Status Burden Research Articles

Deciphering genomic characteristics of ERBB family members potentially involved in the recovery of anti-cancer immunity for intrahepatic cholangiocarcinoma patients.

e16003 Background: Previous studies showed that the efficacy of immune checkpoint inhibitor (ICI) is enhanced in hepatobiliary cancers harboring activating gene alterations of ERBB family members. The purpose of this study was to explore genomic characteristics of ERBB family members as well as the relationship of them with the activity of anti-cancer immunity in Chinese intrahepatic cholangiocarcinoma (ICC) patients. Methods: Fifty-four ICC patients which carried at least one gene mutation of ERBB family members were pre-selected from 508 ICC patients included in the China Pan-cancer project of OrigiMed 2020 (https://www.cbioportal.org/study/summary?id=pan_origimed_2020). Targeted sequencing was implemented with cancer-related 450-gene panel. Tumor mutation burden (TMB) and microsatellite status were evaluated. To explore the molecular mechanisms, two human cholangiocarcinoma cell lines, RBE and HuCCT1, were transfected with a lentivirus to obtain the cells with stable S310F mutation and overexpression of ERBB2. Results: The variation frequencies of EGFR, ERBB2, ERBB3 and ERBB4 were 2.8% (14/508), 3.5% (18/508), 3.3% (17/508) and 2.4% (12/508) in Chinese ICC patients, respectively. All the patients harboring ERBB family gene mutations were classified as TMB-H (cutoff = 10 Muts/Mb), when co-mutated with ACVR2A or TGFBR2. Moreover, ACVR2A and TGFBR2 were identified as driver genes in the cohort with oncodriveCLUST. TMB and the proportion of MSI-H patients were significantly elevated when ERBB family members co-mutated with ACVR2A (mutation vs wild: TMB, 38.2 ± 19.1 vs 7.0 ± 8.6 Muts/Mb, p<0.0001; MSI-H, 77.8% vs 4.9%, p<0.0001), or with TGFBR2 (TMB, 33.1 ± 8.7 vs 9.0 ± 14.4 Muts/Mb, p<0.0001; MSI-H, 83.3% vs 9.1%, p<0.001). Besides, ACVR2A and TGFBR2 were enriched in TGF-β pathway. Flow cytometry analysis revealed that ERBB2 S310F mutation and amplification were increased by approximate 3-fold and 3.5-fold in PD-L1 expression of cell line RBE ( p < 0.0001, respectively); by approximate 2-fold and 3-fold upregulation of PD-L1 expression in cell line HUCCT1 ( p < 0.0001, respectively). Western-blot results suggested that ERBB2 mutation/overexpression mediated PD-L1 upregulation through the RAS/ERK/c-JUN pathway. T cell cytotoxicity-mediated killing assay demonstrated that ERBB2 S310F mutation and overexpression induced the recovery of anti-cancer immunity by about 30% ( p < 0.05) both in RBE and HuCCT1 cells. Conclusions: The present study revealed two distinct genomic characteristics potentially involved in the recovery of anti-cancer immunity of intrahepatic cholangiocarcinoma patients: on one hand, co-mutation of ERBB family genes with ACVR2A or TGFBR2 was enriched in TGF-β pathway, contributing to MSI-H/TMB-H; on the other hand, ERBB2 might impact expression of PD-L1 by regulating the RAS/ERK/c-Jun pathways.

Molecular characteristics of ERBB2-activating mutations in Chinese patients with NSCLC.

8546 Background: Activating mutations in the ERBB2 gene were shown to play an oncogenic role similar to that of ERBB2 amplification. Thus, ERBB2 mutations have emerged as therapeutic targets in non-small cell lung cancers (NSCLC). However, Activating ERBB2 mutations have not been described in detail like other driver gene mutations, such as epidermal growth factor receptor (EGFR)-activating mutations. Methods: In this study, we retrospectively analyzed activating ERBB2 mutations using next-generation sequencing(NGS). From May 2019 to January 2022, 21745 patients who were diagnosed with NSCLC were detected. Results: A total of 686 activating ERBB2 mutations were found, and 12 patients carried double ERBB2-activating mutations. In this cohort, the average age of patients was 58 years (range, 13-90 years). 59.6% of the patients were female and 88.2% were diagnosed with lung adenocarcinoma.A total of 47 ERBB2-activating mutation subtypes were defined in 674 patients. The most common activating mutations were Y772_A775dup (55.0%, 371/674), followed by G776delinsVC (8.3%, 56/674), S310F (7.7%, 52/674), G778_P780dup (5.6%, 38/674) and V659E (4.1%, 28/674). All other mutations occurred in 14 or fewer patients. ERBB2-activating mutations occurred most frequently in the tyrosine kinase domain（TKD） (80.1%), which included mutations in exon 20 (76.2%), exon 19 (3.0%), and exon 21 (1.2%),In addition, 13.2% of activating ERBB2 mutations occur in the extracellular domain, and 5.5% in the Transmembrane domain. 23.1%(156/674) patients with ERBB2 activating mutations could be evaluated for concurrent mutations, tumor mutational burden (TMB) and microsatellite instability (MSI) status. Among these patients, ERBB2-activating mutations were most frequently co-mutated with TP53(54/156) and EGFR(21/156). The frequency of EGFR mutations was much higher in non-TKD mutation patients than in TKD mutation patients (56.7% vs. 3.2%, P < 0.001), but no difference was observed for TP53. All these patients were microsatellite stable (MSS) and low TMB ( < 10 mutations/megabase). Conclusions: We report mutational landscape and characteristics of ERBB2 in Chinese NSCLC patients.The prevalence of activating ERBB2 mutations was 3.1% in Chinese NSCLC patients. 80.1% of ERBB2 activating mutations were in TKD and 19.9% were in the non-TKD. The non-TKD mutations might also be used as a therapeutic target in ERBB2-directed target therapy.

