Pembrolizumab Plus Binimetinib With or Without Chemotherapy for MSS/pMMR Metastatic Colorectal Cancer: Outcomes From KEYNOTE-651 Cohorts A, C, and E.

BACKGROUND: Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab + binimetinib ± chemotherapy in microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. PATIENTS AND METHODS: Patients received pembrolizumab 200 mg every 3 weeks plus binimetinib 30 mg twice daily alone (cohort A; previously treated with any chemotherapy) or with 5-fluorouracil, leucovorin, oxaliplatin (cohort C; previously untreated) or 5-fluorouracil, leucovorin, irinotecan (cohort E; previously treated with 1 line of therapy including fluoropyrimidine + oxaliplatin-based regimen) every 2 weeks. Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary. RESULTS: In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). Objective response rate was 0% in cohort A, 9% in cohort C, and 15% in cohort E. CONCLUSION: Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. Data did not support continued enrollment in cohorts C and E.

Examination of Wnt signaling as a therapeutic target for pancreatic ductal adenocarcinoma (PDAC) using a pancreatic tumor organoid library (PTOL).

Pancreatic ductal adenocarcinoma (PDAC) presents at advanced stages and is refractory to most treatment modalities. Wnt signaling activation plays a critical role in proliferation and chemotherapeutic resistance. Minimal media conditions, growth factor dependency, and Wnt dependency were determined via Wnt inhibition for seven patient derived organoids (PDOs) derived from pancreatic tumor organoid libraries (PTOL). Organoids demonstrating response in vitro were assessed in vivo using patient-derived xenografts. Wnt (in)dependent gene signatures were identified for each organoid. Panc269 demonstrated a trend of reduced organoid growth when treated with ETC-159 in combination with paclitaxel or gemcitabine as compared with chemotherapy or ETC-159 alone. Panc320 demonstrated a more pronounced anti-proliferative effect in the combination of ETC-159 and paclitaxel but not with gemcitabine. Panc269 and Panc320 were implanted into nude mice and treated with ETC-159, paclitaxel, and gemcitabine as single agents and in combination. The combination of ETC-159 and paclitaxel demonstrated an anti-tumor effect greater than ETC-159 alone. Extent of combinatory treatment effect were observed to a lesser extent in the Panc320 xenograft. Wnt (in)dependent gene signatures of Panc269 and 320 were consistent with the phenotypes displayed. Gene expression of several key Wnt genes assessed via RT-PCR demonstrated notable fold change following treatment in vivo. Each pancreatic organoid demonstrated varied niche factor dependencies, providing an avenue for targeted therapy, supported through growth analysis following combinatory treatment of Wnt inhibitor and standard chemotherapy in vitro. The clinical utilization of this combinatory treatment modality in pancreatic cancer PDOs has thus far been supported in our patient-derived xenograft models treated with Wnt inhibitor plus paclitaxel or gemcitabine. Gene expression analysis suggests there are key Wnt genes that contribute to the Wnt (in)dependent phenotypes of pancreatic tumors, providing plausible mechanistic explanation for Wnt (in)dependency and susceptibility or resistance to treatment on the genotypic level.

Population-level comparisons of gene regulatory networks modeled on high-throughput single-cell transcriptomics data.

Single-cell technologies enable high-resolution studies of phenotype-defining molecular mechanisms. However, data sparsity and cellular heterogeneity make modeling biological variability across single-cell samples difficult. Here we present SCORPION, a tool that uses a message-passing algorithm to reconstruct comparable gene regulatory networks from single-cell/nuclei RNA-sequencing data that are suitable for population-level comparisons by leveraging the same baseline priors. Using synthetic data, we found that SCORPION outperformed 12 existing gene regulatory network reconstruction techniques. Using supervised experiments, we show that SCORPION can accurately identify differences in regulatory networks between wild-type and transcription factor-perturbed cells. We demonstrate SCORPION's scalability to population-level analyses using a single-cell RNA-sequencing atlas containing 200,436 cells from colorectal cancer and adjacent healthy tissues. The differences between tumor regions detected by SCORPION are consistent across multiple cohorts as well as with our understanding of disease progression, and elucidate phenotypic regulators that may impact patient survival.

