bluuebunny/crossref_metadata_2025_split huggingface dataset:
STAR-TREC phase II: Can we save the rectum by watchful waiting or transanal surgery following (chemo)radiotherapy versus total mesorectal excision for early rectal cancer?
Authors: Bach Simon Parkinson , de Wilt Johannes H.W. , Peters Femke , Spindler Karen-Lise Garm , Appelt Ane L , Teo Mark , Homer Victoria , Abbott Natalie Louise , Geh Ian , Korsgen Stephan , Al-Najami Issam , Rombouts Anouk J.M. , Christensen Peter , Gilbert Alexandra , Navarro-Nuñez Leyre , Quirke Philip , West Nicholas , Baatrup Gunnar , Marijnen Corrie , Sebag-Montefiore David ,   STAR-TREC Collaborative Group
Published: June 2022

3502 Background: No randomised trials have compared non-operative organ preservation (OP) therapy for early-stage rectal cancer versus standard of care (SoC) using total mesorectal excision (TME) alone. STAR-TREC evaluated the feasibility of recruiting to a study comparing contrasting OP therapies, optimised for treatment of early tumours, versus SoC. Methods: STAR-TREC was a prospective, randomised, open-label, feasibility study in the UK, Netherlands and Denmark. Patients with biopsy proven adenocarcinoma of the rectum, staged ≤mrT3b N0 M0, ≤40mm diameter, ECOG 0-1 were randomised in a 1:1:1 ratio to TME, OP via mesorectal short-course radiotherapy (5x5 Gy), or OP via mesorectal chemo-radiotherapy (25x2 Gy + capecitabine) (Peters FP et al. Mesorectal radiotherapy for early stage rectal cancer: A novel target volume. Clin Transl Radiat Oncol 2020; 21: 104-11). Standardised response assessment classified OP cases as complete response for no further treatment, partial response for transanal endoscopic microsurgery or poor response for TME by 20 weeks. Surveillance following OP consisted of 3-monthly endoscopy/MRI. All cases had CT thorax/abdomen/pelvis at 24 months (m). The primary outcome was recruitment rate over 2 years, with randomisation of 120 international cases calculated as sufficient to support a phase III trial. Secondary outcomes included acute toxicity, stoma and OP rates at 12m, disease free survival (DFS) and non-regrowth DFS (NRDFS) at 24m and EORTC QLQ-C30 summary score at 12 and 24m. Phase II analysis was pre-specified, approved by the data monitoring committee conditional upon grouping of OP arms to inform phase III design, without prejudicing the outcome (STAR-TREC Phase III protocol. Colorectal Disease 2022). Results: Recruitment endpoints were met on 28 Oct 2019. Key secondary outcomes are tabulated by intention to treat. No 6-month mortality occurred. Conclusions: OP pathways optimised for early tumours reduce acute surgical morbidity without introducing substantial radiation toxicity to achieve OP in 60% with no increase in NRDFS at 24m compared to SoC. Overall quality of life was evenly matched. STAR-TREC phase III will determine the optimal strategy for achieving OP (STAR-TREC Phase III protocol. Colorectal Disease 2022). Clinical trial information: NCT02945566. [Table: see text]
Clinical impact of DNA methylation status on first-line antiepidermal growth factor receptor treatment in patients with metastatic colorectal cancer.
