bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of proton-pump inhibitor use on the incidence and severity of gastrointestinal toxicity to checkpoint inhibition.
Authors: Wang Yinghong , Shatila Malek , Catinis Christine , Devalaraju Samanthika , Glombicki Stephen , Jeong-AH Lee Irene , Ngo Sean , Takigawa Kei , Lu Linfeng , Mittal Nitish , Baerman Elliot , Aleem Abdullah Sagar , Pizuorno Machado Antonio , Thomas Anusha 
Published: June 2024

2657 Background: Checkpoint inhibitors (ICIs) for cancer come with the risk of immune-related adverse events (irAE). Upper and lower gastrointestinal (UGI and LGI, respectively) tract inflammation are common toxicities. Proton pump inhibitors (PPIs) are frequently used to treat immune-mediated UGI irAEs. Studies have suggested that these agents may worsen LGI irAEs. Our study aims to observe the effect of PPI use on the incidence and severity of GI irAEs. Methods: This was a single-center retrospective chart review including all patients who received ICIs. Patients were categorized based on PPI usage and screened for upper or lower GI toxicities. PPI use was counted if the medication was received at least three months before starting ICI and one year after the last ICI dose. Results: 16,849 patients were included. 2,114 (12.5%) patients received PPIs (PPI group – PG), while 14,735 (87.5%) did not (non-PPI group - NPG). 46 (2.2%) PG patients developed UGI irAE compared to 43 (0.3%) in the NPG (p<0.001), with no difference in severity or need for immunosuppression (p>0.05). PG patients were more likely to be hospitalized however (p=0.021). 115 (5.4%) PG patients developed an LGI irAE compared to 173 (1.2%) in the nPG (p<0.001). 80.7% of the PG presented with ≥grade 2 diarrhea and 52.0% with ≥grade 2 colitis, compared to 69.1% and 38.5% of the NPG, respectively (p<0.05). PG patients more frequently needed steroid treatment (60.0% vs. 42.2% in the NPG, p=0.004) and SIT (41.7% vs. 24.9%, p=0.003), and were less likely to have symptom resolution (78.5% in the PG vs. 89.6% in the NPG, p=0.020). A dose-dependent effect was observed. Every 10mg increase in PPI dose led to more frequent hospitalization for UGI irAEs (OR: 1.6, p=0.049) and more reliance on steroids (OR:1.3, p=0.044) and SIT (OR: 1.3, p=0.037) for LGI irAEs. This was also associated with less hospitalization and recurrence rates for LGI irAEs (p<0.05). Conclusions: Our study shows that PPI use during immunotherapy may increase the risk of developing a GI irAE. PPI use does not seem to impact the severity of upper GI irAEs aside from a higher hospitalization rate. However, PPI use may lead to a more severe disease course for lower GI toxicities. Prospective studies are needed to validate these results. [Table: see text]
Clinical validation of Northstar Select, a novel liquid biopsy assay for comprehensive genomic profiling of solid tumors.
