Metastatic Colorectal Cancer Patients Research Articles

Evaluation of CSF1R as a potential prognostic biomarker in colorectal cancer (Alliance).

285 Background: Immune checkpoint inhibitors (ICIs) have shown limited efficacy in colorectal cancer (CRC) outside of mismatch repair (MMR) deficient/microsatellite instability-high (MSI-H) tumors. Most CRC cases are MMR proficient /microsatellite stable and demonstrate resistance to ICIs, attributed to the tumor microenvironment. Colony Stimulating Factor 1 Receptor (CSF1R), a regulator of tumor-associated macrophages, has emerged as a potential target due to its association with poor prognosis in CRC. Methods: Data from 433 metastatic CRC (mCRC) patients in the CALGB/SWOG 80405 trial were analyzed. CSF1R RNA was extracted from formalin-fixed, paraffin-embedded tumor samples and sequenced. Patients were divided into tertiles of CSF1R expression (high, medium, low). Progression-free survival (PFS) and overall survival (OS) were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. Subgroup analyses were conducted based on liver metastases, treatment type (Bevacizumab, Cetuximab, FOLFOX, FOLFIRI), and MSI status. Results: Low CSF1R expression (CSF1R-L) was associated with significantly better survival outcomes. Median PFS was 12.9 months for CSF1R-L, compared to 11.2 and 9.2 months for CSF1R-M and CSF1R-H (p = 0.003). Median OS was 35.8 months for CSF1R-L versus 32.5 and 24.4 months for CSF1R-M and CSF1R-H (p = 0.00086). Stratification by liver metastases showed that CSF1R-L remained a strong prognostic factor only in patients with liver metastases. There were no significant survival differences based on CSF1R expression in bevacizumab-treated patients. However, in cetuximab-treated patients, CSF1R-L tumors had significantly longer PFS (12.9 vs 8.8 months, p = 0.037) and OS (35.8 vs 21.4 months, p = 0.002) than CSF1R-H tumors. Similarly, in FOLFOX-treated patients, CSF1R-L tumors showed longer PFS and OS (p = 0.018 and p = 0.013, respectively), and in FOLFIRI-treated patients, OS was significantly longer for CSF1R-L tumors (42.2 vs 24.7 months, p = 0.022) than CSF1R-H tumors. Conclusions: Our data suggests that CSF1R expression may serve as a prognostic biomarker in CRC, with lower expression potentially linked to improved survival, particularly in patients with liver metastases. These findings warrant further investigation of CSF1R as a possible prognostic and predictive biomarker, as well as a potential therapeutic target in CRC. Clinical trial information: NCT00265850 .

Phase II study of trifluridine/tipiracil (TAS-102) plus irinotecan in combination with bevacizumab as a second‐line therapy for patients with metastatic colorectal cancer.

155 Background: Metastatic colorectal cancer (mCRC) patients have poor prognoses with limited response to second-line chemotherapy. Therefore, it is urgent to refine and design an optimal second-line treatment regimen to improve the response rate and prolong the survival of patients with mCRC. This study assessed the safety and efficacy of the trifluridine/tipiracil (TAS-102), irinotecan, and bevacizumab regimen in second-line settings for mCRC patients. Methods: This was a multicenter, single-arm, phase II trial. The mCRC patients who are refractory to standard first-line treatment, including fluoropyrimidine and oxaliplatin, are eligible. Based on the recommended phase II dose established in phase I, enrolled patients received TAS-102 (30 mg/m2 twice daily on days 1-5) and irinotecan (150 mg/m2 on day 1) combined with bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the objective response rate (ORR). Results: Between October 1, 2023, and August 31, 2024, 60 patients were enrolled, and all of them were evaluated for efficacy. As of August 31, 2024, efficacy was assessed in all 60 participants with an ORR of 18.3% (2 had complete response, CR; 9 had partial response, PR; 39 had stable disease, SD). Among the 39 patients with SD, 29 patients experienced tumor shrinkage. The disease control rate (DCR) was 83.3%. The median follow-up was 8.6 months (95% confidence interval [CI], 6.743-10.457). The six-month progression-free survival (PFS) was 59.6%. The median PFS was 6.9 months (95% CI 5.016-8.784), whereas the median overall survival (OS) was not reached. The 1-year OS rate was 92%. At the time of analysis, four patients have died, and 56 patients are still alive. All patients were evaluable for safety assessment. The most common treatment-related adverse events (TRAE) were nausea (100%), neutropenia (86.7%), and anemia (83.3%). The most frequent grade 3/4 TRAE were neutropenia (48.3%), febrile neutropenia (8.3%), nausea (3.3%), and anemia (3.3%). No treatment-related death occurred. Conclusions: The regimen of irinotecan, TAS-102, plus bevacizumab preliminarily demonstrated promising efficacy with tolerable toxicity for mCRC patients as second‐line treatment. This regimen warrants further exploration in refractory mCRC patients. Clinical trial information: NCT06202001 .

Clinical validation of plasma circulating-tumor DNA assay using highly sensitive Safe-SeqS technology for detecting RAS and BRAF V600E in metastatic colorectal cancer.