Biomarker Testing Trends in Patients With Metastatic Colorectal Cancer Who Live in Rural Areas and Urban Clusters in the US.

BACKGROUND: There is a paucity of data on biomarker testing rates in rural populations with metastatic colorectal cancer (mCRC). To assess biomarker testing practices, oncologists in rural areas and urban clusters in the US were surveyed. MATERIALS AND METHODS: A web-based survey was administered to oncologists spending ≥40% of their time practicing in rural areas or urban clusters and who had treated ≥2 patients with stage IV mCRC in the prior month. RESULTS: Ninety-nine oncologists completed the quantitative survey and 17 the qualitative interview. Among respondents, 97% reported ordering biomarker tests. Oncologists reported testing for KRAS, NRAS, BRAF, HER2, and mismatch repair deficiency/microsatellite instability in 72%, 65%, 63%, 56%, and 66% of patients with metastatic disease, respectively. Forty-one percent reported performing reflex testing. The most cited testing barriers were lack of insurance coverage, insufficient tissue samples, and long turnaround times. CONCLUSION: Further assessment of rural testing practices is needed.

Pancreatic Ductal Adenocarcinoma Cells Regulate NLRP3 Activation to Generate a Tolerogenic Microenvironment.

Defining feature of pancreatic ductal adenocarcinoma (PDAC) that participates in the high mortality rate and drug resistance is the immune-tolerant microenvironment which enables tumors to progress unabated by adaptive immunity. In this study, we report that PDAC cells release CSF-1 to induce nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) activation in myeloid cells. Increased NLRP3 expression was found in the pancreas of patients with PDAC when compared with normal pancreas which correlated with the formation of the NLRP3 inflammasome. Using human primary cells and an orthotopic PDAC mouse model, we show that NLRP3 activation is responsible for the maturation and release of the inflammatory cytokine IL1ß which selectively drives Th2-type inflammation via COX2/PGE2 induction. As a result of this inflammation, primary tumors were characterized by reduced cytotoxic CD8+ T-cell activation and increased tumor expansion. Genetic deletion and pharmacologic inhibition of NLRP3 enabled the development of Th1 immunity, increased intratumoral levels of IL2, CD8+ T cell­mediated tumor suppression, and ultimately limited tumor growth. In addition, we observed that NLRP3 inhibition in combination with gemcitabine significantly increased the efficacy of the chemotherapy. In conclusion, this study provides a mechanism by which tumor-mediated NLRP3 activation exploits a distinct adaptive immunity response that facilitates tumor escape and progression. Considering the ability to block NLRP3 activity with safe and small orally active molecules, this protein represents a new promising target to improve the limited therapeutic options in PDAC. SIGNIFICANT: This study provides novel molecular insights on how PDAC cells exploit NLRP3 activation to suppress CD8 T-cell activation. From a translational perspective, we demonstrate that the combination of gemcitabine with the orally active NLRP3 inhibitor OLT1177 increases the efficacy of monotherapy.

The Local Microbiome in Esophageal Cancer and Treatment Response: A Review of Emerging Data and Future Directions.

