tbuckley/cabot-search huggingface dataset:
Proportion and distribution of PD-L1 expression and associated clinicopathologic features in patients with microsatellite instability-high gastric cancer.
Authors: Sun Mi Lee
Journal: Journal of Clinical Oncology (2024)

387 Background: The frequency of microsatellite instability-high (MSI-H) phenotype in sporadic gastric cancers (GCs) widely varies from 8% to 20%. From prior data, MSI-H phenotypes are significantly associated with female sex, older age, antral location of the tumor, well to moderate differentiation, intestinal type, non-signet ring cell component, mucinous histologic type, a moderate to severe lymphoid stromal reaction, and a lower TNM stage. This study investigated the proportion and distribution of PD-L1 expression of MSI-H GCs compared to microsatellite stable (MSS) GCs. Methods:The study consists of 847 cases of unselected GC. MSI analysis was performed on all GC cases by immunohistochemistry for mismatch repair proteins followed by multiplex polymerase chain reaction. Among them, 72 GCs were found to be an MSI-H phenotype. After matching the T category of GCs, 200 cases of GC with MSS phenotype were selected for a control group. Immunohistochemistry for PD-L1 (SP263) was performed on 72 MSI-H GCs and 200 MSS GCs. Results: Patients with MSI-GC were significantly associated with advanced age (p &lt;0.001), advanced tumor (p=0.0173), antral location of the tumor(p=0.0018), and T2 and T3 category (p=0.0031) but not T1 or T4 category. Histologically, MSI-H GCs occurred frequently in ulcerofungating mass (45.8%, p &lt; 0.0001)), intestinal type (73.6%, p=0.0102), well to moderately differentiated tumor (56.9%, p=0.0102), tubular histologic type (66.7%, p=0.0013), tumor necrosis (18.1%, p &lt;0.0001), and peritumoral neutrophilic infiltrate (40.3%, p &lt;0.001) compared to those of 200 MSS GCs. In the evaluation of PD-L1, 55 (76.4%) MSI-H tumors revealed PD-L1 expression with ≥ 1 CPS. The predominant PD-L1 staining was found in intratumoral and peritumoral immune cells (66.7%) than within tumor cells (9.7%). The distribution of positive immune cells was predominantly located in the periphery of the tumor (37.5%) than within the tumor (9.7%). According to the criteria for PD-L1 positivity as at least 10 CPS, approximately 50% of MSI-H GCs were considered PD-L1 positive tumors with at least 10 CPS. Conclusions: In this study, the prevalence of MSI-H phenotype is approximately 8.5% of unselected GCs. Approximately 76% of patients with MSI-H tumors showed PD-L1 expression with at least 1 CPS, and 50% revealed PD-L1 expression with at least 10 CPS, who can respond better to immune checkpoint inhibitors with promising therapeutic benefits. Due to the peritumoral expression of immune cells in PD-L1 positive GCs with MSI-H phenotype, different endoscopic approaches to obtain tumor tissues for PD-L1 evaluation would be considered, such as sampling tissues at the tumor periphery.
Organ-specific response with first-line atezolizumab-bevacizumab versus lenvatinib for patients with advanced hepatocellular carcinoma.
