bluuebunny/crossref_metadata_2025_split huggingface dataset:
The incidence of myelodysplastic syndrome in patients receiving poly-ADP ribose polymerase inhibitors for treatment of solid tumors: A meta-analysis.
Authors: Nitecki Roni , Gockley Allison Ann , Floyd Jessica Lauren , Coleman Robert L. , Melamed Alexander , Rauh-Hain Jose Alejandro 
Published: May 2020

3641 Background: Clinical trials have reported improved outcomes with PARPi (poly [adenosine diphosphate–ribose]-ADP polymerase inhibitor) therapy in ovarian, breast, pancreatic and lung cancers. There is concern that PARPi therapy may cause myelodysplastic syndrome (MDS). In this meta-analysis we seek to quantify the risk of MDS among patients treated with PARPi for solid tumor malignancies. Methods: We searched Medline, Embase, and Cochrane databases (up to January 6, 2020) to abstract randomized controlled trials that include a PARPi in the experimental arm in solid tumors. Combinations included PARPi versus (vs.) placebo, PARPi vs. cytotoxic treatment, and PARPi with cytotoxic treatment vs. cytotoxic treatment. We used to time-to-event curves to estimate person-time and calculated the incidence of MDS among all studies. We used random-effects Poisson regression models to estimate pooled incidence risk ratio (RR) for developing MDS. Results: We identified 14 studies, 10 in ovarian, 3 in breast, and 1 in pancreatic cancer patients. Of 5,646 patients, 62.3% received a PARPi alone or in combination with chemotherapy or bevacizumab, and 37.8% received treatment consisting of placebo alone or with chemotherapy or bevacizumab. PARPi were investigated as an upfront treatment in 2,827 patients, and as treatment for recurrence in 2,819 patients. The incidence of MDS was 6.73 cases vs. 3.85 per 1000 person-years in patients receiving PARPi as compared to control corresponding to a 3-year cumulative incidence of 2.0% and 1.1%. Accounting for intra-study clustering, PARPi use was associated with a 60% increase in risk (incidence RR 1.60, 95% Confidence Interval [CI] 0.89-2.87) of MDS compared to control. In the upfront setting, patients randomized to PARPi were twice as likely to develop MDS (RR 2.08, 95%, CI 1.39-3.64). Among patients treated for recurrence, the risk of MDS appeared to be similar among patient randomized to PARPi or control treatment (RR 1.13, 95% CI 0.35-3.64). In studies that compared PARPi in combination with other cytotoxic treatment vs. cytotoxic treatment alone, PARPi was associated with a large risk of MDS (RR 5.08, 95% CI 1.36-19.03). Conclusions: In pooled estimates from randomized controlled trials in solid tumors PARPi treatment appears to be associated with an increased incidence of MDS particularly in the upfront setting and when combined with cytotoxic treatment. Despite pooling 14 randomized trials our estimates remain imprecise due to the rarity of MDS.
Short-course radiotherapy followed by chemotherapy before TME in locally advanced rectal cancer: The randomized RAPIDO trial.
Authors: Hospers Geke , Bahadoer Renu R. , Dijkstra Esmee A. , van Etten Boudewijn , Marijnen Corrie , Putter Hein , Meershoek – Klein Kranenbarg Elma , Roodvoets Annet G. , Nagtegaal Iris D. , Beets-Tan Regina GH , Blomqvist Lennart K. , Fokstuen Tone , ten Tije Albert J. , Capdevila Jaume , Hendriks Mathijs P. , Edhemovic Ibrahim , Cervantes Andres , Nilsson Per J. , Glimelius Bengt , Van De Velde Cornelis J. H. 
