Phase 1b study to assess the safety, tolerability, and clinical activity of pamiparib in combination with temozolomide in patients with locally advanced or metastatic solid tumors.

BACKGROUND: Pamiparib is a potent, selective, poly (ADP-ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two-stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors. METHODS: Oral pamiparib 60 mg was administered twice daily. During the dose-escalation stage, increasing doses of TMZ (40-120 mg once daily pulsed or 20-40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose-expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed. RESULTS: Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7-day pulsed 60 mg once daily. The most common treatment-emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose-escalation stage, four patients experienced dose-limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression-free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics. CONCLUSIONS: Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted.

Genomic Profiling of Rare Undifferentiated Sarcomatoid Subtypes of Pancreatic Carcinomas: In Search of Therapeutic Targets.

PURPOSE: The highly aggressive undifferentiated sarcomatoid carcinoma (USC) subtype of pancreatic ductal adenocarcinoma (PDAC) remains poorly characterized because of its rarity. Previous case reports suggest that immune checkpoint inhibitors could be a promising treatment strategy, but the prevalence of established predictive biomarkers of response is largely unknown. The objective of this study was to leverage comprehensive genomic profiling of USC PDAC tumors to determine the prevalence of biomarkers associated with potential response to targeted therapies. METHODS: USC tumors (n = 20) underwent central pathology review by a board-certified gastrointestinal pathologist to confirm the diagnosis. These samples were compared with non-USC PDAC tumors (N = 5,562). Retrospective analysis of DNA and RNA next-generation sequencing data was performed. RESULTS: USC PDACs were more frequently PD-L1+ by immunohistochemistry than non-USC PDAC (63% v 16%, respectively, P < .001). Furthermore, USC PDAC had an increase in neutrophils (8.99% v 5.55%, P = .005) and dendritic cells (1.08% v 0.00%, q = 0.022) and an increased expression of PDCD1LG2 (4.6% v 1.3%, q = 0.001), PDCD1 (2.0% v 0.8%, q = 0.060), and HAVCR2 (45.9% v 21.7%, q = 0.107) than non-USC PDAC. Similar to non-USC PDAC, KRAS was the most commonly mutated gene (86% v 90%, respectively, P = 1). CONCLUSION: To our knowledge, this work represents the largest molecular analysis of USC tumors to date and showed an increased expression of immune checkpoint genes in USC tumors. These findings provide evidence for further investigation into immune checkpoint inhibitors in USC tumors.

Molecular Landscape and Clinical Implication of CCNE1-amplified Esophagogastric Cancer.

Cyclin E overexpression as a result of CCNE1 amplification is a critical driver of genomic instability in gastric cancer, but its clinical implication is largely unknown. Thus, we integrated genomic, transcriptomic, and immune profiling analysis of 7,083 esophagogastric tumors and investigated the impact of CCNE1 amplification on molecular features and treatment outcomes. We identified CCNE1 amplification in 6.2% of esophageal adenocarcinoma samples, 7.0% of esophagogastric junction carcinoma, 4.2% of gastric adenocarcinoma samples, and 0.8% of esophageal squamous cell carcinoma. Metastatic sites such as lymph node and liver showed an increased frequency of CCNE1 amplification relative to primary tumors. Consistent with a chromosomal instability phenotype, CCNE1 amplification was associated with decreased CDH1 mutation and increased TP53 mutation and ERBB2 amplification. We observed no differences in immune biomarkers such as PD-L1 expression and tumor mutational burden comparing CCNE1-amplified and nonamplified tumors, although CCNE1 amplification was associated with changes in immune populations such as decreased B cells and increased M1 macrophages from transcriptional analysis. Real-world survival analysis demonstrated that patients with CCNE1-amplified gastric cancer had worse survival after trastuzumab for HER2-positive tumors, but better survival after immunotherapy. These data suggest that CCNE1-amplified gastric cancer has a distinct molecular and immune profile with important therapeutic implications, and therefore further investigation of CCNE1 amplification as a predictive biomarker is warranted. SIGNIFICANCE: Advanced gastric cancer has a relatively dismal outcome with a 5-year overall survival of less than 10%. Furthermore, while comprehensive molecular analyses have established molecular subtypes within gastric cancers, biomarkers of clinical relevance in this cancer type are lacking. Overall, this study demonstrates that CCNE1 amplification is associated with a distinct molecular profile in gastric cancer and may impact response to therapy, including targeted therapy and/or immunotherapy.

