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Immune checkpoint blockade is revolutionizing therapy for advanced cancer, but many patients do not respond to treatment. The identification of robust biomarkers that predict clinical response to specific checkpoint inhibitors is critical in order to stratify patients and to rationally select combinations in the context of an expanding array of therapeutic options. We performed multiparameter flow cytometry on freshly isolated metastatic melanoma samples from 2 cohorts of 20 patients each prior to treatment and correlated the subsequent clinical response with the tumor immune phenotype. Increasing fractions of programmed cell death 1 high/cytotoxic T lymphocyte-associated protein 4 high (PD-1hiCTLA-4hi) cells within the tumor-infiltrating CD8+ T cell subset strongly correlated with response to therapy (RR) and progression-free survival (PFS). Functional analysis of these cells revealed a partially exhausted T cell phenotype. Assessment of metastatic lesions during anti-PD-1 therapy demonstrated a release of T cell exhaustion, as measured by an accumulation of highly activated CD8+ T cells within tumors, with no effect on Tregs. Our data suggest that the relative abundance of partially exhausted tumor-infiltrating CD8+ T cells predicts response to anti-PD-1 therapy. This information can be used to appropriately select patients with a high likelihood of achieving a clinical response to PD-1 pathway inhibition. This work was funded by a generous gift provided by Inga-Lill and David Amoroso as well as a generous gift provided by Stephen Juelsgaard and Lori Cook.

PurposeThe artemisinin class of anti-malarial drugs has shown significant anti-cancer activity in pre-clinical models. Proposed anti-cancer mechanisms include DNA damage, inhibition of angiogenesis, TRAIL-mediated apoptosis, and inhibition of signaling pathways. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of intravenous artesunate (IV AS).MethodsPatients were enrolled in an accelerated titration dose escalation study with planned dose levels of 8, 12, 18, 25, 34 and 45 mg/kg given on days 1 and 8 of a 21-day cycle. Toxicities were assessed using the NCI CTCAE (ver. 4.0), and response was assessed using RECIST criteria (version 1.1). Pharmacokinetic (PK) studies were performed during cycle 1.ResultsA total of 19 pts were enrolled, 18 of whom were evaluable for toxicity and 15 were evaluable for efficacy. DLTs were seen at dosages of 12 (1 of 6 patients), 18 (1 of 6) and 25 mg/kg (2 of 2), and were neutropenic fever (Gr 4), hypersensitivity reaction (Gr 3), liver function test abnormalities (Gr 3/4) along with neutropenic fever, and nausea/vomiting (Gr 3) despite supportive care. The MTD was determined to be 18 mg/kg. No responses were observed, while four patients had stable disease, including three with prolonged stable disease for 8, 10, and 11 cycles, for a disease control rate of 27%. PK parameters of AS and its active metabolite, dihydroartemisinin (DHA), correlated with dose.ConclusionThe MTD of intravenous artesunate is 18 mg/kg on this schedule. Treatment was well tolerated. Modest clinical activity was seen in this pre-treated population.ClinicalTrials.gov IdentifierNCT02353026.

The aim of this study was to investigate outcomes associated with neoadjuvant chemotherapy in patients undergoing pancreatoduodenectomy for early stage pancreatic adenocarcinoma in the era of modern chemotherapy. The National Cancer Database (2010–2016) was queried for patients with clinical stage 0–2 pancreatic adenocarcinoma who underwent pancreatoduodenectomy. Patients who underwent up-front pancreatoduodenectomy were propensity matched to patients who received neoadjuvant chemotherapy. Postoperative outcomes, pathologic outcomes, and overall survival were compared. A total of 2036 patients were in each group. Neoadjuvant chemotherapy was associated with shorter length of stay, lower 30-day readmission rate, and lower 30 and 90-day mortality rates (all p < 0.05). Neoadjuvant chemotherapy was associated with lower rates of positives nodes and positive resection margins (all p < 0.0001). Neoadjuvant chemotherapy was associated with longer survival (26.8 vs. 22.1months, p < 0.0001). Patients who received neoadjuvant chemotherapy followed by surgery and adjuvant therapy had the longest OS, followed by neoadjuvant + surgery, surgery + adjuvant therapy, and surgery alone (29.8 vs. 25.6 vs. 23.9 vs. 13.1 months; p < 0.0001). Neoadjuvant chemotherapy is associated with improved postoperative outcomes, oncologic outcomes, and overall survival in patients with early stage pancreatic adenocarcinoma. Neoadjuvant chemotherapy should be considered in all patients with early stage pancreatic adenocarcinoma. •Rate of use of neoadjuvant therapy is increasing in early stage pancreatic adenocarcinoma.•Neoadjuvant chemotherapy is associated with improved postoperative and pathologic outcomes.•Neoadjuvant chemotherapy is associated with longer overall survival (27 vs 22 months).•One-third of patients who undergo up-front resection do not receive adjuvant chemotherapy.•Those who receive both pre- and postoperative chemotherapy have the longest survival (30 months).

