bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of stereotactic radiotherapy in brain metastases from gastrointestinal cancer.
Authors: Aquilano Michele , Loi Mauro , Valzano Marianna , Frosini Giulio , Morelli Ilaria , Desideri Isacco , Greto Daniela , Bonomo Pierluigi , Galardi Alessandra , Garlatti Pietro , Visani Luca , Livi Lorenzo
Published: January 2025

181

Background:
The incidence of brain metastases from Gastrointestinal primary tumors (GI-BMs) is approximately of 6%. Appropriate management of these patients, who often presents at advanced disease stage, is poorly defined. Stereotactic Radiotherapy (SRT) could be proposed to improve symptoms and extend disease control. The aim of this study is to assess the impact of SRT in this population.
Methods:
Data from consecutive patients treated for GI-BMs with SRT from March 2015 to March 2024 were retrospectively collected. Dose was expressed as Equivalent Dose in 2Gy Fractions (EQD2). lntra-Cranial Control (IC) and Overall Survival (OS) were calculated from date of SRT to event (intracranial relapse and death respectively) or last follow-up.
Results:
Fifty-four patients (median age 68 years, range 46-84) accounting for 98 GI-BMs were included. Primary tumors were colorectal and gastro-oesophageal adenocarcinoma in 37 (68.5%) and 17 (31.5%) patients respectively. Eighteen (33%) patients presented with a single GI-BM. Extra-cranial disease was present in 41 (76%) patients, including unresected/relapsing primary tumor in 9 (17%) cases. Detection of BMs occurred at diagnosis in 8 (15%) patients, as first site of relapse in 27 (50%) or as progression of known metastatic disease in 19 (35%) patients. Before SRT, surgery and/or WBRT were performed in 10 (19%) and 5 (9%) patients respectively. For each SRT course a median of 1 (range 1-5) GI-BMs was treated. Dose regimens consisted of 12-30 Gy in 1-5 fractions, to a median EQD2 of 50 Gy
10
(range 22-68). A second SRT course for out-of-field intracranial progression was performed in 7 patients (13%). First- and further chemotherapy lines were administered in 39 (72%) and 15 (28%) patients respectively. IC rate was 88% at 6 months and 70% at 1 year. At univariate analysis (UVA) no variables were correlated with IC. Median OS was 11 months (IC 95% 9-16), 6-months and 1-year OS rate was respectively 76% and 48%. Only systemic treatment beyond first line was correlated with OS at UVA (4 versus 15 months, p=0.02). Two (4%) patients developed mild symptomatic radionecrosis.
Conclusions:
Onset of GI-BMs can occur at any stage of disease. Despite poor overall outcome, selected patients may benefit from SRT to improve IC, particularly in association with first-line systemic treatment. Multiple SRT courses can be delivered in case of further intracranial recurrence. Symptomatic radionecrosis may occur in less than 5% of cases.
Rechallenge with epidermal growth factor receptor inhibitors for metastatic colorectal cancer: A systematic review and meta-analysis.
Authors: Huang Amy H. , Hsieh Ronan Wenhan , Lu Chuan , Sahin Ibrahim Halil , King Gentry Teng , Safyan Rachael A. , Cohen Stacey A. , Zhen David Bing , Shankaran Veena , Harris William P , Coveler Andrew L. , Lin Po-Jen , Malhotra Jyoti , Forbes Victoria , Chiorean E. Gabriela , Lee Gin Yi
Published: January 2025

184

Background:
Clonal evolution is a mechanism of treatment resistance against epidermal growth factor receptor inhibitors (EGFRi) in metastatic colorectal cancer (mCRC). Upon EGFRi discontinuation, EGFRi-resistant subclones decay with time, which allows for EGFRi rechallenge. We conducted a meta-analysis to investigate the efficacy of EGFRi rechallenge for patients with mCRC.
Methods:
Clinical trials and cohort studies investigating the efficacy of EGFRi rechallenge were extracted from PubMed and Embase from inception to January 31, 2024. Hazard ratios (HR) of overall survival (OS) and progression-free survival (PFS) were aggregated using random-effects models.
Results:
Among 179 studies initially retrieved from the databases, 23 studies (665 patients) were included in the final analysis. There were 11 single-arm trials, 5 randomized controlled trials (including 3 post-hoc analyses), and 7 observational studies. At least 444 patients (66.8%) had left-sided mCRC. In 19 studies, EGFRi rechallenge was given only for patients previously progressing on 5-fluoropyrimadine, oxaliplatin and irinotecan. RAS/RAF mutation status was assessed with circulating tumor DNA (ctDNA) or tissue-based sequencing right before EGFRi rechallenge in 13 studies. Ten clinical trials only enrolled patients with RAS/RAF-wild type mCRC for EGFRi rechallenge. The median EGFRi-free interval before EGFRi rechallenge was ≧4 months in 13 studies (≥10 months in 9 studies) and between 2 to 4 months in 3 studies. Thirteen studies reported an objective response rate (ORR) up to 70%. Eight out of the 13 studies (61.5%) reported an ORR >10% (7 studies with ORR >20%), which is numerically higher than that achieved by FDA-approved third-line agents for mCRC (ORR <10%). EGFRi rechallenge was associated with significantly longer pooled OS (HR 0.62; 95%CI, 0.42-0.92; I
2
=51.9%) and pooled PFS (HR 0.55; 95%CI, 0.38-0.79; I
2
=5.5%) than non-EGFRi systemic therapy. Patients without detectable RAS/RAF mutations by ctDNA right before EGFRi rechallenge had a significantly longer OS (HR, 0.39; 95%CI, 0.23-0.66; I2=32%) and PFS (HR, 0.41; 95%CI, 0.29-0.59; I2=0%) than those with detectable RAS/RAF mutations by ctDNA. Acneiform rash was the most commonly reported non-hematologic adverse event (up to 38.9%). No treatment-related deaths were reported.
Conclusions:
EGFRi rechallenge is associated with significantly longer OS and PFS than conventional systemic therapy and a clinically meaningful ORR in heavily treated patients with mCRC, particularly for patients with RAS/RAF-wild type mCRC tested right before EGFRi rechallenge.
Efficacy and safety of glecirasib (JAB-21822) monotherapy and in combination with cetuximab in patients with KRAS G12C-mutated advanced colorectal cancer.
Authors: Li Jian , Huang Jing , Ba Yi , Cao Baoshan , Luo Suxia , Li Wenhua , Song Zhengbo , Zhu Liangjun , Xiong Jianping , An Guangyu , Zhang Yanqiao , Li Zhihua , Li Yongsheng , Gu Yanhong , Li XingYa , Huang Chenghui , Fu Qihan , Hu Changlu , Shen Lin
Published: January 2025

