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Metastatic colorectal cancer (mCRC) is the second most common cause of cancer-related death worldwide. In the mid-1980s, the median overall survival (OS) for patients with mCRC ranged from 10 to 12 months from the time of initial diagnosis. In more recent studies, this median has more than doubled and is commonly reported at more than 25 to 30 months. These improvements are due, in large part, to the introduction of multiple novel agents during the last 3 decades. Despite these improvements, however, nearly all patients treated with palliative chemotherapy will eventually develop resistance and ultimately succumb to progression of metastatic disease. Understanding the mechanisms by which malignant cells evade treatment could unlock novel therapeutic strategies that overcome resistance and improve survival. In this review, we will discuss some of the drivers of therapeutic resistance in patients with mCRC and present some novel strategies to overcome resistance.

Background Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC. Materials and Methods Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test. Results A total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p < .001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p < .001). Patients aged >65 had significantly worse PFS rates as compared with patients aged ≤65 (p < .001). Conclusion BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings. Implications for Practice The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.

Background Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes. Methods We employed a 3+3 dose escalation design to establish the safety and recommended phase 2 doses (RP2D) of daily everolimus and lenalidomide in patients with advanced solid tumours. The starting doses were 5 and 10 mg, respectively, with planned escalation to maximum single-agent doses of 10 and 25 mg in the absence of dose-limiting toxicity. PD endpoints of lymphocyte subsets and immune cytokines were assessed in peripheral blood using multiparameter flow cytometry and LUMINEX assay. Efficacy was evaluated by cross-sectional imaging after every two cycles of treatment. Results The study enrolled 44 patients, median age of 58 years and 28 males (63.6%). The RP2D was established as 10 and 25 mg daily continuously for everolimus and lenalidomide. Common (>5%) grade ≥3 adverse events included rash (19%), neutropenia (19%), hypokalaemia (11%) and fatigue (9%). Best efficacy outcomes in 36 evaluable patients were partial response in 5 (13.8%), stable disease in 24 (55.8%) and progressive disease in 7 (19.4%) patients. PD assessment revealed significant association of cytokine levels (interleukin-2 (IL2), IL21 and IL17), baseline activated and total CD8+ lymphocytes and change in B cell lymphocytes and activated NK cells with clinical benefit. Conclusions The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers. Clinical Trial Registration NCT01218555

Purpose: Concurrent inhibition of mTOR and PI3K led to improved efficacy in preclinical models and provided the rationale for this phase I study of everolimus and buparlisib (BKM120) in patients with advanced solid tumor. Patients and Methods: We used the Bayesian Escalation with Overdose Control design to test escalating doses of everolimus (5 or 10 mg) and buparlisib (20, 40, 60, 80, and 100 mg) in eligible patients. Pharmacokinetic assessment was conducted using blood samples collected on cycle 1, days 8 and 15. Pharmacodynamic impact on mTOR/PI3K pathway modulation evaluated in paired skin biopsies collected at baseline and end of cycle 1. Results: We enrolled 43 patients, median age of 63 (range, 39–78) years; 25 (58.1%) females, 35 (81.4%) Caucasians, and 8 (18.6%) Blacks. The most frequent toxicities were hyperglycemia, diarrhea, nausea, fatigue, and aspartate aminotransferase elevation. Dose-limiting toxicities observed in 7 patients were fatigue (3), hyperglycemia (2), mucositis (1), acute kidney injury (1), and urinary tract infection (1). The recommended phase II dose (RP2D) for the combination was established as everolimus (5 mg) and buparlisib (60 mg). The best response in 27 evaluable patients was progressive disease and stable disease in 3 (11%) and 24 (89%), respectively. The median progression-free survival and overall survival were 2.7 (1.8–4.2) and 9 (6.4–13.2) months. Steady-state pharmacokinetic analysis showed dose-normalized maximum concentrations and AUC values for everolimus and buparlisib in combination to be comparable with single-agent pharmacokinetic. Conclusions: The combination of everolimus and buparlisib is safe and well-tolerated at the RP2D of 5 and 60 mg on a continuous daily schedule.

Recent studies have identified durable responses with the use of immune checkpoint inhibitors in patients with mismatch repair–deficient (MMR-D)/microsatellite instability–high (MSI-H) metastatic colorectal cancer (CRC). The dramatic improvement in clinical outcomes led to the US Food and Drug Administration approval of pembrolizumab, nivolumab, and nivolumab in combination with ipilimumab in metastatic patients with MSI-H/MMR-D CRC who previously experienced progression on cytotoxic therapies. In the clinical trials investigating these agents, HIV-seropositive patients were not included and therefore the clinical efficacy of these agents in patients with metastatic MSI-H/MMR-D CRC living with HIV is unclear. On the basis of growing evidence, immune checkpoint blockade therapies seem to be a safe approach in patients with well-controlled HIV infection. Research on immunotherapeutic approaches in patients living with HIV and cancer is an area of unmet medical need that can be addressed by clinical trial designs that are inclusive of patients with well-controlled seropositive HIV and trials that specifically evaluate immune therapies in patients living with HIV.

Background: Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms that span from well-differentiated neuroendocrine tumors (NETs) to highly aggressive neoplasms classified as neuroendocrine carcinomas (NECs). The genomic landscape of NENs has not been well studied. The aim of this study is to confirm the feasibility of next generation sequencing (NGS) testing circulating tumor DNA (ctDNA) in patients with NENs and characterize common alterations in the genomic landscape. Results: Of the 320 NEN patients, 182 (57%) were male with a median age of 63 years (range: 8-93) years. Tumor type included pancreatic NET (N = 165, 52%), gastrointestinal NEC (N = 52, 16%), large cell lung NEC (N = 21, 7%), nasopharyngeal NEC (N = 16, 5%) and NEC/NET not otherwise specified (N = 64, 20%). ctDNA NGS testing was performed on 338 plasma samples; 14 patients had testing performed twice and 2 patients had testing performed three times. Genomic alterations were defined in 280 (87.5%) samples with a total of 1,012 alterations identified after excluding variants of uncertain significance (VUSs) and synonymous mutations. Of the 280 samples with alterations, TP53 associated genes were most commonly altered (N = 145, 52%), followed by KRAS (N = 61, 22%), EGFR (N = 33, 12%), PIK3CA (N = 30, 11%), BRAF (N = 28, 10%), MYC (N = 28, 10%), CCNE1 (N = 28, 10%), CDK6 (N = 22, 8%), RB1 (N = 19, 7%), NF1 (N = 19, 7%), MET (N = 19, 7%), FGFR1 (N = 19, 7%), APC (N = 19, 7%), ERBB2 (N = 16, 6%) and PTEN (N = 14, 5%). Conclusions: Evaluation of ctDNA was feasible among individuals with NEN. Liquid biopsies are non-invasive methods that can provide personalized options for targeted therapies in NEN patients. Patients and Methods: Molecular alterations in 338 plasma samples from 320 patients with NEN were evaluated using clinical-grade NGS of ctDNA (Guardant360®) across multiple institutions. The test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes.

