Browse Articles

Prognostic value of circulating tumor DNA for progression-free survival in patients with locally advanced dMMR/MSI-H colorectal cancer managed without surgery.

256 Background: Immunotherapy has shown the ability to induce a high rate of pathologic and clinical complete response in patients with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC). The role of circulating tumor DNA (ctDNA) as a prognostic biomarker for survival in patients who receive non-operative management (NOM) is unknown. Among patients enrolled in a phase II trial (NCT04082572) that evaluated the efficacy of pembrolizumab in patients with locally advanced dMMR/MSI-H solid tumors, we evaluated the impact of ctDNA on progression-free survival (PFS) among 12 patients with locally advanced dMMR/MSI-H CRC who received NOM. Methods: ctDNA testing was performed in the CLIA-certified laboratory at MD Anderson using a 70-gene liquid biopsy panel (LBP-70), which used digital sequencing of cell-free DNA. Formalin-fixed paraffin-embedded tumor samples and germline peripheral blood mononuclear cells were profiled using next-generation sequencing. Mutations in ctDNA were considered tumor-specific if they were confirmed with matched tumor tissue profiling. The lower limit of detection of the LBP-70 assay was a mutational variant allele frequency of <0.3%. "ctDNA clearance" and “ctDNA(-)” status were defined as the absence of any detectable tumor-specific mutations in ctDNA. Two-year progression-free survival (PFS) was estimated using Kaplan-Meier techniques and compared with log-rank tests. Results: The median follow-up between the first cycle of pembrolizumab and last radiographic assessment was approximately three years (36.7 mo; range (range 1.2 – 51.0 mo). Forty-nine LBP-70 assays were performed among the 12 patients over the course of treatment with pembrolizumab. The median number of cycles was 16 (range 1 – 16 cycles). Six patients were ctDNA(-) prior to pembrolizumab, all of whom remained ctDNA(-) after. None of these six patients experienced disease progression (PD) at their last follow-up. The other six patients were ctDNA(+) prior to pembrolizumab (median baseline VAF 0.4%, range 0.3%–4.0%). Of these six patients, three experienced ctDNA clearance while receiving pembrolizumab. None of the three patients who cleared ctDNA experienced PD as of their last follow-up. Of the three patients who did not clear ctDNA, two experienced PD in their primary tumor (at two and six months after their first cycle, respectively), while the third patient remains without PD at their last follow-up. The two-year PFS rate was 100% among the nine patients who were ctDNA(-) after pembrolizumab compared to 33% among the three patients who were ctDNA(+) after pembrolizumab (p = 0.03). Conclusions: ctDNA may be a valuable tool for assessing treatment response and improving the ability to tailor organ-sparing, curative strategies to patients with locally advanced dMMR/MSI-H CRC.

Efficacy of pembrolizumab in advanced esophageal carcinoma: A systematic review and meta-analysis.

438 Background: Pembrolizumab, a monoclonal immunoglobulin G4 antibody is a programmed cell death protein 1 inhibitor, approved for treatment of advanced (metastatic or recurrent) esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). We performed a pooled analysis to assess the efficacy of pembrolizumab in esophageal carcinoma (EC) and to compare it with chemotherapy alone. Methods: We conducted a systemic literature search, using PubMed, EMBASE, and ClinicalTrials.gov, till July 30, 2024. Initial search yielded 412 articles. We excluded duplicates and irrelevant studies and included 4 clinical trials (CT) that reported pembrolizumab’s efficacy in EC. We estimated pooled objective response rate (ORR), partial response (PR), and hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS), along with 95% confidence interval (CI) and p-value in RevMan v.5.4. Subgroup analysis, based on combined positive score (CPS) for programmed cell death ligand-1 (PDL-1) expression and tumor histology type was also performed. Results: We included four CTs in our study; their characteristics are shown in the table. The estimated pooled ORR and PR of pembrolizumab in all patients was 21% (CI: 0.10-0.41) (p < 0.001) and 19% (CI: 0.08-0.37) (p < 0.001), respectively. Pooled median PFS was 3.05 mo (CI: 0.92-5.17) (p = 0.004), and pooled median OS was 8.05 mo (CI: 5.21-10.88) (p < 0.001). Pembrolizumab use in EC showed a reduced risk of disease progression vs chemotherapy alone [HR: 0.85 (CI: 0.75-0.96) (p < 0.05)] and a 21% reduction in mortality [HR: 0.79 (CI: 0.71-0.88) (p < 0.001)]. Safety analysis revealed less grade ≥3 adverse events [OR: 0.56 (CI: 0.35-0.90), p < 0.05)] with pembrolizumab compared with chemotherapy alone. On subgroup analysis between ESSC and EAC, pembrolizumab exhibited statistically nonsignificant responses with ORR (OR: 1.29, CI: 0.89-1.88, p = 0.18), OS (pooled HR: 0.94, CI: 0.76-1.15, p = 0.53). Pembrolizumab in patients with CPS ≥10 vs CPS <10 also showed statistically non-significant responses with ORR [OR: 1.70, CI: 0.99-2.91, p = 0.06), OS (pooled HR: 0.63 vs 1.00) (p = 0.05) and PFS (pooled HR: 0.62 vs 0.83, p = 0.08). Conclusions: Pembrolizumab alone or combined with chemotherapy compared with chemotherapy alone exhibited favorable responses in terms of ORR, OS and PFS with a manageable toxicity profile, setting a benchmark for future studies. Characteristics of included studies. Trial ID, phase Histology Line Number of patients Regimen Median follow-up (mo) ORR (%) Median PFS (mo) Median OS (mo) KEYNOTE-590, III ESCC, EAC 1 st 749 Pembro + chemo vs chemo 58.8 45 vs 29.3 6.3 vs 5.8 12.3 vs 9.8 KEYNOTE-181, III ESCC, EAC 2 nd 628 Pembro vs chemo 7.1 13.1 vs 6.7 2.1 vs 3.4 9.3 vs 6.9 KEYNOTE-180, II ESCC, EAC 3 rd or later 121 Pembro 5.8 9.9 2.0 5.8 KEYNOTE-028, 1b ESCC, EAC 3 rd or later 21 Pembro 7 30 1.8 7 Pembro: pembrolizumab, mo: month.