191

Background:
Glecirasib (JAB-21822), a highly selective, covalent and oral KRAS G12C inhibitor, has demonstrated a favorable safety profile and promising efficacy result as a monotherapy in NSCLC. We previously reported preliminary data of glecirasib monotherapy (NCT05009329) and in combination with cetuximab (NCT05194995) in KRAS G12C-mutated advanced Colorectal Cancer (CRC); here, we present the updated efficacy results.
Methods:
Patients (pts) with advanced CRC harboring KRAS G12C mutation were enrolled and treated with either single agent glecirasib (800mg QD) or glecirasib (800mg QD) combined with cetuximab. The primary endpoint was overall response rate (ORR). The secondary endpoints included duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety.
Results:
As of June 30, 2024, 44 pts received glecirasib (median follow up was 21.9 months). The median age was 55.5 years with female (38.6%) /male (61.4%), ECOG PS 0 (25.0%) /1 (75.0.%), and 79.5% having received ≥ 2 prior lines of therapy. The confirmed ORR and DCR were 22.7% (10/44) and 86.4% (38/44), respectively. Median DoR was 4.4months (95%CI: 4.2, 9.7)
,
median PFS was 5.6 months (95%CI: 4.1, 7.0), and median OS was 16.0 months (95%CI: 8.8, 26.3). Any grade treatment-related adverse events (TRAEs) occurred in 41 (93.2%) pts, the most common ones (>20%) being anemia, blood bilirubin increased, hypertriglyceridemia and white blood cell count decreased. Grade 3-4 TRAEs occurred in 9 (20.5%) pts. No grade 5 TRAEs occurred. No patient discontinued treatment due to TRAEs. Among the47 pts treated with combination regimen (median follow up was 18.7 months), the median age was 54.8 years with female (53.2%)/ male (46.8%), ECOG PS 0 (44.7%) /1 (55.3%), and 74.5% having received ≥ 2 prior lines of therapy. The confirmed ORR and DCR were 50% (23/46) and 87.0% (40/46), respectively. Median DoR was 5.1 months (95%CI: 4.1, 6.9), median PFS was 6.9 months (95%CI: 5.4-6.9), and median OS was 19.3 months (95%CI: 13.1, NE). Any grade TRAEs occurred in 46 (97.9%) pts, the most common ones (>20%) being rash, skin fissures, blood bilirubin increased, ALT increased, AST increased, anemia and proteinuria. Grade 3-4 TRAEs occurred in 9 (19.1%) pts. No grade 5 TRAEs occurred. 2(4.3%) pts discontinued treatment due to TRAEs.
Conclusions:
Glecirasib in combination with cetuximab demonstrated better efficacy compared with glecirasib monotherapy in advanced KRAS G12C mutated advanced CRC, while maintaining a favorable safety profile.

Clinical trial information:
NCT05009329

,

NCT05194995

.
Short-course radiotherapy (SCRT) followed by fruquintinib plus adebrelimab and CAPOX in the total neoadjuvant therapy of locally advanced rectal cancer (LARC): A multicenter, single-arm, open-label, phase II study (UNION TNT).
Authors: Lin Zhenyu , Zhang Peng , Zhao Lei , Ma Hong , Liu Hongli , Liu Junli , Xu Ximing , Lin Dandan , Zhang Zhen , Xia Fan , Tao Kaixiong , Zhang Tao
Published: January 2025

192

Background:
We have demonstrated that neoadjuvant SCRT followed by PD-1 inhibitor plus CAPOX for LARC patients (pts) showed a higher pCR rate and a well-tolerated safety profile in phase III UNION study. Fruquintinib is a potent and highly selective VEGFR inhibitor, which had been approved for previously treated mCRC pts. This study aimed to investigate the efficacy and safety of SCRT followed by fruquintinib plus adebrelimab and CAPOX as a total neoadjuvant therapy for high-risk LARC pts.
Methods:
In this prospective, open-label, multi-centers, single-arm phase 2 study (NCT06234007), pts diagnosed with newly diagnosed and high risk LARC were recruited. Pts received SCRT (25Gy/5f) followed by six cycles of fruquintinib (4mg, qd, po, q3w,for the initial 6 pts in the safety run-in period, dosage would be adjusted based on dose-limited toxicities in the 1st cycle) combined with adebrelimab (1200mg, iv, d1, q3w) and CAPOX (q3w). Primary endpoint was CR rate (including clinical CR & pathologic CR). Secondary endpoints included 3-year EFS rate, OS, R0 resection rate and safety.
Results:
As of 30 Aug 2024, 45 pts were enrolled (median age 59 years [range: 24-75], 26 males, 23 clinical T4 stage and 20 clinical N2 stage, 36 with EMVI positive, 31 with MRF positive, 22 tumor located ≤5cm from the anal verge). Up to 20 Sep 2024, all pts completed SCRT, 73.33% (33/45), 57.78% (26/45) and 31.11% (14/45) pts completed two, four and six cycles of combination therapy, respectively. At data cut-off, of 33 pts included in the efficacy analysis, 28 pts underwent MRI examination and mrTRG results were available, the remaining 5 pts had early surgery due to AEs/serious AEs. 35.7% (10/28) and 46.43% (13/28) pts were classified as mrTRG1 and mrTRG2, respectively. Of 19 pts who underwent surgery, R0 rate was achieved in all 19 pts (100%) and pCR was achieved in 12 pts (63.16%). Moreover, 1 pt achieved cCR during neoadjuvant therapy, thus the treatment strategy provided a CR rate of 65% (1 cCR plus 12 pCR divided by 20). Grade 3/4 adverse effects (AEs) occurred in 16 pts (47.06%), and most commonly were lymphocyte count decreased (n=6, 18.18%), diarrhea (n=5, 15.15%) and AST increased (n=2, 6.06%). 4 serious AEs reported with intestinal perforation and all achieved pCR after surgery therapy. No treatment related death was reported.
Conclusions:
SCRT followed by fruquintinib combined with adebrelimab and CAPOX as a total neoadjuvant therapy showed promising CR rate and favorable pCR for high-risk LARC pts, and the safety profile was generally manageable. This treatment strategy might be a potential option as neoadjuvant therapy for high-risk LARC pts. Updated data will be presented in the future.
Clinical trial information: NCT06234007
.
Efficacy and safety of anlotinib as a later-line treatment for advanced colorectal cancer.
Authors: Song Yang , Liu Lili , Min Jie , You Xianghui , Yang Xue , Zhang Feng , Huang Xiaofeng , Liao Chenggong , Shi Hong , Su Haichuan
Published: January 2025