50 Background: We developed a circulating-tumor DNA (ctDNA) test assay for RAS/BRAF mutations using next-generation sequencing-based Safe-SeqS technology. The clinical performance of detecting RAS and BRAF mutations were evaluated versus approved liquid biopsy and tissue testing, respectively. Methods: Metastatic colorectal cancer (mCRC) patients (pts) were enrolled. The concordance of the RAS mutational status in ctDNA between Safe-SeqS assay and OncoBEAM RAS CRC kit, which is approved as a companion diagnostic in Japan, was evaluated using archival plasma samples. The primary endpoints were positive percent agreement (PPA) and negative percent agreement (NPA). The concordance of the BRAF V600E mutational status between plasma-Safe-SeqS assay and tissue-based testing using MEBGEN RASKET-B kit, which is approved as a companion diagnostic in Japan, was prospectively evaluated. The primary endpoints were sensitivity and specificity of Safe-SeqS assay compared to tissue-based testing. Multivariate analysis using LASSO regression model was performed to evaluate the discordance of BRAF V600E mutational status between Safe-SeqS assay and tissue-based testing. Results: In 125 eligible plasma samples, the PPA and NPA for RAS mutational status in ctDNA were 87.1% (95% confidence interval [CI]: 76.1–94.3) and 95.2% (95% CI: 86.7–99.0), respectively. On the other hand, in 103 eligible pts, the sensitivity and specificity of Safe-SeqS assay for BRAF V600E mutational status were 69.2% (95% CI: 48.2–85.7) and 98.7% (95% CI: 93.0–100.0), respectively. Multivariate analysis revealed the baseline longest diameter and the number of lesions in pts with peritoneal and/or lung metastasis were factors associated with discordance. The sensitivity for BRAF V600E mutations increased to 81.0% (95% CI: 58.1–94.6, fisher’s exact test p =0.02) when the 5 pts with lower tumor burden (peritoneal metastasis with the longest diameter <20 mm, and lung metastasis with the longest diameter <20 mm and <10 lesions, according to the previous report [1] ) were excluded. Conclusions: The clinical validity of the ctDNA assay for detecting RAS/BRAF V600E mutations using Safe-SeqS technology was confirmed in pts with mCRC. Careful attention should be paid for mCRC pts with only peritoneal and/or lung metastases having fewer metastases or smaller diameter lesions. 1. Kagawa Y, et al. Clin Cancer Res 2021.

A cross-sectional analysis from a real-world cohort of patients with microsatellite instability colorectal cancer (MSI-CRC) with metastatic disease from the Spanish RETUD registry.

178 Background: Survival of microsatellite instability (MSI) metastatic colorectal cancer (mCRC) patients (pts) has remarkably increased with immune checkpoint inhibitors (ICI). Here, we present our real-world data regarding the management and clinical outcomes of a cohort of 214 MSI-mCRC patients included in the Spanish Group of Treatment of Digestive Tumors TTD Registry (RETUD). Methods: RETUD is a national, multicenter registry for gastrointestinal tumors from the Spanish TTD Group. In this cross-sectional analysis we evaluated a real-world cohort of MSI-mCRC pts diagnosed from 1 st January 2017 to 29 th April 2024. Baseline characteristics, treatments and treatment response are descriptively presented. Tumoral response was evaluated according to RECIST 1.1 criteria. First line progression-free survival (PFS) and overall survival (OS) analyzed by Kaplan-Meier method are presented along with 95% confidence intervals (CI). Results: Among 679 MSI-CRC pts included in RETUD, a total of 214 mCRC pts were evaluable. Pts’ age at diagnosis was 69.6 (26-96) years, and they were predominantly Caucasian (97.7%) and female (53.7%). Eastern Cooperative Oncology Group (ECOG) performance status was 0-1 for 168 (78.5%) pts. Seventeen (10.7%) pts presented Lynch syndrome. Main tumor biological characteristics are described at Table 1 and the molecular profile (when available) was: KRAS mutation (24.3%), NRAS mutation (3.5%) and BRAF v600E mutation (53.0%). Surgical resections: 158 (73.8%) pts for primary tumor and 42 (19.6%) pts for metastasis. First line systemic treatment was administered to 187 (97.1%) pts: 92 (49.2%) pembrolizumab, 83 (44.4%) chemotherapy (CT), 4 (2.1%) other ICIs, 8 (4.3%) not reported. With a median follow up period of 17.4 months, the median (95% CI) OS and first-line PFS of the total mCRC population were 32.6 (22-72.4) and 11.1 (8.2-17.9) months (m), respectively. In immunotherapy (IT) pts mOS was not achieved (22.0-NA) and PFS was 26.5 m (12.9-NA) while the mOS was 28.9 m (16.3-69.3) and PFS 7.5 (5.4-9.3) m in CT pts. The overall response rate (ORR) was 54.2% in IT pts vs. 37.3% in CT pts. Conclusions: The introduction of IT has changed the evolution of MSI-H mCRC management, offering a beneficial impact in the OS and PFS survival in contrast to other conventional therapies in a real-world context. Tumor characteristics at initial diagnosis of CRC. Stage at initial diagnosis of CRC I/II, n (%) 4 (1.9) / 26 (12.1) III/IV, n (%) 66 (30.8) / 118 (55.1) Location of primary tumor a , n (%) right colon /left colon /rectum 160 (74.8) /37 (17.3) /19 (8.9) Main metastatic location b , n (%) Liver 84 (39.3) Peritoneal 76 (35.5) Lymph 71 (33.2) Lungs 41 (19.2) a Pts with more than 1 primary tumor; the percentage may be over 100%. Data missing for 4 (1.9%) pts. b Pts with more than 1 metastatic site; the percentage may be over 100%.

BXQ-350, a novel sphingolipid metabolism modulator, in combination with mFOLFOX7 and bevacizumab in newly diagnosed metastatic colorectal cancer (mCRC) patients: A phase 1b/2 randomized study.

