bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA mismatch repair deficiency and outcomes of patients with resectable locally advanced gastric cancer treated with preoperative docetaxel, oxaliplatin, and S-1 plus surgery and postoperative S-1 or surgery and postoperative S-1: A sub-analysis of the phase 3 PRODIGY trial.
Authors: Hyung Jaewon , Park Young Soo , Cho Hyungwoo , Kim Hyung-Don , Ryu Min-Hee , Kang Yoon-Koo
Published: January 2023

431

Background: Benefit of perioperative or postoperative chemotherapy for resectable locally advanced gastric cancer (LAGC) with DNA mismatch repair (MMR) deficiency is controversial due to concerns about the potential detrimental effect of perioperative chemotherapy. In this sub-analysis of the phase 3 PRODIGY trial, we evaluated the association between the MMR status and outcomes of resectable LAGC treated with perioperative or postoperative chemotherapy. Methods: Among 249 patients with resectable LAGC enrolled in the PRODIGY trial treated with either perioperative chemotherapy (preoperative docetaxel, oxaliplatin, and S-1 [DOS] followed by surgery and postoperative S-1; CSC arm) or surgery and postoperative S-1 (SC arm) at Asan Medical Center, those in the full analysis set with available tissue for MMR status assessment by immunohistochemistry were included in this study. Progression-free survival (PFS) was compared according to the MMR status and treatment arm. In the CSC arm, the pathologic complete response (pCR) rate was compared according to the MMR status. Results: A total of 231 patients (CSC arm, n = 108; SC arm, n = 123) were included in the study (median age, 58 years [range, 27–75]). Twenty-one patients (CSC arm, n = 8 [7.4%]; SC arm, n = 13 [10.6%]) had deficient MMR (D-MMR) tumors while the rest had proficient MMR (P-MMR) tumors. There was no significant difference in the baseline characteristics including the clinical stage according to the MMR status. Among patients with P-MMR tumors, PFS tended to be superior in the CSC arm than in the SC arm (hazard ratio [HR] 0.67 [95% confidence interval (CI) 0.44–1.03]; log-rank P = 0.07). Among patients with D-MMR tumors, the PFS of the CSC arm was not inferior to that of the SC arm (HR 0.50 [95% CI 0.10–2.60]; log-rank P = 0.41). In the CSC arm, the pCR rate was 5.0% (5/100) and 12.5% (1/8) in patients with P-MMR and D-MMR tumors, respectively. Conclusions: In this sub-analysis of the PRODIGY trial, the PFS of the CSC arm was not inferior to that of the SC arm among patients with D-MMR LAGC. Among patients who received preoperative DOS, the pCR rate was not lower in patients with D-MMR tumors compared with those with P-MMR tumors. Perioperative chemotherapy consisting of preoperative DOS followed by surgery and postoperative S-1 may be recommended for patients with LAGC regardless of the MMR status.
Identification of a subpopulation of patients with gastric cancer responsive to PARP inhibitors.
Authors: Corso Simona , Petrelli Annalisa , Rizzolio Sabrina , Pietrantonio Filippo , Bellomo Sara , Benelli Matteo , De Cecco Loris , Romagnoli Dario , Serra Violeta , Pellegrino Benedetta , Giordano Silvia
Published: January 2023

432

Background: Treatment with PARP inhibitors (PARPi) has been approved in some tumors bearing a deficient Homologous Recombination (HR) system. Despite negative results of clinical trials conducted on the overall population of gastric cancer (GC) patients, we wondered whether a PARPi therapeutic strategy might represent a window of opportunity for a subpopulation of these patients. 7-12% of gastric cancers exhibit a mutational signature associated with HR failure, suggesting that these patients might benefit from PARPi. Methods: To analyze responsiveness to PARPi we exploited a proprietary human Gastro-Esophageal Adenocarcinoma (GEA) annotated platform of Patient-Derived Xenografts (PDXs) and PDX-derived primary cells on which we performed in vivo and in vitro experiments. Results: We selected 10 PDXs with loss-of-function mutations in HR pathway genes. Cell viability assays and preclinical trials showed that treatment with PARPi was effective in PDXs harbouring BRCA2 germline mutations and somatic inactivation of the second allele in a microsatellite stable background. PARPi responsive tumors were sensitive to oxaliplatin as well. Evaluation of HR deficiency and mutational signatures efficiently stratified responder vs non-responder PDXs. A retrospective analysis on 57 GEA patients showed that those carrying BRCA2 inactivating variants had longer PFS upon platinum-based regimens (used as proxy). In 5 out of 7 BRCA2 germline mutated patients we identified the p.K3326* variant, currently classified as “benign”. However, familial history of cancer, the absence of RAD51 foci in the tumor cells and a high HR deficiency score suggest a deleterious effect for this mutation in gastric cancer. Conclusions: PARP inhibition could represent a new therapeutic perspective for BRCA2 mutated and/or high HRD score GEA patients, including familial intestinal gastric cancer patients.
Impact of infiltrating T cell subtypes on survival and response to FLOT chemotherapy in resectable oesophagogastric adenocarcinoma (OGA).
Authors: Athauda Avani , Silveira Tatiany , Lund Thomas , von Loga Katharina , Challoner Benjamin , Rana Isma , Thomas Janet , Starling Naureen , Chau Ian , Rao Sheela , Watkins David J. , Cunningham David , Gerlinger Marco
Published: January 2023