194

Background:
Colorectal cancer (CRC) is increasingly prevalent in China, with rising incidence and mortality rates. Often, early-stage CRC presents with no symptoms, leading to most patients being diagnosed at an advanced stage, where prognosis is poor. First- and second-line treatments for advanced CRC typically include chemotherapy combined with cetuximab or bevacizumab. However, third-line therapies such as regorafenib, furosemide, and TAS102 have shown limited efficacy. Anlotinib, a multi-targeted tyrosine kinase inhibitor (TKI), has demonstrated improved progression-free survival (PFS) in refractory metastatic CRC (mCRC) in a phase III trial (NCT02332499), showing both efficacy and manageable toxicity. This report provides updated results from extended follow-up.
Methods:
This study enrolled 73 patients with advanced colorectal cancer who had undergone at least two prior standard treatments and were treated with oral anlotinib hydrochloride (8-12 mg daily, days 1-14 of a 21-day cycle) between November 2021 and March 2024 at Tangdu Hospital. Patients were treated until disease progression or intolerable adverse events. Efficacy was assessed using RECIST version 1.1, and adverse reactions were evaluated using CTCAE version 5.0. The primary endpoints were PFS, disease control rate (DCR), and adverse events (AEs), while secondary endpoints included overall survival (OS).
Results:
Of the 73 patients included, 38 had an ECOG performance status (PS) of 0-1, and 35 had a PS of 2. Clinical staging identified 18 patients with stage IIIB/IIIC and 55 with stage IV disease. Patients received anlotinib doses of 8 mg (n=11), 10 mg (n=44), or 12 mg (n=18), with 48 patients also receiving chemotherapy and 25 receiving anlotinib alone. The median PFS was 4.0 months (95% CI: 3.4-4.6), and the median OS was 7.0 months (95% CI: 5.7-8.3). Subgroup analysis indicated that patients under 60 years of age, those without liver metastases, and those with ECOG PS 0-1 derived greater benefit from anlotinib. The most common treatment-related adverse event was hypertension (19.2%). Other notable adverse events included elevated AST (11.0%), proteinuria (6.8%), and jaundice (6.8%). Most adverse reactions were grade 1-2, although 1 patient experienced grade ≥3 gastrointestinal bleeding.
Conclusions:
Anlotinib showed promising efficacy and a favorable safety profile as a later-line treatment for advanced colorectal cancer. These findings suggest that anlotinib may be a viable clinical option for advanced CRC, though larger-scale clinical trials are necessary to confirm these results and further define its role in treatment.
Neoadjuvant chemotherapy with FOLFOXIRI for high-risk relapsed locally advanced colon cancer: A single-arm phase II trial.
Authors: Zhou Yuwen , Meng Wenjian , Qiu Meng
Published: January 2025

201

Background:
To evaluate the safety and efficacy of neoadjuvant chemotherapy (NAC) with three drug-intensity chemotherapy (oxaliplatin, irinotecan, and fluorouracil [FOLFOXIRI]) in patients with high-risk factors for recurrence and metastasis of locally advanced colon cancer (hr-LACC).
Methods:
A single-arm, open-label, phase II trial was conducted at West China Hospital of Sichuan University from July 2020 to Oct 2023. Patients with T4a/b or (and) N2/fused lymph nodes) and no distant metastases were considered as the hr-LACC patients. Eligible enrolled patients received four cycles of NAC with FOLFOXIRI followed by surgery and adjuvant chemotherapy with capecitabine and oxaliplatin (CAPOX) for two to five cycles or single-agent capecitabine for five cycles or observation. The primary endpoint was the rate of TRG grade 0-2 according to the criteria of NCCN guideline.
Results:
Of 72 patients enrolled (median age 53 [18-74] years,65 were T4a/b [90.2%], 66 were N2 [91.6%]), 58 patients (80.6%) completed four cycles of FOLFOXIRI. Three patients (4.2%) achieved clinical complete response. Twenty-eight patients (39.4%) obtained clinical partial response. The most common adverse event (AE) was nausea (86.1%, 62/72); grade 3-4 AEs occurred in 37 of 72 patients (51.4%).R0 resection was achieved in 64 of 64 patients, and the TRG (0-2) rate was 87.5% (56/64). The pathologic complete response rate was 7.8% (5/64). The proportions of pT0-2 and pN0 were 21.9% and 68.8%, respectively. Only three (4.7%) patients had prolonged hospital stay due to perioperative complications. No patient died within 30 days and 90 days after surgery. The 2-year tumor recurrence rate was 17.2%.
Conclusions:
For patients with hr-LACC, NAC with FOLFOXIRI regimen was safe and effective. Longer follow-up and larger clinical studies are needed to validate this innovative regimen.
Clinical trial information: NCT05018182
.
Efficacy and safety of trifluridine/tipiracil and bevacizumab (FTD/TPI+BEV) in patients with metastatic colorectal cancer (mCRC) in real-world practice.
Authors: Martinez Lago Nieves , Reboredo Margarita , Gonzalez Gomez Borja , de Frutos González Belén , Riesco Martinez Maria Carmen , Antonilli Paula Carla , Lopez Alfonso Ana , Gallardo Martin Elena , Fernandez Montes Ana Fernandez , Cabezon-Gutierrez Luis , Cousillas Castiñeira Antia , Ferreiro Reyes
Published: January 2025