Prevalence of high tumor mutational burden (TMB-H) and microsatellite instability-high (MSI-H) status in neuroendocrine neoplasms.

2625 Background: Neuroendocrine neoplasms (NENs) encompass a rare group of tumors arising in nearly any organ site. Patients with advanced-stage NENs have limited treatment options, and molecular profiling is not routinely performed in NENs. However, given tissue-agnostic FDA approvals for immunotherapy in biomarker-selected solid tumors, we sought to assess the frequency of TMB-H and MSI-H in NENs by organ site and in comparison to non-NEN counterparts. Methods: We retrospectively analyzed de-identified records from the Tempus database of NENs sequenced with the Tempus xT assay (DNA-seq of 595-648 genes at 500x coverage). Patients were included if their primary cancer arose in the lungs, GI tract (esophagus, stomach, small bowel, colon, rectum), pancreas, or prostate. Histologic diagnoses were grouped as NENs (including high grade or low/intermediate grade), and non-NENs (e.g. adenocarcinoma, squamous cell carcinoma) based on data abstracted from pathology reports. TMB-H was defined as ≥ 10 mutations/megabase. MSI-H was calculated as previously published (PMID: 31570899). Statistical comparisons were limited to groups of 10 or larger. Results: We characterized a total of 1,477 NENs from the following anatomic sites: lung (64%, N=951), pancreas (15%, N= 220), GI (15%, N= 224) and prostate (6%, N=82). TMB-H was most common in NENs arising in the lungs (17%, N=155), followed by the pancreas (5.4%, N=11), GI tract (4.8%, N=10), and prostate (3.8%, N=3) (p< 0.001). Overall, TMB-H was more common in high-grade NENs compared to low/int-grade NENs [17% (N=147) vs. 6.2% (N=31), P<0.001]. This was also observed in lung NENs [high-grade 19% (N=135) v low/int grade 10% (N=19), P=0.006], with other organ site analyses limited by sample size (although a similar trend was noted for GI NENs). The majority of patients with TMB-H lung NENs had a current or prior smoking history (94%, N=119). Overall, TMB-H was similar in NENs compared to non-NENs [13% (N=179) vs. 12% (N=3018), P=0.4]. However, in the pancreas, TMB-H was more common in NENs vs. non-NENs [(5.4% (N=11) v 1.6% (N=59), P<0.001] while the reverse was true in lung NENs [17% (N=155) v 22% (N=2006), P=0.001]. MSI-H was observed in only 0.9% (N=12) of NENs overall, including in 0.4% (N=4) of lung, 1.4% (N=3) of pancreas, 1.9% (N=4) of GI, and 1.2% (N=1) of prostate NENs. MSI-H status was less common in NENs compared to non-NENs [0.9% (N=12) vs. 2.5% (N=614), P<0.001]. Conclusions: In this real-world NEN cohort, the actionable molecular alterations of TMB-H (13%) and MSI-H (0.9%) were observed. Taken together, the data suggest that molecular profiling (regardless of grade) may help identify a small but meaningful subset of patients with NENs who may benefit from immunotherapeutic treatment approaches. Furthermore, the identification of MSI-H NENs has important implications related to germline testing.

Symptoms and psychosocial distress associated with malignant wounds: Secondary analysis of a prospective cohort study.

e24008 Background: Symptoms associated with malignant wounds (MWs) worsen a patient's quality of life. However, MWs’ impact on psychosocial health and end-of-life status is unknown. Methods: This is a secondary analysis of the results of a large prospective cohort study conducted in 23 palliative care units in Japan. Consecutive patients were enrolled and followed up until their death or for six months. Patient demographics, symptom burden, medication use, and MW status were documented on admission. Healthcare professionals rated the symptoms using the Integrated Palliative care Outcome Scale (IPOS), a 5-point Likert scale. Quality of death (QOD) was evaluated at death using the Good Death Scale (GDS). The primary outcome was the prevalence of severe psychological symptom burden, evaluated as an IPOS-feeling score of 2–4. Factors that affected psychological symptoms and their relationship with GDS were also investigated. Results: Among the 1896 enrolled patients, 156 (8.2%) had MWs. MWs predominantly affected females and younger patients, and the most common primary sites were the breast (28.2%) and head and neck (19.2%). Among the patients with MWs, 75 (50.3%), 59 (39.6%), and 42 (28.2%) had exudate, pain, and bleeding, respectively. Among the 32 patients with MWs requiring dressing change at least twice a day and 117 patients with MWs requiring dressing change less than once a day, 20 (62.5%) and 44 (37.6%) had an IPOS-feeling score of 2–4, respectively (p = .015). Patients with MWs required antidepressants and opioids more frequently and received higher doses of opioids. Between the patients with and without MW, there were significant differences in IPOS-feeling and pain scores but not in breathlessness, fatigue, anorexia, somnolence, or dry mouth scores. IPOS-feeling and pain scores were worse in patients with MWs. Patients without MWs did not have better GDS scores (p = .48). Conclusions: Patients with MWs frequently required antidepressants and opioids, suggesting an increased prevalence of depression and severe pain. Psychological distress was influenced by the frequency of dressing changes. The presence of MWs did not affect the QOD.[Table: see text]

Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC): Biomarker (BM) analyses by next-generation sequencing (NGS) from the SOLAR-1 study.

