Randy F. Sweis

Molecular Drivers of the Non-T-cell-Inflamed Tumor Microenvironment in Urothelial Bladder Cancer.

Immunotherapy resistance is a reality for many cancer patients. Three tumor-intrinsic molecular pathways, β-catenin, PPARγ, and FGFR3, were identified and linked to the exclusion of T cells from urothelial tumors. Targeting these pathways may enhance immune checkpoint efficacy. Muscle-invasive urothelial bladder cancer is a common malignancy with poor outcomes for which immune checkpoint blockade is now showing promise. Despite clinical activity of PD-1/PD-L1–targeted therapy in this disease, most patients do not benefit and resistance mechanisms remain unknown. The non–T-cell-inflamed tumor microenvironment correlates with poor prognosis and resistance to immunotherapies. In this study, we determined tumor-oncogenic pathways correlating with T-cell exclusion. We first establish in this report that T-cell–inflamed bladder tumors can be identified by immune gene expression profiling with concordance with CD8+ T-cell infiltration. Upregulation of genes encoding immune checkpoint proteins PD-L1, IDO, FOXP3, TIM3, and LAG3 was associated with T-cell–inflamed tumors, suggesting potential for sensitivity to checkpoint blockade. β-Catenin, PPAR-γ, and FGFR3 pathways were activated in non–T-cell-inflamed tumors. No difference was seen in overall somatic mutational density between groups. The three pathways identified represent targetable potential pathways of tumor-intrinsic immunotherapy resistance. Cancer Immunol Res; 4(7); 563–8. ©2016 AACR.

Post‐prandial reflux suppression by a raft‐forming alginate (Gaviscon Advance) compared to a simple antacid documented by magnetic resonance imaging and pH‐impedance monitoring: mechanistic assessment in healthy volunteers and randomised, controlled, double‐blind study in reflux patients

Alginates form a raft above the gastric contents, which may suppress gastro‐oesophageal reflux; however, inconsistent effects have been reported in mechanistic and clinical studies.

Tumor Endothelial Inflammation Predicts Clinical Outcome in Diverse Human Cancers

Background Vascular endothelial cells contribute to the pathogenesis of numerous human diseases by actively regulating the stromal inflammatory response; however, little is known regarding the role of endothelial inflammation in the growth of human tumors and its influence on the prognosis of human cancers. Methods Using an experimental model of tumor necrosis factor-alpha (TNF-α)-mediated inflammation, we characterized inflammatory gene expression in immunopurified tumor-associated endothelial cells. These genes formed the basis of a multivariate molecular predictor of overall survival that was trained and validated in four types of human cancer. Results We report that expression of experimentally derived tumor endothelial genes distinguished pathologic tissue specimens from normal controls in several human diseases associated with chronic inflammation. We trained these genes in human cancer datasets and defined a six-gene inflammatory signature that predicted significantly reduced overall survival in breast cancer, colon cancer, lung cancer, and glioma. This endothelial-derived signature predicted outcome independently of, but cooperatively with, standard clinical and pathological prognostic factors. Consistent with these findings, conditioned culture media from human endothelial cells stimulated by pro-inflammatory cytokines accelerated the growth of human colon and breast tumors in immunodeficient mice as compared with conditioned media from untreated endothelial cells. Conclusions This study provides the first prognostic cancer gene signature derived from an experimental model of tumor-associated endothelial inflammation. These findings support the notion that activation of inflammatory pathways in non-malignant tumor-infiltrating endothelial cells contributes to tumor growth and progression in multiple human cancers. Importantly, these results identify endothelial-derived factors that could serve as potential targets for therapy in diverse human cancers.

