Metastatic Colon Research Articles

Intratumor heterogeneity in colorectal cancer: Distribution of tumor suppressor gene variants with regard to patient lymph node status.

Intratumor heterogeneity (ITH) results from accumulation of somatic mutations in the fractions of successive cancer cell generations. We aimed to use deep sequencing to investigate ITH in colorectal tumors with particular emphasis on variants in oncogenes (ONC) and tumor suppressor genes (TSG). Samples were collected from 16 patients with colorectal cancer and negative or positive lymph node status (n = 8 each). We deep-sequenced a panel of 56 cancer-related genes in the central and peripheral locations of T3 size primary tumors and healthy mucosa. The central region of T3 tumors has a different frequency profile and composition of genetic variants. This mutation profile is capable of independently discriminating patients with different lymph node status (p = 0.028) in the central region. We noted an increasing number of mutations outside of the central region of the tumor and a higher number of mutations in tumors from node-positive patients. Unexpectedly, in the healthy mucosa, we identified somatic mutations with variant allele frequencies, characteristic not only of heterozygotes and homozygotes but also of other discrete peaks (e.g., around 10%, 20%), suggestive of clonal expansion of certain mutant alleles. We found differences in the distribution of variant allele frequencies in TSGs when comparing node-negative and node-positive tumors (p = 0.029), as well as central and peripheral regions (p = 0.00399). TSGs may play an important role in the escape of the tumor toward metastatic colonization.

Long non-coding RNAs modulate tumor microenvironment to promote metastasis: novel avenue for therapeutic intervention.

Cancer is a devastating disease and the primary cause of morbidity and mortality worldwide, with cancer metastasis responsible for 90% of cancer-related deaths. Cancer metastasis is a multistep process characterized by spreading of cancer cells from the primary tumor and acquiring molecular and phenotypic changes that enable them to expand and colonize in distant organs. Despite recent advancements, the underlying molecular mechanism(s) of cancer metastasis is limited and requires further exploration. In addition to genetic alterations, epigenetic changes have been demonstrated to play an important role in the development of cancer metastasis. Long non-coding RNAs (lncRNAs) are considered one of the most critical epigenetic regulators. By regulating signaling pathways and acting as decoys, guides, and scaffolds, they modulate key molecules in every step of cancer metastasis such as dissemination of carcinoma cells, intravascular transit, and metastatic colonization. Gaining a good knowledge of the detailed molecular basis underlying lncRNAs regulating cancer metastasis may provide previously unknown therapeutic and diagnostic lncRNAs for patients with metastatic disease. In this review, we concentrate on the molecular mechanisms underlying lncRNAs in the regulation of cancer metastasis, the cross-talk with metabolic reprogramming, modulating cancer cell anoikis resistance, influencing metastatic microenvironment, and the interaction with pre-metastatic niche formation. In addition, we also discuss the clinical utility and therapeutic potential of lncRNAs for cancer treatment. Finally, we also represent areas for future research in this rapidly developing field.

Relationship between SUVmax on 18F-FDG PET and PD-L1 expression in liver metastasis lesions after colon radical operation

PurposeOur study was to investigate the correlation correlation between FDG uptake and PD-L1 expression of liver metastasis in patients with colon cancer, and to determine the value of FDG-PET in predicting PD-L1 expression in liver metastasis of colon cancer.MethodsA total of 72 patients with confirmed liver metastasis of colon cancer were included in this retrospective study. The PD-L1 expression and immune cell infiltrating of tumors were determined through immunohistochemistry staining. The SUVmax of liver metastasis lesions were assessed using 18 F-FDG PET/CT. The correlation between PD-L1 expression and the clinicopathological were evaluated by the Cox proportional hazards model and the Kaplan-Meier survival analysis.ResultsPD-L1 expression was significantly correlated with FDG uptake (SUVmax), tumor size, differentiation, survival and cytotoxic T cells infiltration in liver metastasis of colon cancer (P < 0.05). And liver metastases with high counts of infiltrating cytotoxic T cells showed greater FDG uptake than those with low counts of infiltrating cytotoxic T cells. The SUVmax of liver metastases and the degree of differentiation of metastases were closely related to PD-L1 expression, and were independent risk factors.The combined assessment of SUVmax values and tthe degree of differentiation of metastase can help determine PD-L1 expression in liver metastasis of colon cancer.ConclusionsFDG uptake in liver metastasis of colon cancer was positively correlated with the PD-L1 expression and the number of cytotoxic T cells infiltration. The joint evaluation of two parameters, SUVmax and degree of differentiation, can predict PD-L1 expression in liver metastases.