1006 Background: PIK3CA mutations (mut; ~40% of HR+, HER2– ABC) are linked to poor prognosis. In SOLAR-1, ALP (PI3Kα-selective inhibitor and degrader) + FUL improved progression-free survival (PFS) vs placebo (PBO) + FUL in pts with PIK3CA-mutated HR+, HER2– ABC. Here, we focus on efficacy data by gene alterations in SOLAR-1 PIK3CA-altered (alt) cohort. Methods: SOLAR-1 was a phase 3, randomized, double-blind study of ALP (or PBO) + FUL in HR+, HER2– ABC progressing on/after an aromatase inhibitor. Baseline tissue samples with enough quantity/quality (N = 398) were retrospectively tested by NGS (FoundationOne CDx 324-gene panel) and pts grouped by PIK3CA-alteration status. Clinical benefit was assessed using PFS and hazard ratio (HR) based on tumor mutational burden (TMB) and gene alteration status in the PIK3CA-alt cohort. No multiplicity adjustment was made. Results: PIK3CA-alt (ALP, n = 120; PBO, n = 117) and PI3KCA-non-alt (ALP, n = 81; PBO, n = 80) cohorts had differential gene alteration landscapes. In the PIK3CA-alt cohort, ALP + FUL clinical benefit was seen across TMB quartiles (Q1: 0 -<2.52, Q2: 2.52 -<3.78, Q3: 3.78 -<5.04, Q4: ≥ 5.04 mut/megabase). ALP + FUL had greater benefit in pts with alt vs non-alt FGFR1/ 2 (Table). ALP + FUL benefit was independent of alterations in TP53, ESR1, CCND1, MAP3K1, and ARID1A and limited in MYC- and RAD21-alt cohorts . ALP + FUL benefit was seen in pts with alt genes in the MAPK (HR [95% CI] vs PBO: alt 0.43 [0.23 - 0.80]; non-alt 0.56 [0.40 - 0.79]) and PI3K (in addition to PIK3CA; alt 0.68 [0.38 - 1.23]; non-alt 0.48 [0.34 - 0.68]) pathways, and implicated in CDK4/6i resistance (alt 0.52 [0.30 - 0.89]; non-alt 0.53 [0.37 - 0.76]). Conclusions: The unique mut profile of PIK3CA-alt tumors did not affect ALP + FUL benefit in pts with HR+, HER2– ABC. Clinical benefit was maintained regardless of alterations in most BMs, including ESR1 and genes implicated in CDK4/6i resistance, consistent with ALP targeting the PIK3CA driver oncogene. Clinical trial information: NCT#02437318; EUDRA CT#2015-000340-42. [Table: see text]

Methylated circulating tumor DNA (cfMeDIP) as a predictive biomarker of clinical outcome in pan-cancer patients (pts) treated with pembrolizumab (P).

2550 Background: Bespoke mutation-based circulating tumor DNA (ctDNA) predicts response to P but relies on availability of tumor tissue and presence of mutations. Cell-free methylated immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) may overcome these limitations and be applied to more pts. Methods: Pts with mixed solid tumors divided into 5 cohorts received P 200 mg Q3wks in the investigator-initiated INSPIRE trial (NCT02644369). cfMeDIP-seq was performed at baseline (B), pre cycle 3 (C3) and later cycles. Methylation probability was inferred from read depths in 300 bp bins. cfMeDIP score was the probability-weighted sum of 3270 pan-cancer differentially-methylated regions in the TCGA PanCanAtlas. ctDNA concentration was assayed using tissue-informed bespoke targeted NGS (Signatera). ΔctDNA and ΔcfMeDIP denote the change in ctDNA or cfMeDIP between B and C3, respectively. Association with OS or PFS was assessed using Cox proportional hazards model, adjusting for cohort (aHR). Multivariable analysis (MVA) also included tumor mutation burden and PD-L1 status. Results: 194 plasma samples from 87 pts were analysed with cfMeDIP-seq (84 at B, 55 at C3, 55 at later cycles). Demographics: male 33%; median age = 61 yrs (34–82); Cohorts: triple negative breast (26%), ovarian (25%), head & neck (21%), melanoma (12%), others (15%). Median follow-up = 10.6m (0.6–64.4); Median PFS = 1.9m; Median OS = 10.6m. cfMeDIP at B below median was associated with better OS (aHR = 0.51, 95%CI 0.29-0.91; p = 0.02) in MVA. ΔcfMeDIP was evaluable in 53 pts; any decrease in ΔcfMeDIP was predictive for OS (aHR = 0.36, 95%CI 0.18-0.72; p < 0.01) and PFS (aHR = 0.42, 95%CI 0.22-0.82; p = 0.01). Both ΔctDNA and ΔcfMeDIP were evaluable in 51 pts; decrease in ΔctDNA and ΔcfMeDIP predicted for longer OS (aHR = 0.45, 95%CI 0.23-0.86; p = 0.02 vs aHR = 0.39, 95%CI 0.19-0.80; p = 0.01); and PFS (aHR = 0.44, 95%CI 0.23-0.83; p = 0.01 vs aHR = 0.5, 95%CI 0.25-0.99; p = 0.04), respectively. When both ΔctDNA and ΔcfMeDIP are integrated in MVA, ΔcfMeDIP was predictive for OS (aHR = 0.48, 95%CI 0.23-1; p = 0.05). A decrease in ΔcfMeDIP and/or ΔctDNA was associated with longer OS (aHR = 0.2, 95%CI 0.09-0.45) and PFS (aHR = 0.27, 95%CI 0.13-0.58) compared to an increase in both assays (p < 0.01) (Table). Conclusions: We applied for the first time cfMeDIP-seq and mutation-based ctDNA analysis concurrently in pan-cancer pts treated with checkpoint blockade. ΔcfMeDIP correlated strongly with OS and PFS, representing a promising plasma-based predictive epigenetic biomarker in pts treated with P. ΔctDNA and ΔcfMeDIP can complement each other to predict outcomes, demonstrating that they may capture different biological changes. Clinical trial information: NCT02644369. [Table: see text]