Authors: Osumi Hiroki , Ouchi Kota , Shinozaki Eiji , Takahashi Shin , Ooki Akira , Shimozaki Keitaro , Nakayama Izuma , Wakatsuki Takeru , Ogura Mariko , Takahari Daisuke , Chin Keisho , Yamaguchi Kensei , Ishioka Chikashi 
Published: June 2022

3528 Background: The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer. However, there is a lack of consensus of CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. Previously, we reported that genome-wide DNAmethylation statuscould predict the effect of epidermal growth factor receptor (EGFR) inhibitors more accurately than previously reported methylation classifications (Ouchi et al. Cancer Sci 2015). Moreover, we had developed a DNA methylation assay based on MethyLight to reflect genome-wide DNA methylation status and reported its usefulness in predicting prognosis in patients with metastatic colorectal cancer (mCRC) treated with EGFR inhibitors as a third-line chemotherapy (Ouchi et al. Cancer Sci 2022). This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patients with mCRC treated with first-line EGFR inhibitors. Methods: We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment, and analyzed the associations between genome-wide DNA methylation status using a novel comprehensive methylation marker panel and clinical outcomes and evaluated the predictive power and value of the methylation status. Results: Total 169 patients were included in the final analyses. The frequency of highly methylated CRC (HMCC) was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAFV600E mutation (P < 0.001). Patients with HMCC showed worse clinical outcomes than those with low methylated CRC in terms of response rate (P = 0.017), progression-free survival (PFS; P = 0.004), and overall survival (P = 0.019). In the multivariate analysis, peritoneal metastasis (Hazard ratio (HR): 2.24, P = 0.017), methylation status (HR: 3.04, P = 0.037), and BRAFV600E mutations (HR: 5.83, P = 0.0001) were independent factors for shorter PFS. Conclusions: Genome-wide DNA methylation status may be an independent predictor of first-line EGFR inhibitors in patients with mCRC.
Patient-reported outcomes from the GARNET trial in patients with advanced or recurrent mismatch repair deficient (dMMR) colorectal cancer (CRC): A post hoc subgroup analysis.
Authors: Hanlon Jennifer , Veneris Jennifer Taylor , Boklage Susan 
Published: June 2022

3558 Background: Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the US as a monotherapy in patients (pts) with dMMR advanced/recurrent endometrial cancer that has progressed on or after prior treatment with a platinum-containing regimen or in pts with dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options. Here we report on patient-reported outcomes (PROs) in pts with dMMR CRC, a post hoc subgroup analysis. Methods: GARNET is a multicenter, open-label, single-arm phase 1 study. Cohort F enrolled pts with dMMR/microsatellite instabilityhigh or POLε-mutated non-endometrial solid tumors. Pts with CRC must have received prior fluoropyrimidine, oxaliplatin, and irinotecan. Pts received 500 mg of IV dostarlimab Q3W for 4 cycles, then 1000 mg Q6W until discontinuation. PRO assessment, an exploratory endpoint, was measured using the EORTC-QLQ-C30. PROs were collected at baseline, at each dose cycle, and after discontinuation. Multi-item and item-level analyses were collected and scored; improvement was defined as mean change from baseline (directional change dependent on item). A 10-pt change in mean from baseline was considered clinically significant for the analysis. Results: PRO data at baseline were available for 96 pts with CRC who received ≥1 dose of dostarlimab. Improvements from baseline for quality of life (QOL) and most gastrointestinal symptom scales were observed and maintained from cycle 2 through 7 (Table). Stability in diarrhea was seen from cycles 2 through 7. Conclusions: PROs from the GARNET trial in pts with dMMR CRC show that QOL and disease-related gastrointestinal symptoms were improved or maintained while on dostarlimab treatment. These data, with the previously reported efficacy and safety profile, support the use of dostarlimab in pts with dMMR CRC. Clinical trial information: NCT02715284. [Table: see text]
Preoperative chemoradiotherapy with capecitabine with or without temozolomide in patients with locally advanced rectal cancer: A prospective, randomized phase 2 study stratified by MGMT (O6-methylguanine DNA methyltransferase) status: KCSG-CO17-02.