Simultaneous Surgical Approach with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Patients with Concurrent Peritoneal and Liver Metastases of Colon Cancer Origin.

Background: Simultaneous liver resection and peritoneal cytoreduction with hyperthermic intraperitoneal chemotherapy (HIPEC) remains controversial today. The aim of the study was to analyze the postoperative outcomes and survival of patients with advanced metastatic colon cancer (peritoneal and/or liver metastases). Methods: Retrospective observational study from a prospective maintained data base. Patients who underwent a simultaneous peritoneal cytoreduction and liver resection plus HIPEC were studied. Postoperative outcomes and overall and disease free survival were analyzed. Univariate and multivariate analyses were performed. Results: From January 2010 to October 2022, 22 patients operated with peritoneal and liver metastasis (LR+) were compared with 87 patients operated with peritoneal metastasis alone (LR-). LR+ group presented higher serious morbidity (36.4 vs. 14.9%; p: 0.034). Postoperative mortality did not reach statistical difference. Median overall and disease free survival was similar. Peritoneal carcinomatosis index was the only predictive factor of survival. Conclusions: Simultaneous peritoneal and liver resection is associated with increased postoperative morbidity and hospital stay, but with similar postoperative mortality and OS and disease free survival. These results reflect the evolution of these patients, considered inoperable until recently, and justify the trend to incorporate this surgical strategy within a multimodal therapeutic plan in highly selected patients.

Targeting Trop2 by Bruceine D suppresses breast cancer metastasis by blocking Trop2/β-catenin positive feedback loop

IntroductionTumor-associated calcium signal transducer 2 (Trop2) has been used as a transport gate for cytotoxic agents into cells in antibody–drug conjugate designs because of its expression in a wide range of solid tumors. However, the specific role of Trop2 itself in breast cancer progression remains unclear and small molecules targeting Trop2 have not yet been reported. ObjectivesTo screen small molecules targeting Trop2, and to reveal its pharmacological effects and the molecular mechanisms of action. MethodsSmall molecule targeting Trop2 was identified by cell membrane chromatography, and validated by cellular thermal shift assay and point mutation analyses. We investigated the pharmacological effects of Trop2 inhibitor using RNA-seq, human foreskin fibroblast (HFF)-derived extracellular matrix (ECM), Matrigel drop invasion assays, colony-forming assay, xenograft tumor model, 4T1 orthotopic metastasis model and 4T1 experimental metastasis model. The molecular mechanism was determined using immunoprecipitation, mass spectrometry, immunofluorescence, immunohistochemistry and Western blotting. ResultsHere we identified Bruceine D (BD) as the inhibitor of Trop2, and demonstrated anti-metastasis effects of BD in breast cancer. Notably, Lys307 and Glu310 residues of Trop2 acted as critical sites for BD binding. Mechanistically, BD suppressed Trop2-induced cancer metastasis by blocking the formation of Trop2/β-catenin positive loop, in which the Trop2/β-catenin complex prevented β-catenin from being degraded via the ubiquitin-proteosome pathway. Destabilized β-catenin caused by BD reduced nucleus translocation, leading to the reduction of transcription of Trop2, the reversal of epithelial-mesenchymal transition (EMT) process, and the inhibition of ECM remodeling, further inhibiting cancer metastasis. Additionally, the inhibitory effects of BD on lung metastatic colonization and the beneficial effects of BD on prolongation of survival were validated in 4T1 experimental metastasis model. ConclusionsThese results support the tumor-promoting role of Trop2 in breast cancer by stabilizing β-catenin in Trop2/β-catenin positive loop, and suggest Bruceine D as a promising candidate for Trop2 inhibition.

Nicotinamide N-methyltransferase sustains a core epigenetic program that promotes metastatic colonization in breast cancer.