Band structure modulation of chalcogenide perovskite with Eu as A-site cation

Chalcogenide perovskites with distorted structures, such as BaZrS3 and SrZrS3, are promising photovoltaic materials due to their high stability, strong absorption, and excellent electrical transport properties. Researchers have explored BaZr1-xTixS3 and BaZrS3-xSex alloys to reduce their band gaps, allowing them to absorb lower-energy photons. However, the hexagonal structures of BaTiS3 and BaZrSe3, along with the incompatibility of Ti or Se atoms in BaZrS3, lead to phase separation in these alloys. In this work, using EuZrS3 and Sr0.7Eu0.3ZrS3 alloys as examples, we demonstrate that the band structure of chalcogenide perovskites can be tuned by using Eu as the A-site cation. In EuZrS3, the Eu 4f orbitals contribute to the valence band maximum, thereby raising the valence band and resulting in a narrow bandgap of 0.54 eV. Furthermore, due to the structural and atomic compatibility of Eu with SrZrS3, the Sr1-xEuxZrS3 alloy is designed to fine-tune the band structures of both SrZrS3 and EuZrS3. EuZrS3 also exhibits typical semiconducting characteristics, making it promising for potential optoelectronic devices.

A new regulation mechanism for KCNN4, the Ca2+-dependent K+ channel, by molecular interactions with the Ca2+pump PMCA4b

Genomic profiling of matched tumor samples in patients with rectal cancer undergoing total neoadjuvant therapy.

213 Background: Total neoadjuvant therapy (TNT) is increasingly used for locally advanced rectal cancer. However, which patients benefit most from TNT remains to be elucidated. In this study we sequenced a TNT cohort with long-term follow-up to identify genomic correlates of TNT efficacy. Methods: Patients with locally advanced rectal cancer who underwent TNT followed by surgery (Oct 2016-June 2020) were identified at our institution. MSS patients with paired tissues (normal, biopsy, and surgery) with successful DNA extraction and sequencing were analyzed. Retrospective chart review collected patient demographics and clinical outcomes. Genomic analyses were performed with the R maftools package. Descriptive statistics were calculated with Fisher’s exact, Wilcoxon rank sum, and Wilcoxon rank sum exact tests. Univariate survival analyses (UVA) were calculated with Cox proportional hazards regressions. All statistical analyses were performed using R (v4.3.2). Results: 53 patients met inclusion criteria and 32 patients with paired tissues (64 samples) were obtained and successfully sequenced. All patients received chemotherapy, most commonly FOLFOX (81.3%) as part of TNT and a 5-FU based chemoradiation therapy (RT) regimen. Almost all patients received 50.4 Gy (93.8%). Median followup was 57 months (IQR: 47-68). There were 24 pathological responders (R) [complete/partial] and 8 nonresponders (NR) [stable disease/progression]. R vs NR were not statistically different across demographic or treatment characteristics. Local recurrences were infrequent (9.4% 3/32). No covariates were prognostic on UVA survival analyses. However, NR was associated with worse distant metastases free survival (DMFS) (HR = 4.11, CI 1.01-16.8, p = 0.048) on UVA. 5-year DMFS was 83% for R and 50% for NR, and the median DMFS was not reached for R, 41 mo for NR. Tumor mutation burden (TMB) did not change with treatment (pre = 4.5 vs post = 6.2 mutations/Mb; r, 1.7-10.3, p=0.59) and was not different on biopsy between R and NR (4.1 vs 5.9, p=0.09). Pre-treatment, the most mutated gene was APC (81%), [majority nonsense/frameshift (88%)], followed by TP53 (69%), [missense (59%)]. When comparing frequent mutations (n ≥ 5), PIEZO1 was more mutated in NR (63%, 5/8) than R (4% 1/24 patients) (p = 0.023 [multiple testing corrected]). Putative radioresistant KRAS-TP53 co-mutations were uncommon with similar representation in both groups (R 12.5%, 3/24, NR 12.5%, 1/8). Conclusions: Pathologic response positively correlated with DMFS in this cohort with long-term followup. PIEZO1 mutations were negatively prognostic for pathologic NR to TNT. This uncovers a potential new role in chemoRT resistance in addition to a previously reported association with metastatic spread. Further evaluation of PIEZO1 as a prognostic biomarker may help personalize appropriate treatment for patients with locally advanced rectal cancer.

BTN1A1 expression in colon cancer: Implications for immunotherapy and patient stratification.