Analysis of Impact of Post-Treatment Biopsies in Phase I Clinical Trials

PURPOSE The use of biopsy-derived pharmacodynamic biomarkers is increasing in early-phase clinical trials. It remains unknown whether drug development is accelerated or enhanced by their use. We examined the impact of biopsy-derived pharmacodynamic biomarkers on subsequent drug development through a comprehensive analysis of phase I oncology studies from 2003 to 2010 and subsequent publications citing the original trials. METHODS We conducted a search to identify and examine publications of phase I oncology studies including the use of biopsy-derived pharmacodynamic biomarkers between 2003 and 2010. Characteristics of those studies were extracted and analyzed, along with outcomes from the biomarker data. We then compiled and reviewed publications of subsequent phase II and III trials citing the original phase I biomarker studies to determine the impact on drug development. RESULTS We identified 4,840 phase I oncology publications between 2003 and 2010. Seventy-two studies included a biopsy-derived pharmacodynamic biomarker. The proportion of biomarker studies including nondiagnostic biopsies increased over time (P = .002). A minimum of 1,873 tumor biopsies were documented in the 72 studies, 12 of which reported a statistically significant biomarker result. Thirty-three percent of studies (n = 24) were referenced by subsequent publications specifically with regard to the biomarkers. Only five positive biomarker studies were cited subsequently, and maximum tolerated dose was used for subsequent drug development in all cases. CONCLUSION Despite their increased use, the impact of biopsy-derived pharmacodynamic biomarkers in phase I oncology studies on subsequent drug development remains uncertain. No impact on subsequent dose or schedule was demonstrated. This issue requires further evaluation, given the risk and cost of such studies.

Do Clinicians Know Which of Their Patients Have Central Venous Catheters?: A Multicenter Observational Study