Metastatic colonization of distant organs accounts for over 90% of deaths related to solid cancers, yet the molecular determinants of metastasis remain poorly understood. Here, we unveil a mechanism of colonization in the aggressive basal-like subtype of breast cancer that is driven by the NAD+ metabolic enzyme nicotinamide N-methyltransferase (NNMT). We demonstrate that NNMT imprints a basal genetic program into cancer cells, enhancing their plasticity. In line, NNMT expression is associated with poor clinical outcomes in patients with breast cancer. Accordingly, ablation of NNMT dramatically suppresses metastasis formation in pre-clinical mouse models. Mechanistically, NNMT depletion results in a methyl overflow that increases histone H3K9 trimethylation (H3K9me3) and DNA methylation at the promoters of PR/SET Domain-5 (PRDM5) and extracellular matrix-related genes. PRDM5 emerged in this study as a pro-metastatic gene acting via induction of cancer-cell intrinsic transcription of collagens. Depletion of PRDM5 in tumor cells decreases COL1A1 deposition and impairs metastatic colonization of the lungs. These findings reveal a critical activity of the NNMT-PRDM5-COL1A1 axis for cancer cell plasticity and metastasis in basal-like breast cancer.

Geographic distribution of clinical trials for common advanced-stage cancers in the United States.

e18503 Background: This study examines the geographic distribution of clinical trials for common types of metastatic cancer in the United States and the accessibility of these trials to the general population. Methods: We accessed the ClinicalTrials.gov website and conducted a search for interventional clinical trials that were actively recruiting patients for diagnoses of metastatic lung, colon, pancreas, breast, and prostate cancers on November 25, 2022. We identified unique zip codes for all the clinical trials offered and calculated the U.S. population living within 50 miles of a clinical trial site using geographic information system software based on 2020 census data. We created maps for each cancer type, demonstrating the geographic distribution of clinical trial access in the United States. Results: We found a significant number of clinical trials providing access for most Americans diagnosed with the most common types of metastatic cancer. The majority of the United States population lives within 50 miles of a clinical trial. The access varied by cancer type studied, from 75.0% of the United States population for metastatic colon cancer to 90.2% for metastatic lung and breast cancers. See table for details. Conclusions: When considering the accessibility of these trials, we found that a large proportion of the United States population lived within 50 miles of a clinical trial site. This suggests that while many clinical trials are available, they may not be evenly distributed across the country and may not be accessible to all individuals. [Table: see text]

A pilot study of lymphodepletion intensity for PBMC-derived, neoantigen-specific CD8+ T cells (Neo-Ts) therapy in patients with advanced solid tumors.

2545 Background: Adoptive T cell therapy (ACT) using neoantigen-specific CD8+ T cells (Neo-Ts) derived from patient PBMC was recently developed aiming to target individual patient’s unique tumor mutations and increase treatment efficacy. But the optimal lymphodepletion intensity for Neo-T therapy has yet to be determined. Methods: In this phase I clinical trial (NCT02959905), we generated Neo-Ts from patients with locally advanced or metastatic melanoma or colon cancers that were refractory to standard therapies, and evaluated the effects of lymphodepletion at various dosages (high: 2x500 mg/m2 cyclophosphamide and 2x25 mg/ m2 fludarabine; low: 1x500 mg/m2 cyclophosphamide and 2x25 mg/ m2 fludarabine; and no lymphodepletion) during Neo-T therapy. The primary end point was safety and the secondary end point was objective response rate (ORR). Results: We showed that Neo-T therapy was safe with lymphodepletion at dosages from no lymphodepletion to high intensity. The median PFS was 7.1 months (95% CI:3.7-9.8), and median overall survival (OS) was 16.8 months (95% CI: 11.9-31.7). The ORR was 33.3% (3/9) among all groups. Three patients achieved PR, two of them were in the group without lymphodepletion. One of the PR patients refractory to prior anti-PD-1 therapy also responded to Neo-T therapy. Neoantigen specific TCRs were examined in two responding patients and showed expansion and persistence after treatment. Conclusions: Neo-T therapy with low intensity lymphodepletion or no lymphodepletion could be a safe and promising regimen for advanced solid tumors. Clinical trial information: NCT02959905 .