Published: May 2020

4006 Background: Local control in locally advanced rectal cancer (LARC) has improved. However, systemic relapses remain high even with postoperative chemotherapy, possibly due to low compliance. Short-course radiotherapy (SCRT) followed by delayed surgery with, in the waiting period, chemotherapy, may lead to better compliance, downstaging and fewer distant metastases. The main objective of the international multicenter phase III RAPIDO trial is to decrease Disease-related Treatment Failure (DrTF), defined as locoregional failure, distant metastasis, a new primary colon tumor or treatment-related death, by reducing the risk of systemic relapse without compromising local control. Methods: MRI-diagnosed LARC patients with either cT4a/b, extramural vascular invasion, cN2, involved mesorectal fascia or enlarged lateral lymph nodes considered to be metastatic were randomly assigned to SCRT (5x5 Gy) with subsequent six cycles of CAPOX or nine cycles of FOLFOX4 followed by total mesorectal excision (TME) (experimental arm) or, capecitabine-based chemoradiotherapy (25-28 x 2.0-1.8 Gy) followed by TME and optional, predefined by hospital policy, postoperative eight cycles of CAPOX or twelve cycles of FOLFOX4 (standard arm). Results: Between June 2011 and June 2016, 920 patients were randomized. Pathological complete response rates were 27.7% vs 13.8% (OR 2.40 [1.70 – 3.39]; p < 0.001) in the experimental and standard arms, respectively. At three years, cumulative probability of DrTF was 23.7% in the experimental arm and 30.4% in the standard arm (HR 0.76 [0.60 – 0.96]; p = 0.02). Probability at three years of distant metastasis and locoregional failure were, in the experimental and standard arms, 19.8% vs 26.6% (HR 0.69 [0.53 – 0.89]; p = 0.004) and 8.7% vs 6.0% (HR 1.45 [0.93 – 2.25]; p = 0.10), respectively. No differences in DrTF between hospitals with or without policy for postoperative chemotherapy were found (p = 0.37). Overall health ( p = 0.192), quality of life ( p = 0.125) and low anterior resection syndrome score ( p = 0.136) were comparable between the two treatment arms. Conclusions: A lower rate of DrTF, as a result of a lower rate of distant metastases, in high-risk LARC patients can be achieved with preoperative short-course radiotherapy, followed by chemotherapy and TME than by conventional chemoradiotherapy. In addition, the high pCR rate, achieved with the experimental treatment regimen can contribute to organ preservation. This treatment can be considered as a new standard of care. Clinical trial information: NCT01558921 .
Consensus molecular subtypes in colorectal cancer differ by geographic region.
Authors: Korphaisarn Krittiya , Lam Michael , Loree Jonathan M. , Ruiz Erika , Aguiar Samuel , Kopetz Scott 
Published: May 2020

4061 Background: The consensus molecular subtypes (CMS) have emerged as a novel classification in colorectal cancer (CRC). However, these subtypes, were mostly derived from a US/European population, and have scant data in other ethnic groups. This study aimed to demonstrate molecular subtypes of CRC across geographic regions. Methods: Formalin fixed paraffin embedded (FFPE) tissue from untreated patients with stage II-III colon cancer from Brazil, Canada, Mexico, Thailand, and the US were evaluated. Gene expression profiling was performed at the University of Texas MD Anderson Cancer Center using NanoString’s nCounter technology and an optimized classifier for FFPE. Results: A total of 366 samples were included in this study, evenly distributed between the 5 international sites. While the US population matched previously reported distributions, the distribution of CMS subtypes varied substantially by region (P < 0.0001). While CMS1 was still associated with right-sided tumors (P < 0.001) and deficient mismatch repair (dMMR) (P < 0.001), the prevalence varied between 8% in Brazil to 30% in Mexico. CMS2 was found vary from 14% in Mexico to 47% in Brazil. The metabolic CMS3 subtype was present in only 3% in Thailand, but as high as 19% in Brazil. CMS4 was confirmed to be associated with higher stage (P = 0.047), and the prevalence was lowest in Brazil (14%) compared to 44% and 49% in US and Mexico, respectively. Expansion of study cohort is ongoing. Conclusions: CMS subtype prevalence differs substantially by geographic region in CRC. These variations suggest that transcriptomic-defined disease biology in international populations may be more heterogeneous than previously appreciated. Further studies in global populations are required to validate and extend these findings, which may have important impact for novel therapeutic development.
Somatic alterations of NF1 in colorectal cancer.
