bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atypical response patterns in Chinese patients with cancer with immune checkpoint blockade.
Authors: Cui Yu , Guan Yaping , Han Xinyue , Xie Hong , Chen Yingcui , Nie Weiwei , Wang Jun 
Published: June 2023

e14631 Background: As specific patterns of progression, atypical responses, including pseudoprogression (PsPD) and dissociated response (DR), have been recently described. The purpose of the present study was to evaluate the frequency and prognosis of PsPD and DR in Chinese cancer patients treated with immune checkpoint inhibitors. Methods: We retrospectively reviewed patients with advanced cancer who received PD-1/PD-L1 inhibitor alone or combination therapy in a single center between December 2019 and January 2022. We evaluated all measurable lesions in each organ to identify PsPD and DR independently of RECIST 1.1. PsPD was defined as RECIST-defined progression followed by stabilization or decrease at the next imaging, and DR as concomitant decrease in some lesions and increase in others or emerging new lesions at a same timepoint. Progression‐free survival (PFS) and overall survival (OS) was compared between patients with atypical responses and those with true response (CR/PR) or nonresponse (SD/PD) using Cox proportional hazards models. Results: The present study included 178 patients aged 18-81 years (median: 63 years). The overall response rate was 18.5%. PsPD and DR were observed in 12 (6.7%) and 7 (3.9%) patients, respectively, and were not associated with any patient’s baseline characteristics. Median PFS (10.9 vs. 5.3 months; p=0.041) and OS (24.1 vs. 13.2 months; p=0.010) was significantly longer in patients with atypical response versus nonresponse, but shorter versus true responses (PFS: 10.9 vs. 35.4 months; p=0.009; OS: 24.1 vs. NR months; p=0.047). Patients with DR had a longer median PFS (10.1 vs. 1.5 months; p<0.0001) and OS (23.9 vs. 5.6 months; p=0.0001) than those with true PD. All patients with PsPD or DR were administrated with continuing ICIs. Among patients who experienced an initial progression (excluding patients with PsPD and DR), the continuing ICIs treatment cohort (n=20) still had a significantly longer median OS (7.5 vs. 3.1 months; p=0.004) than discontinuing ICIs treatment cohort (n=11). Conclusions: PsPD and DR are uncommon patterns of disease progression. Patients with DR exhibited a relatively favorable clinical outcome. Prognosis or biomarkers are needed to identify early patients with atypical responses who will benefit from immunotherapy.
Effect of trametinib and anti-PD-1 combo on tumor growth and survival of KRAS-mutant lung cancer by ID1 downregulation.
Authors: Puyalto Calvo Ander , Rodríguez-Remírez María , Lopez Ines , Olmedo Maria , Vilalta Anna , Macaya Irati , Welch Connor , Vicent Silvestre , Calvo Alfonso , Ajona Daniel , Gil-Bazo Ignacio 
Published: June 2023

e14633 Background: Although anti-PD-1/PD-L1 antibodies represent a major breakthrough in NSCLC patients’ survival, this treatment efficacy is highly dependent on tumor PD-L1 expression. We reported the role of ID1 and the efficacy of a combined blockade of PD-1-ID1 in a KRAS mutant NSCLC mouse model (Baraibar et al; Cancers 2020). Trametinib, which is an oral MEK1/2 inhibitor, acts downstream of KRAS. Here we evaluate trametinib as an ID1 inhibitor able to enhance immunotherapy efficacy through PD-L1 overexpression. Methods: To explore whether MEK1/2 inhibition reduces ID1 expression in vitro and in vivo, experiments in NSCLC cells (human and murine) and in murine models were performed. RNAseq analysis was conducted to elucidate the pathways implicated in ID1 inhibition. Trametinib resistant (TR) cells were generated to analyze the effect of ID1 in the acquired resistance to treatment. Apoptosis was measured by flow cytometry. PD-L1 expression was evaluated by flow cytometry in control, ID1 silenced, ID1-overexpressing and TR cell lines. Treatment of trametinib combined with anti-PD1 was performed in KRAS-mutant LUAD models. Results: In vitro experiments in NSCLC cells showed ID1 inhibition at protein level after MEK1/2 blockade. However, we observe an increase in ID1 mRNA levels following treatment. In vivo experiments performed in C57BL6J and in ID1-deficient mice showed no significant differences in tumor growth between ID1 knock-out and ID1 wild-type mice treated with trametinib. IHC analysis of those tumor samples showed reduced ID1 levels (LLC p<0.001; CMT-167 p<0.0001). RNAseq analysis revealed an enrichment of ubiquitin-proteasome pathway after trametinib exposure. Blockade of proteasome activity with a specific inhibitor, restored ID1 levels. TR cells did not show MEKi induced ID1 inhibition, moreover, ID1 blockade rescued the sensitivity to trametinib in human and murine NSCLC TR cells (p<0.001). Flow cytometry analysis showed increased PD-L1 expression (p<0.001) in human and murine NSCLC cell lines after trametinib administration. In contrast, ID1-overexpressing cells and TR cells did not show PD-L1 upregulation after MEK inhibition. In vivo experiments confirmed the therapeutic efficacy of trametinib and anti-PD-1 combo, reducing tumor growth (p<0.05) and increasing mice survival (p<0.05), compared with trametinib monotherapy or immunotherapy alone. Conclusions: Pharmacological inhibition of MEK1/2 decreased ID1 expression in vitro and in vivo, replicating the effect of a specific shRNA against ID1, through proteasome activation. PD-L1 upregulation induced by ID1 blockade after trametinib treatment sensitized KRAS-mutant NSCLC cells to PD-1/PD-L1 immunotherapy, blocking tumor growth and improving overall survival.
Meta-analysis of gastrointestinal adverse effects in patients with non-small cell lung cancer treated with a combination therapy of pembrolizumab and chemotherapy versus chemotherapy alone.
Authors: Khosla Akshita , Mukherjee Samiran , Koka Jean Marie , Shore Stephen Arthur 
Published: June 2023