Pattern of molecular testing among US veterans with gastrointestinal cancers: A single center experience.

e13663 Background: In response to the rising global burden of cancers, the Veterans Health Administration's (VHA) National Precision Oncology Program (NPOP) supports the use of molecular testing (MT) among veterans. The Oklahoma City (OKC) VHA is serving patients with cancer in both rural and urban areas by implementing the standard practice of precision oncology testing across our diverse patient population. Identification of molecular biomarkers can facilitate treatment selection and trial access for veterans. Here we report real-world practices of physicians caring for veterans with gastrointestinal (GI) cancers namely gastroesophageal (GE), pancreatobiliary (PB) and colon cancers at OKC VHA and determine the degree to which molecular data is being utilized to prognosticate or alter clinical management. Methods: Patients presenting to the OKC VHA with metastatic GE, PB and colon cancer from June 2020 to September 2022 were included in the study. Data was collected retrospectively, including patient demographics, clinical characteristics, mutational data, actionability (OncoKB), and treatment recommendations. The primary outcome was the percentage of tumor sequencing performed, and actionable alteration annotated by the OncoKB database therapeutic evidence level. Results: 101 veterans were diagnosed with metastatic GI cancers (GE 18.8%, PB 28.7% and colon 52.4%), of which 82 samples (81.2%) were submitted for MT. The cohort was male-dominant (98%) with a median age of 69.5 years, and 46.5% of the veterans were from rural Oklahoma. Time from test order date to test result availability was 11.7 days. 25.7% (n=26) had at least one likely oncogenic mutation according to the OncoKB database, and 12.8% of them (n=13) were changed to FDA-approved targeted medications. The most common aberrant genes were TP53, KRAS, HER2, and MSI-H. Statistically significant differences were seen in the level of evidence by cancer group. In multivariate logistic regression, patients with colon cancer were most likely to receive MT (OR, 45.5 95% CI 2.27, 27.0 for colon over PB; OR 14.7 95% CI 2.27, 29.6 for GE over PB). Provider level (fellow vs faculty) and distance from the VHA (urban vs rural) were not associated with MT. Conclusions: Our study indicates clinical implementation of precision oncology is feasible across the VHA healthcare system, including rural veterans. Further analysis of this large cohort of patients will help to address gaps in MT for veterans with GE and PB cancers. The study also highlights the importance of MT to guide clinical trial enrollment and identify investigational drug opportunities among veterans.[Table: see text]

Resection of primary colon cancer with and without resection of liver metastases: Propensity-score matched analysis.

e15580 Background: Studies show that attempts to treat liver metastases during or before primary colonic cancer resection may improve survival. We aimed to compare overall survival of patients with colon cancer and liver metastases who underwent primary tumor resection with/without resection of liver metastases. Methods: This retrospective cohort study included patients with stage IV colon adenocarcinoma and isolated liver metastases who underwent surgical resection, using data from the National Cancer Database between 2015-2019. Patients with metastases to other organs or who did not have primary tumor resection were excluded. The cohort was divided into Colectomy-only (resection of primary colonic cancer only) and Colectomy-plus (resection of primary tumor and liver metastases) groups. After comparing, significant baseline and treatment confounders were identified and groups were matched using the nearest neighbor, 1:1 propensity-score method. Primary outcome was overall survival; secondary endpoints were short-term mortality and 30-day unplanned readmission. Results: 6780 patients who underwent primary tumor only resection and 4082 who underwent primary tumor and liver metastases resection were included. Patients in the Colectomy-only group were significantly older (63.73±13.59 vs 59.56±13.32 years;p &lt; 0.001), more often male (56% vs 53.5%;p = 0.01), had more comorbidities (Charlson score 3: 4.4% vs 3.3%;p = 0.001) and right-sided colonic cancer (45.7% vs 43.2%;p = 0.002), shorter time before surgery (10 vs 30 days;p &lt; 0.001), and more laparoscopic surgery (40.4% vs 35%;p &lt; 0.001). Colectomy-only group patients had less chemotherapy (48.6% vs 50.7%, p = 0.04) and immunotherapy (34.1% vs 40.6%, p &lt; 0.001) whereas Colectomy-plus group patients had more neoadjuvant systemic therapy (18.8% vs 10.2%;p &lt; 0.001). Median overall survival of the Colectomy-plus group was significantly longer than Colectomy-only group (45.1 vs 24.4 months; p &lt; 0.001). After matching for significant confounders, 2038 patients were included in each group. There were no significant differences between the two groups in 30-day (3.8% vs 3.1%;p = 0.3) and 90-day mortality (7.7% vs 6.6%;p = 0.2). Colectomy-plus group patients had significantly higher 30-day unplanned readmissions (7.2% vs 5.3%, p = 0.02) and significantly longer median overall survival (41.5 vs 28.4 months, p &lt; 0.001). On Cox-regression analysis, resection of liver metastases and primary colonic tumor was associated with 33% mortality reduction (HR: 0.678, 95%CI: 0.618-0.745, p &lt; 0.001). Conclusions: Resection of colonic cancer liver metastasis with the primary tumor is associated with significant survival benefit and may prolong survival by approximately 12 months, versus primary tumor resection alone. Synchronous resection of the primary tumor and liver metastases should be considered as it appears to offer survival benefit.