The incidence of esophageal cancer is increasing worldwide, with established risk factors explaining only a small fraction of cases. Currently, there are no established screening protocols in most countries, and treatment options are limited. The human microbiome has been implicated in carcinogenesis and the cancer treatment response. The advent of nucleic acid sequencing technologies has enabled more comprehensive, culture-independent bacterial identification. Across several tumor types, studies of tissue-specific microbiomes have shown associations between the overall microbiome composition, the relative abundance of specific bacteria, and tumorigenesis. Furthermore, in the era of cancer immunotherapy, several studies have demonstrated that the microbiome and specific bacteria may modify treatment responses and the risk of immune-related adverse events. DESIGN: peer-reviewed, published studies describing the role of local, gastrointestinal-specific microbiota or the role of the gut microbiome in treatment responses were reviewed. PubMed was searched from 1 September 2022 to 1 November 2022, using the following terms in combination: "microbiome", "tumor microbiome", "esophageal cancer", "cancer", "cancer treatment", and "immunotherapy". Original research articles were considered, and other reviews or editorials were discarded. In total, approximately 250 articles were considered. RESULTS: over 70 studies describing microbiome research in either gastrointestinal carcinogenesis or the systemic treatment response were identified and reviewed. CONCLUSIONS: a growing body of evidence supports the role of the esophageal microbiome in both esophageal tumorigenesis and the immune checkpoint inhibitor response. More well-designed, comprehensive studies are required to collect the appropriate clinical, microbial, and immunophenotype data that are needed to clarify the precise role of the microbiome in esophageal carcinogenesis and treatment.

Early-Onset GI Cancers: Rising Trends, Genetic Risks, Novel Strategies, and Special Considerations.

Cancers in young adults (commonly described as early-onset [EO] cancer) represent a group of malignancies that have unique and challenging biology and genetic, treatment, social, and psychological implications. Even more concerning is a rising trend of EO cancers in multiple tumor types. Research and investigation in EO cancers will help elucidate mechanisms of carcinogenesis, differences in biology and response to treatment, and the need for multidisciplinary care to ensure comprehensive treatment and support for young patients.

Podcast article: Biomarker testing in colorectal cancer.

Christopher Lieu, co-director of gastrointestinal medical oncology and the associate director for clinical research at the University of Colorado Cancer Center (CO, USA) discusses the importance of biomarker testing in metastatic colorectal cancer to inform personalized patient care.

Rectal Cancer: Clinical and Molecular Predictors of a Complete Response to Total Neoadjuvant Therapy.