Surgical resection remains the only potentially curative therapy for pancreatic ductal adenocarcinoma (PDAC). There is paucity of literature about morbidity and mortality in older patients with PDAC undergoing pancreaticoduodenectomy. This retrospective analysis evaluates the in-hospital 30-day mortality of this population utilizing the Nationwide Inpatient Sample (NIS) database.All US patients hospitalized for pancreaticoduodenectomy (Whipple procedure) were included. Data was obtained from the NIS provided by the Agency for Healthcare Research and Quality. Pancreaticoduodenectomy diagnoses were identified using Clinical Classifications Software codes based on ICD-9 between 2007 and 2010. Univariable and multivariable analyses were performed using the logistic model, weighted chi-square test, and generalized linear model.A total of 6149 patient discharges for pancreaticoduodenectomy were identified. Mean age was 64.9 years (SD ± 12.3); 21% of patients were ≥ 76 years of age. Majority were White (N = 5257, 77.9%) with a male:female ratio of 1. Patients aged 76 and older (OR: 1.76; 1.36-2.28; p .001), Hispanics (OR: 1.40; 0.92-2.13; p = .12), and high comorbidity score (OR: 5.70; 3.44-9.46; p .001) were found to be associated with a higher risk of 30-day in-hospital mortality. In the multivariable analysis, advanced age (76) remained a significant predictor of longer in-hospital length of stay (OR: 1.09; 1.04-1.14; p .001) and 30-day in-hospital mortality (OR 1.46; 1.07-2.00; p = .016). The 30-day in-hospital mortality rate for all patients across all years was 3.24%, for patients76 years 4.11% and for patients76 years 2.77%. Patients who underwent surgery at teaching hospitals (OR: 0.61; 0.42-0.88; p = .008) had a lower risk of 30-day in-hospital mortality compared to non-teaching hospitals.In-hospital 30 day mortality was higher in selected older patients with PDAC undergoing pancreaticoduodenectomy. Mortality was lower at high volume and teaching centers. Further stringent selection criteria are needed to decrease mortality in the older population.

Introduction Immune-related adverse event (IRAE) onset may represent a clinical biomarker for anti-programmed cell death protein 1 (PD-1) antibody response based on emerging evidence from patients with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)-approved indications to receive immune checkpoint inhibitor therapy. Materials and Methods The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti-PD-1 antibodies for FDA-approved indications. The primary and secondary outcomes of the study were progression-free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes. Results Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached [NR] vs. 3.9 months [hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05–0.3, p < .001]; OS: NR vs. 7.4 months [HR 0.11, 95% CI 0.03–0.36, p < .001]). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset. Conclusion Patients with gastrointestinal cancer who experienced IRAEs while on anti-PD-1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response. Implications for Practice Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno-oncology. Immune-related adverse event onset appears to be one such biomarker. Across tumor types, immune-related adverse event onset has been associated with response to anti-programmed cell death protein 1 (PD-1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti-PD-1 antibodies. Before immune-related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune-related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.

Background Sarcopenia and inflammation have been associated with poor survival in patients with cancer. We explored the combined effects of these variables on survival in patients with cancer treated with immunotherapy. Methods We performed a retrospective review of 90 patients enrolled on immunotherapy‐based phase I clinical trials at Emory University from 2009 to 2017. Baseline neutrophil‐to‐lymphocyte ratio, monocyte‐to‐lymphocyte ratio, and platelet‐to‐lymphocyte ratio (PLR) were used as surrogates of inflammation. The skeletal muscle index (SMI) was derived from the skeletal muscle density calculated from baseline abdominal computed tomography images. Optimal cutoffs for continuous inflammation biomarkers and SMI were determined by bias‐adjusted log‐rank test. A four‐level risk stratification was used to create low‐risk (PLR, The interaction between chronic inflammation and body composition is particularly important in the era of immunotherapy, considering that immune checkpoint inhibitors rely on the host immune system for their efficacy. This article reports on the combined effects of inflammation and sarcopenia on clinical outcomes in patients with solid tumors treated with immunotherapy‐based regimens.

BackgroundHigh-risk features, such as T4 disease, bowel obstruction, poorly/undifferentiated histology, lymphovascular, perineural invasion, and MethodsUnivariate (UVA) and multivariate (MVA) Cox proportional hazards (Cox-PH) models were built to assess the association between clinical and demographic characteristics and overall survival. Kaplan–Meier survival curves were generated with log-rank tests to evaluate the association between adjuvant chemotherapy in high-risk and low-risk cohorts separately.ResultsA total of 2,293 stage II CC patients have dMMR/MSI-H; of those, 29.5% (n = 676) had high-risk features. The high-risk dMMR/MSI-H patients had worse overall survival [5-year survival and 95%CI, 73.2% (67.3–78.1%) vs. 80.3% (76.7–83.5%), p = 0.0001]. In patients with stage II dMMR/MSI-H CC, the high-risk features were associated with shorter overall survival (OS) along with male sex, positive carcinoembryonic antigen, Charlson–Deyo score >1, and older age. Adjuvant chemotherapy administration was associated with better OS, regardless of the high-risk features in dMMR/MSI-H (log-rank test, p = 0.001) or not (p = 0.0006). When stratified by age, the benefit of chemotherapy was evident only in patients age ≥65 with high-risk features.ConclusionHigh-risk features are prognostic in the setting of dMMR/MSI-H stage II CC. Adjuvant chemotherapy may improve survival specifically in patients ≥65 years and with high-risk features.

INTRODUCTION AND OBJECTIVE: Androgen deprivation therapy (ADT) can help maintain remission in advanced prostate cancer (PCa) patients with bone metastases, however, growth and metastatic spread often recur. To address the need for more predictive pre-clinical research platforms and to identify new targets and therapies for bone metastatic castration-resistant prostate cancer (CRPC). METHODS: We used patient-derived xenograft (PDX) tumors from bone metastatic prostate cancer patients to establish threedimensional (3D) organoids and investigated their response to ADT by either withholding di-hydro-testosterone (no DHT) or treating with enzalutamide. Cyst/spheroid quantitation, immunohistopathology, cell viability assay, qRT-PCR, RNA sequencing, gene set enrichment analysis (GSEA) and live cell cycle tracking using Fucci2BL were performed in PDXs: PCSD1, PCSD13 and PCSD25 and compared to PCa Cell lines: P, DU145 and LNCaP. RESULTS: ADT resulted in CRPC spheroids with CK5D CK8D cells, up-regulated stem-cell transcription factors, steroidogenic and neurogenic pathways and down-regulated AR-target genes, interferon, cell cycle, cell division and circadian pacemaker pathways. Enzalutamide-treated spheroids transitioned to G0 and AR protein was decreased but not AR mRNA. Moreover, ADT decreased both ACE2 and TMPRSS2, host cell viral entry factors for the severe acute respiratory syndrome (SARS) SARS-CoV-2. CONCLUSIONS: In organoids, or mini-tumors, established from prostate cancer bone metastasis PDXs, a novel type of dormant ADT-resistant cell with specific gene changes emerged which may be targeted in order to eradicate dormant metastases before they can progress. This study identified a new dormant CRPC basal-luminal hybrid prostate cancer cell and gene signature which may be therapeutically targeted to eradicate dormant CRPC bone metastases in order to prevent disease recurrence. ADT also reduced the cell factors required for SARS-CoV-2 or its variants to infect its host cells and thus may reduce COVID-19 disease severity. The PDX organoid models can be used to screen for therapies that target the dormant CRPC cells and that reduce ACE2 and TMPRSS2 expression to suppress viral load of SARS-CoV-2 and its variants.

