Advanced Colorectal Research Articles

Phase I study of autologous CD8+ and CD4+ transgenic T cells expressing high-affinity KRAS G12V mutation-specific T cell receptors (FH-A11KRASG12V-TCR) in patients with metastatic pancreatic, colorectal, and non-small cell lung cancers with KRAS G12V mutations.

TPS792 Background: KRAS, the most common driver oncogene in human malignancies, has predictable mutations. 85% of RAS mutations occur at the Glycine (G) 12 position with G12V being amongst the most common. Cancers driven by mutant KRAS include pancreatic (PDAC), colorectal (CRC), and non-small cell lung (NSCLC) malignancies. The prognosis of patients with activating KRAS mutations remains poor. Preliminary anti-tumor activity has been observed with T cell receptor (TCR) T cell therapies targeting KRAS mutations, but durable clinical benefit is lacking. FH-A11KRASG12V-TCR is an autologous CD8+ and CD4+ transgenic T cell product expressing (1) an HLA-A*11-restricted, high affinity KRASG12V mutation-specific T cell receptor (TCR) and (2) the wildtype CD8α/β coreceptor enabling CD4+ T cell recognition of KRAS G12V presented on an MHC class I allele mediating helper T cell activity and cytotoxicity. The TCR sequence is derived from the peripheral blood of a healthy HLA-A*11+ adult based on a strong pre-clinical dataset. Methods: This is an ongoing, investigator-initiated, phase 1, first-in-human, single-center, dose escalation study of FH-A11KRASG12V-TCR. The aims are to evaluate the safety, tolerability, maximum tolerated dose (MTD), and preliminary anti-tumor activity of FH-A11KRASG12V-TCR in patients with advanced PDAC, CRC, and NSCLC who express the HLA-A*11-restricted KRAS G12V mutation. Dose modification is guided by the Bayesian Optimal Interval design (BOIN). Patients are initially treated in cohorts of 3 at each dose level (DL). BOIN will be used to identify the recommended dose for subsequent patients. The planned target doses are 5 x 10 9 transgenic TCR T cells in DL 1 with dose escalation up to 15 x 10 9 transgenic TCR T cells in DL 3. This study enrolls patients who are 18 years or older, HLA-A*11:01-positive, with KRAS G12V mutated metastatic PDAC, CRC, or NSCLC. Patients must have progressed on or be intolerant of at least one line of prior therapies including any targeted therapies indicated for their current malignancy. Patients undergo leukapheresis prior to treatment and receive lymphodepleting chemotherapy with either cyclophosphamide intravenously (IV) and fludarabine IV on days -6, -5, and -4 or bendamustine IV on days -4 and -3. FHA11KRASG12V-TCR is administered IV on day 0. The dose-limiting toxicity observation period is 28 days. Patients may receive an additional FHA11KRASG12V-TCR IV infusion at the same or lower dose as soon as 28 days or up to 1 year after the first infusion. The study is actively recruiting. Clinical trial information: NCT06043713 .

Candidate molecular alterations associated with potential resistance in KRAS G12D gastrointestinal cancers.

3519 Background: KRAS G12D commonly occurs in pancreatic (PDAC) and colorectal (CRC) cancers. Though developing KRAS G12D inhibitors is pertinent, it is expected that primary and acquired resistance will limit efficacy, similar to those seen with KRAS G12C inhibitors. Here, we assessed the prevalence and outcomes of candidate mutations co-occurring with KRAS G12D in PDAC and CRC using liquid biopsy data. Methods: Patients with advanced CRC and PDAC tested with Guardant360 genomic profiling from 2020 to 2023 (~2500 & 3500 samples) were included. Candidate resistance mutations were determined based on mutations reported following KRAS G12C inhibition. Patients with advanced CRC and PDAC tested with Guardant360 at Mayo Clinic (2016-2023) (1158 & 904 samples) were assessed for overall survival (OS). Patients were divided into three groups: KRAS G12D alone, KRAS G12D with candidate resistance alterations, and KRAS G12D not detected (ND). OS was estimated using Kaplan-Meier method. Cox regression was used for multivariable survival analyses. Results: The Guardant360 database reported KRAS G12D in 16.5% of CRC and 40.2% of PDAC samples. The Table below summarizes the most frequent candidate resistance alterations co-occurring with KRAS G12Dincluding point mutations of KRASand PIK3CAand amplifications of EGFR, KRAS, BRAFand MYC. In the Mayo cohort, 8.9% of CRC and 23.5% of PDAC patients had KRAS G12D. In CRC, those with KRAS G12Dand ≥1 candidate resistance alteration had a significantly lower OS (mOS 18.7m) than KRAS G12D alone (30.9m), and ND (37.3m) ( p=0.004). The presence of concurrent candidate resistance alterations with KRAS G12D remained a poor prognostic factor with HR 2.1 (95% CI: 1.3 – 3.2, p=0.001) after adjusting for age and other patient characteristics. Similarly, in PDAC, those with KRAS G12D and ≥1 resistance mutation had significantly lower OS (mOS 8.1m) than KRAS G12D alone (10.5m) and ND (16.1m) (p<0.0001). In multivariable analyses, both KRAS G12D with candidate resistance alterations (HR 2.1, 95% CI: 1.4-3.3, p<0.001) and G12Dalone (HR 1.6; 1.3–2.0, p<0.001) were poor prognostic factors. Among patients with serial Guardant360, treatment response trended with KRAS G12D variant allele frequency. Conclusions: Circulating tumor DNA testing is a useful tool to reveal candidate molecular alterations linked to potential resistance to KRAS G12D targeting in patients with KRAS G12D gastrointestinal cancers. KRAS G12D with these concurrent molecular alterations is a poor prognostic factor in both PDAC and CRC. [Table: see text]