Authors: Young-Gyu Park, Hyung-Don Kim, Sejin Kim, Kyu-Pyo Kim, Sook Ryun Park, Min-Hee Ryu, Baek-Yeol Ryoo, Changhoon Yoo
Journal: Journal of Clinical Oncology (2024)

467 Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related death worldwide. Immune checkpoint inhibitor (ICI)-based treatments have become the mainstay of first-line treatment for unresectable HCC, but there has been a concern that intrahepatic HCC lesions may be less responsive to ICI monotherapy. Methods: This retrospective study included 386 patients with Child-Pugh A unresectable HCC who were treated with first-line atezolizumab-bevacizumab (n = 217) or lenvatinib (n = 169). The organ-specific response was separately evaluated according to the site of the lesions: liver, lung, lymph node (LN), and intra-abdomen based on a radiological evaluation adopted from RECIST v 1.1. Up to 2 lesions were chosen as target lesions in each organ for the organ-specific response evaluation. Results: The median age was 60 years. The majority of study patients were male in both groups (83.4% and 85.8% in the atezolizumab-bevacizumab and lenvatinib groups, respectively). The etiology of HCC was similar between the two groups: hepatitis B virus infection was the most common etiology in both groups (73.3% and 65.7% in the atezolizumab-bevacizumab and lenvatinib groups, respectively), while 21.2% and 29.0% of patients had non-viral HCC, respectively. Extrahepatic spread was identified in 76.0% and 74.6% of patients in the atezolizumab-bevacizumab and lenvatinib groups, respectively: lung, LN, and intra-abdominal metastases were present in 39.6% vs. 39.1%, 30.0% vs. 33.1% and 16.6% vs. 15.4% of patients, respectively. The proportion of patients achieving a ≥ 30% reduction in the tumor burden for each organ category was higher overall in the atezolizumab-bevacizumab group than in the lenvatinib group: 20.2% vs. 11.8%, 23.0% vs. 12.2%, 27.9% vs. 17.9%, and 33.3% vs. 15.0% for intrahepatic, lung, LN and intra-abdominal lesions, respectively. The corresponding values for the subgroup with a viral etiology were 17.3% vs. 8.1%, 18.8% vs. 13.3%, 28.9% vs. 3.6% and 36.0% vs. 12.5%, respectively. Among patients with a non-viral etiology, atezolizumab-bevacizumab was not clearly associated with a better organ-specific response for the LN and intra-abdominal lesions: 20.0% vs. 54.5% and 20.0% vs. 25.0%, respectively, for a ≥ 30% reduction in the tumor burden. Conclusions: Compared to lenvatinib, atezolizumab-bevacizumab was associated with a favorable organ-specific response regardless of the site of the tumor lesions. Unlike anti-PD-1 monotherapy, atezolizumab-bevacizumab had a comparable organ-specific response between intrahepatic and extrahepatic lesions, especially for those with viral etiology HCCs.
Assessment of circulating tumor DNA (ctDNA) burden and association with outcomes in metastatic gastric cancer (mGC) patients using real-world data (RWD).
Authors: Senaka A. Peter, Razvan Cristescu, Carol Elaine Pena, Angela Watkins, Carin R. Espenschied, Jiemin Liao
Journal: Journal of Clinical Oncology (2024)

276 Background: CtDNA burden has been shown to have potential uses in early cancer detection, guiding treatment decisions, residual disease and drug resistance detection, and treatment response monitoring. While published literature suggested that ctDNA may be prognostic of clinical outcomes for various tumor types, there is limited RWD assessing its use in mGC. This study uses RWD to evaluate the association of pre-treatment ctDNA burden with clinical outcomes in mGC. Methods: Patients were identified from the Guardant INFORM real-world clinical-genomic database, which links ctDNA results via plasma-based next-generation sequencing Guardant360 assay (G360) to de-identified claims data. Adult mGC patients in the US, who received NCCN guideline treatments post-diagnosis and underwent testing with G360 from June 2014 to March 2022 were included. For those who received first line (1L) therapy within 60 days after a G360 test result, median of the maximum variant allele fraction (mVAF) was used to classify them into high or low ctDNA burden groups, with undetectable ctDNA burden considered low. Associations with time to next treatment (TTNT) and overall survival (OS) were assessed using log rank tests and multivariable Cox proportion hazards models adjusting for age, sex, Elixhauser comorbidity score, and anatomical location. Results: 2,200 mGC patients were identified, of which 824 (37%) initiated 1L therapy within 60 days after a G360 test. Among the 824 patients, mean age was 63 years, 70% were male and 47% had gastric adenocarcinoma and 53% gastroesophageal junction cancer. Median mVAF among these patients was 2.9%, with 91% having detectable ctDNA. Patients with high ctDNA burden treated with 1L chemotherapy (Chemo) showed significantly worse TTNT and OS than low ctDNA burden patients (Median TTNT= 4.7 months vs 7.5 months, p&lt;0.001; Median OS=12.4 months vs 19.1 months, p&lt;0.001). Multivariable Cox analyses showed similar results for 1L Chemo group. Treatment group outcomes based on adjusted Cox models were reported (Table). Conclusions: We used RWD to demonstrate that high pre-treatment ctDNA burden was associated with worse clinical outcomes in a mGC population treated with 1L Chemo. Our analysis adds to the body of evidence that suggest ctDNA burden could be used as a prognostic biomarker for mGC. The small sample size of the other 1L treatment groups warrants further investigation because the use of IO-based therapy is expected to increase with recent approvals. [Table: see text]
Clinical utility of serial circulating tumor DNA (ctDNA) to identify acquired resistance to anti-EGFR antibodies in metastatic colorectal cancer (mCRC).
