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The benefit of radiation therapy for pancreatic ductal adenocarcinoma (PDAC) remains unclear. We hypothesized that a new mechanistic mathematical model of chemotherapy and radiation response could predict clinical outcomes a priori, using a previously described baseline measurement of perfusion from computed tomography scans, normalized area under the enhancement curve (nAUC).We simplified an existing mass transport model that predicted cancer cell death by replacing previously unknown variables with averaged direct measurements from randomly selected pathologic sections of untreated PDAC. This allowed using nAUC as the sole model input to approximate tumor perfusion. We then compared the predicted cancer cell death to the actual cell death measured from corresponding resected tumors treated with neoadjuvant chemoradiation in a calibration cohort (n = 80) and prospective cohort (n = 25). After calibration, we applied the model to 2 separate cohorts for pathologic and clinical associations: targeted therapy cohort (n = 101), cetuximab/bevacizumab + radiosensitizing chemotherapy, and standard chemoradiation cohort (n = 81), radiosensitizing chemotherapy to 50.4 Gy in 28 fractions.We established the relationship between pretreatment computed v nAUC to pathologically verified blood volume fraction of the tumor (r = 0.65; P = .009) and fractional tumor cell death (r = 0.97-0.99; P.0001) in the calibration and prospective cohorts. On multivariate analyses, accounting for traditional covariates, nAUC independently associated with overall survival in all cohorts (mean hazard ratios, 0.14-0.31). Receiver operator characteristic analyses revealed discrimination of good and bad prognostic groups in the cohorts with area under the curve values of 0.64 to 0.71.This work presents a new mathematical modeling approach to predict clinical response from chemotherapy and radiation for PDAC. Our findings indicate that oxygen/drug diffusion strongly influences clinical responses and that nAUC is a potential tool to select patients with PDAC for radiation therapy.

Background Immune checkpoint blockade (ICB) has improved outcomes for patients with microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) tumors. However, not all MSI-H/dMMR patients will exhibit the same ICB efficacy. Previous studies suggest that concomitant antibiotic use while receiving ICB may result in poorer outcomes. We aimed to evaluate this association in patients with MSI-H/dMMR metastatic colorectal cancer (mCRC). Materials and Methods A single-site, retrospective review of 57 patients with MSI-H/dMMR mCRC that received ICB was completed. Data collected included patient demographics, ICB information, and antibiotic use. Antibiotic exposure was considered from 90 days prior to ICB through 6 weeks after initiation. Primary endpoint was overall response rate (ORR). Results The majority of patients received pembrolizumab (27 [47%]) or nivolumab (17 [30%]) monotherapy as their ICB agent. Of the 57 patients, 19 (33.3%) had antibiotic exposure from 90 days prior to ICB initiation through 6 weeks after initiation with most (13 [68%]) having antibiotic use in the 30 days preceding ICB initiation. Similar ORRs were seen in both groups (P-value > .99). No difference was observed in OS (P-value .29) or PFS (P-value .36) between groups. Conclusion Our data show no association of lower response rates or survival in those MSI-H/dMMR patients with mCRC who receive antibiotics around the initiation of ICB. This information needs to be confirmed in a larger prospective cohort.

Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC (NCT03214250). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.

Background: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma. Methods: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed. Findings: Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3–4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47–not estimable [NE]) with nivolumab and 19·53 months (2·33–NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31–2·54); median time to progression was 9·4 months (95% CI 1·47–NE) in the nivolumab group and 19·53 months (2·33–NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31–2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. Interpretation: Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma. Funding: Bristol Myers Squibb and the US National Institutes of Health.

Hepatocellular carcinoma (HCC) has limited systemic therapy options when discovered at an advanced stage. Thus, there is a need for accessible and minimally invasive biomarkers of response to guide the selection of patients for treatment. This study investigated the biomarker value of plasma growth hormone (GH) level as a potential biomarker to predict outcome in unresectable HCC patients treated with current standard therapy, atezolizumab plus bevacizumab (Atezo/Bev).Study included unresectable HCC patients scheduled to receive Atezo/Bev. Patients were followed to determine progression-free survival (PFS) and overall survival (OS). Plasma GH levels were measured by ELISA and used to stratify the HCC patients into GH-high and GH-low groups (the cutoff normal GH levels in women and men are ≤3.7 μg/L and ≤0.9 μg/L, respectively). Kaplan-Meier method was used to calculate median OS and PFS and Log rank test was used to compare survival outcomes between GH-high and -low groups.Thirty-seven patients were included in this analysis, of whom 31 were males and 6 females, with a median age of 67 years (range: 37-80). At the time of the analysis, the one-year survival rate was 70% (95% CI: 0.51, 0.96) among GH low patients and 33% (95% CI: 0.16, 0.67) among GH high patients. OS was significantly superior in GH-low compared to GH-high patients (median OS: 18.9 vs. 9.3 months;Plasma GH is a biomarker candidate for predicting treatment outcomes in advanced HCC patients treated with Atezo/Bev. This finding should be further validated in larger randomized clinical trials in advanced HCC patients.

Recent studies defined a potentially important role of the microbiome in modulating pancreatic ductal adenocarcinoma (PDAC) and responses to therapies. We hypothesized that antibiotic usage may predict outcomes in patients with PDAC. We retrospectively analyzed clinical data of patients with resectable or metastatic PDAC seen at MD Anderson Cancer from 2003 to 2017. Demographic, chemotherapy regimen and antibiotic use, duration, type, and reason for indication were recorded. A total of 580 patients with PDAC were studied, 342 resected and 238 metastatic patients, selected retrospectively from our database. Antibiotic use, for longer than 48 hrs, was detected in 209 resected patients (61%) and 195 metastatic ones (62%). On resectable patients, we did not find differences in overall survival (OS) or progression‐free survival (PFS), based on antibiotic intake. However, in the metastatic cohort, antibiotic consumption was associated with a significantly longer OS (13.3 months vs. 9.0 months, HR 0.48, 95% CI 0.34–0.7, p = 0.0001) and PFS (4.4 months vs. 2 months, HR 0.48, 95% CI 0.34–0.68, p =, We have analyzed the effect of antibiotics’ intake on two cohorts of patients with pancreatic adenocarcinoma, resectable, and metastatic. We have found that on the metastatic cohort, antibiotics use was significantly associated with better outcomes, particularly, on patients that received gemcitabine based‐chemotherapy as the first line.

ObjectivesTumor size measurement is critical for accurate tumor staging in patients with pancreatic ductal adenocarcinoma (PDAC). However, accurate tumor size measurement is challenging in patients who received neoadjuvant therapy before resection, due to treatment-induced fibrosis and tumor invasion beyond the grossly identified tumor area. In this study, we evaluated the correlation between the tumor size and tumor volume measured on post-therapy computed tomography (CT) scans and the pathological measurement. Also, we investigated the correlation between these measurements and clinicopathological parameters and survival.Materials and methodsRetrospectively, we evaluated 343 patients with PDAC who received neoadjuvant therapy, followed by pancreaticoduodenectomy and had pre-operative pancreatic protocol CT imaging. We measured the longest tumor diameter (RadL) and the radiological tumor volume (RadV) on the post-therapy CT scan, then we categorized RadL into four radiologic tumor stages (RTS) based on the current AJCC staging (8th edition) protocol and RadV based on the median. Pearson correlation or Spearman's coefficient (δ), T-test and ANOVA was used to test the correlation between the radiological and pathological measurement. Chi-square analysis was used to test the correlation with the tumor pathological response, lymph-node metastasis and margin status and Kaplan-Meier and Cox-proportional hazard for survival analysis. P-value < 0.05 was considered significant.ResultsAs a continuous variable, RadL showed a positive linear correlation with the post-therapy pathologic tumor size in the overall patient population (Pearson correlation coefficient: 0.72, P&nbsp

Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regressions by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from 35 PDAC patient tumors. This identified a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1) as a putative TAA demonstrating overexpression in multiple tumor types and low or absent expression in essential normal tissues. Here we show that VGLL1-specific CTLs expanded from the blood of a PDAC patient could recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also bladder, ovarian, gastric, lung, and basal-like breast cancers. Gene expression profiling reveals VGLL1 as a member of a unique group of cancer-placenta antigens (CPA) that may constitute immunotherapeutic targets for patients with multiple cancer types., Cytotoxic T lymphocyte (CTL)-based immunotherapies can induce tumor regressions by targeting HLA class I-bound tumor-associated peptides. Here, the authors identified a peptide derived from Vestigial-like 1 (VGLL1) as a shared, potentially therapeutic CTL target expressed by multiple cancer types.