e14634 Background: Pembrolizumab combined with chemotherapy has transformed the treatment of non-small cell lung cancer (NSCLC) and is now the standard of care. It has unique immune-related adverse events (irAE) that have been well defined. There is limited literature reporting its effect on the occurrence of common chemotherapy related AEs such as gastrointestinal adverse effects (GIAEs) (nausea, vomiting and diarrhea). We performed a meta-analysis to evaluate the GIAEs of pembrolizumab in non-small cell lung cancer patients treated with pembrolizumab and chemotherapy (P+C) and drew a comparison with those treated with chemotherapy alone (C). Methods: A literature search was performed in the MEDLINE database for randomized clinical trials of non-small cell lung cancer treated with pembrolizumab reporting gastrointestinal adverse effects. Articles were screened in concordance with PRISMA guidelines. Funnel plots were generated to assess publication bias. The pooled odds ratios (OR) for occurrence of GIAEs with 95% confidence intervals (CI) using random-effects models was calculated. Results: 9 studies (including data from KEYNOTE-021, 407, 189, 604, PROLUNG trial) were included in our analyses (n = 3157 patients). A clear increment in certain GIAEs (constipation (OR 1.16 (0.99- 1.37)), diarrhea (OR 1.51 (1.28- 1.78)), colitis (OR 4.39 (1.81- 10.62)), hepatitis (OR 4.67(1.79-12.18)) was noted the Pembrolizumab plus chemotherapy arm versus chemotherapy alone. No significant differences were noted in the occurrence of nausea, vomiting and pancreatitis. Conclusions: Pembrolizumab plus chemotherapy compared with chemotherapy alone has been studied extensively to highlight the survival advantages of the former therapeutic strategy. The risk of certain GIAEs (constipation, diarrhea, colitis, hepatitis) with pembrolizumab combination therapy for non-small cell lung cancer is significantly higher in comparison to chemotherapy alone. This alludes to the superadded effect of pembrolizumab on the existing AEs of chemotherapy. [Table: see text]
TIGIT transcriptomic expression and high levels of multiple checkpoints across diverse cancers.
Authors: Adashek Jacob J. , Kato Shumei , Pabla Sarabjot , Nesline Mary K , Conroy Jeffrey M. , DePietro Paul , Kurzrock Razelle 
Published: June 2023