Authors: Jonathan M. Loree, Adrian Bubie, Madhulika Eluri, Christine Megerdichian Parseghian, Michael J. Overman, Nicole Zhang, Leylah Drusbosky, Scott Kopetz, Kanwal Pratap Singh Raghav
Journal: Journal of Clinical Oncology (2024)

158 Background: Real-world evidence informing on the value of incorporating serial ctDNA into clinical practice is lacking. We aimed to explore the utility of serial ctDNA for identifying mechanisms of resistance and new targets for patients (pts) receiving anti-EGFR therapy for mCRC. Methods: We retrospectively reviewed 2801 pts with mCRC who had ≥1 alteration detected on a Guardant360 assay (Guardant Health) and subsequently had serial ctDNA assessments with known intervening therapies. We compared detection of new MAPK pathway alterations ( RAS/EGFR/BRAFV600 SNV or indel, MET or ERBB2 amplification) among patients who initially lacked these alterations by whether patients received anti-EGFR antibody alone (panitumumab or cetuximab), in combination with chemotherapy, or if they had never received an anti-EGFR antibody between ctDNA assays. Patients with a subsequent ctDNA assay after therapy initiation were included for analysis of acquired alterations. Results: Of 2801 pts, 1308 (47%) harbored ≥1 MAPK alteration in their first ctDNA timepoint and were excluded from analysis. Of the remaining 1493 without a MAPK alteration prior to therapy, 588 (39.4%) had a MAPK alteration detected in a subsequent ctDNA timepoint. Among 447 of 1493 pts (31.8%) with subsequent exposure to anti-EGFR antibodies, acquisition of a MAPK alteration occurred in 229/447 (51.2%). This was more common (OR 2.01. 95% CI 1.61-2.51, P&lt;0.0001) than in patients without exposure to anti-EGFR antibodies (359/1046 [34.3%]). Acquired MAPK alterations were more common among those receiving single agent antibodies (42/66, 63.6%) than anti-EGFR plus chemotherapy (187/381, 49.1%) (OR 1.82, 95% CI 1.05-3.08, P=0.030). Patients with anti-EGFR antibody exposure were found to have higher blood TMB scores in the first assay after treatment compared to patients treated with chemotherapy alone (11.5 vs. 8.8 mut/MB, respectively; P=0.001), with no significant blood TMB difference between those receiving single agent anti-EGFR versus anti-EGFR plus chemotherapy (median 12.4 vs. 11.5 mut/MB; P=0.52). Patients who acquired MAPK alterations after anti-EGFR therapy had higher blood TMB scores compared to patients who did not acquire MAPK alterations (median 14.3 vs 8.6 mut/MB, respectively; p&lt;0.0001). Conclusions: In this large cohort of pts with mCRC and treatment information, we demonstrate serial ctDNA identified a large proportion of patients acquiring resistance alterations that may impact response to future therapies. These results suggest serial ctDNA analysis may provide additional molecular insights for patients receiving anti-EGFR therapy and inform future anti-EGFR rechallenge strategies.
Prognostic role of platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) in advanced gastric cancer treated with immunotherapy: A systematic review and meta-analysis.
Authors: Silvio Matsas, Pedro N. Aguiar Junior, Auro Del Giglio
Journal: Journal of Clinical Oncology (2024)

397 Background: Recent advances in the treatment of Gastric Cancer (GC) have introduced immunotherapy as a promising approach for advanced disease. In this context, potential biomarkers such as the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) have gained attention for their roles in predicting treatment outcomes. In this meta-analysis, we explore the clinical significance of PLR and NLR as predictors of Overall Survival (OS) and Progression-Free Survival (PFS) in advanced GC patients undergoing immunotherapy. Methods: Two independent reviewers systematically searched electronic databases, including PubMed, Embase and Scopus. The search incorporated controlled vocabulary (MeSH terms) and keywords related to Gastric Cancer, immunotherapy, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR). Eligible studies were selected based on predefined criteria, including HR availability, and were assessed for quality and bias using the Newcastle-Ottawa Scale. Data extraction was independently performed by two reviewers, and discrepancies in study selection and data extraction were resolved by a third reviewer. Subgroup analyses were performed to explore potential variations in the study outcomes. All analyses were conducted with RevMan 5.4 and employed random-effects model. Results: In total, 16 studies encompassing 1176 patients for NLR and 8 studies covering 766 patients for PLR were included in this systematic review and meta-analysis. The studies spanned the years between 2018 and 2023. Our analysis revealed significant associations between high NLR and poor OS (HR: 2.11, 95% CI: 1.70-2.62, p &lt; 0.00001) and PFS (HR: 1.76, 95% CI: 1.43-2.17, p &lt; 0.00001). Similarly, elevated PLR was significantly associated with worse OS (HR: 1.77, 95% CI: 1.44-2.17, p &lt; 0.00001) and PFS (HR: 1.61, 95% CI: 1.33-1.96, p &lt; 0.00001). In all conducted subgroup analyses, high NLR and PLR were consistently associated with poor survival outcomes. Conclusions: Our analysis supports the significance of NLR and PLR as accessible and cost-effective biomarkers for predicting survival outcomes in the context of immunotherapy for advanced GC. These findings underscore their potential significance in guiding clinical decisions. Further investigation should be carried out to validate our findings.