Authors: Bower Xavier , Wignall Jan , Zhu Joyce , O'Sullivan Michael , Searle Naomi , Hong Lenny , Varga Matthew Gordon , Luong Jason , Lin Esther , Simon Marie Erica , Tsao David , ten Bosch John , Zhou Wen 
Published: June 2024

3072 Background: Comprehensive Genomic Profiling (CGP) liquid biopsy tests are vital tools for oncologists that enable the non-invasive detection of diverse somatic mutations, many of which correspond to targeted therapies, in circulating tumor DNA (ctDNA). However, these tests have less utility when ctDNA signal is low, which is common even in late-stage cancer patients. BillionToOne’s Northstar (NS) Select assay is a novel CGP test that seeks to leverage proprietary technology and novel calling algorithms to address this limitation by achieving higher sensitivity. Methods: Clinical samples for 182 unique patients with stage III or IV solid tumors were obtained via a prospective validation study assessing head-to-head concordance with widely adopted, commercially available ‘comparator’ liquid biopsy CGP assays. The study cohort was recruited from 1 large hospital center and 6 community clinics across the US and was diverse in patient demographics and clinical presentations. Over 15 different cancer types were represented in the cohort, with the majority of patients having either Lung, Breast, Colorectal, or Prostate cancer, all of which are commonly tested using liquid biopsies in the US. Pathogenic (including likely pathogenic) variants called by NS Select and/or the comparator assay were analyzed for concordance. For a subset of samples (N=28), white blood cell-derived genomic DNA was also processed to identify which variants were detected due to clonal hematopoiesis of indeterminate potential (CHIP). Results: In the head-to-head comparison, a large number of variants (N=380) were concordant between the two assays. In addition, NS Select detected 43% (N=147) more pathogenic variants than comparators when controlling for matched coverage regions. The majority of these variants were detected below the reported limit of detection of the comparator assays, but above the limit of detection of NS Select. The rate of CHIP mutations was not significantly different in the variants detected by NS Select (19.0% ± 7.6%) vs. comparators (17.2% ± 9.2%). Finally, the proportion of patients with no pathogenic variants detected was shown to be lower by 45% when using NS Select vs. the comparator assays (20/182 vs. 36/182). Conclusions: NS Select reported clinically useful information about the tumor for most patients. For patients in which ctDNA signal was high, NS Select had very high concordance with comparator tests. Furthermore, additional low-VAF pathogenic mutations identified by NS Select translated to a higher diagnostic yield compared to other CGP assays, and CHIP was ruled out as an explanation for these additional detections. This suggests that some patients with low levels of ctDNA would derive clinical benefit from testing with NS Select due to its high sensitivity.
Identification of a patient tissue-based phosphorylation site as a biomarker for epidermal growth factor receptor (EGFR) activity in non-small cell lung cancer.
Authors: Raman Nithya , Flohr Alexander , Pohlmann Daniel , Woodsmith Jonathan , Juhl Hartmut 
Published: June 2024

3143 Background: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths globally. EGFR tyrosine kinase inhibitors (TKIs) have shown promise in treating NSCLC, yet resistance to these agents is common and current biomarkers rely on genetic data alone. Therefore, identifying reliable biomarkers to more comprehensively monitor EGFR activity and predict therapeutic responses is paramount. Here, we report an uncharacterized threonine phosphorylation site within core regulator of the EGFR pathway SHP2, that is strongly predictive of EGFR activity as defined by genetic mutation status that shows potential as a clinically relevant biomarker. Methods: Using DIA mass spectrometry phosphoproteomics, we could quantify >20,000 phosphosites from patient normal adjacent tumor (NAT) and primary tumor tissue. We further characterized these tissues using whole genome sequencing allowing us to define the mutational status of the EGFR. Statistical analysis was undertaken across all phospho-sites that identified a single uncharacterized phospho-site as a strong predictor of EGFR kinase activity. Finally, we generated monoclonal antibodies against the phospho-peptide and tested these in patient FFPE primary tumor tissue using immunohistochemistry to correlate phosphorylation levels with EGFR activation status. Results: Our results highlight how an individual phosphosite on SHP2 closely correlates with EGFR activity as defined by genetic mutation status in patient tissue. Interestingly, we further identify a group of patients who carry wild type EGFR yet have a phospho-signal potentially indicative of high EGFR activation without genetic aberration. These results were corroborated by a phospho-site specific antibody in FFPE tissue IHC, with strong signals observed in patients with an activating EGFR mutation (n=5), and complete absence of signal in patients harboring a wild type EGFR and no detectable mass spec signal (n=5). Conclusions: Our findings suggest that this uncharacterised SHP2 phosphosite may serve as a potent biomarker for EGFR activity in NSCLC. Further validation of the monoclonal antibodies as tools for this clinically relevant biomarker is required in larger patient cohorts to elucidate the role of the phosphosite in therapy response. This novel biomarker has the potential to guide therapeutic decision-making and contribute to personalized medicine strategies for NSCLC patients.