Context Central venous catheters (CVCs) are commonly used to care for hospitalized patients; however, their continued presence creates substantial risks, including infection and thrombosis. Although indwelling CVCs should be removed as soon as they are no longer needed, clinicians may not be aware of their presence. Contribution This study found that many interns, residents, and attending physicians were unaware that their patients had indwelling catheters, including triple-lumen and peripherally inserted central catheters. Implication Increased efforts are needed to ensure that clinicians are mindful of the presence of their patients CVCs. The Editors Central venous catheters (CVCs) are instrumental for the safe and comprehensive care of many hospitalized patients. Often inserted in intensive care unit (ICU) and non-ICU settings, CVCs provide reliable venous access for tasks ranging from hemodynamic monitoring to delivery of irritants, vesicants, and intravenous antibiotics. In adults, 2 devices are most used in this context: nontunneled triple-lumen catheters placed in the subclavian, jugular, or femoral veins and peripherally inserted central catheters (PICCs) inserted into upper-extremity veins (1, 2). Despite their many advantages, triple-lumen catheters and PICCs are associated with important risks, including central lineassociated bloodstream infections (CLABSIs) and venous thromboembolism (3, 4). In particular, PICC-related CLABSI and thromboembolism have recently garnered attention owing to their frequency, attributable cost, and potential for prevention (5, 6). Because the risk for these adverse outcomes increases with time, early removal of CVCs that are no longer clinically warranted is a key strategy for prevention (7, 8). However, accumulating evidence suggests that clinicians often do not remove unnecessary CVCs. For example, a study done at a large academic medical center found many patients with PICCs that were idle and not clinically justifiable (3). In another study, 6.6% of CVCs in non-ICU settings were found to be inappropriate and clinically unnecessary at the time of review (4). These findings are not unique to the United Statesconcerns about inappropriately prolonged use of vascular access devices are well-documented worldwide (912). In survey-based studies of inpatient providers, nearly half of all hospitalists stated that they had, at least once, forgotten that their patient had a PICC in situ (13, 14). These findings mirror trends noted with indwelling urinary catheters, in which 1 in 3 physicians was unaware that these devices were present (15). Given this background, we sought to determine how often interns, residents, general medicine attendings, hospitalists, and subspecialists know which of their hospitalized patients have a PICC or triple-lumen catheter. We hypothesized that clinicians who write orders for or those who are most proximal to patients (for example, interns and hospitalists) would be most likely to correctly identify which of their patients have CVCs. Further, we postulated that clinicians who insert CVCs (such as critical care specialists) or consciously deliberate on the choice of a vascular access device (such as hematologists or oncologists) would be more likely to be aware that a device was present. Methods Patients and Study Population Between April 2012 and September 2013, we conducted face-to-face interviews with hospitalized patients and their responsible clinicians at 3 academic medical centers in the United States. A responsible clinician was defined as an intern, resident, physician extender (for example, nurse practitioner or physician assistant), or attending physician who had provided care to a patient for at least 24 hours. Housestaff were defined as interns (year 1 of training), residents (beyond year 1 of training), or physician extenders who cared for patients under the supervision of an attending physician. At each site, patients and providers were randomly selected from general medicine teaching, hospitalist-only, and subspecialty services that often use CVCs (such as cardiology, gastroenterology and hepatology, hematology and oncology, and critical care) and were primarily responsible for patient care (for example, not consultants). Thus, any provider on duty or patient receiving care in a specialty or discipline of interest was eligible for study inclusion. Eligible patients were identified using electronic patient lists for provider teams at each site. At 2 sites, patients were approached for participation and interviewed for the presence of a CVC. At 1 site, CVCs were identified through use of a validated electronic tool (98% accuracy at correctly identifying CVC presence); these patients were included but not directly examined for device presence. After patients were interviewed or electronically identified, providers were approached to ascertain their awareness of device presence. Clinicians were blinded to which patients were participating in the study and were queried for all patients on their roster. Survey Methods Before morning team rounds, we approached patients to seek written informed consent for participation at 2 of our 3 sites. If patients could not provide consent and a family member was available, consent was obtained from next of kin. Requirement for informed consent was waived at our third site. After consent was obtained, patients were interviewed and a focused examination was done to determine the presence of a PICC or triple-lumen catheter in the jugular, subclavian, or femoral veins at 2 study sites. Central venous catheters were defined as PICCs inserted in any upper-extremity vein or triple-lumen catheters placed in the neck, chest, or groin. Patients with specialty catheters, including hemodialysis catheters, small-bore catheters (such as Pro-Line CTs [Medcomp]), tunneled lines, and midlines were excluded. We surveyed patients in ICU and non-ICU settings; those on surgical services were excluded. Patients were surveyed only once during hospitalization; surveys were done weekly at all sites. After team rounds, we interviewed medical providers for each patient and asked, As of this morning, does your patient have a PICC or a triple-lumen catheter in the neck, chest, or groin? All clinicians were interviewed after morning rounds to ensure that they had seen the patient the day that the survey was administered. Clinicians were interviewed separately and were not notified of our visit beforehand. We allowed clinicians to use such materials as written notes or sign-outs during the interview but they were not allowed access to electronic health records. Because teaching attendings were responsible for all patients on the team, they were queried about CVC presence for all patients on their list. Subspecialists were similarly queried for all patients on their inpatient specialty teams. Interns, residents, and physician extenders were questioned only about patients for whom they were primarily responsible, regardless of assignment to a general medicine or specialist team. All clinicians were surveyed the day that patients were examined. Statistical Analysis Descriptive statistics for patient, provider, device, and site characteristics were used to define the study samples. The primary outcome of interest was unawareness of PICC or triple-lumen catheter presence. Given the categorical nature of the data, differences among provider types and training levels were compared using chi-square tests, where appropriate. Stata MP, version 13.0 (StataCorp), was used for all statistical analyses, and Pvalues less than 0.050 were considered statistically significant. Institutional review boards at each site provided ethical and regulatory approval for the study. Role of the Funding Source The study was not funded by any agency. Results Of the 1082 patients approached, 990 (91.5%) consented to participate in the study. For these 990 patients, we did 1881 clinician assessments across the 3 study sites (Table 1). Clinician responses from interns (454), residents and physician extenders (513), general medicine teaching attendings (245), subspecialty attendings (176), intensivists (95), and hospitalists (398) were included. An average of 1.9 clinician assessments were associated with each patient. Table 1. Patient, Provider, and Site Characteristics The overall prevalence of CVCs (triple-lumen catheter or PICC) was 21.1% (209 of 990). More than one half of the 209 devices were PICCs (n= 126 [60.3%]); the remaining 83 devices were triple-lumen catheters inserted in the neck (n= 41 [19.6%]), chest (n= 24 [11.5%]), or groin (n= 18 [8.6%]). A total of 47.0% (39 of 83) of triple-lumen catheters were found in patients in ICU settings; conversely, 92.9% (117 of 126) of PICCs were found in non-ICU patients. For the 209 patients with CVCs, 21.2% (90 of 425) of responsible clinicians were unaware of the presence of a triple-lumen catheter or PICC (Table 2). Unawareness of PICCs was greatestmore than 1 in 4 responsible clinicians (25.1% [60 of 239]) were not aware of their presence. Lack of awareness of a triple-lumen catheter or PICC varied from 16.3% to 31.1% across sites (P= 0.038) and was most pronounced in non-ICU settings, where PICCs are most common (24.8% vs. 12.6% in non-ICU and ICU settings; P= 0.005). Of note, a small but substantial number of clinicians (5.6% [82 of 1456]) stated that their patients had a CVC when no device was found on examination. Table 2. Awareness of CVC Presence We tested whether proximity to patients was associated with awareness of device presence. Although interns were the clinicians most likely to write orders, almost 1 of every 5 surveyed was not aware that his or her patient had a triple-lumen catheter or PICC (19.1% [22 of 115]). Although medical residents were more frequently aware of device presence than interns, the difference did not reach statistical significance (13.8% vs. 19.1%; P= 0.27). However, teaching