TPS320 Background: Ceramides and sphingosine-1-phosphate (S1P) are key bioactive signaling molecules. Ceramides are proapoptotic and mitigate chemoresistance. Conversely, S1P promotes cancer cell proliferation, activates multiple oncogenic pathways, and stimulates immuno-suppressor cell populations promoting a pro-tumoral microenvironment. Several studies in colorectal cancer patients have shown high levels of ceramides are associated with improved survival, while high S1P levels are associated with a poor prognosis. Hence, modulation of sphingolipid metabolism could be a promising therapeutic approach. BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that lowers systemic S1P and increases C18 ceramide. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in cancer patients with advanced solid malignancies (NCT02859857). BXQ-350 was safe and well-tolerated (no DLT, no MTD). Also, 13 patients (~17.8% of evaluable patients) had a clinical benefit up to cycle 6 and beyond (PR, SD). Among patients with PFS > 6 months, there were 4 recurrent CRC patients: 1 patient had a PFS of ~12 months, 2 of ~18 months, and 1 is still on study after 7 years suggesting potential long-term benefit. Furthermore, there were signs that BXQ-350 may alleviate symptoms of CIPN as 4 out of 10 patients with chronic CIPN at time of enrollment experienced an improvement of their symptoms. Methods: BXQ-350 is being investigated in a Phase 1b/2 study in combination with mFOLFOX7 and Bevacizumab in newly diagnosed mCRC patients (NCT05322590) to assess the efficacy and safety of BXQ-350. Design of the Phase 1b (open label study): 1) A safety dose escalation part to establish the RP2D: patients will initially receive 1.8 mg/kg BXQ-350 in combination with mFOLFOX7 and Bevacizumab. If safe (no MTD), dose of BXQ-350 will be increased to 2.4 mg/kg and 9 additional patients will be entered at this dose level. If safe, then this dose will be the RP2D and 21 additional patients will be enrolled, completing a 30 patient expansion cohort 2) Efficacy will then be evaluated for all patients entered at the RP2D. Primary objectives of the Phase 1b are to assess safety, identify RP2D, and assess preliminary efficacy of BXQ-350 in this combination. A secondary objective is to determine if BXQ-350 decreases CIPN. Enrollment in the expansion cohort of 30 patients is nearly complete, with 26 patients enrolled as of September 2024. Clinical trial information: NCT05322590 .

Impact of RAS and BRAF heterogeneity on the efficacy of EGFR blockade in patients with metastatic colorectal cancer.

255 Background: Epidermal growth factor receptor (EGFR) blockade can effectively shrink tumors in metastatic colorectal cancer (CRC) patients without RAS nor BRAF mutations. However, some patients without RAS or BRAF mutations in their primary tumors may develop these mutations in metastatic tumors (heterogeneity). Circulating tumor DNA (ctDNA) can reflect this heterogeneity in metastatic tumors. Here, we evaluated the efficacy of EGFR blockade in patients who had no RAS or BRAF mutations in their primary tumors but did have them in ctDNA. Methods: We prospectively enrolled 100 patients with confirmed metastatic CRC without RAS or BRAF mutations in their primary tumors. Patients were treated with first-line systemic chemotherapy including EGFR blockade. We obtained ctDNA from each patient before they started chemotherapy. RAS, BRAF (V600E), and PIK3CA mutations were detected using digital PCR. Results: One of the 100 cases were excluded due to protocol violation. In the ctDNA obtained before starting chemotherapy, RAS, BRAF, and PIK3CA mutations were detected in 12, 4, and 6 patients, respectively. No patients had both RAS and BRAF mutations in their ctDNA; however, one patient had both BRAF and PIK3CA mutations and one had both RAS and PIK3CA mutations. Eighty-nine patients had measurable tumor lesions. Among these, 3 experienced a complete response (CR), 71 had a partial response (PR), 13 had stable disease (SD), and 2 had progressive disease (PD). The response rates for patients with RAS or BRAF mutations and for patients with neither mutation were 81% and 83%, respectively (P=0.73). Median progression-free survival (PFS) for patients with RAS or BRAF mutations and those without mutations were 251 days and 216.5 days, respectively (P=0.82). The presence or absence of PIK3CA mutations did not affect the response rate or PFS. Conclusions: Previously, we reported that the incidence of RAS and BRAF heterogeneity were 10% (1) and 4% (2). In the present study, RAS and BRAF heterogeneity were 12% and 4%, respectively. The heterogeneity of RAS and BRAF mutations had no effect on the response rate and PFS of EGFR blockade as first line chemotherapy. The effect of heterogeneity on the overall survival is of great interest; however, about half of the patients are still alive. 1. Yamada T, et al. Cancer Science 2016. 2. Ueda K, et al. Eur J Surg Oncol 2022. Clinical trial information: UMIN000031177 .

Real-world outcomes of targeted therapies and local interventions in BRAF V600E–mutated metastatic colorectal cancer: A single-center retrospective study.

203 Background: Metastatic colorectal cancer (mCRC) patients with BRAF V600E mutations, especially those with microsatellite stable (MSS) tumors, have poor prognoses. Chemotherapy has limited efficacy in this subgroup, especially for second-line or subsequent-line treatments. Current research is increasingly focusing on the integration of targeted therapies and local interventions, but real-world evidence remains scarce, particularly from Asian cohorts. This study leverages real-world data to evaluate the impact of novel therapeutic combinations, including triplet and doublet targeted therapies, alongside local treatments in this high-risk patient population. Methods: This retrospective study includes MSS-type mCRC patients with BRAF V600E mutations treated at the Sixth Affiliated Hospital of Sun Yat-sen University between April 2014 and May 2024. Patients receiving targeted therapies were stratified into three groups: Triplet group (BRAF, EGFR, and MEK inhibitors, including Dabrafenib, Cetuximab and Trametinib), Doublet group (BRAF and EGFR inhibitors, including Dabrafenib and Cetuximab or Encorafenib and Cetuximab), and Doublet target-chemotherapy group (BRAF and EGFR inhibitors combined with chemotherapy, including Vemurafenib, Irinotecan, and Cetuximab). Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and objective response rate (ORR). Results: Among 239 enrolled patients, 58 received targeted therapy and 68 underwent conventional chemotherapy as second-line treatment. 63.5% (80/126) of these patients underwent local interventions, including primary tumor resection, metastasectomy, CRS±HIPEC, and liver ablation. Targeted therapy demonstrated significantly improved mPFS compared to conventional chemotherapy (5.5 vs. 4.2 months, HR = 0.44; 95% CI: 0.29-0.68, p < 0.001). OS did not differ significantly between the two treatment arms (12.7 vs. 12.1 months, HR = 0.80; 95% CI: 0.50-1.25, p = 0.330). In the triplet group, ORR, mPFS, and mOS were 21%, 5.8 months and 18.0 months, respectively, showing a trend towards enhanced efficacy compared to the other targeted therapy groups, albeit without statistical significance. Patients who received targeted therapy (n=35) or chemotherapy (n=45) in combination with local interventions demonstrated significantly prolonged OS compared to those without local therapy (mOS: 22.3 vs. 9.6 months; HR = 0.19; 95% CI: 0.09-0.42; p < 0.001 and 14.3 vs. 10.9 months; HR = 0.53; 95% CI: 0.29-0.98; p = 0.042, respectively). Conclusions: Optimal treatment for BRAF V600E mCRC remains under investigation. This study suggests that combining targeted therapies with selective local interventions may significantly improve patient survival in this challenging subgroup, warranting further prospective evaluation.