BACKGROUND Body mass index (BMI) is used to define obesity, but it is an imperfect measure of body composition. In the current study, the authors explored the association between types of fat and survival in patients treated with immunotherapy. METHODS A retrospective analysis of 90 patients who were treated with immunotherapy on phase 1 clinical trials at the Winship Cancer Institute in Atlanta, Georgia, from 2009 through 2017 was performed. Overall survival (OS) and progression-free survival (PFS) were used to measure clinical outcomes. Baseline BMI and radiographic images at the middle of the third lumbar vertebrae were obtained. Fat densities were calculated and converted to indices (subcutaneous fat index [SFI], intermuscular fat index [IFI], and visceral fat index [VFI]) after dividing by height in meters squared. Risk groups were created using recursive partitioning and the regression trees method for SFI and IFI, which were selected by stepwise variable selection among all fat-related variables. The Cox proportional hazards model and Kaplan-Meier method were used for the association with OS and PFS. RESULTS The majority of patients (59%) were male and diagnosed with melanoma (33%) or gastrointestinal cancers (22%). The median BMI was 27.4 kg/m2 , the median SFI was 62.78, the median IFI was 4.06, and the median VFI was 40.53. Low-risk patients (those with an SFI ≥73) had a significantly longer OS (hazard ratio, 0.20; 95% CI, 0.09-0.46 [P

BACKGROUND Hepatitis C (HCV) is the primary etiology of hepatocellular carcinoma (HCC) in the US multidisciplinary disease management teams (DMT) that optimize oncologic care. The impact of DMT for HCC in safety-net hospitals is unknown. METHODS Patients diagnosed with HCC from 2009 to 2016 at Grady Memorial Hospital (GMH) were included. The primary aim was to evaluate referrals to care, receipt of therapy, and overall survival (OS) after DMT formation. Screening patterns of HCV patients for HCC were also examined. RESULTS Of 204 HCC patients, median age was 58 years, with 81% male, 83% black. 46% presented with stage 4 disease, 53% had treatment with median OS 9.8 months. DMT formation was associated with increased referrals to surgery (49% vs 30%; P = .02), liver-directed therapy (58% vs 31%; P = .001), and radiation (13% vs 3%; P = .019). Patients were also more likely to get treatment (59% vs 41%; P = .026), with improved median OS (30.7 vs 4.9 months; P

Metastatic colorectal cancer (CRC) with a mismatch repair-deficiency (MMR-D)/microsatellite instability-high (MSI-H) phenotype carries unique characteristics such as increased tumour mutational burden and tumour-infiltrating lymphocytes. Studies have shown a sustained clinical response to immune checkpoint inhibitors with dramatic clinical improvement in patients with MSI-H/MMR-D CRC. However, the observed response rates range between 30% and 50% suggesting the existence of intrinsic resistance mechanisms. Moreover, disease progression after an initial positive response to immune checkpoint inhibitor treatment points to acquired resistance mechanisms. In this review article, we discuss the clinical trials that established the efficacy of immune checkpoint inhibitors in patients with MSI-H/MMR-D CRC, consider biomarkers of the immune response and elaborate on potential mechanisms related to intrinsic and acquired resistance. We also provide a perspective on possible future therapeutic approaches that might improve clinical outcomes, particularly in patients with actionable resistance mechanisms.

Background HCC variants are rare primary hepatic tumors. The aim of this study is to compare clinical characteristics and outcomes of HCC variants with pure HCC. Methods Patients diagnosed between 2004 and 2013 with ICD-O-3 8180/3 and 8170/3-8175/3 were identified from the National Cancer Database. Univariate and multivariate survival analyses were conducted to analyze the association between histology and overall survival (OS). Results 80,280 patients were identified; pure HCC 78,461 (97.7%), fibrolamellar (FLHCC) 310 (0.4%), scirrhous 161 (0.2%), spindle cell 72 (0.1%), clear cell 487 (0.6%), pleomorphic 23 (0.0%), and combined HCC and cholangiocarcinoma (mixed HCC) 766 (1.0%). 76.7% were male and 72% Caucasian. Liver transplant was performed in 10.1% of pure HCC, 14.5% of mixed HCC, 16.2% of scirrhous, 6.9% of spindle cell, 8.8% of clear cell, 8.7% of pleomorphic, and 3.2% of FLHCC (p

Purpose: This first-in-human phase I study (NCT 01417546) evaluated the safety profile, optimal immunologic/biological dose (OID/OBD), and immunogenicity of the combination of two peptide B-cell epitope vaccines engineered to represent the trastuzumab- and pertuzumab-binding sites. Although trastuzumab and pertuzumab have been approved for clinical use, patients often develop resistance to these therapies. We have advanced a new paradigm in immunotherapy that focuses on humoral responses based on conformational B-cell epitope vaccines. Patients and Methods: The vaccine is comprised of two chimeric HER-2 B-cell peptide vaccines incorporating a “promiscuous T-cell epitope.” Patients were immunized with the vaccine constructs emulsified with nor-muramyl-dipeptide adjuvant in a water-in-oil Montanide ISA 720VG vehicle. Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks. Results: Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease. Conclusions: The study vaccine is safe, exhibits antitumor activity, and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.

BackgroundTumor sidedness as a prognostic factor in advanced stage colon cancer (CC) is well established. The impact of tumor sidedness on the clinical outcomes of stage II and III CC has not been well studied.MethodsThe National Cancer Database (NCDB) was utilized to identify patients with pathological stage II and III primary adenocarcinoma of the colon from 2010 to 2015 using ICD-O-3 morphology and topography codes: 8140-47, 8210-11, 8220-21, 8260-63, 8480-81, 8490 and C18.0, 18.2,18.3, 18.5,18.6, 18.7. Univariate (UVA) and multivariable (MVA) survival analyses and Kaplan–Meier Curves with Log-rank test were utilized to compare overall survival (OS) based on tumor location and treatment received.ResultsA total of 35,071 patients with stage II (n = 17,629) and III (n = 17,442) CC were identified. 51.3% female; 81.5% Caucasian; median age 66 (range, 18–90). Majority of stage II and III tumors were right sided, 61.2% (n = 10,794) and 56.0% (n = 9,763). Microsatellite instability high (MSI-H) was more common in stage II compared to III, 23.3% (n = 4,115) vs 18.2% (n = 3,171) (p < 0.0001). In stage II MSI-H CC right was more common than left, 78.3% (n = 3223) vs 21.7% (n = 892). There was no significant difference in survival between stage II MSI-H left vs right (5-year OS 76.2 vs 74.7%, p = 0.1578). Stage II MSS CC right was more common than left, 56.0% (n = 7571) vs 44.0% (n = 5943), and survival was better in the left vs right (5-year OS 73.2 vs 70.8%, p = 0.0029). Stage III MSI-H CC was more common in the right than in the left, 75.6% (n = 2,397) vs 24.4% (n = 774) and survival was better in the left (5-year OS 62.5 vs 56.5%, p = 0.0026). Stage III MSS CC was more common in the right than in the left, 51.6% (n = 7,366) vs 48.4% (n = 6,905), and survival was better in the left vs right (5-year OS 67.0 vs 54.4%, p < 0.001).ConclusionSurvival was better in left sided tumors compared to right in stage II MSS, stage III MSS, and stage III MSI-H CC.

