Adjuvant Modified FOLFIRINOX for Resected Pancreatic Adenocarcinoma (PDAC): Clinical Insights and Genomic Features from a Large Contemporary Cohort.

BACKGROUND: Adjuvant mFOLFIRINOX (mFFX) is standard of care for fit individuals with resected pancreatic ductal adenocarcinoma (PDAC). There are limited data on adjuvant mFFX outcomes outside clinical trials. METHODS: Institutional databases queried to identify patients with resected PDAC who received ≥1 dose adjuvant mFFX. Primary endpoints: recurrence free survival (RFS), overall survival (OS). Secondary endpoints: clinical factors, genomic features associated with outcomes. RFS and OS were estimated with Kaplan-Meier. Cox proportional hazards regression model was used to associate clinico-genomic features correlated with survival outcomes. RESULTS: N = 147 identified between 01/2015-01/2023. Median age: 67 years; N = 57 (39%) >70 years. Unfavorable prognostic features: N = 52 (36%) N2 nodal status, N = 115 (78%) lymphovascular invasion), and N = 133 (90%) perineural invasion. Median time from surgery to start mFFX: 1.78 months (m) (IQR 1.45, 2.12). N = 124 (84%) completed 12 doses; N = 98 (67%) stopped oxaliplatin early for neuropathy (median 10 doses; range 4-12). Further dosing characteristics are summarized in Supplementary Table 3. With median follow up of 35.1 m, median RFS (mRFS) 26 m (95% CI 19, 39) and median OS (mOS) not reached. For >70 cohort, mRFS 23 m (95% CI 14, NR) and mOS 51 m (95% CI 37, NR). mFFX started <8 weeks from resection associated with improved RFS (HR 0.62; 95% CI 0.41, 0.96; p = .033) and OS (HR 0.53; 95% CI 0.3, 0.94; p = .030). KRAS mutation and whole genome doubling trended to shorter RFS and OS. Homologous recombination deficiency status did not confer improved survival outcomes. CONCLUSIONS: Adjuvant mFFX is effective and tolerable in resected PDAC in a non-trial setting, including for patients >70 years.

Long term outcomes in patients with advanced intrahepatic cholangiocarcinoma treated with hepatic arterial infusion chemotherapy.

INTRODUCTION: Hepatic artery infusion (HAI) of chemotherapy has demonstrated disease control and suggested improvement in overall survival (OS) in intrahepatic cholangiocarcinoma (IHC). We report herein the long-term results and role of molecular alterations of a phase II clinical trial of HAI chemotherapy plus systemic chemotherapy, with a retrospective cohort of patients treated with HAI at Memorial Sloan Kettering Cancer Center. METHODS: This secondary analysis of a single-institution, phase 2 trial and retrospective cohort of unresectable IHC treated with HAI floxuridine (FUDR) plus systemic gemcitabine and oxaliplatin. The primary aim was to assess long-term oncologic outcomes. A subset underwent tissue-based genomic sequencing, and molecular alterations were correlated with progression-free survival (PFS) and OS. RESULTS: Thirty-eight patients were treated on trial with a median follow up of 76.9 months. Median PFS was 11.8 months (95% CI11-15.1). The median OS was 26.8 months (95% CI20.9-40.6). The 1-, 2- and 5-year OS rate was 89.5%, 55%, and 21% respectively. Nine (24%) received HAI with mitomycin C post FUDR progression with an objective response rate of 44% and a median PFS of 3.93 (2.33-NR) months. One-hundred and seventy patients not treated on the clinical trial were included in a retrospective analysis. Median PFS and OS was 7.93 (95%CI: 7.27-10.07) and 22.5 (95%CI : 19.5-28.3) months, respectively. Alterations in the TP53 and cell-cycle pathway had a worse PFS to HAI based therapy compared to wildtype disease. CONCLUSION: In locally advanced IHC, HAI with FUDR in combination with systemic therapy can offer long term durable disease control. Molecular alterations may predict for response.

Clinicogenomic predictors of outcomes in patients with hepatocellular carcinoma treated with immunotherapy.

