bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating the impact of reducing the age of colorectal cancer screening on cancer incidence, mortality, and costs in Canada using OncoSim.
Authors: Kalyta Anastasia , Loree Jonathan M. , De Vera Mary A. , Peacock Stuart , Telford Jennifer J. , Brown Carl J , Donnellan Fergal , Gill Sharlene 
Published: June 2022

3526 Background: Organized colorectal cancer (CRC) screening programs currently cover Canadians aged ≥50 at average-risk of developing CRC and have contributed to declining CRC incidence. Rising incidence of early-onset CRC in individuals < 50 has led to lowering of the recommended screening start age to 45 rather than 50 in some jurisdictions. We used OncoSim, a publicly-available simulation tool, to model the effects of earlier screening initiation on Canadian CRC incidence, mortality and healthcare costs. Methods: OncoSim uses Canadian population and cancer registry data to simulate a representative sample of individuals from birth to death. We modeled four scenarios: no screening in average-risk individuals, screening initiation at age 50, initiation age lowered to 45 in 2022, and initiation age lowered to 40 in 2022. Each includes 32 million simulated participants. In the model, average-risk screening involves biennial FIT, available to all simulated participants regardless of family history with participation of 60% at the first recruitment attempt and 80% for repeat screening. Participants with a family history in all 4 scenarios were eligible for additional screening by colonoscopy every 5 years. Results: In our model, earlier screening yields reduced CRC incidence and mortality with increasing benefit over time. By 2051, screening initiation at age 45 or 40 reduces age-standardized incidence by 3.4% and 4.8% respectively, and age-standardized mortality by 3.3% and 4.6% respectively, compared to initiation at age 50. Screening initiation at age 45 yields 3,848 additional quality-adjusted life-years (QALYs) in 2051 at a cost of $9,350 per QALY gained and a 5% increase in colonoscopies performed. Initiation at age 40 yields 6,255 additional QALYs at $16,350 per QALY gained and a 9% increase in colonoscopies. The difference in screening costs compared to screening from age 50 is consistent year-to-year after 2024. In 2051 screening costs increase by $75mil and $155mil per year with initiation at ages 45 and 40 respectively, while costs of cancer management (including diagnosis, treatment, recurrence, palliative and end of life care) decrease by $42mil and $57mil respectively. Conclusions: Our model predicts that lowering the CRC screening initiation age for average-risk Canadians to 45 or 40 could reduce CRC incidence and mortality. Costs per QALY gained are high in the first few decades but decrease over time. Costs are modest after 30 years of screening compared to other life-preserving interventions such as dialysis. Our results suggest that lowering the screening age in Canada may be warranted, but further investigation is needed to assess capacity for increased colonoscopy demand.
Analysis of plasma angiogenesis factors on the efficacy of first-line (1L) chemotherapy (chemo) combined with biologics in RAS wild-type metastatic colorectal cancer (mCRC): Results from GI-SCREEN CRC Ukit study.