Authors: Oh Chung Ryul , Jeong Jae Ho , Lee Ji Sung , Kim Jeong Eun , Kim Sun Young , Kim Tae Won , Choi Jene , Kim Jihun , Park In Ja , Lim Seok-Byung , Park Jin-hong , Kim Jong Hoon , Choi Moon Ki , Cha Yongjun , Baek Ji Yeon , Beom Seung-Hoon , Hong Yong Sang 
Published: June 2022

3605 Background: We aimed to evaluate the clinical efficacy of adding temozolomide (TMZ) to preoperative capecitabine (CAP)-based chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC) and validate O6-methylguanine DNA methyltransferase (MGMT) methylation status as a predictive marker for TMZ combined regimens. Methods: : LARC patients with clinical stage II (cT3-4N0) or III (cTanyN+) disease were enrolled. They were stratified into MGMT unmethylated (uMGMT) and MGMT methylated (mMGMT) groups by methylation-specific PCR before randomization, and then were randomly assigned (1:1) to one of four treatment arms: uMGMT/CAP (arm A), uMGMT/TMZ+CAP (arm B), mMGMT/CAP (arm C), and mMGMT/TMZ+CAP (arm D). The primary endpoint was the pathologic complete response (pCR) rate. Results: Between November 2017 and July 2020, 64 patients were randomized. Slow accrual caused early study termination. After excluding 4 ineligible patients, 60 were included in the full analysis set. The pCR rate was 15.0% (9/60), 0%, 14.3%, 18.8%, and 26.7% for arms A, B, C, and D, respectively ( p= 0.0498 between arms A and D). The pCR rate was 9.7% in the CAP group (arms A+C), 20.7% in the TMZ+CAP group (arms B+D), 6.9% in the uMGMT group (arms A+B), and 22.6% in the mMGMT group (arms C+D). Grade 1–2 nausea or vomiting was significantly more frequent in the TMZ+CAP treatment groups (arms B+D) than in the CAP treatment groups (arms A+C, p< 0.001) with no difference in grade 3 adverse events (AEs). There were no grade 4 or 5 AEs. Conclusions: The addition of TMZ to CAP-based CRT tended to improve pCR rates, particularly in those with mMGMT LARC. MGMT status may warrant further investigation as a predictive biomarker for chemotherapeutic agents and radiotherapy. Clinical trial information: NCT03156036.
Label-free and automated approach to rapidly classify microsatellite instability (MSI) in early colon cancer (CC) analyzing the AIO ColoPredictPlus 2.0 (CPP) registry trial.
Authors: Schörner Stephanie , Großerueschkamp Frederik , Kraeft Anna-Lena , Schuhmacher David , Sternemann Carlo Willy , Feder Inke Sabine , Wisser Sarah , Lugnier Celine , Christmann Jens , Heuer Vera , Teschendorf Christian , Mueller Lothar , Mosig Axel , Arnold Dirk , Tannapfel Andrea , Gerwert Klaus , Reinacher-Schick Anke C. 
Published: June 2022

3616 Background: MSI due to mismatch repair defects accounts for 15-20% of all CC, has high prognostic and predictive value and is broadly utilized in treatment decisions. Artificial intelligence (AI) integrated, label-free quantum cascade laser (QCL) based infrared (IR) imaging resolves spatial and molecular alterations such as MSI in unstained cancer tissue sections. We aimed to evaluate the method for microsatellite instability/stability (MSI/MSS) classification in samples from the prospective multicenter AIO CPP registry trial. Methods: Paraffin-embedded unstained cancer tissue slides from patients (pts.) participating in CPP were measured (avg. 30 min/slide) and analyzed. The cohort was split into training (train), test (test), and validation (vali) sets. Cancer regions were first preselected based on a self-developed convolutional neural network (CNN) CompSegNet (Schuhmacher, medrxiv 2021). A VGG-16 CNN then classified MSI/MSS in these regions. Endpoints were area under receiver operating characteristic (AUROC) and area under precision recall curve (AUPRC). Results: 547 pts. (train n=331, test n=69, vali n=147) were analyzed. The baseline characteristics for the sub-cohorts are illustrated in the table. Mutation (MT) status: RAS MT: train 30% / test 30% / vali 37%; BRAF MT: train 27% / test 23% / vali 14%. The preselection of cancer regions reached a validation AUROC of 1.0. The subsequent MSI/MSS classifier reached a validation AUROC of 0.9 and AUPRC of 0.74 (sensitivity 85%, specificity 84%). Conclusions: Our multicenter approach using AI integrated label-free IR imaging provides an automated, fast, and reliable classification for MSI/MSS with an AUROC of 0.9 (sensitivity 85%, specificity 84%) almost comparable to the present gold standard immunohistochemistry. The method described here requires less samples for training when compared to other AI approaches which could facilitate the development of prognostic/predictive classifiers in the setting of randomized controlled trials. This novel technique may support further understanding of the increasingly important MSI CC cohort and support treatment decisions e.g. in specific subgroups such as targetable fusions. We expect our approach to be a broadly applicable diagnostic tool in the future.[Table: see text]
Impact of the COVID-19 pandemic on colorectal cancer (CRC) care: Data from 22 German cancer centers (CC) and the Institute of Pathology, Ruhr-University Bochum - the AIO (Working Group for Internal Oncology of the German Cancer Society) CancerCOVID Consortium - AIO-YMO/KRK 520/ass.