249 Background: Butyrophilin 1A1 (BTN1A1) is a promising immune checkpoint protein offering a novel option for immunotherapy. We discovered that BTN1A1 and PD-L1 expression are mutually exclusive through the JAK/STAT pathway in various tumors. Recently, Nelmastobart, an antibody targeting BTN1A1, successfully completed a Phase 1 clinical trial at three sites in the United States and two in the Republic of Korea, spanning 98 weeks. This abstract focuses on the results from the Phase 1 trial in patients with colorectal cancer (CRC), emphasizing biomarker diagnostics and therapeutics derived from translational research. Methods: We conducted a first-in-human, multicenter, open-label Phase I clinical trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of hSTC810 monotherapy in CRC patients. Extensive analyses of BTN1A1 expression were performed using patient specimens through immunohistochemistry and multi-immunofluorescence techniques to identify critical biomarkers and accurately assess nelmastobart's anticancer activity. We then analyzed progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety alongside translational research findings using patient tissue samples. Results: A total of 47 patients were enrolled in the study. The median PFS across all cohorts was 1.9 months, while the median Kaplan-Meier estimate for OS was 12.8 months. Among the 16 CRC patients enrolled, tissue samples were obtained and analyzed using IHC in 12 patients and OPAL staining in 7 patients. The objective response rate (ORR) for CRC was 2.3%. The median progression-free survival (PFS) and overall survival (OS) were 3.6 months and 11 months, respectively. Notably, PFS, OS, and ORR strongly correlated with BTN1A1 expression levels in CRC patients. High levels of BTN1A1 expression in colorectal tumor tissues correlated with clinical outcomes, identifying BTN1A1 as a potential biomarker for predicting patient responses to targeted therapies. The mutual exclusivity of BTN1A1 and PD-L1 expression suggests that BTN1A1 could serve as a diagnostic marker to identify patients who may be unresponsive to PD-1/PD-L1 blockade therapy and might benefit from BTN1A1 blockade therapy. Conclusions: This Phase 1 clinical trial demonstrated that antibody-mediated BTN1A1 blockade effectively suppresses tumor growth in patients with BTN1A1-positive CRC. These findings suggest that BTN1A1-targeted therapies could provide a viable treatment option for patients with colon cancers that are refractory or resistant to anti-PD-1/PD-L1 therapies. Clinical trial information: NCT05231746 .

Association between adjuvant component of perioperative chemotherapy and survival outcomes in resected gastric cancer (GC).

378 Background: Perioperative chemotherapy is the standard of care for resectable GC but many patients do not proceed to or complete adjuvant chemotherapy (AC). It remains unclear whether AC following neoadjuvant chemotherapy (NAC) improves survival. Methods: Patients with GC who received NAC and underwent curative-intent gastrectomy from 2006-2022 were identified from an institutional database. Patients with mismatch repair-deficient/microsatellite instability-high tumors, GEJ tumors, M1 disease, neoadjuvant radiotherapy, total neoadjuvant intent treatment, incomplete NAC (<66% of planned cycles), and incomplete data were excluded. A lymph node ratio (LNR) risk cutoff was determined using maximally selected rank statistics. Kaplan-Meier analysis with log-rank tests were used to compare overall survival (OS) and disease-free survival (DFS). Cox proportional hazards regression models were used to identify independent predictors of OS and DFS. All analyses were performed in R statistical software. Results: Of 340 patients included, 264 (78%) received AC. Most common reasons for incomplete AC were postoperative complications (20%), poor performance status (16%), minimal pathologic response to NAC (14%), patient choice (14%), and NAC toxicity (9%). Median follow-up was 6.4 years. In the overall cohort, there was no significant difference in OS (median 10 vs. 8.3 years; p=0.14) or DFS (7.0 vs. 7.5 years; p=0.12) between AC and non-AC groups. In node-negative (ypN-) patients (n=170), there was no association between receipt of AC and OS (12 vs. 10 years; p=0.6) or DFS (12 vs. 10 years; p=0.8). On univariable analysis, lack of AC receipt was not associated with shorter OS (p=0.3) or DFS (p=0.4). In the node-positive (ypN+) cohort (n=170), AC receipt was associated with significantly longer DFS (4.8 vs. 2.7 years; p=0.031) but not OS (5.5 vs. 2.8 years; p=0.071). However, on multivariate analysis, AC only showed a non-significant trend towards longer DFS (HR 0.77 [95% CI 0.49-1.19]; p=0.20). High-risk patients based on LNR (LNR>0.0684; n=112) who received AC (n=87; 78%) had longer OS (p=0.033) and DFS (p=0.014). No such differences were observed in the low risk LNR subgroup (LNR<0.0684; n=227). Conclusions: Following NAC, AC was not associated with improved survival in patients with ypN- GC. The association between AC and survival in ypN+ GC remains unclear but LNR may be used to identify patients with ypN+ disease who may benefit from AC. These observations require prospective validation but may have implications for clinical care and future trial design.

Plasma shallow whole-genome sequencing profiling in patients with <i> RAS ^WT </i> metastatic colorectal cancer (mCRC) undergoing first-line anti-EGFR therapy.