Metastatic squamous cell carcinoma anal cancer (SCCA) is rare. Prospective data recommends front-line platinum doublet combinations and second-line anti-programmed death-1 therapy. Standard therapy beyond these treatments are currently unknown. We evaluated anti-EGFR monoclonal antibody (mAb) outcomes in metastatic SCCA.Metastatic SCCA patients given anti-EGFR mAb from Oct 2011-May 2018 were included. Primary endpoints included best response, progression-free survival, and overall survival.56 patients were evaluated with a median of one prior therapy. Most patients (~90%) received anti-EGFR mAbs with chemotherapy. Response rate (any response) was 41%. Median PFS was 4.3 months with a median OS of 16 M. Seven patients with disease control proceeded onto maintenance therapy (anti-EGFR mAb ± a fluoropyrimidine) with a median PFS of 13.8 M. Next generation sequencing of 16 pts (28%) showed 4 pts had a PIK3CA mutation with 3 of these 4 patients demonstrating progression on initial restaging.Our analysis suggests anti-EGFR mAb therapy with chemotherapy provides clinical benefit in previously treated metastatic SCCA. Our maintenance therapy and the role of PIK3CA MT outcomes were thought-provoking.Metastatic SCCA patients have limited options; therefore, anti-EGFR mAbs may provide benefit in the treatment armamentarium and should be further explored.

Background Gemcitabine (GEM) plus nab‐paclitaxel (NabP) (GEM 1000 mg/m2 IV over 30 minutes + NabP 125 mg/m2 IV given days 1, 8, and 15 every 28 days) is one of the two standard of care combination therapies for metastatic pancreatic ductal adenocarcinoma (PDAC). Our cancer center has utilized GEM‐NabP given every two‐weeks due to tolerability and patient convenience. Here, we review the safety and efficacy of this modified regimen. Methods Metastatic PDAC patients (pts) who initiated front‐line or second‐line GEM‐NabP during 2013‐2017 were retrospectively reviewed. Primary objective was overall survival. Secondary objectives were disease control rate, progression‐free survival, and the incidence of dose delays and/or adjustments. Results From a total of 235 patients, 140 pts received GEM‐NabP front‐line while 95 pts received GEM‐NabP second‐line. Median dosing was 600 mg/m2 at fixed‐dose rate for GEM and 125 mg/m2 for NabP given predominantly (~90%) every two‐weeks. Eastern Cooperative Group performance status of 0 and 1 pts had front‐line OS of 12.7 and 9.6 months and when given second‐line had OS of 8 months and 7.3 months, respectively. ECOG 0 and 1 pts had front‐line progression‐free survival (PFS) of 5.3 months and 2.8 months and second‐line PFS was 3.5 months and 2.4 months, respectively. Treatment was well tolerated with limited dose modifications. Conclusion Our analysis revealed safety with every two‐week low dose GEM‐NabP while maintaining efficacy. Patient schedule convenience should factor into metastatic incurable malignancies. We suggest the use of every two‐week GEM‐NabP particularly in patients desiring a modified schedule., Our real‐world data, outside the context of a clinical trial, suggests that every two‐week Gem‐NabP can be administered safely without compromising efficacy in patients with metastatic pancreatic adenocarcinoma (PDAC). In particular, the alternate (bi‐weekly) dosing regimen showed low rates of grades 3 and 4 toxicities and no treatment‐related deaths. This regimen is better tolerated than weekly Gem‐NabP, is convenient, and allows similar palliative benefits to patients with metastatic PDAC.

The outbreak of coronavirus disease 2019 (COVID‐19) has rapidly spread globally since being identified as a public health emergency of major international concern and has now been declared a pandemic by the World Health Organization (WHO). In December 2019, an outbreak of atypical pneumonia, known as COVID‐19, was identified in Wuhan, China. The newly identified zoonotic coronavirus, severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), is characterized by rapid human‐to‐human transmission. Many cancer patients frequently visit the hospital for treatment and disease surveillance. They may be immunocompromised due to the underlying malignancy or anticancer therapy and are at higher risk of developing infections. Several factors increase the risk of infection, and cancer patients commonly have multiple risk factors. Cancer patients appear to have an estimated twofold increased risk of contracting SARS‐CoV‐2 than the general population. With the WHO declaring the novel coronavirus outbreak a pandemic, there is an urgent need to address the impact of such a pandemic on cancer patients. This include changes to resource allocation, clinical care, and the consent process during a pandemic. Currently and due to limited data, there are no international guidelines to address the management of cancer patients in any infectious pandemic. In this review, the potential challenges associated with managing cancer patients during the COVID‐19 infection pandemic will be addressed, with suggestions of some practical approaches. Implications for Practice The main management strategies for treating cancer patients during the COVID‐19 epidemic include clear communication and education about hand hygiene, infection control measures, high‐risk exposure, and the signs and symptoms of COVID‐19. Consideration of risk and benefit for active intervention in the cancer population must be individualized. Postponing elective surgery or adjuvant chemotherapy for cancer patients with low risk of progression should be considered on a case‐by‐case basis. Minimizing outpatient visits can help to mitigate exposure and possible further transmission. Telemedicine may be used to support patients to minimize number of visits and risk of exposure. More research is needed to better understand SARS‐CoV‐2 virology and epidemiology., Cancer patients have an increased risk of contracting COVID‐19. This article addresses the challenges associated with managing cancer patients during the COVID‐19 infection pandemic and suggests some practical approaches.

Effective consolidative chemoradiation (CRT) regimens are lacking. In this phase 1 trial, we evaluated the safety and efficacy of nab-paclitaxel, capecitabine, and radiation therapy after induction chemotherapy in patients with locally advanced and borderline-resectable pancreatic cancer (LAPC and BRPC). Also, we evaluated a computed tomography (CT)-based biomarker of response.Eligible patients had pathologically confirmed pancreatic ductal adenocarcinoma, underwent computed tomography-imaging, received a diagnosis of LAPC or BRPC, and received induction chemotherapy. Standard 3 + 3 study design was used, with 3 escalating nab-paclitaxel dose levels (50, 75, and 100 mg/mTwenty-three patients started and finished on protocol (LAPC = 14, BRPC = 9). No grade 3 and 4 toxicities were reported in level 1 (n = 3) or level 2 (n = 3) initial groups. Two patients in the initial level 3 group developed dose limiting toxicity, establishing level 2 dose as the maximal tolerated dose. Level 2 group was expanded for additional 15 patients (for a total of 23 on trial), 5 of whom developed grade 3 toxicities. Seven patients underwent surgical resection. Median OS and PFS were 21.2 and 8.1 months, respectively. Type I IR was associated with better OS (P = .004) and PFS (P = .03) compared with type II IR.We established the maximum tolerated dose for nab-paclitaxel in a consolidative CRT regimen for pancreatic ductal adenocarcinoma. Preliminary efficacy results warrant phase 2 trial evaluation. IR may be used for personalized treatment.

Introduction Squamous cell carcinoma of the anal canal (SCCA) presents rising incidence in the US. Standard of care for locally advanced disease is comprised of infusional 5FU plus mitomycin C or cisplatin concurrent with radiation therapy (RT). We designed this trial to evaluate the efficacy and safety of a more convenient regimen composed of capecitabine and oxaliplatin. Methods Single-arm, phase II trial, with treatment-naive stage II-IIIB (T X,1-4 N x M 0 ) SCCA patients. The regimen was composed of capecitabine (825 mg/m 2 BID, 5d) and oxaliplatin (50 mg/m 2 weekly) during weeks 1-6, concurrent with RT (XELOX-XRT) (Group 1). After the first 11 patients, the study was amended to omit chemotherapy during the 3 rd and 6 th weeks (Group 2). The primary objective was 3-year time-to-treatment-failure (TTF) and safety. Secondary objectives were complete response (CR) rate, locoregional control (LRC), colostomy-free survival (CFS), and overall survival (OS). Results Twenty patients were enrolled. Seven patients of group 1 (63%) developed grade 3 toxicity, which reduced to 22% in group 2. No grade 4 toxicities were noted. The median RT dose was 55 Gy. CR occurred in 100% of the 19 patients evaluable for response at 12-14 weeks. After median follow-up of 47.6 months, two patients had local recurrence and one had distant. 3-year TTF was 90.0%, with similar rates between group 1 and 2, respectively (90.9% versus 88.8%, p: 0.984). 3-year CFS was 90.0%. The median OS has not been reached. Conclusions The XELOX-XRT regimen is safe, with promising efficacy, and should be explored in larger trials in for the treatment of locally advanced SCCA.

Purpose: VEGF receptor-2 (VEGFR-2)–mediated angiogenesis contributes to pathogenesis of biliary tract cancers (BTC). We investigated ramucirumab, a mAb targeting VEGFR-2 for treatment of advanced, chemorefractory BTC. Patients and Methods: This is a phase II, single-arm trial for advanced, unresectable, pre-treated patients with BTC with ECOG 0/1, adequate liver, renal, and marrow functions. Ramucirumab was administered at 8 mg/kg, 2 weekly with restaging performed 8 weekly. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Exploratory endpoints included correlation of tumor mutational status with PFS and OS. Results: 61 patients were enrolled: the median age was 58.5 years; 59 with stage IV disease; 62%, intrahepatic cholangiocarcinoma; 22%, gallbladder cancer; and 16%, extrahepatic cholangiocarcinoma. All received prior chemotherapy: 52% had 1 prior, and rest ≥2 prior lines. Median treatment duration was 10.1 weeks (range, 2.1–86). Median PFS was 3.2 months [95% confidence interval (CI), 2.1–4.8]; median OS, 9.5 months (95% CI, 5.8–13.6). One (1.7%) patient achieved partial response; 26 (43.3%), stable disease; and 25 (41.7%), disease progression; DCR, 45%. Median 6-month PFS and OS rates were 32% (95% CI, 0.22–0.46) and 58% (95% CI, 0.47–0.72). The majority of toxicities were grade 1 or 2; grade 3 proteinuria (1, 2%), hypertension (13, 22%), and pulmonary embolism (1, 2%), and grade 4 gastrointestinal bleeding (1, 2%) occurred. Conclusions: Ramucirumab was well tolerated and resulted in PFS similar to that achieved with other chemotherapy regimens used historically for chemorefractory BTC.

