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ImportanceExtended-interval dosing of pembrolizumab (400 mg every 6 weeks) was approved by US Food and Drug Administration (FDA) in April 2020 as an alternative to standard-interval dosing (200 mg every 3 weeks). Extended-interval dosing may enhance access, alleviate patient and health system financial toxicity, and improve patient quality of life, particularly during the COVID-19 pandemic. Neither adoption nor effectiveness of extended interval in the US has been adequately described.ObjectiveTo describe adoption of extended-interval dosing of pembrolizumab since its FDA approval and to measure its preliminary real-world effectiveness compared with standard-interval dosing.Design, Setting, and ParticipantsThis was a retrospective cohort study that used data from the Veterans Health Administration (VHA), a US-based, nationwide single-payer health system. Participants were veterans who were prescribed single-agent pembrolizumab within the VHA between April 1, 2020, and July 1, 2021. Patients receiving combinations of pembrolizumab and cytotoxic chemotherapy or tyrosine kinase inhibitors were excluded. A subcohort of veterans with non−small cell lung cancer (NSCLC) was also identified using claims-based codes.ExposuresSingle-agent pembrolizumab at extended or standard intervals.Main Outcomes and MeasuresThe number and proportion of single-agent pembrolizumab prescriptions that were extended compared with standard interval. Effectiveness was described in terms of time-to-treatment discontinuation (TTD) and extended- to standard-interval pembrolizumab prescriptions were compared using Cox proportional hazards regression.ResultsA total of 835 veterans (mean age [SD], 70.9 [8.7] years; 809 [96.9%] men) began single-agent pembrolizumab during the study period (all-diseases cohort), and of these, 234 (mean [SD] age, 71.6 [7.3] years; 225 [96.2%] men) had NSCLC (NSCLC cohort). Extended-interval adoption reached its steady state plateau of approximately 35% by January 2021; 65% of participants who began standard-interval single-agent pembrolizumab received only standard-interval dosing during the treatment course. In analysis consistent with the intention-to-treat principle, no differences in TTD were observed between standard- and extended-interval dosing in either the all-diseases cohort (HR, 1.00; 95% CI, 1.00-1.00) or the NSCLC cohort (HR, 1.00; 95% CI, 1.00-1.00).Conclusions and RelevanceThis retrospective cohort study found that extended-interval dosing comprised a minority of single-agent pembrolizumab prescriptions despite the FDA approval and its potential health system and public health benefits. The findings support the TTD equivalence of standard- and extended-interval pembrolizumab across indications, complementing clinical pharmacology and single-arm clinical trial data in melanoma. This study provides further support for extended-interval pembrolizumab dosing.

One year of adjuvant durvalumab following concurrent chemoradiotherapy significantly improves progression-free survival (PFS) and overall survival (OS) for patients with stage III non-small cell lung cancer (NSCLC). However, the optimal length of adjuvant therapy has not been determined.We identified patients with stage III NSCLC treated with definitive chemoradiation and adjuvant durvalumab from November 2017 to April 2021 from the United States Veterans Affairs system. Predictors of early durvalumab discontinuation were evaluated with Cox proportional hazards regression. The effect of differing durations of durvalumab treatment (up to 6, 9, and 12 months) on PFS and OS were compared with a marginal structural model and time-dependent Cox modelling.We included 1006 patients with stage III non-small cell lung cancer who received concurrent chemoradiotherapy and at least one dose of adjuvant durvalumab. The median duration of durvalumab treatment was 7 months (interquartile range 2.8-11.5) and 31% completed the intended durvalumab course. The most common reasons for early discontinuation were tumour progression (22%), immune-related adverse events (15%), and non-immune-related toxicity (6.0%), Marginal structural models suggested similar PFS for 9 months versus 12 months of durvalumab treatment and inferior PFS for 6 months versus 12 months.A substantial proportion of patients undergoing adjuvant durvalumab discontinue therapy early due to toxicity, and shorter durvalumab treatment durations may provide similar disease control to 12 months of therapy. Prospective randomised controlled studies are needed to characterise the optimal durvalumab treatment duration in locally advanced NSCLC patients.