Improved response prediction to immune checkpoint inhibition by combining TMB and WGS-based genomic features in NSCLC.

e21077 Background: The appearance of immune checkpoint inhibitors (ICIs) has revolutionized treatment strategies in advanced NSCLC. The clinical efficacy and indications for ICIs are currently estimated using the immunohistochemistry (IHC) profile of programmed death-ligand 1 (PD-L1) protein. Recent findings indicate that tumor mutational burden (TMB) is a unique feature that may improve response prediction to ICIs across multiple cancer types [1]. Nevertheless, only a minority of NSCLC patients will benefit from ICIs. Therefore, unraveling the genomics of NSCLC and the subsequent discovery of novel predictive biomarkers remains a high unmet need. Whole-genome sequencing (WGS) bounded with AI may identify biomarkers and composed signatures which will better than TMB or PD-L1 predict response to ICIs. Methods: To develop the PD1Dx classifier with the highest predictive value for ICI response, we combined WGS data analyses with machine learning approaches. Consistently, we divided WGS data of 57 NSCLCs derived from the Hartwig Medical Foundation (HMF) database into training (n = 39) and hold-out (n = 18) sets. Patients treated with pembrolizumab or nivolumab alone were labeled based solely on clinical metadata provided by the repository, reaching a total of 22 responders and 35 non-responders. Results: Recursive Feature Elimination using SHAP importance (ShapRFECV) selected 15 top predictive genomic features, based on which the final random forest model was built. The random forest model achieved the best performance, with an accuracy of 0.72, a recall of 0.73, and a precision of 0.80. Using the same learning method and dataset, we built a model based on a single TMB feature whose performance determined by accuracy, recall and precision was 0.67, 0.64, and 0.78, respectively. Apart from TMB, we also identified other predictive features, among the 15 top of which were, e.g., features related to transcriptional strand bias and C > A/T single nucleotide variants correlating with mismatch repair. Conclusions: Our results confirm the predictive value of features other than TMB alone in predicting ICI responses in NSCLC. Further investigation is required to validate biomarkers of sensitivity and resistance to ICIs. Krieger T, Pearson I, Bell J, Doherty J, Robbins P. Targeted literature review on use of tumor mutational burden status and programmed cell death ligand 1 expression to predict outcomes of checkpoint inhibitor treatment. Diagn Pathol 2020;15:6.

Exploring Real World Outcomes with Nivolumab Plus Ipilimumab in Patients with Metastatic Extra-Pulmonary Neuroendocrine Carcinoma (EP-NEC).

Simple SummaryExtrapulmonary neuroendocrine carcinomas (EP-NEC) are a group of tumors which are often metastatic and characterized by poor outcomes. Platinum-etoposide chemotherapy is the current front-line therapy for metastatic EP-NEC, and has been adapted from small cell lung cancer. There are limited treatment options for patients with platinum-resistant EP-NEC, with no current established second-line standard of care. Recently, there has been mixed evidence for the role of immunotherapy in EP-NEC, with limited existing prospective data. In this multicenter retrospective analysis, we compared outcomes between patients with refractory EP-NEC who received single, dual immune check point inhibitors (ICPIs) and cytotoxic chemotherapy in the second-line setting. This real world experience suggests that utilizing ipilimumab and nivolumab in patients with second-line pretreated EP-NEC may be more effective than other existing treatment options.Background: Dual utilization of the immune checkpoint inhibitors (ICPIs) nivolumab plus ipilimumab has demonstrated clinical promise in the treatment of patients with refractory high-grade neuroendocrine neo-plasms (NENs) in phase II clinical trials (DART SWOG 1609 and CA209), while single agent ICPIs have largely been ineffective for these types of tumors. While both trials demonstrated promising results in high grade NENs, there was no adequate description of the association between tumor differentiation (high-grade well-differentiated neuroendocrine tumor vs poorly-differentiated extra-pulmonary neuroendocrine carcinoma (EP-NEC) and ICPI outcomes in the DART SWOG 1609 trial. Our study reports on the effectiveness and toxicity profile of dual ICPIs in a real world second-line EP-NEC patient population. Methods: Data on metastatic EP-NEC patients, treated with either ICPIs (single and dual ICPIs) or chemo-therapy in the second-line setting, were retrieved from databases of three comprehensive cancer centers. Associations between treatment characteristics and outcomes, including progression-free survival (PFS) and overall survival (OS), were evaluated. Results: From 2007 to 2020, we identified 70 patients with metastatic EP-NEC (predominantly of gastro-enteropancreatic origin), of whom 42 patients (23 males, 19 females, median age 62 years old) were eligible for the final analysis. All patients were refractory to platinum etoposide doublet chemotherapy in the first-line setting. The median PFS for patients who received dual ICPIs (11 patients), single agent ICPI (8 patients), and cytotoxic chemotherapy (23 patients) was 258 days, 56.5 days, and 47 days, respectively (p = 0.0001). Median overall survival (OS) for those groups was not reached (NR), 18.7 months, and 10.5 months, respectively (p = 0.004). There were no significant differences in treatment outcomes in patients according to tumor mismatch repair (MMR) or tumor mutational burden (TMB) status. Grade 3–4 adverse events (AEs) were reported in 11.1% of the patients who received dual ICPIs; however, none of these AEs led to permanent treatment discontinuation. Conclusions: In the second-line setting, patients with EP-NECs treated with dual ICPIs (nivolumab plus ipilimumab) experienced improved PFS and OS compared to patients treated with single agent ICPI or cytotoxic chemotherapy. These results echo some of the current evidence for ICPIs in grade 3 NENs and need to be validated in future prospective studies.