INTRODUCTION: Immune checkpoint inhibitor (ICI) combinations extend overall survival (OS) while anti-PD-1/L1 monotherapy is non-inferior to sorafenib in treatment-naïve, patients with advanced hepatocellular carcinoma (HCC). Clinicogenomic features are posited to influence patient outcomes. METHODS: The primary objective of this retrospective study was to define the clinical, pathologic, and genomic factors associated with outcomes to ICI therapy in patients with HCC. Patients with histologically confirmed advanced HCC treated with ICI at Memorial Sloan Kettering Cancer Center from 2012 to 2022 were included. Association between clinical, pathological, and genomic characteristics were assessed with univariable and multivariable Cox regression model for progression-free survival (PFS) and OS. RESULTS: Two-hundred and forty-two patients were treated with ICI-based therapy. Patients were predominantly male (82%) with virally mediated HCC (53%) and Child Pugh A score (70%). Median follow-up was 28 months (0.5-78.4). Median PFS for those treated in 1st line, 2nd line and ≥ 3rd line was 4.9 (range: 2.9-6.2), 3.1 (2.3-4.0), and 2.5 (2.1-4.0) months, respectively. Median OS for those treated in 1st line, 2nd line, and ≥ 3rd line was 16 (11-22), 7.5 (6.4-11), and 6.4 (4.6-26) months, respectively. Poor liver function and performance status associated with worse PFS and OS, while viral hepatitis C was associated with favorable outcome. Genetic alterations were not associated with outcomes. CONCLUSION: Clinicopathologic factors were the major determinates of outcomes for patients with advanced HCC treated with ICI. Molecular profiling did not aid in stratification of ICI outcomes. Future studies should explore alternative biomarkers such as the level of immune activation or the pretreatment composition of the immune tumor microenvironment.

A Novel Approach to Quantify Heterogeneity of Intrahepatic Cholangiocarcinoma: The Hidden-Genome Classifier.

PURPOSE: Intrahepatic cholangiocarcinoma (IHC) is a heterogeneous tumor. The hidden-genome classifier, a supervised machine learning-based algorithm, was used to quantify tumor heterogeneity and improve classification. EXPERIMENTAL DESIGN: A retrospective review of 1,370 patients with IHC, extrahepatic cholangiocarcinoma (EHC), gallbladder cancer (GBC), hepatocellular carcinoma (HCC), or biphenotypic tumors was conducted. A hidden-genome model classified 527 IHC based on genetic similarity to EHC/GBC or HCC. Genetic, histologic, and clinical data were correlated. RESULTS: In this study, 410 IHC (78%) had >50% genetic homology with EHC/GBC; 122 (23%) had >90% homology ("biliary class"), characterized by alterations of KRAS, SMAD4, and CDKN2A loss; 117 IHC (22%) had >50% genetic homology with HCC; and 30 (5.7%) had >90% homology ("HCC class"), characterized by TERT alterations. Patients with biliary- versus non-biliary-class IHC had median overall survival (OS) of 1 year (95% CI, 0.77, 1.5) versus 1.8 years (95% CI, 1.6, 2.0) for unresectable disease and 2.4 years (95% CI, 2.1, NR) versus 5.1 years (95% CI, 4.8, 6.9) for resectable disease. Large-duct IHC (n = 28) was more common in the biliary class (n = 27); the HCC class was composed mostly of small-duct IHC (64%, P = 0.02). The hidden genomic classifier predicted OS independent of FGFR2 and IDH1 alterations. By contrast, the histology subtype did not predict OS. CONCLUSIONS: IHC genetics form a spectrum with worse OS for tumors genetically aligned with EHC/GBC. The classifier proved superior to histologic subtypes for predicting OS independent of FGFR2 and IDH1 alterations. These results may explain the differential treatment responses seen in IHC and may direct therapy by helping stratify patients in future clinical trials.

Precision medicine for pancreatic cancer: characterizing the clinicogenomic landscape and outcomes of KRAS G12C-mutated disease.

