Tumour extracellular vesicles and particles induce liver metabolic dysfunction.

Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.

Cancer of the esophagus and esophagogastric junction-Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual.

Answer questions and earn CME/CNE New to the eighth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual for epithelial cancers of the esophagus and esophagogastric junction are separate, temporally related cancer classifications: 1) before treatment decision (clinical); 2) after esophagectomy alone (pathologic); and 3) after preresection therapy followed by esophagectomy (postneoadjuvant pathologic). The addition of clinical and postneoadjuvant pathologic stage groupings was driven by a lack of correspondence of survival, and thus prognosis, between both clinical and postneoadjuvant pathologic cancer categories (facts about the cancer) and pathologic categories. This was revealed by a machine-learning analysis of 6-continent data from the Worldwide Esophageal Cancer Collaboration, with consensus of the AJCC Upper GI Expert Panel. Survival is markedly affected by histopathologic cell type (squamous cell carcinoma and adenocarcinoma) in clinically and pathologically staged patients, requiring separate stage grouping for each cell type. However, postneoadjuvant pathologic stage groups are identical. For the future, more refined and granular data are needed. This requires: 1) more accurate clinical staging; 2) innovative solutions to pathologic staging challenges in endoscopically resected cancers; 3) integration of genomics into staging; and 4) precision cancer care with targeted therapy. It is the responsibility of the oncology team to accurately determine and record registry data, which requires eliminating both common errors and those related to incompleteness and inconsistency. Despite the new complexity of eighth edition staging of cancers of the esophagus and esophagogastric junction, these key concepts and new directions will facilitate precision cancer care. CA Cancer J Clin 2017;67:304-317. © 2017 American Cancer Society.

Circulating tumor and invasive cell expression profiling predicts effective therapy in pancreatic cancer.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) remains a refractory disease; however, modern cytotoxic chemotherapeutics can induce tumor regression and extend life. A blood-based, pharmacogenomic, chemosensitivity assay using gene expression profiling of circulating tumor and invasive cells (CTICs) to predict treatment response was previously developed. The combination regimen of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel (G/nab-P) are established frontline approaches for treating advanced PDAC; however, there are no validated biomarkers for treatment selection. A similar unmet need exists for choosing second-line therapy. METHODS: The chemosensitivity assay was evaluated in metastatic PDAC patients presenting for frontline treatment. A prospective study enrolled patients (n = 70) before receiving either FOLFIRINOX or G/nab-P at a 1:1 ratio. Six milliliters of peripheral blood was collected at baseline and at time of disease progression. CTICs were isolated, gene-expression profiling was performed, and the assay was used to predict effective and ineffective chemotherapeutic agents. Treating physicians were blinded to the assay prediction results. RESULTS: Patients receiving an effective regimen as predicted by the chemosensitivity assay experienced significantly longer median progression-free survival (mPFS; 7.8 months vs. 4.2 months; hazard ratio [HR], 0.35; p = .0002) and median overall survival (mOS; 21.0 months vs. 9.7 months; HR, 0.40; p = .005), compared with an ineffective regimen. Assay prediction for effective second-line therapy was explored. The entire study cohort experienced favorable outcomes compared with historical controls, 7.1-month mPFS and 12.3-month mOS. CONCLUSIONS: Chemosensitivity assay profiling is a promising tool for guiding therapy in advanced PDAC. Further prospective validation is under way (clinicaltrials.gov NCT03033927).

PD-L1 expression and overall survival in Asian and western patients with gastric cancer.

Aim: Data are limited on PD-L1 expression and its association with overall survival (OS) in gastric cancer (GC) patients receiving routine care in different regions. Materials & methods: In a retrospective study, PD-L1 expression was assayed using the 22C3 pharmDx on GC tumor samples collected between 2003 and 2017 at South Korean and US cancer centers. PD-L1 positivity was defined as combined positive score (CPS) ≥1. The relationship between PD-L1 and OS was analyzed. Results: Of 574 GC tumor samples, 67.4% were CPS ≥1 (68.7% in Korean and 65.7% in US patients). PD-L1 expression was not associated with OS (adjusted hazard ratio: 0.94; 95% CI: 0.75-1.17). Conclusion: PD-L1 prevalence and its association with OS was similar between South Korean and US GC patients.

Attitudes toward preimplantation genetic testing and quality of life among individuals with hereditary diffuse gastric cancer syndrome.