Authors: Arai Hiroyuki , Elliott Andrew , Xiu Joanne , Wang Jingyuan , Battaglin Francesca , Soni Shivani , Zhang Wu , Sohal Davendra , Goldberg Richard M. , Hall Michael J. , Scott Aaron James , Khushman Mohd , Hwang Jimmy J. , Lou Emil , Weinberg Benjamin A. , Marshall John , Lockhart Albert Craig , Shields Anthony Frank , Korn W. Michael , Lenz Heinz-Josef 
Published: May 2020

4066 Background: NF1 encodes neurofibromin, which is a key GTPase-activating protein that downregulates RAS activation. Inactivating mutations in NF1 result in sustained activation of RAS signaling, a key driver for development of colorectal cancer (CRC), and have been suggested to be a potential mechanism of resistance to EGFR inhibition in RAS-wild type (WT) CRC. Little is known about molecular characteristics of NF1-mutated (MT) CRC. Methods: Tumor profiles from 8150 CRC patients (pts) with available NF1 mutation status were retrospectively reviewed. NextGen sequencing by a customized 592-gene panel was performed. Microsatellite instability (MSI) / mismatch repair (MMR) status, tumor mutational burden (TMB) and PD-L1 expression were tested. Molecular profiles between NF1-MT and NF1-WT pts were compared. Results: Out of 8150 pts, 176 (2.2%) had somatic NF1 mutations with pathogenic or presumed pathogenic function. A higher NF1-MT frequency was observed in MSI-H/dMMR vs MSS/pMMR (13.5% vs 1.4%, p < 0.0001), in right-sided vs left sided (2.9% vs 1.8%, p < 0.01), and in RAS-WT vs RAS-MT (3.0% vs 1.4%, p < 0.0001). In MSS/pMMR tumors, no association with sidedness was observed (right: 1.3% vs left: 1.2%, NS). The most prevalent co-mutations with NF-1 were APC (63.2%), ARID1A (57.5%), TP53 (51.5%), KMT2D (32.9%) and KRAS (32.4%) in all cases, and APC (76.2%), TP53 (69.5%), KRAS (38.8%), ARID1A (34.4%) and FBXW7 (21.5%) in MSS/pMMR cases. POLE mutation was observed in 18.4% of NF1-MT/MSS/pMMR pts. Compared to NF1-WT pts, NF1-MT pts had more frequent mutations in ARID1A (All: 57.5% vs 23.3%, p < 0.0001; MSS/pMMR: 34.4% vs 15.2%, p < 0.05), and less frequent mutations in KRAS (All: 32.4% vs 49.0%, p < 0.0001; MSS/pMMR: 38.8% vs 50.3%, p < 0.05). Also, NF1-MT pts had more frequent alterations in homologous recombination pathway compared to NF1-WT pts (All: 39.8% vs 7.5%, p < 0.0001; MSS/pMMR: 17.5% vs 4.4%, p < 0.0001). Mean TMB was significantly greater in NF1-MT than NF1-WT (All: 48.9/Mb vs 10.0/Mb, p < 0.0001; MSS/pMMR: 48.3/Mb vs 8.2/Mb, p < 0.0001). Also, PD-L1 positivity was higher in NF1-MT compared to NF1-WT (All: 12.9% vs 3.6%, p < 0.0001; MSS/pMMR: 7.1% vs 2.6%, p < 0.05). Conclusions: While more frequent than in RAS-MT pts, NF1-MT CRC was a small subset in RAS-WT pts. NF1-MT was associated with alterations in chromatin remodeling and DNA damage response pathways, as well as elevated TMB and PD-L1 expression, which may provide alternative therapeutic strategies beyond EGFR inhibition.
Prognostic differences of RAS mutations: Results from South Australian (SA) metastatic colorectal (mCRC) registry.