Immune checkpoint inhibitors (ICI) are important treatment options for metastatic non-small cell lung cancer (NSCLC). However, not all patients benefit from ICIs and can experience immune related adverse events (irAEs). Limited understanding exists for germline determinants of ICI efficacy and toxicity, but human leukocyte antigen (HLA) has emerged as a potential predictive biomarker. We obtained HLA genotypes from 85 metastatic NSCLC patients on ICI therapy and analyzed the impact of HLA Class II genotype on progression free survival (PFS), overall survival (OS), and irAEs. Most patients received pembrolizumab (83.5%). HLA-DRB4 correlated with improved survival in both univariable (PFS 9.9 months, p = 0.040; OS 26.3 months, p = 0.0085) and multivariable analysis (PFS p = 0.0310, HR 0.55, 95% CI [0.31, 0.95]); OS p = 0.003, HR 0.40, 95% CI [0.21, 0.73]). 11 patients developed endocrine irAEs. HLA-DRB4 was expressed in 39/85 (45.9%) patients and was the predominant genotype for endocrine irAEs (9/11, 81.8%). Cumulative incidence of endocrine irAEs was higher in patients with HLA-DRB4 (p = 0.0139). Our study is the first to suggest metastatic NSCLC patients on ICI therapy with HLA-DRB4 genotype experienced improved survival outcomes. Additionally, we found a correlation between HLA-DRB4 and endocrine irAEs.

Liquid biopsy refers to the identification of tumor-derived materials in body fluids including in blood circulation. In the age of immunotherapy and targeted therapies used for the treatment of advanced malignancies, molecular analysis of the tumor is considered a crucial step to guide management. In lung cancer, the concept of liquid biopsies is particularly relevant given the invasiveness of tumor biopsies in certain locations, and the potential risks of biopsy in a patient population with significant co-morbidities. Liquid biopsies have many advantages including non-invasiveness, lower cost, potential for genomic testing, ability to monitor tumor evolution through treatment, and the ability to overcome spatial and temporal intertumoral heterogeneity. The potential clinical applications of liquid biopsy are vast and include screening, detection of minimal residual disease and/or early relapse after curative intent treatment, monitoring response to immunotherapy, and identifying mutations that might be targetable or can confer resistance. Herein, we review the potential role of circulating tumor DNA and circulating tumor cells as forms of liquid biopsies and blood biomarkers in non-small cell lung cancer. We discuss the methodologies/platforms available for each, clinical applications, and limitations/challenges in incorporation into clinical practice. We additionally review emerging forms of liquid biopsies including tumor educated platelets, circular RNA, and exosomes.

SF1: ATM regulates type I interferon signaling in pancreatic cancer. SF2: ATM regulation of the type I interferon pathway is cGAS/STING independent but SRC dependent. SF3: ATM inhibition cooperates with radiation to activate type I interferon signaling. SF4: ATM regulates pancreatic tumor immunity and ICB efficacy in vivo.

Purpose: African Americans have higher incidence and poorer response to lung cancer treatment compared with Caucasians. However, the underlying molecular mechanisms for the significant ethnic difference are not known. The present study examines the ethnic differences in the type and frequency of MET proto-oncogene (MET) mutation in lung cancer and correlated them with other frequently mutated genes such as epidermal growth factor receptor (EGFR), KRAS2, and TP53.Experimental Design: Using tumor tissue genomic DNA from 141 Asian, 76 Caucasian, and 66 African American lung cancer patients, exons coding for MET and EGFR were PCR amplified, and mutations were detected by sequencing. Mutation carriers were further screened for KRAS2 and TP53 mutations. Functional implications of important MET mutations were explored by molecular modeling and hepatocyte growth factor binding studies.Results: Unlike the frequently encountered somatic mutations in EGFR, MET mutations in lung tumors were germline. MET-N375S, the most frequent mutation of MET, occurred in 13% of East Asians compared with none in African Americans. The frequency of MET mutations was highest among male smokers and squamous cell carcinoma. The MET-N375S mutation seems to confer resistance to MET inhibition based on hepatocyte growth factor ligand binding, molecular modeling, and apoptotic susceptibility to MET inhibitor studies.Conclusions: MET in lung cancer tissues contained nonsynonymous mutations in the semaphorin and juxtamembrane domains but not in the tyrosine kinase domain. All the MET mutations were germline. East Asians, African-Americans, and Caucasians had different MET genotypes and haplotypes. MET mutations in the semaphorin domain affected ligand binding. (Clin Cancer Res 2009;15(18):5714–23)

Supplementary Data from Ethnic Differences and Functional Analysis of MET Mutations in Lung Cancer