Abstract CT082: Phase I study of autologous CD8+ and CD4+ transgenic T cells expressing high-affinity KRAS G12V mutation-specific T cell receptors (FH-A11KRASG12V-TCR) in patients with metastatic pancreatic, colorectal and non-small cell lung cancers with KRAS G12V mutations

Abstract Background: KRAS, the most common driver oncogene in human malignancies, has predictable mutations. 85% of RAS mutations occur at the Glycine (G) 12 position with G12V being amongst the most common. Cancers driven by mutant KRAS include pancreatic (PDAC), colorectal (CRC), and non-small cell lung (NSCLC) malignancies. The prognosis of patients with activating KRAS mutations remains poor. Preliminary anti-tumor activity has been observed in the clinic with T cell receptor (TCR) T cell therapies targeting KRAS mutations, but durable clinical benefit is lacking. Rationale: FH-A11KRASG12V-TCR is an autologous CD8+ and CD4+ transgenic T cell product expressing (1) an HLA-A11-restricted, high affinity KRASG12V mutation-specific T cell receptor (TCR) and (2) the wildtype CD8α/β coreceptor enabling CD4+ T cell recognition of KRAS G12V presented on an MHC class I allele mediating helper T cell activity and cytotoxicity. The TCR sequence is derived from the peripheral blood of a healthy HLA-A11+ adult based on a strong pre-clinical dataset. Methods: This is an ongoing, investigator-initiated, Phase 1, first-in-human, single-center, open-label dose escalation study of FH-A11KRASG12V-TCR. The aims are to evaluate the safety, tolerability, maximum tolerated dose (MTD), and preliminary anti-tumor activity of FH-A11KRASG12V-TCR in patients with advanced PDAC, CRC, and NSCLC who express the HLA-A11-restricted KRAS G12V mutation. Dose modification will be guided by the Bayesian Optimal Interval design (BOIN). Patients will initially be treated in cohorts of 3 at each dose level (DL). BOIN will be used to identify the recommended dose for subsequent patients. The planned target doses are 5 x 109 transgenic TCR T cells in DL 1 with dose escalation up to 15 x 109 transgenic TCR T cells in DL 3. This study enrolls patients who are 18 years or older, HLA-A*11:01-positive, with KRAS G12V mutated metastatic PDAC, CRC, or NSCLC. Patients must have progressed on or be intolerant of at least two lines of prior therapies including any targeted therapies indicated for their current malignancy. Patients undergo leukapheresis prior to treatment and receive lymphodepleting chemotherapy with either cyclophosphamide intravenously (IV) and fludarabine IV on days -6, -5, -4, and -3 or bendamustine IV on days -4 and -3. FHA11KRASG12V-TCR is administered IV on day 0. The dose-limiting toxicity observation period is 28 days. Patients may receive an additional FHA11KRASG12V-TCR IV infusion at the same or lower dose as soon as 28 days or up to 1 year after the first infusion. One patient enrolled to date and the study is actively recruiting (NCT06043713). Citation Format: Elena Gabriela Chiorean, Andrew Coveler, Rachael Safyan, Stacey Cohen, Sylvia Lee, Cecilia Yeung, Mary Redman, Thomas Schmitt, Aude Chapuis, Philip D. Greenberg. Phase I study of autologous CD8+ and CD4+ transgenic T cells expressing high-affinity KRAS G12V mutation-specific T cell receptors (FH-A11KRASG12V-TCR) in patients with metastatic pancreatic, colorectal and non-small cell lung cancers with KRAS G12V mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT082.