Effect of homologous recombination deficiency on survival in patients with metastatic colorectal cancer with KRAS mutations.

252 Background: Metastatic colorectal cancer (mCRC) patients exhibit intertumoral genetic heterogeneity, making it difficult to apply precision medicine. In the molecular genetic profile of mCRC, there are relatively few other gene alterations that significantly impact treatment decisions beyond KRAS and MSI status. We aim to investigate the prognostic impact of Homologous recombination deficiency (HRD)-related genetic alterations in mCRC patients, focusing on how mutation status influences on patient outcomes. Methods: The analysis included 364 mCRC patients who underwent comprehensive genomic profiling at Korea University Anam Hospital from Sep. 2016 to Dec. 2020. HRD was defined by the presence of pathogenic variants in genes including ATM, ATR, BARD1, BRCA1/2, BRIP1, CDK12, CHEK2, FANCA, MRE11A, PALB2, RAD50/51. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method. Multivariate Cox proportional hazards regression analyses were performed to assess the independent impact of HRD status. Results: Of the total cohort, 181 of patients (49.78%) harbored KRAS mutations. HRD gene mutations were identified in 38 of patients (10.4%) of patients, predominantly in ATM, BRCA 1/2, ARID1A genes. KRAS-HRD co-mutations were present in 18 of patients (4.7%). There is no significant difference in HRD status between the KRAS mutant and wild-type groups (p=0.73). While first-line treatment PFS was independent of KRAS mutational status (wt 10.8 vs. mut 9.6 months, p=0.31), it was significantly associated with HRD gene mutation status (16.2 vs. 10.6 months, p=0.001). OS was similar with KRAS mutations (34.7 vs. 32.9 months, p=0.72) and HRD mutations (34.7 vs. 39.1 months, p=0.73). However, patients with both KRAS and HRD mutations had significantly worse OS compared to those with either KRAS and HRD mutation (21.3 vs. 36.7 vs. 65.3 months, p=0.034, <0.001). A multivariate analysis was performed to evaluate factors affecting OS in mCRC patients. Among the variables, metastasectomy, which 44% of patients underwent, had a significantly low HR (=0.28) and would contributed to more favorable outcomes when evaluating OS. Neither KRAS nor HRD mutation alone was a significant prognostic factor, but their co-mutation was significantly associated with poor survival (HR=2.39, p=0.048). Conclusions: Poor OS in patients with KRAS-HRD co-mutations, despite metastasectomy, highlights the need for additional treatment strategies beyond surgery. Future studies with larger sample sizes and analyses stratified by metastasectomy status are necessary to strengthen these findings. Variables HR (95% CI) p-value Metastasis site Liver 2.16 (1.60 – 2.92) < 0.001 Peritoneum 1.52 (1.01 – 2.11) 0.013 Bone 1.69 (0.96 – 2.97) 0.067 Metastasectomy 0.28 (0.47 – 0.74) < 0.001 KRAS 1.03 (0.77 – 1.37) 0.826 HRD 0.75 (0.40 – 1.41) 0.367 Co-mutation 2.39 (1.01 – 5.66) 0.048

Clinical and molecular characterization of FAP and SPP1 in colorectal cancer (CRC), CALGB (Alliance)/SWOG 80405 and real-world data.