The Genomic, Transcriptomic, and Immunologic Landscape of HRAS Mutations in Solid Tumors.

Tipifarnib is the only targeted therapy breakthrough for HRAS-mutant (HRASmt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The molecular profiles of HRASmt cancers are difficult to explore given the low frequency of HRASmt. This study aims to understand the molecular co-alterations, immune profiles, and clinical outcomes of 524 HRASmt solid tumors including urothelial carcinoma (UC), breast cancer (BC), non-small-cell lung cancer (NSCLC), melanoma, and HNSCC. HRASmt was most common in UC (3.0%), followed by HNSCC (2.82%), melanoma (1.05%), BC (0.45%), and NSCLC (0.44%). HRASmt was absent in Her2+ BC regardless of hormone receptor status. HRASmt was more frequently associated with squamous compared to non-squamous NSCLC (60% vs. 40% in HRASwt, p = 0.002). The tumor microenvironment (TME) of HRASmt demonstrated increased M1 macrophages in triple-negative BC (TNBC), HNSCC, squamous NSCLC, and UC; increased M2 macrophages in TNBC; and increased CD8+ T-cells in HNSCC (all p < 0.05). Finally, HRASmt was associated with shorter overall survival in HNSCC (HR: 1.564, CI: 1.16-2.11, p = 0.003) but not in the other cancer types examined. In conclusion, this study provides new insights into the unique molecular profiles of HRASmt tumors that may help to identify new targets and guide future clinical trial design.

Impact of carbamazepine on SMARCA4 (BRG1) expression in colorectal cancer: modulation by KRAS mutation status.

SMARCA4 is a gene traditionally considered a tumor suppressor. Recent research has however found that SMARCA4 likely promotes cancer growth and is a good target for cancer treatment. The drug carbamazepine, an autophagy inducer, was used on colorectal cancer cell lines, HCT1116 and Hke3 (KRAS mutant and wildtype). Our study finds that Carbamazepine affects SMARCA4 levels and that this effect is different depending on the KRAS mutation status. This study analyzes the effect of carbamazepine on early-stage autophagy via ULK1 as well as simulates the docking of carbamazepine on KRAS, depending on the mutation status. Our study highlights the therapeutic uses of carbamazepine on cancer, and we propose that carbamazepine in conjunction with other chemotherapies may prove useful in targeting KRAS-mutated colorectal cancer.

Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer.

BACKGROUND: CDC37 is a key determinant of client kinase recruitment to the HSP90 chaperoning system. We hypothesized that kinase-specific dependency on CDC37 alters the efficacy of targeted therapies for metastatic colorectal cancer (mCRC). MATERIAL AND METHODS: Two independent mCRC cohorts were analyzed to compare the survival outcomes between CDC37-high and CDC37-low patients (stratified by the median cutoff values): the CALGB/SWOG 80405 trial (226 and 207 patients receiving first-line bevacizumab- and cetuximab-containing chemotherapies, respectively) and Japanese retrospective (50 refractory patients receiving regorafenib) cohorts. A dataset of specimens submitted to a commercial CLIA-certified laboratory was utilized to characterize molecular profiles of CDC37-high (top quartile, N = 5055) and CDC37-low (bottom quartile, N = 5055) CRCs. RESULTS: In the bevacizumab-treated group, CDC37-high patients showed significantly better progression-free survival (PFS) (median 13.3 vs 9.6 months, hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44-0.79, p < 0.01) than CDC37-low patients. In the cetuximab-treated group, CDC37-high and CDC37-low patients had similar outcomes. In the regorafenib-treated group, CDC37-high patients showed significantly better overall survival (median 11.3 vs 6.0 months, HR 0.24, 95% CI 0.11-0.54, p < 0.01) and PFS (median 3.5 vs 1.9 months, HR 0.51, 95% CI 0.28-0.94, p = 0.03). Comprehensive molecular profiling revealed that CDC37-high CRCs were associated with higher VEGFA, FLT1, and KDR expressions and activated hypoxia signature. CONCLUSIONS: CDC37-high mCRC patients derived more benefit from anti-VEGF therapies, including bevacizumab and regorafenib, but not from cetuximab. Molecular profiles suggested that such tumors were dependent on angiogenesis-relating pathways.