An international phase II trial and immune profiling of SBRT and atezolizumab in advanced pretreated colorectal cancer

BackgroundImmuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the colorectal (CRC) cohort analysis from the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in advanced cancer patients.MethodsEligible patients received atezolizumab 1200 mg every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2nd cycle (recommended dose of 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-year progression-free survival (PFS) rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling.ResultsSixty pretreated (median of 2 prior lines) advanced CRC patients (38 men [63%]; median age, 59 years [range, 20–81 years]; 77% with liver metastases) were enrolled in five centers (France: n = 4, Spain: n = 1) from 11/2016 to 04/2019. All but one (98%) received atezolizumab and 54/60 (90%) received SBRT. The most frequently irradiated site was lung (n = 30/54; 56.3%). Treatment-related G3 (no G4-5) toxicity was observed in 3 (5%) patients. Median OS and PFS were respectively 8.4 [95%CI:5.9–11.6] and 1.4 months [95%CI:1.2–2.6], including five (9%) patients with PFS > 1 year (median time to progression: 19.2 months, including 2/5 MMR-proficient). Best overall responses consisted of stable disease (n = 38; 64%), partial (n = 3; 5%) and complete response (n = 1; 2%). Immune-centric multiplex IHC and RNAseq showed that SBRT redirected immune cells towards tumor lesions, even in the case of radio-induced lymphopenia. Baseline tumor PD-L1 and IRF1 nuclear expression (both in CD3 + T cells and in CD68 + cells) were higher in responding patients. Upregulation of genes that encode for proteins known to increase T and B cell trafficking to tumors (CCL19, CXCL9), migration (MACF1) and tumor cell killing (GZMB) correlated with responses.ConclusionsThis study provides new data on the feasibility, efficacy, and immune context of tumors that may help identifying advanced CRC patients most likely to respond to immuno-radiotherapy.Trial registrationEudraCT N°: 2015–005464-42; Clinicaltrial.gov number: NCT02992912.

Continuous maintenance (Maint) capecitabine (Cape) dosing for colorectal (CRC) and pancreatic cancers (PC): A single-institution, retrospective, real-world study.

789 Background: Cape is an oral fluoropyrimidine (FP) used as maint therapy in CRC and PC. While the standard FDA dosing is 1250 mg/m2 twice daily (BID) for 14 days followed by 7 days off in a 21-day cycle, there are variations across institutions as to the preferred schedule. To improve tolerability and convenience, our institution adopted a “continuous” dosing schedule where cape is taken BID Monday-Friday (M-F) with a treatment break on Saturday and Sunday. Here, we describe our institution’s experience with continuous maint dosing in advanced CRC and PC patients (pts) and explore real-world outcomes. Methods: Pts ≥ 18 years of age treated with continuous maint cape (+/- bevacizumab) after any line of therapy for stage 4 CRC/PC or locally advanced PC between 1/2016-12/2020 were identified in the COTA real-world database. The final study population included 35 PC and 85 CRC pts. Pt characteristics were analyzed descriptively and progression-free survival (PFS) was calculated using Kaplan Meier methods. Results: Among the 35 PC pts, the median age was 66 years (IQR: 61-73), 57.1% were females, and 65.7% were Caucasian. Among the 85 CRC pts, the median age was 54 years (IQR: 47-66), 47.1% were females, and 55.3% were Caucasian. Most PC (71.4%) and CRC (57.7%) pts were initially prescribed a total daily cape dose of 2 g (range 0.5-4 g). Dose adjustments, including dosage/schedule changes, occurred 11 times amongst PC and 36 times amongst CRC pts, and the leading cause was toxicity (72.7% in PC, 55.6% in CRC). Among PC pts, 14.3% had a dose reduction, 3% had a dose increase, and 11.4% switched to an alternative dosing schedule. Among CRC pts, these rates were 32.9%, 12.9%, and 9.4%, respectively. The leading cause of maint discontinuation was progression of disease (POD) (55.6% in PC, 59.3% in CRC). Additional outcomes are summarized in the table. Conclusions: Although maint FP is an established standard of care, it is often underutilized due to inherent inconveniences and toxicities associated with FDA cape dosing or intravenous FP therapy. The PFS reported here using a continuous cape dosing (predominantly starting at 2 g daily dosing) was in range with those previously reported in PC/CRC 1st-line maint studies using FDA cape dosing or intravenous FP. The rates of cape discontinuation attributed to toxicity we report may be confounded by not controlling for the treatment setting. We argue fixed cape dosing (1 g BID) M-F should be considered a standard maint regimen based on efficacy, convenience, tolerability, and feasibility of dose adjustments.[Table: see text]

ARTIFICIAL INTELLIGENCE, VIRTUAL REALITY AND ROBOTICS IN COLORECTAL SURGERY USING MASTER-CLASS TECHNOLOGICAL INNOVATIONS

ARTIFICIAL INTELLIGENCE, VIRTUAL REALITY AND ROBOTICS IN COLORECTAL SURGERY USING MASTER-CLASS TECHNOLOGICAL INNOVATIONS

Phase I expansion study of P-cadherin-targeted 90Y-FF-21101 antibody in advanced chemorefractory colorectal and pancreatic-biliary cancers.