204

Background:
In Sunlight trial, the combination of FTD/TPI + BEV showed a significant improvement in Overall Survival (OS) and Progression-Free Survival (PFS), along with better Objective Response Rate (ORR) and Disease Control Rate (DCR), compared to FTD/TPI alone, in patients with mCRC progressing after two chemotherapy regimens. The BeTAS trial aimed to evaluate the effectiveness and safety of the FTD/TPI + BEV combination in real-world practice.
Methods:
This was a retrospective, observational, multicenter study of mCRC patients treated with FTD/TPI+BEV in routine clinical practice across 11 Spanish university hospitals. It included patients with mCRC who were refractory or intolerant to standard therapies.
Results:
A total of 208 patients treated with FTD/TPI+BEV between July 2019 and December 2023 were included. The median age was 69 years (range 33 to 88 years), with 59.8% being male. 15.3% had an ECOG performance status of 2, 55.9% had RAS mutations, 30.3% had three or more metastatic sites, and 81.2% had liver metastases. Additionally, 19.8% had a time from diagnosis of first metastasis of less than 18 months, and 55.3% were categorized in Tabernero's Unfavorable Prognostic Subgroup. Most patients (81.3%) received FTD/TPI+BEV as third-line therapy, with 90.5% having previously received anti-VEGF therapy. The median number of treatment cycles was 4 (range 1 to 31 cycles). The ORR was 4.6%, and the DCR was 50%. The median PFS was 4.9 months (95% CI, 4.0-5.7 months), and the median OS was 11.1 months (95% CI, 9.5-12.8 months). The most common grade 3-4 toxicities included neutropenia (41.8%), asthenia (7.2%), and hepatic toxicity (5.5%). No treatment-related deaths were reported.
Conclusions:
Our series confirms the efficacy and safety of FTD/TPI + BEV in routine clinical practice, even in a population with poor prognosis and an extensive history of previous treatments.
Sensitizing K-Ras G12D mutant colorectal patient-derived organoids via ferroptosis pathway.
Authors: De Dechokyab , Cohen David , Mitani Yosuke , Li Tianxia , Bethancourt Casidhe-Nicole , Gabre Joel
Published: January 2025

211

Background:
Colorectal cancer remains the third most fatal form of cancer for males and females combined, with K-Ras mutations present in approximately 40% of all cases. These mutations drive cancer progression and confer resistance to conventional therapies, underscoring the need for novel treatment strategies. Ferroptosis, a regulated non-apoptotic form of cell death characterized as iron-dependent lipid peroxidation, has emerged as a target for cancer therapy. A study published in 2023 found that K-Ras mutant pancreatic ductal adenocarcinoma and non-small cell lung cancer cells lack ferroptosis induced lipid peroxidation and concurrently upregulated ferroptosis suppressing protein (FSP-1). It is unknown if K-Ras mutant colorectal tumors also evade ferroptosis-induced cell death as a method of cancer progression and therapy resistance. This study aims to measure the effects of inhibiting K-Ras G12D, the most common K-Ras mutation found in CRC, on ferroptosis through a patient derived colorectal cancer organoid (PDO) model. We hypothesize that blocking K-Ras G12D using a MRTX-1133, a K-Ras G12D specific inhibitor, can induce ferroptosis and synergistically work with ferroptosis inducers.
Methods:
As a pilot study, two patient derived organoid lines were established. Surveillance screening and whole exome sequencing was performed to verify K-Ras mutation. CRC9T has wild-type and CRC30T has mutant K-Ras. Additionally, Columbia Pathology Core confirmed tissues used to generate organoids were moderately differentiated colorectal adenocarcinoma. CTG-3D assays were performed to measure IC50 using ferroptosis inducers RSL3, iFSP, and K-Ras inhibitor MRTX-1133. Organoids were cultured in standard gut media for 72 hours, treated, and collected after 72 hours. After treatment, organoids were imaged and stained with BODIPY-C11, a lipid peroxidation fluorescence dye. Flow cytometry was performed, and results were analyzed using FlowJo to show ferroptosis-induced lipid peroxidation in stained organoids.
Results:
Inhibiting K-Ras G12D and inducing ferroptosis showed a synergistic effect on ferroptosis-induced lipid peroxidation. CRC9T was more sensitive (IC50 RLS3: 2.96 uM, iFSP 3.46 uM) to ferroptosis inducers than CRC30T (IC50: RSL3: 5.68 uM, iFSP: 8.6 uM). Blocking K-Ras in was only efficacious in CRC30T (IC50: MRTX1133: 9.73 uM). Cells from the mutant line showed greatest lipid peroxidation when combining ferroptosis inducers with K-Ras G12D inhibitors in flow cytometry analysis.
Conclusions:
These findings demonstrate a synergistic effect when blocking K-Ras G12D and inducing ferroptosis and align with previous studies that showed a connection between ferroptosis suppression and oncogenic KRAS expression. We plan to validate these findings in other patient derived organoid model systems and to assess the effects of pan-KRAS inhibition and ferroptosis inducer on non-K-Ras G12D PDOs.
Risk factors for relapse based on the molecular profiling of Japanese patients with stage II colorectal cancer.
Authors: Kasai Shunsuke , Hatakeyama Keiichi , Shiomi Akio , Kagawa Hiroyasu , Manabe Shoichi , Yamaoka Yusuke , Tanaka Yusuke , Igaki Takahiro , Yamaguchi Ken
Published: January 2025