The current management and biomarkers of immunotherapy in advanced gastric cancer.

Background:Gastric carcinoma (GC) is the fourth most common cause of cancer-related death worldwide. Most patients are diagnosed at later stage, because of few treatment options, the prognosis is poor. In recent years, however, Immune checkpoint inhibitors(ICIs), such as anti- programmed death-1 (PD-1), anti-PD-L1, and anti-cytotoxic T lymphocyte antigen 4, have emerged as promising therapeutic agents in GC. Here, we summary the current treatment and advances of immune checkpoint inhibitors in the advanced stage of GC.Methods:WANFANG MED ONLINE, CNKI, NCBI PUBMED and clinicaltrials.gov were used to search literature spanning from 2000 to 2021, and all literatures about “advanced gastric or gastro-oesophageal junction cancer, Immune checkpoint inhibitors, PD-1, PD-L1, Cytotoxic T lymphocyte antigen 4, immune therapy” with detailed data were included.Results:Nivolumab and pembrolizumab have been recommended for the third line or subsequent therapy in advanced GC. Nivolumab plus chemotherapy has been recommended for the first line treatment in advanced GC in China. Many other ICIs have been demonstrating encouraging efficacy. PD-L1, MSI-H, Epstein Barr virus, and tumor mutational burden (TMB) status maybe potential biomarkers for response to clinical outcomes for ICIs in GC.Conclusion:ICIs have shown encouraging treatment efficacy and manageable safety profile in GC. Some biomarkers including PD-L1, MSI-H, EBV, and TMB status could evaluate the efficacy of ICIs in GC.

Effect of Hospital Safety Net Burden on Survival for Patients With Sinonasal Squamous Cell Carcinoma.

To examine factors associated with hospital safety net burden and its impact on survival for patients with sinonasal squamous cell carcinoma (SNSCC). Retrospective database study. National Cancer Database from 2004 to 2016. SNSCC cases were identified in the National Cancer Database. Hospital safety net burden was defined by percentage of uninsured/Medicaid patients treated, namely ≤25% for low-burden hospitals, 26% to 75% for medium-burden hospitals, and >75% for high-burden hospitals (HBHs). Univariate and multivariate analyses were used to investigate patient demographics, clinical characteristics, and overall survival. An overall 6556 SNSCC cases were identified, with 1807 (27.6%) patients treated at low-burden hospitals, 3314 (50.5%) at medium-burden hospitals, and 1435 (21.9%) at HBHs. On multivariate analysis, Black race (odds ratio [OR], 1.39; 95% CI, 1.028-1.868), maxillary sinus primary site (OR, 1.31; 95% CI, 1.036-1.643), treatment at an academic/research program (OR, 20.63; 95% CI, 8.868-47.980), and treatment at a higher-volume facility (P < .001) resulted in increased odds of being treated at HBHs. Patients with grade III/IV tumor (OR, 0.70; 95% CI, 0.513-0.949), higher income (P < .05), or treatment modalities other than surgery alone (P < .05) had lower odds. Survival analysis showed that hospital safety net burden status was not significantly associated with overall survival (log-rank P = .727). In patients with SNSCC, certain clinicopathologic factors, including Black race, lower income, treatment at an academic/research program, and treatment at facilities in the West region, were associated with treatment at HBHs. Hospital safety net burden status was not associated with differences in overall survival.

Predictors of primary prevention implantable cardioverter-defibrillator use in heart failure with reduced ejection fraction: impact of the predicted risk of sudden cardiac death and all-cause mortality.