BACKGROUND: Hereditary Diffuse Gastric Cancer (HDGC) syndrome is an autosomal dominant hereditary cancer predisposition associated with germline pathogenic/likely pathogenic variants in the CDH1 gene. Identifying early stage HDGC is difficult, and prophylactic measures can be effective in preventing incidence. Preimplantation Genetic Testing (PGT) can provide information about CDH1 variant status, HDGC risk, and limit familial transmission of CDH1 variants. To date, however, little is known about the attitudes of individuals with CDH1 variants towards PGT. METHODS: Given that little is known about the reproductive attitudes of individuals with HDGC, we recruited participants with CDH1 variants from a familial gastric cancer registry and administered a cross-sectional survey with open- and closed-ended response items. We assessed attitudes regarding PGT and the effect of HDGC on quality of life. RESULTS: Participants (n = 21) were predominantly partnered (61.9%), had a personal cancer history (71.4%), and had biological children (71.4%). Interest in learning about PGT was high; 66.7% of participants were interested in PGT and 90.5% approved of healthcare providers discussing PGT with individuals with CDH1 variants. Attitudes regarding personal use were varied. Among all participants, 35% would not, 25% were uncertain, and 40% would use PGT. Personal philosophy and preferences for family and reproduction were key factors related to PGT attitudes. HDGC had moderate effects on participants' quality of life, including social relationships, health behaviors, and emotional experiences including worry about cancer risk and guilt regarding familial implications. CONCLUSION: PGT was identified by participants as acceptable for use in a variety of contexts and benefits of reproductive counseling involving PGT may extend beyond CDH1 carriers to family members' reproductive behaviors. Dispositions towards PGT are governed by personal philosophy or belief systems. These findings can help guide providers counseling individuals with CDH1 variants.

Pancreas cancer and BRCA: A critical subset of patients with improving therapeutic outcomes.

BACKGROUND: Patients with germline/somatic BRCA1/BRCA2 mutations (g/sBRCA1/2) comprise a distinct biologic subgroup of pancreas ductal adenocarcinoma (PDAC). METHODS: Institutional databases were queried to identify patients who had PDAC with g/sBRCA1/2. Demographics, clinicopathologic details, genomic data (annotation sBRCA1/2 according to a precision oncology knowledge base for somatic mutations), zygosity, and outcomes were abstracted. Overall survival (OS) was estimated using the Kaplan-Meier method. RESULTS: In total, 136 patients with g/sBRCA1/2 were identified between January 2011 and June 2020. Germline BRCA1/2 (gBRCA1/2) mutation was identified in 116 patients (85%). Oncogenic somatic BRCA1/2 (sBRCA1/2) mutation was present in 20 patients (15%). Seventy-seven patients had biallelic BRCA1/2 mutations (83%), and 16 (17%) had heterozygous mutations. Sixty-five patients with stage IV disease received frontline platinum therapy, and 52 (80%) had a partial response. The median OS for entire cohort was 27.6 months (95% CI, 24.9-34.5 months), and the median OS for patients who had stage IV disease was 23 months (95% CI, 19-26 months). Seventy-one patients received a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor (PARPi), and 52 received PARPi monotherapy. For maintenance PARPi, 10 patients (36%) had a partial response, 12 (43%) had stable disease, and 6 (21%) had progression of disease as their best response. Six patients (21%) received maintenance PARPi for >2 years. For those with stage IV disease who received frontline platinum, the median OS was 26 months (95% CI, 20-52 months) for biallelic patients (n = 39) and 8.66 months (95% CI, 6.2 months to not reached) for heterozygous patients (n = 4). The median OS for those who received PARPi therapy was 26.5 months (95% CI, 24-53 months) for biallelic patients (n = 25) and 8.66 months (95% CI, 7.23 months to not reached) for heterozygous patients (n = 2). CONCLUSIONS: g/sBRCA1/2 mutations did not appear to have different actionable utility. Platinum and PARPi therapies offer therapeutic benefit, and very durable outcomes are observed in a subset of patients who have g/sBRCA1/2 mutations with biallelic status.

First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial.