78 Background: Overexpression of the cell-cell adhesion protein P-cadherin has been associated with a more aggressive cancer cell phenotype, cancer stem cell properties, tumor invasion and metastasis. We determined the safety and recommended Phase II dose of the yttrium-labeled P-cadherin-targeted 90Y-FF-21101 monoclonal antibody (mAb) in patients (pts) with advanced tumors, and focused our expansion study in advanced colorectal (CRC) and pancreatic-biliary cancers (non-CRC tumors). We report the safety, efficacy, and correlative pharmacokinetics (PK)/pharmacodynamics (PD) in this cohort. Methods: Pts enrolled must have progressed on all standard therapies. 25 mCi/m2 (8 mCi/mg mAb) 90Y-FF-21101 was administered intravenously every 12 weeks (wks) until disease progression or unacceptable toxicity. Disease response was assessed based on RECIST v1.1 every 8 wks (1 cycle = 28 days). Serum mAb PK, existence of anti-drug antibodies (ADA) and tumor P-cadherin expression were also evaluated. Results: 31 pts [mean age 63 (range, 39-89); 14F/17M; median number of prior therapies, 3 (range, 1-11)] with CRC (18) and non-CRC tumors [pancreatic (8), cholangiocarcinoma (3), duodenal (2)] received a median of 1 (range, 1-2) dose of 90Y-FF-21101. Median duration on study was 8.1 (3.9 – 27) wks (CRC) and 8 (1.1-17.1) wks (pancreatic-biliary). Myelosuppression was the most common treatment-related adverse event [thrombocytopenia (87%; Grade (Gr) 3/4 in 45%), lymphopenia (74%; Gr 3/4 in 61%), anemia (52%; Gr 3/4 in 13%), leukopenia (32%; Gr 3/4 in 16%)], in addition to fatigue (68%, 1 Gr 3) and nausea (39%, 1 Gr 3). Three pts required dose reduction to 20 mCi/m2 with subsequent infusion after Gr 3/4 thrombocytopenia [(pancreatic (2), CRC (1)]. The clinical benefit rate in pts with CRC based on stable disease (SD) for ≥8 wks is 43.8% (7/16 pts), with a median PFS of 8.1 wks and OS of 27 wks [median PFS, 7.9 wks; OS, 17.1 wks in non-CRC]. Longer-term SD was maintained in 2 pts with CRC for 17-24 wks; one continues on treatment. Enrollment is ongoing in the non-CRC cohort. FF-21101 has a mean t1/2 of approximately 65 hours, and post-treatment ADA titers have been observed in < 5% of pts. Tumor P-cadherin expression analysis by IHC demonstrated H-scores > 150 in 88% (14/16) of CRC pts, 75% (9/12) for non-CRC; 2 CRC pts with SD ≥17 wks had H-scores ≥190. Conclusions: 90Y-FF-21101 administered every 12 wks demonstrated expected toxicities and has been generally well-tolerated, with preliminary evidence of benefit demonstrated in heavily pre-treated pts with advanced CRC. The optimal dose and schedule for this radioimmunotherapeutic will continue to be explored, along with pre-treatment P-cadherin expression as a predictive biomarker for disease response. Clinical trial information: NCT02454010.

597P - Meta-analysis of KRAS mutation as prognostic factor in patients (pts) with resection of colorectal (CRC) liver metastases: Tumour burden and Sidedness analysis