ImportanceThe potential relationship between obesity and colorectal cancer (CRC) outcome is poorly understood in patients with late-stage disease. Increased body mass index may negate aspirin use for cancer prevention, but its role as a factor on the effectiveness of postdiagnosis aspirin use is unclear.ObjectiveTo evaluate how prediagnosis obesity and postdiagnosis aspirin use may be associated with overall survival in patients with late-stage colorectal cancer.Design, Setting, and ParticipantsThis cross-sectional study used self-reported data from patients with metastatic or treatment-refractory disease who consented to a clinical protocol at MD Anderson Cancer Center, a large US cancer treatment center. Patients were enrolled between 2010 and 2018 and followed up for mortality through July 2020. Analyses were conducted through March 2022.ExposuresBody mass index in the decade prior to initial diagnosis and regular aspirin use at survey completion.Main Outcomes and MeasuresOverall survival was measured from stage IV diagnosis until death or last follow-up. Cox proportional hazards models were constructed to estimate associations of prediagnosis obesity and postdiagnosis aspirin use with overall survival.ResultsOf 656 patients included in this analysis, 280 (42.7%) were women, 135 (20.6%) were diagnosed with CRC before age 45 years, 414 (63.1%) were diagnosed between ages 45 and 65 years, and 107 (16.3%) were diagnosed at 65 years or older; 105 patients (16.0%) were Black or Hispanic, and 501 (76.4%) were non-Hispanic White. Controlling for age, sex, race, stage at initial diagnosis, and weight change between prediagnosis and survey date, patients with obesity in the decade prior to CRC diagnosis had significantly higher likelihood of death (hazard ratio, 1.45; 95% CI, 1.11-1.91) compared with those with normal prediagnosis body mass index. Furthermore, only patients with normal prediagnosis body mass index experienced significant survival benefit with postdiagnosis aspirin use (hazard ratio, 0.59; 95% CI, 0.39-0.90).Conclusions and RelevanceIn this cross-sectional study, our findings suggest potentially differential tumor development in the long-term physiologic host environment of obesity. Confirmation and further evaluation are needed to determine whether prediagnosis body mass index may be used to estimate the benefit from postdiagnosis aspirin use.

BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with unpredictable responses to chemotherapy. Approaches to assay patient tumors before treatment and identify effective treatment regimens based on tumor sensitivities are lacking. We developed an organoid-based platform (OBP) to visually quantify patient-derived organoid (PDO) responses to drug treatments and associated tumor-stroma modulation for personalized PDAC therapy.METHODSWe retrospectively quantified apoptotic responses and tumor-stroma cell proportions in PDOs via 3D immunofluorescence imaging through annexin A5, α-smooth muscle actin (α-SMA), and cytokeratin 19 (CK-19) levels. Simultaneously, an ex vivo organoid drug sensitivity assay (ODSA) was used to measure responses to standard-of-care regimens. Differences between ODSA results and patient tumor responses were assessed by exact McNemar's test.RESULTSImmunofluorescence signals, organoid growth curves, and Ki-67 levels were measured and authenticated through the OBP for up to 14 days. ODSA drug responses were not different from patient tumor responses, as reflected by CA19-9 reductions following neoadjuvant chemotherapy (P = 0.99). PDOs demonstrated unique apoptotic and tumor-stroma modulation profiles (P0.0001). α-SMA/CK-19 ratio levels of more than 1.0 were associated with improved outcomes (P = 0.0179) and longer parental patient survival by Kaplan-Meier analysis (P = 0.0046).CONCLUSIONHeterogenous apoptotic drug responses and tumor-stroma modulation are present in PDOs after standard-of-care chemotherapy. Ratios of α-SMA and CK-19 levels in PDOs are associated with patient survival, and the OBP could aid in the selection of personalized therapies to improve the efficacy of systemic therapy in patients with PDAC.FUNDINGNIH/National Cancer Institute grants (K08CA218690, P01 CA117969, R50 CA243707-01A1, U54CA224065), the Skip Viragh Foundation, the Bettie Willerson Driver Cancer Research Fund, and a Cancer Center Support Grant for the Flow Cytometry and Cellular Imaging Core Facility (P30CA16672).

PURPOSE: The primary aim of this study was to determine the attitudes and beliefs of hematology and medical oncology (HMO) fellows regarding palliative care (PC) after they completed a 4-week mandatory PC rotation. METHODS: The PC rotation included a 4-week standardized curriculum covering all PC domains. HMO fellows were provided educational materials and attended all didactic sessions. All had clinical rotation in an acute PC unit and an outpatient clinic. All HMO fellows from 2004 to 2017 were asked to complete a 32-item survey on oncology trainee perception of PC. RESULTS: Of 105 HMO fellows, 77 (73%) completed the survey. HMO fellows reported that PC rotation improved assessment and management of symptoms (98%); opioid prescription (89%), opioid rotation (78%), and identification of opioid adverse effects (87%); communication with patients and families (91%), including advance care planning discussion (88%) and do-not-resuscitate discussion (88%); and they reported comfort with discussing ethical issues (74%). Participants reported improvement in knowledge of symptom assessment and management (n = 76; 98%) as compared with efficacy in ethics (n = 57 [74%]; P = .0001) and for coping with stress of terminal illness (n = 45 [58%]; P = .0001). The PC rotation educational experience was considered either far better or better (53%) or the same (45%) as other oncology rotations. Most respondents (98%) would recommend PC rotations to other HMO fellows, and 95% felt rotation should be mandatory. CONCLUSION: HMO fellows reported PC rotation improved their attitudes and knowledge in all PC domains. PC rotation was considered better than other oncology rotations and should be mandatory.

Objectives Epithelial-mesenchymal transition (EMT) plays an important role in the progression, metastasis, and chemoresistance of pancreatic duct adenocarcinoma (PDAC); however, the expression of EMT markers and their clinical significance in PDAC patients who received neoadjuvant therapy (NAT) are unclear. Methods We examined the expression of EMT markers, including Zeb-1 (zinc finger E-box-binding homeobox 1), E-cadherin, and vimentin by immunohistochemistry in 120 PDAC patients who received NAT and pancreatectomy from 1999 to 2007. The results were correlated with clinicopathologic parameters and survival. Results Among 120 cases, 45 (37.5%) and 14 (11.7%) were positive for Zeb-1 and vimentin, respectively, and 25 (20.8%) were E-cadherin-low. The median overall survival and disease-free survival were 35.3 (standard deviation [SD], 2.8) and 15.9 (SD, 3.6) months, respectively, in vimentin-negative group compared with 16.1 (SD, 1.1) (P = 0.03) and 7.0 (SD, 1.1) months (P = 0.02) in the vimentin-positive group. In multivariate analysis, vimentin expression was an independent predictor of shorter disease-free survival (hazard ratio, 2.50; 95% confidence interval, 1.31-4.78; P = 0.016) and overall survival (hazard ratio, 2.55; 95% confidence interval, 1.33-4.89; P = 0.01). Conclusions Epithelial-mesenchymal transition markers are frequently expressed in treated PDAC. Vimentin expression is a prognostic biomarker for survival in PDAC patients who received NAT.

BACKGROUND: There is considerable interest in a neoadjuvant approach for resectable pancreatic ductal adenocarcinoma (PDAC). This study evaluated perioperative gemcitabine + erlotinib (G+E) for resectable PDAC. METHODS: A multicenter, cooperative group, single-arm phase II trial was conducted between April 2009 and November 2013 (ACOSOG Z5041). Patients with biopsy-confirmed PDAC in the pancreatic head without evidence of involvement of major mesenteric vessels (resectable) were eligible. Patients (n=123) received an eight-week cycle of G+E before and after surgery. The primary endpoint was two-year overall survival (OS), and secondary endpoints included toxicity, response, resection rate, and time to progression. Resectability was assessed retrospectively by central review. The study closed early due to slow accrual; no formal hypothesis testing was performed. RESULTS: One hundred fourteen patients were eligible, consented, and initiated protocol treatment. By central radiologic review, 97 (85%) of the 114 patients met protocol resectability criteria. Grade 3+ toxicity was reported in 60% and 79% of patients during the neoadjuvant phase and overall, respectively. Twenty-two of 114 (19%) patients did not proceed to surgery, 83 patients (73%) were successfully resected. R0 and R1 margins were obtained in 67 (81%) and 16 (19%) resected patients, respectively. Fifty-four patients completed postoperative G+E (65%). The two-year OS rate for the entire cohort (n=114) was 40% (95%CI 31–50) with a median OS of 21.3 months (95%CI 17.2–25.9). The two-year OS for resected patients (n=83) was 52% (95%CI 41–63) with a median OS of 25.4 months (95%CI 21.8–29.6). CONCLUSIONS: For resectable PDAC, perioperative G+E is feasible. Further evaluation of neoadjuvant strategies in resectable PDAC is warranted with more active systemic regimens.