ID: 220962 Inpatient Spinal Cord Stimulation Trial in Patient With Metastatic Colon Cancer Hospitalized for Pain Control

A 55-year-old female with metastatic colon cancer with a soft tissue mass at S1 extending into the vertebral body and posterior epidural space and neuroforamina at L5-S1 was hospitalized for severe lumbar back and bilateral radicular pain. She was initially managed inpatient with escalating dosing of opioid pain medication with minimal improvement of her symptoms. She was unable to ambulate more than 2-3 steps secondary to weakness and pain.

Results of a retrospective multicenter study comparing the effectiveness of regorafenib and the rechallenge of chemotherapy in patients (pts) with metastatic colorectal cancer (mCRC).

e15561 Background: Regorafenib is considered the standard third-line therapy of mCRC. However, the modest efficacy and significant toxicity of regorafenib urges the search for new therapeutic approaches. In various countries, the re-challenge of the previously effective treatment regimens is being considered. We compared the effectiveness of various variants of systemic therapy in the third and subsequent lines of the treatment. Methods: We analyzed the prospective database of pts with mCRC from two clinics of the Russian Federation. The statistical hypothesis implied the equivalence of the 6-month overall survival on the repeated chemotherapy (CT) and targeted therapy with the third line regorafenib therapy, provided the equivalence boundaries from 0.8 to 1.25. With α = 0.05, the study power is 80% with 178 patients, 89 people in each group. We conducted statistical analysis with the SPSS statistical software package (v. 20, IBM). Results: In the database, we identified 215 patients with morphologically confirmed metastatic colon cancer who received two or more lines of antitumor drug therapy from 2010 to 2021. Of them, we selected 132 patients with a history of regorafenib therapy, and 83 patients with the re-challenge of CT as the third line of the therapy. Overall survival (OS) in the re-challenge and regorafenib groups did not differ (hazard ratio [HR] 1.01 with 95%CI 0.7-1.45; p = 0.9) and the 6-month OS was 74 and 70%, respectively. Progression-free survival was significantly higher in the re-challenge group (HR 1.94 with 95%CI 1.3-2.7; p &lt; 0.001); In the multifactorial analysis, the re-challenge of previous treatment regimens kept its independent positive effect on progression-free survival (HR 1.9 with 95%CI 1.3-2.8; p = 0.0001) also as index T &lt; 3 (HR 0.7, 95CI 0.55-0,94); ECOG ≥1 a (HR 1.5 with 95%CI 1.16-2.05; p &lt; 0.01) affected PFS negatively. The reduction of the regorafenib dose did not affect PFS (HR 0.9 with 95% CI from 0.9 to 1.0; p = 0.1), its starting dose (HR 0.9 with 95 CI from 0.9 to 1.0; p = 0.2), and a break in the regorafenib treatment (HR 0.9 with 95% CI from 0.5 to 1.8; p = 0.9). Conclusions: Regorafenib and the re-challenge of previously effective CT in the third-line of mCRP therapy show the similar 6-mon. OS. However, progression-free survival is significantly higher in the re-challenge group in third line therapy.

Translationally controlled tumor protein as a prognostic marker in metastatic colon cancer.