Combinatorial strategies are needed to overcome the resistance of pancreatic cancer to immune checkpoint blockade (ICB). DNA damage activates the innate immune response and improves ICB efficacy. Because ATM is an apical kinase in the radiation-induced DNA damage response, we investigated the effects of ATM inhibition and radiation on pancreatic tumor immunogenicity. ATM was inhibited through pharmacologic and genetic strategies in human and murine pancreatic cancer models both in vitro and in vivo. Tumor immunogenicity was evaluated after ATM inhibition alone and in combination with radiation by assessing TBK1 and Type I interferon (T1IFN) signaling as well as tumor growth following PD-L1/PD-1 checkpoint inhibition. Inhibition of ATM increased tumoral T1IFN expression in a cGAS/STING-independent, but TBK1- and SRC-dependent, manner. The combination of ATM inhibition with radiation further enhanced TBK1 activity, T1IFN production, and antigen presentation. Furthermore, ATM silencing increased PD-L1 expression and increased the sensitivity of pancreatic tumors to PD-L1–blocking antibody in association with increased tumoral CD8+ T cells and established immune memory. In patient pancreatic tumors, low ATM expression inversely correlated with PD-L1 expression. Taken together, these results demonstrate that the efficacy of ICB in pancreatic cancer is enhanced by ATM inhibition and further potentiated by radiation as a function of increased tumoral immunogenicity, underscoring the potential of ATM inhibition in combination with ICB and radiation as an efficacious treatment strategy for pancreatic cancer.Significance:This study demonstrates that ATM inhibition induces a T1IFN-mediated innate immune response in pancreatic cancer that is further enhanced by radiation and leads to increased sensitivity to anti–PD-L1 therapy.See related commentary by Gutiontov and Weichselbaum, p. 3815

Purpose: To determine whether different subtypes of lung adenocarcinoma (AC) have distinct microRNA (miRNA) expression profiles, and to identify miRNAs associated with aggressive subgroups of resected lung AC.Experimental Design: miRNA expression profile analysis was performed in 91 resected lung AC and 10 matched nonmalignant lung tissues using a PCR-based array. An independent cohort of 60 lung ACs was used for validating by quantitative PCR the top 3 prognostic miRNAs. Gene-expression data from 51 miRNA profiled tumors was used for determining transcript-specific miRNA correlations and gene-enrichment pathway analysis.Results: Unsupervised hierarchical clustering of 356 miRNAs identified 3 major clusters of lung AC correlated with stage (P = 0.023), tumor differentiation (P < 0.003), and IASLC histologic subtype of lung AC (P < 0.005). Patients classified in cluster 3 had worse survival as compared with the other clusters. Eleven of 22 miRNAs associated with poor survival were encoded in a large miRNA cluster at 14q32. The top 3 prognostic 14q32 miRNAs (miR-411, miR-370, and miR-376a) were validated in an independent cohort of 60 lung AC. A significant association with cell migration and cell adhesion was found by integrating gene-expression data with miR-411, miR-370, and miR-376a expression. miR-411 knockdown significantly reduced cell migration in lung AC cell lines and this miRNA was overexpressed in tumors from patients who relapsed systemically.Conclusions: Different morphologic subtypes of lung AC have distinct miRNA expression profiles, and 3 miRNAs encoded at 14q32 (miR-411, miR-370, and miR-376a) were associated with poor survival after lung AC resection. Clin Cancer Res; 20(12); 3107–17. ©2014 AACR.

PDF file - 147KB, Additional Material and Methods. Table S1- Clinicopathological characteristics of the 151 lung AC patients. Table S2- Differentially expressed miRs between lung adenocarcinoma and matched nonmalignant lung samples. Table S3- MiRs significantly associated with the presence of solid or lepidic-mucinous invasive component in the tumor. Table S4- Survival analysis based on clinicopathological characteristics. Table S5- Statistically significant miRs in the univariate and multivariate Cox regression for OS. Table S6- DFS and OS analysis (Multivariate Cox model) of risk score in the validation set. Table S7- Gene Ontology terms based upon the transcripts significantly correlated with miR-370, miR-411 and miR-376a expression in 51 lung ACs. Table S8- EMT genes significantly correlated with miR-411 expression in 51 lung ACs.

XLSX file - 19KB, Table S9- List of studies that identified prognostic miRs in lung cancer by miR profiling.

SF1 Legend: ATM regulates type I interferon signaling in pancreatic cancer. SF2 Legend: ATM regulation of the type I interferon pathway is cGAS/STING independent but SRC dependent. SF3 Legend: ATM inhibition cooperates with radiation to activate type I interferon signaling. SF4 Legend: ATM regulates pancreatic tumor immunity and ICB efficacy in vivo.

Supplementary Figures S1-S4; Supplementary Tables S1-S4.

Supporting information showing CTC enumeration and gene expression profiling data for CTC clusters from early stage lung cancer.

PDF file - 1289KB, Fig S1- Box plots of the risk score values in the training and test set. Fig S2- SAM plot of 10 lung AC versus 10 matched nonmalignant lung samples. Fig S3- Pathway enrichment analysis based on predicted genes targeted by top 10 miRs discriminating lung AC vs. nonmalignant lung. Fig S4- Hierarchical clustering based on miR expression in 91 lung ACs, without including nonmalignant samples. Fig S5- Hierarchical clustering based on 306 most variable expressed miRs in 474 lung ACs from TCGA-Lung Adenocarcinoma cohort. Fig S6- Box plots of average expression of genes involved in Notch pathway, c-Myc targets, embryonic stem-cell signature among the 3 miR clusters in 51 lung AC. Fig S7- Kaplan-Meier plots of OS in the training set for 3 miRs encoded at the 14q32 region and selected for validation. Fig S8- Scatterplot matrix showing the correlation between 21 miRs encoded at 14q32.