BACKGROUND: Total neoadjuvant therapy in rectal cancer may increase pathological complete response rates, potentially allowing for a nonoperative approach. OBJECTIVE: The objective of this study was to identify patient and tumor characteristics that predict a complete response following total neoadjuvant therapy. DESIGN: This was a retrospective cohort study. SETTINGS: This study was conducted at a university-based National Cancer Institute-designated Comprehensive Cancer Center. PATIENTS: The patients include those with stage 2 or 3 rectal adenocarcinoma. INTERVENTIONS: Interventions included total neoadjuvant therapy, total mesorectal excision, and nonoperative management. MAIN OUTCOME MEASURES: Complete response was defined as either patients with a clinical complete response undergoing nonoperative management who remained cancer-free or patients undergoing surgery with a pathological complete response. RESULTS: Among 102 patients, median age was 54 years, 69% were male, median carcinoembryonic antigen level was 3.0 ng/mL, and the median distance of the tumor above the anorectal ring was 3 cm. Thirty-eight (37%) patients had a complete response, including 15 of 18 (83%) nonoperative patients who remained cancer free at a median of 22 months (range, 7-48 months) and 23 of 84 (27%) patients who underwent surgery and had a pathological complete response. The incomplete response group consisted of 61 patients who underwent initial surgery and 3 nonoperative patients with regrowth. There were no differences in gender, T-stage, or tumor location between groups. Younger age (median, 49 vs 55 years), normal carcinoembryonic antigen (71% vs 41%), clinical node-negative (24% vs 9%), smaller tumors (median 3.9 vs 5.4 cm), and wild-type p53 (79% vs 47%) and SMAD4 (100% vs 81%) were more likely to have a complete response (all p < 0.05). LIMITATIONS: This was a retrospective study with a small sample size. CONCLUSIONS: In patients with rectal cancer treated with total neoadjuvant therapy, more than one-third will achieve a pathological complete response or sustained clinical complete response with nonoperative management, making oncological resection superfluous in these patients. Smaller, wild-type p53 and SMAD4, and clinically node-negative cancers are predictive features of a complete response. See Video Abstract at http://links.lww.com/DCR/B889 . CNCER DE RECTO PREDICTORES CLNICOS Y MOLECULARES DE UNA RESPUESTA COMPLETA A LA TERAPIA NEOADYUVANTE TOTAL: ANTECEDENTES:La terapia neoadyuvante total en el cáncer de recto puede aumentar las tasas de respuesta patológica completa y permitir potencialmente un enfoque no quirúrgico.OBJETIVO:El objetivo fue identificar las características tanto del paciente y del tumor que logren predecir una respuesta completa después de la terapia neoadyuvante total.DISEÑO:Este fue un estudio de cohorte retrospectivo.AJUSTES:Este estudio se realizó en un Centro Integral de Cáncer designado por el Instituto Nacional del Cáncer con sede universitaria.PACIENTES:Los pacientes incluyen aquellos con adenocarcinoma de recto en estadio 2 o 3.INTERVENCIONES:Terapia neoadyuvante total, escisión total del mesorrecto, manejo conservador no quirúrgico.PRINCIPALES MEDIDAS DE RESULTADO:La respuesta completa se definió como pacientes con una respuesta clínica completa sometidos a tratamiento no quirúrgico que permanecieron libres de cáncer o pacientes sometidos a cirugía con una respuesta patológica completa.RESULTADOS:Entre 102 pacientes, la mediana de edad fue de 54 años, el 69% fueron hombres, la mediana del nivel de antígeno carcinoembrionario fue de 3.0 ng/ml y la mediana de la distancia del tumor por encima del anillo anorrectal fue de 3 cm. Thirty-eight (37%) pacientes tuvieron una respuesta completa que incluyó a 15 de 18 (83%) pacientes con manejo no operatorio y que permanecieron libres de cáncer en una mediana de 22 meses (rango 7- 48 meses) y 23 de 84 (27%) pacientes que fueron sometidos a cirugía y tuvieron una respuesta patológica completa. El grupo de respuesta incompleta consistió en 61 pacientes que fueron sometidos inicialmente a cirugía y 3 pacientes no quirúrgicos con recrecimiento. No se encontró diferencias de género, estadio T o ubicación del tumor entre los grupos. Edad más joven (mediana 49 frente a 55), antígeno carcinoembrionario normal (71% frente a 41%), ganglios clínicos negativos (24% frente a 9%), tumores más pequeños (mediana de 3,9 frente a 5,4 cm) y p53 de tipo salvaje (79 % vs 47%) y SMAD4 (100% vs 81%) tenían más probabilidades de tener una respuesta completa (todos p < 0,05).LIMITACIONES:Este fue un estudio retrospectivo y con un tamaño de muestra pequeño.CONCLUSIONES:En pacientes con cáncer de recto tratados con terapia neoadyuvante total, más de un tercio logrará una respuesta patológica completa o una respuesta clínica completa sostenida con manejo no operatorio, logrando que la resección oncológica sea superflua en estos pacientes. Los cánceres más pequeños, clínicamente con ganglios negativos, con p53 de tipo salvaje y SMAD4, son características predictoras de una respuesta completa. Consulte Video Resumen en http://links.lww.com/DCR/B889 . (Traducción-Dr. Osvaldo Gauto ).

Informational Needs of Surgical Oncology Patients: A Cross-Sectional Patient Survey.