e15513 Background: The translationally controlled tumor protein (TCTP) is a highly conserved protein present in virtually all eukaryotic organisms. TCTP is involved in a variety of normal cell functions and disease processes. Preclinical studies reveal that TCTP has anti-apoptotic properties, promotes cell growth and division, and is involved in cancer progression by promoting invasion and metastasis. Our study explores the potential value of TCTP as a prognostic marker in metastatic colon cancer. Methods: A retrospective analysis of 54 patients with primary metastatic colon cancer was performed. Using immunohistochemistry, TCTP levels in the primary tumor were assessed semiquantitatively via the calculation of cytoplasmic and nuclear H-score. Results: Cytoplasmic TCTP levels in the primary tumor had no statistically significant association with progression-free survival in first-line therapy (PFS1) and overall survival (OS) in our patient population. Patients whose primary tumors had a negative nuclear TCTP expression had significantly better clinical outcomes. The PFS1 for the negative nuclear TCTP expression group was 7.4 months (95% CI, 5.3-9.6) vs 4.5 months (95% CI, 3.4-5.6) in the group with positive nuclear expression (p = 0.023). Patients with a negative nuclear expression of TCTP had a significantly higher median OS (17.1 months; 95% CI, 13.5–20.6) compared to those with positive TCTP nuclear expression (median 11.5 months; 95% CI, 8.5-14.5) (p = 0.031). In Cox regression analyses, a positive nuclear TCTP H-score conferred a higher risk for worse PFS1 (HR 1.960; 95% CI, 1.086-3.537; p = 0.025) and OS (HR 1.882; 95% CI, 1.050-3.371; p = 0.034). The 1-year OS rate in the group with negative nuclear TCTP expression was 80.0% compared to 47.4% in patients with positive nuclear TCTP expression (p = 0.03). Conclusions: The present study suggests that semiquantitative H-score measurement of TCTP levels in the nuclei of tumor cells from the primary tumor is a potential prognostic marker for clinical outcomes in patients with metastatic colon cancer.

P-183 BRAF mutant metastatic colon cancer expect the unexpected: A single centre study

P-183 BRAF mutant metastatic colon cancer expect the unexpected: A single centre study

P-357 Place of CEA in the evaluation of the treatment of metastatic colon cancer

P-357 Place of CEA in the evaluation of the treatment of metastatic colon cancer

Use of clinical pathways to identify patients with cancer who may benefit from serious illness conversations.

12027 Background: Treatment pathways are widely used to provide decision support and encourage guideline adherence. Pathways data may be used to identify patients for targeted interventions to improve cancer care. For example, pathways data may enable the identification of patients with poor prognoses for whom serious illness conversations (SICs) should be prioritized to ensure goal-concordant care. Methods: For patients starting new therapies at Dana-Farber, oncologists select a node in clinical pathways to indicate the line of treatment. Subspecialty oncologists identified “poor prognosis” nodes in pathways, defined as therapies for patients with expected survivals of &lt; 12 months and for whom an SIC would be appropriate (e.g., 3rd-line treatment for metastatic colon cancer). Pathway node navigations for patients with metastatic solid tumor malignancies with poor prognosis nodes (n = 21 disease pathways) were combined with electronic medical record data to identify SIC documentation in an advance care planning module within 6 months of pathway navigation and patients’ dates of death if present. For each node, we calculated the median overall survival (OS), the proportion of patients with an SIC, and the proportion of patients who died before reaching the next node. Results: There were 10,132 navigations for 7,031 patients (median age 67 years, 52% female, 86% White) between 8/16/2019 and 1/4/2023. With each treatment line, patients’ median OS decreased and SIC rates increased (examples for 3 diseases in Table). Among patients who reached poor prognosis nodes, the median OS was 4.9 months, mean SIC rate was 43.8%, and 60.2% of patients died without reaching a subsequent node. For nodes immediately prior to poor prognosis nodes, the median OS was 7.1 months, the mean SIC rate was 25.2%, and 31.3% of patients died without reaching the next node. 46.3% of patients died without reaching a poor prognosis node. The proportion of patients having an SIC at death was 40.9% among all decedents, 50.8% for decedents reaching a poor prognosis node, and 29.3% for decedents who do not reach a poor prognosis node. Conclusions: Clinical pathways can be used as a scalable method to identify patients with metastatic solid tumors and poor prognoses. In our study, only half of patients who reached a poor prognosis node had an SIC before death and nearly half of decedents never reached a poor prognosis node, underscoring the importance of identifying this population to improve end-of-life care. A clinical trial using pathways to identify and deliver interventions to increase SICs is ongoing. [Table: see text]

P-423 Place of CEA in the evaluation of the treatment of metastatic colon cancer

P-423 Place of CEA in the evaluation of the treatment of metastatic colon cancer

A phase I study of isunakinra, an IL-1 alfa/beta inhibitor, in combination with nivolumab for patients with solid tumors refractory to standard therapies.