Early detection of metastasis can be aided by circulating tumor cells (CTC), which also show potential to predict early relapse. Because of the limited CTC numbers in peripheral blood in early stages, we investigated CTCs in pulmonary vein blood accessed during surgical resection of tumors. Pulmonary vein (PV) and peripheral vein (Pe) blood specimens from patients with lung cancer were drawn during the perioperative period and assessed for CTC burden using a microfluidic device. From 108 blood samples analyzed from 36 patients, PV had significantly higher number of CTCs compared with preoperative Pe (P < 0.0001) and intraoperative Pe (P < 0.001) blood. CTC clusters with large number of CTCs were observed in 50% of patients, with PV often revealing larger clusters. Long-term surveillance indicated that presence of clusters in preoperative Pe blood predicted a trend toward poor prognosis. Gene expression analysis by RT-qPCR revealed enrichment of p53 signaling and extracellular matrix involvement in PV and Pe samples. Ki67 expression was detected in 62.5% of PV samples and 59.2% of Pe samples, with the majority (72.7%) of patients positive for Ki67 expression in PV having single CTCs as opposed to clusters. Gene ontology analysis revealed enrichment of cell migration and immune-related pathways in CTC clusters, suggesting survival advantage of clusters in circulation. Clusters display characteristics of therapeutic resistance, indicating the aggressive nature of these cells. Thus, CTCs isolated from early stages of lung cancer are predictive of poor prognosis and can be interrogated to determine biomarkers predictive of recurrence. Cancer Res; 77(18); 5194–206. ©2017 AACR.

Purpose The addition of carboplatin has improved pathological complete response (PCR) and event-free survival (EFS) and is becoming a new standard of care for early triple-negative breast cancer (TNBC). However, this comes at the expense of increased toxicity. Here, we aimed to evaluate a novel cisplatin-based chemotherapy regimen for early TNBC. Methods Women with early TNBC who were administered neoadjuvant chemotherapy consisting of four cycles of docetaxel and cyclophosphamide alternated with cisplatin and epirubicin (ddDCEP) given every two weeks over a 16-week period were analyzed in this retrospective real-world study, driven by physician preference. The major outcomes assessed were PCR and EFS. Other outcomes included overall survival, treatment delivery, and adverse events. Results From January 2017 to January 2020, 116 women with stage I-III TNBC received neoadjuvant ddDCEP. PCR (ypT0/TisN0) was observed in 55.2% of evaluable patients. The PCR in stage I/II disease was 62.2%, and stage III was 49.5%. 37.9% of patients developed grade 3 anemia during treatment. Incidence of grade 3/4 neutropenia was 16.3%, and febrile neutropenia was 4.3%. 86% of patients completed all 8 cycles of planned chemotherapy, and 98% at least 6 out of 8 cycles. 12% patients required dose reduction of taxane and 19% for cisplatin. At 30 months of median follow-up, the EFS was 91.2%, and overall survival was 97%. Cost analysis showed this regimen was more cost-effective than carboplatin-based regimens. Conclusion Treatment with ddDCEP led to pCR in a significant proportion of patients, with high completion rates and lower toxicity, particularly neutropenia. These findings suggest that ddDCEP may be a promising, cost-effective treatment option for early TNBC.