Background: Clinico-pathological high-risk features are frequently utilized in adjuvant chemotherapy (AC) decisions in stage II colorectal cancer and their utility in stage II appendiceal adenocarcinoma (AA) is not established. The aim of this study is to determine the impact of high-risk features in clinical outcomes and whether high risk features are predictive of AC benefit in stage II AA. Methods: Patients with pathological stage II AA between 2010 and 2015 were identified from the National Cancer Database (NCDB) using ICD-O-3 morphology and topography codes: 8140, 8480 and C18.1. High risk stage II AA was defined as having at least one of the following clinicopathological features: T4 tumor

BACKGROUND Sarcopenia and inflammation are independently associated with worse survival in cancer patients. This study aims to determine the impact of sarcopenia, body mass index (BMI), and inflammatory biomarkers on survival in advanced hepatocellular carcinoma (HCC) patients treated with anti-PD-1 antibody-based immunotherapy. METHODS A retrospective review of advanced HCC patients treated with immunotherapy at Winship Cancer Institute between 2015 and 2019 was performed. Baseline computed tomography and magnetic resonance images were collected at mid-L3 level, assessed for skeletal muscle density using SliceOmatic (TomoVision, version 5.0) and converted to skeletal muscle index (SMI) by dividing it by height (m2). Sex-specific sarcopenia was defined by the median value of SMI. The optimal cut for continuous inflammation biomarker was determined by bias-adjusted log-rank test. Overall survival (OS) was set as primary outcome and Cox proportional hazard model was used for association with survival. RESULTS A total of 57 patients were included; 77.2% male, 52.6% Caucasian, 58.5% Eastern Cooperative Oncology Group performance status 0-1, 80.7% Child Pugh A. Treatment was second line and beyond in 71.9% of patients. The median follow-up time was 6 months. Sarcopenia cut-off for males and females was SMI of 43 and 39, respectively. 49.1% of patients had sarcopenia. Median OS was 5 versus 14.3 months in sarcopenic versus nonsarcopenic patients (Log-rank P=0.054). Median OS was 5 and 17.5 months in patients with BMI

Modified FOLFOX6 is an established therapy for patients with metastatic colorectal cancer (mCRC). We conducted a single-arm phase Ib study to address the hypothesis that addition of pembrolizumab to this regimen could safely and effectively improve patient outcomes (NCT02375672). The relationship between immune biomarkers and clinical response were assessed in an exploratory manner. Patients with mCRC received concurrent pembrolizumab and modified FOLFOX6. The study included safety run-in for the first six patients. The primary objective was median progression free survival (mPFS), with secondary objectives including median overall survival (mOS), safety, and exploratory assessment of immune changes. To assess immunological impact, peripheral blood was collected at baseline and during treatment. The levels of soluble factors were measured via bioplex, while a panel of checkpoint molecules and phenotypically-defined cell populations were assessed with flow cytometry and correlated with RECIST and mPFS. Due to incidences of grade 3 and grade 4 neutropenia in the safety lead-in, the dose of mFOLFOX6 was reduced in the expansion cohort. Median PFS was 8.8 months and median OS was not reached at data cutoff. Best responses of stable disease, partial response, and complete response were observed in 43.3%, 50.0%, and 6.7% of patients respectively. Several soluble and cellular immune biomarkers were associated with improved RECIST and mPFS. Immunosuppressive myeloid and T cell subsets that were analyzed were not associated with response. Primary endpoint was not superior to historic control. Biomarkers that were associated with improved response may be informative for future regimens combining chemotherapy with immune checkpoint inhibitors.

Background Both pancreatic ductal adenocarcinoma (PDAC) and metastatic colorectal cancer (mCRC) have yet to widely benefit from T cell-targeted immunotherapy and have universally poor prognoses. Thus, enhancing the activity of immunotherapy is a high priority. Our laboratory recently reported that heat shock protein-90 (Hsp90) inhibition enhances the efficacy of PD-1 blockade in preclinical models of PDAC.1 Mechanistically, Hsp90 inhibitors can limit activation of cancer associated fibroblasts (CAF) and promote infiltration of T cells when combined with PD-1 blockade. Based on these data, we are conducting a Phase Ib/II clinical trial to evaluate the combination of XL888 (Hsp90 inhibitor) and pembrolizumab in patients with metastatic pancreatic and colorectal cancers. We hypothesize that this combination will be safe and elicit pronounced microenvironmental changes, leading to enhanced efficacy. Methods During the phase II portion, PDAC or mCRC patients (n=16 each) were randomized to receive a three week lead in with either pembrolizumab or pembrolizumab and XL888. Paired biopsies were obtained at baseline and at week two on treatment. A comprehensive panel of immunologic correlatives studies is being conducted to examine treatment-induced alterations in the tumor microenvironment and peripheral blood. Results As of August 23rd, 2020, paired liver biopsy specimens from sites of metastasis have been successfully obtained from a total of 15 patients (n=7 PDAC and n=8 mCRC). These specimens underwent single cell mass cytometry (CyTOF) analysis to assess immunophenotypic markers of T and myeloid cells. Using this approach, we have generated a comprehensive view of the immune landscape at baseline and following treatment. These data will be validated by immunohistochemical analysis of FFPE biopsy specimens obtained in parallel at the time of CyTOF analysis. In addition to these correlative studies, using immortalized and primary CAF from PDAC patients, we have shown XL888 dampens production of IL-6 and other cytokines in vitro. The impact of XL888 on systemic cytokines and chemokines (n=48 total) in the peripheral blood from patients enrolled in the clinical trial is therefore also being assessed. Conclusions Our correlative analysis of paired biopsies and peripheral blood from a novel clinical trial of XL888 and pembrolizumab will allow for further mechanistic insight into treatment-induced immune modulation. These data will also serve to validate whether alterations of CAF phenotype, cytokine and chemokine release, and T cell infiltration observed preclinically are mirrored in patients. Trial Registration This clinical trial is underway and registered with the ID NCT03095781. Ethics Approval The study was approved by Emory University’s Ethics Board, approval IRB00087397. Reference Zhang Y, Ware MB, Zaidi M, Ruggieri AN, Olson B, Komar H, Farren MR, Nagaraju GP, Zhang C, Chen Z, Sarmiento J, Ahmed R, Maithel SK, El-Rayes BF, Lesinski GB. Heat shock protein-90 inhibition alters activation of pancreatic stellate cells and enhances the efficacy of PD-1 blockade in pancreatic cancer. Molecular Cancer Therapeutics 2020.

BACKGROUND Multimodality therapy of metastatic colorectal cancer (mCRC) is currently considered the standard of care. The aim of this study was to evaluate the impact of perioperative therapy on surgical resection in mCRC. METHODS The National Cancer Database was analyzed for affected patients between 2004 and 2013. Univariate and multivariate analyses were done to identify factors associated with patient outcomes. Kaplan-Meier analysis and Cox proportional hazards models were used for the association between patient characteristics and survival. RESULTS About 61,940 patients with mCRC were identified. Mean age = 63.4 years (SD ± 14). About 69% had a colon primary and 32% had only one metastatic site. Only 49% of those who underwent surgery for both primary and metastatic sites received postoperative chemotherapy (p

Background Pegfilgrastim, a long-acting granulocyte-colony-stimulating factor used to prevent neutropenia, is not indicated for administration within 24 h of completion of chemotherapy. The safety of administering pegfilgrastim in gastrointestinal cancer chemotherapy regimens containing continuous intravenous infusion of 5-fluorouracil (5-FUCI) on the day of completion of 5-fluorouracil has not been adequately studied. Methods An institutional review board-approved retrospective analysis of patients with a gastrointestinal malignancy receiving pegfilgrastim on the final day of 5-FUCI was conducted. The primary end point was to determine the incidence of grade 3 and grade 4 neutropenia and febrile neutropenia when pegfilgrastim was administered on the final day of 5-FUCI. The secondary endpoint was to determine rate of dose reductions and treatment delays. Results A total of 300 patients were reviewed from January 2010 to May 2017. The most common cancers were colorectal (25%) and pancreatic (60%), with 77% of patients having late stage disease. The risk of a patient developing grade 3 neutropenia was 0.010 (95% CI 0.002–0.029) and grade 4 neutropenia was 0.007 (95% CI 0.001–0.024). The risk of febrile neutropenia was 0.007 (95% CI 0.001–0.024). The risks of treatment delay and treatment reduction were 0.013 (95% CI 0.004–0.034) and 0.010 (95% CI 0.002–0.029), respectively. Conclusion The low risk of grade 3 and grade 4 neutropenia, febrile neutropenia, as well as dose delays and/or reduction suggests that pegfilgrastim can be administered on the final day of 5-FUCI. Limitations of this study were that it was retrospective in nature and was conducted at a single institution.