e14580 Background: Interleukin-1 is a master cytokine produced by macrophages (IL-1 β) and released upon cell death (IL-1 α). IL-1 upregulates other cytokines in the tumor microenvironment (i.e. IL-6 and IL-8), drives chronic non-resolving inflammation in the tumor, induces cancer cell invasion and metastasis (EMT), has profound effects on immune cells and cancer associated fibroblasts and can attract granulocytic myeloid suppressor cells to the tumor (PMN-MDSC), that in turn inhibit cytotoxic T cell responses. Isunakinra is a small recombinant protein resembling IL-1Ra, with an inhibitory potency 10-20 times higher, that binds to the IL1-R1 and blocks activation of the receptor by both IL-1α and IL-1β. We conducted a phase I dose escalation study with isunakinra as monotherapy and in combination with a PD-1 inhibitor in patients with locally advanced or metastatic solid tumors that had exhausted all treatment options. Methods: Enrolled patients with refractory metastatic solid tumor, ECOG 0-2, on a 3 + 3 dose-escalation trial at three dose levels of isunakinra (15, 25 or 50 mg). Isunakinra was self-administered once daily SC for three weeks followed by 4 additional weeks in combination with nivolumab Q4W at 480 mg, flat dose to complete the DLT period of 7 weeks. Thereafter, isunakinra/nivolumab was continued until week 28. Primary endpoints: DLTs, safety, and pharmacokinetics. Secondary endpoints: tumor and immune monitoring. Results: Enrolled fifteen patients with metastatic or unresectable locally advanced solid tumors (colorectal, pancreatic, triple-negative BC, anal, prostatic, CCA, and appendix) that had received 2-5 prior lines of therapy. Seven SAE occurred in three rapidly deteriorating subjects, all disease related hospitalizations, leading to study withdrawal during the DLT period. No DLTs, irAE or predefined laboratory deviations occurred in any subject. The highest dose, 50 mg, was selected as RP2D. Twelve subjects completed visit week 8, six of them week 12, and four completed the trial. One patient with metastatic colon cancer (MSS, KRAS mut, high TMB) was granted extended treatment for PR and continued response at end of study. Isunakinra exposure totaled 1575 daily doses, 81% during combination with nivolumab, t 1/2 5 hours with no accumulation over time. At 50mg of isunakinra, plasma levels where well above 100 ng/mL, a target for complete IL-1 inhibition. Conclusions: Isunakinra is safe and well-tolerated in combination with standard dose nivolumab. Ongoing expansion cohorts and future studies will explore the safety and efficacy of isunakinra in specific tumors and with other immunotherapy combinations. Clinical trial information: NCT04121442 .

Sclerodermatous eruption in a patient with metastatic colon cancer treated with an FLT3/CDK inhibitor.

Sclerodermatous eruption in a patient with metastatic colon cancer treated with an FLT3/CDK inhibitor.

HRG inhibits liver cancer lung metastasis by suppressing neutrophil extracellular trap formation.

Distant metastasis is a sign of poor prognosis for cancer patients. Extrahepatic liver cancer metastases commonly spread to the lung. Remodelling of the metastatic microenvironment is essential for tumour metastasis. Neutrophil-associated metastatic microenvironment contributes to the early metastatic colonisation of cancer cells in the lung. The lung metastasis models were constructed via treated cancer cells by tail vein injection into mice. And samples of lung were harvested at the indicated time to analyze tumor growth and immune cells in the microenvironment. Tumors and lung metastasis specimens were obtained via surgical operations for research purposes. Neutrophils were obtained from peripheral blood of patients with liver cancer or healthy donors (HD). Hepatocellular carcinoma cells reduce the secretion of histidine-rich glycoprotein (HRG), regulate the recruitment and activation of neutrophils in the metastatic microenvironment and promote the production of neutrophil extracellular traps (NETs), thereby promoting liver cancer lung metastasis. HRG binds to FCγR1 on the neutrophil membrane while inhibiting PI3K and NF-κB activation, thereby reducing IL-8 secretion to reduce neutrophil recruitment. Meanwhile, HRG inhibited IL8-MAPK and NF-κB pathway activation and ROS production, resulting in reduced NETs formation. Our study reveals that liver cancer regulates neutrophil recruitment and NETs formation in the metastatic microenvironment by reducing HRG secretion, thereby promoting tumour lung metastasis. The results of this study will contribute to the development of possible strategies for treating metastases.