OBJECTIVE: We sought to identify potential radiologic and serologic markers of pancreatic tumor response to therapy, using pathologic major response (pMR) as the objective endpoint. BACKGROUND: We previously demonstrated that a pMR to preoperative therapy, defined as detection of

BackgroundMonotherapy with immune checkpoint blockade is ineffective for patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). This study investigates whether the combination of trametinib (T) with durvalumab (D) can alter the immune tumor microenvironment (TME) by successfully priming and activating T-cells.MethodsOpen-label, single-center, phase II trial with primary endpoint of immune-related response rate for combination of T+D in refractory MSS mCRC pts (NCT03428126). T is 2 mg/day orally starting 1 week prior to D, which is given 1500 mg intravenously every 4 weeks. Simon 2-stage design used to enroll 29 pts into first stage, requiring a response in two or more pts to proceed to stage 2. Tumor biopsies were collected at baseline (BL) and early on-treatment (OT) at week 4.ResultsTwenty nine treated pts include 48% females, median age 48 years (range 28–75), and median prior therapies 2 (range 1–5). No grade (G) 4 or 5 treatment-related adverse events (TRAE). The most common TRAE of any grade was acneiform rash, 17% being G3. One of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an overall response rate of 3.4%. Seven pts had stable disease (SD) and five pts (1 PR, 4 SD) demonstrated decrease in total carcinoembryonic antigen ng/mL (best percentage reduction: 94%, 95%, 42%, 34%, and 22%, respectively). Median progression-free survival was 3.2 mo (range 1.1–9.3 months). Three pts with both liver and lung metastases demonstrated discrepant responses in which clinical benefit was present in the lung metastases but not liver metastases. Comparison of BL and 4-week OT tumor tissue flow cytometry demonstrated no changes in T-cell infiltration but upregulation expression of PD-1 and Tim3 on CD8 T cells. However, expression of PD-1 and Tim3 as single markers and as coexpressed markers was observed to increase OT relative to BL (p=0.03, p=0.06 and p=0.06, respectively).ConclusionsT+D demonstrated acceptable tolerability in pts with refractory MSS mCRC. The response rate in the first stage of the study did not meet efficacy criteria to proceed to the second stage. Specific site of metastatic disease may impact outcomes in novel immunotherapy combination trials.Trial registration numberNCT03428126.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with variable presentations and natural histories of disease. We hypothesized that different morphologic characteristics of PDAC tumors on diagnostic computed tomography (CT) scans would reflect their underlying biology. Experimental Design: We developed a quantitative method to categorize the PDAC morphology on pretherapy CT scans from multiple datasets of patients with resectable and metastatic disease and correlated these patterns with clinical/pathologic measurements. We modeled macroscopic lesion growth computationally to test the effects of stroma on morphologic patterns, hypothesizing that the balance of proliferation and local migration rates of the cancer cells would determine tumor morphology. Results: In localized and metastatic PDAC, quantifying the change in enhancement on CT scans at the interface between tumor and parenchyma (delta) demonstrated that patients with conspicuous (high-delta) tumors had significantly less stroma, higher likelihood of multiple common pathway mutations, more mesenchymal features, higher likelihood of early distant metastasis, and shorter survival times compared with those with inconspicuous (low-delta) tumors. Pathologic measurements of stromal and mesenchymal features of the tumors supported the mathematical model's underlying theory for PDAC growth. Conclusions: At baseline diagnosis, a visually striking and quantifiable CT imaging feature reflects the molecular and pathological heterogeneity of PDAC, and may be used to stratify patients into distinct subtypes. Moreover, growth patterns of PDAC may be described using physical principles, enabling new insights into diagnosis and treatment of this deadly disease.

Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients’ advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.

BackgroundGlucose-regulated protein 78 (GRP78) plays an essential role in protein folding, transportation, and degradation, thus regulates ER homeostasis and promotes cell survival, proliferation and invasion. GRP78 expression in PDAC patients who received neoadjuvant therapy has not been reported.MethodsThis retrospective study of resected PDAC patients included 125 patients treated with neoadjuvant therapy (NAT) and 140 patients treated with surgery first (SF). The expression of GRP78 was evaluated by immunohistochemistry on tissue microarrays and the results were correlated with clinicopathologic parameters and survival.ResultsGRP78 expression was higher in SF patients compared to NAT patients (P&nbsp

IMPORTANCE: The subtype of pancreatic ductal adenocarcinoma cancer (PDAC) with DNA damage repair (DDR) deficiency from BRCA1/2 variants has a favorable prognosis and is sensitive to platinum analogues and poly–(adenosine diphosphate–ripose) polymerase (PARP) inhibition with olaparib. Approximately 10% to 20% of patients with PDAC have DDR genetic alterations other than germline BRCA variants. This population has been termed as having BRCAness. An opportunity exists to define the clinical phenotype, molecular underpinnings, and effectiveness of PARP inhibitors for this population. OBJECTIVE: To examine the therapeutic effectiveness of the PARP inhibitor olaparib for patients with pancreatic cancer with BRCAness. DESIGN, SETTING, AND PARTICIPANTS: Two parallel phase 2 nonrandomized clinical trials were conducted from November 11, 2016, to October 2, 2018, among 46 patients in Israel and Texas to determine the effectiveness of olaparib as monotherapy in advanced, previously treated PDAC with BRCAness. Inclusion criteria were treatment with 1 or more prior systemic therapies for advanced PDAC, Eastern Cooperative Oncology Group performance status of 0 to 1, and lack of the germline BRCA1/2 variant. BRCAness in these studies was defined as previously known DDR genetic alterations (DDR-GAs), personal or family history of BRCA-associated cancers (without DDR-GAs), or ATM protein loss as determined by immunohistochemistry. MAIN OUTCOMES AND MEASURES: The primary study end point was the objective response rate, and the secondary end points were progression-free survival and overall survival (OS). RESULTS: Forty-eight patients were enrolled, and 46 (26 women [57%]; mean [SD] age, 65.5 [11.1] years) were evaluable. The median treatment duration with olaparib was 3.0 months (interquartile range, 1.8-6.4 months). A total of 24 patients had the DDR phenotype (DDR-GAs), 17 had a family history of BRCA-associated cancers without DDR-GAs, and 5 had ATM loss as determined by immunohistochemistry. The DDR-GAs included ATM (n = 14), PALB2 (n = 2), ARID1A (n = 3), BRCA somatic (n = 1), PTEN (n = 1), RAD51 (n = 1), CCNE (n = 1), and FANCB (n = 2). Common toxic effects were grade 1 to 2 anemia, fatigue, anorexia, and nausea. One patient had a confirmed partial response (2%), 33 patients experienced stable disease (72%), of whom 11 (24%) experienced disease stability longer than 4 months and 12 patients had progressive disease (26%). The response duration for the patient with confirmed partial response was 3.9 months. Median progression-free survival was 3.7 months (95% CI, 2.9-5.7) and was significantly higher for patients with DDR-GAs (5.7 months; 95% CI, 3.6-8.8 months; P = .008) and platinum-sensitive PDAC (4.1 months; 95% CI, 3.6-7.8 months; P = .01). The estimated median OS was 9.9 months (95% CI, 7.6-16.1 months) in the study and 13.6 months (95% CI, 9.69 to not reached) in the prespecified DDR-GA cohort. CONCLUSIONS AND RELEVANCE: The definition of the BRCAness phenotype in PDAC may be limited to patients harboring DDR-GAs. In these 2 phase 2 nonrandomized clinical trials, olaparib was well tolerated and showed limited antitumor activity in patients with advanced, platinum-sensitive PDAC with DDR-GAs. These conclusions suggest a potential therapeutic opportunity for a subset of patients with PDAC.

BACKGROUND: CD73, a newly recognized immune checkpoint mediator, is expressed in several types of malignancies. However, CD73 expression and its impact on tumor microenvironment and clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) remain unclear. METHODS: This study included two cohorts: 138 patients from our institution (MDA) and 176 patients from TCGA dataset. CD73 expression, CD4+, CD8+, CD21+ and CD45RO+ tumor infiltrating lymphocytes (TILs) were evaluated by immunohistochemistry using tissue microarrays. The results of CD73 expression were correlated with clinicopathologic parameters, survival and TILs. RESULTS: CD73 overexpression correlated with poorly differentiation (P = 0.002) and tumor size (P = 0.049). For CD73-low group, median overall survival (OS) and recurrence-free survival (RFS) were 26.9 ± 3.8 months and 12.6 ± 2.6 months, respectively, compared to 16.9 ± 4.4 months (P = 0.01) and 7.9 ± 1.2 months (P = 0.01), respectively, in CD73-high group. CD73 was an independent predictor for both RFS (P = 0.015) and OS (P = 0.01) by multivariate variate analysis. Similarly, CD73-high tumors had significantly shorter OS than CD73-low tumors in TCGA dataset (P < 0.0001). CD73-high correlated with decreased CD4+ TILs in MDA cohort and decreased CD8A and CR2 (CD21) expression in TCGA cohort. CONCLUSIONS: CD73 overexpression is associated with poor differentiation, tumor size, and shorter survival, and is an independent prognostic factor in PDAC patients. CD73 overexpression is associated with decreased CD4+, CD8+ and CD21+ TILs. Our data support that CD73 plays an important role in immunosuppressive tumor microenvironment and promote tumor progression in PDAC.