PURPOSE Preoperative long course chemoradiation (LCCRT) followed by total mesolectal excision (TME) results in excellent local control but distant failure rates remain high. Total neoadjuvant therapy (TNT) with pre-operative delivery of systemic chemotherapy and chemoradiotherapy results in a higher pathological response, improved event free and overall survival and is becoming the new standard of care. We describe our experience with a hybrid TNT consisting of induction chemotherapy followed by chemoradiotherapy using full dose 5FU without oxaliplatin. METHODS In this single center study, adults with a LARC were included. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, biopsy-proven, newly diagnosed LARC, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumor [cT] stage cT4a or cT4b, extramural vascular invasion (EMVI), clinical nodal [cN] stage cN2, mesorectal fascia involvement and enlargement/tumor deposits on lateral lymph nodes). The hybrid TNT protocol comprised of six biweekly courses of modified FOLFOX6 (m FOLFOX6) followed by addition of pelvic LCCRT with four concurrent cycles of biweekly 5-FU 2600 mg/m2 + LV 200 mg/m2 without oxaliplatin to complete uninterrupted 20 weeks of full dose 5FU + LV chemotherapy. Pelvic chemoradiotherapy consisted of 28 daily fractions of 2 Gy up to 50.4-54Gy including boost to extra-mesorectal nodes. Surgery was planned 11-13 weeks after completing chemoradiotherapy. Outcomes of interest were pathological complete response (pCR), 2 year disease free survival (DFS) and overall survival (OS). RESULTS Between July 2017 to August 2020, 84 adults, predominantly male (65.5%) aged 42.5±13 years with LARC were treated with the TNT protocol. High risk features were T3/T4 in 80 (95.3%), N2 nodes 51(60.7%), signet ring cell histology 22(26.2%), meso-rectal fascia involvement 73(86.9%), EMVI 54 (64.3%) and lateral pelvic nodes 25(29.8%). Eighty- one (96.4%) completed all planned chemotherapy. All but two patients completed the planned RT. pCR was noted in 27 (32%). Twenty-five (29%) did not undergo surgery- 6(7%) opted for non-operative management (NOM) after complete clinical response (cCR), 5 refused surgery, 13(15.4%) were deemed inoperable due to inadequate tumor regression despite TNT (R0 resection was not feasible) and 2 did not complete treatment. Grade 3 &4 toxicities included neutropenia in 20 (23.8%), diarrhea in 12 (14.2%) and anemia in 9(10.7%) patients. Grade 5 toxicities were seen in one patient who died from neutropenic sepsis, and another who developed a cerebrovascular accident on therapy. After 24.5 months of median follow-up, 23 (27%) patients recurred, with local recurrence in 5(6%), systemic recurrence in 16 (19%) and both in 2(2.4%). The median disease-free survival (DFS) of the whole cohort was 22.5 months. Those who did not undergo surgery(n=19) despite residual disease (no cCR) had the worst outcomes (mDFS 11.4 months versus 27.7months, p= and mOS 15 months versus 29.2 months p= CONCLUSION The hybrid TNT regimen was administered without significant dose delays or interruptions. Toxicity was manageable but with two treatment related deaths. pCR of 32% is comparable to contemporary trials, however the 2-year recurrence rates were not improved. Ability to undergo surgery after TNT predicted for improved DFS and OS.

Small extracellular vesicles, often termed as “exosomes” carry informative cargo containing proteins and lipids, reflective of their cellular origin. Thus, they are promising biomarkers for early diagnosis of cancer. However, conventional profiling methods like quantitative polymerase chain reaction (qPCR) require complex procedures, thereby limiting the analytical sensitivity of exosomes for liquid biopsies. Here, we demonstrate a sensitive microfluidic device (CDEXO) that isolates and profiles cancer-associated exosomes directly from blood plasma using assembled chiral gold nanoparticles (AuNPs). The unique changes in chiral signals are associated with specific biomolecules on the exosomes’ membranes. Thus, we can distinguish exosomes of lung cancer patients from those of healthy individuals and detect mutated EGFR proteins on the membrane. Hence, this low-cost microfluidic device is an attractive technique for rapid, sensitive, and versatile profiling of various extracellular vesicles. Methods: The top layer of CDEXO devices were fabricated by soft lithography using polydimethylsiloxane (PDMS). The bottom glass slide was functionalized with a layer-by-layer assembly of cationic poly(dimethyl diallyl ammonium chloride) and anionic polystyrene sulfonate. AuNPs were prepared by adding gold nanoplates to a growth solution. Next, AuNPs were conjugated with biotinylated Annexin-V, using Neutravidin-biotin chemistry. Exosomes were harvested from lung cancer cell lines (A549, H1650, H3255) and lung fibroblasts (MRC5) and spiked into the CDEXO chip. EDTA was used to release the captured exosomes and quantified using nanoparticle tracking analysis (NTA). CD spectra were measured by spectrometry. Imaging of AuNPs and exosomes were done using scanning electron microscope (SEM). Results: CDEXO captures cancer-associated exosomes with an efficiency of 81.1±1.5%. H3255 derived exosomes that exhibited EGFR point mutation showed the greatest change in spectral signals from the baseline, followed by A549 (wild type), H1650, (EGFR exon19 deletion) and MRC5 (healthy). The CD responses were measurable at exosome numbers as low as 100. Further validation with 19 lung cancer patients showed an average 40% change in chiral signals from isolated exosomes that were 5.6 times higher in patients than healthy donors. Conclusions: A microfluidic device with chiral AuNPs allows sensitive and accurate detection of lung cancer-associated exosomes by conjugation with Annexin V. The resulting strong CD peaks that arise from specific interactions between exosomal surface proteins and chiral AuNPs facilitate in-depth profiling of target exosomes, including EGFR mutation expression. Citation Format: Yoon-Tae Kang, Ji-Young Kim, Emine Sumeyra Turali-Emre, Hee-Jeong Jang, Minjeong Cha, Abha Kumari, Colin Palacios-Rolston, Chitra Subramanian, Emma Purcell, Sarah Owen, Chung-Man Lim, Rishindra Reddy, Shruthi Jolly, Nithya Ramnath, Nicholas A. Kotov, Sunitha Nagrath. Chiroptical detection and mutation analysis of cancer-associated extracellular vesicles in microfluidic devices with oriented chiral nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 994.