443

Background: The prognostic and predictive relevance of tumour infiltrating T cell subtypes and of PD-L1 expression in localised OGA treated with FLOT chemotherapy (CTx) and surgery is poorly understood. Methods: Pre-CTx biopsy tissue was retrospectively collected from 46 patients (pts) with localised OGA who received perioperative FLOT and underwent surgery at a single institution. Opal Multicolour immunofluorescence was performed with primary antibodies against CD4, CD8, FOXP3, CD45RO, PD-1 and cytokeratin. Digital image analysis was performed using inForm and HALO softwares. PD-L1 CPS was determined using the E1L3N clone and the standard CPS assessment algorithm (CPS≥5 = high; CPS <5 = low). CTx responses were assessed according to Mandard Tumour Regression Grade (TRG). For each immune cell marker and T cell phenotype, high vs low groups were defined using median cell density (count/mm2) as the cut-off. Association of high vs low cell density with disease free survival (DFS) was assessed using the log-rank test and correlation with pathological response to CTx was assessed using the Chi-squared test. The paired Wilcoxon rank-sum test was used to compare differences in immune cell densities between paired pre-CTx biopsy and post-CTx resection samples in a subset of 35 pts. Results: Pts with a PD-1+ cell density above median in biopsy had significantly longer DFS compared to those with a density below median (median DFS not reached vs 1111 days; HR 0.3, 95% CI 0.1 – 0.8; p=0.028). A trend towards longer survival was also observed in the CD8+ high, FOXP3+ high, and activated CD8+ (CD8+ PD-1+) high groups. There was no association between PD-L1 CPS, CD4+, CD45RO+, memory CD8+ (CD8+ CD45RO+), regulatory CD4+ (CD4+ FOXP3+), memory CD4+ (CD4+ FOXP3- CD45RO+), and activated CD4+ (CD4+ FOXP3- PD-1+) cells and survival. Pts with higher density of PD-1+ cells achieved better responses than those with low PD-1+ cells (TRG1/2 48% vs 9%, p=0.017). Pts with PD-L1 CPS ≥10 in biopsy were numerically more likely to achieve better responses to FLOT (46% TRG1/2). PD1+ cell density decreased in resection specimens in good CTx responders but did not differ in non-responders. FOXP3+ cells significantly decreased whereas CD45RO+ cells and memory CD8+ cells significantly increased in non-responders only. Conclusions: These results indicate prognostic and predictive value of PD-1 expressing tumour infiltrating T cells in resectable OGA treated with perioperative FLOT CTx. CD8+, activated CD8+ and FOXP3+ cells were associated with a trend in longer survival. This analysis provides candidate biomarkers for further study in larger cohorts on the association between infiltrating immune cells and prognosis as well as response to standard cytotoxic CTx in Western patients.
IL-1β and IL-6 as predictors of ypN and early response to neoadjuvant chemotherapy in patients with locally advanced GC and GEJ cancer.
Authors: Marcisz-Grzanka Katarzyna , Fuksiewicz Małgorzata , Kotowicz Beata Urszula , Wieszczy Paulina , Kowalska Maria Małgorzata , Winiarek Mariola , Pałucki Jakub , Olesiński Tomasz , Wyrwicz Lucjan
Published: January 2023

454

Background: Perioperative chemotherapy remains a standard of care in locally advanced gastric cancer. About 10-15% patients do not respond to such therapy and there are currently no biomarkers which could be used to predict early response to the neoadjuvant treatment. Methods: This prospective biomarker study aimed at identification of serum biomarkers of early response to neoadjuvant chemotherapy. Here we report only the results for serum cytokine assessments. It was an academic, nonrandomized, prospective study, conducted in MSCNRIO. Between January 2018 and November 2019 we analysed 42 patients aged 30-77 (median 63 years, 52.5% male and 47.5% female) with histologically confirmed GC or GEJ cancer qualified by MDT for perioperative FLOT. Exclusion criteria were: inflammatory and autoimmune diseases, other cancers, chronic steroid and immunosuppressive therapy. Blood sample was collected a.c. prior to the administration of cycle one (C1), two (C2) and three (C3) FLOT regimen. Serum levels of IL-1β and IL-6 were measured twice using ELISA. Results: All patients with pre-treatment IL-1β levels above 0.5 ng/ml on the postoperative histopathological report had positive lymph nodes (ypN+). There was a statistically significant difference in the level of IL-1β in the blood serum of patients before the start of treatment in the subgroups ypN0 vs ypN+ vs unresectable tumor (p = 0.003), ypN0 vs ypN+ (p = 0.002) as well as ypN+ vs unresectable tumor (p = 0.075). There was a trend for change in IL-1β level between cycles C1 and C3 in the ypN0 vs ypN+ subgroups (p = 0.056). The difference in IL-1β level before C1 between the groups TGR-G1-2/ypN0 vs TGR-G1-2/ypN+ vs TGR-G3/ypN0 vs TGR-G3/ypN+ was statistically significant (p = 0.017). The difference in IL-6 level between C3 and C1 in the subgroups TGR-G1-2/ypN0 vs TGR-G1-2 / ypN + vs TGR-G3 / ypN0 vs TGR-G3 / ypN + vs unresectable tumor was statistically significant (p = 0.009). Among the analyzed factors, only the difference in serum IL-6 level between C3 and C1 may be a predictor of ypN+ response to preoperative FLOT regimen. Among ypN0 patients, 76% had an IL-6 difference between C3 and C1> 1.1, i.e. C3 greater than C1 by at least 1.1 (specificity), and among ypN+ patients 83% had an IL-6 difference between C3 and C1 <1.1 (specificity). Conclusions: Low IL-1β levels before starting treatment is a prognostic factor while an early decrease in IL-6 could be considered a predictive marker of response to FLOT.
Genomic and immune landscape of ERBB2/ERBB3 alterations in gastroesophageal adenocarcinoma.
Authors: Mukherjee Sarbajit , Mauer Elizabeth , Ronski Karyn , Shah Manish A.
Published: January 2023