276 Background: FAP and SPP1 contribute to immune modulation in the CRC tumor microenvironment (TME). FAP is expressed by cancer associated fibroblasts, aiding in tissue remodeling and tumor invasion. SPP1 is an integrin-binding protein expressed by tumor associated macrophages that promotes tumor growth, adhesion, and metastasis. We present a clinical and molecular characterization of FAP and SPP1 in CRC. Methods: We analyzed 24,257 CRC samples tested at Caris Life Sciences (Phoenix, AZ) with WTS (Illumina NovaSeq), NextGen DNA sequencing (NextSeq), and PD-L1 expression (SP142, positive ≥ 2+, 5%). RNA deconvolution analysis estimated cell infiltration in the TME. Data from the phase 3 CALGB/SWOG 80405 trial (NCT00265850) on 433 metastatic CRC patients treated with bevacizumab (Bev, n = 226) or cetuximab (Cet, n = 207) in combination with first-line chemotherapy were also evaluated. RNA isolated from FFPE tumor samples were sequenced with HiSeq 2500 (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared using Cox regression in categorical gene expression tertiles (high (T3), medium (T2), and low (T1)) for FAP and SPP1 . Results: FAP -T3 and SPP1 -T3 had increased PD-L1 positivity (q<0.05), while SPP1 -T3 also demonstrated increased MSI-H (8.4% vs 5.3%) and TMB-H(>10 mt/mb, 15.0% vs 10.1%) status relative SPP1 -T1 (all q<0.001). T3 of both genes of correlated with increased M1/M2 macrophages, NK cells and T cell inflamed score (q<0.001); dendritic cells and neutrophils were increased in SPP1 -T3 and FAP -T1 tumors (q<0.05). FAP -T3 and SPP1 -T3 had increased pathway activation of epithelial-mesenchymal transition (EMT), inflammatory response, TNF-a signaling, angiogenesis and KRAS signaling (all q < .005). In Caris cohorts, FAP -T3 demonstrated worse OS in Cet/panitumumab treated CRC (T3: 23.6 vs T1: 21.0 months [mo], P = .005; HR 0.85, 95% CI [0.77-0.95]), but SPP1 did not correlate with OS. In 80405, FAP -T3 showed shorter PFS (T3: 9.5 vs T2: 11.5 vs T1: 12.6 mo, T3 vs T1 (reference) adjusted HR 1.27 [1.07-1.51]) and OS (25.2 vs 29.4 vs 35.5 mo, adjusted HR 1.31 [1.10-1.57]). Similarly, SPP1 -T3 demonstrated worse PFS (9.0 vs 12.7 vs 14.0 mo, adjusted HR 1.29 [1.12-1.48]) and OS (20.9 vs 34.0 vs 36.3 mo, HR 1.24 [1.07-1.44], P < 0.001). Treatment interaction tests noted FAP -T1 CRC benefited from Cet over Bev with respect to PFS ( P = 0.003) and OS ( P = 0.044), while SPP1-T1 tumors demonstrated a PFS benefit with Cet ( P = 0.009). Conclusions: Our results indicate that increased FAP and SPP1 expression is associated with immune cell infiltration, EMT, and inflammatory signaling. Additionally, their expression may be prognostic and predictive of targeted therapy. These data support the evaluation of FAP and SPP1 as predictive markers and therapeutic targets in CRC.

Disparities in prophylactic tetracycline use among patients with metastatic colorectal cancer undergoing treatment with EGFR inhibitors.

109 Background: Epidermal growth factor receptor (EGFR) inhibitors have been shown to improve survival in metastatic colorectal cancer and are considered a standard of care option for patients with RAS/RAF wild-type disease. However, anti-EGFR agents are associated with an acneiform rash that can lead to decreased quality of life and early discontinuation of treatment. Prophylactic doxycycline has been shown in a randomized clinical trial to decrease any skin toxicity ≥ grade 2 by 50%. In this study we sought to determine the rate of prophylactic tetracycline use in metastatic colorectal cancer patients receiving anti-EGFR therapy in the United States. Methods: The Flatiron Health Electronic Health Record-derived, de-identified database was used to analyze the records of patients who were at least 18 years old, diagnosed with metastatic colorectal cancer, and received treatment with an anti-EGFR agent (cetuximab or panitumumab). Patients were stratified by receipt of prophylactic tetracycline versus not. This was defined by an order for a tetracycline 28 days before to 1 day after initiation of an anti-EGFR agent. Demographic and clinical characteristics were compared via multivariable logistic regression. The change in percentage of patients who received a prophylactic tetracycline over time was assessed and was compared to the rate of anti-emetic prescription which served as a control to ensure drug administration data was accurately captured. Results: The records of 6,713 patients who met inclusion criteria and received an anti-EGFR agent between 2013 and 2023 were included in our analysis. A logistic regression model assessing the association between patient characteristics and the receipt of a prophylactic tetracycline suggested that older age, race (black/African American or Other), presence of RAS mutation, and higher line of therapy were all significantly associated with not receiving prophylactic tetracyclines. Other patient characteristics including gender, ECOG status, mismatch repair status, and RAF mutation status did not appear to impact the likelihood of receiving a prophylactic tetracycline. The rate of prophylactic tetracycline use increased from 10.9% in 2013 to 22.3% in 2023 while the rate of prophylactic anti-emetic remained stable at around 82%. Conclusions: This real-world analysis suggests the use of preemptive treatment for skin toxicity in patients with metastatic colorectal cancer who are treated with an anti-EGFR in US is suboptimal. Disparities in cancer care are also evidenced by lower use of tetracyclines in elderly and African Americans. Randomized controlled trials support the use of prophylactic tetracycline in these patients; thus, further research into the reason for this practice gap is necessary. Educational efforts should be undertaken to improve tetracycline prescribing rates in this population.

The Efficacy and Safety of Durvalumab and Tremelimumab with Concomitant Treatment for MSS/pMMR Metastatic Colorectal Cancer: A Single Arm Meta-Analysis.

To address the issue that most microsatellite-stable (MSS) and proficient mismatch repair (pMMR) metastatic colorectal cancer (mCRC) patients have minimal response to immunotherapy, this meta-analysis evaluated the efficacy and safety of durvalumab and tremelimumab with concomitant treatment in treating MSS/pMMR metastatic colorectal cancer. All included trials were prospective studies with a median patient age of 63years, of which 94.2% were MSS/pMMR mCRC patients, with a male to female ratio of 1.5:1. Based on durvalumab and tremelimumab treatment, one study performed surgical resection on resectable cases, while the other four studies performed radiotherapy or chemotherapy on unresectable cases. Analyses include objective response rate (ORR).etc. for drug activity, overall survival (OS) and progression-free survival (PFS) for therapeutic efficacy, and adverse events (AEs) for safety. The risk of bias was assessed by sensitivity analysis. 5 studies involving 228 patients were included in this meta-analysis. The pooled estimates showed a median OS of 9.26months, median PFS of 2.53months, partial response (PR) of 13.6%, stable disease (SD) of 32.8%, ORR of 12.5% and disease control rate (DCR) of 65.4%. AEs were generally low, with pruritus (27.5%), diarrhea (28.8%), and fatigue (53.9%) being the most common, while other AEs occurred at less frequencies. Durvalumab and tremelimumab with concomitant treatment for MSS/pMMR mCRC patients is relatively effective and safe, which is helpful in addressing the problem of mCRC with MSS/pMMR that has minimal response to immunotherapy.