The administration schedule of capecitabine for the treatment of metastatic colorectal cancer (mCRC) in clinical trials has been 14 days of drug with 7 days off in a 21 day cycle (14/7). In an effort to improve tolerability, an alternative every other week treatment (7/7) is often administered. The purpose of this study was to determine the safety and efficacy of administering 7/7 compared with 14/7 capecitabine dosing.In this retrospective study, mCRC patients received capecitabine on a 7/7 or 14/7 schedule. The primary objective was to determine the tolerability of the respective dosing schedules, defined according to frequency of dose reductions and treatment delays. Secondary objectives included comparisons of objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety of dosing strategies.Of 175 included patients, 73 (41.7%) received the capecitabine 7/7 schedule and 102 (58.3%) received the 14/7 schedule. There was a statistically significant difference between the 7/7 and 14/7 groups with regard to dose reductions (4% vs. 29%; P .001) and treatment delays (22% vs. 43%; P = .004). The incidence of any adverse effects (45% vs. 72%; P .001) and specifically, palmar-plantar erythrodysesthesia (18% vs. 45%; P .001), were significantly higher in the 14/7 group. No significant difference was seen with regard to ORR, PFS, or OS.Patients with mCRC who received the 7/7 schedule had significantly fewer dose reductions and treatment delays compared with patients who received the 14/7 schedule. Although no difference in efficacy outcomes were observed, prospective studies are needed to confirm these findings.

Background Goblet cell carcinoma (GCC), formerly known as goblet cell carcinoid, of the appendix constitutes less than 14% of all primary appendiceal neoplasms. Surgical resection is the main treatment and the role of adjuvant chemotherapy (AC) is not established. This study aims to evaluate the impact of AC in stage II-III appendiceal GCC. Methods Patients with pathological stage II and III GCC who underwent surgical resection between 2006 and 2015 were identified from the National Cancer Database (NCDB) using ICD-O-3 morphology and topography codes: 8243/3 (goblet cell carcinoid) and C18.1. Patients treated with neoadjuvant systemic and/or radiation therapy and adjuvant radiation were excluded. Univariate and multivariable analyses were conducted, and Kaplan-Meier Curves were used to compare overall survival (OS) based on treatment received with Log-rank test. Results A total of 619 patients were identified. 54.4% males and 89.0% Caucasian; median age 56 (range, 23–90) years. Distribution across pathological stages II-III was 82.7% (N = 512) and 17.3% (N = 107) respectively. AC was administered in 9.4% (N = 48) of stage II and 47.7% (N = 51) of stage III patients. For stage II patients, AC was not associated with better OS in univariate (HR 0.32; 95% CI 0.04–2.34; p = 0.261) or multivariable analyses (HR 0.29; 95% CI 0.04–2.12; p = 0.221). By contrast, in stage III patients, AC was associated with better OS in univariate (HR 0.35; 95% CI 0.17–0.71; p = 0.004) and multivariable analyses (HR 0.25; 95% CI 0.07–0.88; p = 0.031). In the entire cohort 5-year OS for patients that received AC was 85.5% (74.0%, 92.1%) versus 82.7% (77.5%, 86.8%) (p = 0.801) with no AC. For stage II patients, 5-year OS was 96.9% with AC vs. 89.1% with no AC (p = 0.236). For stage III patients, 5-year OS was 77.1% with AC vs. 42.8% with no AC (p = 0.003). Conclusion AC was associated with improved OS in patients with pathological stage III GCC of the appendix, but not with pathological stage II.

PURPOSE: Debate continues over whether explicit recommendations for a clinical trial should be included as an element of shared decision making within oncology. We aimed to determine if and how providers make explicit recommendations in the setting of phase I cancer clinical trials. METHODS: Twenty-three patient/provider conversations about phase I trials were analyzed to determine how recommendations are made and how the conversations align with a shared decision-making framework. In addition, 19 providers (9 of whose patient encounters were observed) were interviewed about the factors they consider when deciding whether to recommend a phase I trial. RESULTS: We found that providers are comprehensive in the factors they consider when recommending clinical trials. The two most frequently stated factors were performance status (89%) and patient preferences (84%). Providers made explicit recommendations in 19 conversations (83%), with 12 of those being for a phase I trial (12 [63%] of 19). They made these recommendations in a manner consistent with a shared decision-making model; 18 (95%) of the 19 conversations during which a recommendation was made included all steps, or all but 1 step, of shared decision making, as did 11 of the 12 conversations during which a phase I trial was recommended. In 7 (58%) of these later conversations, providers also emphasized the importance of the patient’s opinion. CONCLUSION: We suggest that providers not hesitate to make explicit recommendations for phase I clinical trials, because they are able to do so in a manner consistent with shared decision making. With further research, these results can be applied to other clinical trial settings.

Background: The induction of reactive oxygen species (ROS) represents a viable strategy for enhancing the activity of radiotherapy. The authors hypothesized that napabucasin would increase ROS via its ability to inhibit NAD(P)H:quinone oxidoreductase 1 and potentiate the response to chemoradiotherapy in rectal cancer via distinct mechanisms. Method: Proliferation studies, colony formation assays, and ROS levels were measured in HCT116 and HT29 cell lines treated with napabucasin, chemoradiation, or their combination. DNA damage (pγH2AX), activation of STAT, and downstream angiogenesis were evaluated in both untreated and treated cell lines. Finally, the effects of napabucasin, chemoradiotherapy, and their combination were assessed in vivo with subcutaneous mouse xenograft models. Results: Napabucasin significantly potentiated the growth inhibition of chemoradiation in both cell lines. Napabucasin increased ROS generation. Inhibition of ROS by N-acetylcysteine decreased the growth inhibitory effect of napabucasin alone and in combination with chemoradiotherapy. Napabucasin significantly increased pγH2AX in comparison with chemoradiotherapy alone. Napabucasin reduced the levels of pSTAT3 and VEGF and inhibited angiogenesis through an ROS-mediated effect. Napabucasin significantly potentiated the inhibition of growth and blood vessel formation by chemoradiotherapy in mouse xenografts. Conclusion: Napabucasin is a radiosensitizer with a novel mechanism of action: increasing ROS production and inhibiting angiogenesis. Clinical trials testing the addition of napabucasin to chemoradiotherapy in rectal cancer are needed.