Benefit of immune checkpoint inhibitors (ICI) for patients with advanced esophageal squamous cell carcinoma and low PD-L1 expression: A systematic review and meta-analysis.
Authors: Mario Machado Lopes, Viviane Alencar, Isadora Martins de Sousa, Ana Carolina Marin Comini, Marcos Pedro Guedes Camandaroba
Journal: Journal of Clinical Oncology (2024)

346 Background: Immunotherapy has improved survival for patients with advanced esophageal squamous cell carcinoma (aESCC) and currently is the standard of care for patients with a positive PD-L1 status (CPS ≥10; TPS ≥1%) in the first-line setting. For PD-L1 negative/low, treatment options are limited, and chemotherapy is usually the first choice and associated with adverse events that may impair quality of life. Immunotherapy trials harbor conflicting results in this subgroup of patients, therefore, we performed a systematic review and meta-analysis to evaluate the potential benefit of ICI as single treatment for patients with aESCC and a PD-L1 expression negative/low. Methods: Studies that enrolled patients with aESCC treated with ICI versus chemotherapy in first and second-line settings and provided separate outcomes for patients with PD-L1 negative/low were identified by searching the EMBASE, PubMed and Cochrane databases. The outcomes evaluated were Overall Survival (OS), Progression Free-Survival (PFS) and Treatment-Emergent Adverse Events (TEAE). We pooled hazard ratio (HR) for PFS and OS endpoints and odds ratio (OR) with 95% confidence intervals (CI) for TEAE. Statistical analyses were performed using Revman 5.4 and a random-effects model. I² analysis was used to assess heterogeneity. This meta-analysis was recorded on Prospero ID CRD42023411251. Results: We included 6 randomized clinical trials with a total of 674 individuals in the final analysis. Most studies (5/6) included previously treated patients. ICI monotherapy in aESCC patients and PD-L1 expression negative/low was associated with a better OS (HR 0.86; 95% CI 0.76-0.97; p = 0.02; I² = 0%) and worse PFS (HR 1.37; 95% CI 1.10-1.71; p = 0.005; I² = 0%). Regarding the safety profile, it showed higher grade 3-5 toxicity rates (OR 1.8; 95% CI 1.17-2.78; p = 0.007; I² = 85%) for chemotherapy. Conclusions: ICI is effective for patients with aESCC and low/negative PD-L1 expression with an improvement in OS and a favorable safety profile.