Survival impact of KRAS mutation in metastatic colorectal cancer (mCCR) under first-line treatment.
Authors: Mathias Maria Cecilia , Lazar Neto Felippe , Gouveia Mariana Carvalho , Stangler Lucas , Claro Mateus Zapparoli , de Mello Evandro Sobroza , Sabbaga Jorge , Braghiroli Maria Ignez , Venchiarutti Moniz Camila M , Hoff Paulo Marcelo 
Published: June 2024

3547 Background: Activating mutations in the MAPK pathway are predictive biomarkers in mCCR and 50% of patients (pts) present KRAS mutations. There is a large spectrum of molecular aberrations with a lack of data regarding tumor side correlations and their impact on treatment response and overall survival. Methods: Retrospective cohort of mCRC pts and KRAS activating mutations treated between 2019-2022 in a tertiary cancer center in Brazil. KRAS gene was analyzed by next-generation sequencing in tumor tissue samples. Electronic medical records were reviewed with case report forms registered in RedCap software. The primary endpoint was Overall survival (OS), estimated using Kaplan-Meir and compared with the log-rank test. Cox proportional models were applied to estimate hazard ratios (HR). Results: We included 490 patients with a mean age of 59 years (y), mostly male, 51.4%. Primary left-side location was present in 65.5% and liver metastasis in 66.7%. The spectrum of KRAS mutations found were G12D (31.2%), G12V (20.2%), G13D (15.1%), G12C (9.4%), G12A (4.9%), G12S (3.5%), and G12R (2%). First line regimen was 5-FU and Oxaliplatin (mFLOX) in 84.9% (n=388), with a median PFS of 9.2 months (95%CI 7.8 - 11.6) and OS of 21 months (95%CI;19-23) in this group. Treatment related outcomes in first-line therapy at first evaluation were 40% partial response, 20.4% stable disease, 30,9% disease progression and 1.3% complete response. G12S mutation was associated with better PFS 18.62 vs. 8.75m compared with other codon mutations (HR:0.52;95%CI 0.28-0.98) and OS NR vs. 21.58m HR (HR:0.48;95%CI;0.24-0.97). G12R was associated with worse PFS 5.31 vs. 9.90 m (HR:2.2;95%CI;1.09-4.47) and OS 17.89 vs. 21.88m (HR:1.61;0.79-3.24). Sideness was not associated with prolonged response or overall survival right-sided tumors 20.72 vs. vs. left-sided tumors 22.14m (HR:1.04;95%CI;0.82-1.31). Conclusions: Specific mutated codons in the KRAS gene impact PFS and OS independently of primary tumor sidedness. G12S mutation demonstrated an improved OS and PFS. [Table: see text]
Exploratory biomarker analysis for predicting treatment effects of aflibercept in the VELOUR trial.