AimsUse of implantable cardioverter‐defibrillators (ICD) for primary prevention of sudden cardiac death (SCD) in heart failure with reduced ejection fraction (HFrEF) is limited. We aimed to investigate barriers to ICD use in HFrEF while considering the predicted risk of mortality and SCD.Method and resultsPatients from the SwedeHF registered in 2011–2018 and with an indication for primary prevention ICD were analysed. The Seattle Proportional Risk and Seattle Heart Failure Models were used to predict the proportional SCD and all‐cause mortality risk, respectively. A multivariable logistic regression model was fitted to identify independent predictors of ICD use/non‐use; Cox regression models to evaluate the interaction between predicted SCD/mortality risk and ICD use for mortality. Of 13 475 patients, only 15.5% had an ICD. Those with higher predicted proportional SCD risk (>45%) had an ∼80% higher likelihood to have an ICD. Other predictors of non‐use were follow‐up in primary versus specialty care, higher comorbidity burden and lower socioeconomic status. ICD use was associated with lower mortality only in patients with higher predicted SCD and lower mortality risk (34% and 37% relative risk reduction for 3‐year all‐cause and cardiovascular mortality, respectively). In this subgroup of patients, underuse of ICD was 81.8%.ConclusionIn a contemporary registry, only 15.5% of patients with an indication for primary prevention ICD received the device. While a high predicted proportional SCD risk was appropriately linked to ICD use, the lack of specialized follow‐up, higher comorbidity burden, and lower socioeconomic status were major unjustified impediments to implementation. Our findings suggest areas for improving ICD use for primary prevention of SCD in clinical practice.

The Molecular Landscape of Pancreatobiliary Cancers for Novel Targeted Therapies From Real-World Genomic Profiling.

Chemotherapies have limited efficacy in pancreatic cancer (PC) and biliary tract cancer (BTC), underscoring the need for new regimens. Recently, tumor-agnostic approaches have been developed for some targeted therapies in advanced solid tumors; however, the frequency of alterations by clinical and genomic background is unclear in PC and BTC. To assess the frequencies of druggable gene alterations and investigate new potential therapeutic targetable genomic alterations, advanced PC and BTC patients were tested with comprehensive genomic profiling at Foundation Medicine during the course of clinical care. A total of 16 913 PC patients and 3031 BTC patients were available for analyses, and frequencies of genomic alterations were stratified by age (≥40 years or <40 years), microsatellite instability status, tumor mutational burden status (high ≥10 or low <10 Muts/Mb), and select genomic alterations. Alterations in BRCA2, BRAF, ERBB2, CDK12, PIK3CA, FGFR2, EGFR, and other potential targets were seen across cohorts, with enrichment observed within particular subsets such as in PC patients lacking a KRAS mutation. In BTC patients, the rate of ERBB2 amplification was statistically significantly higher in the tumor mutational burden-high population (23.3% vs 13.7%). Interestingly, CDK12 rearrangement was observed in BTC patients with ERBB2 amplification tumors. In patients younger than 40 years, FGFR2 rearrangement (4%) was observed in PC: GATA6 amplification (11.1%) and rearrangement of BRAF (2.8%)FGFR2 (5.6%) was observed in BTC patients. We identified an appreciable frequency of immunotherapy biomarkers and targetable gene alterations in both PC and BTC, with notable frequencies in PC samples lacking KRAS mutations and children or adolescent and young adult populations, that should encourage comprehensive genomic profiling testing.

Decreasing rates of cost-related medication non-adherence by age advancement among American generational cohorts 2004–2014: a longitudinal study

ObjectivesThe access barrier to medication has been a persistent and elusive challenge in the US healthcare system and around the globe. Cost-related medication non-adherence (CRN) is an important measure of...

OA39 Online Patient Reported Outcome Measure (PROM) engagement is dependent on demographics and locality: findings from an observational cohort

Abstract Background/Aims Online patient-reported outcome measures (PROMs) enable remote collection of perceptions of health status, function and wellbeing. Single-centre studies report that PROM completion is dependent on patient demographics. Here we use a large national prospective dataset to explore patterns of PROM completion. Methods Patients with a new diagnosis of early inflammatory arthritis (EIA) were recruited to the National Early Inflammatory Arthritis Audit (NEIAA) between May 2018 and March 2020 and followed up for one year. PROMs capturing the impact of disease using the MSK-HQ, disability using HAQ, mental health using PHQ4ADS, and work using the WPAI were requested at baseline, 3 and 12 months. Multivariable logistic regression was constructed to examine patient level associations with PROM completion. Mean PROM completion by clinical commissioning groups (CCG) were mapped across England and spatial regression models used to identify regional patterns. Results A total of 34,856 patients with suspected EIA were recruited to NEIAA. Of these, 11,986 were diagnosed with EIA across England, recruited from 205 CCGs. The cohort was evenly distributed across the indices of multiple deprivation (IMD) deciles. Thirteen percent were Black, Asian, or minority ethnic (BAME). At least one PROM was completed by 5,331 (44.5%) patients. Of these, 3,846 (72.1%) had completed half of all the available PROMs whilst 412 (7.7%) had completed all available PROMs. BAME participants were less likely to return a PROM in adjusted regression modelling (adj OR 0.57, 95% CI 0.48-0.66). Deprivation quintile (adj OR 0.73, 95% CI 0.64-0.83), male gender (adj OR 0.86, 95% CI 0.78-0.94), comorbidity burden (adj OR 0.95, 95% CI 0.91-0.99) and current smoker status (adj OR 0.73, 95% CI 0.64-0.82) also reduced the odds of PROM completion. The proportion with PROM completion varied across CCGs. Spatial analysis identified two autocorrelated regions in England with a hotspot of high PROM completion in the North and a cold spot in the South East. Conclusion This study defines key participant characteristics that influence PROM engagement in a national clinical audit and identifies a novel association between locality and PROM completion. Integral to the utility of PROMs in NEIAA is that they are representative of the population with EIA. Our results suggest there are under-represented groups with the potential to bias in favour of those likely to experience better outcome. Disclosure K. Bechman: None. M. Yates: None. H. Wright: None. M. Russell: None. D. Nagra: None. B.D. Clarke: None. J. Ledingham: None. S. Norton: None. J. Galloway: Consultancies; Abbvie, Sanofi, Novartis, Pfizer, UCB, Janssen. Grants/research support; Eli Lilly.