Authors: Yuki Satoshi , Sunakawa Yu , Yamazaki Kentaro , Shirasu Hiromichi , Taniguchi Hiroya , Masuishi Toshiki , Shiozawa Manabu , Bando Hideaki , Nishina Tomohiro , Yasui Hisateru , Ohta Takashi , Takahashi Naoki , Denda Tadamichi , Esaki Taito , Kawakami Hisato , Satake Hironaga , Takashima Atsuo , Abe Yukiko , Nomura Shogo , Yoshino Takayuki 
Published: June 2022

3530 Background: Angiogenesis factors have been reported as prognostic and predictive biomarkers of angiogenesis inhibitors for mCRC (Weickhardt AJ. Br J Cancer 2015. Tabernero J. Ann Oncol 2018). We investigated whether plasma angiogenesis factors could predict the efficacy of biologics combined with chemo in 1L treatment in patients (pts) with RAS wild-type mCRC. Methods: Serial plasma samples were prospectively collected at the time points of pre- and post-treatments in mCRC pts receiving biologics in either 1L or 2nd-line (2L) chemo. From Sep 2017 to Dec 2020, 497 pts were enrolled [1L chemo plus bevacizumab (1L BEV, n=102), 1L chemo plus anti-EGFR antibody (1L aEGFR, n=100), 2L chemo plus bevacizumab (n=100), 2L FOLFIRI plus RAM (n=99), 2L FOLFIRI plus aflibercept (n=85) and other treatment (n=11)]. Total of 17 plasma angiogenesis factors (HGF, PlGF, VEGF-A, VEGF-D, Angiopoietin-2, IFN-γ, IL-6, IL-8, sNeuropilin-1, TSP-2, OPN, sVEGFR1, sVEGFR2, sVEGFR3, sICAM-1, sVCAM-1, and TIMP-1) were analyzed by the multiplex assay with Luminex® technology. Interactions of their pre-treatment measurements with treatment groups on PFS and OS were assessed via Cox proportional hazards model. The strength of interactions was estimated using a propensity score weighting analysis, and the continuous plasma angiogenesis variables were categorized according to the median. The significance level in the interaction was defined as p≤0.1. Results: 133 pts were included in adjusted RAS wild-type 1L cohort (1L BEV: n=33, 1L aEGFR [reference]: n=100). Baseline characteristics of adjusted RAS wild-type 1L cohort were as follows; median age 64 years; male 62.4%; left-sided tumor 88.7%; triplet chemo 15.0%. Propensity-score weighted Cox model for OS showed significant interactions in IL-8 (median 8.03 pg/mL, high: HR 1.738, p=0.0838, Low: HR 0.479, p=0.2624, interaction p=0.0283), sVEGFR-1 (median 1,350 pg/mL, high: HR 0.333, p=0.1770, Low: HR 1.311, p=0.3004, interaction p=0.0777), and sVCAM-1 (median 1,020,000 pg/mL, high: HR 0.100, p=0.0558, Low: HR 1.616, p=0.1765, interaction p=0.0011). In terms of PFS, there were significant interactions in IL-8 (high: HR 1.322, p=0.0418, Low: HR 0.517, p=0.0528, interaction p=0.0752) and sVCAM-1 (high: HR 0.285, p=0.0414, Low: HR 1.200, p=0.7725, interaction p=0.0156). Conclusions: Pre-treatment plasma IL-8 and sVCAM-1 could be predictive biomarkers for efficacy of biologics combined with chemo in 1L treatment of RAS wild-type mCRC. Clinical trial information: UMIN000028616. [Table: see text]
Molecular characteristics of advanced colorectal cancer and multi-hit PIK3CA mutations.
Authors: Cecchini Michael , Sokol Ethan , Vasan Neil , Pavlick Dean C. , Huang Richard S.P. , Pelletier Maureen , Levy Mia Alyce , Pusztai Lajos , Lacy Jill , Eder Joseph Paul , Zhang Janie Yue , Ross Jeffrey S. 