Frequent mutations of genes in the histone-lysine N-methyltransferase 2 (KMT2) family members were identified in gastric cancers (GCs). Understanding how gene mutations of KMT2 family affect cancer progression and tumor immune microenvironment may provide new treatment strategies. A total of 1245 GCs were analyzed using next-generation sequencing, whole transcriptome sequencing, immunohistochemistry (Caris Life Sciences, Phoenix, AZ). The overall mutation rate of genes in the KMT2 family was 10.6%. Compared to KMT2 -wild-type GCs, genes involved in epigenetic modification, receptor tyrosine kinases/MAPK/PI3K, and DNA damage repair (DDR) pathways had higher mutation rates in KMT2 -mutant GCs ( p  < 0.05). Significantly higher rates of high tumor mutational burden, microsatellite instability-high/mismatch-repair deficiency (dMMR), and PD-L1 positivity were observed in KMT2 -mutant GCs ( p  < 0.01), compared to KMT2 -wild-type GCs. The association between PD-L1 positivity and KMT2 mutations remained significant in the proficient-MMR and microsatellite stable subgroup. Based on transcriptome data from the TCGA, cell cycle, metabolism, and interferon-α/β response pathways were significantly upregulated in KMT2 -mutant GCs than in KMT2 -wild-type GCs. Patients with KMT2 mutation treated with immune checkpoint inhibitors had longer median overall survival compared to KMT2 -wild-type patients with metastatic solid tumors (35 vs. 16 months, HR = 0.73, 95% CI: 0.62–0.87, p  = 0.0003). In conclusion, this is the largest study to investigate the distinct molecular features between KMT2 -mutant and KMT2- wild-type GCs to date. Our data indicate that GC patients with KMT2 mutations may benefit from ICIs and drugs targeting DDR, MAPK/PI3K, metabolism, and cell cycle pathways.

Background Circulating biomarkers are urgently needed in hepatocellular carcinoma (HCC). The aims of this study were to determine the feasibility of detecting and isolating circulating tumor cells (CTCs) in HCC patients using enrichment for epithelial cell adhesion molecule (EpCAM) expression, to examine their prognostic value, and to explore CTC-based DNA sequencing in metastatic HCC patients compared to a control cohort with non-malignant liver diseases (NMLD). Methods Whole blood was obtained from patients with metastatic HCC or NMLD. CTCs were enumerated by CellSearch then purified by immunomagnetic EpCAM enrichment and fluorescence-activated cell sorting. Targeted ion semiconductor sequencing was performed on whole genome-amplified DNA from CTCs, tumor specimens, and peripheral blood mononuclear cells (PBMC) when available. Results Twenty HCC and 10 NMLD patients enrolled. CTCs ≥ 2/7.5 mL were detected in 7/20 (35%, 95% confidence interval: 12%, 60%) HCC and 0/9 eligible NMLD ( p  = 0.04). CTCs ≥ 1/7.5 mL was associated with alpha-fetoprotein ≥ 400 ng/mL ( p  = 0.008) and vascular invasion ( p  = 0.009). Sequencing of CTC DNA identified characteristic HCC mutations. The proportion with ≥ 100x coverage depth was lower in CTCs (43%) than tumor or PBMC (87%) ( p  < 0.025). Low frequency variants were higher in CTCs ( p  < 0.001). Conclusions CTCs are detectable by EpCAM enrichment in metastatic HCC, without confounding false positive background from NMLD. CTC detection was associated with poor prognostic factors. Sequencing of CTC DNA identified known HCC mutations but more low-frequency variants and lower coverage depth than FFPE or PBMC.