457

Background: HER2/ERBB2 is a known therapeutic target in gastroesophageal adenocarcinoma (GEAC). HER3/ERBB3 is an emerging target in a variety of cancers but less defined in GEAC. Insights into the genomic and immunologic landscape of ERBB2/ERBB3 alterations (ERBB2/3-alt) are required to develop effective treatments. Methods: We analyzed de-identified data from 2,050 GEAC patient tumor samples which underwent next generation sequencing with the Tempus xT assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq). Bivariate analyses were performed to compare demographics, immuno-oncology (IO) biomarkers, and co-mutations between ERBB2/3-alt groups. P-values comparing individual co-mutations between groups were adjusted for false discovery. Results: Overall, 17.8% (365/2050) of tumors harbored an ERBB2 or ERBB3-alt, 3 of which had both and were excluded from analyses. Alterations were defined as pathogenic/likely pathogenic mutations, copy number amplifications (CN amp), or copy number loss (CN loss). Tumors were divided into ERBB2 CN amp (n=252, 12.3%), ERBB2 other (CN loss/mutation) (n=71, 3.5%), ERBB3 CN amp (n=17, 0.8%), ERBB3 other (n=22, 1%), and WT (n=1685, 82%) for both. No differences were observed between groups regarding baseline demographics (age of onset, race, ethnicity) aside from the percentage of females (p=0.002). Significant differences in IO markers and the co-occurring genetic alterations were seen. ERBB3 other (N = 22 mutations - No CN loss) had increased TMB, microsatellite instability high (MSI-H), and median neoantigen tumor burden. Conclusions: ERBB2/ERBB3-alt are associated with significant changes in the tumor microenvironment in GEAC. Co-occurring genetic or immunologic alterations can be exploited to develop effective targeted or immune therapies. [Table: see text]
Microsatellite instability (MSI), mismatch repair (MMR), and tumor mutational burden (TMB) as predictive biomarkers for immune checkpoint inhibitor (ICI) effectiveness in real-world patients with metastatic colorectal cancer (mCRC).
Authors: Ellis Haley , Klempner Samuel J , C. F. Quintanilha Julia C. F. , Myer Parvathi , Lin Douglas I. , Panarelli Nicole , Fisher Virginia , Li Gerald , Huang Richard S.P. , Ross Jeffrey S. , Oxnard Geoffrey R. , Graf Ryon
Published: January 2023

46

Background: The KEYNOTE-177 randomized controlled trial demonstrated that mCRC patients with MSI high (MSI-H) and/or deficient MMR (dMMR) have better outcomes on first-line ICI than chemotherapy. This study aimed to evaluate MSI by next-generation sequencing (NGS) as a predictive biomarker of ICI effectiveness in real-world settings, and compare MSI (NGS), dMMR (immunohistochemistry, IHC), and TMB (10 mut/Mb cutoff) in predicting ICI outcomes. Methods: A prospectively declared statistical analysis plan compared the effectiveness of first-line treatment ICI versus chemotherapy in patients with MSI-H mCRC, and compared the predictive power of ICI outcomes associated with biomarkers in any line of therapy (LOT). Patient data was obtained by the US-based de-identified Flatiron Health-Foundation Medicine real-world mCRC clinico-genomic database (FH-FMI CGDB), originating from ~280 US cancer clinics between Jan/2011 and Dec/2021. Differences in progression-free survival (PFS) and overall survival (OS) were evaluated by Cox proportional hazard models, adjusted for a risk score generated from prognostic clinical features. The likelihood ratio test evaluated the superiority of a biomarker in anticipating outcomes. Results: Patients with MSI-H mCRC had more favorable outcomes receiving first-line ICI (n=49) than chemotherapy (n=89) for PFS (median 24.87 vs. 5.65 months, hazard ratio (HR): 0.31, 95% confidence interval (CI) 0.18-0.52, p <0.0001) and OS (median not reached (NR) vs. 24.1 months, HR: 0.45, 95% CI 0.23-0.88, p = 0.02). mCRC patients receiving ICI in any LOT (n=182) had favorable outcomes when MSI-H, dMMR, or TMB ≥10 (all p <0.001). MSI (NGS) and MMR (IHC) were 90% concordant. MSI reclassified six cases that were proficient (p)MMR (all with TMB >10, three with mutations in MMR genes, and 5 with BRAF mutation, consistent with MSI biology). When MSI (NGS) is added to dMMR (IHC) evaluation, there is an improvement in the prediction of TTNT (p = 0.0013), PFS (p = 0.0202), and OS (p = 0.0717), but adding MMR status to MSI did not improve explanatory power. Conclusions: MSI (NGS) robustly identifies mCRC patients with favorable outcomes on first-line ICI vs. chemotherapy, and is a nominally better predictor of ICI outcomes when compared with dMMR (IHC) alone. dMMR (IHC), MSI (NGS), and TMB have similar predictive power for ICI benefit. [Table: see text]
Gene expression profiles in Hispanic patients with early-onset gastric cancer.
Authors: Ju Michelle R , Hong Changjin , Karalis John D , Hammer Suntrea , Porembka Matthew R. , Hwang Tae Hyun , Wang Sam C.
Published: January 2023

464

Background: A larger proportion of Hispanic gastric cancer patients are diagnosed at a young age than patients of other ethnicities. Despite diagnosis at an early age, young Hispanic patients also present more frequently with advanced disease. Whether there are molecular differences between tumors from young and old Hispanic gastric cancer patients is unknown. Methods: We performed RNA-sequencing on pre-treatment tumor samples of gastric cancer patients of self-identified Hispanic ethnicity. We stratified patients into two groups: <50 years and ≥50 years. Differentially expressed genes between groups were detected using the DESeq2 package (RStudio). We performed Gene Set Enrichment Analysis (GSEA) to identify pathways that were uniquely overexpressed in each age group. Results: 57 patients were included in our study. 23 patients were <50 years and 33 patients were ≥50 years. Comparison of the top 10% most differentially expressed genes showed no clustering based on age. However, visual inspection of the top 40 most differentially expressed genes revealed 2 distinct patterns of gene expression between age groups. GSEA revealed upregulation of DNA replication, cell cycle, and DNA repair pathways in the younger patients The tumors in younger patients also had upregulation of multiple immune activation pathways. Cancers from older patients had upregulation of programmed cell death pathways. Conclusions: Early-onset gastric cancer in Hispanic patients may represent a distinct biologic process.
Nomogram to predict peritoneal dissemination in gastric cancer.
Authors: Penumadu Prasanth , Kohli Pavneet , Dubashi Biswajit , Ganapathy Sachit
Published: January 2023