Summary Background Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose. Methods This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0–1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov , NCT03214250 and is ongoing. Findings Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0–19·4; cohort B1 22·0 months [21·4–22·7], cohort B2 18·2 months [17·0–18·9], cohort C1 17·9 months [14·3–19·7], cohort C2 15·9 months [12·7–16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3–4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2). Interpretation APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population. Funding Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.

Objective Small bowel adenocarcinoma (SBA) is a rare malignancy with limited evidence regarding outcomes after curative resection of localised disease. We aimed to evaluate presentation and prognostic factors affecting overall survival (OS), relapse-free survival (RFS) and recurrence of SBA. Methods Consecutive patients with completely resected localised SBA (1979–2019) were retrospectively reviewed for presentation, patient and tumour characteristics, perioperative treatment, recurrence, outcomes, and prognostic factors. Results Among 257 total patients, median age was 58 years. Primary location was in the duodenum, jejunum and ileum in 52%, 29%, and 19% of patients, respectively. Median OS was 57.5 months and median follow-up was 40 months. In multivariate analysis, lymph node involvement, lymphovascular invasion, histologic grade and race were independent predictors of RFS, while race, stage and histologic grade were independent predictors of OS. No significant difference in OS or RFS was seen when evaluating the role of perioperative treatment. Median time to diagnosis from first medical evaluation was 31 days and did not change over time. Overall recurrence rate was 56%. Recurrence rate was higher in ileal (77%), than duodenal (54%) and jejunal (65%) SBA (p=0.01). Recurrence presented most commonly as distant metastasis (71%). Proficient mismatch repair was associated with decreased risk of locoregional recurrence (LR) but increased risk of distant recurrence (DR) when compared with deficient mismatch repair (dMMR) in univariate analysis. Conclusions Despite advances in diagnostic modalities, this study did not show any improvement in earlier diagnosis of SBA over the course of the past three decades. The predominant pattern of disease recurrence was distant across all SBA locations, but dMMR status demonstrated a robust predilection for LR as opposed to DR. Perioperative treatment did not improve outcomes; however, a lower stage disease was seen in patients that received neoadjuvant therapy, suggesting further exploration of this approach.

IMPORTANCE: Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nanoparticle albumin-bound (nab)–paclitaxel (GA) are first-line chemotherapy regimens for pancreatic cancer. Their relative efficacy in the setting of localized disease is unknown. OBJECTIVE: To evaluate radiographic and serologic measures of responses associated with first-line chemotherapy with FOLFIRINOX or GA, and to determine the association between these drug regimens, putative measures of response, and survival. DESIGN, SETTING, AND PARTICIPANTS: This case series assessed 485 consecutive patients who were diagnosed as having previously untreated localized pancreatic ductal adenocarcinoma at The University of Texas MD Anderson Cancer Center between January 1, 2010, and December 31, 2017, and who received at least 3 cycles of first-line chemotherapy with FOLFIRINOX or GA. The median (range) follow-up duration was 33 (2-28) months. EXPOSURES: Administration of FOLFIRINOX (285 patients [59%]) or GA (200 patients [41%]) as first-line chemotherapy. MAIN OUTCOMES AND MEASURES: Resection rate, radiographic metrics (Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1, and change in tumor volume or anatomic staging), a serologic metric (serum cancer antigen 19-9 level), and overall survival after administration of first-line chemotherapy. RESULTS: In total, 485 patients (266 [55%] male) were included in the analysis. Patients treated with FOLFIRINOX were generally younger (median [range] age at diagnosis: 61 [30-81] vs 71 [36-89] years; P = .001) and had better performance status as indicated by the Eastern Cooperative Oncology Group scale (range 0-4, with lower numbers representing better performance) score of 2 or lower (274 patients [96%] vs 165 patients [82%] P = .001) but more invasive tumors than patients who received GA (91 [32%] vs 90 [45%] resectable tumors; P = .01). After propensity score matching to control for these biases, many objective serologic and radiographic metrics of response associated with administration of FOLFIRINOX or GA—including low rates of local tumor downstaging—did not differ. However, RECIST partial response was more common among patients treated with FOLFIRINOX (27 of 140 patients [19%]) than with GA (8 of 140 patients [6%]; P = .001). Moreover, (chemo)radiation (50% vs 34%; P = .001) was more commonly administered to and pancreatectomy (27% vs 16%; P = .01) was subsequently performed more frequently for patients initially treated with FOLFIRINOX. The overall survival duration of patients treated with either regimen was similar (hazard ratio, 1.48; 95% CI, 0.97-2.26; P = .07). CONCLUSIONS AND RELEVANCE: In this cohort of patients with localized pancreatic adenocarcinoma who received FOLFIRINOX or GA as their first line of therapy, FOLFIRINOX was associated with higher rates of RECIST partial response and subsequent pancreatectomy than GA, but the overall survival associated with these regimens was similar.

PURPOSE: KRAS p.G12C mutations occur in approximately 3% of metastatic colorectal cancers (mCRC). Recently, two allosteric inhibitors of KRAS p.G12C have demonstrated activity in early phase clinical trials. There are no robust studies examining the behavior of this newly targetable population. METHODS: We queried the MD Anderson Cancer Center data set for patients with colorectal cancer who harbored KRAS p.G12C mutations between January 2003 and September 2019. Patients were analyzed for clinical characteristics, overall survival (OS), and progression-free survival (PFS) and compared against KRAS nonG12C. Next, we analyzed several internal and external data sets to assess immune signatures, gene expression profiles, hypermethylation, co-occurring mutations, and proteomics. RESULTS: Among the 4,632 patients with comprehensive molecular profiling, 134 (2.9%) were found to have KRAS p.G12C mutations. An additional 53 patients with single gene sequencing were included in clinical data but excluded from prevalence analysis allowing for 187 total patients. Sixty-five patients had de novo metastatic disease and received a median of two lines of chemotherapy without surgical intervention. For the first three lines of chemotherapy, the median PFS was 6.4 months (n = 65; 95% CI, 5.0 to 7.4 months), 3.9 months (n = 47; 95% CI, 2.9 to 5.9 months), and 3.0 months (n = 21; 95% CI, 2.0 to 3.4 months), respectively. KRAS p.G12C demonstrated higher rates of basal EGFR activation compared with KRAS nonG12C. When compared with an internal cohort of KRAS nonG12C, KRAS p.G12C patients had worse OS. CONCLUSION: PFS is poor for patients with KRAS p.G12C metastatic colorectal cancer. OS was worse in KRAS p.G12C compared with KRAS nonG12C patients. Our data highlight the innate resistance to chemotherapy for KRAS p.G12C patients and serve as a historical comparator for future clinical trials.

Introduction It has been determined that right-sided metastatic colorectal cancer (mCRC) has a worse prognosis for overall survival (OS). Currently, there is no consensus on the best systemic regimen for treatment-naive right-sided tumors. We compared the impact of subsequent therapies on OS of patients treated with FOLFOXIRI (leucovorin, 5-fluorouracil, oxaliplatin, irinotecan) versus doublet regimens. Patients and Methods Data of patients with treatment-naive right-sided mCRC who received FOLFOXIRI or doublet regimens between January 2001 to December 2018 were retrospectively analyzed. OS was compared between the two groups, and prognostic factors were assessed by multivariate analysis. Results A total of 196 patients were selected; 33 patients received FOLFOXIRI and 163 patients doublet therapy. Median follow-up was 82.3 months. The FOLFOXIRI cohort received fewer subsequent lines of therapies (61% vs. 78%, P = .043). The greater the number of subsequent lines of therapy, the lower the risk of death (hazard ratio [95% confidence interval] 0.67 [0.46-0.99], 0.62 [0.45-0.86], and 0.56 [0.39-0.81] for > 1, > 2, and > 3 lines, respectively). By multivariate analysis, metastasectomy and bevacizumab with subsequent lines of therapy were the variables with greatest positive impact on OS (respectively, hazard ratio [95% confidence interval] 0.54 [0.38-0.78] and 0.61 [0.44-0.84]). Conclusion Patients with treatment-naive right-sided mCRC who received front-line FOLFOXIRI had a lower number of subsequent therapies than patients who received doublet regimens. Our findings highlight the relevance of the continuum of care in mCRC, regardless of the first-line regimen, and the importance of careful selection of patients for the FOLFOXIRI regimen.