Authors: Pu Ting , Peddle Allyson , Wirapati Pratyaksha , Hong Yourae , Samuel Leslie , Desai Jayesh , Riener Maigo , Saridaki Zacharenia (Zenia) , Cunningham David , Tejpar Sabine , Tsantoulis Petros 
Published: June 2024

3592 Background: Second-line treatment with aflibercept and FOLFIRI in patients with metastatic colorectal carcinoma (mCRC) previously treated with oxaliplatin improved overall survival (OS) versus placebo [Hazard ratio (HR), 0.81; 95% CI, 0.71–0.93; P=0.003]1. However, colorectal cancer (CRC) is a heterogenous disease and the new intrinsic consensus molecular (iCMS) allows for tumours to be subtyped into unique genetic and transcriptional features2. We present a post hoc analysis of VELOUR patient data, to assess the impact of KRAS or BRAF mutation status and iCMS on efficacy parameters. Methods: Patient samples were classified as either KRAS or BRAF mutant or wild-type (WT) via a targeted mutation panel1. Gene expression data was used to classify samples as either iCMS2 or iCMS3 using a modified classifier based on iCMS signatures which are specifically up-regulated in tumour samples2. Results: Of the 439 patients with available RNA data, 54.9% (241/439) were classified as iCMS2; 45.1% (198/439) as iCMS3; 48.3% (212/439) as RAS mutant and 8.4% (37/439) as RAF mutant. A favourable aflibercept treatment effect was observed for patients within the KRAS WT group (Median OS from 11 to 17.7 months; HR 0.87; 95% CI 0.79-0.96, P=0.005), particularly for patients with KRAS WT iCMS2 tumours (Median OS from 15.5 to 30.4 months; HR 0.81; 95% CI 0.70-0.94, P=0.004). This is in comparison to the KRAS WT iCMS3 patients where no treatment benefit was seen (HR 0.97; 95% CI 0.82-1.14, P=0.683). In addition, no treatment benefit was seen in the KRAS mutant group (OS HR 1.03; 95% CI 0.96-1.12, P=0.405). Progression-free survival (PFS) data followed the same trend. Aflibercept seemed to also strongly benefit the 37 patients with BRAF-mutated tumours, (PFS HR 0.46, 95% CI 0.20-1.09; OS HR 0.65, 95% CI 0.29-1.48), although differences were not statistically significant. Irrespective of treatment, improved OS (HR 0.60; 95% CI 0.48-0.75, P< 0.001) and PFS (HR 0.75; 95% CI 0.60-0.94, P=0.011) were observed in all patients with iCMS2 versus iCMS3 tumours, as expected. Treatment-by-mutation status interaction tests (OS P=0.40, PFS P=0.33) indicated that the aflibercept benefit was not statistically different among the mutation sub-groups, although the small sample size limited the analysis. Conclusions: In the VELOUR study, the benefit of the addition of aflibercept to FOLFIRI appears to be primarily in patients with KRAS WT tumours, especially those with KRAS WT iCMS2. The improved OS and PFS seen in all patients with iCMS2 tumours in comparison to iCMS3 is prognostic but not predictive of aflibercept treatment response in addition to FOLFIRI. On the contrary, the addition of aflibercept to FOLFIRI provided a numerical benefit in BRAF-mutated tumours, however the P-values were not statistically significant.
Association of circulating DNA with recurrence in CRS-HIPEC patients with colorectal and appendiceal peritoneal carcinomatosis: Insights from a phase II randomized trial.
Authors: Kasi Anup , Al-Rajabi Raed Moh'd Taiseer , Saeed Anwaar , Sun Weijing , Baranda Joaquina Celebre , Li Haoran , Wick Jo , Mullangi Sanjana , Eberhardt Kenda , Bradbury Shannon , Romero Rebecca , Carroll Erin , Barbosa Lori , Al-Kasspooles Mazin Francis 
Published: June 2024

3598 Background: There is a need for biomarkers to guide patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) in cases of peritoneal carcinomatosis from colorectal and appendiceal cancer. SigNatera is a blood-based quantitative test to detect colorectal cancer recurrence by indicating the presence of at least two altered colorectal cancer-associated genes in Circulating tumor DNA (ctDNA). We performed a correlative study to help determine if using SigNatera ctDNA would be a predictive and prognostic biomarker of recurrent cancer in patients who underwent CRS-HIPEC on a Phase II Randomized Trial Comparing Morbidity and Mortality of CRS-HIPEC using Mitomycin-C versus Melphalan for Colorectal and Appendiceal Peritoneal Carcinomatosis. Methods: 30 patients on the phase II trial had the option for consenting for the ctDNA