Evaluation of Optimal Threshold of Neutrophil-Lymphocyte Ratio and Its Association With Survival Outcomes Among Patients With Head and Neck Cancer

Given the role of inflammation in cancer progression, neutrophil-lymphocyte ratio (NLR) from peripheral blood has been suggested as a readout of systemic inflammation and a prognostic marker in several solid malignant neoplasms. However, optimal threshold for NLR in US patients with head and neck cancer remains unclear. To evaluate the optimal NLR threshold as a potential prognostic biomarker for survival outcomes. This retrospective cohort study was conducted at a single institution. Participants included 496 patients with nonmetastatic head and neck cancer who underwent chemoradiation from April 2007 to March 2021. Statistical analysis was performed from September to December 2021. High vs low NLR. Overall survival (OS) and cancer-specific survival (CSS). A total of 496 patients (411 male patients [82.9%]; 432 White patients [87.1%]; 64 patients with other race or ethnicity [12.9%]; median [IQR] age, 61 [55-67] years) were identified. Median (IQR) follow-up was 44.4 (22.8-74.0) months. Thresholds of NLR for both OS and CSS were 5.71. High NLR above 5.71 was associated with worse OS (adjusted hazard ratio [aHR], 1.97; 95% CI, 1.26-3.09; P = .003) and CSS (aHR, 2.33; 95% CI, 1.38-3.95; P = .002). On logistic multivariable analysis, patients were more likely to have high NLR if they had higher T and N staging (T3-4: aOR, 4.07; 95% CI, 1.92-9.16; P < .001; N2: aOR, 2.97; 95% CI, 1.04-9.17; P = .049; N3: aOR, 11.21; 95% CI, 2.84-46.97; P < .001), but less likely if they had a good performance status (Karnofsky Performance Status 90-100: aOR, 0.29; 95% CI, 0.14-0.59; P < .001). Among 331 patients (66.7%) with available human papillomavirus (HPV) data, high NLR was not associated with OS (HPV-negative: aHR, 2.46; 95% CI, 0.96-6.31; P = .06; HPV-positive: aHR, 1.17; 95% CI, 0.38-3.56; P = .78) and CSS (HPV-negative: aHR, 2.55; 95% CI, 0.81-7.99; P = .11; HPV-positive: aHR, 1.45; 95% CI, 0.44-4.76; P = .54). High NLR was associated with worse survival. Patients with substantial disease burden and poor performance status were more likely to have high NLR. These findings suggest that further studies would be warranted to investigate the role of such prognostic marker to identify patients at risk to tailor interventions.

Catholic-Confucian Mortuary Practices in a Rural Manchurian Cemetery

Catholic missionaries were active among rural populations in Manchuria, in northeast China, around the turn of the 20th century. Their presence influenced everything from the role of women in religious and family life, to the adoption of new material culture, to local burial customs. This investigation of the Pianliancheng cemetery in Jilin Province, in use from the 1890s to the 1930s, reveals the material and embodied traces of this history. Archaeological, bioarchaeological, and historical evidence for cultural hybridization and transnational connections are presented. Specific findings include the history of individual Catholic priests in the mission, the hybridization of Catholic and Confucian burial practices by the Chinese converts, material connections to Chinese immigrant communities abroad, the labor burden and nutritional status of various members of the community, the continuation of foot binding in rural Manchuria, and the influence of conversion on gender roles and family life.

The impact of the COVID-19 pandemic on pediatric developmental services: a cross-sectional study on overall burden and mental health status

BackgroundThe COVID-19 outbreak has taken a heavy toll on the mental well-being of healthcare workers, even those who have not been directly involved in the care of acutely ill patients. The aims of this study were to identify the overall burden and mental health status of healthcare workers in pediatric developmental services under the influence of the COVID-19 pandemic, and to identify the risk and protective factors associated with mental health.MethodsThis cross-sectional web-based study was part of a large multicenter VOICE study conducted among employees ((neuro-)pediatricians, psychologists, speech therapists, occupational therapists, etc.) from various pediatric developmental services between June and July 2020. A total of 1291 questionnaires regarding overall burden, mental health status (depression, generalized anxiety disorder and emotional exhaustion) and risk and protective factors for mental health (working conditions, potential problems during the COVID-19 pandemic and psychological resources) were analyzed. Descriptive statistics and multiple linear regression were used for data analysis.ResultsA total of 44.5% (574/1291) participants felt a high or very high overall burden during the COVID-19 pandemic. Of all the participants, 14.6% (171/1173) reported clinically significant levels of depressive symptoms, 17.0% (199/1173) reported generalized anxiety disorder symptoms and 44.6% (532/1192) reported emotional exhaustion. Multiple linear regression analyses identified several common risk and protective factors for mental health status variables. The burden of an increase in the quantity of work, fear of work and fear of becoming infected showed the strongest negative associations, whereas psychological resources and sufficient relaxation in leisure time exhibited the strongest positive associations.ConclusionEmployees who were not directly involved in the care of acutely ill patients were also exposed to considerable stress, some of which was not different from that experienced by professionals who were directly affected. These employees should not be lost sight of and must be offered appropriate support.