e14637 Background: The T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is an immune inhibitory receptor present on some T- and natural killer (NK) cells. It plays an important role in restricting innate and adaptive immunity. Given this, studies to combine other checkpoint inhibitors with anti-TIGIT therapies are currently in development. Methods: The RNA expression levels of 397 genes in various types of solid tumors from 514 patients seen at the UCSD Moores Cancer Center were analyzed at a CLIA-licensed laboratory, (OmniSeq (https://www.omniseq.com/)). Transcript abundance was normalized to internal housekeeping gene profiles and ranked (0-100 percentile) in a standardized manner to a reference population of 735 tumors spanning 35 histologies. Odds ratio for high TIGIT expression (≥75 percentile rank) was calculated and Bonferroni corrected for multiple genes and cancer histologies with > 10 samples. Results: Of 514 tumors, 99 (19%) tumors had high TIGIT expression (32 different histologies). Cancers with the greatest proportion of high TIGIT expression were small intestine (33%; 4/12) pancreatic (31%; 17/55), lung (25%; 5/20), stomach (20%; 5/25), breast (20%; 10/49), colorectal (18%; 25/140), head and neck (17%; 2/12), sarcoma (13%; 3/24), and uterine (13%; 3/23), though there were no statistically significant associations between these histologies and high TIGIT. There were significant associations between high TIGIT and high PD-L1 (P < 0.0021), PD-1 (P < 0.0021), PD-L2 (P < 0.0021), CTLA-4 (P < 0.0021), OX40 (P < 0.0021), LAG3 (P < 0.0021), FOXP3 (P < 0.0021) expressions (p values Bonferroni adjusted for multiple comparisons). However, there was no significant association between tumor mutation burden ≥10 mutations/mb and high TIGIT. Conclusions: High TIGIT expression was found in 19% of 514 tumors (pan-cancer) and significantly associated with high RNA expression of other immune checkpoints (PD-L1, PD-1, PD-L2, CTLA-4, OX40, LAG3, FOXP3), many of which can be targeted by FDA-approved drugs or drugs in clinical trials. Ongoing studies combining TIGIT inhibitors and specific immune checkpoint inhibitors may yield more clinical benefit after personalized tumor immune profiling.
Correlation between biomarkers and treatment outcomes in diverse cancers: A meta-analysis of phase I and II immunotherapy clinical trials.
Authors: Fountzilas Elena , Vo Henry Hiep , Müller Peter , Kurzrock Razelle , Tsimberidou Apostolia Maria 
Published: June 2023

e14638 Background: Many immuno-oncology (IO) trials are conducted without biomarker selection. We performed a meta-analysis of phase I/II clinical trials evaluating immune checkpoint inhibitors (ICIs) to determine the association between biomarkers and clinical outcomes, if any. Methods: We searched PubMed for phase I/II clinical trials of drugs approved by the Food and Drug Administration (labeled, off-label, or combined with investigational ICIs or other treatment modalities) from 2018 to 2020. We compared the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) between biomarker-positive and biomarker-negative groups, using data from correlative studies. Results: Overall, 174 clinical studies that included 19,178 patients were identified and 131 studies investigated >30 correlative biomarkers, that included PD-L1 expression (≥1%, 111 studies), tumor mutational burden (20 studies), and microsatellite instability/mismatch repair deficiency (10 studies). Overall, 123, 46, and 30 cohorts (drugs, tumor types, or biomarkers) with 11,692, 3,065, and 2,256 patient outcomes for ORR, PFS, and OS, respectively, were analyzed in correlation with biomarkers. Meta-analyses demonstrated that ICIs in patients with biomarker-positive tumors were associated with higher ORR (odds ratio 2.15 [95% CI, 1.79-2.58], p<0.0001); and longer PFS (hazard ratio [HR] 0.55 [95% CI, 0.45-0.67], p<0.0001), and OS (HR 0.65 [95% CI, 0.53-0.80], p<0.0001) compared with those with biomarker-negative tumors. Significance for ORR and PFS was retained in multivariate analysis (p<0.001) (OS, not included owing to the small number of trials reporting OS). Conclusions: Our data suggest that IO biomarkers should be used in patient selection for ICIs. Prospective studies are warranted.
PD-L1 expression in Chinese patients with solid tumor and its correlation with gene alternations.
Authors: Zhang Xin , Liu Jiayu , Zhao Xin , Sun Li , Liu Chuang , Zhang Yaxuan , Du Pengyao , Meng Fanfan , Li Ling 
Published: June 2023