Assessment of the quality of life in metastatic colorectal cancer patients with KRAS gene mutant: a case-control study

BackgroundThe mutation of the KRAS (Kirsten rat sarcoma virus) gene is a prevalent genetic alteration in metastatic colorectal cancer (mCRC). According to previous research, this mutation significantly affects clinical outcomes and quality of life (QOL). This research investigated the association between KRAS mutant status and various aspects of QOL in mCRC patients.MethodsThis case-control study involved 90 admitted patients with mCRC. The patients were either mCRC with positive KRAS mutants (case group) or those without the mutation (control group). The KRAS mutation status of each patient was determined using standard molecular testing. The QOL was evaluated through validated questionnaires from the European Organization for Research and Treatment of Cancer (EORTC), including QLQ-C30 and the QLQ-CR29 questionnaire for colorectal cancer patients. Differences in QOL between the groups and the association of QOL with the odds of KRAS mutation were analyzed using appropriate statistical tests.ResultsPatients in the wild-type KRAS group had significantly higher scores on the global health status (GHS) of the QLQ-C30 scale compared to those with a KRAS mutation [(64.26 ± 4.63 vs. 49.63 ± 4, crude; p = 0.019, adjusted; p = 0.024). The mean score of the social functioning scale of the KRAS mutation group was significantly higher than the wild-type [(40 ± 5.84 vs. 24.81 ± 4.39, crude; p = 0.040, adjusted; p = 0.021)]. Based on the QLQ-CR29 questionnaire, average QOL scores were suboptimal for both groups but insignificant. Further, both crude and adjusted analyses showed that KRAS mutation odds were significantly linked to improved social functioning [(crude; OR = 1.013; P = 0.044), (adjusted; OR = 1.017; P = 0.019)] and negatively associated with GHS [(crude; OR = 0.983; P = 0.022), (adjusted; OR = 0.982; P = 0.022)].ConclusionThe study revealed a low QOL in mCRC, a notable difference in social functioning, and the GHS among patients with and without mutations. Further research is needed to develop targeted interventions to enhance QOL in patients with KRAS mutation.

Safety and efficacy of trifluridine/tipiracil +/− bevacizumab plus XB2001 (anti-IL-1α antibody): a single-center phase 1 trial

In the tumour microenvironment, IL-1α promotes neoangiogenesis, matrix remodelling, tumour proliferation, chemoresistance, and metastases. Highly expressed in human colorectal cancers, IL-1α is associated with poor prognosis. XB2001, a fully human monoclonal antibody neutralizing IL-1α, was evaluated for safety and preliminary efficacy with trifluridine/tipiracil (FTD/TPI) and bevacizumab in metastatic colorectal cancer patients previously treated with oxaliplatin- and irinotecan-based chemotherapies. This single institution, phase 1 study used a 3 + 3 design to assess XB2001 at doses of 250 mg, 500 mg and 1000 mg every 14 days, associated with FTD/TPI 35 mg/m² (days 1–5 and 8-12, every 28 days) (NCT05201352). The Maximum Tolerated Dose of XB2001 + FTD/TPI was then associated in combination with bevacizumab (5 mg/kg, days 1 and 15). Safety, efficacy, pharmacokinetics and pharmacodynamics were assessed. Seventeen patients (median age: 67.4 years) were enroled. No patient exhibited dose-limiting toxicity at any dose. The most common treatment-related adverse events (TRAE) of any grade (G) were diarrhoea (35.3%), nausea (47.1%) and anaemia (35.3%). G3-4 TRAE were neutropenia (17.6%) hypertension and infection (5.9% each). The RP2D (recommended phase 2 dose) of XB2001 was 1000 mg. The disease control rate was 76%, with 23% of patients achieving an objective response, including one complete response. Response and longer progression-free survival were associated with a decrease in serum IL-6 levels during therapy. High intratumoral IL-1α expression at baseline and CD8/PD-L1 infiltration are associated with a better progression-free survival. The combination of XB2001 with FTD/TPI and bevacizumab is feasible and safe, and showed encouraging clinical activity in chemotherapy-resistant mCRC.

The Impact of COVID-19 Pandemic on the Diagnosis, Treatment, and Outcomes of Colorectal Cancer in Singapore.

Background and Objectives: During the COVID-19 pandemic, many countries implemented lockdowns and social distancing measures, which may delay the early diagnosis of colorectal cancer (CRC). This study aims to review the impact of the pandemic on the diagnosis and treatment outcomes of CRC. Materials and Methods: Patients who underwent colonoscopy or surgery for CRC were included. The study was divided into the pre-COVID-19 (January 2019-January 2020), early COVID-19 (February-May 2020), recovery (June-December 2020), and heightened alert (January-December 2021) periods. Cox regression was used to model the waiting time to colonoscopy. Multivariable logistic regression identified associations between time periods and incidence of CRC diagnosed. The characteristics and outcomes of the surgical procedures that were performed were compared across the time periods. Results: A total of 18,662 colonoscopies and 1462 surgical procedures were performed in the study period. Compared to the pre-COVID-19 period, there was a longer time to colonoscopy during the recovery (HR: 0.91; 95% CI: 0.87, 0.94) and heightened alert periods (HR: 0.88; 95% CI 0.85, 0.91). The early COVID-19 (OR: 1.36; 95% CI: 1.04, 1.77) and recovery (OR: 1.20; 95% CI: 1.01, 1.43) periods were associated with higher odds of diagnosing CRC. Compared to the pre-COVID-19 period, there was a higher proportion of ASA 4 patients (4.3% vs. 1.3%; p < 0.001) and stage 4 CRC patients (22.2% vs. 16.9%; p = 0.001) that required surgery during the heightened alert period. Similarly, there was a higher proportion of emergency surgeries (22% vs. 13.3%; p = 0.002); diverting stomas (13.5% vs. 10.5%; p = 0.005), and Hartmann's procedures (4.4% vs. 0.4%; p = 0.001) performed during the heightened alert period. Conclusions: The pandemic was associated with a higher proportion of metastatic CRC patients requiring surgery. Healthcare policies should facilitate early cancer screening, diagnosis, and treatment to reduce cancer-related morbidity for future pandemics.

