival (OS) at 5 years stratified by PTS. Secondary outcomes were the probability of disease-free survival (DFS) at 5 years and an analysis of the prognostic impact of clinical and molecular biomarkers. Kaplan‒Meier curves were used, and Cox models were used to evaluate prognostic factors associated with OS and DFS. ResultsOverall, 265 patients were evaluated. Transverse colon tumors, multicentric tumors, and undetermined primary subsites were excluded, resulting in 234 patients classified according to PTS: 95 with right sidedness (40.6%) and 139 with left sidedness (59.4%). The median follow-up time was 66 months [interquartile range (IQR): 39-81]. The 5-year OS probabilities for right-sided and left-sided tumors were 67% (95% CI: 58%-77%) and 82% (75%-89%), respectively [hazard ratio (HR): 2.02, 95% CI: 1.18-3.46; P = .010]. The 5-year probabilities of DFS for right-sided and left-sided tumors were 58% (49%-69%) and 65% (58%-74%), respectively (HR: 1.29, 0.84-1.97; P = 0.248). ConclusionThese data suggest that there may be a worse prognosis (inferior OS at 5 years) for resected right-sided stage III CRC patients treated in the real world. However, these data need to be confirmed by prospective studies with a larger number of participants.

KRAS Sequence Variation as Prognostic Marker in Patients With Young- vs Late-Onset Colorectal Cancer

The understanding of the association between KRAS sequence variation status and clinical outcomes in colorectal cancer (CRC) has evolved over time. To characterize the association of age at onset, tumor sidedness, and KRAS sequence variation with survival among patients diagnosed with CRC. This cross-sectional study used data extracted from the Surveillance, Epidemiology, and End Results database. Patients diagnosed with adenocarcinoma of the colon or rectum from 2010 through 2015 were included and were classified as having young-onset (YO) cancer if diagnosed between ages 20 to 49 years and late-onset (LO) cancer if diagnosed at age 50 years or older. Data were analyzed from April 2021 through August 2023. CRC cause-specific survival (CSS) was summarized using Fine and Gray cumulative incidence and Kaplan-Meier curves. Estimation of subdistribution hazard ratios (sHRs) for the association of KRAS status, age at onset, and tumor location with CRC CSS was conducted using the Fine and Gray competing risk model. Cox proportional hazards regression was used to estimate and compare HRs. Among 21 661 patients with KRAS sequence variation status (mean [SD] age at diagnosis, 62.50 [13.78] years; 9784 females [45.2%]), 3842 patients had YO CRC, including 1546 patients with KRAS variants, and 17 819 patients had LO CRC, including 7311 patients with KRAS variants. There was a significant difference in median CSS time between patients with variant vs wild-type KRAS (YO: 3.0 years [95% CI, 2.8-3.3 years] vs 3.5 years [95% CI, 3.3-3.9 years]; P = .02; LO: 2.5 years [95% CI, 2.4-2.7 years] vs 3.4 years [95% CI, 3.3-3.6 years]; P < .001). Tumors with variant compared with wild-type KRAS were associated with higher risk of CRC-related death (YO: sHR, 1.09 [95% CI, 1.01-1.18]; P = .03; LO: sHR, 1.06 [95% CI, 1.02-1.09]; P = .002). Among patients with YO cancer, mortality hazards increased by location, from right (sHR, 1.02 [95% CI, 0.88-1.17) to left (sHR, 1.15 [95% CI, 1.02-1.29) and rectum (sHR, 1.16 [95% CI, 0.99-1.36), but no trend by tumor location was seen for LO cancer. In this study of patients diagnosed with CRC, KRAS sequence variation was associated with increased mortality among patients with YO and LO tumors. In YO cancer, variant KRAS-associated mortality risk was higher in distal tumors than proximal tumors.

Prognostic impact of colorectal cancer patients with bone metastases: a single-center experience.

The incidence of bone metastasis (BM) in colorectal cancer (CRC) patients is low and the prognosis is poor. There is no clear conclusion on the risk factors affecting the survival of CRC patients with BM. The aim of this study was to investigate the factors that may affect the prognosis of CRC patients with BM. The clinical and pathological data of CRC patients with BM were retrospectively analyzed. The overall survival after BM diagnosis was estimated using the Kaplan-Meier method and Log-rank test, and a multivariable cox regression model was used to identify the prognostic factors of overall survival. This study included 178 CRC patients with BM, of whom 151 had left-sided CRC and 27 had right-sided colon cancer. 1124 CRC patients with BM from the SEER database were included to perform a sensitivity analysis of the primary outcome. Multivariate analysis showed that the N staging, site of BM, and primary tumor sidedness (PTS) were independent prognostic factors for CRC with BM. Among them, right-sided colon cancer patients with BM had a poorer prognosis. Sensitivity analyses showed that PTS was an independent prognostic factor in CRC patients with BM. Primary tumor sidedness and N stage may be potential prognostic markers for BM of CRC. The prognosis of N0 stage CRC with BM is better, while the prognosis of right-sided colon cancer is poor.

Negative hyperselection of elderly patients with RAS and BRAF wild-type metastatic colorectal cancer receiving initial panitumumab plus FOLFOX or 5-FU/LV

BackgroundUpfront anti-EGFR therapy represents the standard of care for patients with left-sided, MSS/pMMR, RAS and BRAF wild-type mCRC. Molecular ‘hyperselection’ may optimize EGFR inhibition by detecting additional resistance alterations. Materials and methodsWe used comprehensive genomic profiling on archival samples of elderly patients enrolled in the PANDA trial to detect: HER2 amplification/mutations; MET amplification; NTRK/ROS1/ALK/RET rearrangements; PIK3CA exon 20 mutations; PTEN alterations; AKT1 mutations; MAP2K1 mutations. We defined ‘Gene Altered’ (GA) patients whose tumour harboured at least one alteration, and ‘Hyperselected’ (HS) those without. Survival and tumour response outcomes were correlated to hyperselection status alone or combined with primary tumour sidedness or treatment arm. ResultsGenomic alterations were detected in 41/147 patients (27.9%). PFS, OS and ORR were inferior in GA versus HS (median PFS: 7.6 versus 12.8 months, HR = 2.08, 95% CI: 1.43–3.03, p < 0.001; median OS: 20.0 versus 29.5 months, HR = 1.82, 95% CI:1.23–2.69, p = 0.002; ORR: 51% versus 71%; OR = 0.43, 95% CI: 0.21–0.91, p = 0.02). In the multivariable models, the impact of hyperselection on PFS and OS was confirmed. Lower ORR was observed with 5-FU/LV/panitumumab in GA (40% versus 62%), but not in HS (70% versus 72%). GA was associated with worse survival and response regardless of primary tumour sidedness, whereas in the HS subgroup, right-and left sided tumours had similar outcomes. ConclusionsMolecular hyperselection and comprehensive genomic profiling have a potential usefulness in elderly patients with RAS/BRAF wild-type, pMMR/MSS mCRC, eligible for upfront EGFR inhibition.

607P Impact of primary tumour sidedness (PTS) on demographics, resectability, and outcome after metastasectomy +/- local ablative therapy (LAT), or systemic therapy in metastatic colorectal cancer patients (a RAXO substudy)

607P Impact of primary tumour sidedness (PTS) on demographics, resectability, and outcome after metastasectomy +/- local ablative therapy (LAT), or systemic therapy in metastatic colorectal cancer patients (a RAXO substudy)