The risk of peripherally inserted central catheter (PICC)-related complications in patients hospitalized with solid tumors remains unclear. Existing studies are limited by single-center, outpatient designs and include heterogenous patients.A retrospective cohort study was designed and included adult patients with solid organ cancers who were admitted to a general medicine ward or intensive care unit and received a PICC. Data were collected from November 2013 to December 2019 at 50 Michigan hospitals. Major complications were defined as central line-associated bloodstream infection, deep vein thrombosis, pulmonary embolism, and catheter occlusion. Hospital variation in PICC use and outcomes was examined.Data included 3235 hospitalized patients with solid tumors who had PICCs placed for 51,047 catheter days. Most catheters were double-lumen devices (57.0%). Notably, 17.5% of patients had another central venous catheter at the time of PICC insertion. The most common indications for PICC use were antibiotics (34.5%) and difficult access or blood draws (21.6%); chemotherapy was the primary indication in only 15.7% of patients. A major PICC-related complication occurred in 491 patients (15.2%); catheter occlusion was the most prevalent complication (n = 322; 10.0%) followed by deep vein thrombosis (n = 116; 3.6%), central line-associated bloodstream infection (n = 82; 2.5%), and pulmonary embolism (n = 20; 0.6%). Significant variation in indications for PICC use, device characteristics, and frequency of major complications across hospitals was observed (p .001).PICCs were associated with significant complications in hospitalized patients who had solid malignancies and were often used for reasons other than chemotherapy. Policies and guidance for the appropriate use of PICCs in oncologic patients appear necessary.Peripherally inserted central catheters (PICCs) are devices placed in peripheral veins to deliver medication to large veins near the heart. PICCs are used frequently in oncology. The objective of this report was to describe PICC-associated complications in hospitalized patients with solid tumors. This study was performed across 50 Michigan hospitals and included 3235 patients with solid tumor cancers and who had a PICC. Overall, 15.2% of patients experienced a complication, including central line-associated bloodstream infections, deep vein thrombosis, pulmonary embolism, or catheter occlusion. Complication rates varied across hospitals. PICCs are associated with substantial complications in hospitalized patients with solid tumors.

Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity. Liver metastases reduce clinical and preclinical immune-checkpoint inhibitor efficacy through hepatic siphoning of circulating activated CD8+ T cells, but therapeutic benefit can be improved by combining immunotherapy with liver-directed radiotherapy.

PURPOSE: Increased access and utilization of tumor profiling of cancers in our veteran population uncovered a modest number of potentially pathogenic germline variants (PPGVs) that require genetics referral for follow-up evaluation and germline sequencing. Challenges identified specific to the veteran population include paucity of genetics providers, either at a veteran's VA facility or nearby non-VA facilities. We sought to investigate the number of veterans who would benefit from having such resources at both local and national levels. METHODS: Annotated clinical reports of mutations identified by tumor-only profiling and medical records of veterans with solid tumors at the Veterans Administration Ann Arbor Healthcare System (VA AAHS) between 2015 and 2020 were reviewed. PPGVs were identified according to society recommendations (such as ESMO and American Board of Medical Genetics and Genomics), expert review, and/or previously published criteria. After the analysis of our local VA population, these same criteria were then applied to veterans in the National Precision Oncology Program (NPOP). RESULTS: Two hundred eight veterans underwent tumor profiling at the VA AAHS over the defined time period. This included 20 different primary tumor sites with over half (n = 130) being advanced cancer at diagnosis. Of these, 18 veterans (8.5%) had mutations suggestive of a PPGV. Applying these criteria to the larger NPOP database (n = 20,014), a similar percentage (6%) of PPGVs were identified. CONCLUSION: These results indicate a PPGV frequency (6%-9% of veterans) consistent with the prevalence of inherited cancer predisposition syndromes in the general population, underscoring the need for medical genetics as part of standard oncologic care for veterans. We explore current and future care delivery models to optimize incorporation of medical genetics and genetic counseling to best serve veterans needing such services.