BACKGROUND: Addition of trastuzumab to first-line chemotherapy improves overall survival in patients with HER2-positive metastatic gastric cancer. We assessed the safety and activity of pembrolizumab in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric (gastric, oesophageal, or gastroesophageal junction) cancer. METHODS: This study was an investigator-initiated, open-label, non-randomised, single-arm, single centre, phase 2 trial in patients aged 18 years or older with HER2-positive metastatic oesophagogastric cancer. Eligible patients had measurable or evaluable non-measurable disease, Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and left ventricular ejection fraction of at least 53%. Patients were eligible to receive an initial induction cycle of 200 mg flat dose of intravenous pembrolizumab and 8 mg/kg loading dose of intravenous trastuzumab. For subsequent cycles, patients received 130 mg/m2 of intravenous oxaliplatin or 80 mg/m2 of cisplatin on day 1, 850 mg/m2 of oral capecitabine twice a day for 2 weeks followed by 1 week off (or intravenous 5-fluorouracil, 800 mg/m2 per day on days 1-5), and a 200 mg flat dose of intravenous pembrolizumab, and 6 mg/kg of trastuzumab, administered on day 1 of each 3-week cycle. The primary endpoint was 6-month progression-free survival, defined as the proportion of patients alive and free of progression at 6 months, assessed in patients who received at least one dose of trastuzumab and pembrolizumab. The regimen would be considered worthy of further investigation if 26 or more of 37 patients were progression-free at 6 months. This trial is registered with ClinicalTrials.gov, NCT02954536, and is ongoing, but closed to enrolment. FINDINGS: Between Nov 11, 2016, and Jan 23, 2019, 37 patients were enrolled. At the time of data cutoff on Aug 6, 2019, median follow-up among survivors was 13·0 months (IQR 11·7-23·5). The primary endpoint was achieved; 26 (70%; 95% CI 54-83) of 37 patients were progression-free at 6 months. The most common treatment-related adverse event of any grade was neuropathy, which was reported in 36 (97%) of 37 patients. The most common grade 3 or 4 adverse events were lymphocytopenia (seven [19%] patients with grade 3 and two [5%] with grade 4), grade 3 decreased electrolytes (six [16%] patients), and grade 3 anaemia (four [11%] patients). Serious adverse events occurred in two patients patients (both grade 3 nephritis leading to treatment discontinuation). Four patients discontinued pembrolizumab because of immune-related adverse events. There were no treatment-related deaths. INTERPRETATION: Pembrolizumab can be safely combined with trastuzumab and chemotherapy and has promising activity in HER2-positive metastatic oesophagogastric cancer. A randomised phase 3 clinical trial assessing the efficacy and safety of pembrolizumab versus placebo in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric cancer is underway. FUNDING: Merck & Co.

Alterations in driver genes are predictive of survival in patients with resected pancreatic ductal adenocarcinoma.

BACKGROUND: KRAS, TP53, CDKN2A, and SMAD4 are established driver genes in pancreatic ductal adenocarcinoma (PDAC). This study was aimed at determining whether the mutational status of driver genes and those involved in DNA repair pathways are associated with clinical outcomes for individuals who undergo resection. METHODS: Eligible individuals were those who underwent resection of PDAC and consented to targeted sequencing of their primary tumor via Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). Genomic alterations were determined on the basis of MSK-IMPACT results from formalin-fixed, paraffin-embedded samples. Associations between genomic alterations and clinical outcomes were assessed. RESULTS: Targeted sequencing was performed on 283 primary tumors resected between 2004 and 2017. The median follow-up was 23 months among survivors. Alterations in KRAS and TP53 were associated with worse overall survival (OS) in comparison to wild type (median for KRAS, 38.8 months [95% CI, 33.0-45.5 months] vs 91.0 months [95% CI, 34.8 months to not available (NA)]; P = .043; median for TP53, 37.4 months [95% CI, 32.1-42.8 months] vs 65.0 months [95% CI, 33.0 months to NA]; P = .035). KRAS G12D mutations were associated with worse OS (median, 31.6 months [95% CI, 25.3-45.5 months] vs 39.2 months [95% CI, 37.4-75.2 months]; P = .012). TP53 truncating mutations (median, 39.6 months [95% CI, 32.4-75.2 months] vs 33.9 months [95% CI, 24.0-39.0 months]; P = .020) and those associated with loss of heterozygosity (median, 26.6 months [95% CI, 21.6-44.2 months] vs 39.2 months [95% CI, 34.5-49.1 months]; P = .048) had decreased OS. TP53 alterations were independently associated with OS in a multivariate analysis (hazard ratio, 1.54; 95% CI, 1.01-2.33; P = .042). Individuals with germline alterations in homologous recombination deficiency (HRD) genes had improved OS in comparison with those without them (median, not reached vs 37.0 months; 95% CI, 33.0-49.8 months; P = .035). CONCLUSIONS: In patients with resected PDAC, genomic alterations in KRAS and TP53 are associated with worse outcomes, whereas alterations in HRD genes are associated with a favorable prognosis. Further studies are needed to better define these alterations as biomarkers in resected PDAC.