Mechanistic and pharmacologic insights on immune checkpoint inhibitors

&NA; The concept of augmenting the immune system to eradicate cancer dates back at least a century. A major resurgence in cancer immunotherapy has occurred over the past decade since the identification and targeting of negative regulators with antibody therapies to augment the anti‐tumor immune response. Unprecedented responses across a broad array of cancer types elevated this class of therapies to the forefront of cancer treatment. The most successful drugs to date target the cytotoxic T‐lymphocyte‐associated antigen‐4 (CTLA‐4) and programmed cell death‐1 (PD‐1) pathways. The immune biology of these pathways was illuminated through thoughtful pre‐clinical experiments over the past 20 years. The characterization of these negative immune regulators, also known as immune checkpoints, subsequently led to the successful clinical development four drugs in six different cancer types to date, and progress continues. Despite these successes, significant challenges remain including the development of predictive biomarkers, recognition and management of immune related toxicities, and elucidating and reversing mechanisms of primary and secondary resistance. Ongoing work is expected to build upon recent accomplishments and allow more patients to benefit from this class of therapies. Graphical abstract Figure. No caption available.

Emerging role of immunotherapy in urothelial carcinoma—Immunobiology/biomarkers

Urothelial bladder cancer is one of the first cancers recognized to be immunogenic since 40 years ago when the use of bacillus Calmette-Guerin was shown to prevent recurrence. Since that time, our knowledge of immune biology of cancer has expanded tremendously, and patients with bladder cancer finally have new active immunotherapeutic drugs on the horizon. Anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) therapy has shown impressively durable responses in urothelial bladder cancer (UBC), but the reported response rates warrant improvement. To outline potential strategies to overcome tumor immune resistance, herein, we summarize current models of tumor immunology with a specific focus on bladder cancer. Recognition of tumor-specific antigens through cross-presentation, T-cell priming and activation, and trafficking of immune cells to the tumor microenvironment are some of the critical steps we now understand to be necessary for an effective antitumor immune response. Many of the involved steps are important targets for therapeutic interventions. As new immunotherapies are developed, predictive biomarkers would also be important to select patients most likely to respond and to better understand tumor biology. Several potential biomarkers are reviewed including PD-L1 expression, identification of T-cell-inflamed/non-T-cell-inflamed tumors based on immune gene expression, intrinsic molecular subtyping based on luminal/basal or the cancer genome atlas (TCGA) groups, T-cell receptor sequencing, and somatic mutational density. Even within the past few years, our current knowledge of immune biology has exploded, and we are highly optimistic about the future of UBC therapy that will be available to patients.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a Pharmacodynamic Biomarker for Pazopanib in Metastatic Renal Carcinoma