Authors: Lugnier Celine , Foerster Sarah , Kraeft Anna-Lena , Feder Inke Sabine , Christmann Jens , Kourti Eleni , Overheu Oliver , Sommerlatte Sabine , Uhl Waldemar , Schoenlein Martin , Rosery Vivian , Biermann Christoph , Müller Lothar , Schoffer Olaf , Schmitt Jochen , Modest Dominik Paul , Heinemann Volker , Schildmann Jan , Reinacher-Schick Anke C. , Tannapfel Andrea 
Published: June 2022

3626 Background: CRC still is one of the leading causes of cancer related death though prognosis has improved through guideline based management. The COVID-19 pandemic lead to re-allocation of resources subordinating all sections of care for CRC patients. We present data on changes of CRC care during the pandemic from 22 German AIO CC and our high volume Institute of Pathology (pathology). Methods: Data was collected retrospectively comparing the months (mo) of the first wave (fw) (4-6/2020) and second wave (sw) (11-12/2020) of the pandemic with corresponding periods (cp) in 2019 focusing on the number of precancerous (ICD-O/0+2) and malignant (ICD-O/3+6) colorectal lesions (CRL) diagnosed by our pathology, the number/stage of primary diagnoses (PD) and the number of surgeries (surg) at AIO CC. There, quality criteria of CRC care were also assessed (number of PD discussed within a multidisciplinary tumor board (tb), received social service (soc)/ psychological (psy) counseling or recruited into a clinical trial). Statistical analysis was performed using students t-test for paired data. Results: Numbers of CRL detected upon histology (row 1-3), number of cases, surg and quality criteria from AIO CC (row 4-9) are displayed in the table. We saw a dip in diagnosed CRL and number of surg (p=0.007) only during fw, whereas PD dipped significantly in both waves. A significant reduction in diagnosis of stage III CRC was detected for 2019 vs. 2020 (p=0.001), not for other stages. Quality criteria showed a significant reduction in clinical trial inclusion, a small dip in soc/psy counseling and persistently high tb presentation. Conclusions: We detected a significant decrease of premalignant lesions and primary cancers during the first year of the pandemic which may impact cancer mortality in the future. Certified German CC provided CRC care with significant reduction in clinical trial inclusion only, suggesting high stability of established certified cancer care infrastructure.[Table: see text]
The first report of K-Umbrella Gastric Cancer Study: An open label, multi-center, randomized, biomarker-integrated trial for second-line treatment of advanced gastric cancer (AGC).
Authors: Rha Sun Young , Lee Choong-kun , Kim Hyo Song , Jung Minkyu , Kim Hyunki , Woo Kyun Bae , Koo Dong-Hoe , Jeung Hei-Cheul , Park Sook Ryun , Hwang In Gyu , Zang Dae Young , Lee Hyun Woo , Park Sejung , Nam Jung Mo , Chung Hyun Cheol Cheol 
Published: June 2022

4001 Background: To explore proper agents for AGC patients as 2nd-line treatment based on optimal biomarker, we conducted K-Umbrella GC study with standard of care (SOC) controlled umbrella trial design. Methods: HER2-negative AGC patients from 6 Korean cancer centers were centrally screened for druggable targets by IHC and in situ hybridization. Patients were randomized to the biomarker vs. control group with SOC as 4:1 ratio. In the biomarker group, patients were treated with specific targeted agents in combination with weekly paclitaxel; 1) EGFR 2+/3+ patients for pan-ERBB inhibitor (afatinib; EGFR cohort), 2) PTEN loss/null (H-score <100) patients for PIK3Cβ inhibitor (GSK2636771; PTEN cohort), and 3) PD-L1+, dMMR/MSI-high, or EBV-related cases for anti-PD-1 inhibitor (nivolumab; NIVO cohort). Control group and NONE cohort in biomarker group without predefined biomarkers were treated with SOC (weekly Paclitaxel±Ramucirumab). Primary endpoint was PFS between control and biomarker groups. Secondary endpoints included efficacy and safety of each cohort. Results: Between Feb 2016 and Feb 2021, total 722 patients were centrally screened. 