BackgroundIn patients with colorectal cancer (CRC), the therapeutic effects of conventional immune checkpoint inhibitors targeting the adaptive immune system are largely limited to those with microsatellite instability-high tumors. Meanwhile, new immunotherapies targeting the innate immune system are attracting increasing attention. CD47 is a representative innate immune checkpoint involved in the evasion of tumor cell phagocytosis by macrophages. This large-scale study comprehensively examined the molecular significance of CD47 gene expression in CRC.MethodsWe analyzed the next-generation sequencing data of DNA and RNA from 14,287 CRC cases included in the data set of a commercial Clinical Laboratory Improvement Amendments-certified laboratory (Caris Life Sciences). The cases were divided into two groups based on the median value of CD47 gene expression levels. The molecular and immune profiles between the groups were compared, and the relationship between CD47 expression and survival outcomes was further examined.ResultsIn CD47-high tumors, the proportion of consensus molecular subtypes 1 and 4 was significantly higher than in CD47-low tumors. The expression levels of damage-associated molecular pattern-related genes showed a positive correlation with CD47 expression levels. Major oncogenic pathways, such as mitogen-activated protein kinase, phosphoinositide 3-kinase, angiogenesis, and transforming growth factor beta, were significantly activated in CD47-high tumors. Additionally, the expression levels of a panel of adaptive immune checkpoint genes and estimates of immune cells constituting the tumor microenvironment (TME) were significantly higher in CD47-high tumors.Conclusions CD47 expression in CRC was associated with the activation of several oncogenic pathways and an immune-engaged TME. Our findings may provide valuable information for considering new therapeutic strategies targeting innate immune checkpoints in CRC.

Although histological and molecular classifications have been extensively studied for gastric cancer (GC), targeted therapies for GC remain limited. CDH1 mutations (MT) are characteristic of genomically stable GC and are associated with poor prognosis, but lack effective or targeted therapies. Here, we showed the overall mutation frequency of CDH1 was 9.7% (155 of 1596). CDH1 -MT GC showed significantly lower rates of PD-L1 positivity (CPS score ≥1) than CDH1 -wildtype (WT) GC (56.7% vs. 73.3%, p  <  0.05 ). Compared to CDH1 -WT GC, mutations of ARID1A , WRN , POT1 , CDK12 , and FANCC were significantly higher, while TP53 and APC were significantly lower in CDH1 -MT GC ( p  < 0.05); The rates of KRAS and HER2 amplifications were significantly lower, while CRKL and IGF1R amplifications were significantly higher in CDH1 -MT GC, compared to CDH1 -WT GC ( p  < 0.05). Frequently altered genes in CDH1 -MT GC were especially enriched in DNA damage repair and cell cycle checkpoint pathways. Inhibition of E-cadherin sensitized GC cell lines to PARP and Wee1 inhibitors by disrupting DNA damage repair pathway and cell cycle checkpoint. This is the largest study to investigate the distinct genomic landscape of CDH1 -MT GC. Our data indicated GC patients with CDH1 mutations could potentially benefit from agents targeting PARP and Wee1.