Regorafenib in Combination with First-Line Chemotherapy for Metastatic Esophagogastric Cancer.

BACKGROUND: Angiogenesis is critical to gastroesophageal adenocarcinoma growth and metastasis. Regorafenib is a multikinase inhibitor targeting angiogenic and stromal receptor tyrosine kinases. We evaluated whether regorafenib augments the antitumor effect of first-line chemotherapy in metastatic esophagogastric cancer. MATERIALS AND METHODS: Patients with previously untreated metastatic gastroesophageal adenocarcinoma received 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) every 14 days and regorafenib 160 mg daily on days 4 to 10 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS). To identify predictive biomarkers of outcome, we examined correlations between genomic characteristics of sequenced pretreatment tumors and PFS. RESULTS: Between August 2013 and November 2014, 36 patients with metastatic esophagogastric cancer were accrued to this single-center phase II study (NCT01913639). The most common grade 3-4 treatment-related adverse events were neutropenia (36%), leucopenia (11%) and hypertension (8%). The 6-month PFS was 53% (95% confidence interval [CI], 38%-71%), the objective response rate was 54% (95% CI, 37%-70%), and the disease control rate was 77% (95% CI, 67%-94%). Next-generation sequencing did not identify any genomic alterations significantly correlated with response, and there was no association between homologous recombination deficiency and PFS with platinum-based chemotherapy. CONCLUSION: Regorafenib (one week on-one week off schedule) is well tolerated in combination with first-line FOLFOX but does not improve 6-month PFS relative to historical control. IMPLICATIONS FOR PRACTICE: Prognosis for metastatic esophagogastric cancer remains poor despite modern systemic therapy regimens. This phase II trial indicates that the combination of regorafenib and FOLFOX is well tolerated but does not add to the efficacy of first-line chemotherapy in metastatic esophagogastric cancer. Notably, recently reported data suggest potential synergy between regorafenib and the PD-1 inhibitor nivolumab. As this study demonstrates that regorafenib plus FOLFOX is safe, and combined chemotherapy and immunotherapy show favorable toxicity profiles, future studies combining immunotherapy with regorafenib and chemotherapy may be feasible.

Pilot study of rapid MR pancreas screening for patients with BRCA mutation.

PURPOSE: To develop and optimize a rapid magnetic resonance imaging (MRI) screening protocol for pancreatic cancer to be performed in conjunction with breast MRI screening in breast cancer susceptibility gene (BRCA)-positive individuals. METHODS: An IRB-approved prospective study was conducted. The rapid screening pancreatic MR protocol was designed to be less than 10 min to be performed after a standard breast MRI protocol. Protocol consisted of coronal NT T2 SSFSE, axial NT T2 SSFSE and axial NT rFOV FOCUS DWI, and axial T1. Images were acquired with the patient in the same prone position of breast MRI using the built-in body coil. Image quality was qualitatively assessed by two radiologists with 12 and 13 years of MRI experience, respectively. The imaging protocol was modified until an endpoint of five consecutive patients with high-quality diagnostic images were achieved. Signal-to-noise ratio and contrast-to-noise ratio were assessed. RESULTS: The rapid pancreas MR protocol was successfully completed in all patients. Diagnostic image quality was achieved for all patients. Excellent image quality was achieved for low b values; however, image quality at higher b values was more variable. In one patient, a pancreatic neuroendocrine tumor was found and the patient was treated surgically. In four patients, small pancreatic cystic lesions were detected. In one subject, a hepatic mass was identified and confirmed as adenoma by liver MRI. CONCLUSION: Rapid MR protocol for pancreatic cancer screening is feasible and has the potential to play a role in screening BRCA patients undergoing breast MRI. KEY POINT: • Develop and optimize a rapid magnetic resonance imaging (MRI) screening protocol for pancreatic cancer to be performed in conjunction with breast MRI screening in BRCA mutation positive individuals.

Phase II study of trastuzumab with modified docetaxel, cisplatin, and 5 fluorouracil in metastatic HER2-positive gastric cancer.