BACKGROUND: Mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogene alteration in pancreatic ductal adenocarcinoma, and KRAS glycine to cystine substitution at codon 12 (G12C) mutations (KRAS G12Cmut) are observed in 1%-2%. Several inhibitors of KRAS G12C have recently demonstrated promise in solid tumors, including pancreatic cancer. Little is known regarding clinical, genomics, and outcome data of this population. METHODS: Patients with pancreatic cancer and KRAS G12Cmut were identified at Memorial Sloan Kettering Cancer Center and via the American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange database. Clinical, treatment, genomic, and outcomes data were analyzed. A cohort of patients at Memorial Sloan Kettering Cancer Center with non-G12C KRAS pancreatic cancer was included for comparison. RESULTS: Among 3571 patients with pancreatic ductal adenocarcinoma, 39 (1.1%) with KRAS G12Cmut were identified. Median age was 67 years, and 56% were female. Median body mass index was 29.2 kg/m2, and 67% had a smoking history. Median overall survival was 13 months (95% CI: 9.4 months, not reached) for stage IV and 26 months (95% CI: 23 months, not reached) for stage I-III. Complete genomic data (via American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange database) was available for 74 patients. Most common co-alterations included TP53 (73%), CDKN2A (33%), SMAD4 (28%), and ARID1A (21%). Compared with a large cohort (n = 2931) of non-G12C KRAS-mutated pancreatic ductal adenocarcinoma, ARID1A co-mutations were more frequent in KRAS G12Cmut (P < .05). Overall survival did not differ between KRAS G12Cmut and non-G12C KRAS pancreatic ductal adenocarcinoma. Germline pathogenic variants were identified in 17% of patients; 2 patients received KRAS G12C-directed therapy. CONCLUSION: Pancreatic cancer and KRAS G12Cmut may be associated with a distinct clinical phenotype. Genomic features are similar to non-G12C KRAS-mutated pancreatic cancer, although enrichment of ARID1A co-mutations was observed. Targeting of KRAS G12C in pancreatic cancer provides a precedent for broader KRAS targeting in pancreatic cancer.

The Prognostic Nutritional Index in patients with microsatellite instability-high metastatic gastric or gastroesophageal cancers receiving immune checkpoint inhibitors.

BACKGROUND: Microsatellite instability high (MSI-H) and/or mismatch repair deficient (dMMR) status is the strongest predictive factor for immune checkpoint inhibitors (ICIs) benefit in patients with metastatic gastroesophageal cancer (mGC). Primary resistance to ICIs is a relevant issue, but prognostic and predictive factors are lacking. MATERIALS AND METHODS: In this multinational, retrospective cohort of patients with MSI-H/dMMR mGC treated with ICIs without chemotherapy we collected baseline laboratory values to establish the prognostic nutritional index (PNI). We evaluated the association between baseline PNI with the activity and efficacy of ICIs. RESULTS: At a median follow-up of 31.6 months, median progression-free survival (PFS) and 2-year PFS rate were not reached and 73.6 % in the PNI-high subgroup versus 6.3 months and 38.3 % in the PNI-low one (HR 0.32, 95 % CI: 0.16-0.61, p < .001). Median overall survival (OS) and 2-year OS rate were not reached and 81.9 % in the PNI-high subgroup versus 24.4 months and 50.5 % in the PNI-low one (HR 0.26, 95 % CI: 0.12-0.56, p < .001). In multivariable models, high PNI was associated with longer PFS and OS (HR 0.30, 95 % CI: 0.15-0.61, p <0.001 and 0.37, 95 % CI: 0.15-0.91, p = .031). CONCLUSIONS: High PNI is associated with longer PFS and OS, in patients with MSI-H mGC receiving ICIs. Patients with low baseline PNI may benefit from intensive therapeutic approaches.

Clinical utility of plasma cell-free DNA in pancreatic neuroendocrine neoplasms.