214 Background: Acquired resistance (AR) to first-line (1L) chemotherapy (CT) + anti-EGFR inhibitors is a major challenge in the management of RAS WT mCRC patients (pts). While AR in later lines has been explained with point mutations in the EGFR pathway, its real mechanisms in 1L remain poorly understood. Tumor molecular biology can be dynamically studied through circulating tumor DNA (ctDNA) analysis, a real-time, non-invasive approach to detect AR. In this context, we conducted the multicenter prospective PLATFORM-B study, which enrolled 100 RAS WT mCRC pts receiving 1L CT + cetuximab across 15 Spanish Medical Oncology Departments, alongside 30 RAS MUT pts (control) treated with 1L CT + bevacizumab. Peripheral blood samples have been collected at baseline (BL), week 8, and disease progression (PD). Next-generation sequencing analysis (Ion S5 system) of ctDNA at PD revealed AR mutations in only 10% of pts, suggesting that alterations in the EGFR pathway may only partially explain AR in 1L. Therefore, we conducted shallow whole-genome sequencing (shWGS) to further characterize genomic profiles possibly related with novel mechanisms of AR. Methods: Baseline and PD samples with sufficient remaining plasma were considered for this analysis. shWGS was performed with a coverage ranging 0.5X to 2.0X and analyzed using ichorCNA pipeline to evaluate various genomic characteristics such as copy number alterations (CNA), tumor fraction (TF), subclonal fraction (SF), and ploidy. Molecular results were correlated to clinical-pathological features and outcomes. Results: Overall, 35 mCRC pts (27 RAS WT and 8 RAS MUT ) were included in the study. At BL ( N = 26), median TF (mTF) was 0.19, median ploidy 2, median SC fraction 0.5, median SC genome fraction 0.21, and median subclonal CNA fraction 0.41. At PD ( N = 33), mTF was 0.08, median ploidy 2, median SC fraction 0.5, median SC genome fraction 0.17, and median subclonal CNA fraction 0.38. Of all the features analyzed, only the TF showed potential prognostic value. At BL, pts with TF levels above the median had poorer overall survival (OS) compared to those with lower levels, approaching statistical significance ( P = .055). At PD, higher TF levels were statistically significantly associated with worse OS ( P = .02). No meaningful differences between the RAS WT and RAS MUT groups were observed. Specific variations in CNA, TF, SF, or ploidy under treatment are being correlated to clinical data to seek for predictive value. Conclusions: This preliminary analysis of the PLATFORM-B using shWGS showed the prognostic value of TF. Further analyses are undergoing to better understand the molecular landscape of acquired resistance to 1L anti-EGFR-based therapy in RAS WT mCRC pts.

High-pressure modulation of altermagnetism in MnF2

We investigate the phase transition behavior and electronic band structure of MnF2 under high pressures ranging from 0 to 20 GPa based on first-principles calculations. At ambient pressure, MnF2 in the rutile structure displays antiferromagnetic properties along with significant altermagnetic characteristics. Upon increasing pressure, MnF2 undergoes sequential phase transitions from the rutile structure to the SrI2-type structure and further to the α-PbCl2-type structure. Under high pressure, all three structures of MnF2 exhibit stable altermagnetism, with the maximum spin splitting of 307.5 meV at 3 GPa for the rutile structure, 133.6 meV at 12 GPa for the SrI2-type structure, and 58.4 meV at 20 GPa for the α-PbCl2-type structure. Additionally, our findings suggest that the magnitude of spin splitting can be effectively controlled by modulating the antiferromagnetic exchange interactions and the electron hopping parameters between sublattices. This work elucidates the crystal structure, electronic structure, and altermagnetic properties of MnF2 under high pressure, providing important theoretical foundations for expanding the library of altermagnetic materials.

Hypusinated and unhypusinated isoforms of the translation factor eIF5A exert distinct effects in models of pancreas development and function

Robot-assisted esophagectomy with extended mediastinal lymph node dissection: The learning curve and surgical outcomes.

457 Background: We have performed thoracoscopic surgery (TMIE) and robot-assisted surgery (RAMIE) for esophageal cancer with extensive mediastinal lymph node dissection, including resection of the sympathetic nerve layers and the thoracic duct. We studied the learning curve, short-term results, and mid-to-long-term outcomes of RAMIE for esophageal cancer at our institution. Methods: We compared surgical times at different stages of the procedure. For mid to long-term outcomes, we analyzed 360 cases of TMIE/RAMIE performed between January 2009 and June 2022, comparing the incidence of postoperative complications, recurrence-free survival, and patterns of recurrence between RAMIE and TMIE. Recurrent laryngeal nerve palsy (C-D I) was evaluated using postoperative endoscopy or contrast swallowing tests to assess even mild paralysis. Results: The average console time in the thoracic procedure was 234.4 minutes, with Group A (294.5 minutes, range: 211-397 minutes) showing significantly longer times compared to Group B (190.5 minutes, range: 130-257 minutes). Blood loss was almost 0ml in 10 cases (50%) in Group A and 25 cases (62.5%) in Group B. Postoperative complications included pneumonia in 5 cases (8.3%) and recurrent laryngeal nerve palsy (C-D III) in 5 cases (8.3%), with no significant difference between the groups. However, surgical time for lymph node dissection around the recurrent laryngeal nerve was significantly shorter in Group B compared to Group A. Long-term analysis included 326 TMIE and 34 RAMIE cases. Mild recurrent laryngeal nerve palsy (&gt;C-D I) was observed in 92 cases (28%) of TMIE and 7 cases (21%) of RAMIE, showing a lower tendency in the RAMIE group (p=0.338). Pneumonia (&gt;C-D II) occurred in 57 cases (18%) in the TMIE group and 3 cases (9%) in the RAMIE group, with a relatively lower incidence in the RAMIE group (p=0.178). For patients with cT1N0M0 who did not receive preoperative chemotherapy, the 3-year recurrence-free survival rates were 95% for TMIE and 93% for RAMIE. Conclusions: RAMIE demonstrated a significant reduction in operative time due to the standardization of the procedure, particularly in the dissection of recurrent laryngeal nerve lymph nodes and other upper mediastinal maneuvers. RAMIE also showed a potential reduction in the incidence of recurrent laryngeal nerve palsy and pneumonia compared to TMIE. In terms of long-term outcomes, RAMIE maintained local control similar to TMIE, with further improvements in safety expected.