correlative study utilizing SigNatera sponsored by Natera. Pre-op samples were collected prior to CRS-HIPEC on Day 0 and post-op samples ~2 weeks post-hospital discharge, followed by every 3 months x 2 years. The exploratory objective of the prognostic impact of ctDNA is evaluated by correlating pre-op ctDNA status and Disease-Free Survival (DFS) Results: All 30 pts that underwent ctDNA testing were treated with neoadjuvant chemotherapy prior to CRS-HIPEC. Pre-op ctDNA was negative in 20 pts (8 recurrences, median DFS = 15.9 months) and positive in 10 pts (7 recurrences, median DFS = 39.9 months), p =0.19. Of the 20 pre-op ctDNA(-) pts, 18 remained ctDNA(-) in post-op (12 recurrences, median DFS = 15.6 months) and 2 turned ctDNA(+) (0 recurrences). Of the 10 pre-op ctDNA(+) pts, 2 remained ctDNA(+) post-op (1 recurrence, median DFS = 9.5 months) and 8 turned ctDNA(-) (2 recurrences, median DFS = 39.9 months), p=0.1. Conclusions: The unexpected numerically favorable DFS in the pre-op ctDNA(+) group, in comparison to the pre-op ctDNA(-) group, challenges the utility of preop ctDNA status in guiding CRS + HIPEC decision-making. Though limited by small sample size, this finding may be likely due to the impact of post-op therapy which notably converted 10 preop ctDNA(+) pts to post-op ctDNA(-) status. Our findings warrant validation in a larger study to unravel the multifaceted factors influencing ctDNA’s prognostic value. Clinical trial information: NCT03073694 . [Table: see text]
Individualized tumor-informed circulating tumor DNA analysis for molecular residual disease detection in predicting recurrence and efficacy of adjuvant chemotherapy in colorectal cancer.
Authors: Cao Di , Zhou Qiaoxia , Fan Xuning , Yang Jinyu , Li Cong , Wang Fulong , Zhang Rongxin , Wu Xiaojun , Li Liren , Lu Zhenhai , Pan Zhizhong , Lin Junzhong , Wu Miaoqing , Liu Yifan , Lv Guangzhao , Qiu Fujun , Xin Haoyang , Xu Yu , Wang Guoqiang , Chen Gong 
Published: June 2024

3615 Background: Molecular residual disease (MRD) using circulating tumor DNA (ctDNA) may identify recurrent risk and guide adjuvant chemotherapy (ACT) in colorectal cancer (CRC). This study explored the feasibility of a tumor-informed personalized approach to predict recurrence, comparing with tumor-informed (TI) and tumor naïve (TN) fixed panel approaches. Methods: Patients with stage I-IV CRC eligible for R0 resection were recruited. Blood samples were collected preoperatively, at postoperative day 7 and 30 (POD7/30), and every 3-6 months thereafter, which were tested by brPROPHET assay, using up to 50 highly ranked variants identified by whole-exome sequencing of surgical tissue samples. A fixed 168-gene panel was applied for TI and TN fixed panel tests. Results: A total of 214 patients were enrolled. With a median follow-up of 13.2 months, 20 (9.3%) participants relapsed. The brPROPHET assay had a positivity rate of 96% in preoperative samples. ctDNA positivity indicated by brPROPHET predicted worse recurrence-free survival (RFS) at both POD7 (hazard ratio [HR]=7.35, 95% confidence interval [95% CI], 3.04-17.78, P<0.001) and POD30 (HR=5.18, 95% CI, 2.00-13.38, P<0.001). Higher mean tumor molecules (MTM) level >0.0316/mL was observed in surveillance of 15 relapsed patients, which was associated with worse RFS (HR=44.47, 95% CI, 12.83-154.12, P<0.001). In ctDNA positive patients at POD7, patients benefit from ACT (HR=0.23, 95% CI, 0.05-1.00, P=0.03), which was not observed in ctDNA negative patients (HR=1.80, 95% CI, 0.48-6.81, P=0.38). Among the patients with results of all three approaches (n=168), the brPROPHET assay outperformed TI and TN fixed-panel assays in predicting RFS at POD7 (HR, 7.52 vs 3.43 and 5.60). Of note, the brPROPHET assay identified 6 additional relapsed patients beyond the fixed panels, with more than 87.5% of the positive sites derived from personalized designs. Conclusions: The individualized tumor-informed brPROPHET assay effectively identified postoperative patients with high risk of recurrence and benefit from ACT. Using a personalized tumor-informed panel that covers sites outside fixed panels may improve the utility of MRD detection. [Table: see text]
NRG Oncology/RTOG 0848: Results after adjuvant chemotherapy +/- chemoradiation for patients with resected periampullary pancreatic adenocarcinoma (PA).