INTRODUCTION: Patients newly diagnosed with cancer often seek information prior to being seen by a specialist. Little is known about the type of information desired and the sources used. We asked how patients find information about their new cancer diagnoses to improve information provision. METHODS: An anonymous seven-question survey was provided to new patients in the surgical and medical oncology clinics at a comprehensive cancer center from February 2021 to June 2021. RESULTS: Of 503 consecutive patients, 405 (81%) returned surveys; 49% female, 57% aged 51-75 y, and 71% Caucasian. Many (74%) sought information before their visit. Most (57%) relied on prior medical providers and 77% reported them as a trusted source. Nearly 80% of patients used at least one nonvalidated resource; 21% friends and relatives, 20% nongovernment or hospital resources, and 12% social media. Importantly, 23% found conflicting information. Respondents desired information on cancer treatment (58%), alternative therapies (35%), and nutrition and supplements (31%). CONCLUSIONS: Patients with cancer trust information from medical providers but seek information from a variety of sources that can provide conflicting information. These data support encouraging patients to use validated sources, providing robust organization-based resources, and engaging patients on topics such as alternative therapies and nutrition.

Prognostic Impact of the Presence of Barrett's Esophagus and Intestinal Metaplasia on Esophageal Adenocarcinoma Survival.

Background/Aims: Barrett's esophagus (BE), defined by the presence of intestinal metaplasia (IM) on histology, is thought to be the only identifiable precursor lesion for esophageal adenocarcinoma (EAC). Recent studies have suggested the possibility of an alternate, non-IM associated EAC that is a more aggressive form of EAC with worse survival. Among EAC patients, we aimed to compare survival of patients with and without IM at the time of diagnosis. Methods: This was a retrospective cohort study of all patients with histologic confirmed EAC evaluated at a tertiary care center from 2013 to 2019. Cases were categorized according to the presence or absence of IM on histologic specimens (Group I-IM-EAC and Group II-non-IM-EAC). We compared demographic characteristics, clinical stage, therapy, and survival between the 2 groups using the Chi-square and ANOVA tests (for categorical and continuous variables, respectively). We used Cox proportional hazards regression to determine the association of IM with overall survival, adjusting for sex, age at diagnosis, tumor location, histologic grade, and clinical stage. Results: A total of 475 patients were included in this analysis (mean age 64.8 years [SD 10.8], 89% white) and 109 (23.0%) had no evidence of IM. Compared with IM-EAC (Group I), individuals in the non-IM-EAC group were younger (P = .01) and had a greater proportion of patients diagnosed with advanced disease (49.5 vs 20.2% for stage 4, P < .001). These patients were less likely to undergo endoscopic therapy alone (0.92% vs 29.78%, P < .001) or surgery alone (0 vs 9.84%, P = .001). On multivariable analysis, the presence of IM-EAC was associated with improved overall survival compared to non-IM-EAC (HR 0.69, 95% CI 0.49-0.96). Additional factors associated with poor survival was increasing stage of diagnosis (HR 6.49: 95% CI 3.77-11.15 for stage 4, HR 2.19: 95% CI 1.25-3.84 for stage 3, HR 2.04: 95% CI 0.98-4.25 for stage 2 compared to stage 1) and more advanced histologic stage (HR 2.00, 95% CI 1.26-3.19) for poorly/undifferentiated compared to well differentiated). Conclusions: EAC without the presence of IM on histology was associated with worse survival compared to those with IM. Future prospective studies with detailed molecular sequencing are required to clarify if 2 separate phenotypes of EAC exist (IM-EAC and non-IM-EAC). If confirmed, this may have significant implications for screening and management strategies.

Cabozantinib sensitizes microsatellite stable colorectal cancer to immune checkpoint blockade by immune modulation in human immune system mouse models.