215

Background:
The association between the molecular profiles and prognosis of Stage II colorectal cancer (CRC) remains unclear. This study aimed to evaluate the long-term outcomes of Stage II CRC based on the molecular profiling and to examine the risk factors for relapse.
Methods:
We retrospectively enrolled Japanese patients with pStage II CRC without pre- and/or postoperative adjuvant therapy and whose surgically resected specimens were evaluated using gene expression and whole exome analyses from January 2014 to December 2018. We evaluated the 5-year overall survival (OS) and relapse-free survival (RFS), and examined the risk factors for RFS.
Results:
We evaluated 322 patients with pStage II CRC, including 126 (39.1%) with right colon cancer, 133 (41.3%) with left colon cancer and 63 (19.6%) with rectal cancer. There were 87 patients (27.0%) with pT4, 175 (54.3%) with venous invasion, 120 (37.3%) with lymphatic invasion, and 68 (21.1%) with perineural invasion. Whole exome analyses revealed that there were 48 patients (14.9%) with MSI-High, and the presence of mutations in key genes for colorectal cancer development was as follows:
APC
, 245 (76.1%);
TP53
, 208 (64.6%);
KRAS
, 134 (6.5%);
PIK3CA
, 64 (19.9%);
FBXW7
, 27 (8.4%); and
BRAF
, 21 (6.5%). The 5-year OS and RFS rates were 98.0% and 90.7%, respectively. According to the consensus molecular subtype (CMS) classification based on gene expression, 76 patients (23.6%) had CMS4 and a significantly lower RFS than the other patients (5-year RFS: 83.8% vs. 92.9%, p=0.017). The independent risk factors for RFS were perineural invasion (Hazard ratio [HR] 5.316, p<0.001) and CMS4 (HR 2.399, p=0.020).
Conclusions:
Molecular profiling of Stage II CRC to assess the risk factors for relapse may contribute to the indication and drug selection for postoperative adjuvant chemotherapy and lead to personalized treatment to improve prognosis.
Impact of education on clinical confidence utilizing HER2-targeted therapies in colorectal cancer.
Authors: Cohen-Solal Karine , Ackbarali Tariqa , Strickler John H , Bekaii-Saab Tanios S.
Published: January 2025

225

Background:
Novel targeted therapies entered the treatment landscape in patients with HER2-positive metastatic colorectal cancer (mCRC). To ensure that these therapies are used effectively, clinicians must assess tumor HER2 status and recognize how HER2-directed treatment modalities fit into the current paradigm. To further enable clinicians to integrate HER2-targeted therapies, an educational program was designed in 2023.
Methods:
A one-hour online, video-based program was designed for clinicians and their teams and hosted on MedLive from February 2023 for one year. Knowledge and competence questions were administered pre-, and immediate post-activity. Additional questions assessed attitudes, barriers, and intended practice changes related to HER-positive mCRC.
Results:
Over 4,000 participants engaged in the educational activity, 67% of whom were physicians, and 63% noting their specialty as oncology. Approximately 68% identified as treaters seeing 14 patients with CRC per week with 78% of those patients have HER2-positive CRC. All pre-post questions showed significant improvements in knowledge and competence related to HER2 amplification testing methodologies, trial eligibility criteria, identification of patients who would benefit from anti-HER2 targeted regimens, and adverse events associated with anti-HER2 agents. Following the activity, 51% were more likely to incorporate testing for HER2 expression level or amplification prior to the selection of targeted therapy for their patients. The greatest challenges faced when managing patients with HER2-positive mCRC were affordability of therapy for patients (50%), adherence to treatment schedules (25%) and patient anxiety about treatment efficacy (24%). The most common barriers to patient enrollment in clinical trials identified by clinicians were lack of trials at their institutions (35%), lack of trials in their geographic region (21%), and patient lack of interest (20%). Qualitative insights on intended practice changes were shared by learners post-activity.
Conclusions:
The outcomes of this educational activity demonstrate the effectiveness of education in improving knowledge and confidence from testing to adverse event management to better integrate new regimens into practice. Encouraging practice changes were also seen from the write-in responses from learners. Additional needs were also identified to further solidify HER2 testing as a prerequisite for anti-HER2 targeted therapies, selecting eligible patients, and timely management of adverse events.
Performance of a blood-based screening test for the early detection of colorectal cancer.
Authors: Nakamura Yoshiaki , Reiter Johannes , Babiarz Joshua , Srinivasan Preethi , Haghshenas Ehsan , Chen Tzu-Chun , Liang Nathan , Joshi Jayashree , Huang Hsiao-Yun , Kordi Misagh , Gutman Boris , Chan Wen-Ching , Tunc Ilker , Natarajan Prashanthi , Jurdi Adham A , Rabinowitz Matthew , Mitchell Bree , Kawli Trupti , Aleshin Alexey , Yoshino Takayuki
Published: January 2025