Authors: Abrams Ross A. , Winter Kathryn A. , Goodman Karyn A. , Regine William , Safran Howard , Berger Adam C. , Guha Chandan , Kachnic Lisa A. , Gillin Michael , Seaward Samantha A. , Wu Abraham Jing-Ching , Wu Jennifer J. , Aljumaily Raid , DiPetrillo Thomas A. , Geva Ravit , Anne Pramila R. , Yannucci Jennifer , Liles Darla K. , Moughan Jennifer , Crane Christopher H. 
Published: June 2024

4005 Background: If 5FU/Capecitabine sensitized radiotherapy (RT) is beneficial in the adjuvant (adj) management of PA after adj chemotherapy (chemo) is controversial. NRG/RTOG 0848 was designed to address this issue. Methods: This was a 2 step NCTN randomized (rndmzd) trial. Step 1 rndmzd patients (pts) to 5 cycles of gemcitabine +/- Erlotinib. Step 2 rndmzd pts to a 6th cycle of the same chemo +/- 5FU/Capecitabine with 50.4 Gy in 28 fractions RT (chemo+CRT). Step 1 eligibility included: R0/R1 resection, M0, ECOG PS 0-1, CA19-9≤180. Step 2 eligibility included > 4 cycles chemo (gem, gem combo, (m)FOLFIRINOX). RT included real time 3D/IMRT treatment (RX) plan review, scoring, and approval. At Step 2, pts stratified by nodal status (+ vs -), CA19-9 (≤90 vs > 90-180), surgical margins (R0 vs R1), and adjuvant chemo. Primary endpoint was OS. Secondary endpoints are DFS and AEs (CTCAEv4). Assuming 17 months median OS (chemo) and hypothesized 22.5 months (chemo+CRT), sample size was 354 pts (HR = 0.76, 80% power, 1-sided α = 0.05, 316 OS events). Due to lower than projected event rate, trial was amended to report at the earlier of (a) 316 observed OS events or (b) 5 years of follow-up time from Step 2 accrual closure (265 OS events, 72% power, same α). OS and DFS were estimated by Kaplan-Meier and arms compared using log-rank test. Multivariable analyses (MVA) used Cox proportional hazards models. Results: Accrual began 11/2009; closed 10/2018. 354 pts rndmzd (174 chemo, 180 chemo+CRT). Median follow-up for all & alive pts = 2 & 7 years, respectively, with 270 OS events. Median age 63, 45% female, 81% white, 13% AA. 83% R0, 26% node negative, 96% CA19-9 < 90. 13% of chemo+CRT pts did not receive RT. AEs were comparable (grade 4: 10% [chemo] vs 11% [chemo+CRT] and 1 grade 5 AE in each arm). Univariate OS/DFS results shown in Table. In initial MVA, RX, CA19-9, surgical margins were not statistically significantly associated with OS or DFS, but nodal status (OS, DFS) and race (OS) were. In further analyses, significant interactions were found between RX and nodal status for both OS and DFS. Node negative pts treated with chemo+CRT had better outcome than chemo pts; node positive pts did not (Table). Conclusions: Chemo+CRT did not improve OS overall, but did improve DFS. Both OS and DFS were improved with Chemo+CRT in node negative pts. Chemo+CRT did not increase Gr 4 or 5 AEs compared to chemo. Clinical trial information: NCT01013649 . [Table: see text]