BackgroundIn patients with advanced CRC, KRAS mutations predicts response to treatment with EGFR inhibitor. The Liver metastases selection criteria include anatomic and biological variables. Recent evidence support the prognostic value of KRAS (molecular criteria) in pts with resectable hepatic metastases irrespective of systemic treatment. PURPOSE: To investigate the prognostic value of KRAS in patients undergoing liver resection for colorectal liver metastases (CRLM). Tumour sidedness and tumour burden was also evaluated. MethodsPubmed, Emabase and Cochrane Library databases were searched systematically. Data from published full-text articles reporting KRAS-stratified survival outcomes, recurrence free survival (RFS) and/or overall survival (OS) after resection of CRLM cancer. METHEPAR results, a local multi-institutional CRLM database, was also included. Hazard ratios (HR) and 95% CI from analyses were pooled in meta-analysis, and a random-effects model was used to calculate overall results. ResultsThe search returned 69 articles, of which 20, including METHEPAR, met the inclusion criteria. A total of 3819 patients were included. The mutation rate was 33.5% (IQR: 26.3-38.5). Pooled analysis showed that KRAS mutations predicted a significantly worse both RFS (HR: 1.55; 95% CI: 1.38-1.75) and OS (HR: 1.85; 95% CI: 1.57-2.19) in patients who underwent surgical resection of CRLM. In a subgroup analysis regarding sideness, studies involving more proportion of ptes with right sided tumours, had similar OS compare to those with proportion (HR:1.74; 95% CI 1.40; 2.16) p=0.19. Liver-only mets had a similar OS compare to those with more disseminated diseasés burden (HR:1.76;95% CI1.46; 2.12). ConclusionsThis meta-analysis confirm, as in previous one that KRAS mutations is a poor prognostic biomarker, associated with worse survival outcomes, in patients undergoing hepatic resection of CRLM, regardless of tumor sidedness and disease burden. KRAS mutation should be considered in the evaluation of pts. having liver metastasis for surgical resection. Legal entity responsible for the studyAlexander Fleming Institute. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Camrelizumab Combined With Apatinib in the Treatment of Patients With Advanced Gastric Cancer and Colorectal Cancer

Camrelizumab Combined With Apatinib in the Treatment of Patients With Advanced Gastric Cancer and Colorectal Cancer

Abstract 616: Literature review and meta-analyses of the prevalence of microsatellite instability high (MSI-H) and deficient mismatch repair (dMMR) for colorectal (CRC), gastric (GC), endometrial (EC) and ovarian cancers (OC) in Chinese population

Abstract Purpose Given the high prevalence of MSI-H/dMMR in gastrointestinal and gynecologic cancers we systematically collected published studies and investigated its’ prevalence for Chinese CRC, GC, EC, OC subjects to better understand the size of potential target population available for pembrolizumab treatment in China. Experimental Design Both Chinese and English literature were searched in WanFang and PubMed database respectively. Studies were included if they assessed prevalence of MSI-H by PCR based method investigating 5 markers from NCI or Promega panel, and/or dMMR by immunohistochemistry (IHC) for all 4 MMR proteins. Studies focusing only on hereditary or sporadic cancer were filtered out. Among eligible studies, meta-analyses (DerSimonian Laird random effect model) were performed on the proportion of MSI-H/dMMR for each tumor type by R metafor package. Prevalence for advanced stage (III/IV) were also extracted if the data were available. Results For CRC, the prevalence of MSI-H estimated from 11 studies (13.7% [10.2-17.6%]) was similar as that of dMMR from 22 studies (14.6% [12.3-17.1%]). Pooled prevalence of MSI-H/dMMR from 32 studies (12,341 subjects) was estimated at 14.1% (12.2-16.1%), and 9.7% (7.2-12.5%) from 17 studies (3,933 subjects) for advanced stage CRC. The prevalence estimation for GC, EC and OC were 18.5%, 26% and 12.9% respectively. Further, the prevalence in advanced stage cancer, regardless of the cancer type, tended to be numerically lower than the all-stage combined prevalence. Conclusions This was the first study comprehensively integrating published studies to estimate prevalence of MSI-H/dMMR across 4 main tumor types for Chinese subjects. The meta-analysis indicated the prevalence of MSI-H/dMMR for all or advanced stage Chinese cancer patients might be similar as that for western population. Citation Format: Xiaoqiao Liu, Jiaqi Fan, Kai-Li Liaw, Mo Xu, Yu Zhou, Mayur Amonkar, Gefei Zeng. Literature review and meta-analyses of the prevalence of microsatellite instability high (MSI-H) and deficient mismatch repair (dMMR) for colorectal (CRC), gastric (GC), endometrial (EC) and ovarian cancers (OC) in Chinese population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 616.

Providing complex GI surgical care with minimally invasive approaches: a survey of the practice patterns of Fellowship Council alumni.