In advanced pancreatic neuroendocrine neoplasms (PanNEN), there are little data detailing the frequency of genetic alterations identified in cell free DNA (cfDNA), plasma-tissue concordance of detected alterations, and clinical utility of cfDNA. Patients with metastatic PanNENs underwent cfDNA collection in routine practice. Next-generation sequencing (NGS) of cfDNA and matched tissue when available was performed. Clinical actionability of variants was annotated by OncoKB. Thirty-two cfDNA samples were analyzed from 25 patients, the majority who had well-differentiated intermediate grade disease (13/25; 52%). Genomic alterations were detected in 68% of patients and in 66% of all cfDNA samples. The most frequently altered genes were DAXX (28%), TSC2 (24%), MEN1 (24%), ARID1B (20%), ARID1A (12%), and ATRX (12%). Twenty-three out of 25 (92%) patients underwent tumor tissue NGS. Tissue-plasma concordance for select genes was as follows:DAXX (95.7%), ARID1A (91.1%), ATRX (87%), TSC2 (82.6%), MEN1 (69.6%). Potentially actionable alterations were identified in cfDNA of 8 patients, including TSC2 (4; level 3b), ATM (1; level 3b), ARID1A (2; level 4), and KRAS (1; level 4). An ETV6:NTRK fusion detected in tumor tissue was treated with larotrectinib; at progression, sequencing of cfDNA identified an NTRK3 G623R alteration as the acquired mechanism of resistance; the patient enrolled in a clinical trial of a second-generation TRK inhibitor with clinical benefit. In metastatic PanNENs, cfDNA-based NGS identified tumor-associated mutations in 66% of plasma samples with a high level of plasma-tissue agreement in PanNEN-associated genes. Clonal evolution, actionable alterations, and resistance mechanisms were detected through circulating cfDNA genotyping.

Impact of Helicobacter pylori infection status on outcomes among patients with advanced gastric cancer treated with immune checkpoint inhibitors.

BACKGROUND: Gut microbiota composition can influence cancer immunotherapy response. Recent evidence suggests Helicobacter pylori infection may reduce immune checkpoint inhibitor (ICI) efficacy in lung cancer and melanoma, but thorough characterization of this association in patients with gastric cancer is lacking. We aimed to determine the impact of H. pylori on survival in this population. METHODS: This single-center, retrospective study included all ICI-treated individuals with metastatic gastric cancer and documented H. pylori status at Memorial Sloan Kettering between July 2013 and October 2021. H. pylori-positive status was defined as history of infection obtained via breath test, stool antigen test, histopathology, and/or chart documentation. Negative status was defined as explicitly negative testing, histopathology, and/or chart documentation. Primary outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: Of 215 included patients, 49 had documented history of H. pylori infection. Compared with H. pylori-negative patients, positive individuals tended to be younger, non-white, and Hispanic with non-cardia and intestinal-type gastric cancer. H. pylori-positive patients had significantly shorter median PFS (3.2 vs 6.8 months, HR 1.96, p<0.01) and OS (9.8 vs 17.9 months, HR 1.54, p=0.02). Multivariable analysis confirmed H. pylori infection as an independent predictor of PFS (HR 3.04, p<0.01) and OS (HR 2.24, p=0.01). CONCLUSIONS: In this largest study of its kind, H. pylori infection was associated with inferior survival in ICI-treated patients with gastric cancer. This suggests H. pylori status may be a prognostic marker of immune responsiveness. Future studies are needed to elucidate immunoregulatory mechanisms and whether treatment of active infections would improve immunotherapy outcomes.

Targeted Molecular Profiling of Circulating Cell-Free DNA in Patients With Advanced Hepatocellular Carcinoma.

PURPOSE: Next-generation sequencing (NGS) of tumor-derived, circulating cell-free DNA (cfDNA) may aid in diagnosis, prognostication, and treatment of patients with hepatocellular carcinoma (HCC). The operating characteristics of cfDNA mutational profiling must be determined before routine clinical implementation. METHODS: This was a single-center, retrospective study with the primary objective of defining genomic alterations in circulating cfDNA along with plasma-tissue genotype agreement between NGS of matched tumor samples in patients with advanced HCC. cfDNA was analyzed using a clinically validated 129-gene NGS assay; matched tissue-based NGS was analyzed with a US Food and Drug Administration-authorized NGS tumor assay. RESULTS: Fifty-three plasma samples from 51 patients with histologically confirmed HCC underwent NGS-based cfDNA analysis. Genomic alterations were detected in 92.2% of patients, with the most commonly mutated genes including TERT promoter (57%), TP53 (47%), CTNNB1 (37%), ARID1A (18%), and TSC2 (14%). In total, 37 (73%) patients underwent paired tumor NGS, and concordance was high for mutations observed in patient-matched plasma samples: TERT (83%), TP53 (94%), CTNNB1 (92%), ARID1A (100%), and TSC2 (71%). In 10 (27%) of 37 tumor-plasma samples, alterations were detected by cfDNA analysis that were not detected in the patient-matched tumors. Potentially actionable mutations were identified in 37% of all cases including oncogenic/likely oncogenic alterations in TSC1/2 (18%), BRCA1/2 (8%), and PIK3CA (8%). Higher average variant allele fraction was associated with elevated alpha-fetoprotein, increased tumor volume, and no previous systemic therapy, but did not correlate with overall survival in treatment-naïve patients. CONCLUSION: Tumor mutation profiling of cfDNA in HCC represents an alternative to tissue-based genomic profiling, given the high degree of tumor-plasma NGS concordance; however, genotyping of both blood and tumor may be required to detect all clinically actionable genomic alterations.