Micro‐Abstract Metastatic renal cancer is commonly treated with drugs that block tumor blood vessel growth, such as pazopanib. Response often cannot be determined accurately using standard imaging scans. In this study, we evaluated patients with a magnetic resonance imaging parameter that reflects tumor blood vessel changes. It declined consistently after treatment, and higher baseline values correlated with longer time to disease progression. Introduction/Background: Traditional imaging assessment criteria might not correlate well with clinical benefit from vascular endothelial growth factor pathway‐directed therapy in metastatic renal cancer. Preclinical data suggest tumor growth is preceded by a rise in Ktrans level, a parameter derived from dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI) that reflects vascular permeability. We thus hypothesized that Ktrans might be a predictive biomarker for pazopanib. Patients and Methods: Patients with metastatic renal cancer were treated with pazopanib at 800 mg oral daily until disease progression. MRI of the abdomen and pelvis with a DCE‐MRI sequence was obtained at baseline and every 8 weeks. Results: Seventy‐three DCE‐MRI scans were completed and 66 were technically assessable. Of the 17 patients with at least 1 DCE‐MRI scan after the baseline scan, 16 (94%) had a decline in Ktrans level. Changes in Ktrans compared with baseline after 1, 8, 16, and 24 weeks were −49%, −65%, −63%, and −53%, respectively (P = .0052, repeated measures analysis of variance). The median Ktrans nadir occurred at 8 weeks. The median progression‐free survival (PFS) was 32.1 weeks. PFS was longer in patients with higher baseline Ktrans values (P = .036, log rank). Baseline Ktrans did not reach significance in a Cox proportional hazard model including clinical prognostic index and previous treatments (P = .083). Conclusion: We show that Ktrans is a pharmacodynamic biomarker for pazopanib therapy in metastatic renal cancer. Because of the small sample size, the predictive capacity of Ktrans recovery could not be assessed, but baseline Ktrans correlated with PFS.

Concurrent EGFR Mutation and ALK Translocation in Non-Small Cell Lung Cancer.

Epidermal growth factor receptor (EGFR) mutations and anaplastic large-cell lymphoma kinase (ALK) rearrangements are now routine biomarkers that have been incorporated into the practice of managing non-small cell lung cancer (NSCLC). Historically, the two molecular alterations have been viewed as mutually exclusive, but recent identified cases suggest otherwise. In this report, we describe cases of lung cancer with concurrent EGFR mutation and ALK rearrangement and identify their clinical characteristics. Non-small cell lung cancer patients with multiple molecular alterations were retrospectively analyzed from an academic referral center from 2011–2013. An additional review was conducted of reported cases with dual alterations. Four cases of NSCLC with alterations in both EGFR and ALK were identified and evaluated with 16 published cases for a total of 20 cases. The age of patients ranged from 37 to 77 years. Nine patients were never smokers. The disease control rates in patients treated with EGFR inhibitors and ALK inhibitors were 46% (6/13) and 71% (5/7), respectively. This series highlights the importance of comprehensive molecular profiling of newly diagnosed lung cancer, as NSCLC may be driven by concurrent molecular alterations. EGFR- and ALK-targeted therapies appear to have modest activity in patients with tumors possessing both alterations. Dual-altered NSCLC patients may have distinct clinical characteristics warranting further study. Combination targeted therapy or novel multi-targeted tyrosine kinase inhibitors may prove important in these patients, though necessary studies remain ongoing.