Real-world evidence of nanoliposomal irinotecan and fluorouracil with folinic acid in patients with unresectable or recurrent pancreatic cancer: Final results of a multicenter observational study.

721 Background: Nanoliposomal irinotecan (NAL-IRI) and fluorouracil with folinic acid (NFF) is the standard regimen after gemcitabine-based therapy for unresectable or recurrent pancreatic cancer (urPC). However, we have almost no prospective data on its efficacy and safety in the real-world, so we conducted this study to investigate them both retrospectively and prospectively (NAPOLEON-2 study). We previously reported the retrospective data in ASCO-GI 2023, and here we report the final results of the prospective part. Methods: We prospectively collected data of urPC patients treated with NFF who had received at least one previous chemotherapy line in 17 hospitals in Japan from June 2021 to October 2023. The primary endpoint was overall survival (OS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), dose intensity (DI) and adverse events (AEs). In addition, OS and PFS among the therapeutic lines of NFF were also analyzed. Results: A total of 150 urPC patients were prospectively enrolled. The median follow-up period was 7.2 months (95% confidence interval [CI], 6.3–8.8); median age, 72 years (range, 45–85), with 81 female patients (54%). The Eastern Cooperative Oncology Group performance status was 0/1/2/3 in 46/93/10/1 patients, respectively. Sixteen patients (11%) had locally advanced disease; 134 (89%) had metastatic disease; 77 (51%) had liver metastasis; and 47 (31%) had peritoneal metastasis. All patients previously received gemcitabine-based therapy. NFF was administered as 2nd/3rd/4th-or-later-line therapy to 87/53/10 patients, respectively. The median OS was 7.8 months (95% CI, 6.6–9.2); median PFS, 3.7 months (95% CI, 2.8–4.9); overall response rate, 11%; and disease control rate, 56%. The relative dose intensity was 72.7% with NAL-IRI and 79.4% with fluorouracil. The initial dose of NAL-IRI was reduced in 84 patients (56%), mainly owing to decreased organ function (17%), followed by age (12%), worsened performance status (10%), or UGT1A1 examination status (5%). Dosage reduction of NAL-IRI during treatment (independent of the initial dose reduction) was performed in 74 patients (49%), mainly owing to neutropenia (22%) and anorexia (11%). Frequent Grade 3/4 adverse events were neutropenia (27%), anorexia (19%), and leukopenia (16%). Grade 5 peritoneal infection was observed in only one patient. The median OS and PFS for NFF in the 2nd-line group, compared with the 3rd-or-later-line group, were 7.4 vs 7.8 months (hazard ratio [HR], 0.97; 95% CI, 0.68–1.39; p=0.88) and 3.3 vs 4.2 months (HR, 1.04; 95% CI, 0.74–1.45; p=0.84), respectively. Conclusions: NFF had appropriate efficacy and manageable toxicity profiles, consistent with our previous report. NFF can be a candidate for 2nd-or-later-line regimens in the real-world. Clinical trial information: UMIN000043939 .

Effectiveness of anti-epidermal growth factor receptor agents in elderly patients (age ≥ 70 years) with <i>RAS</i> wild-type metastatic colorectal cancer: Nationwide real-world data.

57 Background: This study investigated the efficacy and safety of anti-epidermal growth factor receptor (EGFR) agents plus chemotherapy for elderly patients (aged &gt; or = 70 years) with RAS wild-type metastatic colorectal cancer (mCRC) from nationwide data in Taiwan. Methods: Total 756 patients with RAS wild-type mCRC who received first-line therapy with anti-EGFR agents (Cetuximab) plus chemotherapy at nationwide multiple institutions from November 2016 to January 2021. The study explored the prognostic impact between two age groups (≥70 vs &lt;70). Progression-free survival (PFS) and cancer-specific survival (CSS) were compared. Additionally, severe adverse events (SAEs) were also compared between two age groups. Results: The median PFS and CSS were comparable between the two age groups (14.0 vs 14.0 months, p = 0.098; 32.0 vs 35.0 months, p = 0.226, respectively). Moreover, subgroup analysis revealed similar PFS and CSS between two age groups in patients with synchronous or metachronous mCRC and left-sided or right-sided tumors (all p &gt; 0.05). Regarding hematologic SAEs, a significant higher incidence of grade ≥ 3 anemia was found in elderly patient group (13.3% vs 5.0%, p = 0.003). However, no significant difference was observed in the incidence of non-hematologic SAEs (all p &gt; 0.05). Conclusions: According to this nationwide real-world data, for patients carrying RAS wild-type mCRC treated with cetuximab plus chemotherapy, elderly patients could have comparable benefit as younger ones. Except for grade ≥ 3 anemia, other hematologic SAEs and non-hematologic SAEs revealed no significant difference between two age groups.