The Impact of Medicaid Expansion Under the Affordable Care Act on the Gap Between American Indians and Whites in Breast Cancer Management and Prognosis.

BACKGROUND: Breast cancer (BC) death rates in the USA have not significantly declined for American Indians (AIs) in comparison to Whites. Our objective was to determine whether Medicaid Expansion as part of the Affordable Care Act led to improved BC outcomes for AIs relative to Whites. PATIENTS AND METHODS: Using the National Cancer Database, we conducted a retrospective cohort study. Included were BC patients who were AI and White; 40 to 64 years of age; diagnosed in 2009 to 2016; lived in states that expanded Medicaid in January 2014, and states that did not expand Medicaid. Our outcomes were stage at diagnosis, insurance status, timely treatment, and 3-year mortality. RESULTS: There were 359,484 newly diagnosed BC patients, 99.49% White, 0.51% AI. Uninsured rates declined more in the expansion states than in the nonexpansion states (OR = 0.44, 95% CI: 0.15-0.97, P < 0.001). Lower rates of Stage I BC diagnosis was found in AIs compared to Whites (46.58% vs. 55.33%, P < .001); these differential rates did not change after Medicaid expansion. Rates of definitive treatment initiation within 30 days of diagnosis declined after Medicaid expansion (P < .001); there was a smaller decline in the expansion states (OR 1.118, 95% CI: 1.09, 1.15, P < .001). Three year mortality was not different between expansion and nonexpansion states post Medicaid expansion. CONCLUSIONS: In newly diagnosed BCs, uninsured rates declined more in the states that expanded Medicaid in January 2014. Timely treatment post Medicaid expansion declined less in states that expanded Medicaid. There was no differential benefit of Medicaid expansion in the 2 races.

Effectiveness of Biologic Agents Among Hispanic Patients With Metastatic Colorectal Cancer.

BACKGROUND: Randomized clinical trials have defined the survival advantage with the addition of biologic drugs to chemotherapy in patients with metastatic colorectal cancer (mCRC). Under representation of Hispanics contributes to poorly defined outcomes in this group. We aim to determine whether the real-world benefit of biologics extends to Hispanics using a comparative effectiveness research approach. METHODS: This retrospective cohort study included all treatment centers contributing to SEER registry with available claims in the SEER-Medicare linked database (2001-2011) and 2 hospitals (2004-2016) catering to minorities. Metastatic CRC patients were classified as receiving chemotherapy or biochemotherapy (CT plus biologics; if initiated within 3 months of chemotherapy). The primary outcome was overall survival (OS) among the Hispanic patients calculated from time of administration of first dose of chemotherapy to death or last follow-up. A weighted Cox regression model was used to assess differences in survival. RESULTS: We identified 182 Hispanic patients with mCRC from the Patient Entitlement and Diagnosis Summary (PEDSF) file (n = 101) and hospital database (n = 81). Overall, 52% were women and 72% received biologics. The median OS was 11.3 and 17.0 months in chemotherapy and biochemotherapy group, respectively. Biochemotherapy offered a survival benefit compared with chemotherapy alone, with an average hazard rate reduction of 39% (95% CI 6%-60%, p = .0236) using inverse probability of treatment weighting (IPTW) based analysis. CONCLUSION: In this cohort of Hispanic patients with mCRC, biochemotherapy was associated with longer survival. Clinicians may offer biochemotherapy therapy to all patients regardless of race/ethnicity to maximize clinical benefit.