Published: June 2022

3535 Background: Approximately 20% of colorectal cancer (CRC) has an activating mutation in the PIK3CA oncogene. PIK3CA codes for the catalytic subunit of phosphoinositide 3-kinase alpha (PI3Kα), which ultimately activates the AKT and mammalian target of rapamycin (mTOR) pathway. The PI3Kα inhibitor alpelisib has been approved for breast cancer where a single PIK3CA activating mutation is sufficient for response. However, two activating mutations (multi-hit) in the PIK3CA allele substantially increases PI3Kα signaling compared to single hot spot mutations and results in exceptional response to PI3Kα inhibition. We aimed to identify the prevalence of PIK3CA multi-hit mutations in CRC to identify patients potentially susceptible to PI3K inhibitors. Methods: Tissue-based comprehensive genomic profiling (CGP) was performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified, CAP (College of American Pathologists)-accredited laboratory (Foundation Medicine Inc., Cambridge, MA, USA) on all-comers during the course of routine clinical care from 2013-2021. Approval was obtained from the Western Institutional Review Board (Protocol No. 20152817). Hybrid capture was carried out for at least 324 cancer-related genes, including PIK3CA. Results: We identified 48,836 patients with advanced CRC who underwent Foundation Medicine testing and 846 (1.7%) patients with multi-hit PIK3CA mutations. Additional clinical and molecular data was available for 41,154 of these patients of which 710 (1.7%) had multi-hit PIK3CA and 7627 (19%) had any deleterious PIK3CA mutation . The local colon tumor was used for sequencing in 70% of cases and a separate site in 30% of cases. Patients with PIK3CA multi-hit mutations were 53% male with a median age of 60 (interquartile range 50-70). The microsatellite status was available for 697 of 710 patients with multi-hit PIK3CA and 123/697 (18%) were microsatellite instability-high. The Table outlines the genes with cooccurring mutations of >10% prevalence for multi-hit PIK3CA CRC, including the clinically relevant mutations in KRAS (65%) and BRAF (13%). The four most common PIK3CA variants were H1047R (9.8%), E545K (9.2%), E542K (9.0%) and R88Q (7.1%). The most common variant pair was E542K with E545K in 4.7% of multi-hit cases. Conclusions: Double-hit mutations in PIK3CA are seen in 1.7% of advanced CRC patients and may represent a subset of patients that may have enhanced sensitivity to PI3K inhibitors. Given the high prevalence of CRC in the United States and worldwide this represents a clinically meaningful prevalence of multi-hit PIK3CA. Future investigation on the clinical utility of PI3K inhibitors may be warranted in multi-hit PIK3CA CRC.[Table: see text]
Negative hyperselection for mutations associated with anti-EGFR antibody resistance in RAS wildtype metastatic colorectal cancer (mCRC): Evaluation of the PANAMA trial (AIO-KRK-0212, maintenance therapy with 5-FU, folinic acid (FU/FA) with or without panitumumab).
Authors: Kind Andreas Jay , Modest Dominik Paul , Sers Christine , Mamlouk Soulafa , Karthaus Meinolf , Fruehauf Stefan , Graeven Ullrich , Von Weikersthal Ludwig Fischer , Goekkurt Eray , Reinacher-Schick Anke C. , Kasper Stefan , Kurreck Annika , Hoppe Beeke , Held Swantje , Heinemann Volker , Horst David , Jarosch Armin , Stintzing Sebastian , Trarbach Tanja , Stahler Arndt 
Published: June 2022

3536 Background: We evaluated the prognostic and predictive impact of DNA mutations related to anti-EGFR antibody resistance in patients of the PANAMA trial, which compared Panitumumab (Pmab) and FU/FA versus FU/FA maintenance therapy after Pmab-FOLFOX induction therapy in RAS wild-type (wt) mCRC. Methods: Next generation panel sequencing was conducted on 201 of 248 tumors obtained prior to study inclusion from the full analysis set using the Cancer Hotspot Panel v2 on an Illumina MiSeq system. Hyperselection covered mutations of the following genes: KRAS, NRAS, BRAF, HER2, PTEN, AKT1, PIK3CA. Median progression-free (PFS) and overall survival (OS) since start of maintenance were estimated by Kaplan-Meier and Cox-regression (log rank test). Objective response rates (ORR) of maintenance therapy were compared by Chi-square-test. Results: From 201 tumors, 41 (20.4 %) carried at least one mutation: KRAS: 7 (3.5%), BRAF: 23 (11.4%), PTEN: 4 (2.0%), AKT1: 2 (1.0%), PIK3CA: 12 (6.0%), with 6 tumors harboring co-occuring mutations. No mutations were found in NRAS and HER2. Negative hyperselection (wt for all genes) was associated with (numerically) favourable prognosis in terms of PFS (HR 0.79 (95% CI 0.55 – 1.12), p=0.184), OS (HR 0.61 (95% CI 0.40 – 0.95), p=0.028) and ORR (39.4% vs. 29.3%, p=0.279). The benefit of adding Pmab to FU/FA during maintenance was limited to the hyperselection wt subgroup, with significantly longer PFS (9.9 vs. 6.0 months, 0.64 (95% CI 0,46 – 0.90), p = 0.011), numerically longer OS and significantly higher ORR (49.4% vs 26.6%, p=0.009) compared to FU/FA (Table). Conclusions: Mutations related to resistance concerning anti-EGFR antibodies were detected in 41 of 201 (20.4%) of analysed tumors and associated with a worse prognosis compared to hyperselected wt tumors. Negative hyperselection may aid in the identification of patients with relevant benefit from maintenance therapy including Pmab. [Table: see text]
BRAF-mutant metastatic colorectal cancer: Prognostic and predictive value of primary tumor location—A pooled analysis of the AIO studies FIRE-1, CIOX, XELAVIRI, FIRE-3, and VOLFI.