Background Antiangiogenics attenuate chemotherapy-related hepatotoxicity and portal hypertension. The potential impact of bevacizumab on the efficacy and safety of partial splenic embolization (PSE) in the management of chemotherapy-induced hypersplenism (CIH) has never been investigated. Patients and Methods We conducted a retrospective study with gastrointestinal cancer patients who have undergone PSE for the treatment of thrombocytopenia resulting from hypersplenism. Pre- and post-PSE platelet count (PC), the percentage of patients who resumed systemic therapy, and complication rates were compared between patients exposed and not exposed to bevacizumab. Results A total of 110 patients were eligible. Colorectal cancer was the predominant neoplasm (60%), and 5-fluorouracil, oxaliplatin, and bevacizumab were the most commonly provided drugs (70%, 65%, and 65% of patients, respectively). After PSE, 80% of patients recovered PC ≥ 100 × 109/L (100K). Systemic therapy was resumed in 81% of patients. Seventy-one patients exposed to bevacizumab had a median PC before PSE of 77.5K and after PSE of 167.0K, with a mean difference of 108K (P Conclusion PSE is a safe and effective procedure in the management of CIH, regardless of the provision of bevacizumab. Splenic infarction rate should be optimized to enhance patient outcomes.

Background Although FOLFIRINOX (5-Fluorouracil + leucovorin + irinotecan + oxaliplatin) is now the standard of care for patients (pts) with metastatic pancreatic cancer (PC) based on the 2011 study by Conroy et al. which demonstrated improved median overall survival (mOS), pts > 75 yrs old were excluded from this study. The purpose of this study was to assess the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) in this population. Methods We retrospectively analyzed unresectable PC pts, age ≥ 75, treated with mFOLFIRINOX at MD Anderson from 2011 to 2017. Primary outcome was rate of grade 3 or 4 hematologic toxicity (HT). Results 24 pts were included. Grade 3 or 4 HT occurred in 11 pts 6 pts required hospitalization for any toxicity, and 10 stopped mFOLFIRINOX due to toxicity. The most frequently used starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400, 150 and 75 mg/m2, respectively. Median PFS was 3.7 months (95% CI: 3.0–5.7) with a median OS of 11.6 months (95% CI: 6.14–15.7). For first line pts, median PFS and OS were 5.1 (95% CI: 2.0–12.8) and 12.2 months (95% CI: 4.8–30.8), respectively. Conclusions In this single-center retrospective analysis of unresectable PC pts age 75 or older given mFOLFIRINOX, toxicities and survival outcomes were similar to those reported in the initial study. These data indicate that the use of modified dosing FOLFIRINOX in advanced PC pts older than 75 appears to maintain similar toxicity and efficacy when compared to younger pts.

Preoperative chemotherapy provides early treatment of micro-metastases and guaranteed delivery of all components of multimodality therapy for localized pancreatic ductal adenocarcinoma (PDAC). For locally advanced (LA) PDAC, induction chemotherapy is the standard of care. This study evaluated the use of gemcitabine and nab-paclitaxel (Gem/nab-P) as first-line therapy for localized PDAC. Clinicopathologic features, treatment, and outcomes were evaluated for 99 patients with localized PDAC. The patients were staged using previously published criteria as follows: potentially resectable (PR), borderline type A (BR-A) (anatomy amenable to vascular resection), BR-B (biology suspicious for metastatic disease including high CA19-9), BR–C (comorbidities requiring medical optimization), and LA. The 99 patients (PR/BR/LA: 45/14/40) were treated with Gem/nab-P. Clinical staging showed that 20 patients had PR or BR-A disease, whereas 39 patients had BR-B or BR-C disease. The BR-B+C cases included one or more of the following: age of 80 years or older (13%), Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or more (13%), moderate to severe comorbidities (55%), CA19-9 of 1000 or higher (28%), and suspicion for metastases (21%). The majority of the patients received biweekly Gem/nab-P dosing, which was well tolerated. Pancreatectomy was performed for 12 (60%) of 20 patients with PR+BR-A, 2 (5%) of 39 patients with BR-B+C, and 1 (3%) of 40 patients with LA disease. During a median follow-up period of 26 months, the median overall survival (OS) period was 18 months (95% confidence interval [CI], 15.6–20.5 months) for all the patients, 17 months (95% CI, 14.6–19.5 months) for the unresected patients, and not reached for the resected patients (p = 0.028 for resected vs unresected patients). A significant number of patients with radiographically resectable PDAC albeit aggressive biology (BR-B), medically inoperable conditions (BR-C), or both received biweekly first-line Gem/nab-P. The resection rates were lower for the BR-B/BR-C patients than for the PR/BR-A patients (hazard ratio [HR], 0.43; 95% CI, 0.19–1.00; p = 0.05).

Background Detection of circulating tumor DNA can be limited due to their relative scarcity in circulation, particularly while patients are actively undergoing therapy. Exosomes provide a vehicle through which cancer-specific material can be enriched from the compendium of circulating non-neoplastic tissue-derived nucleic acids. We carried out a comprehensive profiling of the pancreatic ductal adenocarcinoma (PDAC) exosomal ‘surfaceome' in order to identify surface proteins that will render liquid biopsies amenable to cancer-derived exosome enrichment for downstream molecular profiling. Patients and methods Surface exosomal proteins were profiled in 13 human PDAC and 2 non-neoplastic cell lines by liquid chromatography–mass spectrometry. A total of 173 prospectively collected blood samples from 103 PDAC patients underwent exosome isolation. Droplet digital PCR was used on 74 patients (136 total exosome samples) to determine baseline KRAS mutation call rates while patients were on therapy. PDAC-specific exosome capture was then carried out on additional 29 patients (37 samples) using an antibody cocktail directed against selected proteins, followed by droplet digital PCR analysis. Exosomal DNA in a PDAC patient resistant to therapy were profiled using a molecular barcoded, targeted sequencing panel to determine the utility of enriched nucleic acid material for comprehensive molecular analysis. Results Proteomic analysis of the exosome ‘surfaceome' revealed multiple PDAC-specific biomarker candidates: CLDN4, EPCAM, CD151, LGALS3BP, HIST2H2BE, and HIST2H2BF. KRAS mutations in total exosomes were detected in 44.1% of patients undergoing active therapy compared with 73.0% following exosome capture using the selected biomarkers. Enrichment of exosomal cargo was amenable to molecular profiling, elucidating a putative mechanism of resistance to PARP inhibitor therapy in a patient harboring a BRCA2 mutation. Conclusion Exosomes provide unique opportunities in the context of liquid biopsies for enrichment of tumor-specific material in circulation. We present a comprehensive surfaceome characterization of PDAC exosomes which allows for capture and molecular profiling of tumor-derived DNA.

Currently, treatment of small bowel adenocarcinoma (SBA) mirrors that of colorectal cancer (CRC). Recent genomic data have demonstrated SBA to be a genetically unique entity, suggesting that therapies not traditionally utilized in CRC should be explored. In order to further characterize the activity of taxanes in this rare cancer, we completed a single-center retrospective study. Twenty patients were found to have been treated with taxane-based regimens (monotherapy in 3, combination therapy in 17). Median time to progression was 3.8 months (95% confidence interval [CI] 2.9–4.6), and median overall survival was 10.7 months (95% CI: 3.1–18.3). The results of this study demonstrate clinical activity from taxane-based therapy in advanced SBA and support further clinical trial investigation.

Background Metastatic small bowel adenocarcinoma (SBA) has a poor prognosis. Due to its rarity, high-quality data are lacking to guide treatment. This retrospective analysis was conducted to help characterize the treatment options for patients with metastatic SBA while providing clinically meaningful prognostic information. Patients and methods In total, 437 patients who initially presented with or developed metastatic SBA between September 1977 and September 2019 were identified from the MD Anderson Tumor Registry. Clinical data were collected from review of the medical record. Overall response rates (ORR), time to progression (TTP), and overall survival (OS) were assessed across various treatments and treatment lines. Results The median OS from diagnosis of metastatic disease was 15.9 months [95% confidence interval (CI): 14.3-17.9]. Seventy-five patients (17.1%) underwent metastasectomy, which was associated with a median OS of 34.5 versus 17.1 months among patients who received chemotherapy alone (P < 0.001). Fluoropyrimidine plus platinum (n = 164) was the most common first-line chemotherapy, associated with an ORR of 59% and TTP of 8.1 months. Irinotecan with 5-FU (n = 101) was the most common second-line therapy associated with an ORR of 31% and TTP of 4.0 months. Twenty-two patients received immunotherapy; 5 of 6 patients with deficient mismatch repair (dMMR) responded, while 0 of 16 with proficient mismatch repair (pMMR) responded. Taxane-based chemotherapy was given to 34 patients with an ORR of 21% and a median TTP of 2.4 months. Among 11 patients who received anti-epidermal-growth-factor-receptor (EGFR) monotherapy, the best response was stable disease (SD) in 1 patient. Conclusions In well-selected patients with SBA, metastasectomy appears to be associated with improved OS. This improvement was seen across metastasectomy sites, including liver, lung and peritoneal. Anti-programmed cell death protein 1 (PD-1) based immunotherapy was active for dMMR SBA but not pMMR SBA. While taxane-based chemotherapy demonstrates therapeutic activity, the activity of anti-EGFR therapy was limited., Highlights • Metastasectomy for well-selected metastatic SBA patients was associated with improved OS. • Anti-PD1-based immunotherapy was active for dMMR SBA but not pMMR SBA. • Taxane-based chemotherapy demonstrated clinical activity in refractory SBA. • Anti-EGFR therapy demonstrated minimal activity in SBA.