Noncoding RNA Profile in Reovirus Treated KRAS-Mutated Colorectal Cancer Patients.

PURPOSE: To investigate the alterations in the expression of noncoding, micro, and small RNA expression during treatment with oncolytic reovirus in KRAS-mutated colorectal cancer. METHODS: Oncolytic reovirus treatment was administered in phase 1 clinical trial (NCT01274624) for 5 days every 28 days, and blood samples were collected before the administration of the reovirus and 48 h, 8 days, and 15 days after its administration on day 1. Data from the blood samples were sorted using Transcriptome Analysis Software (TAC) 4.0, where a two-tailed t-test and a fold change filter were used to ascertain which sample signals had a statistically significant relative fold change of greater than 2 at multiple timepoints before or after oncolytic reovirus administration. RESULTS: The long noncoding RNA's RP11-332M2.1 (-6.1 x), LINC01506 (-16.18 x), and LINC00534 (-1.94 x) were downregulated at 48 h after reovirus administration [p < 0.05]. ncRNA's EPB41L4A-AS1 (-6.34 x, 48 h; 11.99 x, day 8), JAK2 (2.2 x, 48 h; -2.23 x, day 8), ANXA4 (20.47 x, day 8; -7.54 x, day 15), and PCDH9 (-2.09, day 8; 1.82 x, day 15) were affected by the reovirus treatment and reflected the progress of the treatment [p < 0.05]. The small RNA SNORA26 (-1.59 x, day 8) was downregulated 48 h after the reovirus administration [p < 0.05]. The microRNA MIR-4461 (6.18 x, day 8; -3.76 x, day 15) was also affected by the reovirus administration [p < 0.05]. CONCLUSION: The administration of oncolytic reovirus to treat KRAS-mutated colorectal cancer is reflected in a noncoding RNA profile, and expression levels of the ncRNAs in that profile may thus be able to be used as a potential predictive marker for reovirus-treated colorectal cancer.

Effect of Medicaid Expansion in Reducing Racial Disparities in Early Onset Colorectal Cancer.

BACKGROUND: The burden of early onset colorectal cancer (EOCRC) falls disproportionately on minorities and individuals in specific geographic regions. While these disparities are likely multi-factorial, access to high-quality health care plays a significant role. We sought to determine if Medicaid expansion is associated with reducing racial disparities in EOCRC detection in Hispanics and non-Hispanic Blacks (NHB), compared to non-Hispanic Whites (NHW). METHODS: Analysis of data from National Cancer Database was undertaken to compare incidence of EOCRC among those aged 40-49 between Medicaid expansion states (ES) and non-expansion states (NES) by racial/ethnic groups. Data was classified by race (NHW, NHB, or Hispanic), state of residence (ES or NES), and time (pre- or post-expansion). The primary outcome was change in incidence rate of EOCRC among racial/ethnic groups, according to whether patients resided in Medicaid expansion or non-expansion states. RESULTS: Among Hispanics, the ES showed a significant increase in EOCRC incidence post expansion as compared to NES (p = 0.03). The rate of increase in annual incidence of EOCRC among Hispanics was 4.3% per year (pre-expansion) and 9.8% (post-expansion) for ES; and 6.4% (pre-expansion) and 1% (post-expansion) in NES. However, no difference was noted among NHB (p = 0.33) and NHW (p = 0.94). CONCLUSIONS: Medicaid expansion has improved detection rates of EOCRC in ES especially in Hispanic population. This is the first study to demonstrate the effect of Medicaid expansion on the incidence of EOCRC. Based on our study findings we suggest that racial and ethnic disparities should be considered in the earlier CRC screening debates.

Differences in Breast Cancers Among American Indian/Alaska Native and non-Hispanic Whites in the USA.