Immune checkpoint inhibitors have been found to be effective in metastatic MSI-high colorectal cancers (CRC), however, have no efficacy in microsatellite stable (MSS) cancers, which comprise the majority of mCRC cases. Cabozantinib is a small molecule multi-tyrosine kinase inhibitor that is FDA approved in advanced renal cell, medullary thyroid, and hepatocellular carcinoma. Using Human Immune System (HIS) mice, we tested the ability of cabozantinib to prime MSS-CRC tumors to enhance the potency of immune checkpoint inhibitor nivolumab. In four independent experiments, we implanted distinct MSS-CRC patient-derived xenografts (PDXs) into the flanks of humanized BALB/c-Rag2nullIl2rγnullSirpαNOD (BRGS) mice that had been engrafted with human hematopoietic stem cells at birth. For each PDX, HIS-mice cohorts were treated with vehicle, nivolumab, cabozantinib, or the combination. In three out of the four models, the combination had a lower tumor growth rate compared to vehicle or nivolumab-treated groups. Furthermore, interrogation of the HIS in immune organs and tumors by flow cytometry revealed increased Granzyme B+, TNFα+ and IFNγ+ CD4+ T cells among the human tumor infiltrating leukocytes (TIL) that correlated with reduced tumor growth in the combination-treated HIS-mice. Notably, slower growth correlated with increased expression of the CD4+ T cell ligand, HLA-DR, on the tumor cells themselves. Finally, the cabozantinib/nivolumab combination was tested in comparison to cobimetinib/atezolizumab. Although both combinations showed tumor growth inhibition, cabozantinib/nivolumab had enhanced cytotoxic IFNγ and TNFα+ T cells. This pre-clinical in vivo data warrants testing the combination in clinical trials for patients with MSS-CRC.

Minimal Residual Disease-Directed Adjuvant Therapy for Patients With Early-Stage Colon Cancer: CIRCULATE-US.

BACKGROUND: The ability to detect circulating tumor DNA (ctDNA), a novel surrogate for minimal residual disease (MRD) for patients with solid tumors, has significantly evolved over the past decade. Several studies have shown that ctDNA may provide clinical insight into the biological dynamics of MRD. The CIRCULATE-US (NRG-GI008; NCT05174169) trial will aim to address the role of ctDNA for risk stratification to intensify and deintensify adjuvant chemotherapy for patients with early-stage colon cancer. METHODS: CIRCULATE-US, a prospective phase 2/3 randomized trial, is investigating the molecular dynamics and prognostic role of ctDNA (evaluated by Natera's Signatera assay) for patients with resected colon cancer. Patients with negative postoperative ctDNA will be enrolled in cohort A and randomized to receive either immediate treatment with 5-fluorouracil and folinic acid or capecitabine plus oxaliplatin (FOLFOX6 or CAPEOX; Arm 1) or serial ctDNA surveillance with delayed adjuvant therapy (Arm 2). Patients randomized to Arm 2 with subsequent positive ctDNA results will be enrolled in cohort B for a second randomization to receive either FOLFOX6/CAPEOX (Arm 3) or 5-fluorouracil, folinic acid, oxaliplatin, and irinotecan (FOLFIRINOX; Arm 4) for 6 months. Patients with positive postoperative ctDNA results will be directly enrolled in cohort B and randomized to receive either FOLFOX6/CAPEOX (Arm 3) or FOLFIRINOX (Arm 4). Patients with stage II or stage IIIC colon cancer with positive ctDNA results (tested as standard of care with commercial testing) will be eligible for enrollment in cohort B. The primary end point for cohort A is time to positive ctDNA status for phase 2 and disease-free survival for phase 3 with a noninferiority design. The primary end point for cohort B is disease-free survival for both phase 2 and phase 3 with a superiority design. DISCUSSION: CIRCULATE-US will aim to understand postoperative ctDNA dynamics in early-stage colon cancer and will investigate escalation and de-escalation approaches by using ctDNA status as a surrogate for MRD status.

ATM kinase inhibitor AZD0156 in combination with irinotecan and 5-fluorouracil in preclinical models of colorectal cancer.