Meta-analysis of phase II/III randomized controlled trials (RCTs) to determine the incidence of hypertension and proteinuria in patients with gastrointestinal (GI) cancers treated with fruquintinib.

119 Background: Fruquintinib is a selective inhibitor of vascular endothelial growth factor receptors which impedes angiogenesis associated with tumor growth. On November 8th, 2023, the US FDA approved fruquintinib for use as a third-line treatment for metastatic colorectal cancer (mCRC). With the introduction of novel cancer therapies, monitoring for adverse events is critical. This meta-analysis aims to assess the risk of hypertension (HTN) and proteinuria in patients with GI cancers treated with fruquintinib. Methods: We conducted a comprehensive search of MEDLINE, EMBASE, and COCHRANE databases from inception through August 12th, 2024, identifying Phase II/III RCTs that employed fruquintinib in GI cancers and reported HTN and proteinuria as adverse effects. The Mantel-Haenszel method was used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). Heterogeneity was assessed using Cochran’s Q-statistic, and a random effects model was applied. Results: Our analysis included 1872 patients, 1131 (60%) of whom received fruquintinib, from three Phase III RCTs (FRESCO, FRESCO-2, FRUTIGA) and one Phase II RCT. FRESCO, FRESCO-2, and the phase II trials compared fruquintinib to placebo in patients with mCRC. FRUTIGA trial involved patients with gastric or gastroesophageal junction adenocarcinoma, comparing fruquintinib + paclitaxel to placebo + paclitaxel. The incidence of any-grade HTN was higher in the fruquintinib group, 34.92% vs 7.55% (RR 3.96; 95% CI: 3.05-5.13; P&lt;0.00001); the rate of high-grade HTN was 13.96% vs 1.21% (RR 9.01; 95% CI: 4.67-17.40; P&lt;0.00001). In the mCRC subgroup, incidence of any-grade and high-grade HTN was 43.02% vs 10.45% (RR 3.97; 95% CI: 2.95-5.33; P&lt;0.00001), and 17.28% vs. 1.27% (RR 12.06; 95% CI: 5.19-28.01; P&lt;0.00001), respectively. Incidence of any-grade proteinuria was also found to be statistically significant and higher in the fruquintinib arm in both GI cancer cohort and mCRC subgroup: 27.3% vs 16.19% (RR 1.89; 95% CI: 1.30-2.74; P=0.0008), and 25.22% vs 11.73% (RR 2.29; 95% CI: 1.17-4.51; P=0.02). The rate of high-grade proteinuria was not statistically significant in both cohorts. In GI cancer group, 1.85% vs 0.53% (RR, 2.49; 95% CI: 0.86-7.16; P=0.09), and mCRC subgroup 2.17% vs 0.51% (RR, 2.87; 95% CI: 0.74-11.12; P=0.13). Conclusions: This meta-analysis revealed a higher incidence of any-grade and high-grade HTN with fruquintinib in GI cancer patients, with significant association in the mCRC subgroup. Fruquintinib was also noted to be associated with increased risk of any-grade proteinuria, however, incidence of high-grade proteinuria was not different in patients treated with fruquintinib compared to placebo. Prompt identification and early management of these adverse events are crucial.

Molecule design enabled high efficiency flexible zirconium-based lead-free perovskite scintillator

Metal halide perovskites are the most promising candidates in the field of X-ray detection and imaging. However, the self-absorption and toxicity of lead-based perovskites severely limit their widespread application. Herein, zirconium-based halide perovskites have attracted much attention due to their excellent stability, low toxicity, and suitable bandgap, self-free absorption, wide emission spectrum. In this work, (C8H20N)2ZrCl6 single crystals are synthesized by evaporation crystallization, which presents a large Stokes shift of 203 nm, a high PLQY of 80.77%, and good stability over 180 days. Then, the assembled (C8H20N)2ZrCl6@PDMS films show good flexibility (bending and stretching) and a spatial resolution of 5.8 lp/mm. Thus, this work not only provides a route to explore lead-free metal halide perovskites with broadband emission but also demonstrates flexible zirconium-based scintillators for X-ray scintillation imaging.

The steroid hormone 20-hydroxyecdysone induces lipophagy via the brain-adipose tissue axis by promoting the adipokinetic hormone pathway

Unbiased transcriptomic analysis of primary early-onset vs late-onset colorectal cancer.