IMPORTANCE: Breast cancer (BC) death rates have not improved for American Indian/Alaska Native (AI/AN) women, whereas, it has significantly decreased for non-Hispanic White (White) women. OBJECTIVE: Delineate the differences in patient and tumor characteristics among AI/AN and Whites with BC, and its impact on age and stage at diagnosis as well as overall survival (OS). METHODS: Hospital-based, cohort study using the National Cancer Database to identify female AI/AN and Whites diagnosed with BC between the years 2004 and 2016. RESULTS: BC in 6866 AI/AN (0.3%) and 1,987,324 Whites (99.7%) were studied. The median age at diagnosis was 58 for AI/AN and 62 for Whites. AI BC patients traveled double the distance for treatment, lived in lower median income zip codes, had a higher percentage of uninsured, higher comorbidities, lower percentage of Stage 0/I, larger tumor size, greater number of positive lymph nodes, higher proportion of triple negative and HER2-positive BC than Whites. All the above comparisons were significant, p<0.001. Association between patient/tumor characteristics with age and stage at diagnosis was not significantly different between AI/AN and Whites. Unadjusted OS was worse for AI/AN as compared to Whites (HR=1.07, 95% CI=1.01-1.14, p=0.023). After adjustment of all covariates, OS was not different (HR=1.038, 95%CI=0.902-1.195, p=0.601). CONCLUSION: There were significant differences in patient/tumor characteristics among AI/AN and White BC which adversely impacted OS in AI/AN. However, when adjusted for various covariates, the survival was similar, suggesting that the worse survival in AI/AN is mostly the impact of known biological, socio-economic, and environmental determinants of health.

Phase 1 dose-escalation study of SEA-CD40: a non-fucosylated CD40 agonist, in advanced solid tumors and lymphomas.

BACKGROUND: SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma. METHODS: SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 µg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity. RESULTS: A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10-30 µg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma. CONCLUSIONS: SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen. TRIAL REGISTRATION NUMBER: NCT02376699.

Direct oral anticoagulant (DOACs) prescribing practices of members of the Society of Gynecologic Oncology and American Society of Clinical Oncology.

BACKGROUND: Cancer associated venous thromboembolism (VTE) is associated with significant morbidity and mortality. Direct oral anticoagulants (DOACs) have emerged as alternatives to injectable medications for both thromboprophylaxis and treatment of VTE. Several recent clinical trials have demonstrated safety and efficacy of DOACs in high risk patients receiving systemic chemotherapy as well as postoperative prophylaxis after surgery for gynecologic cancer. Major consensus guidelines from multiple organizations support the use of DOACs for these indications but prescription practices are not well characterized. METHODS: A survey study was sent concurrently to members of the Society of Gynecologic Oncology (SGO) and American Society of Clinical Oncology (ASCO) Research Survey Pool between May and June of 2021. The study was designed to assess DOAC prescription practices amongst members of these societies who routinely prescribe chemotherapy. Bivariate analyses comparing responses from ASCO participants and SGO participants were compared using chi-squared and Fisher exact tests. RESULTS: A total of 103 physicians were included in the ASCO group and 139 in the SGO group. A majority of participants in both groups reported familiarity with prescribing DOACs (99% of ASCO and 96% of SGO respondents). ASCO respondents were more likely to consider DOACs as first line therapy for treatment of cancer-associated VTE than SGO members (82% vs 63%, p < 0.01) and SGO members were more likely to consider low molecular weight heparin (LMWH) the standard of care treatment (66% vs 25% p < 0.01). Most respondents in both groups (75%) felt DOACs were equally safe and effective compared to LMWH but more ASCO members felt DOACs were cost effective (70% vs 49%, p < 0.01). More SGO respondents reported having prescribed prophylactic anticoagulation during chemotherapy than ASCO members (53% vs 35%, p < 0.01). CONCLUSION: ASCO respondents were more likely to prescribe DOACs for both treatment and prophylaxis of cancer-associated VTE than SGO members. However, SGO members were more likely to prescribe prophylactic anticoagulation to high risk patients initiating chemotherapy compared to ASCO members.