232

Background:
While the clinical benefit of highly sensitive screening tools for colorectal cancer (CRC) has been established, adherence rates remain low. The convenience and familiarity of blood-based testing may reduce disease burden through greater access and compliance to regular and recommended asymptomatic screening. We report on preliminary findings from a minimally invasive blood-based early cancer detection (ECD) screening test for CRC.
Methods:
Plasma samples from healthy individuals and CRC patients sourced from biobanks were included. A targeted panel composed of differentially methylated genomic regions was developed. Using an independent cohort of plasma samples, a machine-learning model was trained to classify patient samples into cancer-free and CRC based on observed differential methylation patterns in circulating cell-free DNA (cfDNA). The assay performance was calculated based on concordance with clinical diagnosis (CRC, cancer-free).
Results:
The test set included 440 individuals: 127 with a confirmed CRC diagnosis (47% stage I/II, mean age 65±12 years, male 46%) and 313 without cancer (mean age 56±10 years, male 41%). Overall sensitivity was 95% (95% CI: 88-100%), and specificity was 91% (95% CI: 84-98%). Among patients with stage I disease, sensitivity was 92% overall, and 88% in screen-detected individuals. Sensitivity was 100% (n=14/14) in microsatellite-high tumors and 95% (n=107/113) in microsatellite-stable tumors. Multivariate analysis demonstrated associations between methylation signal and tumor size, cancer stage, and sex. Compared with a tumor-informed, variant-based circulating tumor DNA (ctDNA) test (Signatera), we observed a PPA (positive percent agreement) of 100%. Moreover, the differentially methylated allele fraction (DMAF) across target regions strongly correlated with variant allele frequencies (VAFs) from the tumor-informed test (Spearman’s correlation coefficient, 0.85).
Conclusions:
Using epigenetic markers specific for CRC, we developed a sensitive and specific blood-based test to detect cfDNA from early-stage and asymptomatic disease. The methylation signal strongly correlated with ctDNA VAFs from a clinically validated tumor-informed test and increased with cancer stage and disease burden. This test could serve as a means to increase patient adherence rates for CRC screening, thereby improving patient outcomes.
Utilization of
SDC2
gene in conjunction with
SEPTIN9
gene methylation analysis for the diagnosis and efficacy assessment of colorectal cancer.
Authors: Xie Rongjia , Liu Zhuqing , Yin Xiaolan , Yuan Min , Luo Xinpei , Xu Qing
Published: January 2025

240

Background:
SDC2 gene encodes the transmembrane proteoglycan molecule Syndecan-2. Syndecan-2 protein affects the proliferation, migration and invasion of colorectal cancer cells by participating in the regulation of cell adhesion, tissue differentiation and angiogenesis. Plasma methylated SEPTIN9 gene has been shown to be a sensitive and specific biomarker for the detection of CRC, which is involved in apoptosis, pseudopod projection, tumor cell migration and invasion. The aim of this study is to validate the value of SDC2 and S9 gene methylation detection in the diagnosis and efficacy evaluation of CRC.
Methods:
A total of 102 patients were enrolled in the study. The methylation levels of fecal SDC2 gene and blood SEPTIN9 gene were detected by fluorescence PCR. The clinical diagnostic accuracy of SDC2 kit was evaluated by patients with benign gastrointestinal lesions, gastrointestinal tumors and healthy subjects. Combined detection of SDC2 and S9 to improve the detection rate of CRC. SDC2m levels were analyzed in 26 patients with partial remission or stable disease after palliative treatment and 32 patients with complete remission after radical surgery.
Results:
The detection rate of SDC2 in patients was 0.0% for UC and CD, 66.7% for AA and 60.0% for NA, 25.0% for HOP. For 8 healthy subjects with negative colonoscopies, the true negative rate was 100%. The detection rates of GC and EC were 50.0% and 0.0%, respectively. Data from 72 patients with CRC were evaluated, with a sensitivity of 89.1% (41/46,95%CI 0.798-0.985) for patients with untreated CRC. The sensitivity of SDC2 was 46.2% (12/26,95%CI 0.256-0.667) in patients with partial response or stable disease after palliative treatment. The difference was statistically significant (P < 0.001). The sensitivity of S9 for CRC detection was 88.2% (15/17, 95%CI 0.712-1.053). By two tests, 94.1%(16/17, 95%CI 0.816-1.066) of CRC cases could be detected.The sensitivity was 89.1% (41/46 95%CI 0.798-0.985) in untreated CRC and 46.2% (12/26 95%CI 0.256-0.667) in patients with PR and SD after chemotherapy/radiotherapy/targeted/immunotherapy. The difference rate of SDC2m between two groups was statistically significant (P < 0.001). Among 46 untreated patients with CRC, 32 patients with positive SDC2m underwent radical surgery, of which 30 CR patients turned SDC2m test negative after surgery. We found reduced SDC2m in stool from patients with clinical benefit (CR+PR+SD).
Conclusions:
Detection of SDC2m in untreated CRC patients has high sensitivity and has the potential to become a non-invasive diagnostic tool for CRC. Combination of S9 and fecal SDC2 could improve the detection rate of SDC2 in non-dominant population. The methylation level of SDC2 may be helpful for postoperative follow-up of CRC after radical surgery, prediction of recurrence, and monitoring the efficacy of a series of palliative treatments for CRC.
Impact of baseline alterations in HER2-pathway oncogenic drivers on response to anti-HER2 therapy in patients (pts) with HER2-amplified advanced colorectal cancer (aCRC).
Authors: Hoyek Celine , Pirozzi Angelo , Zheng-Lin Binbin , Abidoye Oluseyi , Eslinger Cody , Nakamura Yoshiaki , Ramaker Ryne , Sonbol Mohamad Bassam , Wu Christina , Borad Mitesh J. , Ahn Daniel H. , Ikeda Masafumi , Shibuki Taro , Yoshino Takayuki , Strickler John H , Bekaii-Saab Tanios S.
Published: January 2025