The Fellowship Council (FC) oversees 172 non-ACGME surgical fellowships offering 211 fellowship positions per year. These training programs cover multiple specialties including Advanced gastrointestinal (GI), Advanced GI/MIS, Bariatric, Hepatopancreaticobiliary (HPB), Flexible Endoscopy, Colorectal, and Thoracic Surgery. Although some data have been published detailing the practice environments (i.e., urban vs. rural) and yearly total case volumes of FC alumni, there is a lack of granular data regarding the practice patterns of FC graduates. The aim of this study was to gather detailed data on the specific case types performed and surgical approaches employed by recent FC alumni. A 21-item survey covering 64 data points was emailed to 835 FC alumni who completed their fellowship between 2013 and 2017. Email addresses were obtained from FC program directors and FC archives. We received 327 responses (39% response rate). HPB, Advanced Colorectal, and Advanced Thoracic alumni appear to establish practices focused on their respective fields. Graduates from Advanced GI, Adv GI/MIS, and Bariatric programs appear to build practices with a mix of several complex GI case types including bariatrics, colorectal, foregut, HPB, and hernia cases. This is the first large data set to provide granular information on the practice patterns of FC alumni. FC trained surgeons perform impressive volumes of complex procedures, and minimally invasive approaches are extremely prevalent in these practices. Further, many graduates carve out practices with large footprints in robotics and endoscopy.

Meta-analysis of KRAS mutation as prognostic factor in patients (pts.) with resection of colorectal (CRC) liver metastases: Tumor burden and sideness analysis.

e15533Background: In pts. with advanced CRC, KRAS mutations predicts response to treatment with EGFR inhibitor. The Liver metastases selection criteria include anatomic and biological variables. Re...

Analysis of the Lipid Profile in Patients with Colorectal Cancer in Advanced Stages

Backgrounds:Colorectal (CRC) is one of the main cause of cancer worldwide. The search for noninvasive markers for diagnosis and monitoring as the use of analytical technologies such as mass spectrometry (MS), which allowed the search for lipid metabolites as candidates for probable biomarkers are needed.Objective and Methods:The objective was to establish the lipid profile of patients with locally advanced, unresectable or metastatic CRC. Peripheral blood was collected from patients with CRC and controls with normal colonoscopy. After lipid extraction, the samples were processed and analyzed in the MALDI TOF / TOF equipment. From the data matrix, the statistical analyzes were performed by the principal component analysis methods and the least squares discriminant analysis. The importance of the variable in the projection was used to identify the ions that had the greatest discriminatory effect between the groups.Results:Eight lipids were identified as potential biomarkers and a multiple logistic regression model was proposed to calculate the performance of the test where we observed values of AUC 0.87, sensitivity 88.33% and specificity 83.78% and for a validation test with 1,000 permutations a p <0.001. The classes of lipids found were sphingolipids, glycerophospholipids and policetidis. The strength of the association between the peak intensities of these lipids and the presence of CRC make these metabolites candidates for possible biomarkers. The sphingolipid (m / z = 742.98869) could be a biomarker in monitoring patients with CRC. In the survival analysis, three lipids showed a prognostic value for colorectal cancer, sphingolipid (m / z = 857.11525) and policetidis (m / z = 876.20796) and glycerophospholipid (m / z = 1031.54773).

Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model.

BackgroundDysregulation of the Src pathway has been shown to be important at various stages of cancer. Dasatinib is a potent Src/Abl inhibitor and has demonstrated to have anti-proliferative and anti-invasive activity in many preclinical models. The objective of this study was to determine the anti-tumor activity of dasatinib using in vitro and in vivo preclinical colorectal (CRC) models.MethodsCRC cell lines and patient-derived tumor explant (PDX) models were used to investigate the efficacy of dasatinib. We treated 50 CRC cell lines with dasatinib for 72 hours and proliferation was assayed by a sulforhodamine B (SRB) assay; an IC50 ≤ 0.08 μmol/L was considered sensitive. We treated 17 patient-derived CRC explants with dasatinib (50 mg/kg/day, administered once-daily) for 28 days to determine in vivo efficacy. Tumor growth inhibition (TGI) ≥ 50% was considered sensitive.ResultsWe found that 8 out of 50 CRC cell lines reached an IC50 ≤ 0.08 μmol/L with dasatinib treatment. In addition, of 17 CRC explants grown in the xenograft mouse model, 2 showed sensitivity to dasatinib. The anti-tumor effects observed in this study were a result of G1 cell cycle arrest as the dasatinib sensitive CRC cell lines exhibited G1 inhibition. Moreover, those CRC cell lines that were responsive (0.08 μmol/L) to treatment demonstrated a significant baseline increase in Src and FAK gene expression.ConclusionDasatinib demonstrated significant anti-proliferative activity in a subset of CRC cell lines in vitro, especially in those with increased Src expression at baseline, but only showed modest efficacy in CRC explants. Dasatinib is currently being studied in combination with chemotherapy in patients with advanced CRC, as its use as a single agent appears limited.