Effect of Pevonedistat, an Investigational NEDD8-Activating Enzyme Inhibitor, on the QTc Interval in Patients With Advanced Solid Tumors.

The purpose of this study was to assess the effect of pevonedistat, a neural precursor cell expressed, developmentally down-regulated protein 8 (NEDD8)-activating enzyme inhibitor, on the heart rate-corrected QT (QTc) interval in cancer patients. Patients were randomized 1:1 to receive pevonedistat 25 or 50 mg/m2 on day 1 and the alternate dose on day 8. Triplicate electrocardiograms were collected at intervals over 0-11 hours and at 24 hours via Holter recorders on days -1 (baseline), 1, and 8. Changes from time-matched baseline values were calculated for QTc by Fridericia (QTcF), PR, and QRS intervals. Serial time-matched blood samples for analysis of pevonedistat plasma pharmacokinetics were collected and a concentration-QTc analysis conducted. Safety was assessed by monitoring vital signs, physical examinations, and clinical laboratory tests. Forty-four patients were included in the QTc analysis. Maximum least square (LS) mean increase from time-matched baseline in QTcF was 3.2 milliseconds at 1 hour postdose for pevonedistat at 25 mg/m2 , while the LSs mean change from baseline in QTcF was -1.7 milliseconds 1 hour postdose at 50 mg/m2 . The maximum 2-sided 90% upper confidence bound was 6.7 and 2.9 milliseconds for pevonedistat at 25 and 50 mg/m2 , respectively. Pevonedistat did not result in clinically relevant effects on heart rate, nor on PR or QRS intervals. Results from pevonedistat concentration-QTc analysis were consistent with these findings. Administration of pevonedistat to cancer patients at a dose of up to 50 mg/m2 showed no evidence of QT prolongation, indicative of the lack of clinically meaningful effects on cardiac repolarization. ClinicalTrials.gov identifier: NCT03330106 (first registered on November 6, 2017).

Mesothelin expression correlates with elevated inhibitory immune activity in patients with colorectal cancer.

The expression of the protein Mesothelin (MSLN) is highly variable in several malignancies including colorectal cancer (CRC) and high levels are associated with aggressive clinicopathological features and worse patient survival. CRC is both a common and deadly cancer; being the third most common in incidence and second most common cause of cancer related death. While systemic therapy remains the primary therapeutic option for most patients with stage IV (metastatic; m) CRC, their disease eventually becomes treatment refractory, and 85% succumb within 5 years. Microsatellite-stable (MSS) CRC tumors, which affect more than 90% of patients with mCRC, are generally refractory to immunotherapeutic interventions. In our current work, we characterize MSLN levels in CRC, specifically correlating expression with clinical outcomes in relevant CRC subtypes and explore how MSLN expression impacts the status of immune activation and suppression in the peritumoral microenvironment. High MSLN expression is highly prevalent in CMS1 and CMS4 CRC subtypes as well as in mCRC tissue and correlates with higher gene mutation rates across the patient cohorts. Further, MSLN-high patients exhibit increased M1/M2 macrophage infiltration, PD-L1 staining, immune-inhibitory gene expression, enrichment in inflammatory, TGF-ß, IL6/JAK/STAT3, IL2/STAT5 signaling pathways and mutation in KRAS and FBXW7. Together, these results suggest MSLN protein is a potential target for antigen-specific therapy and supports investigation into its tumorigenic effects to identify possible therapeutic interventions for patients with high MSLN expressing MSS CRC.

Metformin: Activation of 5' AMP-activated protein kinase and its emerging potential beyond anti-hyperglycemic action.