Purpose Molecular diagnostic testing has become an integral part of the evaluation of patients with metastatic colorectal cancer (CRC). Expanded mutational testing, such as next-generation sequencing (NGS), often identifies mutations with unclear clinical or prognostic implications. One such example is BRAF mutations that occur outside of codon 600 (non-V600 BRAF mutations). Methods We conducted this multicenter, retrospective cohort study to characterize the clinical, pathologic, and survival implications of non-V600 BRAF mutations in metastatic CRC. We pooled patients in whom non-V600 BRAF mutations were identified from NGS databases at three large molecular genetics reference laboratories. Results A total of 9,643 patients with metastatic CRC underwent NGS testing. We identified 208 patients with non-V600 BRAF mutations, which occurred in 2.2% of all patients tested and accounted for 22% of all BRAF mutations identified. Cancers with non-V600 BRAF mutations, compared with cancers with V600E BRAF (V600E BRAF) mutations, were found in patients who were significantly younger (58 v 68 years, respectively), fewer female patients (46% v 65%, respectively), and patients who had fewer high-grade tumors (13% v 64%, respectively) or right-sided primary tumors (36% v 81%, respectively). Median overall survival was significantly longer in patients with non-V600 BRAF-mutant metastatic CRC compared with those with both V600E BRAF-mutant and wild-type BRAF metastatic CRC (60.7 v 11.4 v 43.0 months, respectively; P < .001). In multivariable analysis, non-V600 BRAF mutation was independently associated with improved overall survival (hazard ratio, 0.18; P < .001). Conclusion Non-V600 BRAF mutations occur in approximately 2.2% of patients with metastatic CRC and define a clinically distinct subtype of CRC with an excellent prognosis.

// Krittiya Korphaisarn 1, 2 , Van Karlyle Morris 1 , Michael J. Overman 1 , David R. Fogelman 1 , Bryan K. Kee 1 , Kanwal Pratap Singh Raghav 1 , Shanequa Manuel 1 , Imad Shureiqi 1 , Robert A. Wolff 1 , Cathy Eng 1 , David Menter 1 , Stanley R. Hamilton 3 , Scott Kopetz 1 and Arvind Dasari 1 1 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Bangkok, Thailand 3 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Arvind Dasari, email: adasari@mdanderson.org Keywords: colorectal cancer, FBXW7 , mutation, missense, prognosis Received: January 25, 2017 Accepted: March 02, 2017 Published: April 05, 2017 ABSTRACT Background: FBXW7 functions as a ubiquitin ligase tagging multiple dominant oncogenic proteins and commonly mutates in colorectal cancer. Data suggest missense mutations lead to greater loss of FBXW7 function than other gene aberrations do. However, the clinicopathologic factors and outcomes associated with FBXW7 missense mutations in metastatic colorectal cancer (mCRC) have not been described. Methods: Data were obtained from mCRC patients whose tumors were evaluated by next-generation sequencing for hotspot mutations at The University of Texas MD Anderson Cancer Center. Alterations in FBXW7 were identified, and their associations with clinicopathologic features and overall survival (OS) were evaluated. Results: Of 855 mCRC patients, 571 had data on FBXW7 status; 43 (7.5%) had FBXW7 mutations, including 37 with missense mutations. R465C mutations in exon 9 were the most common missense mutations (18.6%). PIK3CA mutations were associated with FBXW7 missense mutations (p=0.012). On univariate analysis, patients with FBXW7 missense mutations had significantly worse OS (median 28.7 mo) than those with wild-type FBXW7 (median 46.6 mo; p=0.003). On multivariate analysis including other known prognostic factors such as BRAF mutations, FBXW7 missense mutations were the strongest negative prognostic factor for OS (hazard ratio 2.0; p=0.003). Conclusions : In the largest clinical dataset of mCRC to date, FBXW7 missense mutations showed a strong negative prognostic association.

To determine whether severity of lymphopenia is dependent on radiation dose and fractional volume of spleen irradiated unintentionally during definitive chemoradiation (CRT) in patients with locally advanced pancreatic cancer (LAPC).177 patients with LAPC received induction chemotherapy (mainly gemcitabine-based regimens) followed by CRT (median 50.4 Gy with concurrent capecitabine) from January 2006 to December 2012. Absolute lymphocyte count (ALC) was recorded at baseline, before CRT, and 2 to 10 weeks after CRT. Splenic dose-volume histogram (DVH) parameters were reported as mean splenic dose (MSD) and percentage of splenic volume receiving at least 5- (V5), 10- (V10), 15- (V15), and 20-Gy (V20) dose. Overall survival (OS) was analyzed with use of the Cox model, and development of post-CRT severe lymphopenia (ALC0.5 K/UL) was assessed by multivariate logistic regression with use of baseline and treatment factors.The median post-CRT ALC (0.68 K/UL; range, 0.13-2.72) was significantly lower than both baseline ALC (1.42 K/UL; range, 0.34-3.97; P.0001) and pre-CRT ALC (1.32 K/UL, range 0.36-4.82; P.0001). Post-CRT ALC0.5 K/UL was associated with inferior OS on univariate analysis (median, 11.1 vs 15.3 months; P=.01) and multivariate analysis (hazard ratio = 1.66, P=.01). MSD (9.8 vs 6 Gy, P=.03), median V10 (32.6 vs 16%, P=.04), V15 (23.2 vs 9.5%, P=.03), and V20 (15.4 vs 4.6%, P=.02) were significantly higher in patients with severe lymphopenia than in those without. On multivariate analysis, postinduction lymphopenia (P.001; odds ratio [OR] = 5.25) and MSD (P=.002; OR= 3.42) were independent predictors for the development of severe post-CRT lymphopenia.Severe post-CRT lymphopenia is an independent predictor of poor OS in LAPC patients receiving CRT. Higher splenic doses increase the risk for the development of severe post-CRT lymphopenia. When clinically indicated, assessment of splenic DVHs before the acceptance of treatment plans may minimize the risk of severe post-CRT lymphopenia.

Although preoperative therapy is increasingly administered to patients with pancreatic adenocarcinoma, the role of preoperative therapy for patients with adenocarcinoma of the ampulla of Vater is undefined. All patients with ampullary cancer who were evaluated between 1999 and 2014 were retrospectively reviewed. Differences in clinicopathologic characteristics, perioperative complications, and overall survival were compared between patients who underwent surgery de novo and those who received preoperative therapy before pancreatoduodenectomy. A total of 142 patients underwent pancreatoduodenectomy: 43 (30.3%) who received preoperative therapy and 99 (69.7%) who did not. Preoperative therapy consisted of chemoradiation (65%), chemotherapy (7%), or both (28%). Patients who underwent surgery first had a lower comorbidity index (p

This letter to the editor reflects on the recently published article about management of cancer patients during the COVID‐19 pandemic by Al‐Shamsi et al., specifically as regards the management of febrile neutropenia in the context of the pandemic.

Neoadjuvant therapy has been increasingly used to treat patients with potentially resectable pancreatic ductal adenocarcinoma (PDAC). Although the College of American Pathologists (CAP) grading scheme for tumor response in post-therapy specimens has been used, its clinical significance has not been validated. Previously, we proposed a three-tier histologic tumor regression grading (HTRG) scheme (HTRG 0, no viable tumor; HTRG 1, < 5% viable tumor cells; HTRG 2, ≥5 % viable tumor cells) and showed that the three-tier HTRG scheme correlated with prognosis. In this study, we sought to validate our proposed HTRG scheme in a new cohort of 167 consecutive PDAC patients who completed neoadjuvant therapy and pancreaticoduodenectomy. We found that patients with HTRG 0 or 1 were associated with a lower frequency of lymph node metastasis (p=0.004) and recurrence (p=0.01), lower ypT (p 0.05). In multivariate analysis, HTRG grade 0 or 1 was an independent prognostic factor for better DFS (p =0.03), but not OS. Therefore we validated the proposed HTRG scheme from our previous study. The proposed HTRG scheme is simple and easy to apply in practice by pathologists and might be used as a successful surrogate for longer DFS in patients with potentially resectable PDAC who completed neoadjuvant therapy and surgery.

Purpose: Molecular profiling has been used to select patients for targeted therapy and determine prognosis. Noninvasive strategies are critical to hepatocellular carcinoma (HCC) given the challenge of obtaining liver tissue biopsies. Experimental Design: We analyzed blood samples from 206 patients with HCC using comprehensive genomic testing (Guardant Health) of circulating tumor DNA (ctDNA). Results: A total of 153/206 (74.3%) were men; median age, 62 years (range, 18–91 years). A total of 181/206 patients had ≥1 alteration. The total number of alterations was 680 (nonunique); median number of alterations/patient was three (range, 1–13); median mutant allele frequency (% cfDNA), 0.49% (range, 0.06%–55.03%). TP53 was the common altered gene [>120 alterations (non-unique)] followed by EGFR, MET, ARID1A, MYC, NF1, BRAF, and ERBB2 [20–38 alterations (nonunique)/gene]. Of the patients with alterations, 56.9% (103/181) had ≥1 actionable alterations, most commonly in MYC, EGFR, ERBB2, BRAF, CCNE1, MET, PIK3CA, ARID1A, CDK6, and KRAS. In these genes, amplifications occurred more frequently than mutations. Hepatitis B (HBV)-positive patients were more likely to have ERBB2 alterations, 35.7% (5/14) versus 8.8% HBV-negative (P = 0.04). Conclusions: This study represents the first large-scale analysis of blood-derived ctDNA in HCC in United States. The genomic distinction based on HCC risk factors and the high percentage of potentially actionable genomic alterations suggests potential clinical utility for this technology.