BACKGROUND: Trastuzumab with cisplatin and fluoropyrimidine is the standard treatment in metastatic HER2-positive gastric or gastroesophageal (GE) junction adenocarcinoma; however, there is limited data on the efficacy of trastuzumab in combination with a three-drug regimen in this setting. We examined the efficacy and safety of modified docetaxel, cisplatin and 5 fluorouracil (mDCF) plus trastuzumab in a single-arm multicenter phase II trial. METHODS: Previously untreated patients with HER2-positive metastatic gastric or GE junction adenocarcinoma were treated with mDCF and trastuzumab every 2 weeks. The primary endpoint was 6-month progression-free survival (PFS); secondary endpoints included objective response rate, overall survival (OS), and toxicity. RESULTS: We enrolled 26 patients with metastatic HER2-positive gastric or GE junction adenocarcinoma between February 2011 and June 2015. The median age of patients was 62 years; 96% had a Karnofsky performance status equal to or greater than 80%. With a median follow-up of 25.4 months, the 6-month PFS was 73% (95% CI 51-86%). The objective response rate was 65%, the median PFS was 13 months (95% CI 6.4-20.7) and the median OS was 24.9 months (95% CI 14.4-42.5). Grade 3/4 toxicities included neutropenia (42%), fatigue (23%), and hypophosphatemia (15%). There were no episodes of febrile neutropenia. CONCLUSION: The combination of mDCF and trastuzumab is effective and safe in patients with metastatic HER2-positive gastric or GE junction adenocarcinoma and can be considered as an option for selected patients. This trial is registered at ClinicalTrials.gov, number NCT00515411.

Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma.

BACKGROUND: A phase 1 trial was used to evaluate a combination of cisplatin, gemcitabine, and escalating doses of veliparib in patients with untreated advanced pancreatic ductal adenocarcinoma (PDAC) in 2 cohorts: a germline BRCA1/2-mutated (BRCA+) cohort and a wild-type BRCA (BRCA-) cohort. The aims were to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D) of veliparib combined with cisplatin and gemcitabine and to assess the antitumor efficacy (Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival. METHODS: Gemcitabine and cisplatin were dosed at 600 and 25 mg/m2 , respectively, over 30 minutes on days 3 and 10 of a 21-day cycle. Four dose levels of veliparib were evaluated: 20 (dose level 0), 40 (dose level 1), and 80 mg (dose level 2) given orally twice daily on days 1 to 12 and 80 mg given twice daily on days 1 to 21 (dose level 2A [DL2A]). RESULTS: Seventeen patients were enrolled: 9 BRCA+ patients, 7 BRCA- patients, and 1 patient with an unknown status. DLTs were reached at DL2A (80 mg twice daily on days 1 to 21). Two of the 5 patients in this cohort (40%) experienced grade 4 neutropenia and thrombocytopenia. Two grade 5 events occurred on protocol. The objective response rate in the BRCA+ cohort was 7 of 9 (77.8%). The median overall survival for BRCA+ patients was 23.3 months (95% confidence interval [CI], 3.8-30.2 months). The median overall survival for BRCA- patients was 11 months (95% CI, 1.5-12.1 months). CONCLUSIONS: The RP2D of veliparib was 80 mg by mouth twice daily on days 1 to 12 in combination with cisplatin and gemcitabine; the DLT was myelosuppression. Substantial antitumor activity was seen in BRCA+ PDAC. A randomized phase 2 trial is currently evaluating cisplatin and gemcitabine with and without veliparib for BRCA+ PDAC (NCT01585805). Cancer 2018;124:1374-82. © 2018 American Cancer Society.

In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F-(2S,4R)-4-Fluoroglutamine.

Purpose To assess the clinical safety, pharmacokinetics, and tumor imaging characteristics of fluorine 18-(2S,4R)-4-fluoroglutamine (FGln), a glutamine analog radiologic imaging agent. Materials and Methods This study was approved by the institutional review board and conducted under a U.S. Food and Drug Administration-approved Investigational New Drug application in accordance with the Helsinki Declaration and the Health Insurance Portability and Accountability Act. All patients provided written informed consent. Between January 2013 and October 2016, 25 adult patients with cancer received an intravenous bolus of FGln tracer (mean, 244 MBq ± 118, <100 µg) followed by positron emission tomography (PET) and blood radioassays. Patient data were summarized with descriptive statistics. FGln biodistribution and plasma amino acid levels in nonfasting patients (n = 13) were compared with those from patients who fasted at least 8 hours before injection (n = 12) by using nonparametric one-way analysis of variance with Bonferroni correction. Tumor FGln avidity versus fluorodeoxyglucose (FDG) avidity in patients with paired PET scans (n = 15) was evaluated with the Fisher exact test. P < .05 was considered indicative of a statistically significant difference. Results FGln PET depicted tumors of different cancer types (breast, pancreas, renal, neuroendocrine, lung, colon, lymphoma, bile duct, or glioma) in 17 of the 25 patients, predominantly clinically aggressive tumors with genetic mutations implicated in abnormal glutamine metabolism. Acute fasting had no significant effect on FGln biodistribution and plasma amino acid levels. FGln-avid tumors were uniformly FDG-avid but not vice versa (P = .07). Patients experienced no adverse effects. Conclusion Preliminary human FGln PET trial results provide clinical validation of abnormal glutamine metabolism as a potential tumor biomarker for targeted radiotracer imaging in several different cancer types. © RSNA, 2018 Online supplemental material is available for this article. Clinical trial registration no. NCT01697930.