465

Background: Peritoneal metastasis is a poor prognostic factor in patients with gastric cancer and cannot be predicted, that can tailor oncological treatment. We retrospectively analyzed the clinicopathological data among 110 gastric cancer patients. Methods: Univariate logistic regression was performed with peritoneal disease as the outcome to assess potential risk factors associated with it. We found that age, gastric outlet obstruction, VEGF, Ki67, p53 and NLR ratio were significant factors associated with peritoneal disease. Using multiple logistic regression, the adjusted odds ratio and 95% confidence interval were estimated. The predictive accuracy of this regression model was estimated using ROC curve analysis and Area under the curve, sensitivity and specificity were estimated. A nomogram was plotted based on the regression coefficient for the prediction of peritoneal disease. Results: It was estimated that age less than 40 years had 0.19 (0.05, 0.79), GOO positive had 2.04 (0.69, 6.03), VEGF positive had 4.69 (1.79, 12.33), elevated Ki67 had 3.94 (1.55, 9.97), positive p53 had 0.43 (0.17, 1.11) and NLR ratio had 1.15 (0.88, 1.51) odds of having peritoneal disease from multiple logistic regression. The regression model had significant goodness of fit for the data (Hosmer-Lemeshow test P value < 0.001). On estimating the AUC from the ROC curve for the model, we found that it had a good discriminatory ability with AUC = 0.81. Sensitivity was estimated to be 71.15%, whereas specificity was estimated to be 72.41% for the model. Subsequently, a nomogram was plotted based on the regression estimated from this model. Conclusions: The nomogram could risk-stratify those at risk of developing peritoneal disease and modify therapeutic strategies like selecting patients for prophylactic intraperitoneal chemotherapy or other novel therapeutic strategies. However, the nomogram needs to be validated prospectively.
Risk of gastric cancer among patients with newly diagnosed ulcerative colitis: A nationwide population-based study.
Authors: Kim Hee Man , Kang Dae Ryong , Kim Hyun-Soo
Published: January 2023

471

Background: We aimed to assess gastric cancer risk in patients with newly diagnosed ulcerative colitis (UC). Methods: Based on claims data of the Korean National Health Insurance from January 2006 to December 2015, we identified 30,546 patients with UC and randomly selected 88,829 age- and sex-matched non-UC individuals (controls). Hazard ratios (HRs) adjusted for covariates were calculated using multivariate Cox proportional-hazards regression. Results: Overall, 77 (0.25%) patients with UC and 383 (0.43%) non-UC individuals developed gastric cancer during the period. HR of UC was 0.60 (95% CI: 0.47–0.77) for gastric cancer, compared to non-UC individuals. When stratified according to age and sex, HRs in 20-39, 40-59, and ≥ 60 years of age at diagnosis of UC were 0.19 (95% CI: 0.04–0.98), 0.65 (95% CI: 0.45–0.94), and 0.60 (95% CI: 0.49–0.80), and HR of male UC patients was 0.54 (95% CI: 0.41–0.73) for gastric cancer. However, among UC patients, multivariable analysis revealed that HR in ≥ 60 years of age at diagnosis of UC were 12.34 (95% CI: 2.23-68.16), consistent with old age as a risk factor of gastric cancer in general population. Conclusions: Patients with UC had a decreased gastric cancer risk compared with non-UC individuals. Further research is needed to elucidate the reason.
The impact of race and ethnicity on survival in primary liver cancer: A propensity-adjusted analysis.
Authors: Ozer Muhammet , Goksu Suleyman Yasin , Kazmi Syed Mohammad Ali
Published: January 2023

500

Background: Primary liver cancer is the fifth most common malignancy and the second most frequent cause of cancer-related death worldwide. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, followed by Intrahepatic cholangiocarcinoma (ICC), and the incidence of liver cancer is rapidly rising in the United States. Race and ethnicity affect the outcomes in many solid cancers; therefore, we aimed to study the effect of race and ethnicity on overall survival (OS) in primary liver cancer. Methods: We selected adult patients who had primary liver cancer (HCC and ICC) diagnosed between 2004 and 2016 using the NCDB database. We stratified the patients into two groups as white and black. We performed the Kaplan-Meier method for median overall survival (OS), and the Cox regression method for multivariate analyses after adjusting for clinically significant confounding variables. Also, we used 1:1 nearest neighbor propensity score matching to reduce selection bias. Results: A total of 122,049 patients, 83.1% was white, 16.9% was black. Black patients were more likely to be young ( p<.001), to live in the metropolitan area ( p<.001) and South Atlantic states ( p<.001), to be treated academic/research facility ( p<.001), to be uninsured ( p<.001). In contrast, white patients were most frequently to be highly educated ( p<.001), to have higher income ( p<.001), to travel longer distances (≥50 miles) for treatment ( p<.001). Also, black patients had a higher rate of HCC ( p<.001), advanced stage ( p<.001), high metastasis rate ( p<.001), whereas white patients had a higher rate of ICC ( p<.001), higher comorbidity ( p<.001), high treatment rate (surgery, chemotherapy, and radiotherapy) ( p<.001). The gender percentage was similar in both groups. In unmatched groups, white patients had significantly better median OS compared to black (9.9 vs. 8.4 months, p<.001), but this difference did not continue after adjusted for age, sex, facility type, insurance status, income, education, rurality, travel distance, comorbidity, metastatic rate, treatment receipt (surgery, chemotherapy, radiotherapy), primary site (HR=1.01 95% CI: 0.99-1.03, p=.18). In ethnic groups, Hispanics had significantly improved OS compared to non-Hispanic white (NHW) and non-Hispanic black patients (NHB) (median OS 12 vs. 9.7 vs. 8.5 months, respectively, p<.001), and this significance was persisted with multivariate analysis (HR=0.80 95% CI: 0.78-0.82, p<.001). After propensity score matching, white and black patients were similar OS (p=NS) but Hispanics were still significantly improved OS versus NHW and NHB patients (HR=0.76 95% CI: 0.71-0.80, p<.001). Conclusions: Black patients had a higher stage, percentage of metastasis and lower treatment rate, but they had a similar OS compared to white patients. Hispanics had significantly improved OS than others, even after adjusted for clinically important confounding variables.
Health-related quality of life (HRQoL) impact of lenvatinib (len) plus pembrolizumab (pembro) versus len plus placebo (pbo) as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC): Phase 3 LEAP-002 study.
Authors: Llovet Josep M , Kudo Masatoshi , Merle Philippe , Meyer Tim , Qin Shukui , Ikeda Masafumi , Xu Ruocai , Edeline Julien , Ryoo Baek-Yeol , Ren Zhenggang , Cheng Ann-Lii , Galle Peter R , Kaneko Shuichi , Kumada Hiromitsu , Kamble Shital , Norquist Josephine M , Mody Kalgi , Dubrovsky Leonid , Siegel Abby B. , Finn Richard S.
Published: January 2023