First-line regorafenib with nivolumab and chemotherapy in advanced oesophageal, gastric, or gastro-oesophageal junction cancer in the USA: a single-arm, single-centre, phase 2 trial.

BACKGROUND: The addition of nivolumab to chemotherapy improves survival in patients with advanced oesophagogastric (oesophageal, gastric, or gastro-oesophageal junction) adenocarcinoma; however, outcomes remain poor. We assessed the safety and activity of regorafenib in combination with nivolumab and chemotherapy in the first-line treatment of advanced oesophagogastric adenocarcinoma. METHODS: This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with previously untreated, HER2-negative, metastatic oesophagogastric adenocarcinoma was done at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients had measurable disease or non-measurable disease that was evaluable (defined by Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received FOLFOX chemotherapy (fluorouracil [400 mg/m2 bolus followed by 2400 mg/m2 over 48 h], leucovorin [400 mg/m2], and oxaliplatin [85 mg/m2]) and nivolumab (240 mg) intravenously on days 1 and 15, and oral regorafenib (80 mg) on days 1-21 of a 28-day cycle. Treatment was continued until disease progression (defined by RECIST version 1.1), unacceptable toxicity, or withdrawal of consent. The primary endpoint was 6-month progression-free survival in the per-protocol population (ie, all participants who received a dose of all study treatments). The regimen would be considered worthy of further investigation if at least 24 of 35 patients were progression free at 6 months. Safety was assessed in all participants who received at least one dose of any study treatment. This trial is registered with ClinicalTrials.gov, NCT04757363, and is now complete. FINDINGS: Between Feb 11, 2021, and May 4, 2022, 39 patients were enrolled, received at least one dose of study drug, and were included in safety analyses. 35 patients were evaluable for 6-month progression-free survival. Median age was 57 years (IQR 52-66), nine (26%) patients were women, 26 (74%) were men, 28 (80%) were White, and seven (20%) were Asian. At data cutoff (March 3, 2023), median follow-up was 18·1 months (IQR 12·7-20·4). The primary endpoint was reached, with 25 (71%; 95% CI 54-85) of 35 patients progression free at 6 months. Nine (26%) of 35 patients had disease progression and one (3%) patient died; the death was unrelated to treatment. The most common adverse event of any grade was fatigue (36 [92%] of 39). The most common grade 3 or 4 adverse events were decreased neutrophil count (18 [46%]), hypertension (six [15%]), dry skin, pruritus, or rash (five [13%]), and anaemia (four [10%]). Serious treatment-related adverse events occurred in ten (26%) patients, which were acute kidney injury (three [8%]), hepatotoxicity (two [5%]), sepsis (two [5%]), dry skin, pruritus, or rash (one [3%]), nausea (one [3%]), and gastric perforation (one [3%]). There were no treatment-related deaths. INTERPRETATION: Regorafenib can be safely combined with nivolumab and chemotherapy and showed promising activity in HER2-negative metastatic oesophagogastric cancer. A randomised, phase 3 clinical trial is planned. FUNDING: Bristol Myers Squibb, Bayer and National Institutes of Health/National Cancer Institute.

Clinical Utility of 18F-2-Fluoro-deoxy-d-glucose PET Imaging in Locally Advanced Esophageal/Gastroesophageal Junction Adenocarcinoma.