The newly proposed clinical and post-neoadjuvant treatment staging classifications for gastric adenocarcinoma for the American Joint Committee on Cancer (AJCC) staging.

PURPOSE: New stage grouping classifications for clinical (cStage) and post-neoadjuvant treatment (ypStage) stage for gastric adenocarcinoma have been proposed for the eighth edition of the AJCC manual. This article summarizes the analysis for these stages. METHODS: Gastric adenocarcinoma patients diagnosed in 2004-2009 were identified from the National Cancer Database (NCDB). The cStage cohort included both surgical and nonsurgical cases, and the ypStage cohort included only patients who had chemotherapy or radiation therapy before surgery. Survival differences between the stage groups were determined by the log-rank test and prognostic accuracy was assessed by concordance index. Analysis was performed using SAS 9.4 (SAS, Cary, NC, USA). RESULTS: Five strata for cStage and four strata for ypStage were developed. The 5-year survival rates for cStages were 56.77%, 47.39%, 33.1%, 25.9%, and 5.0% for stages I, IIa, IIb, III, and IV, respectively, and the rates for ypStage were 74.2%, 46.3%, 19.2%, and 11.6% for stages I, II, III, and IV, respectively. The log-rank test showed that survival differences were well stratified and stage groupings were ordered and distinct (p < 0.0001). The proposed cStage and ypStage classification was sensitive and specific and had high prognostic accuracy (cStage: c index = 0.81, 95% CI, 0.79-0.83; ypStage: c index = 0.80, 95% CI, 0.73-0.87). CONCLUSION: The proposed eighth edition establishes two new staging schemata that provide essential prognostic data for patients before treatment and for patients who have undergone surgery following neoadjuvant therapy. These additions are a significant advance to the AJCC staging manual and will provide critical guidance to clinicians in making informed decisions throughout the treatment course.

A phase 1/1B trial of ADI-PEG 20 plus nab-paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma.

BACKGROUND: ADI-PEG 20 is a pegylated form of the arginine-depleting enzyme arginine deiminase. Normal cells synthesize arginine with the enzyme argininosuccinate synthetase (ASS1); ADI-PEG 20 selectively targets malignant cells, which lack ASS1. METHODS: A single-arm, nonrandomized, open-label, phase 1/1B, standard 3 + 3 dose escalation with an expansion cohort of 9 patients at the recommended phase 2 dose (RP2D) was conducted. Patients who had metastatic pancreatic cancer, up to 1 line of prior treatment (the dose-escalation cohort) or no prior treatment (the expansion cohort), and an Eastern Cooperative Oncology Group performance status of 0 to 1 were included. Patients received both gemcitabine (1000 mg/m2 ) and nab-paclitaxel (125 mg/m2 ) for 3 of 4 weeks and intramuscular ADI-PEG 20 at 18 mg/m2 weekly (cohort 1) or at 36 mg/m2 weekly (cohort 2 and the expansion cohort).The primary endpoint was to determine the maximum tolerated dose and RP2D of ADI-PEG 20 in combination with nab-paclitaxel and gemcitabine. RESULTS: Eighteen patients were enrolled. No dose-limiting toxicities (DLTs) were observed in cohort 1; cohort 2 was expanded to 6 patients because of 1 DLT occurrence (a grade 3 elevation in bilirubin, aspartate aminotransferase, and alanine aminotransferase). The most frequent adverse events (AEs) of any grade were neutropenia, thrombocytopenia, leukopenia, anemia, peripheral neuropathy, and fatigue; all 18 patients experienced grade 3/4 AEs. The most frequent grade 3/4 toxicities, regardless of the relation with any drugs, included neutropenia (12 patients or 67%), leukopenia (10 patients or 56%), anemia (8 patients or 44%), and lymphopenia (6 patients or 33%). The RP2D for ADI-PEG 20 was 36 mg/m2 weekly in combination with standard-dose gemcitabine and nab-paclitaxel. The overall response rate among patients treated at the RP2D in the first-line setting was 45.5% (5 of 11).The median progression-free survival time for these patients treated at the RP2D was 6.1 months (95% confidence interval, 5.3-11.2 months), and the median overall survival time was 11.3 months (95% confidence interval, 6.7 months to not reached). CONCLUSIONS: ADI-PEG 20 was well tolerated in combination with gemcitabine and nab-paclitaxel. Activity was observed in previously treated and untreated patients with advanced pancreatic cancer and in patients with ASS1-deficient and -proficient tumors. Cancer 2017;123:4556-4565. © 2017 American Cancer Society.