Metronomic S-1 dosing and thymidylate synthase silencing have synergistic antitumor efficacy in a colorectal cancer xenograft model

Metronomic chemotherapy is currently considered an emerging therapeutic option in clinical oncology. S-1, an oral formulation of Tegafur (TF), a prodrug of 5-fluorouracil (5-FU), is designed to improve the antitumor activity of 5-FU in tandem with reducing its toxicity. Clinically, metronomic S-1 dosing has been approved for the standard first- and second-line treatment of metastatic or advanced stage of colorectal (CRC). However, expression of intratumor thymidylate synthase (TS), a significant gene in cellular proliferation, is associated with poor outcome to 5-FU-based chemotherapeutic regimens. In this study, therefore, we examined the effect of a combination of TS silencing by an RNA interfering molecule, chemically synthesized short hairpin RNA against TS (shTS), and 5-FU on the growth of human colorectal cancer cell (DLD-1) both in vitro and in vivo. The combined treatment of both shTS with 5-FU substantially inhibited cell proliferation in vitro. For in vivo treatments, the combined treatment of metronomic S-1 dosing with intravenously injected polyethylene glycol (PEG)-coated shTS-lipoplex significantly suppressed tumor growth, compared to a single treatment of either S-1 or PEG-coated shTS-lipoplex. In addition, the combined treatment increased the proportion of apoptotic cells in the DLD-1 tumor tissue. Our results suggest that metronomic S-1 dosing combined with TS silencing might represent an emerging therapeutic strategy for the treatment of patients with advanced CRC.

252 Risk of Advanced Adenoma, Colorectal Cancer, and Colorectal Cancer Mortality in Individuals With Low Risk Adenomas on Baseline Colonoscopy: A Systematic Review and Meta-Analysis

252 Risk of Advanced Adenoma, Colorectal Cancer, and Colorectal Cancer Mortality in Individuals With Low Risk Adenomas on Baseline Colonoscopy: A Systematic Review and Meta-Analysis

Efficacy and safety of FOLFIRI regimen in elderly versus nonelderly patients with advanced colorectal and gastric cancer.

701 Background: Irinotecan-based chemotherapy is a standard backbone in patients (pts) with advanced colorectal (CRC) or gastric cancer (GC). However, there is still a paucity of information concerning the efficacy and safety of irinotecan-based regimen in elderly pts. Methods: Using pt cohort (N = 1,545) of the UGT1A1 genotype study (Kim KP, et al. J Clin Oncol 33, 2015 (suppl; abstr 3600)), we performed subgroup analysis comparing the efficacy and safety between elderly (age ≥ 70 years, median 73 years, N = 245) and non-elderly ( &lt; 70 years, median 57 years, N = 1,300) pts with advanced CRC or GC who received first- or second-line FOLFIRI chemotherapy. Results: In both CRC (N = 934) and GC cohorts (N = 611), elderly pts received significantly lower dose of irinotecan (CRC: mean 74.8% vs. 80.9%, P &lt; 0.001; GC: 72.4% vs. 76.2%, P = 0.018) and infusional 5-fluorouracil (CRC: 61.6% vs. 71.8%, P &lt; 0.001; GC: 47.1% vs. 55.8%, P = 0.004). However, the response rate was similar between elderly and non-elderly pts in both CRC (28.7% vs. 32.9%, P = 0.347) and GC cohorts (22.9% vs. 18.3%; P = 0.369). The progression-free survival was also similar between the two age groups in both CRC (median 27.9 vs. 29.1 weeks, P = 0.202) and GC cohorts (20.1 vs. 17.0 weeks, P = 0.407). In addition, the overall survival was comparable between the two age groups in both CRC (81.9 vs. 91.8 weeks, P = 0.965) and GC cohorts (33.6 vs. 49.3 weeks, P = 0.085). In both cohorts, asthenia was significantly more frequent in elderly pts, while nausea and vomiting were significantly more frequent in non-elderly pts. In CRC cohort, grade 3-4 toxicities that were significantly more frequent in elderly pts were asthenia (1.3% vs. 0.2% per cycle, P &lt; 0.001), mucositis (0.4% vs. 0.1%, P = 0.021), and anorexia (0.8% vs. 0.2%, P = 0.005) in CRC cohort. However, in GC cohort, grade 3-4 toxicities were not significantly different between the two age groups. Conclusions: Despite relatively lower dose intensity in elderly pts, efficacy of FOLFIRI regimen in this subset was comparable to that of non-elderly pts. FOLFIRI regimen was relatively well tolerated in elderly pts. Taken together, FOLFIRI is a considerable standard backbone in elderly pts with advanced CRC or GC.