Metformin is a plant-based drug belonging to the class of biguanides and is known to treat type-2 diabetes mellitus (T2DM). The drug, combined with controlling blood glucose levels, improves the body's response to insulin. In addition, trials have identified the cardioprotective potential of metformin in the diabetic population receiving the drug. Activation of 5' AMP-activated protein kinase (AMPK) is the major pathway for these potential beneficial effects of metformin. Historically, much emphasis has been placed on the potential indications of metformin beyond its anti-diabetic use. This review aims to appraise other potential uses of metformin primarily mediated by the activation of AMPK. We also discuss various mechanisms, other than AMPK activation, by which metformin could produce beneficial effects for different conditions. Databases including PubMed/MEDLINE and Embase were searched for literature relevant to the review's objective. Reports from both research and review articles were considered. We found that metformin has diverse effects on the human body systems. It has been shown to exert anti-inflammatory, antioxidant, cardioprotective, metabolic, neuroprotective, anti-cancer, and antimicrobial effects and has now even been identified as effective against SARS-CoV-2. Above all, the AMPK pathway has been recognized as responsible for metformin's efficiency and effectiveness. Owing to its extensive potential, it has the capability to become a part of treatment regimens for diseases apart from T2DM.

Potentiating effect of reovirus on immune checkpoint inhibition in microsatellite stable colorectal cancer.

The majority of colorectal cancers (CRCs) are microsatellite stable (MSS) and resistant to immunotherapy. The current study explores the possibility of using oncolytic reovirus to sensitize MSS CRC to immune checkpoint inhibition. While reovirus reduced metabolic activity among KRAS Mut cells, microarray/computational analysis revealed microsatellite status-oriented activation of immune-response pathways. Reovirus plus anti-PD-1 treatment increased cell death among MSS cells ex vivo. Reduced tumorigenicity and proliferative index, and increased apoptosis were evident among CT26 [MSS, KRAS Mut], but not in MC38 [microsatellite unstable/MSI, KRAS Wt] syngeneic mouse models under combinatorial treatment. PD-L1-PD-1 signaling axis were differentially altered among CT26/MC38 models. Combinatorial treatment activated the innate immune system, pattern recognition receptors, and antigen presentation markers. Furthermore, we observed the reduction of immunosuppressive macrophages and expansion of effector T cell subsets, as well as reduction in T cell exhaustion. The current investigation sheds light on the immunological mechanisms of the reovirus-anti-PD-1 combination to reduce the growth of MSS CRC.

Induction Chemotherapy With FOLFIRINOX Followed by Chemoradiation With Gemcitabine in Patients With Borderline-Resectable Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: Perioperative therapy is standard for patients with borderline-resectable pancreatic ductal adenocarcinoma (BR-PDAC); however, an optimal neoadjuvant regimen is lacking. We assessed the efficacy of FOLFIRINOX chemotherapy followed by gemcitabine-based chemoradiation as preoperative therapy. METHODS: Patients received 4 cycles of FOLFIRINOX, followed by 6-weekly gemcitabine with concomitant intensity-modulated radiation. The primary endpoint was the R0 resection rate. Secondary outcomes included resection rate, overall-response, overall survival (OS), progression-free survival (PFS), and tolerability. The trial was terminated early due to slow accrual. A Simon's optimal two-stage phase II trial single arm design was used. The primary hypothesis of treatment efficacy was tested using a multistage group sequential inference procedure. The secondary failure time analysis endpoints were assessed using the Kaplan-Meier procedure and the Cox regression model. RESULTS: A total of 22 patients enrolled in the study, 18 (81.8%) completed neoadjuvant treatment. The bias corrected R0 rate was 55.6% (90% CI: 33.3, 68.3; P value = .16) among patients that received at least 1 cycle of FOLFIRINOX and was 80% among patients that underwent surgery. The median OS was 35.1 months. The median PFS among patients that underwent surgery was 34 months. CONCLUSION: An R0 resection rate of 55.6% is favorable. Neoadjuvant FOLFIRINOX followed by concomitant Gemcitabine with radiation was well-tolerated. NCT01897454.

Prevalence and Assessment of Factors Associated with COVID-19 Vaccine Hesitancy in an Ethnic Minority Oncology Patient Population.