Esophageal adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, is uncommon in the United States, but is associated with a rising incidence in young adults, and has a traditionally poor prognosis. Despite the incremental benefits that have been made with multimodality approaches to locally advanced disease, most patients will go on to develop metastatic disease, and long-term outcomes remain suboptimal. Over the last decade, PET-CT has emerged as a key tool in the management of this disease, with several prospective and retrospective studies evaluating its role in this disease. Herein, we review the key data pertaining to the use of PET-CT in the management of locally advanced esophageal and GEJ adenocarcinoma, with a focus on staging, prognostication, PET-CT adapted therapy in the neoadjuvant setting, and surveillance.

Outcomes and a prognostic classifier in patients with microsatellite instability-high metastatic gastric cancer receiving PD-1 blockade.

BACKGROUND: Subgroup analyses of randomized trials suggest the superiority of immune checkpoint inhibitor-based therapy over chemotherapy in patients with mismatch-repair deficient (dMMR) and/or microsatellite instability-high (MSI-high) advanced gastric or gastroesophageal junction adenocarcinoma. However, these subgroups are small and studies examining prognostic features within dMMR/MSI-high patients are lacking. METHODS: We conducted an international cohort study at tertiary cancer centers and collected baseline clinicopathologic features of patients with dMMR/MSI-high metastatic or unresectable gastric cancer treated with anti-programmed cell death protein-1 (PD-1)-based therapies. The adjusted HRs of variables significantly associated with overall survival (OS) were used to develop a prognostic score. RESULTS: One hundred and thirty patients were included. At a median follow-up of 25.1 months, the median progression-free survival (PFS) was 30.3 months (95% CI: 20.4 to NA) and 2-year PFS rate was 56% (95% CI: 48% to 66%). Median OS was of 62.5 months (95% CI: 28.4 to NA) and 2-year OS rate was 63% (95% CI: 55% to 73%). Among the 103 Response Evaluation Criteria in Solid Tumors-evaluable patients, objective response rate was 66% and disease control rate 87% across lines of therapy. In the multivariable models, Eastern Cooperative Oncology Group Performance Status of 1 or 2, non-resected primary tumor, presence of bone metastases and malignant ascites were independently associated with poorer PFS and OS. These four clinical variables were used to build a three-category (ie, good, intermediate, and poor risk) prognostic score. Compared with patients with good risk, patients with intermediate risk score had numerically inferior PFS and OS (2-year PFS rate: 54.3% versus 74.5%, HR 1.90, 95% CI: 0.99 to 3.66; 2-year OS rate: 66.8% versus 81.2%, HR 1.86, 95% CI: 0.87 to 3.98), whereas patients with poor risk score had significantly inferior PFS and OS (2-year PFS rate: 10.6%, HR 9.65, 95% CI: 4.67 to 19.92; 2-year OS rate: 13.3%, HR 11.93, 95% CI: 5.42 to 26.23). CONCLUSIONS: Overall outcomes with anti-PD-1-based therapies are favorable in MSI-high gastroesophageal adenocarcinomas. However, within this overall favorable subgroup a more accurate prognostication using baseline clinical characteristics might identify patients at higher risk of rapid disease progression who may deserve intensified immunotherapy combination strategies.

Durvalumab and PET-Directed Chemoradiation in Locally Advanced Esophageal Adenocarcinoma: A Phase Ib/II Study.

OBJECTIVE: To determine the safety and efficacy of adding the anti-PD-L1 antibody durvalumab to induction FOLFOX and preoperative chemotherapy in locally advanced esophageal adenocarcinoma. BACKGROUND: Neoadjuvant induction FOLFOX followed by positron emission tomography (PET) directed chemoradiation has demonstrated improved survival for esophageal adenocarcinoma. There is clear benefit now for the addition of immune checkpoint inhibitors both in early and advanced stage disease. Given these results we investigated the safety and efficacy of adding durvalumab to induction FOLFOX and preoperative chemoradiotherapy. METHODS: Patients with locally advanced resectable esophageal/gastroesophageal junction adenocarcinoma received PET-directed chemoradiation with durvalumab before esophagectomy. Patients who had R0 resections received adjuvant durvalumab 1500 mg every 4 weeks for 6 treatments. The primary endpoint of the study was pathologic complete response. RESULTS: We enrolled 36 patients, 33 of whom completed all preoperative treatment and underwent surgery. Preoperative treatment was well tolerated, with no delays to surgery nor new safety signals. Pathologic complete response was identified in 8 [22% (1-sided 90% lower bound: 13.3%)] patients with major pathologic response in 22 [61% (1-sided 90% lower bound: 50%)] patients. Twelve and 24-month overall survival was 92% and 85%, respectively. CONCLUSIONS: The addition of durvalumab to induction FOLFOX and PET-directed chemoradiotherapy before surgery is safe, with a high rate of pathologic response, as well as encouraging survival data.