BACKGROUND. High‐grade neuroendocrine carcinomas are rare in the gastrointestinal tract. However, treatment patterns and outcomes have not been well described. SUBJECTS, MATERIALS, AND METHODS. The National Cancer Database was analyzed. The primary objective was to describe the clinical outcomes and identify prognostic factors. Univariate and multivariate analyses were done to identify factors associated with patient outcome. RESULTS. A total of 1,861 patients were identified between 2004 and 2013. The mean age was 63 years (standard deviation ±13). The majority of the patients (78.1%) were non‐Hispanic whites. The most common primary sites were pancreas (pancreatic neuroendocrine tumor [PNET] = 19.4%), large intestine (18.1%), esophagus (17.8%), and rectum (15.5%). Stage at presentation was I (6.6%), II (10.5%), III (18%) and IV (64.6%). Only 1.6% of the patients had brain metastases. Surgical resection was the primary therapy in 27.9%, and their median overall survival (OS) was 13.3 months. Patients treated with palliative chemotherapy had a median OS of 11.2 months, compared with 1.7 months for untreated patients. The median OS for high‐grade PNET was 6 months, compared with 9.9 months for other high‐grade gastrointestinal neuroendocrine carcinomas (HG GI NEC). On univariable analysis, age < 65 years (hazard ratio [HR] 0.72; 0.66–0.8; p < .001) and treatment at an academic center (HR 0.88; 0.79–0.99; p < .034) were associated with improved survival. Multivariable analysis confirmed prognostic advantage of treatment at an academic center. CONCLUSION. This is the largest series of HG GI NEC. Most patients present with metastatic disease, and overall survival remains poor. Treatment at an academic center, younger age, and use of chemotherapy were associated with improved survival. Multiagent chemotherapy was found to be associated with superior survival compared with single‐agent chemotherapy, which was superior to no chemotherapy. Temporal sequences of chemotherapy, surgery, and radiation administration were not found to be associated with survival differences on multivariable analysis. IMPLICATIONS FOR PRACTICE. Management of patients with high‐grade gastrointestinal neuroendocrine carcinomas (HG GI NEC) is based on experience with small‐cell lung cancer. In this retrospective review, most patients had advanced disease and pancreatic primary had worse outcomes. Treatment at an academic center, younger age, and use of chemotherapy are associated with improved survival. Patients with early‐stage disease treated with resection alone had inferior outcomes compared with patients who received neoadjuvant or adjuvant therapy, suggesting that micrometastases contribute to poor surgical outcomes. The relatively high proportion of positive surgical margin favors downstaging with neoadjuvant therapy to improve resection and lower the risk of systemic recurrence.

BACKGROUND The prognostic impact of DNA mismatch repair (MMR) status remains controversial in patients with stage III colon cancer who are treated with adjuvant chemotherapy (AC). The aim of this study was to evaluate the survival outcome of AC in deficient mismatch repair (dMMR)/microsatellite instable (MSI) stage III CC. METHODS Patients with pathological stage III CC between 2010 and 2013 were identified from the National Cancer Database using International Classification of Diseases for Oncology (3rd Edition) morphology and topography codes 8140, 8480, and C18.0-18.8. Patients with pathologic stage T3N2, T4N1, or T4N were considered high risk; patients with stage T3N1 were considered low risk. Univariate and multivariable analyses were conducted, and Kaplan-Meier analysis and Cox proportional hazards models were used to identify the association between AC and overall survival (OS). RESULTS A total of 9226 patients with pathological stage III CC were identified, of which 2384 (25.8%) were MSI-high (MSI-H) and met the inclusion criteria of the final analysis. MSI-low (MSI-L) patients (n = 6842) were excluded. There was a preponderance of women (55.0% [n = 1311]), and 76.6% (n = 1825) of patients were non-Hispanic white. The median age was 65 years (range, 19-90 years). The primary sites were the cecum (29.7% [n = 707]), ascending colon (26.0% [n = 620]), sigmoid colon (17.2% [n = 410]), and transverse colon (10.8% [n = 257]). The most common tumor grade was moderately differentiated (n = 50.4% [1202]), followed by poorly differentiated (34.1% [n = 813]) and well differentiated (5.1% [n = 121]). High-risk pathologic stage III CC (T4N1, TxN2) constituted 51.0% (n = 1215) of the study population. High-risk stage III was associated with worse OS compared with low-risk stage III on univariate (P

OBJECTIVES The treatment and outcomes of patients younger than 50 years (young adults [YAs]) with pancreatic cancer are largely unknown. We evaluated the presentation, treatment, and outcomes of these patients. METHODS The National Cancer Database was analyzed. Univariate and multivariate Cox proportional hazards models were performed to identify variables associated with overall survival. RESULTS A total of 124,442 patients with pancreatic cancer were identified, with 9657 between 18 and 50 years of age. Mean age was 45.4 years (standard deviation, 4.6 years). About 30.9% of YA patients and 25% of patients older than 50 years underwent resection of the primary tumor. Survival advantage was seen for patients 18 to 39 years (hazard ratio, 1.14; 95% confidence interval, 1.07-1.23; P < 0.001). This age advantage was similar across all the racial groups. Overall, YAs treated between 2009 and 2013 had higher survival rates compared with 2004 to 2008 (hazard ratio, 0.85; 95% confidence interval, 0.81-0.89; P < 0.001). This survival improvement was highest in American Indians and Asian/Pacific Islanders (16.6% vs 6.5%), African Americans (10.6% vs 8.5%), and Hispanics (14.5% vs 12.6%). CONCLUSIONS Survival of YAs with pancreatic cancer patients is superior to older patients and has improved over time, especially in minority populations.

BACKGROUND The standard of care for patients with resected stage I to stage III pancreatic ductal adenocarcinoma (PDAC) is adjuvant gemcitabine-based chemotherapy. The role of adjuvant treatment in patients with subcentimeter, stage IA PDAC is unknown. The current study evaluated the effect of adjuvant treatment on survival outcomes among patients with American Joint Committee on Cancer/International Union Against Cancer stage IA (T1N0) resected PDAC using the National Cancer Data Base (NCDB). METHODS A retrospective review of the NCDB was conducted for patients diagnosed with T1 (tumor limited to the pancreas and measuring ≤2 cm in greatest dimension), lymph node-negative (N0), resected PDAC between 2004 and 2013. Patient demographics, histology, adjuvant treatment, and survival trends were examined. Kaplan-Meier analysis and log-rank tests were performed to determine the unadjusted association between overall survival (OS), tumor size, and treatment. RESULTS A total of 876 patients met the inclusion criteria. The patients had a mean age of 66.2 years (range, 32-90 years); approximately 83.3% were white (730 patients) and 53.1% were female (465 patients). Approximately 45.9% of the patients had moderately differentiated tumor histology (402 patients); 70.0% (613 patients) had tumors measuring 1 to 2 cm (T1c) and 30.0% (263 patients) had tumors measuring

BACKGROUND Optimal prognostic and predictive biomarkers for patients with advanced-stage cancer patients who received immunotherapy (IO) are lacking. Inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), and the platelet-to-lymphocyte ratio (PLR), are readily available. The authors investigated the association between these markers and clinical outcomes of patients with advanced-stage cancer who received IO. METHODS A retrospective review was conducted of 90 patients with advanced cancer who received treatment on phase 1 clinical trials of IO-based treatment regimens. NLR, MLR, and PLR values were log-transformed and treated as continuous variables for each patient. Overall survival (OS), progression-free survival (PFS), and clinical benefit were used to measure clinical outcomes. For univariate associations and multivariable analyses, Cox proportional-hazards models or logistic regression models were used. RESULTS The median patient age was 63 years, and most were men (59%). The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). High baseline NLR, MLR, and PLR values were associated significantly with worse OS and PFS (P < .05) and a lower chance of benefit (NLR and PLR; P < .05). Increased NLR, MLR, and PLR values 6 weeks after baseline were associated with shorter OS and PFS (P ≤ .052). CONCLUSIONS Baseline and early changes in NLR, MLR, and PLR values were strongly associated with clinical outcomes in patients who received IO-based treatment regimens on phase 1 trials. Confirmation in a homogenous patient population treated on late-stage trials or outside of trial settings is warranted. These values may warrant consideration for inclusion when risk stratifying patients enrolled onto phase 1 clinical trials of IO agents.

Purpose: The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC). Patients and Methods: Patients with stage II/III rectal cancer were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m2/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples. Results: Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses. Conclusions: The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.