243

Background:
HER2-amplified aCRC is associated with poor prognosis despite new anti-HER2 regimens. Insight on biomarkers that predict response to these therapies is limited. This study aims to evaluate whether baseline alterations in oncogenic drivers along the HER2 pathway predict response to anti-HER2 therapy in HER2-amplified aCRC.
Methods:
In this international multi-center study involving Mayo Clinic, Duke Cancer Institute and National Cancer Center Hospital East (Japan), we collected baseline genomic alterations from tissue or blood samples using next-generation sequencing (NGS) prior to anti-HER2 therapy initiation. We defined PIK3CA, RAS, RAF, MAP2K, and MET as oncogenic drivers of resistance within the HER2 pathway. Overall survival (OS) was evaluated with the Kaplan-Meier method and a log-rank test was used to compare median OS (mOS) between pts with and without alterations in the above genes. A chi-square test (significance level 0.05) was performed to compare overall response rate (ORR) and disease control rate (DCR).
Results:
We identified 39 pts with HER2-amplified aCRC and baseline NGS. Median age was 57 (range 30-77), 54% were male. Baseline alterations in HER2 pathway oncogenic drivers were identified in 17 pts (43.5%). 18 (46%) received monoclonal antibodies (mAbs) plus tyrosine kinase inhibitors, 12 (30%) received dual mAbs and 7 (18%) received trastuzumab deruxtecan. The mOS was 41.9 months (mos) (95%CI 23.7-60.1) for other alterations vs 24.2 mos (95%CI 14.1-34.3) in pts with HER2 pathway alterations (p = 0.1). ORR was 47% vs 41% (p = 0.7) and DCR 82% vs 73% (p = 0.4), for pts with HER2 pathway alterations and without HER2 pathway alterations, respectively. 4 pts receiving trastuzumab/tucatinib had complete response, none of which had HER2 pathway alterations.
Conclusions:
Pts with baseline alterations in oncogenic drivers of the HER2 pathway had clinically worse outcomes compared to pts without such alterations despite receiving HER2-targeted therapy, though results lacked statistical significance. Larger studies are needed to confirm the lack of benefit from anti-HER2 therapy in this subgroup.
Effects of targeting CTMP on immunogenicity of MSI-L colon adenocarcinoma cells by metabolism and cell cycle modulation.
Authors: Gu Cheng , He Rong , Gao Jie , Xie Rongjia , Liu Zhuqing , Xu Qing
Published: January 2025

246

Background:
Regimen of metastatic colon cancer (mCOAD) is moving towards combination of immune checkpoint inhibitors (ICBs) and targeted therapy, however ICBs are rarely effective in MSI-L metastatic colon cancers, limiting options for backline treatments, new targeted therapy is on demand to improve immunogenicity of MSI-L mCOAD. As targeting fatty acid metabolism or cell cycle has shown potential in improving the efficacy of ICBs, our team focused on CTMP, a thioesterase (ACOT) family member, mainly modulates fatty acid β oxidation, meanwhile it binds to phosphorylation sites of AKT thus intervenes cell cycle, currently its role on immunogenicity of COAD is not clear.
Methods:
Correlation between CTMP and OS in MSI-L colon cancer patients was assessed by KM plotter in GEO database.11 Clinical samples of MSI-L colon cancer, who received a third-line treatment regimen of anti-PD-1 and fruquintinib, were collected then applied in immunofluorescence and western blot analyses to evaluate CTMP and MHC-I expression. In vitro, Lentiviral transfection of targeted genes were stably established,then applied in RNA-seq and metabolic assays. Proteomic analysis and co-IP were applied to explore CTMP-modulating pathway. In vitro, IFNγ was intratumorally injected.
Results:
KM curve showed CTMP was negatively correlated with OS in MSI-L COAD in GEO database. In clinical samples, lower CTMP expression and higher MHC-I expression were observed in partial response (PR) than progressive disease (PD) group. In vitro, CTMP-OE reduced MHC-I, increased AKT phosphorylation and immune checkpoints (PD-L1, IDO-1), promoted clone formation. Seahorse assay showed increased capacity of glycolysis and oxidative phosphorylation in CTMP-OE than vector. RNA-seq showed CTMP-OE reduced MHC-I augmentation under IFN-γ treatment, meanwhile glucose metabolism genes, ACOT family ,immune checkpoints were also up-regulated, indicating ACOT family related metabolism promotion and immunogenicity suppression of COAD. Proteomic analysis and co-IP assay indicated CTMP interacts REV7, a key mitotic regulatory protein. Enzyme activity assay showed REV7 negatively regulates CDK1. Furthermore, REV7-OE alone is capable to induce MHC I augmentation and G2 arrest, accordingly CTMP-KD enhanced REV7's negative modulation on CDK1,contributing to G2 arrest, that also augmented MHC I . In homologous mice tumor-bearing model, tumor shrinkage was observed in CTMP-KD/ REV7-OE group. CTMP-KD/ REV7-OE increases MHC I expression,CD8+ T cell infiltration under IFN γ intra-tumoral injection.
Conclusions:
In summary, our studies suggested that CTMP regulates the metabolism of colorectal cancer and intervenes MHC-I molecules expression, and targeting CTMP is potential in suppressing tumor cell cycle and promoting immunogenicity through its modulation on REV7.
BTN1A1 expression in colon cancer: Implications for immunotherapy and patient stratification.
Authors: Yoo Stephen S. , Hong Bong-Ki , Wu Chunai , Lee Seung Hoon , Kim Youngseung , Lee Soohyeon , Jung Hyunjin
Published: January 2025

249

Background:
Butyrophilin 1A1 (BTN1A1) is a promising immune checkpoint protein offering a novel option for immunotherapy. We discovered that BTN1A1 and PD-L1 expression are mutually exclusive through the JAK/STAT pathway in various tumors. Recently, Nelmastobart, an antibody targeting BTN1A1, successfully completed a Phase 1 clinical trial at three sites in the United States and two in the Republic of Korea, spanning 98 weeks. This abstract focuses on the results from the Phase 1 trial in patients with colorectal cancer (CRC), emphasizing biomarker diagnostics and therapeutics derived from translational research.
Methods:
We conducted a first-in-human, multicenter, open-label Phase I clinical trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of hSTC810 monotherapy in CRC patients. Extensive analyses of BTN1A1 expression were performed using patient specimens through immunohistochemistry and multi-immunofluorescence techniques to identify critical biomarkers and accurately assess nelmastobart's anticancer activity. We then analyzed progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety alongside translational research findings using patient tissue samples.
Results:
A total of 47 patients were enrolled in the study. The median PFS across all cohorts was 1.9 months, while the median Kaplan-Meier estimate for OS was 12.8 months. Among the 16 CRC patients enrolled, tissue samples were obtained and analyzed using IHC in 12 patients and OPAL staining in 7 patients. The objective response rate (ORR) for CRC was 2.3%. The median progression-free survival (PFS) and overall survival (OS) were 3.6 months and 11 months, respectively. Notably, PFS, OS, and ORR strongly correlated with BTN1A1 expression levels in CRC patients. High levels of BTN1A1 expression in colorectal tumor tissues correlated with clinical outcomes, identifying BTN1A1 as a potential biomarker for predicting patient responses to targeted therapies. The mutual exclusivity of BTN1A1 and PD-L1 expression suggests that BTN1A1 could serve as a diagnostic marker to identify patients who may be unresponsive to PD-1/PD-L1 blockade therapy and might benefit from BTN1A1 blockade therapy.
Conclusions:
This Phase 1 clinical trial demonstrated that antibody-mediated BTN1A1 blockade effectively suppresses tumor growth in patients with BTN1A1-positive CRC. These findings suggest that BTN1A1-targeted therapies could provide a viable treatment option for patients with colon cancers that are refractory or resistant to anti-PD-1/PD-L1 therapies.
Clinical trial information: NCT05231746
.
Analysis of tumor microenvironmental features of primary and synchronous liver metastases from patients with colorectal cancer using a deep learning algorithm.
Authors: Emiloju Oluwadunni Eunice , Saberzadeh Ardestani Bahar , Smoot Rory L , Graham Rondell P. , Pai Rish , Sinicrope Frank A.
Published: January 2025