Low clinical adoption of tumor genomic profiling: cause for concern?

The way people with cancer are diagnosed, counseled, and treated has shifted dramatically in the precision oncology era. Precision medicine is broadly defined as “prevention and treatment strategies that take individual variability into account”. Practically speaking, these efforts encompass genetically profiling both tumor and germline tissues in an effort to tailor care for an individual patient. Success in precision oncology, however, has been mixed. Most clinical gains have been limited to tumor-specific advances, such as the utilization of BCR-ABL-targeted therapy for chronic myeloid leukemia (CML). Other incremental successes include the recent immunotherapy indication for microsatellite instability-high (MSI-high) colorectal cancers (CRCs), and the development of mutation-directed therapies, such as osimertinib for the T790M EGFR mutation in metastatic non-small cell lung cancer. Precision oncology has also produced novel indications for therapies, such as a germline-based approach to therapy for individuals with advanced ovarian cancer who possess pathogenic germline BRCA1/2 mutations (olaparaib) and a tumor agnostic indication for MSI-H or mismatch repair machinery-deficient metastatic tumors (pembrolizumab). It remains unclear if these examples will become a universal trend in oncology, or whether tissue histology will continue to be the primary driver of most therapeutic decisions. The tumor agnostic approach has been promoted through dramatic success stories, but in practice has been profoundly underwhelming when rigorously investigated in prospective randomized clinical trials. In a recent publication in the Journal of Medical Economics, authors from Foundation Medicine and consultants reported that the clinical uptake of tumor genomic profiling has been lower than anticipated. They conclude that this deficiency represents an opportunity to better tailor treatment strategies for patients with cancer. This study has some important methodological limitations. For instance, the frequency measurement of tumor genomic profiling was restricted to the metastatic setting, which would not capture profiling performed on a primary tumor. Methodological issues aside, we question the conclusion that low uptake is characterized as a missed opportunity, since this notion rests on the unproven presumption that increased uptake of broad genomic profiling in a general cancer population is directly linked with improved clinical outcomes. It is worth reviewing the ongoing challenges confronting the successful implementation of precision oncology, which might justify the finding of low uptake of genomic profiling. One major issue is the shifting definition of what constitutes a “targetable” mutation. Should a mutation be considered “targetable” if it is found in a tumor type for which no high quality prospective data exists regarding efficacy of the matched intervention? Or, should a mutation only be considered “targetable” if the utilization of the targeted therapy results in a meaningful improvement in patient outcomes, as demonstrated through well-run, prospective, randomized trials? We argue that testing and intervention should only be broadly adopted under the latter scenario. This more stringent expectation should not diminish the current value of well-established targeted therapies, nor should it preclude ongoing efforts to investigate novel therapeutic approaches in the context of clinical research. It would, however, bring pause to the widespread adoption of unproven therapies outside of research trials. A formidable challenge to precision oncology is the fact that most tumors lack “targetable” mutations, even when utilizing imprecise definitions. It is unclear why head and neck cancers were included in this analysis, since there are no approved genomically-matched targeted therapies, and current guidelines do not recommend genomic testing. Human papilloma virus (HPV) testing is recommended, but this is performed by immunohistochemistry for p16, and subsequent treatments involve chemotherapy and radiation. Cetixumab is approved for head and neck cancer, but its use is not tied to any genomic sequencing results. In a study of 10,000 tumors across 11 cancer types, only 37% of tumors in a large prospective study possessed targetable mutations, and only 11% of patients were enrolled in clinical trials based on a genomic profile. The likelihood of identifying a targetable mutation also varies enormously by tumor type. While 78% of tumors from patients with melanoma will possess a targetable mutation, only 21% of patients with CRC possess targetable mutations. Even more importantly, this latter proportion likely over-estimates the proportion of targetable mutations in CRC.