e14640 Background: Immune checkpoint blockade are recommended in more and more solid tumors for first-line or posterior treatment, and PD-L1 expression is a crucial predictive biomarker for immunotherapy. However, the expression can be influenced by many factors. Methods: A total of 1743 Chinese patients with solid tumor was retrospectively identified. The Dako PD-L1 IHC 22C3 pharmDx assay was used to detect PD-L1 protein expression. And Tumor Proportion Score (TPS) ≥ 1% was defined as positive expression, TPS ≥ 50% was defined as high expression. Genomic profiling was performed on tumor tissue and matched peripheral blood samples. Only the tumor subtypes with sufficient sample size were used for correlation analysis. Results: PD-L1 positive expression occurred in 45.6% patients and high expression occurred in 8.1% patients. The highest expression incidences occurred in cervical cancer as of 78.8%, followed by lung cancer (53.8%), esophageal cancer (53.7%) and gastric cancer (42.7%). The PD-L1 expression assessed by TPS was consistent with that assessed by Combined Positive Score (CPS) in multiple tumors. However, it was significantly different in gastrointestinal tumors, especially in colorectal cancer (TPS>1%: 30.4% vs. CPS>1: 80.6%). In addition, gene alternations including TP53, CDKN2A, LRP1B, KRAS and PIK3CA apparently occurred in patients with high PD-L1 expression. Moreover, high tumor mutation burden (TMB-H) was associated with PD-L1 positive expression in these Chinese patients. Besides, no correlation was found between microsatellite instability (MSI) and PD-L1 expression. Conclusions: Our results illustrated genomic correlates of PD-L1 expression in Chinese solid tumor patients. These findings may broaden the application of immune checkpoint blockade to patients harboring specific molecular characteristics.
Thoracic SMARCA4-deficient undifferentiated tumor: A clinicopathologic study.
Authors: Shold Janna , Hamza Ameer 
Published: June 2023

e14642 Background: Thoracic SMARCA4-deficient undifferentiated tumor is a high-grade malignant neoplasm that frequently shows undifferentiated morphology and deficiency of SMARCA4. There is limited data in literature for this entity. The purpose of this report is to describe clinicopathologic features of this rare tumor in a series of 5 patients, diagnosed and treated at our institution. Methods: After approval from institutional review board, pathology department archive was searched for the patients with diagnosis of Thoracic SMARCA4-deficient undifferentiated tumor from January 2020 to December 2022. Data such as patient demographics, pathologic features including immunohistochemical stains, treatment and clinical outcome were collected. Results: Among 5 patients, 3 were male and 2 were female. Median age was 62 years (range 49 to 77 years). In three patients the primary site of the tumor was lung. One patient had tumor of the gastroesophageal junction while one patient had epicenter of the tumor in the paraspinous muscle. Diagnosis was made on biopsy specimen in all cases. All tumor showed undifferentiated histologic appearance. Rare cells with keratin positivity were observed in 2 specimens while 3 were completely negative for keratin stains. Focal TTF1 positivity was observed in one specimen while 4 were negative. Among neuroendocrine markers performed on variable number of cases, synaptophysin was positive in 4/4 cases while chromogranin was negative in 2/2 cases and INSM1 was negative in 1/1 case. PD-L1 (Dako 22C3) was performed on two specimens and showed less than 1% tumor cells to be positive. Next generation sequencing was performed on one specimen and showed pathogenic variants in TP53, CDKN2A, and APC genes and likely pathogenic variants in ATR, SMARCA4, and BCOR genes. Two patients received carbotaxol and radiation, one patient received FOLFOX, nivolumab and radiation, 1 patient pursued hospice care and 1 patient lost follow up. Two patients died 2 and 7 months after diagnosis. One patient is alive with metastatic disease 4 months after initial diagnosis. Conclusions: SMARCA4-deficient undifferentiated tumor is an aggressive malignancy that shows undifferentiated histology with synaptophysin positivity. From a diagnosis standpoint, Pathologists need to keep this entity in mind while working up tumors showing poorly differentiated to undifferentiated histology that are negative for most immunohistochemical markers. From clinical standpoint there is need to develop targeted therapy for this aggressive tumor.
Evaluation of immunotherapy response score (IRS) for predicting pembrolizumab (pembro) clinical benefit in patients (pts) with advanced solid tumors.
Authors: Thomas Sachdev P. , Achacoso Ninah , Jiang Chen , Chung Elaine , Solorzano-Pinto Aleyda V. , Tse Pamela , Bulen Benjamin J. , Khazanov Nickolay A. , Lamb Laura Elaine , Hovelston Daniel H. , Kwiatkowski Kat , Johnson D. Bryan , Rhodes Daniel R. , Tomlins Scott A. , Suga Jennifer Marie , Habel Laurel A. 
Published: June 2023