Talazoparib (Tala) in patients (pts) with colorectal cancer (CRC) with <i>BRCA1/2</i> mutations (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Kathleen J Yost, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Herbert Leon Duvivier, Eugene R. Ahn, Timothy Lewis Cannon, Vi Kien Chiu, Maged F. Khalil, Brian Kim, Allison Marie Prinz, Gina N. Grantham, Abby Gregory, Dominique C. Hinshaw, Susan Halabi, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2024)

106 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with CRC with BRCA1/2 mut treated with Tala are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 1 mg of Tala orally daily until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete or partial response or stable disease of at least 16 weeks (wks) duration (SD16+) per RECIST v 1.1. Simon 2-stage design tested the null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled; otherwise, the cohort is closed. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints were objective response (OR), progression-free survival (PFS), overall survival (OS), and safety. Results: 10 pts with advanced CRC and BRCA1 mut (n=3), BRCA2 mut (n=5), or both (n=2) were enrolled from February 2020 to June 2021. Germline or somatic status was not reported in 7 of 10 pts, 2 pts had somatic BRCA2 muts and 1 pt had a germline BRCA2 mut. 2 pts had left sided tumors, 2 had right sided, 3 had rectal tumors, and 3 pts had tumors that were site undetermined. All pts were evaluable for efficacy and toxicity. Table summarizes pt demographics and outcomes. No pts experienced DC, median PFS was 8 wks (95% CI, 6 to 8) and median OS was 24 wks (95% CI, 7 to 43). Co-alterations were observed in the following genes: KRAS (3 pts) and BRAF (2 pts). 2 pts had 3 separate grade 3 adverse events of anemia or fatigue at least possibly related to Tala. Conclusions: Monotherapy Tala did not demonstrate sufficient clinical activity in pts with advanced CRC with BRCA1/2 mut. Other tx should be considered for these pts, including tx offered in clinical trials. Clinical trial information: NCT02693535 . [Table: see text]
Safety and efficacy of nanosomal docetaxel lipid suspension (NDLS) in patients with advanced gastric adenocarcinoma.
Authors: Vikas S. Ostwal, ATUL SHARMA, Joydeep Ghosh, Rakesh Reddy, Lakshmi Priyadarshini K, B. J. Srinivas, Ramaiyer Raghu Raman, Rajesh Kota, Soumya Surath Panda, Amit Agarwal, Arun Seshachalam, Bhushan Tapiram Nemade, Ateeq Ahmad, Saifuddin Sheikh, Shoukath M Ali, Mahesh Paithankar, Lav Patel, Anil Rajani, Deepak Bunger, Imran Ahmad
Journal: Journal of Clinical Oncology (2024)

348 Background: Nanosomal docetaxel lipid suspension (NDLS) was developed to overcome toxicity issues associated with conventional docetaxel. Docetaxel, cisplatin, 5-fluorouracil (5-FU; DCF) or modified DCF (mDCF) is one of the recommended first-line regimens for patients with metastatic gastric adenocarcinoma (GAC). However, majority of the patients experienced grade 3/4 toxicities with DCF regimen using conventional docetaxel. The present study evaluated the safety and efficacy of NDLS-based mDCF/DCF regimens in patients with metastatic GAC. Methods: In this multicentric, open-label, clinical trial, patients with previously untreated metastatic GAC were enrolled. Patients received either mDCF [NDLS 40 mg/m 2 on day 1 (D1), C 40 mg/m 2 on D2 or D3, 5-FU 400 mg/m 2 bolus on D1, leucovorin 400 mg/m 2 on D1, 5-FU 1000 mg/m 2 /day continuous infusion D1 &amp; 2; q2w] for 9 cycles, or DCF [NDLS 75 mg/m 2 on D1, C 75 mg/m 2 on D1, 5-FU 750 mg/m 2 /day for 5 days given as continuous infusion; q3w] for 6 cycles. Prophylactic GCSF (Granulocyte Colony Stimulating Factor)/Peg-GCSF support was allowed in all patients. The primary endpoint was overall response rate (ORR) at week 18. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety outcomes. Patients were followed up to 1 year. Results: Fifty-two patients were enrolled, with mean (±SD) age of 52 (±9.6) years &amp; male:female ratio of 32:20. Thirty-eight patients qualified for modified intent-to-treat (mITT) analysis for efficacy evaluation (mDCF: 33; DCF:5). At week 18, ORR was 57.9% &amp; DCR was 81.6% in mITT population. In the per-protocol population (n=26), ORR was 61.5% at 18 weeks (mDCF:63.6%; DCF:50%). Safety set included all 52 patients. Any grade adverse events (AEs) were reported in 90.4% (n=47) of the patients; with 40.4% experiencing grade 3/4 AEs. All-grade AEs reported in ≥10% of the patients included anemia, neutropenia, abdominal pain, diarrhea, nausea, vomiting, fatigue, mucositis, decreased appetite, peripheral neuropathy; with majority of AEs being grade 1/2. Most common grade 3/4 AE was neutropenia; observed in 17.3% (n=9) patients (mDCF: 14%; DCF: 33.3%). Conclusions: NDLS-based regimens demonstrated efficacy &amp; improved safety profile in the treatment of metastatic GAC. Clinical trial information: CTRI/2018/01/011450 . [Table: see text]