329 patients were enrolled and randomized to control group (n=63) or biomarker group (n=266; EGFR cohort n=67; PTEN cohort n=42; NIVO cohort n=54; NONE cohort n=103). With a median follow-up of 35 months (95%CI 26.1-55.3), median PFS and OS were 3.8 (95%CI 3.2-4.3) and 8.9 (95%CI 7.8-10.1) months for biomarker group and 4.1 (95%CI 3.0-4.8) and 8.7 months (95%CI 7.2-10.2) for control group. In control group, PTEN loss/null was poor prognostic marker; patients with PTEN loss/null (n=12) showed worse survival compared to PTEN intact patients (n=51) (mPFS, 2.8 vs 4.3 months, P=0.03; mOS, 8.7 vs 9.1 months), where other biomarkers showed similar prognosis. Afatinib for EGFR cohort or GSK2636771 for PTEN cohort did not show significant survival benefit compared to control group (Table). Among patients with immune-related biomarkers, addition of nivolumab showed durable survival benefit (mOS 12.0 vs 7.6 months, P=0.08) compared to SOC. Conclusions: Considering the characteristics of umbrella design with multiple biomarkers having different biological roles, biomarker group did not show the improved survival over control arm with these 3 drugs. For optimal biomarker-driven targeted agent applications, NGS-based biomarker driven K-Umbrella GC-2 study is ongoing. Clinical trial information: NCT02951091. [Table: see text]
Distinct biosignatures associate with survival after chemoimmunotherapy in a randomized, three-arm phase II study in patients with metastatic pancreatic cancer.
Authors: Padrón Lacey J. , Maurer Deena M. , O'Hara Mark H. , O'Reilly Eileen Mary , Wolff Robert A. , Wainberg Zev A. , Ko Andrew H. , Fisher George A. , Rahma Osama E. , Lyman Jaclyn P. , Cabanski Christopher R. , Yu Jia , Pfeiffer Shannon M. , Spasic Marko , Hollmann Travis J , Chen Richard , O'Donnell-Tormey Jill , Bucktrout Samantha , LaVallee Theresa , Vonderheide Robert H. 
Published: June 2022

4010 Background: Preclinical and small clinical studies of chemoimmunotherapy for metastatic pancreatic ductal adenocarcinoma (mPDAC) point to a yet unrealized potential of clinically significant immune activation. In our phase II study of the CD40 agonist antibody sotigalimab (sotiga) and/or nivolumab (nivo) with gemcitabine and nab-paclitaxel (chemo), we observed promising improvements in overall survival (OS) in 105 patients with newly diagnosed mPDAC (NCT03214250); the primary endpoint of 1-year OS rate was 57.7% (p = 0.006) in the nivo/chemo arm, 48.1% (p = 0.062) in the sotiga/chemo arm and 41.3% (p = 0.233) in the nivo/sotiga/chemo arm (O’Hara, ASCO 2021) as compared to a historical control of 35%. Here, we report results of multi-omic translational analyses designed to identify signatures predictive of OS benefit. Methods: Longitudinal blood and tumor tissue samples were collected for immune and tumor biomarker analysis. Tumor samples underwent RNA sequencing and multiplex immunofluorescence (mIF). Peripheral blood was analyzed by mass cytometry time of flight (CyTOF), high parameter flow cytometry, and proteomics. Machine learning (ML) algorithms were applied to the data to identify biosignatures related to OS in each arm. Results: Comprehensive multi-omic, multi-parameter immune and tumor biomarker analyses identified distinct pretreatment immune signatures predictive of longer OS specific to nivo/chemo or sotiga/chemo (Table, representative examples). Because patients in each arm received chemotherapy, these and other arm-unique biomarkers suggest a relationship to the immunotherapy rather than chemotherapy in this randomized study. There was evidence of immune exhaustion in the sotiga/nivo/chemo arm that may explain the lack of survival benefit. Conclusions: From in-depth translational and ML analyses of randomized phase II trial of first-line chemoimmunotherapy in mPDAC patients, we identified novel biomarkers that associated with OS distinctly in each arm. Clinical trials in first-line mPDAC exploiting these previously unappreciated biomarkers and aiming to enrich patients for response, are warranted to further advance chemoimmunotherapy in this disease. Clinical trial information: NCT03214250. [Table: see text]