e14646 Background: IRS is a multivariable biomarker algorithm combining tissue-based tumor mutation burden (TMB) with quantitative gene expression biomarkers, previously validated to predict anti-PD-1 and anti-PD-L1 monotherapy (mono) benefit in an observational clinical trial (PMID: 36750617). Herein, we evaluated IRS in pts with advanced solid tumors across the Kaiser Permanente Northern California (KPNC) health system following a pre-specified statistical analysis plan. Methods: KPNC pts with valid IRS results (from 2018 – 2022; specimen collection years 2011-2021) and electronic health record (EHR) documented > 1st line systemic pembro mono treatment were included; pts with gliomas or previous immunotherapy were excluded. All oncologic treatments were obtained from the EHR and standardized to determine time to next treatment (TTNT) as a real-world progression free survival endpoint. A within-pt evaluation was performed, comparing pembro TTNT to the pt’s immediate prior therapy line (prior) TTNT. The primary objective was to determine if IRS status (-H vs. Low [-L]) predicts pembro clinical benefit in Cox proportional hazards models through testing for interaction between IRS status and pembro/prior therapy TTNT. Results: With a data cutoff of 06/15/2022, 211 KPNC pts (142 2nd line and 69 > 2nd line pembro) were eligible and included (from 24 solid tumor types). The median (m) pembro follow-up was 16.0 months. IRS-H pts (n = 77, 36%) had significantly longer pembro vs. prior TTNT (mTTNT 20.3 mo vs. 4.5 mo, log-rank p-value < 0.0001), whereas IRS-L pts (n = 134, 64%) did not (mTTNT 3.3 mo vs. 5.2 mo, log-rank p-value 0.75); the interaction between IRS status and pembro/prior treatment was significant (interaction test p-value < 0.0001). Conclusions: IRS predicted pan-solid tumor pembro mono benefit compared to prior therapy and may be a potential marker for pembro mono treatment decisions. Clinical trial information: NCT03061305 .
Quantitative analysis of MMR deficiency in dMMR/MSI high CRC and levels of instability: Implications for ICI therapy of dMMR tumors.
Authors: Staninova Stojovska Marija , Matevska Geshkovska Nadica , Jovanovic Rubens , Kubelka Sabit Katerina , Angelovska Biljana , Mitrevski Nenad , Panovski Milco , Josifovski Toni , Dimovski Aleksandar J 
Published: June 2023

e14650 Background: Mismatch repair deficiency (dMMR) is observed in ~15% of newly diagnosed colorectal cancer (CRC) tumors. It is routinely scored as a qualitative trait (positive or negative) and, if present, is considered a positive predictive marker for immune checkpoint inhibitors (ICI) therapy not only in patients with metastatic CRC (mCRC), but also in patients with other dMMR solid tumors. However, a significant proportion of these patients experience failure of ICI treatment and no predictive biomarkers exist that can identify such patients. Methods: A total of 42 patients with dMMR tumors were selected for analysis, of which 26 had a hereditary Lynch Syndrome (LS) with known pathogenic variants in the MMR genes (MLH1, MSH2, MSH6, PMS2) and 16 had sporadic dMMR CRC due to epigenetic silencing of the MLH1 gene. All tumors were also analyzed for the presence of the RAS/RAF pathway mutations. MMR deficiency was initially evaluated by two standard methods: immunohistochemistry (IHC) and by microsatellite instability (MSI)-PCR on DNA isolated from FFPE tissues with > 50% tumor content. Subsequently, whole exome sequencing (WES) with a mean depth of >150 reads was performed on the same DNA samples using the NovaSeq 6000 platform. NGS data were analyzed using the MSI sensor package which evaluates >2000 sites with mono- to pentanucleotide repeats. Each site was scored as NGS-MSI unstable if it contained at least 20% unstable reads. The percent of unstable loci was referred to as NGS-MSI level. All tumors with >3.5% of unstable loci were classified as NGS-MSI positive. Results: A considerable variability in the NGS-MSI levels ranging from 1.5 – 76% was observed in patients that were initially classified as dMMR/PCR-MSI high. CRC tumors of LS patients with deleterious MMR gene mutations and the majority of patients with sporadic CRC due to MLH1 gene promotor methylation had >50% unstable loci. In contrast, more than 1/3 of patients with isolated loss of MSH6 and PMS2 detected by IHC had substantially lower NGS-MSI levels of 1.5 to 12%. These patients had a negative PCR-MSI result and their molecular defects were primarily missense mutations in MSH6 and PMS2 genes. It is interesting to note that a low NGS-MSI score (<10%) was also detected in patients with sporadic CRC that had MLH1 gene promotor methylation but also the BRAF V600E mutation. Conclusions: Our results indicate that dMMR/MSI-H tumors exhibit a high variability in the percentage of unstable loci that correlates with particular molecular backgrounds. A larger study on different types of tumors is warranted, especially in the context of the efficacy of ICI therapy in patients with MMR tumors classified by qualitative MMR/MSI assays.