251

Background:
The development of colorectal liver metastases (CRLM) is associated with poor prognosis, and recent data suggest that metastasis to the liver is associated with resistance to immunotherapy. We characterized the microenvironment of primary colorectal carcinomas (CRCs) relative to their synchronous CRLM using a validated segmentation algorithm that quantifies 15 distinct morphologic tumor features.
Methods:
Adult CRC patients with synchronous CRLM (N=57) at Mayo Clinic were identified from the electronic health record using Epic Slicer Dicer and from an internal database. Tumor H&E sections were digitized and reviewed for quality control (RKP). QuantCRC (Aiforia, Inc) was applied to digitized images to extract 15 GI pathologist pre-defined morphological features. Tumor features were compared between primaries and CRLM using the Kruskal–Wallis test. The project was approved by the Mayo Clinic Institutional Review Board.
Results:
The study included 57 patients (median age 59 years [IQR 50, 73], 51% female) with CRC primaries and synchronous CRLM. Among primaries, 20 (35%) were right-sided and 37 (65%) were left-sided. QuantCRC identified 6 of 15 morphological features that differed significantly between primaries and their CRLM, including reduced stroma, more high-grade and necrosis, and a higher tumor: stromal ratio (TSR) in CRLM (Table). The increase in TIL density in CRLM vs the primary tumor was of borderline significance (p =0.053). Among patients with left-sided primary tumors, their CRLM had significantly higher TSR, percent high-grade, percent necrosis, and TIL density compared to the primary (all p values ≤ 0.02). Among right sided primaries, CRLM had a significantly reduced percent mature stroma (p=0.034) whereas percent necrosis was increased (p =0.01).
Conclusions:
Using deep learning, we identified tumor morphological features that differed significantly between primary CRC and their synchronous CRLM. This included higher TSR in CRLMs compared to primaries that is associated with epithelial-mesenchymal transition and has been shown to contribute to treatment resistance. Analysis of tumor morphological features with patient prognosis is ongoing.

Deep learning-derived morphological features of primary CRC and CRLM.

Morphological feature (Median)
Primary tumor
Liver metastasis

P-value

Tumor-Stroma Ratio
0.78
1.50

0.008

% High-grade

23.08
31.72

0.005

TIL Count
44.36
60.20
0.053

% Necrosis
6.35
19.32

<0.001

%Signet Ring Cells
0.25
0.13
0.088

TB/PDC
0.89
1.13
0.484

% Stroma
54.89
40.98

<0.001

% Immature Stroma
46.76
34.13

<0.001

% Mature Stroma
6.27
5.08

0.030
Leveraging large-scale PDO-based assays to optimize antibody-drug conjugate efficacy in CRC.
Authors: Polit Lélia , Mathieu Jacques RR , Jerome Cartry , Bedja Sabrina , Boileve Alice , Ducreux Michel Pierre , Jaulin Fanny , Ronteix Gustave
Published: January 2025

261

Background:
Clinical trials are one of the major barriers in contemporary drug development. Functional assays based on patient-derived organoids (PDO) are a promising new tool for derisking clinical development of new therapies, but their use has been limited due to small cohort sizes and the absence of systematic validation studies. Using the largest cohort of matched PDOs, longitudinal clinical data, transcriptomic and WES data in CRC, we explore the use of large PDOs collections to characterize ADC efficacy and affinity through systematic mapping of the relationship between target antigen affinity and payload efficacy.
Methods:
We have assembled a collection of 85 PDOs from colorectal cancer (CRC), generated from primary tumour samples and metastatic biopsies. Patients ranged from 32 to 89 years old and had experienced an average of 1.54 lines of treatment prior to the PDO-generating tissue sampling. Using gene expression levels of well known target antigens such as CEACAM5, ERBB2, MSLN and TROP2 as a proxy for protein concentration, we explore the relationship between the target antigen affinity and the efficacy of a subset of common payloads including topoisomerase and microtubule inhibitors. This allows us to identify the relationship between two of the three main vectors of ADC efficacy in CRC.
Results:
We show that topoismerase inhibitor and microtubule inhibitor efficacy relates to the RNA expression level of multiple target antigens commonly used in active clinical trials in CRC. These data match the target antigen and payload couples currently under development or approved in the clinic. We are developing a tool to optimize clinical trial design. This approach will allow us to match patients more accurately with the appropriate payload, ensuring a higher likelihood of response.
Conclusions:
We report that large-scale PDO-based assays can be a useful tool to anticipate clinical readouts. This work suggests that well-characterized PDO collections could also help redefine patient populations, increasing the likelihood of identifying those more likely to respond to a given ADC, and thus improving the success rates of clinical studies for new treatments in CRC.