506

Background: In LEAP-002 (NCT03713593), len + pembro achieved a median OS of 21.2 mo vs 19.0 mo with len + pbo with manageable safety in both arms in 1L aHCC, although the significance thresholds for OS and PFS were not met. We present here the results of prespecified exploratory patient (pt)-reported outcomes (PROs). Methods: 794 pts were randomized. PROs were assessed by EORTC QLQ-C30, EuroQol-5D5L (EQ5D-5L), and EORTC QLQ-HCC18 questionnaires. Analysis population for HRQoL endpoints included pts who received ≥1 dose of study Tx and completed ≥1 HRQoL assessment. Least squares mean (LSM) score changes from baseline (BL) to wk 27 were compared using a constrained longitudinal data analysis model (covariates: Tx, time, Tx by time interaction, and stratification factors). Kaplan-Meier method was used to estimate time to deterioration (TTD, time to 1st onset of ≥10 [out of 100] deterioration from BL in a given scale or subscale/confirmed by a 2nd adjacent ≥10 deterioration from BL) for EORTC QLQ-C30 global health status (GHS)/QoL, physical functioning (PF), and EORTC QLQ-HCC18 abdominal swelling, pain and fatigue, as reported by pts. Stratified Cox proportional hazards model was used to assess the magnitude of the Tx difference (HR) between arms in TTD. Results: Compliance with PRO assessments was >91% from BL until wk 27 in both arms. From BL to wk 27, LSM changes in GHS/QoL, PF, role functioning (RF), QLQ-HCC18 functional/domain scores and EQ5D-5L VAS were generally similar between the two arms (Table). Treatment with len + pembro delayed deterioration of patient-reported quality of life vs len + pbo (median TTD, 11.5 vs 4.3 mo; HR, 0.80; 95% CI, 0.65-0.98). LSM score difference (95% CI) was 0.5 (-2.5, 3.4) for GHS/QoL, -1.7 (-4.5, 1.1) for PF, -1.0 (-4.9, 2.9) for RF, 1.0 (-2.2, 4.3) for abdominal swelling, 2.0 (-1.2, 5.2) for fatigue, 2.0 (-1.0, 5.0) for pain, and 0.6 (-2.0, 3.2) for EQ5D-5L VAS. Median TTD in QLQ-C30 PF (5.7 vs 9.1 mo; HR, 1.14; 95% CI, 0.93-1.41) and QLQ-HCC18 abdominal swelling (NR vs NR; HR, 1.19; 95% CI, 0.89-1.60) /fatigue (2.9 vs 2.8 mo; HR, 0.98; 95% CI, 0.81-1.19)/pain (9.6 vs 7.9 mo; HR, 0.93; 95% CI, 0.75-1.16) was similar between the arms. Conclusions: Len + pembro generally preserved HRQoL vs len + pbo in 1L for aHCC. Combined with efficacy and safety results from LEAP-002, these findings support continued development of len + pembro in HCC. Clinical trial information: NCT03713593 . [Table: see text]
Outcome of receiving lenvatinib following immunotherapy in patients with advanced hepatocellular carcinoma.
Authors: Gile Jennifer , Palmer Mathias Earl , Storandt Michael H. , Bekaii-Saab Tanios S. , Tran Nguyen H. , Mahipal Amit
Published: January 2023