Overall survival and clinical characteristics of BRCA mutation carriers with stage I/II pancreatic cancer.

BACKGROUND: BRCA1/BRCA2 germ line (GL) mutation carriers with pancreatic adenocarcinoma (PDAC) may have distinct outcomes. We recently described an apparent more favourable prognosis of surgically resected BRCA-associated PDAC patients in a single-arm, uncontrolled, retrospective study. However, the prognostic impact of GL BRCA1/2 mutations in surgically resected PDAC has not been compared with a matched control population. METHODS: A larger multi-centre, case-control retrospective analysis was performed. Cases were patients with surgically resected, BRCA1/2-associated PDAC from 2004 to 2013. Controls included surgically resected PDAC cases treated during the same time period that were either BRCA non-carriers, or had no family history of breast, ovarian or pancreatic cancers. Cases and controls were matched by: age at diagnosis (within ±5-year period) and institution. Demographics, clinical history, overall survival (OS) and disease-free survival (DFS) were abstracted from patient records. Statistical comparisons were assessed using χ2- and Fisher's exact test, and median DFS/OS using Kaplan-Meier method and log-rank testing. RESULTS: Twenty-five patients with BRCA1-(n=4) or BRCA2 (N=21)-associated resectable PDAC were identified. Mean age was 55.7 years (range, 34-78 years), 48% (n=12) were females and 76% (n=19) were Jewish. Cases were compared (1 : 2) with 49 resectable PDAC controls, and were balanced for age, ethnicity and other relevant clinical and pathological features. BRCA-associated PDAC patients received neoadjuvant, or adjuvant platinum-based treatment more frequently than controls (7 out of 8 vs 6 out of 14) and (7 out of 21 vs 3 out of 44), respectively. No significant difference in median OS (37.06 vs 38.77 months, P=0.838) and in DFS (14.3 vs 12.0 months, P=0.303) could be demonstrated between cases and controls. A trend to increased DFS was observed among BRCA-positive cases treated with neoadjuvant/adjuvant platinum-containing regimens (n=10) compared with similarly treated controls (n=7) (39.1 vs 12.4 months, P=0.255). CONCLUSIONS: In this retrospective analysis, the prognosis of surgically resectable BRCA-associated PDAC is no different than that of sporadic PDAC from the same institution. The role of platinum-based adjuvant therapy in this setting requires prospective investigation.

Total Gastrectomy for Hereditary Diffuse Gastric Cancer at a Single Center: Postsurgical Outcomes in 41 Patients.

OBJECTIVE: The aim of this study was to describe postoperative outcomes of total gastrectomy at our institution for patients with hereditary diffuse gastric cancer (HDGC). BACKGROUND: HDGC, which is mainly caused by germline mutations in the E-cadherin gene (CDH1), renders a lifetime risk of gastric cancer of up to 70%, prompting a recommendation for prophylactic total gastrectomy. METHODS: A prospective gastric cancer database identified 41 patients with CDH1 mutation who underwent total gastrectomy during 2005 to 2015. Perioperative, histopathologic, and long-term data were collected. RESULTS: Of the 41 patients undergoing total gastrectomy, median age was 47 years (range 20 to 71). There were 14 men and 27 women, with 25 open operations and 16 minimally invasive operations. Median length of stay was 7 days (range 4 to 50). In total, 11 patients (27%) experienced a complication requiring intervention, and there was 1 peri-operative mortality (2.5%). Thirty-five patients (85%) demonstrated 1 or more foci of intramucosal signet ring cell gastric cancer in the examined specimen. At 16 months median follow-up, the median weight loss was 4.7 kg (15% of preoperative weight). By 6 to 12 months postoperatively, weight patterns stabilized. Overall outcome was reported to be "as expected" by 40% of patients and "better than expected" by 45%. Patient-reported outcomes were similar to those of other patients undergoing total gastrectomy. CONCLUSION: Total gastrectomy should be considered for all CDH1 mutation carriers because of the high risk of invasive diffuse-type gastric cancer and lack of reliable surveillance options. Although most patients have durable weight loss after total gastrectomy, weights stabilize at about 6 to 12 months postoperatively, and patients report outcomes as being good to better than their preoperative expectations. No patients have developed gastric cancer recurrence after resections.