Authors: Price Timothy Jay , Piantadosi Cynthia , Townsend Amanda Rose , Padbury Rob , Roy Amitesh Chandra , Moore James , Maddern Guy , Roder David , Karapetis Christos Stelios 
Published: May 2020

4067 Background: Effective targeting of RAS mutations has proven elusive until recently. AMG 510, a novel agent which targets KRAS G12C mutations (G12C MT), has shown promise in early phase clinical trials that included patients with mCRC. Prior reports have suggested that G12C MT may be predictive of poor outcome. Methods: We aimed to assess the prognostic implications of individual RAS in a population-based registry. The SAmCRCR collects data from all patients diagnosed with mCRC in South Australia prospectively. Individual RAS mutation data from patients entered into the SAmCRCR between February 2006 and December 2018 was reviewed. Survival was analysed for the more frequent mutations using Kaplan Meier method. Results: 1605 (33%) of the 4905 patients entered onto the registry had RAS mutation results available. Of these, 658 (41%) had RAS MT. The nature of the RAS MT was available in 563 (85.7% of those with RAT MT). Patient characteristics, frequency of individual RAS MT and median overall survival (OS) per RAS MT are noted in table. Low frequency MT made up an additional 16.3%. There were numerical differences in survival however there was no statistical difference in survival when comparing the various RAS MT, including the comparison of G12C to G12S (p = 0.38). Conclusions: Whilst the G12S mutation was associated with the longest survival numerically, the observed survival for patients with the most common RAS mutations (G12C, G12V, G12A, G12D and G13D) did not significantly differ. [Table: see text]
Utility of circulating tumor DNA (ctDNA) versus tumor tissue genotyping for enrollment of patients with metastatic colorectal cancer (mCRC) to matched clinical trials: SCRUM-Japan GI-SCREEN and GOZILA combined analysis.
Authors: Nakamura Yoshiaki , Taniguchi Hiroya , Bando Hideaki , Esaki Taito , Komatsu Yoshito , Kato Ken , Takahashi Naoki , Kagawa Yoshinori , Kato Takeshi , Nishina Tomohiro , Satoh Taroh , Oki Eiji , Sunakawa Yu , Shiozawa Manabu , Yamamoto Yoshiyuki , Kawakami Hisato , Denda Tadamichi , Ohtsu Atsushi , Yoshino Takayuki 
Published: May 2020

4071 Background: We recently reported that ctDNA genotyping had advantages compared with tumor tissue testing in terms of enrollment to matched clinical trials across a wide range of GI cancers (Nakamura Y, et al. ASCO-GI 2020). Here, we investigated the utility of ctDNA genotyping in mCRC in a SCRUM-Japan GI-SCREEN and GOZILA combined analysis. Methods: In GI-SCREEN, tumor tissue genotyping was performed using a next generation sequencing (NGS)-based assay, Oncomine Comprehensive Assay since Feb 2015. In GOZILA, NGS-based ctDNA genotyping was performed using Guardant360 since Feb 2018. All tests were conducted centrally in a CLIA-certified and CAP-accredited laboratory. Patients with actionable alterations were enrolled into matched company-sponsored or investigator-initiated interventional clinical trials. Results: As of Apr 2019, 2,791 mCRC patients (2,754 eligible for analysis) in GI-SCREEN and 470 (464 eligible for analysis) in GOZILA were enrolled. There were no significant differences in baseline patient characteristics between GI-SCREEN and GOZILA. Most of trials affiliated with GI-SCREEN (81%) or GOZILA (78%) targeted the RTK/RAS/RAF pathway. Compared with tumor testing, ctDNA genotyping significantly improved turnaround time (median, 12 vs. 34 days, P < 0.0001), sequencing success rate (96.1 vs. 92.3%, P = 0.002), and detection rate of actionable alterations (73.3 vs. 62.2%, P = 0.02). Among patients with actionable alterations, enrollment to matched clinical trials was achieved in 5.0% in GI-SCREEN and 12.1% in GOZILA ( P < 0.0001). Median time from enrollment in the respective screening study to enrollment in a matched clinical trial was 6.5 months in GI-SCREEN and 0.9 months in GOZILA, respectively ( P < 0.0001). Objective response rate and progression-free survival were similar in both groups (tissue vs. ctDNA; ORR: 18.8 vs. 17.1%, P = 1.00; median PFS: 2.2 vs. 2.2 months, HR=1.05 [95% CI, 0.71–1.55], P = 0.79). Conclusions: For patients with mCRC, ctDNA genotyping had advantages over tissue genotyping with shorter turnaround time and higher sequencing success and actionable alteration detection rate, which were associated with improved clinical trial enrollment without compromising the efficacy. Funding: SCRUM-Japan Funds. Clinical trial information: UMIN000029315 .