OBJECTIVE Type 1 diabetes mellitus (T1DM) is a rare, irreversible immune-related adverse event reported in patients receiving treatment with immune checkpoint inhibitors (ICI). However, clinical risk factors for ICI-induced T1DM (ICI-T1DM) and its impact on survival in patients remain unknown. RESEARCH DESIGN AND METHODS We used Optum’s Clinformatics Data Mart database for assessment of the incidence and characteristics of T1DM in a large de-identified cohort of patients treated with ICI between 2017 and 2020. We applied Fine-Gray and cause-specific hazard models to study associations between patient/treatment characteristics and ICI-T1DM and applied the Cox model with ICI-T1DM as a time-varying covariate to assess the impact of ICI-T1DM on survival. RESULTS ICI-T1DM was observed in 261 of 30,337 (0.86%) patients. Dual use of antibodies to cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) was associated with increasing risk of ICI-T1DM (hazard ratio [HR] 1.62; 95% CI 1.15–2.26) vs. anti–PD-L1 or anti–PD-1 alone. Younger age (HR 1.19 for every 5-year decrease; 95% CI 1.13–1.25) and preexisting non-T1DM diabetes (HR 4.48; 95% CI 3.45–5.83) were also associated with higher risk of ICI-T1DM. Conversely, prior use of immunosuppressive medications (HR 0.57; 95% CI 0.34–0.95) was associated with lower incidence of ICI-T1DM, but part of its protective effect may be due to the increased mortality rate. Development of ICI-T1DM does not seem to significantly impact patient survival. CONCLUSIONS The risk of ICI-T1DM is associated with the type of ICI therapy, patient age, and preexisting non-T1DM diabetes. These data may help guide risk assessment and screening practices for patients during ICI therapy.

PURPOSE: It is unclear whether time from radiation (RT) completion to durvalumab influences the outcomes of stage III non-small-cell lung cancer (NSCLC) treated with definitive chemoradiation and adjuvant durvalumab. METHODS AND MATERIALS: Using the United States Veterans Health Administration database, we retrospectively identified 728 patients with stage III NSCLC treated with definitive chemoradiation who started durvalumab within 120 days of radiation completion. Time between the last radiation treatment and first durvalumab infusion was analyzed in multivariable Cox regression models for the primary outcomes of progression-free survival (PFS) and overall survival (OS), adjusting for baseline patient and disease characteristics. The primary analysis used a 120-day landmark, measuring OS and PFS from 120 days after radiation completion. RESULTS: Among 728 patients, the median time from RT completion to durvalumab start was 41 days (interquartile range [IQR] 30–58). In multivariable Cox regression, time from RT completion to durvalumab start showed no association with PFS (adjusted hazard ratio [aHR] 1.01 per week, 95% confidence interval [CI] 0.98–1.04, p=0.4) or OS (aHR 1.02 per week, 95% CI 0.98–1.06, p=0.3). Starting durvalumab ≤ 14 days after RT was also not associated with improved PFS or OS. Results were robust in sensitivity analyses varying analytical technique. CONCLUSION: Timing of durvalumab initiation up to 120 days after RT completion is not associated with PFS or OS in this real-world patient cohort.

It is unclear whether programmed death ligand 1 (PD-L1) expression is prognostic or predictive of immunotherapy benefit among patients with stage III non-small cell lung cancer (NSCLC) treated with definitive chemoradiation and adjuvant durvalumab.We determined pretreatment tumor PD-L1 expression for 312 patients with stage III NSCLC treated with definitive chemoradiation and at least 1 dose of adjuvant durvalumab between November 2017 and April 2021 across the national Veterans Health Administration. Progression-free survival (PFS) and overall survival (OS) in PD-L1 expression subgroups (1%, 1%-49%, and 50%-100%) were compared with 994 patients with stage III NSCLC treated without adjuvant durvalumab from 2015 to 2016.PD-L1 expression was1%, 1% to 49%, and 50% to 100% in 109 (34.9%), 96 (30.7%), and 107 (34.3%) patients, respectively. Increasing PD-L1 expression was associated with longer PFS (adjusted hazard ratio [aHR], 0.84 per 25% absolute increase in expression; 95% confidence interval [CI], 0.75-0.94; P = .003) and OS (aHR, 0.86 per 25% absolute increase in expression; 95% CI, 0.74-0.99; P = .036). Compared with the no-durvalumab group, PFS was longer for PD-L1 50% to 100% (aHR, 0.44; 95% CI, 0.32-0.60; P.001) and PD-L1 1% to 49% (aHR, 0.64; 95% CI, 0.47-0.86; P = .003) but not PD-L11% (aHR, 0.84; 95% CI, 0.64-1.10; P = .19). Similar results were found for OS, with no significant difference between the no-durvalumab group and PD-L11% (aHR, 0.81; 95% CI, 0.58-1.13; P = .22).Increasing tumor PD-L1 expression is prognostic for PFS and OS among patients with stage III NSCLC treated with adjuvant durvalumab, and patients with PD-L1 expression1% may have limited benefit from adjuvant durvalumab.