507

Background: Lenvatinib, a multikinase inhibitor, is an FDA approved treatment for advanced hepatocellular carcinoma (HCC) in the first line setting. Atezolizumab and bevacizumab are considered new standard of care as first line therapy after results of the IMBrave 150 trial. Currently, we do not have data to suggest any second-line treatment after administration of immunotherapy. We describe the clinical outcomes in patients with advanced HCC who received lenvatinib following treatment with immunotherapy. Methods: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010 and 2021 at Mayo Clinic in Minnesota, Arizona, and Florida. The study was reviewed and approved by the intuitional review board. The primary outcomes were overall survival (OS) and progression free survival (PFS). Results: We identified 53 patients with advanced HCC who received lenvatinib following immunotherapy. Most patients (83%) were male. Median age at start of lenvatinib was 67 years old. Forty-two (79%) patients had a Child-Pugh score of A at diagnosis while 30 (58%) patients were still Child-Pugh A at time of lenvatinib initiation. Risk factors for HCC included Hep C (43%), alcohol use (34%), NASH (15%) and hepatitis B (7%). Forty-five (85%) patients received lenvatinib in the 2nd line and 8 (15%) patients received it as third line or later. At time of data extraction, 38 (72%) patients had died. Median PFS was 4 months (95% CI: 3 – 6) and median OS from time of lenvatinib initiation was 13 months (95% CI: 6 – 24). The most common adverse events of any grade included fatigue (53%), hypertension (37%), AST elevation (30%), anorexia (28%), bilirubin elevation (25%) and diarrhea (25%). Twenty-one (40%) patients experienced grade 3 or higher adverse events including hypertension (25%), confusion (6%), acute kidney injury (2%), hyperkalemia (2%), ALT elevation (2%), proteinuria (2%), arthralgia (2%), heart failure (2%), AST elevation (2%), bilirubin elevation (2%), palmar-plantar erythrodysesthesia (2%), oral mucositis (2%), weight loss (2%), hypothyroidism (2%), anorexia (2%), fatigue (2%) and diarrhea (2%). Seven patients stopped treatment due to adverse events: 1 for hypertension, 2 for confusion, 1 for heart failure, 2 for fatigue, and 1 for elevated bilirubin. Conclusions: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown. We found that median OS was 13 months in patients who received lenvatinib after immunotherapy which is comparable to survival in other studies when used as first line therapy. Our experience demonstrates that patients may benefit from treatment with lenvatinib following initial progression on immunotherapy.
Immunohistochemical and genetic profiles do not predict behavior of mixed hepatocellular intrahepatic cholangiocarcinoma.
Authors: Sucre Santiago , Paredes Rodrigo , Peters Mary Linton Bounetheau
Published: January 2023

516

Background: Combined hepatocellular intrahepatic cholangiocarcinoma (HCC CC) is a rare tumor defined by pathologic characteristics of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immunohistochemical (IHC) and genetic profiles (GP) are used for diagnosis and therapeutic decisions, however often mixed tumors are treated as ICC given the presumption this subtype dominates response. Recent studies challenged this practice by demonstrating improved response with immune oncology (IO) therapy. Methods: We identified nine patients with biopsy-proven mixed HCC CC between September 2013 and March 2022. We classified IHC as related to either HCC (HepPar1, Glypican3, CD10, Glutamine Synthetase, CEA, AFP, Arginase1) or ICC (CK19, CK7, CK20, CDX2, Mucicarmine, CA9, MOC31). GP results were classified as HCC-related (TERT, CTNNB1, MYC) or ICC-related (ARID1A, FGFR2, IDH1). Treatment selection, duration of response, and survival were recorded. Results: All subjects had a mix of IHC markers, although six had a preponderance of HCC-related IHC. GP information was available for seven patients, of whom six demonstrated mutations relating only to HCC, and one demonstrated mutations relating only to ICC. All sequenced tumors were MSS, and six of the seven were TMB low. Four subjects used only liver directed therapy for small intrahepatic tumors. Four subjects underwent systemic therapy, a mix of HCC and ICC regimens, three of whom used IO agents. Median survival was 12 months. Conclusions: HCC CC tumor profiling by IHC and GP was more closely aligned with HCC than ICC. However, the median survival for these patients was lower than expected for liver-restricted HCC, more congruent with an ICC phenotype. Although liver-directed therapy was used, the duration of response was shorter than expected for HCC, even in HCC-like tumors. For those receiving systemic therapy, most subjects did not achieve median response with any regimen. Although a previous case series showed good response to IO agents, in our cohort we did not see this effect. In this series, mixed HCC CC was more aggressive than HCC, with largely poor response to both liver directed and systemic therapy. We have insufficient information to correlate systemic treatment response relative to IHC or GP.[Table: see text]
An active trend of immunotherapy combination regimen as second-line therapy for advanced biliary tract cancer: A multicenter retrospective study.
Authors: Ying Jieer , Weng Haimin , Xu Qi , Li Jingjing , Wei Qing , Zeng Pengfei , Chen Yuemiao
Published: January 2023

520

Background: FOLFOX as second-line therapy remains the standard of care in patients with biliary tract cancer (BTC), but its efficacy is suboptimal. Currently, cytotoxic chemotherapy, targeted therapy, and immunotherapy alone or in combination are being tested in patients with pretreated advanced BTC for in clinical trials. This study aimed to evaluate and compare the anticancer of distinct treatment regimen in patients with advanced BTCs who progress after first-line chemotherapy. Methods: Patients diagnosed BTC who received second-line therapy were retrospectively identified at 3 sites across the Zhejiang province between January 1, 2018, and June 31, 2022. Clinicopathological information and therapeutic outcome, including subtype of BTC, response per RECIST v1.1, treatment duration, adverse events (AE), progression-free survival (PFS), and overall survival (OS), were recorded and estimated. Results: A total of 98 patients with BTCs were reviewed and recruited eventually: the chemotherapy group (cohort A, n=30), the chemotherapy plus ICIs group (cohort B, n=25), the TKIs group (cohort C, n=17), and the TKIs plus ICIs group (cohort D, n=26). The median PFS and OS were 2.4 months (95%CI: 1.6–3.2) and 7.0 months (95% CI: 6.4–7.5) for cohort A, 3.9 months (95%CI: 2.8–5.0) and 10.7 months (95% CI: 6.9–14.5) for cohort B, 1.6 months (95%CI: 0.8–2.4) and 7.1 months (95% CI: 0.7–13.5) for cohort C, and 4.7 months (95%CI: 3.1–6.2) and 10.1 months (95% CI: 4.1–16.1) for cohort D, respectively. In the cohort A, B, C, and D, confirmed ORRs were 10%, 20%, 11.8% and 19.2%, separately, and DCRs were 46.7%, 68%, 43.8% and 76.9%, respectively. The efficacy of ICIs plus TKIs was optimal in terms of tumor response and associated with prolong PFS. Six patients (20%), nine patients (36%), five patients (29.4%), and elven patients (42.3%) were experienced ≥ grade 3 treatment-related AEs in cohort A, B, C, and D, respectively. Conclusions: Immunotherapy combination strategy beyond first-line systemic chemotherapy plays a positive role in advanced BTCs. Both TKIs plus ICIs and chemotherapy plus ICIs could be considered as candidates to second-line trails and turn into a competitive second-line treatment regimen for advanced BTCs in clinical practice.
Short- and long-term real-world survival for metastatic bile duct cancer, 2000 to 2018.
Authors: Wood Sarah Jeanne , Nghiem Van , Williams Grant Richard , Paluri Ravi Kumar , Outlaw Darryl Alan , Gbolahan Olumide B.
Published: January 2023