Circulating tumor DNA as a promising biomarker of relapse risk for stage II-III colorectal cancer.
Authors: Chen Gong , Wang Feng , Peng Jun-Jie , Cai San-Jun , Ding Ke-Feng , Xiao Qian , Wang Fu-Long , Wu Xiao-Jun , Pan Zhi-Zhong , Ding Pei-Rong , Kong Ling-Heng , Wan De-Sen , Fan Xiaojun , Liu Rui , Bao Hua , Zhang Junli , Pang Jiaohui , Wu Xue , Shao Yang , Xu Rui-hua 
Published: May 2020

4079 Background: About 30-50% colorectal cancer patients undergoing a curative resection will experience disease recurrence ultimately. Early detection of recurrence is of great significance for improving the prognosis of colorectal cancer patients. Circulating tumor DNA (ctDNA) has been suggested to be a promising biomarker for postoperative surveillance and prognosis prediction in various cancers including colorectal cancer. However, its performance in predicting early recurrence of colorectal cancer as well as appropriate testing procedures still needs large-scale prospective studies to evaluate. Methods: A total of 246 patients with stage II-III colorectal cancer and underwent curative resection from three clinical centers of China were enrolled in this multicenter prospective cohort study. Tissue samples as well as serial plasma samples before surgery, 7 days and 6 months after surgery and 3 months interval afterwards until recurrence were collected, and subjected to deep targeted-panel sequencing containing 425 cancer-related genes. ctDNA baseline genomic alterations and dynamic changes were analyzed. Its performance in predicting early recurrence was evaluated and compared with other clinical routine investigations, including serum biomarkers CEA and CA199, and CT examination. Results: The ctDNA positive rates at baseline (before surgery) and 7 days after surgery were 72.9% and 18.1% respectively. Among 199 patients with complete survival data, 18 patients were recurrent during follow up period with a median disease-free survival of 280.5 days (114-461 days). At baseline, high clinical stage (p = 0.035), and PTEN mutation (p = 0.009) were significantly associated with increased recurrent risk; while APC mutation (p = 0.04) predicted a decreased recurrent risk. Detection of ctDNA 7 days after surgery [HR: 5.9 (1.94-17.97); p = 0.0004] or any time point before clinical recurrence [HR: 6.14 (2.3-16.38); p < 0.0001] was associated with a significantly higher recurrent risk, and the HR increased accordingly with ctDNA mutation level. In multivariate analyses, ctDNA status was independently associated with relapse after adjusting for known clinicopathological risk factors. CEA status was not significantly (p > 0.4) associated with disease-free survival. A risk scoring model comprising of clinical variables and ctDNA detection after surgery was constructed and can predict 18-month recurrence with an AUC of 0.77. Conclusions: ctDNA is a promising marker of risk stratification, and early relapse detection in resected stage II/III CRC patients. Clinical trial information: NCT03312374 .
Consensus molecular subtypes (CMS) as a marker for treatment and disease biology in metastatic colorectal cancer (CRC).