Targeting KRAS in Pancreatic Cancer.

Pancreatic cancer is mainly driven by mutations in the KRAS oncogene. While this cancer has shown remarkable therapy resistance, new approaches to inhibit mutated KRAS, KRAS activators and effectors show promise in breaking this therapeutic deadlock. Here, we review these innovations in therapies that target RAS signaling in pancreatic cancer from a clinical point of view. A number of promising approaches are currently in clinical trials or in clinical development. We focus on small-molecule drugs but also discuss immunotherapies and tumor vaccines.

Outcomes and Molecular Features of Brain Metastasis in Gastroesophageal Adenocarcinoma.

Importance: Brain metastasis (BrM) in gastroesophageal adenocarcinoma (GEA) is a rare and poorly understood phenomenon associated with poor prognosis. Objectives: To examine the clinical and genomic features of patients with BrM from GEA and evaluate factors associated with survival. Design, Setting, and Participants: In this single-institution retrospective cohort study, 68 patients with BrM from GEA diagnosed between January 1, 2008, and December 31, 2020, were identified via review of billing codes and imaging reports from the electronic medical record with follow-up through November 3, 2021. Genomic data were derived from the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets clinical sequencing platform. Exposures: Treatment with BrM resection and/or radiotherapy. Main Outcomes and Measures: Overall survival after BrM diagnosis. Results: Sixty-eight patients (median age at diagnosis, 57.4 years [IQR, 49.8-66.4 years]; 59 [86.8%] male; 55 [85.9%] White) participated in the study. A total of 57 (83.8%) had primary tumors in the distal esophagus or gastroesophageal junction. Median time from initial diagnosis to BrM diagnosis was 16.9 months (IQR, 8.5-27.7 months). Median survival from BrM diagnosis was 8.7 months (95% CI, 5.5-11.5 months). Overall survival was 35% (95% CI, 25%-48%) at 1 year and 24% (95% CI, 16%-37%) at 2 years. In a multivariable analysis, an Eastern Cooperative Oncology Group performance status of 2 or greater (hazard ratio [HR], 4.66; 95% CI, 1.47-14.70; P = .009) and lack of surgical or radiotherapeutic intervention (HR, 7.71; 95% CI, 2.01-29.60; P = .003) were associated with increased risk of all-cause mortality, whereas 3 or more extracranial sites of disease (HR, 1.85; 95% CI, 0.64-5.29; P = .25) and 4 or more BrMs (HR, 2.15; 95% CI, 0.93-4.98; P = .07) were not statistically significant. A total of 31 patients (45.6%) had ERBB2 (formerly HER2 or HER2/neu)-positive tumors, and alterations in ERBB2 were enriched in BrM relative to primary tumors (8 [47.1%] vs 7 [20.6%], P = .05), as were alterations in PTPRT (7 [41.2%] vs 4 [11.8%], P = .03). Conclusions and Relevance: This study suggests that that a notable proportion of patients with BrM from GEA achieve survival exceeding 1 and 2 years from BrM diagnosis, a more favorable prognosis than previously reported. Good performance status and treatment with combination surgery and radiotherapy were associated with the best outcomes. ERBB2 positivity and amplification as well as PTPRT alterations were enriched in BrM tissue compared with primary tumors; therefore, further study should be pursued to identify whether these variables represent genomic risk factors for BrM development.

Advanced Bile Duct Cancers: A Focused Review on Current and Emerging Systemic Treatments.