523

Background: Real-world survival outcomes in metastatic biliary tract cancer (BTC) are largely unknown. Quoted numbers are often based on reports of clinical trials and hospital registry data and may not be representative of patients treated in the real world. Furthermore, the impact of more widespread adoption of standard combination chemotherapy since 2010 on survival is unclear. We performed a population-based survival analysis of patients who presented with metastatic BTC, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and gallbladder cancer. Methods: Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we collected data for patients diagnosed with metastatic BTC from 2000 to 2018 and stratified by overall survival (OS) of ≤ 3 months (short-term survivors) or ≥ 12 months (long-term survivors), before and after 2010. Additional patient and tumor characteristics, including anatomic location, prior surgical intervention, age, sex, race, and marital status were retrieved. Survival was analyzed using the Kaplan-Meier method. Multivariate cox regression models assessing effects of patient and tumor characteristics between short-term and long-term survivors were employed. Results: Of the 13,287 cases retrieved, 57% were female. Median age was 68 years (range 10-100). Prognosis correlated with anatomic location, marital status, and period of diagnosis. 41% of patients were short term survivors and only 20% were long term survivors. Median OS was 4.5 months for the entire cohort. Median OS only improved marginally from 3.5 months pre-2010 to 4.5 months post-2010 ( p<0.001). Long-term survivors tended to be younger, with a median age at diagnosis of 64 years vs 72 years ( p<0.001). Within the long-term survivor cohort, intrahepatic disease was significantly associated with improved outcomes (HR 0.81, 95% CI 0.73 – 0.90, p= 0.001). Conclusions: The real-world prognosis of metastatic BTC is remarkably poorer than described in clinical trials as a large proportion of patients survive less than three months. Over the last decade, the improvement in survival has been minimal.
Primary percutaneous stenting above the ampulla for palliative biliary drainage of malignant hilar biliary obstruction.
Authors: Franssen Stijn , Van Driel Lydi M.J.W. , Moelker Adriaan , Groot Koerkamp Bas
Published: January 2023

527

Background: Most patients with malignant hilar biliary obstruction (MHBO) are ineligible for surgical resection due to distant metastasis, locally advanced disease, or poor performance status. These patients mostly undergo biliary drainage with endoscopic stents or percutaneous drains that cross the ampulla. This approach causes bacterial colonization of the bile ducts, recurrent cholangitis, and biliary reinterventions. Few patients become eligible for palliative systemic chemotherapy, because of inadequate drainage and drainage-related complications. The solution is primary percutaneous stenting (PPS) with one or more fenestrated self-expandable metal stent (SEMS) across the biliary obstruction, without crossing the ampulla. After PPS, the percutaneous transhepatic puncture tract is sealed with glue without leaving an external biliary drain. The aim of this study was to assess the safety, feasibility, and effectiveness of PPS in patients with unresectable MHBO. Methods: A single center prospective study was performed from October 2020 till September 2022 including 35 patients with MHBO who underwent PPS. We made a comparison with a historical cohort of 90 consecutive patients treated with primary endoscopic biliary drainage at our center from 2011 till 2020. Results: All 35 patients had technical successful percutaneous SEMS placement. Perihilar cholangiocarcinoma was present in 15 patients (43%), intrahepatic cholangiocarcinoma in 14 patients (40%), and gallbladder cancer in 6 patients (17%). Two patients required two attempts because the stricture could not be passed at the first attempt. Two patients developed cholecystitis and one patient had melaena due to intrahepatic bleeding of a portal venous branch requiring blood transfusion. One patient (3%) developed cholangitis after the first biliary drainage procedure because the tumor extended up to the ampulla, requiring additional stenting. No cholangitis was seen in the other 34 patients. We made a comparison with a historical cohort of 90 consecutive patients treated with primary endoscopic biliary drainage at our center from 2011 till 2020. Only 3 patients (9%) required a readmission and 3 patients (9%) a reintervention. Palliative systemic chemotherapy was administered in 26 patients (75%) versus 18 patients (20%) after primary endoscopic biliary drainage. The median overall survival was 10.6 months (95% CI 8.1 – not reached) versus 4.3 months (95% CI 3.1 – 6.4) after primary endoscopic biliary drainage. After PPS, no patients died because of cholangitis or drainage-related complications. Conclusions: Primary percutaneous stenting with fenestrated SEMS without crossing the ampulla is safe, feasible, and effective for palliative treatment of patients with MHBO. These promising results need to be confirmed in a randomized controlled trial. Clinical trial information: NL9624 .
A study of pembrolizumab (pembro) in combination with Y90 radioembolization in patients (pts) with poor prognosis hepatocellular carcinoma (HCC).
Authors: Somasundaram Ashwin , Helft Paul R. , Harris William Proctor , Sanoff Hanna Kelly , Johnson Guy E. , Yu Menggang , Johnson Matthew , O'Neil Bert , McRee Autumn Jackson
Published: January 2023