Background Neuroendocrine tumors (NETs) metastasize to the liver. Everolimus and selective internal radioembolization (SIRT) are approved treatments. Pasireotide is a somatostatin analogue with an affinity for somatostatin receptors 1, 2, 3, and 5. Everolimus and pasireotide may potentiate SIRT radiosensitization and inhibit rebound angiogenesis. This study evaluated the safety of pasireotide, everolimus, and SIRT. Methods This 3 + 3 phase 1 trial evaluated 3 dose levels of everolimus (2.5, 5, and 10 mg/day), pasireotide (600 μg twice daily), and SIRT (SIR-Spheres dose on days 9 and 37). Eligibility criteria included well or moderately differentiated NETs, bilobar liver metastases, and progression on long-acting octreotide. Toxicities and responses were evaluated with the Common Terminology Criteria for Adverse Events and the Response Evaluation Criteria in Solid Tumors (version 1.1). Dose-limiting toxicities (DLTs) were defined in the first 28 days. Correlative markers-angiopoietin 1, angiopoietin 2, basic fibroblast growth factor, collagen V, insulin-like growth factor binding protein 1, insulin-like growth factor binding protein 1, interleukin 8, M30, M65, placenta growth factor, and vascular endothelial growth factor receptor 2-were assessed. The Norfolk Quality of Life-Neuroendocrine Tumor Questionnaire was used to assess the quality of life (QOL). Results Thirteen patients were enrolled; 1 was not evaluable for the primary endpoint. Eleven patients had well-differentiated tumors. The primary sites included small bowel (4), pancreas (3), lung (2), colon (1), gastric (1), and unknown primary (2) were unknown. Four had liver-only disease; 12 completed the planned treatment. No DLTs were observed. There was no treatment-related mortality. The most common toxicity was hyperglycemia. Clinically significant liver toxicity was not observed. One patient had liver progression. QOL improved on treatment. The median progression-free survival and overall survival were 18.6 and 46.3 months, respectively. Conclusions The recommended phase 2 dose of everolimus is 10 mg daily in combination with pasireotide and SIRT. The regimen is well tolerated. Preliminary activity appears promising. Cancer 2018;124:1992-2000. © 2018 American Cancer Society.

Background Management of pancreatic cancer (PC) in elderly patients is unknown; clinical trials exclude patients with comorbidities and those of extreme age. This study evaluated treatment patterns and survival outcomes in elderly PC patients using linked Surveillance, Epidemiology, and End Results (SEER) and Medicare data. Materials and Methods Histology codes 8140, 8500, 8010, 8560, 8490, 8000, 8260, 8255, 8261, 8263, 8020, 8050, 8141, 8144, 8210, 8211, or 8262 in Medicare Parts A and B were identified. Data regarding demographic, characteristics, treatments, and vital status between 1998 and 2009 were collected from the SEER. Determinants of treatment receipt and overall survival were examined using logistic regression and Cox proportional hazards models, respectively. Results A total of 5,975 patients met inclusion. The majority of patients were non-Hispanic whites (85%) and female (55%). Most cases presented with locoregional stage disease (74%); 41% received only chemotherapy, 30% chemotherapy and surgery, 10% surgery alone, 3% radiation, and 16% no cancer-directed therapy. Patients with more advanced cancer, older age, and those residing in areas of poverty were more likely to receive no treatment. Among patients 66–74 years of age with locoregional disease, surgery alone (hazard ratio [HR] = 0.54; 95% confidence interval [CI]: 0.39–0.74) and surgery in combination with chemotherapy (HR = 0.69; 95% CI: 0.53–0.91) showed survival benefit as compared with the no treatment group. Among patients ≥75 years of age with locoregional disease, surgery alone (HR = 2.04; 95% CI: 0.87–4.8) or in combination with chemotherapy (HR = 1.59; 95% CI: 0.87–2.91) was not associated with better survival. Conclusion Treatment modality and survival differs by age and stage. Low socioeconomic status appears to be a major barrier to the receipt of PC therapy among Medicare patients. Implications for Practice Elderly patients with cancer are under-represented on clinical trials and usually have comorbid illnesses. The management of elderly patients with pancreatic cancer is unknown, with many retrospective experiences but low sample sizes. Using Surveillance, Epidemiology, and End Results-Medicare linked data to analyze treatment patterns and survival of elderly patients with pancreatic cancer on a larger population scale, this study highlights treatment patterns and their effect on survival and proposes possible obstacles to access of care in elderly patients with pancreatic cancer other than Medicare coverage.

OBJECTIVES Surgical resection for locally advanced rectal adenocarcinoma commonly occurs 6 to 10 weeks after completion of neoadjuvant chemoradiation (nCRT). We sought to determine the optimal timing of surgery related to the pathologic complete response rate and survival endpoints. METHODS The study is a retrospective analysis of 92 patients treated with nCRT followed by surgery from 2004 to 2011 at our institution. Univariate and multivariate analyses were performed to assess the impact of timing of surgery on locoregional control, distant failure (DF), disease-free survival, and overall survival (OS). RESULTS Time-to-surgery was ≤8 weeks (group A) in 72% (median 6.1 wk) and >8 weeks (group B) in 28% (median 8.9 wk) of patients. No significant differences in patient characteristics, locoregional control, or pathologic complete response rates were noted between the groups. Univariate analysis revealed that group B had significantly shorter time to DF (group B, median 33 mo; group A, median not reached, P=0.047) and shorter OS compared with group A (group B, median 52 mo; group A, median not reached, P=0.03). Multivariate analysis revealed that increased time-to-surgery showed a significant increase in DF (HR=2.96, P=0.02) and trends toward worse OS (HR=2.81, P=0.108) and disease-free survival (HR=2.08, P=0.098). CONCLUSIONS We found that delaying surgical resection longer than 8 weeks after nCRT was associated with an increased risk of DF. This study, in combination with a recent larger study, questions the recent trend in promoting surgical delay beyond the traditional 6 to 10 weeks. Larger, prospective databases or randomized studies may better clarify surgical timing following nCRT in rectal adenocarcinoma.

The benefit of adjuvant chemotherapy in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT) and surgery is controversial. We examined the association of perineural invasion (PNI) with outcomes to determine whether PNI could be used to risk-stratify patients. We performed a retrospective study of 110 patients treated with nCRT and surgery for LARC at our institution from 2004 to 2011. Eighty-seven patients were identified in our final analysis. We evaluated the association of PNI with locoregional control, distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival, using log-rank and Cox proportional hazard modeling. Fourteen patients (16%) were PNI+ and 73 patients (84%) were PNI−. The median follow-up was 27 months (range, 0.9 to 84 mo). The median DMFS was 13.5 months for PNI+ and median not reached (>40 mo) for PNI− (P