Purpose Patients with metastatic, gemcitabine-refractory pancreatic cancer typically have poor survival. Erlotinib, a targeted therapy that inhibits epidermal growth factor receptor (EGFR) activity (overexpressed in 40–60 % of pancreatic cancers), was FDA approved for the treatment of patients with advanced pancreatic cancer. Human epidermal growth factor receptor 2 (HER-2), another member of the ErbB family of growth factor receptor tyrosine kinases, has also been a therapeutic target of interest in pancreatic cancer; HER-2 overexpression is found in 20 % of pancreatic cancers. Lapatinib is a tyrosine kinase inhibitor that binds to both EGFR and HER-2. We conducted a single-arm phase II study to evaluate the combination of lapatinib and capecitabine in the second-line treatment of metastatic, gemcitabine-refractory pancreatic cancer. Methods Seventeen patients with metastatic, unresectable pancreatic cancer whose disease had progressed on first-line gemcitabine-based therapy were selected for this study. Patients were required to have an adequate performance status (ECOG 0–2) and normal hepatic and renal function prior to being enrolled. Patients received lapatinib 1250 mg PO daily 1 h before or after meals, and capecitabine 1000 mg/m 2 PO twice daily on days 1–14 of the 21-day cycle. The primary endpoint was median overall survival (OS), and the secondary endpoints were objective response rate, progression-free survival (PFS) and the safety profile of the combination therapy. Clinical toxicities were assessed according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0. Radiographic response was evaluated by RECIST criteria. Results Clinically, six of the 17 patients treated had disease progression (PD) after two cycles, six of 17 patients had stable disease (SD) and received more than four cycles (SD, range 4–22 cycles). For all patients, median PFS was 2.6 months (95 % CI 1.3–3.8) and median OS was 5.2 months (95 % CI 3.4–9). Treatment-related toxicities were limited to three (17 %) patients developing grade 3 adverse events such as nausea, vomiting, diarrhea and fatigue. When stratifying patients by treatment response, we found a statistically significant difference in median PFS and OS: median PFS was 1.4 months (95 % CI 1.0–1.8) in the PD group versus 4.0 months (95 % CI 1.8–6.3) in the SD group ( P value = 0.001). Median OS was 2.9 months (95 % CI 0–7.3) in the PD group versus 8.3 months (95 % CI 0–21.2) in the SD group ( P value = 0.023). Conclusions The combination of lapatinib and capecitabine is a tolerable regimen for patients with gemcitabine-refractory pancreatic cancer; however, this observation is based on the small number of patients enrolled in the trial. A subset of the enrolled patients had clinical benefit from treatment. Predictive biomarkers that allow selection of patients that will respond to this regimen should be further investigated.

Loss-of-function alterations of Neurofibromin 1 ( NF1 ) activate RAS, a driver of colorectal cancer. However, the clinical implications of NF1 alterations are largely unknown. We performed a comprehensive molecular profiling of NF1 -mutant colorectal cancer using data from 8150 patients included in a dataset of commercial CLIA-certified laboratory (Caris Life Sciences). In addition, NF1 expression levels were tested for associations with clinical outcomes using data from 431 patients in the CALGB/SWOG 80405 trial. In the Caris dataset, 2.2% of patients had pathogenic or presumed pathogenic NF1 mutations. NF1 -mutant tumors more frequently harbored PIK3CA (25.0% vs. 16.7%) and PTEN mutations (24.0% vs. 4.2%) than wild type tumors. Gene set enrichment analysis revealed that MAPK and PI3K pathway signatures were enriched in NF1 -mutant tumors. In the CALGB/SWOG 80405 cohort, low NF1 expression was associated with poor prognosis, and high NF1 expression was associated with better efficacy of cetuximab than bevacizumab. Together, we revealed concurrent genetic alterations in the PI3K pathways in NF1 -mutant tumors, suggesting the need to simultaneously block MAPK and PI3K pathways in treatment. The potential of NF1 alteration as a novel biomarker for targeted therapy was highlighted, warranting further investigations in clinical settings.

PurposeLittle is known about the use of palliative and hospice care and their impact on healthcare utilization near the end of life (EOL) in early-onset pancreatic cancer (EOPC).MethodsPatients with EOPC (≤ 50 years) were identified using the institutional tumor registry for years 2011–2018, and demographic, clinical, and rates of referral to palliative and hospice services were obtained retrospectively. Predictors of healthcare utilization, defined as use of ≥ 1 emergency department (ED) visit or hospitalization within 30 days of death, place of death (non-hospital vs. hospital), and time from last chemotherapy administration prior to death, were assessed using descriptive, univariable, and multivariable analyses including chi-square and logistic regression models.ResultsA total of 112 patients with EOPC with a median age of 46 years (range, 29–50) were studied. Forty-four percent were female, 28% were Black, and 45% had metastatic disease. Fifty-seven percent received palliative care at a median of 7.8 weeks (range 0–265) following diagnosis. The median time between last chemotherapy and death was 7.9 weeks (range 0–102). Seventy-four percent used hospice services prior to death for a median of 15 days (range 0–241). Rate of healthcare utilization at the EOL was 74% in the overall population. Black race and late use of chemotherapy were independently associated with increase in ED visits/hospitalization and hospital place of death.ConclusionsAlthough we observed early referrals to palliative care among patients with newly diagnosed EOPC, short duration of hospice enrollment and rates of healthcare utilization prior to death were substantial.