228 Background: Colorectal cancer is the 3rd most diagnosed and 2nd leading cause of cancer death. Despite the decline in incidence late-onset colorectal cancer (LOCRC), there is an increase in early onset of colorectal cancer (EORC). Clinicopathologic examinations from single centers revealed left-sided and rectal enrichment, poorly differentiated, and higher stage at presentation. Genomic studies examining the potential germline mutations/variants for EOCRC demonstrated mixed results. Transcriptomic analysis of the EOCRC compared to LOCRC remains limited. We hypothesized that EOCRC present with enrichment in aggressive molecular signatures consisting of CMS4 and iCMS3 signatures. To understand the mechanism behind EOCRC, we performed an unbiased RNA-Seq analysis in age groups of 32-82 in 95 patients. Methods: We utilized RNA-Seq data from the Orien Network, a collaborative between 19 NCI/NCCN cancer centers. We identified 95 patients diagnosed with colorectal cancer ranging in age from 32-82 and undergone RNA-sequencing of their primary tumors. Clinicopathologic assessment were analogously performed. We collected unnormalized raw-count RNA-Seq data from these patients. To account for differences in sequencing depth across samples, raw counts were scaled using the Reads Per Million (RPM) formula. The scaled reads in RPM were then utilized to assess the Consensus Molecular Subtypes (CMS) classification through two distinct approaches: the R package CMScaller and a deconvolution analysis using the R package SpatialDecon with the iCMS gene signature. Differences in age at the sample collection across patients with different CMS classifications were assessed by performing two-tailed unpaired T-tests. Additionally, differential expression analysis between EOCRC and LOCRC patients, defined by the upper and lower quartiles of the patients’ ages at the sample collection, was conducted using the LIMMA R package. Results: Clinicopathologic assessment of the primary tumors revealed left-sided tumors with poorly differentiated phenotype. Differential gene expression analysis between EOCRC and LOCRC demonstrated no significant differences. Stratification of transcriptomic data by decades also did not reveal any significant differences. Furthermore, there were no differences in CMS or iCMS classifications between different age groups. Conclusions: The RNA-Seq analysis comparing EOCRC and LOCRC did not identify any differential gene expression patterns. There was no significant differences were observed in CMS or iCMS classifications. These findings suggest that EOCRC and LOCRC share similar tumor biology based on molecular phenotypes. This implies that the initiating events for the disease may occur earlier in life while triggering a same disease process. As such, the findings underscores the importance of considering preventive measures, including earlier colonoscopy screenings.

Impact of tislelizumab + chemotherapy versus placebo + chemotherapy on patient-reported symptoms and disease progression by programmed death-ligand 1 expression in gastroesophageal adenocarcinoma: A post hoc analysis of the RATIONALE-305 trial.

365 Background: The relationship between patient-reported outcome (PRO)-based symptom scores, recurrent PRO-based symptomatic deterioration events (RDEs), and terminal events such as progression-free survival (PFS) are rarely examined in the oncology therapeutic domain. Thus, we applied a 3-component joint model (JM) framework aiming to illuminate more clinically interpretable associations between PRO-based treatment effects, RDEs, and PFS among subgroups of patients with programmed death-ligand 1 (PD-L1) expression of ≥1%, ≥5%, and ≥10%. Methods: The final analytic sample included 378 patients in the tislelizumab + chemotherapy arm (T+C) vs 401 in the placebo + chemotherapy arm (P+C) for the PD-L1 ≥1% subgroup, 238 in the T+C arm vs 237 in the P+C for the PD-L1 ≥5% subgroup, and 118 in the T+C arm vs 125 in the P+C arm for the PD-L1 ≥10% subgroup. Symptom domain scores from the EORTC QLQ-C30 and QLQ-STO22 symptom were modeled. Change from baseline (CFBL) in each domain was analyzed every cycle up to cycle 6, then every other cycle thereafter (up to cycle 25). The joint model was applied to all PD-L1 subgroups and comprised three components: 1) linear mixed model (LMM) predicting CFBL symptom scores, 2) Cox proportional hazard (CPH) model for disease progression (PFS as terminal event), and 3) frailty (random effects for RDEs) CPH model for time to PRO-based RDEs. Osoba’s 10-point threshold was used to define RDEs. Results: In the LMM, significant treatment efficacy for the T+C arm compared with the P+C arm was observed for the GHS/QoL ( P =0.0080) and dietary restriction scores ( P =0.0475) in the PD-L1 ≥5% subgroup. In the PD-L1 ≥1% subgroup, compared with the P+C arm, the T+C arm was associated with less worsening in pain/discomfort ( P =0.0376), upper gastrointestinal symptoms ( P =0.0088), and dietary restrictions ( P =0.0352). In the CPH model, the average hazard ratio indicated that compared with the P+C arm, the T+C arm was associated with a reduction in risk of disease progression across all PRO domains and PD-L1 subgroups. Lastly, the PRO-based RDE frailty predictions were strongly associated with PFS risk in the PD-L1 ≥1% and ≥5% subgroups for GHS/QoL, and in the PD-L1 ≥1% subgroup for physical functioning, fatigue, dysphagia-odynophagia, pain/discomfort, and dietary restrictions, as well as for pain/discomfort and dietary restrictions in the PD-L1 ≥5% subgroup. Conclusions: Through the 3-component JM, PRO-based effects were detected and demonstrated strong associations between PRO-based RDEs, and investigator-assessed PFS among varying PD-L1 expression levels. This framework may be a promising alternative for analyzing and interpreting PRO data in the context of PFS.

MUC5AC levels as predictors of adjuvant therapy outcomes in pancreatic ductal adenocarcinoma: A study of post-surgical gemcitabine-based regimens.