Genomic Alterations Observed in Colitis-Associated Cancers Are Distinct From Those Found in Sporadic Colorectal Cancers and Vary by Type of Inflammatory Bowel Disease.

BACKGROUND & AIMS: Patients with inflammatory bowel diseases, such as Crohn's disease (CD) and ulcerative colitis (UC), are at increased risk for small bowel or colorectal cancers (colitis-associated cancers [CACs]). We compared the spectrum of genomic alterations in CACs with those of sporadic colorectal cancers (CRCs) and investigated differences between CACs from patients with CD vs UC. METHODS: We studied tumor tissues from patients with CACs treated at Memorial Sloan Kettering Cancer Center or Weill Cornell Medical College from 2003 through 2015. We performed hybrid capture-based next-generation sequencing analysis of >300 cancer-related genes to comprehensively characterize genomic alterations. RESULTS: We performed genomic analyses of 47 CACs (from 29 patients with UC and 18 with CD; 43 primary tumors and 4 metastases). Primary tumors developed in the ileum (n = 2), right colon (n = 18), left colon (n = 6), and rectosigmoid or rectum (n = 21). We found genomic alterations in TP53, IDH1, and MYC to be significantly more frequent, and mutations in APC to be significantly less frequent, than those reported in sporadic CRCs by The Cancer Genome Atlas or Foundation Medicine. We identified genomic alterations that might be targeted by a therapeutic agent in 17 of 47 (36%) CACs. These included the mutation encoding IDH1 R132; amplification of FGFR1, FGFR2, and ERBB2; and mutations encoding BRAF V600E and an EML4-ALK fusion protein. Alterations in IDH1 and APC were significantly more common in CACs from patients with CD than UC. CONCLUSIONS: In an analysis of CACs from 47 patients, we found significant differences in the spectrum of genomic alterations in CACs compared with sporadic CRCs. We observed a high frequency of IDH1 R132 mutations in patients with CD but not UC, as well as a high frequency of MYC amplification in CACs. Many genetic alterations observed in CACs could serve as therapeutic targets.

Change in chemotherapy during concurrent radiation followed by surgery after a suboptimal positron emission tomography response to induction chemotherapy improves outcomes for locally advanced esophageal adenocarcinoma.

BACKGROUND: A positron emission tomography (PET) scan after induction chemotherapy before preoperative chemoradiation and surgery for esophageal adenocarcinoma predicts outcomes. Some patients with progression on PET after induction chemotherapy had long-term overall survival (OS) when they were changed to alternative chemotherapy during radiation. METHODS: This study retrospectively reviewed esophageal adenocarcinoma patients who received induction chemotherapy and chemoradiation before planned surgery; all had undergone a PET scan before and after induction chemotherapy. RESULTS: There were 201 patients, and 113 (56%) were PET responders (≥35% decrease in the maximum standardized uptake value of the tumor). All PET responders received the same chemotherapy during radiation, whereas 38 of the 88 PET nonresponders (43%) changed chemotherapy. Among the 152 patients who underwent surgery, the pathologic complete response rate was 15% for PET responders and 3% for PET nonresponders who did not change chemotherapy (P = .046). The median progression-free survival (PFS; 18.9 vs 10.0 months, P < 0.01) and OS (37 vs 25.3 months, P = .02) were significantly better for PET responders versus PET nonresponders who did not change chemotherapy. The median PFS for PET nonresponders who changed chemotherapy was 17.9 months, and it was superior to the median PFS for PET nonresponders who did not change chemotherapy (P = .01). For PET nonresponders, the 5-year OS rates were 37% for those who changed chemotherapy and 25% for those who did not change chemotherapy (P = .18). CONCLUSIONS: A PET scan after induction chemotherapy predicts outcomes for locally advanced esophageal adenocarcinoma patients who undergo chemoradiation and surgery. The median PFS is improved, and trends toward improved OS appear possible in PET nonresponders who change chemotherapy during radiation. The fully accrued Cancer and Leukemia Group B 80803 study (NCT01333033) is evaluating this strategy. Cancer 2016;122:2083-90. © 2016 American Cancer Society.