Cancers arising in the biliary tract are rare, with varied incidence depending on geographical location. As clinical presentation is typically vague with non-specific symptoms, a large proportion of patients present with unresectable or metastatic disease at diagnosis. When unresectable, the mainstay of treatment is cytotoxic chemotherapy; however, despite this, 5-year overall survival remains incredibly poor. Diagnostic molecular pathology, using next-generation sequencing, has identified a high prevalence of targetable alterations in bile duct cancers, which is transforming care. Substantial genomic heterogeneity has been identified depending on both the anatomical location and etiology of disease, with certain alterations enriched for subtypes. In addition, immune checkpoint inhibitors with anti-PD-1/PD-L1 antibodies in combination with chemotherapy are now poised to become the standard first-line treatment option in this disease. Here, we describe the established role of cytotoxic chemotherapy, targeted precision treatments and immunotherapy in what is a rapidly evolving treatment paradigm for advanced biliary tract cancer.

ATM Germline-Mutated Gastroesophageal Junction Adenocarcinomas: Clinical Descriptors, Molecular Characteristics, and Potential Therapeutic Implications.

BACKGROUND: Gastroesophageal junction (GEJ) adenocarcinoma is a rare cancer associated with poor prognosis. The genetic factors conferring predisposition to GEJ adenocarcinoma have yet to be identified. METHODS: We analyzed germline testing results from 23 381 cancer patients undergoing tumor-normal sequencing, of which 312 individuals had GEJ adenocarcinoma. Genomic profiles and clinico-pathologic features were analyzed for the GEJ adenocarcinomas. Silencing of ATM and ATR was performed using validated short-interfering RNA species in GEJ, esophageal, and gastric adenocarcinoma cell lines. All statistical tests were 2-sided. RESULTS: Pathogenic or likely pathogenic ATM variants were identified in 18 of 312 patients (5.8%), and bi-allelic inactivation of ATM through loss of heterozygosity of the wild-type allele was detected in all (16 of 16) samples with sufficient tumor content. Germline ATM-mutated GEJ adenocarcinomas largely lacked somatic mutations in TP53, were more likely to harbor MDM2 amplification, and harbored statistically significantly fewer somatic single nucleotide variants (2.0 mutations/Mb vs 7.9 mutations/Mb; P < .001). A statistically significantly higher proportion of germline ATM-mutated than ATM-wild-type GEJ adenocarcinoma patients underwent a curative resection (10 [100%] vs 92 [86.8%], P = .04; Fisher's exact test.), A synthetic lethal interaction between short-interfering RNA silencing of ATM and ATR was observed in the models analyzed. CONCLUSIONS: Our results indicate that germline pathogenic variants in ATM drive oncogenesis in GEJ adenocarcinoma and might result in a distinct clinical phenotype. Given the high prevalence of germline ATM-mutated GEJ adenocarcinomas, genetic testing for individuals with GEJ adenocarcinomas may be considered to better inform prognostication, treatment decisions, and future cancer risk.

Early infection is an independent risk factor for increased mortality in patients with culture-confirmed infected pancreatic necrosis.

BACKGROUND: Mortality in infected pancreatic necrosis (IPN) is dynamic over the course of the disease, with type and timing of interventions as well as persistent organ failure being key determinants. The timing of infection onset and how it pertains to mortality is not well defined. OBJECTIVES: To determine the association between mortality and the development of early IPN. METHODS: International multicenter retrospective cohort study of patients with IPN, confirmed by a positive microbial culture from (peri) pancreatic collections. The association between timing of infection onset, timing of interventions and mortality were assessed using Cox regression analyses. RESULTS: A total of 743 patients from 19 centers across 3 continents with culture-confirmed IPN from 2000 to 2016 were evaluated, mortality rate was 20.9% (155/734). Early infection was associated with a higher mortality, when early infection occurred within the first 4 weeks from presentation with acute pancreatitis. After adjusting for comorbidity, advanced age, organ failure, enteral nutrition and parenteral nutrition, early infection (≤4 weeks) and early open surgery (≤4 weeks) were associated with increased mortality [HR: 2.45 (95% CI: 1.63-3.67), p < 0.001 and HR: 4.88 (95% CI: 1.70-13.98), p = 0.003, respectively]. There was no association between late open surgery, early or late minimally invasive surgery, early or late percutaneous drainage with mortality (p > 0.05). CONCLUSION: Early infection was associated with increased mortality, independent of interventions. Early surgery remains a strong predictor of excess mortality.