Purpose Preclinical data and subset analyses from immunotherapy clinical trials indicate that prior radiation therapy was associated with better progression-free survival and overall survival when combined with immune checkpoint inhibitors in patients with non-small cell lung cancer. We present a prospective study of hypofractionated image guided radiation therapy (HIGRT) to a single site of metastatic disease concurrently with atezolizumab in patients with metastatic non-small cell lung cancer. Methods and Materials Patients meeting eligibility criteria received 1200 mg of atezolizumab intravenously every 3 weeks with concurrent 3- or 5-fraction HIGRT starting no later than the second cycle. The 3-fraction regimen employed a minimum of 8 Gy per fraction compared with 6 Gy for the 5-fraction regimen. Imaging was obtained every 12 weeks to assess response. Results From October 2015 to February 2017, 12 patients were enrolled in the study (median age 64; range, 55-77 years). The best response by the Response Evaluation in Solid Tumors criteria was partial response in 3 and stable disease in 3, for a disease control rate of 50%. Five patients had a grade 3 immune-related adverse event, including choreoretinitis (n = 1), pneumonitis (n = 1), transaminitis (n = 1), fatigue (n = 1), and peripheral neuropathy (n = 1). The median progression-free survival was 2.3 months, and the median overall survival was 6.9 months (range, 0.4-not reached). There was no clear association between peripheral blood T cell repertoire characteristics at baseline, PD-L1, or tumor mutations and response or outcome. One long-term survivor exhibited oligoclonal T cell populations in a baseline tumor biopsy that were consistently detected in peripheral blood over the entire course of the study. Conclusions HIGRT plus atezolizumab resulted in an overall response rate of 25% and disease control rate of 50% in this pilot study. The incidence of grade 3 adverse events was similar to that of atezolizumab alone. Alhough it was a pilot study with limited sample size, the results generated hypotheses worthy of further investigation.

We previously reported that overexpression of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) increases lung cancer cell proliferation by activating RAS signaling and that CYP24A1 knockdown inhibits tumor growth. However, the mechanism of CYP24A1-mediated cancer cell proliferation remains unclear. Here, we conducted cell synchronization and biochemical experiments in lung adenocarcinoma cells, revealing a link between CYP24A1 and anaphase-promoting complex (APC), a key cell cycle regulator. We demonstrate that CYP24A1 expression is cell cycle–dependent; it was higher in the G(2)-M phase and diminished upon G(1) entry. CYP24A1 has a functional destruction box (D-box) motif that allows binding with two APC adaptors, CDC20-homologue 1 (CDH1) and cell division cycle 20 (CDC20). Unlike other APC substrates, however, CYP24A1 acted as a pseudo-substrate, inhibiting CDH1 activity and promoting mitotic progression. Conversely, overexpression of a CYP24A1 D-box mutant compromised CDH1 binding, allowing CDH1 hyperactivation, thereby hastening degradation of its substrates cyclin B1 and CDC20, and accumulation of the CDC20 substrate p21, prolonging mitotic exit. These activities also occurred with a CYP24A1 isoform 2 lacking the catalytic cysteine (Cys-462), suggesting that CYP24A1's oncogenic potential is independent of its catalytic activity. CYP24A1 degradation reduced clonogenic survival of mutant KRAS-driven lung cancer cells, and calcitriol treatment increased CYP24A1 levels and tumor burden in Lsl-KRAS(G12D) mice. These results disclose a catalytic activity-independent growth-promoting role of CYP24A1 in mutant KRAS-driven lung cancer. This suggests that CYP24A1 could be therapeutically targeted in lung cancers in which its expression is high.

Background Our previous studies have identified a serum-based 4-microRNA (4-miRNA) signature that may help distinguish patients with lung cancer (LC) from non-cancer controls (NCs). Here, we used an extended independent cohort of 398 subjects to further validate the diagnostic ability of this 4-miRNA signature. Methods Using quantitative reverse transcription polymerase chain reaction (qRT-PCR), expression of the 4-miRNAs was assessed in a total of 398 sera that included 213 LC patients and 185 NCs. A logistic regression model using training-test sets, receiver operating characteristic (ROC) curve analysis and t-test were used to test the impact of varying expression of these miRNAs on its diagnostic accuracy for LC. The cell proliferation and colony formation affected by these miRNAs, as well as gene ontology (GO) analysis of miRNA target genes were performed. Results The levels of the 4-miRNAs were significantly higher in the serum of patients with LCs as compared to NCs. Using a logistic regression prediction model based on training and test sets analysis, we obtained the area under the curve (AUC) of 0.921 [95% confidence interval (CI), 0.876-0.966] on the test set with specificity 90.6%, sensitivity 77.9%, accuracy 84.1%, positive predictive value (PPV) 89.8% and negative predictive value (NPV) 79.5%. Conclusions We have verified that this serum 4-miRNA signature could provide a promising noninvasive biomarker for the prediction of LC, particularly in patients with indeterminate lung nodules on screening CT scans.