Outcomes of Broader Genomic Profiling in Metastatic Colorectal Cancer: A Portuguese Cohort Study

Background: Colorectal cancer (CRC) is the third most diagnosed cancer globally and the second leading cause of cancer-related deaths. Despite advancements, metastatic CRC (mCRC) has a five-year survival rate below 20%. Next-generation sequencing (NGS) is recommended nowadays to guide mCRC treatment; however, its clinical utility when compared with traditional molecular testing in mCRC is debated due to limited survival improvement and cost-effectiveness concerns. Methods: This retrospective study included mCRC patients (≥18 years) treated at a single oncology centre who underwent NGS during treatment planning. Tumour samples were analysed using either a 52-gene Oncomine™ Focus Assay or a 500+-gene Oncomine™ Comprehensive Assay Plus. Variants were classified by clinical significance (ESMO ESCAT) and potential benefit (ESMO-MCBS and OncoKBTM). The Mann–Whitney and Chi square tests were used to compare characteristics of different groups, with significance at p &lt; 0.05. Results: Eighty-six metastatic colorectal cancer (mCRC) patients were analysed, all being MMR proficient. Most cases (73.3%) underwent sequencing at diagnosis of metastatic disease, using primary tumour samples (74.4%) and a focused NGS assay (75.6%). A total of 206 somatic variants were detected in 86.0% of patients, 31.1% of which were classified as clinically significant, predominantly KRAS mutations (76.6%), with G12D and G12V variants as the most frequent. Among 33.7% RAS/BRAF wild-type patients, 65.5% received anti-EGFR therapies. Eleven patients (12.8%) had other actionable variants which were ESCAT level I-II, including four identified as TMB-high, four KRAS G12C, two BRAF V600E, and one HER2 amplification. Four received therapies classified as OncoKbTM level 1–2 and ESMO-MCBS score 4, leading to disease control in three cases. Conclusions: NGS enables the detection of rare variants, supports personalised treatments, and expands therapeutic options. As new drugs emerge and genomic data integration improves, NGS is poised to enhance real-world mCRC management.

Prognostic impact and risk factors of severe neutropenia in the early phase of treatment with trifluridine-tipiracil for metastatic colorectal cancer patients: a single-center retrospective study

PurposeWe aimed to identify the risk factors for severe neutropenia in the early phase of trifluridine-tipiracil (FTD/TPI) treatment, and their impact on overall survival (OS).MethodsThis single-center retrospective study included patients with unresectable metastatic colorectal cancer who were treated with FTD/TPI. The primary endpoint was OS, and the secondary endpoint was severe neutropenia during the first and second cycles of FTD/TPI. We assessed the association between outcomes and potential confounders using multivariate analysis.ResultsOf the 77 total patients, 33 developed severe neutropenia during the first and second treatment cycles. In Cox hazard analysis, the independent factors associated with OS were neutropenia ≥ grade 1 during cycles 1 and 2 (adjusted hazard ratio 0.43; 95% confidence interval (CI) 0.21–0.87), combined treatment with bevacizumab (0.47; 95% CI 0.27–0.83), number of metastatic organs ≥ 3 (2.15; 95% CI 1.22–3.82), and time since diagnosis of metastasis until commencement of FTD/TPI < 18 months (1.94; 95% CI 1.13–3.33). Severe neutropenia during cycles 1 and 2 was not associated with OS (0.75; 0.44–1.27). The risk of severe neutropenia adjusted for initial dose reduction was defined as renal impairment with creatinine clearance (Ccr) of < 60 ml/min (adjusted odds ratio, 4.67; 95% CI, 1.38–15.80) and absolute neutrophil count (per 1000/μl, 0.47; 0.27–0.81).ConclusionThe neutropenia ≥ grade 1 during cycles 1 and 2 of FTD/TPI is a predictor of favorable outcomes; however, the effect of severe neutropenia on OS was not clear. Renal impairment was also associated with severe neutropenia.

ANXA10 sensitizes microsatellite instability-high colorectal cancer to anti-PD-1 immunotherapy via assembly of HLA-DR dimers by regulating CD74

BackgroundMicrosatellite instability-high (MSI-H) metastatic colorectal cancer (CRC) patients are the dominant population in immune checkpoint blockade treatments, while more than half of them could not benefit from single-agent immunotherapy. We tried to identify the biomarker of MSI-H CRC and explore its role and mechanism in anti-PD-1 treatments. Tumor-specific MHC-II was linked to a better response to anti-PD-1 in MSI-H CRC and CD74 promoted assembly and transport of HLA-DR dimers.MethodsThe characteristic gene was screened by data analysis of single-cell and bulk transcriptome sequencing from public datasets. MSI-H CRC cells co-cultured with peripheral blood mononuclear cells and syngeneic model in C57BL/6 mice were performed to detect the sensitivity to anti-PD-1 treatments respectively.ResultsANXA10 was identified as a characteristic gene of MSI-H CRC and its expression was obviously greater in MSI-H than MSS CRC. ANXA10 significantly sensitized MSI-H CRC to anti-PD-1 treatments in vitro and in vivo. Specifically, ANXA10 promoted HLA-DR dimers in and on the surface of MSI-H CRC by increasing CD74 expression. Besides, this work demonstrated that ANXA10 contributed to better clinical benefits with anti-PD-1 therapy in MSI-H CRC patients.ConclusionsOur results provided a novel molecular marker ANXA10 to identify benefit population of MSI-H CRC for improving efficacy of anti-PD-1 and contributed to selection of treatment strategies.