BackgroundPancreatic ductal adenocarcinoma (PDAC) has yet to widely benefit from T cell-targeted immunotherapy and displays universally poor prognosis. Thus, enhancing the activity of immunotherapy is a high priority. Our laboratory recently reported that heat shock protein-90 (Hsp90) inhibition enhances the efficacy of PD-1 blockade in murine models of PDAC (Zhang Y. et al., Mol Cancer Ther, 2020). Hsp90 inhibitors can limit activation of cancer associated fibroblasts (CAF) and promote infiltration of T cells when combined with PD-1 blockade in preclinical systems.MethodsBased on these data, we are conducting a Phase Ib/II clinical trial to evaluate the combination of XL888 (Hsp90 inhibitor) and pembrolizumab in patients with metastatic pancreatic cancer. We hypothesize that this combination will be safe and elicit pronounced microenvironmental changes, leading to enhanced efficacy of checkpoint blockade in a tumor type that is otherwise refractory to this approach. During the phase II portion patients were randomized to receive a three week lead in with either pembrolizumab or pembrolizumab and XL888. Paired biopsies and blood samples were obtained at baseline and at week two on treatment and CyTOF was used to assess changes in circulating and tumor infiltrating immune populations. Further, CyTOF profiling of circulating immune cells was performed to assess impacts of XL888 on over thirty phenotypically defined immune populations (figure 1).ResultsAs of June 2021, paired liver biopsy specimens from sites of metastasis have been successfully obtained from a total of 8 patients and paired peripheral blood mononuclear cell samples have been analyzed in 24 patients. Our CyTOF analysis illustrated a surprising increase in myeloid cell populations within the tumor following treatment. Analysis of circulating immune cells illustrated a decrease in natural killer cells and Th17 populations following treatment while naïve B cells were increased. These data will be validated by immunohistochemical analysis of FFPE biopsy specimens obtained in parallel at the time of CyTOF analysis. The impact of XL888 on systemic cytokines and chemokines (n=48 total) in the peripheral blood from patients enrolled in the clinical trial is therefore being assessed as a potential mechanism to explain this observation.Abstract 403 Figure 1Clinical trial and correlative analysis schema. Patients were randomized to receive either pembrolizumab alone or in combination with the HSP90 inhibitor XL888 for a two week cycle prior to crossover to the combination arm. Plasma, peripheral blood mononuclear cells (PBMC), and biopsies were assayed to evaluate immunomodulatory effects of the therapies.ConclusionsClinical data from this trial indicates that this combination is safe in patients. As clinical data matures, changes in soluble and cellular biomarkers will be correlated with response to elucidate mechanisms of response or resistance to this combination therapy.Trial RegistrationThis clinical trial is underway and registered with the ID NCT03095781Ethics ApprovalThe study was approved by Emory University’s Ethics Board, approval IRB00087397.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Treatment with cisplatin and gemcitabine demonstrates a survival benefit in patients with advanced biliary tract cancer (ABTC). However, the weekly administration can add significant toxicities that may prohibit prolonged treatment. Based on previous studies, we implemented a modified biweekly regimen of GC in an attempt to optimize the prescribed regimen with an improved toxicity profile, added convenience to patients while maintaining efficacy. Patients with ABTC were treated with fixed dose rate (FDR) gemcitabine (1,000 mg/m2 /min) and cisplatin 20 mg/m2 on days 1 and 15 of every 28-day cycle. Patients received treatment until time of progression, death, or discontinuation due to intolerance. Collected data included demographics, clinico-pathologic features, toxicities, and survival. Kaplan-Meier curves were used to calculate the median overall survival (OS) and progression free survival (PFS). The study included 107 evaluable pts with unresectable ABTC who received the biweekly regimen. Sites of tumor included gallbladder (21.5%), ampullary (3.7%), and bile duct (74.8%). Median number of cycles was 6 (1-27). Median PFS was 8.34 (6.74, 9.23) months and median OS was 10.32 (9.10, 11.43) months. Most common grade ≥3 adverse events included neutropenia (11%), fatigue (10%), and thrombocytopenia (6.4%). Biweekly FDR GC in ABTC is associated with a more favorable toxicity profile while maintaining efficacy similar to that observed in prior clinical trials. Minimal toxicities were observed despite a prolonged course for many patients. Further prospective trials should consider evaluating the role of biweekly GC regimen in ABTC, including a potentially more favorable platform in novel experimental strategies.

Oncogenic mutations in B-type Raf kinase (BRAF) occur in 7-10% of metastatic colorectal cancers (mCRC). Despite recent improvements in survival in the general population of patients with mCRC, patients with BRAF-mutant mCRC continue to have poor response to most systemic therapies, and prognosis remains poor. There is a substantial unmet need for novel therapeutic strategies to treat patients with BRAF-mutant mCRC. This review outlines the epidemiology, molecular pathogenesis, prognosis, and mechanisms of treatment resistance of BRAF-mutated CRC. Additionally, this review highlights novel therapeutic strategies aimed at enhancing response and improving outcomes.

AIMS Heart failure (HF) is a multi-organ, pro-inflammatory syndrome that impairs bone metabolism. Pro-inflammatory cytokines and bone catabolism enhance periodontal disease, a local inflammatory, bacteria-induced disease that causes bone loss and periodontal soft tissue destruction. METHODS AND RESULTS Medical and dental examinations were performed on patients with HF (n = 39), following heart transplantation (post-HTx, n = 38) and controls (n = 32). Blood, saliva, and gingival crevicular fluid were analysed for bone metabolism and inflammation markers. HF average New York Heart Association classification was III. Average time since HTx was 1414 days. Pro-inflammatory tumour necrosis factor-alpha was higher in HF and HTx as compared with controls (P

BackgroundAppendiceal cancers (ACs) are rare. The genomic landscape of ACs has not been well studied. The aim of this study was to confirm the feasibility of next-generation sequencing (NGS) using circulating tumor DNA (ctDNA) in ACs and characterize common genomic alterations.Materials and MethodsMolecular alterations in 372 plasma samples from 303 patients with AC using clinical-grade NGS of ctDNA (Guardant360) across multiple institutions were evaluated. Test detects single nucleotide variants in 54–73 genes, copy number amplifications, fusions, and indels in selected genes.ResultsA total of 303 patients with AC were evaluated, of which 169 (56%) were female. Median age was 56.8 (25–83) years. ctDNA NGS testing was performed on 372 plasma samples; 48 patients had testing performed twice, 9 patients had testing performed three times, and 1 patient had testing performed four times. Genomic alterations were defined in 207 (n = 207/372, 55.6%) samples, and 288 alterations were identified excluding variants of uncertain significance and synonymous mutations. Alterations were identified in at least one sample from 184 patients; TP53-associated genes (n = 71, 38.6%), KRAS (n = 33, 17.9%), APC (n = 14, 7.6%), EGFR (n = 12, 6.5%), BRAF (n = 11, 5.9%), NF1 (n = 10, 5.4%), MYC (n = 9, 4.9%), GNAS (n = 8, 4.3%), MET (n = 6, 3.3%), PIK3CA (n = 5, 2.7%), and ATM (n = 5, 2.7%). Other low-frequency but clinically relevant genomic alterations were as follows: AR (n = 4, 2.2%), TERT (n = 4, 2.2%), ERBB2 (n = 4, 2.2%), SMAD4 (n = 3, 1.6%), CDK4 (n = 2, 1.1%), NRAS (n = 2, 1.1%), FGFR1 (n = 2, 1.1%), FGFR2 (n = 2, 1.1%), PTEN (n = 2, 1.1%), RB1 (n = 2, 1.1%), and CDK6, CDKN2A, BRCA1, BRCA2, JAK2, IDH2, MAPK, NTRK1, CDH1, ARID1A, and PDGFRA (n = 1, 0.5%).ConclusionEvaluation of ctDNA is feasible among patients with AC. The frequency of genomic alterations is similar to that previously reported in tissue NGS. Liquid biopsies are not invasive and can provide personalized options for targeted therapies in patients with AC.Implications for PracticeThe complexity of appendiceal cancer and its unique genomic characteristics suggest that customized combination therapy may be required for many patients. Theoretically, as more oncogenic pathways are discovered and more targeted therapies are approved, customized treatment based on the patient's unique molecular profile will lead to personalized care and improve patient outcomes. Liquid biopsies are noninvasive, cost-effective, and promising methods that provide patients with access to personalized treatment.