Importance Administration of gemcitabine-cisplatin, the current standard therapy for advanced biliary tract cancers, results in median progression-free survival and overall survival of 8.0 and 11.7 months, respectively. New treatments offering improved survival outcomes are therefore needed. Objective To evaluate the association between progression-free survival and the addition of nanoparticle albumin-bound (nab)–paclitaxel to gemcitabine-cisplatin for the treatment of patients with advanced biliary tract cancer. Design, Setting, and Participants This open-label, single-arm, phase 2 clinical trial conducted at the University of Texas MD Anderson Cancer Center and the Mayo Clinic in Phoenix, Arizona, enrolled 62 patients with advanced biliary tract cancers between April 14, 2015, and April 24, 2017. Interventions Patients initially received gemcitabine, 1000 mg/m2, cisplatin, 25 mg/m2, and nab-paclitaxel, 125 mg/m2, on days 1 and 8 of 21-day cycles. Owing to hematologic adverse events among the first 32 patients enrolled, these starting doses were reduced to 800, 25, and 100 mg/m2, respectively, for the remaining 28 patients. Main Outcomes and Measures The primary trial end point was investigator-assessed progression-free survival in the intention-to-treat population. Results Of 60 patients who started treatment, the mean (SD) age was 58.4 (11.0) years, 38 (63%) had intrahepatic cholangiocarcinoma, 9 (15%) had extrahepatic cholangiocarcinoma, 13 (22%) had gallbladder cancer, 47 (78%) had metastatic disease, and 13 (22%) had locally advanced disease. Median follow-up was 12.2 (95% CI, 9.4-19.4) months, and median progression-free survival was 11.8 (95% CI, 6.0 to 15.6) months. The partial response rate was 45%, and the disease control rate was 84%. Median overall survival was 19.2 months (95% CI, 13.2 months to not estimable). Patients in the safety population (n = 57) received a median of 6 (interquartile range, 3-11) cycles of treatment; 26 patients (46%) remained on their starting dose throughout the trial. Grade 3 or higher adverse events occurred in 58% of patients, and 9 patients (16%) withdrew owing to adverse events. Neutropenia was the most common grade 3 or higher adverse event, occurring in 19 patients (33%) overall. Post hoc analyses showed that treatment efficacy was not significantly associated with starting dose, tumor type, or disease status and that tolerability was improved with reduced- vs high-dose treatment. Conclusions and Relevance Treatment with nab-paclitaxel plus gemcitabine-cisplatin prolonged median progression-free survival and overall survival vs those reported for historical controls treated with gemcitabine-cisplatin alone. These findings will be tested in a phase 3 randomized clinical trial. Trial Registration ClinicalTrials.gov identifier:NCT02392637

Background Signet ring cell carcinoma (SRCC) is a rare subtype of colorectal cancer (CRC). The aim of this study was to characterise the genomic alterations and outcomes of SRCC. Methods Medical records of metastatic CRC (mCRC) patients whose tumours were evaluated by NGS analysis were reviewed. SC-mCRC were classified into two groups: SRCC (>50% signet ring cells) and adenocarcinoma (AC) with SC component (≤50% signet ring cells). Results Six hundred and sixty-five mCRC patients were included. Of the 93 mCRC cases with SC features, 63 had slides for review. Of those 63 cases, 35 were confirmed SRCC, and 28 were AC with SC component. Compared with AC group, KRAS and PIK3CA mutations (mts) were found in only 11% (OR: 0.13) and 3% (OR: 0.15) of SRCC cases, respectively. In contrast to the 44% rate of APC mts in AC group, only 3% of SRCC patients had APC mts (OR = 0.04). Conclusions SRCC has distinct molecular features, including low rates of KRAS, PIK3CA and APC mts. Further study to identify activation pathways and potential therapeutic targets are needed.

Background: Liver reserve affects survival in hepatocellular carcinoma (HCC). Model for End-Stage Liver Disease (MELD) score is used to predict overall survival (OS) and to prioritize HCC patients on the transplantation waiting list, but more accurate models are needed. We hypothesized that integrating insulin-like growth factor 1 (IGF-1) levels into MELD score (MELD-IGF-1) improves OS prediction as compared to MELD. Methods: We measured plasma IGF-1 levels in training (n = 310) and validation (n = 155) HCC cohorts and created MELD-IGF-1 score. Cox models were used to determine the association of MELD and MELD-IGF-1 with OS. Harrell’s c-index was used to compare the predictive capacity. Results: IGF-1 was significantly associated with OS in both cohorts. Patients with an IGF-1 level of ≤26 ng/mL in the training cohort and in the validation cohorts had significantly higher hazard ratios than patients with the same MELD but IGF-1 >26 ng/mL. In both cohorts, MELD-IGF-1 scores had higher c-indices (0.60 and 0.66) than MELD scores (0.58 and 0.60) (p < 0.001 in both cohorts). Overall, 26% of training and 52.9% of validation cohort patients were reclassified into different risk groups by MELD-IGF-1 (p < 0.001). Conclusions: After independent validation, the MELD-IGF-1 could be used to risk-stratify patients in clinical trials and for priority assignment for patients on liver transplantation waiting list.

The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights discuss important updates to the 2019 version of the guidelines, focusing on postoperative adjuvant treatment of patients with pancreatic cancers.

Purpose: Family history of BRCA-related tumors may correlate with response to chemotherapy and overall survival (OS) in pancreatic cancer. The frequency of germline mutations has been reported in patients predominantly under the age of 60 or with strong family history. We examine the incidence of deleterious germline mutations and compare the chemotherapy responses and OS in an unselected group of patients with metastatic pancreatic cancer. Experimental Design: Patients with metastatic pancreatic cancer, who were seen at a single cancer center between 2010 and 2016, were included. Germline DNA was sequenced using a 263-gene panel to identify novel mutations (N = 133 MD Anderson cohort, N = 127 TCGA cohort). Chemotherapy response and OS were determined by review of medical records. Results: Deleterious germline mutations were identified in 26 of 133 patients (19.5%). Patients with DNA damage repair (DDR) gene mutations (ATM, BRCA1/2, CDKN2A, CHEK2, ERCC4, PALB2, n = 15) had an improved OS as compared with patients without (16.8 vs. 9.1 months, P = 0.03). Conversely, patients with other deleterious mutations had a trend toward worse OS. However, survival in the latter group was longer (P = NS) in those mutants initially treated with gemcitabine/nab-paclitaxel. A family history of multiple breast, ovarian, and pancreatic cancers was associated with DDR gene mutations and better survival. Conclusions: We have identified novel germline mutations that are prognostic for survival in patients with pancreatic cancer. We observe improved survival in patients with DDR gene mutations and worsened survival in patients with deleterious mutations in non-DDR genes.

BACKGROUND Capecitabine with oxaliplatin (CAPOX) has previously demonstrated clinical activity in patients with small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (AAC). Herein, the authors conducted a phase 2 trial to evaluate the benefit of adding bevacizumab to CAPOX. METHODS In this phase 2, single-arm, single-center, open-label study, patients aged ≥18 years with untreated, advanced SBA or AAC were recruited. Patients received capecitabine at a dose of 750 mg/m2 orally twice daily on days 1 to 14, oxaliplatin at a dose of 130 mg/m2 intravenously on day 1, and bevacizumab at a dose of 7.5 mg/kg intravenously on day 1 of a 21-day cycle. The primary endpoint was progression-free survival (PFS) at 6 months. Secondary objectives included response rate, overall PFS, overall survival, and toxicity. RESULTS Between August 2011 and November 2014, a total of 30 patients were enrolled into the study (male/female ratio of 13/17; median age of 63 years [range, 33-78 years]; and 7 patients with an Eastern Cooperative Oncology Group performance status [ECOG PS] of 0, 20 patients with an ECOG PS of 1, and 3 patients with an ECOG PS of 2). Of the 30 patients, 23 (77%) had SBA (18 of duodenal origin and 5 of jejunal/ileal origin) and 7 patients (23%) had AAC (5 of pancreaticobiliary subtype, 1 of mixed subtype, and 1 of intestinal subtype). The most common grade 3 toxicities observed were fatigue and hypertension (7 patients each [23%]), neutropenia (6 patients [20%]), and diarrhea (3 patients [10%]) (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The probability of PFS at 6 months was 68% (95% confidence interval [95% CI], 52% to 88%). The response rate was 48.3%, with 1 complete response and 13 partial responses; 10 patients achieved stable disease. At a median follow-up of 25.9 months, the median PFS was 8.7 months (95% CI, 4.9-10.5 months) and the median overall survival was 12.9 months (95% CI, 9.2-19.7 months). CONCLUSIONS The results of the current study indicate that CAPOX with bevacizumab is an active and well-tolerated regimen for patients with SBA and AAC. These findings support the need for further investigation into the clinical benefit of targeting angiogenesis in patients with SBA and AAC. Cancer 2017;123:1011–17. © 2016 American Cancer Society.