bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-line anti-EGFR or anti-VEGF therapy, tumour sidedness, and survival: Results from the South Australian (SA) Metastatic Colorectal Cancer (mCRC) Registry.
Authors: Krishnan Tharani , Ullah Shahid , Piantadosi Cynthia , Karapetis Christos Stelios , Townsend Amanda Rose , Roy Amitesh , Geerinckx Barbara , Maddern Guy , Roder David , Padbury Rob , Price Timothy 
Published: January 2023

42 Background: The anti-EGFR monoclonal antibodies panitumumab (Pmab) and cetuximab (Cmab) and the anti-VEGF antibody bevacizumab (bev) have demonstrated clinical efficacy in mCRC in combination with first-line chemotherapy. Clinical and molecular characteristics, such as primary tumour sidedness, RAS, BRAF and MMR status are prognostic and predictive biomarkers for response to treatment. Our aim was to compare the survival and tumour characteristics of patients receiving first-line chemotherapy and antibody combinations using the SA mCRC Registry. Methods: This real-world registry has collected data from all patients diagnosed with mCRC in SA prospectively since 2006. We identified patients who had received first-line Pmab, Cmab or bev. Survival was analysed using the Kaplan-Meier method and log-rank test to compare outcomes based on primary tumour location. Results: Of the 5537 patients currently entered onto the registry, 1313 with RAS results available had received first-line anti-EGFR/VEGF antibodies and had colon tumour side recorded. The table summarises median overall survival (mOS) and patient characteristics. Survival was significantly shorter for those with right colon cancers (P < 0.001). There were more high-grade (P < 0.001), KRAS mutant (P = 0.004) and BRAF mutant (P = 0.036) tumours in those with right colon cancers, and a trend towards fewer curative liver resections (P = 0.059). There was no significant difference in mOS seen between Pmab, Cmab or bev for both left (P = 0.14) and right-sided (P = 0.88) primary tumours. Conclusions: There were more high-grade, BRAF and KRAS mutant patients with right colon tumours, and lower rates of liver resection, which may explain the significantly shorter mOS. The survival seen for Pmab and Cmab was almost identical for both right and left primary tumours. When comparing Pmab, Cmab and bev as first-line therapy, there was no significant difference in mOS for both left- and right-sided CRC. [Table: see text]
FGFR2-amplified gastroesophageal adenocarcinoma is a distinct genomic class: Lessons learned from a liquid biopsy platform.
Authors: Shariff Bushra , Barnett Reagan , Dayyani Farshid , Maron Steven Brad , Klempner Samuel J , Masannat Jude , Drusbosky Leylah , Mcgriskin Rory , Mehta Rutika 
Published: January 2023

429 Background: Gastroesophageal cancers (GECs) are the 2nd highest cause of cancer mortality globally. Biomarkers such as MMR, PD-L1, and HER2 are critical for treatment strategies. Emerging biomarkers in late-stage clinical development include FGFR2b. Approximately 30% of GECs express FGFR2b, which is associated with a poor prognosis. FGFR2 amplification ( FGFR2amp) is seen in a subset of patients and may be particularly responsive to FGFR2-targeted approaches. We sought to elucidate the genomic landscape of FGFR2ampGECs using a ctDNA platform. Methods: We retrospectively queried the Guardant Health database from 2017-2022 for patients with advanced GECs who had ctDNA NGS (Guardant360, Redwood City, CA) performed as part of clinical care. Co-alterations were evaluated for patients who harbor FGFR2amp vs those without FGFR2amp detected via ctDNA. Fisher’s exact test was used for group comparisons. Results: Approximately 7100 patients met the diagnosis criteria. FGFR2amp was detected in 263 patients (3.7%). The majority were males (66 and median age in the cohort of FGFR2amp patients was 66 years (range 22-81 yrs). Most amps were high (+++) in gastric and GEJ (plasma CN≥4) and more frequently observed in patients who are tested at diagnosis (44%) vs progression (19%) (p=0.0147). The mean VAF across samples with high-level FGFR2amp is 22.42%. Patients with FGFR2amp were enriched for EGFR co-occuring amplifications and cell cycle pathway alterations. CDH1 was frequently mutated in pts under 50 who harbor FGFR2amp (p=0.0028). Thirty nine percent of patients with FGFR2amp were also found to harbor a gene fusion and 14% of patients with FGFR2amps harbored an activating fusion in FGFR1/2/3. Conclusions: FGFR2 is a validated target in GECs, and the contexture of FGFR2amp will be important to defining patient subgroups with responses to FGFR2-directed therapy. Here we define the FGFR2amp landscape which may help inform future combination strategies for this emerging biomarker.[Table: see text]
Assessment of complete pathologic response after neoadjuvant immunotherapy for MSI-H gastrointestinal cancers.
Authors: Vora Kruti Bhagirath , Ouyang Ben , Pappas Leon , Reynolds Kerry Lynn , Strickland Matthew , Allen Jill N. , Weekes Colin D. , Corcoran Ryan Bruce , Blaszkowsky Lawrence Scott , Ryan David P. , Franses Joseph Wang , Chakrabarti Sakti , Klempner Samuel J , Parikh Aparna Raj 
Published: January 2023

43 Background: Immunotherapy (IO) has shown remarkable efficacy in gastrointestinal (GI) cancers with high microsatellite instability (MSI-H). We evaluated real world outcomes of patients treated with neoadjuvant IO for MSI-H colorectal (CRC) and gastroesophageal (GE) cancers. Methods: We queried diagnoses, pathology reports, and clinic notes of patients receiving IO at Massachusetts General Hospital from October 2014 to March 2022 using the Research Patient Data Registry and MATLAB. 1140 patients were identified with esophageal, gastric, colon, or rectal primaries. Of these, 56 were MSI-H and seven received neoadjuvant IO with curative intent. Results: Of the seven patients who received neoadjuvant IO for MSI-H CRC or GE cancers, three patients achieved complete pathologic response (pCR). Three patients had partial responses; one had a single residual lymph node tumor cell, one had residual T1b tumor and negative nodes, and one had residual T3 tumor and positive nodes. All patients with pCR had non-metastatic disease. Three of four patients with partial responses or progression had metastatic disease. Five patients had no recurrence by median follow-up of 10 months post-resection. One patient's cancer recurred 15 months post-resection, and one patient had progressive disease on neoadjuvant IO so did not undergo primary resection. Conclusions: Neoadjuvant IO shows promise for MSI-H GI cancers. Three of seven patients (43%) had pCR and three others (43%) had notable partial responses. There is a need to understand IO-refractory primary tumors and the differing effects of IO in local versus metastatic disease. While our data is limited by sample size, larger clinical trials can establish the safety and utility of neoadjuvant IO, potentially sparing many patients from surgery. We will collaborate with other centers for a larger scale analysis on neoadjuvant IO in MSI-H GI cancers. [Table: see text]
DNA mismatch repair deficiency and outcomes of patients with resectable locally advanced gastric cancer treated with preoperative docetaxel, oxaliplatin, and S-1 plus surgery and postoperative S-1 or surgery and postoperative S-1: A sub-analysis of the phase 3 PRODIGY trial.
Authors: Hyung Jaewon , Park Young Soo , Cho Hyungwoo , Kim Hyung-Don , Ryu Min-Hee , Kang Yoon-Koo 
Published: January 2023

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

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

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

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

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

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