759 Background: The role of tissue mucin 5 AC (MUC5AC) in PDA is not fully understood. In our previous work we showed that mature MUC5AC (MM) detected in the extracellular (EC) space and in apical region has better prognostic value than perinuclear immature MUC5AC (IM). Our previous research demonstrated that mature MUC5AC (MM), present in the extracellular (EC) space and apical region, offers better prognostic value than perinuclear immature MUC5AC (IM). Preclinical studies suggest that MM may confer chemoresistance to gemcitabine (Gem), commonly used in adjuvant therapy (AT) either alone or with capecitabine (Cap) or nab-paclitaxel (NP) in patients not eligible for FOLFIRINOX. This study investigates MM’s effect on outcomes in PDA patients undergoing post-surgical treatment with Gem-only, Gem-NP, and Gem-Cap. Methods: Formalin-fixed, paraffin-embedded tissue samples from resected PDA cases (January 2010 - June 2021) were sourced from the Ohio State University biorepository. Immunohistochemistry using monoclonal antibodies 45M1 (for MM) and CLH2 (for IM) was employed to examine cellular MM and IM expression, with H-scores calculated. Statistical analysis of progression-free survival (PFS) and overall survival (OS) was done using the log-rank test. Results: We had 49 patients available for analysis. The median age of the group was 66 years (range: 38 to 89) with majority Caucasians (90%) and 53% (n=26) females. AT distribution within this group was, 31 Gem-only, 7 Gem-NP, and 11 Gem and capecitabine (Cap). Median expression levels for MM and IM were both 150, and 82% (n=40) were EC-MM positive. Using the median MM H-score as a threshold (&lt; 150 vs. ≥ 150), outcomes were evaluated within each therapy subgroup (Table). Conclusions: This preliminary study suggests that PDA patients with low MM expression may benefit from Gem-Cap therapy. However, larger, prospective studies are needed for definitive conclusions. Comparing outcomes in the sub-groups. Sub-group (n) OS in days (p-value) PFS in days (p-value) MM H-score &lt; 150 vs. ≥ 150 Gem-only (11 vs. 20) 775 vs. 1006 (0.4) 444 vs. 413 (0.4) Gem NP (4 vs. 3) 1409 vs. 551 (0.8) 391 vs. 418 (0.5) Gem-Cap (4 vs. 7) not evaluable (NE) vs. 766 (0.02) NE vs. 415 (0.01)

Molecular profiling of a gastroesophageal adenocarcinoma (GEA) multicohort using next-generation sequencing (NGS).

494 Background: The mutational landscape of GEA is rapidly evolving with the identification of promising molecular targets. However, histological subtypes are insufficient to capture the molecular heterogeneity in these patients (pts). We aim to assess the histopathological and molecular features in a GEA cohort using NGS techniques, and to evaluate the mutational frequency and its prognostic correlation. Methods: We conducted a retrospective study on GEA from 2019 to 2024. Immunohistochemistry (IHC) was used to evaluate HER2 expression, microsatellite instability (MSI), Epstein-Barr virus (EBV) and PD-L1 status. In-house and commercial NGS platforms were used to detect molecular alterations from tumor samples. Cox regression model was used to analyze overall survival (OS) based on the clinicopathological and molecular subgroups. Results: Using NGS techniques, we identified the following alterations with potential clinical relevance in the 115-pts included: pathogenic mutations in PIK3CA (5.2%), BRCA1/2 (3.5%) and POLD1 (0.9%), along with copy number alterations (CNA) in ERBB2 (10.4%), EGFR (8.7%), MET (5.2%) and FGFR2 (4.3%) genes, among others. Additionally, a high tumor mutational burden (≥ 13 Mut/Mb) was observed in 6 pts (5.2%). Clinical characteristics are detailed in the table. We detected a higher rate of alterations in CDH1 (10.42% vs 4.48%; p=0.22) and PIK3CA (8.33% vs 2.99%; p=0.20) genes in early (&lt;50y) vs late-onset (≥50y) GEA. Additionally, we identified a significantly higher mutation frequency in diffuse vs intestinal tumors; ARID1A (17.6% vs 2.2%; p=0.01) and CDH1 (11.8% vs 0%; p=0.02) genes. Also, pts with peritoneal involvement showed a greater prevalence of mutations in CDH1 (12% vs 0%; p=0.04) and RHOA (10% vs 0%; p=0.06) compared to those with liver disease. We observed a significantly worse OS in pts with diffuse vs intestinal tumors (15.7m vs 19.1m; p=0.04) and a trend toward shorter survival in pts with CDKN2A mutations (11.97m vs 17.83m; p=0.42). Although not significantly, CNA in ERBB2 were associated with a better prognosis (22.2m vs 16.2m; p=0.09). Conclusions: Our results support the utility of NGS platforms in detecting novel molecular targets with prognostic and clinical impact, beyond ERBB2 . Additionally, we observed poorer prognosis in diffuse subtype tumors, which exhibited a higher frequency of mutations in ARID1A and CDH1 genes. Clinicopathological characteristics of the 115-pts with GEA. N=115 (%) AgeMedian years [range] 54 [18-83] Sex Male 69 (60.0) Tumor site Gastric 72 (62.6) Gastroesophageal junction 37 (32.2) Esophagus 6 (5.2) Histological subtype Diffuse or pooly cohesive 51 (44.3) Intestinal or tubular 46 (40.0) Others 18 (15.7) Stage at diagnosis Advanced 74 (66.9) Localized 41 (33.1) Metastatic site Peritoneum 53 (46.1) Liver 34 (29.6) Molecular profile (IHC) HER2 (+) 20 (17.4) MSI 5 (4.3) EBV (+) 2 (1.8) PDL1 (CPS) ≥1 35 (30.4)