BACKGROUND: Complicating the COVID-19 pandemic are the healthcare disparities experienced by ethnic minorities, especially those with comorbidities including cancer. The introduction of COVID-19 vaccines has been instrumental in blunting the morbidity and mortality from the pandemic; however, vaccine hesitancy, particularly among ethnic minorities, has been a major concern. Thus, we sought to evaluate the knowledge and perspectives of COVID-19 and vaccines among our ethnic minority cancer patient population. METHODS: Following an IRB approved protocol, questionnaires were completed by patients in a predominantly ethnic minority population at a single institution between 1 February and 30 June 2021. Included were any adult cancer patients with either a solid or hematologic malignancy. RESULTS: Among the 84 patients that were offered the questionnaires, 52 patients responded, with a median age of 63.5 years. Overall, 36% were non-Hispanic Blacks and 30% were Hispanics; 65% were receiving active treatment for their cancer. Seventy-nine percent believed COVID-19 to be dangerous or harmful to them, 61% were concerned about the side effects, yet 65% considered COVID-19 vaccines as safe. Among the seven patients that refused the vaccine, (71%, n = 5) cited side effects and/or (57%, n = 4) believed that the vaccine was not needed. Overall, there was a significantly higher chance of being vaccinated if patients were receiving active cancer treatment, believed COVID-19 was harmful, or that the vaccine was safe, and knew COVID-19 was a virus. CONCLUSIONS: This exploratory study demonstrates that most ethnic minority cancer patients are receptive to vaccines, with a majority being vaccinated. However, we also discovered various reasons why this group of patients may not want be vaccinated, including concerns about side effects and perception that COVID-19 is not harmful. These findings can help us further understand the complex nature of vaccine hesitancy in ethnic minority cancer patients, and aid in developing future vaccine awareness strategies as the COVID-19 pandemic continues to evolve.

Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021).

BACKGROUND: Patients with metastatic castration-resistant prostate cancer have few treatment options after novel hormonal therapy (eg, abiraterone or enzalutamide). We aimed to evaluate cabozantinib, a tyrosine kinase inhibitor with immunomodulatory properties, in combination with the PD-L1 inhibitor atezolizumab in metastatic castration-resistant prostate cancer. METHODS: COSMIC-021 is an ongoing, multicentre, open-label, phase 1b study with a dose-escalation stage followed by tumour-specific expansion stages. Expansion cohort 6 in metastatic castration-resistant prostate cancer was enrolled at 42 cancer research centres in France, Italy, the Netherlands, Spain, and the USA. Eligible patients were aged 18 years or older and had metastatic castration-resistant prostate cancer with radiographic soft tissue progression following treatment with either enzalutamide or abiraterone, or both; measurable soft tissue disease per Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received oral cabozantinib 40 mg per day and intravenous atezolizumab 1200 mg once every 3 weeks. Study treatment continued until progressive disease or unacceptable toxicity. All enrolled patients were assessed for efficacy and safety. The primary endpoint was objective response rate per RECIST version 1.1 as assessed by the investigator. This study is registered with ClinicalTrials.gov, NCT03170960. FINDINGS: Between April 24, 2018, and Aug 31, 2020, 132 patients were enrolled and received at least one dose of study treatment. At data cutoff (Feb 19, 2021), median duration of follow-up was 15·2 months (IQR 9·6-21·7). Objective response rate was 23% (95% CI 17-32; 31 of 132 patients), with three (2%) confirmed complete responses and 28 (21%) confirmed partial responses. 72 (55%) of 132 patients had grade 3-4 treatment-related adverse events, with the most common being pulmonary embolism (11 [8%] patients), diarrhoea (nine [7%]), fatigue (nine [7%]), and hypertension (nine [7%]). There was one grade 5 treatment-related adverse event (dehydration). 74 (56%) of 132 patients had serious adverse events of any causality. 28 (21%) of 132 patients had treatment-related adverse events leading to discontinuation of either study drug. INTERPRETATION: Cabozantinib plus atezolizumab showed promising antitumour activity in patients with metastatic castration-resistant prostate cancer after novel hormonal therapy with an acceptable safety profile, supporting further evaluation of this combination. FUNDING: Exelixis.