BACKGROUND: AZD0156 is an oral inhibitor of ATM, a serine threonine kinase that plays a key role in DNA damage response (DDR) associated with double-strand breaks. Topoisomerase-I inhibitor irinotecan is used clinically to treat colorectal cancer (CRC), often in combination with 5-fluorouracil (5FU). AZD0156 in combination with irinotecan and 5FU was evaluated in preclinical models of CRC to determine whether low doses of AZD0156 enhance the cytotoxicity of irinotecan in chemotherapy regimens used in the clinic. METHODS: Anti-proliferative effects of single-agent AZD0156, the active metabolite of irinotecan (SN38), and combination therapy were evaluated in 12 CRC cell lines. Additional assessment with clonogenic assay, cell cycle analysis, and immunoblotting were performed in 4 selected cell lines. Four colorectal cancer patient derived xenograft (PDX) models were treated with AZD0156, irinotecan, or 5FU alone and in combination for assessment of tumor growth inhibition (TGI). Immunofluorescence was performed on tumor tissues. The DDR mutation profile was compared across in vitro and in vivo models. RESULTS: Enhanced effects on cellular proliferation and regrowth were observed with the combination of AZD0156 and SN38 in select models. In cell cycle analysis of these models, increased G2/M arrest was observed with combination treatment over either single agent. Immunoblotting results suggest an increase in DDR associated with irinotecan therapy, with a reduced effect noted when combined with AZD0156, which is more pronounced in some models. Increased TGI was observed with the combination of AZD0156 and irinotecan as compared to single-agent therapy in some PDX models. The DDR mutation profile was variable across models. CONCLUSIONS: AZD0156 and irinotecan provide a rational and active combination in preclinical colorectal cancer models. Variability across in vivo and in vitro results may be related to the variable DDR mutation profiles of the models evaluated. Further understanding of the implications of individual DDR mutation profiles may help better identify patients more likely to benefit from treatment with the combination of AZD0156 and irinotecan in the clinical setting.

Current status and future of targeted peptide receptor radionuclide positron emission tomography imaging and therapy of gastroenteropancreatic-neuroendocrine tumors.

Theranostics is the highly targeted molecular imaging and therapy of tumors. Targeted peptide receptor radionuclide therapy has taken the lead in demonstrating the safety and effectiveness of this molecular approach to treating cancers. Metastatic, well-differentiated gastroenteropancreatic neuroendocrine tumors may be most effectively imaged and treated with DOTATATE ligands. We review the current practice, safety, advantages, and limitations of DOTATATE based theranostics. Finally, we briefly describe the exciting new areas of development and future directions of gastroenteropancreatic neuroendocrine tumor theranostics.

The rising tide of early-onset colorectal cancer: a comprehensive review of epidemiology, clinical features, biology, risk factors, prevention, and early detection.

The incidence of early-onset colorectal cnacer-ie, colorectal cancer diagnosed in patients under the age of 50 years- has been increasing around the world. This Series paper provides a comprehensive review on the topic of early-onset colorectal cancer, including examining the epidemiology of early-onset colorectal cancer around the world, clinical and pathological features, genetic and epigenetic landscapes, and emerging data on the clinical risk factors associated with this malignancy. Evidence-based approaches to prevention and early detection are also presented.

A comprehensive framework for early-onset colorectal cancer research.

Sporadic colorectal cancer has traditionally been viewed as a malignancy of older individuals. However, as the global prevalence of the disease diagnosed in younger individuals (<50 years) is expected to increase within the next decade, greater recognition is now being given to early-onset colorectal cancer. The cause of the predicted rise in prevalence is largely unknown and probably multifactorial. In this Series paper, we discuss the potential underlying causes of early-onset colorectal cancer, the role of energy balance, biological and genomic mechanisms (including microbiome aspects), and the treatment of early-onset colorectal cancer. We have specifically considered the psychosocial challenges of being diagnosed with colorectal cancer at younger age and the potential financial toxicity that might ensue. This Series paper brings a comprehensive review based on the existing data in the hopes of optimising the overall outcomes for patients with early-onset colorectal cancer.