Association between plasma somatic copy number variations and response to immunotherapy in patients with programmed death-ligand 1-negative non-small cell lung cancer.

ObjectiveTo determine how patients with non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1)-negative and/or a low tumor mutation burden status benefit from immune checkpoint inhibitors (ICI).MethodsWe determined the plasma cell-free DNA profiles of 25 patients with PD-L1-negative advanced NSCLC before ICI therapy using low-coverage whole-genome sequencing.ResultsElevated cell-free copy number variations (CNVs) were associated with progressive disease, with a cutoff CNV score of 0.10 evaluated with an area under the curve of 0.790 in PD-L1-negative NSCLC. CNV changes were also correlated with poor survival. Progression-free survival and overall survival were both significantly shorter in CNVhigh compared with CNVlow patients.ConclusionsCell-free CNV may be a useful peripheral blood biomarker for predicting the response to ICIs in patients with NSCLC.

Protein-based prognostic signature for predicting the survival and immunotherapeutic efficiency of endometrial carcinoma

BackgroundEndometrial cancer (EC) is the most frequent malignancy of the female genital tract worldwide. Our study aimed to construct an effective protein prognostic signature to predict prognosis and immunotherapy responsiveness in patients with endometrial carcinoma.MethodsProtein expression data, RNA expression profile data and mutation data were obtained from The Cancer Proteome Atlas (TCPA) and The Cancer Genome Atlas (TCGA). Prognosis-related proteins in EC patients were screened by univariate Cox regression analysis. Least absolute shrinkage and selection operator (LASSO) analysis and multivariate Cox regression analysis were performed to establish the protein-based prognostic signature. The CIBERSORT algorithm was used to quantify the proportions of immune cells in a mixed cell population. The Immune Cell Abundance Identifier (ImmuCellAI) and The Cancer Immunome Atlas (TCIA) web tools were used to predict the response to immunochemotherapy. The pRRophetic algorithm was used to estimate the sensitivity of chemotherapeutic and targeted agents.ResultsWe constructed a prognostic signature based on 9 prognostic proteins, which could divide patients into high-risk and low-risk groups with distinct prognoses. A novel prognostic nomogram was established based on the prognostic signature and clinicopathological parameters to predict 1, 3 and 5-year overall survival for EC patients. The results obtained with Clinical Proteomic Tumor Analysis Consortium (CPTAC), Human Protein Atlas (HPA) and immunohistochemical (IHC) staining data from EC samples in our hospital supported the predictive ability of these proteins in EC tumors. Next, the CIBERSORT algorithm was used to estimate the proportions of 22 immune cell types. The proportions of CD8 T cells, T follicular helper cells and regulatory T cells were higher in the low-risk group. Moreover, we found that the prognostic signature was positively associated with high tumor mutation burden (TMB) and high microsatellite instability (MSI-H) status in EC patients. Finally, ImmuCellAI and TCIA analyses showed that patients in the low-risk group were more inclined to respond to immunotherapy than patients in the high-risk group. In addition, drug sensitivity analysis indicated that our signature had potential predictive value for chemotherapeutics and targeted therapy.ConclusionOur study constructed a novel prognostic protein signature with robust predictive ability for survival and efficiency in predicting the response to immunotherapy, chemotherapy and targeted therapy. This protein signature represents a promising predictor of prognosis and response to cancer treatment in EC patients.

Concordance Study of a 520-Gene Next-Generation Sequencing-Based Genomic Profiling Assay of Tissue and Plasma Samples.

Next-generation sequencing (NGS) enables simultaneous detection of actionable somatic variants and estimation of genomic signatures such as tumor mutational burden (TMB) or microsatellite instability (MSI) status, which empowers therapeutic decisions in clinical oncology. Our retrospective study investigated the clinical performance of somatic variant detection in paired tissue and blood samples using a large targeted gene panel, the OncoScreen Plus, which interrogates 520 cancer-related genes. We analyzed sequencing data derived from paired tissue and blood samples of 3005 patients spanning 20 solid tumor types, including lung (n = 1971), gastrointestinal (n = 625), breast (n = 120) and gynecological (n = 110), genitourinary (n = 38), and other cancers (n = 141). Across tumor types, the OncoScreen Plus panel achieved a high tissue detection rate, with an average of 97.9%. The average plasma detection rate was 72.2%, with an average tissue concordance rate of 36.6%. Considering all variant types, the plasma assay yielded an average sensitivity/true positive rate of 45.7%, with a positive predictive value of 64.7% relative to tissue assay. Pearson correlation analysis revealed a strong correlation in TMB estimated from blood and tissue samples (correlation coefficient 0.845, R2 = 0.756). MSI-high status was identified in five tumor types, including endometrial cancer (28.6%), colorectal cancer (2.5%), ovarian cancer (2.0%), gastric cancer (1.5%), and lung adenocarcinoma (0.2%). Paired tumor and blood samples from a large cohort of patients spanning 20 tumor types demonstrated that the OncoScreen Plus is a reliable pan-cancer panel for the accurate detection of somatic variants and genomic signatures that could guide individualized treatment strategies to improve the care of patients with advanced cancer.