534

Background: HCC is an aggressive cancer as a sequela of cirrhosis. For pts with no extrahepatic metastases and well-compensated liver function, Y90 radioembolization is a therapeutic option. However, high-risk patients with macrovascular invasion (MVI) or multifocal disease treated with Y90 alone have a median time to progression of less than 6 months. Pembro is an anti-PD-1 monoclonal antibody that is FDA-approved for advanced HCC pts who have progressed on sorafenib. Given pre-clinical evidence that radiotherapy can increase PD-L1 expression and enhance tumoral T-cell recruitment, this study explored the safety and efficacy of pembro with Y90 radioembolization in pts with poor prognosis HCC. Methods: GI15-225 was a multi-center, single-arm study in poor prognosis HCC pts, defined as having multifocal disease, MVI, or diffuse disease. Eligible pts had disease amenable to 1-2 embolization procedures, Child Pugh A/B7 cirrhosis, no prior Y90 treatment; previous locoregional therapy and resection were allowed. Pts with extrahepatic mets were excluded. Treatment consisted of pembro 200mg every 3 weeks with standard dose Y90 performed 7-10 days after first dose of pembro. The primary objective was to estimate the progression free survival (PFS) rate at 6 months per RECIST 1.1; secondary endpoints included safety, time to progression (TTP), overall response rate (ORR) and overall survival (OS). Imaging was performed every 9 weeks. Results: A total of 29 pts were enrolled 10/23/17 to 11/24/20. Median age 66 years, 89% male, 7% Child’s Pugh B, and 47% with MVI. 27 pts were evaluable for primary endpoint having received Y90 and at least one dose of pembro. The 6-month PFS rate was 57.7% (95% CI 36.9 – 76.6). Median PFS was 9.95 months (95% CI 4.14 – 15.24) and median TTP was 9.95 months (95% 4.14 – 18.56). Median OS was 27.30 months (95% CI 10.15 – 39.52). The ORR was 30.8% (Table). Three patients (11%) have ongoing treatment response with one of these patients off treatment for 16 weeks. Most common treatment related grade 3-4 AEs were decreased lymphocytes (n=5), increased bilirubin (n=3), hypertension (n=3), ascites (n=2), and AST/ALT elevation (n=2). One pt experienced grade 5 toxicity of hepatic failure after receiving one dose of pembro and Y90 that was attributed to Y90 and disease progression. Conclusions: Concurrent administration of pembro with Y90 in pts with poor prognosis HCC demonstrated promising clinical activity with median TTP and OS that exceeds historical data with three patients having ongoing response. With a 6-month PFS rate of 57.7%, median OS of 27.30 months and an acceptable toxicity profile, the combination of checkpoint blockade and Y90 deserves further evaluation in larger randomized clinical trials. Clinical trial information: NCT03099564 .[Table: see text]
Risk factors for early relapse in patients with biliary tract cancers who underwent curative resection: An exploratory subgroup analysis of JCOG1202.
Authors: Yanagimoto Hiroaki , Nakachi Kohei , Ikeda Masafumi , Konishi Masaru , Ogawa Gakuto , Sano Yusuke , Nomura Tatsuya , Yanagibashi Hiroo , Shibuya Kazuto , Shirakawa Hirofumi , Takahashi Amane , Sakamoto Yoshihiro , Makino Isamu , Hatano Etsuro , Gotohda Naoto , Ozaka Masato , Terashima Takeshi , Okusaka Takuji , Furuse Junji , Ueno Makoto
Published: January 2023

541

Background: Relapse after highly invasive surgery for biliary tract cancers (BTCs), especially in the early postoperative period, causes medical, psychological, social, and economic disadvantages to the patients. However, approximately 30% of patients with curatively resected BTCs experience relapse within the first 12 months. JCOG1202 (UMIN000011688) is a randomized phase III trial conducted in patients with resected BTCs showing the benefit of adjuvant S-1 for overall survival. This study aimed to investigate the risk factors for early relapse of resected BTCs in the JCOG1202 cohort. Methods: Of the 440 patients enrolled in the JCOG1202, 217 patients who received surgery alone (arm A) and 207 patients who received adjuvant S-1 (arm B) were eligible and included in this analysis. Early relapse was defined as relapse or death within 12 months after enrollment. Predictive factors for early relapse were assessed using logistic regression analyses. Results: Postoperative early relapse was observed in 59 (27.2%) and 38 (18.4%) of patients in arm A and arm B, respectively. In multivariable logistic regression analysis for the 424 eligible patients, postoperative CA19-9 levels >37 u/ml (odds ratio (OR): 2.790, 95% confidence interval (CI): 1.262-6.170), poorly differentiation (vs. well-differentiated/papillary) (OR: 4.746, 95% CI:1.927-11.688), moderate differentiation (vs. well-differentiated/papillary) (OR: 1.955, 95% CI:1.071-3.567), lymph node metastases > 4 (vs. 0) (OR: 3.991, 95% CI: 1.674-9.514), lymph node metastases 1-3 (vs. 0) (OR: 2.661, 95% CI: 1.471-4.814), and presence of residual tumor (OR: 2.171, 95% CI: 1.070-4.408) were independent risk factors for early relapse. Importantly, adjuvant S-1 chemotherapy significantly reduced early relapse (OR: 0.491, 95% CI: 0.290-0.833). Similar results were observed in arm B. Conclusions: Postoperative CA19-9 level, tumor differentiation, lymph node metastases, and the residual tumor significantly impact early relapse in patients with curatively resected BTCs. Although adjuvant S-1 chemotherapy was effective in reducing early relapse, similar factors tended to be the risk factors in patients receiving adjuvant S-1 chemotherapy. Patients at high risk of early relapse may need more intensive perioperative therapy. Clinical trial information: UMIN000011688 .