Famitinib plus camrelizumab in patients with advanced colorectal cancer: Data from a multicenter, basket study.

Concurrent inhibition of angiogenesis and immune checkpoints represents a potent therapeutic approach. We conducted a phase 2, multicenter, basket study to assess the efficacy and safety of combination therapy of famitinib (anti-angiogenic agent) plus camrelizumab (PD-1 antagonist) in patients with metastatic solid tumors across 11 cohorts (this study was registered at Clinicaltrials.gov [NCT04346381]). This report focuses on the cohort of patients with metastatic or advanced colorectal cancer. Eligible patients, who had previously received ≥2 lines of systemic treatments for their metastatic disease, were treated with famitinib (20mg once daily) in combination with camrelizumab (200mg intravenously every 3weeks). The primary endpoint was the objective response rate, with secondary endpoints encompassing progression-free survival, overall survival, duration of response, safety and exploratory biomarkers. A total of 44 patients were enrolled and treated. With a median follow-up time of 9.46months (range 2.0-22.5months), objective responses were observed in 6 patients (13.6%; 95% confidence interval [CI], 5.2%-27.4%), all of whom had rectal cancer. The median duration of response is 6.2months (95% CI, 2.3-10.6months). Median progression-free survival was 3.3months (95% CI, 2.1-4.1months), and median overall survival was 10.9months (95% CI, 7.6-15.2months). Among the 44 patients, 29 (65.9%) experienced grade 3 or 4 treatment-related adverse events, predominantly hypertension and proteinuria. In conclusion, the combination of famitinib and camrelizumab demonstrates promising antitumor activity with a manageable safety profile in metastatic colorectal cancer patients. Further research is warranted to confirm and extend these findings.

Panitumumab plus 5-fluorouracil and folinic acid or 5-fluorouracil and folinic acid alone as maintenance therapy in RAS wild-type metastatic colorectal cancer (PanaMa, AIO KRK 0212): final efficacy analysis of a randomised, open-label, phase 2 trial.

The PanaMa trial aimed to compare the efficacy of 5-fluorouracil and folinic acid (FU/FA)±panitumumab maintenance in untreated RAS wild-type metastatic colorectal cancer (mCRC) patients. In this final phase 2 trial analysis, adult mCRC patients responding to six cycles of FU/FA, oxaliplatin and panitumumab were randomized (1:1, open-label) to maintenance of either FU/FA+panitumumab or FU/FA alone. The primary endpoint was superiority of progression-free survival of maintenance (PFS; time from random assignment to progression/death) in favour of FU/FA+panitumumab. Secondary endpoints included PFS of re-induction (PFS re-ind.), time to failure of strategy (TFS) and overall survival (OS). The trial is registered with ClinicalTrials.gov (NCT01991873). In 248 patients of the Full Analysis Set recruited between May 2014 and February 2021, with a median observation of 64.0 (range 12.5-86.3) months and 59.7 (range 3.7-97.3) months in the treatment arms, 230 events for PFS (92.7%) and 196 events for OS (79.0%) were recorded. Adding panitumumab to FU/FA resulted in significantly longer PFS (8.8 versus 5.8 months, HR=0.73 (95% CI 0.56-0.94), P=0.015), shorter PFS re-ind. (4.1 versus 7.4 months, HR=1.93 (95% CI 1.33-2.82), P<0.001), comparable TFS (17.1 versus 15.7 months, HR=0.98 (95% CI 0.68-1.42), P=0.92) and numerically longer OS (29.9 versus 24.7 months, HR=0.85 (95% CI 0.64-1.12), P=0.24). The most frequent adverse event (AE) grade ≥3 was rash (FU/FA+panitumumab: n=15, 12.0%, FU/FA: n=17, 6.9%). 141 patients (37.3%) experienced at least one serious AE One treatment-related death occurred (neutropenic sepsis, FU/FA). Panitumumab plus FU/FA might be considered a standard of care maintenance regimen since a potential re-induction therapy with panitumumab cannot be guaranteed at the time of maintenance treatment decision. Amgen.

Flow Cytometric Assessment of FcγRIIIa-V158F Polymorphisms and NK Cell Mediated ADCC Revealed Reduced NK Cell Functionality in Colorectal Cancer Patients.

Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells is a key mechanism in anti-cancer therapies with monoclonal antibodies, including cetuximab (EGFR-targeting) and avelumab (PDL1-targeting). Fc gamma receptor IIIa (FcγRIIIa) polymorphisms impact ADCC, yet their clinical relevance in NK cell functionality remains debated. We developed two complementary flow cytometry assays: one to predict the FcγRIIIa-V158F polymorphism using a machine learning model, and a 15-color flow cytometry panel to assess antibody-induced NK cell functionality and cancer-immune cell interactions. Samples were collected from healthy donors and metastatic colorectal cancer (mCRC) patients from the FIRE-6-Avelumab phase II study. The machine learning model accurately predicted the FcγRIIIa-V158F polymorphism in 94% of samples. FF homozygous patients showed diminished cetuximab-mediated ADCC compared to VF or VV carriers. In mCRC patients, NK cell dysfunctions were evident as impaired ADCC, decreased CD16 downregulation, and reduced CD137/CD107a induction. Elevated PD1+ NK cell levels, reduced lysis of PDL1-expressing CRC cells and improved NK cell activation in combination with the PDL1-targeting avelumab indicate that the PD1-PDL1 axis contributes to impaired cetuximab-induced NK cell function. Together, these optimized assays effectively identify NK cell dysfunctions in mCRC patients and offer potential for broader application in evaluating NK cell functionality across cancers and therapeutic settings.