Abstract A76: Enhancement of cetuximab-induced antibody-dependent cellular cytotoxicity with lenalidomide in advanced solid tumors: A Phase I trial.

Abstract Introduction: Antibody-dependent cellular cytotoxicity (ADCC) is one mechanism of action of monoclonal antibody (mAb) therapy. ADCC occurs via the innate immune system's ability to recognize mAb coated cancer cells and activate effector cells. Lenalidomide is an immunomodulatory agent with capacity to stimulate T cell proliferation, activate natural killer cells, and effect immune cytokines including IL-2, IL-12, and interferon gamma. Both preclinical and clinical data demonstrate the ability of lenalidomide to increase ADCC activity of mAb therapy. This Phase I CTEP sponsored trial aims to evaluate the combination of cetuximab with lenalidomide to enhance ADCC activity in advanced colorectal (CRC) and head and neck squamous cell cancers (HNSCC). Patients/Methods: This Phase I dose escalation trial included patients with locally advanced or metastatic CRC (KRAS wild type) or HNSCC. Treatment consisted of cetuximab 500 mg/m2 IV every 2 weeks with lenalidomide orally days 1-21 every 28 days. Cetuximab dose was the same in all cohorts although dose reductions were permitted for toxicity. Three dose levels of lenalidomide were evaluated (15 mg, 20 mg, and 25 mg). Prior treatment with cetuximab, panitumumab, or other EGFR directed therapy was allowed. Planned correlative studies include measurement of ADCC using an in vitro chromium release assay, serum interferon gamma and NK cytokine profiles, and Fc gamma receptor polymorphisms. Results: A total of 22 patients have been treated (19 CRC, 3 HNSCC). Grade 3 fatigue has been the only observed dose-limiting toxicity. One partial response was observed and 7 patients had stable disease as best response. Two patients remain on treatment. The recommended Phase II dose is cetuximab 500 mg/m2 with lenalidomide 25 mg daily days 1-21. Conclusions: Cetuximab and lenalidomide was well-tolerated with minimal activity. Although response was not a primary endpoint, there is evidence of anti-tumor activity and clinical efficacy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A76. Citation Format: Erin M. Bertino, Jeffrey S. Rose, Christina Wu, Tanios Bekaii-Saab, Panayiotis S. Savvides, Richard M. Goldberg, Miguel Villalona, Gerard Lozanski, William Carson, Michael Grever, Gregory Otterson. Enhancement of cetuximab-induced antibody-dependent cellular cytotoxicity with lenalidomide in advanced solid tumors: A Phase I trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A76.

1258 Changing perceptions of oncologists referring advanced colorectal (ACRC) patients (pts) to phase 1 trials: an evidence based approach

1258 Changing perceptions of oncologists referring advanced colorectal (ACRC) patients (pts) to phase 1 trials: an evidence based approach

Disparities in the Use of Chemotherapy and Monoclonal Antibody Therapy for Elderly Advanced Colorectal Cancer Patients in the Community Oncology Setting

The clinical trials on which the treatment of advanced colorectal (CRC) is based enroll few elderly patients. Furthermore, few investigations have determined the use and outcomes of the treatment of advanced CRC in practice. This study evaluated the treatment of advanced CRC in community oncology practices, focusing on age-related differences in treatment and outcome. A national, retrospective chart review was conducted to evaluate the management of advanced CRC in 10 community practices across the U.S. All medical records of patients diagnosed with advanced CRC initiating chemotherapy treatment after January 1, 2003 through 2006 were included. The primary aim was to compare the proportion receiving doublet chemotherapy (irinotecan or oxaliplatin with a fluoropyrimidine) as initial therapy in young (age <or=65 years) and elderly (age >65 years) patients. Additional aims included age-based comparisons of the addition of bevacizumab to chemotherapy, overall chemotherapy use, all-cause mortality, and toxicity-related events. Overall, 520 patients (56% elderly) received 6,253 cycles of chemotherapy. Of the younger patients, 84% received doublet chemotherapy first-line, compared with 58% of elderly patients (p < .001). The use of each of the medications--irinotecan, oxaliplatin, and bevacizumab--was lower in elderly patients (p < .001). Independent predictors of a higher risk for mortality were age >65 (adjusted hazards ratio [HR],1.19; 95% confidence interval [CI], 1.02-1.39) and performance status score >or=2 (HR, 1.65; 95% CI, 1.41-1.91). Elderly patients are less likely to receive first-line doublet chemotherapy than younger patients. Age and performance status are independent predictors of treatment and overall survival.