Authors: Lam Michael , Kanikarla Marie Preeti , Mehrvarz Sarshekeh Amir , Morris Van K. , Duose Dzifa Yawa , Zhang BaiLi , Chen Huiqin , Morris Jeffrey , Mehta Trupti R. , Katkhuda Riham , Kopetz Scott 
Published: May 2020

4089 Background: Consensus molecular subtypes (CMS) categorize colorectal cancer (CRC) into groups based on gene transcription and are prognostic in early-stage and first-line metastatic settings. Their impact on treatment history is unknown. We hypothesized that the best prognosis CMS2 would have higher utilization of liver-directed therapies and maintenance chemotherapy over the worst prognosis CMS4. Methods: Primary surgical resection specimens were annotated for CMS on a translational protocol in a 5FU-refractory metastatic CRC population. Specimens that had neoadjuvant chemotherapy or radiation were excluded. CMS1, CMS3 and indeterminate CMS were also excluded. Liver-directed therapies were defined as any surgery, direct injection of cytotoxics or microspheres, radiation or radiofrequency ablation. Multiple occurrences of liver-directed therapies or maintenance chemotherapy in the same patient were recorded once for statistical tests of association. Results: CMS1 (7.4%), CMS3 (8.2%) and indeterminate calls (4.1%) accounted for 20% of all samples tested. There were 43 (44%) CMS2 and 55 (56%) CMS4 patients eligible. Age, stage at diagnosis, mismatch repair and RAS mutational status were similar in both groups. Left-sided tumors were more common in CMS2 (79%) than CMS4 (42%), p = .001. The median overall survival (OS) from stage IV diagnosis was 40 [34 - 51] versus (vs) 28 [21 – 33] months (p < .0001) for CMS2 vs CMS4 respectively. Liver-directed therapy was greater in CMS2 (53%) vs CMS4 (31%), p = .024. The number further increased when multiple treatments in a single patient were taken into account. Microsphere injection, radiation and liver surgery combined with RFA were the most skewed towards CMS2 over CMS4. No difference in median OS was seen from first liver-directed therapy in CMS2 vs CMS4 (29 vs 27 months, p = .31). There was a trend towards greater maintenance chemotherapy in CMS2 (47%) vs CMS4 (29%), p = .076. Conclusions: Better prognosis with CMS2 is consistent with other studies. Significantly increased liver-directed therapy was observed in CMS2. Selection criteria for liver-directed therapy such as slowly progressing, oligometastatic and hepatic-confined disease may be enriching for CMS2 and gives insight into the natural history of this subtype.
Can FIT rule out colorectal cancer in symptomatic patients? Diagnostic test accuracy results from 9,822 patients in the NICE FIT study.
Authors: Georgiou Delisle Theo , D'Souza Nigel , Chen Michelle , Benton Sally , Abulafi Muti ,   NICE FIT Steering Group
Published: May 2020

4093 Background: The faecal immunochemical test (FIT) is a non-invasive quantitative test that measures occult blood in faeces (faecal haemoglobin, FHb). FIT is already used worldwide in colorectal cancer (CRC) screening programmes. Bowel symptoms have low specificity for CRC; to diagnose one patient with CRC, a large number of symptomatic patients require investigation. A negative FIT test, when blood is not detected, could be used to rule out CRC in symptomatic patients without invasive investigations such as colonoscopy. We report on the largest diagnostic accuracy study to date of FIT in symptomatic patients. Methods: Patients were eligible for recruitment if they experienced bowel symptoms meeting national high-risk criteria and were triaged to investigation with colonoscopy. Patients were excluded from analysis if they did not provide a valid FIT or did not undergo complete colonoscopy. Colonoscopy results were compared to FIT measurements of FHb, and the conduct of the tests was double-blinded. Quality assurance of endoscopy and clinical data was performed by senior clinicians. External statisticians analysed anonymised data. Results: 9822 patients from 50 sites across England participated in the study between October 2017 to March 2019. The most common colonoscopy finding was absence of any colorectal disease (31%). The prevalence of CRC at colonoscopy was 3.3%. The sensitivity of FIT at FHb thresholds of 2, 10 and 150 μg/g significantly decreased from 97.0% to 90.9% and 70.8% respectively (p < 0.01). FIT positivity rate at these thresholds increased from 7.6%, to 19% and 37.2% respectively (p < 0.01). The positive predictive value of FIT for CRC at FHb thresholds of 2, 10 and 150 μg/g was 8.7%, 16.1% and 31.1% respectively and the negative predictive value of FIT at these thresholds was 99.8%, 99.6% and 98.9% respectively. Conclusions: The results of this study support the use of FIT at the threshold of detectable blood (2μg/g) as an initial CRC rule-out test to triage patients with high risk CRC symptoms, reducing the number of unnecessary investigations. This is the first study to report that at the lowest threshold of detectable blood, FIT sensitivity is equivalent to the current gold standard investigation of colonoscopy. Clinical trial information: ISRCTN49676259 .