Authors: Alig Annabel Helga Sophie , Heinemann Volker , Stintzing Sebastian , Geissler Michael , von Weikersthal Ludwig , Decker Thomas , Kaiser Florian , Moosmann Nicolas , Heinrich Kathrin , Held Swantje , Holch Julian Walter , Stahler Arndt , Kurreck Annika , Reinacher-Schick Anke C. , Tannapfel Andrea , Klauschen Frederick , Jung Andreas , Giessen-Jung Clemens , Modest Dominik Paul 
Published: June 2022

3576 Background: Primary tumor location (PTL: left vs. right) is an established prognostic marker in metastatic colorectal cancer (mCRC) and has predictive impact for anti-EGFR antibody (mAb) efficacy in patients with RAS ( KRAS and NRAS) wild-type (WT) mCRC. This analysis of five pooled studies evaluates PTL as a prognostic and - concerning anti-EGFR mAb efficacy - predictive marker in BRAF V600E-mutant/ RAS WT and mCRC. Methods: The analysis is based on individual patient data of five pooled 1st-line studies with varying treatment strategies: the pooled population comprises of BRAF V600E-mutant/ RAS WT ( BRAFmt) mCRC with known PTL. For analysis, treatment was stratified into two groups: treated with or without anti-EGFR mAb. Dichotomous variables (overall response rate, ORR; characteristics) were compared by Chi-Square or Fisher’s exact test and time-to event endpoints (progressive-free survival, PFS; overall survival, OS) by Kaplan-Meier method, log rank test and Cox regression. Results: Of 102 patients (pts) with BRAFmt mCRC, 55 pts (54%) presented with right-sided primary tumors (RPT), 47 (46%) presented with left-sided primary tumors (LPT). Pts with RPT were more likely to be female ( p= 0.04). ORR was inferior in RPT compared to LPT (35% vs. 55%; p= 0.04). No difference was seen in PFS (HR 0.8 (95% CI 0.6-1.3; p= 0.32) or OS (HR 0.8; 95% CI 0.8-1.3; p= 0.46). In male pts PTL trended to be associated with longer OS (HR 0.6; 95% CI 0.3-1.0; p= 0.06). 25 pts with RPT (45%) and 21 with LPT (45%) received anti-EGFR mAb. In pts with LPT anti-EGFR mAb based treatment was associated with higher ORR (81% vs. 35%; p< 0.01). No effect was seen in RPT (ORR 35% vs. 36%; p= 0.82). Anti-EGFR mAb treatment resulted in inferior PFS in RPT (HR 2.0; 95% CI 1.1-3.5; p= 0.02) and showed a trend towards improved PFS in LPT (HR 0.6; 95% CI 0.3-1.1; p= 0.11). Pts with RPT had a worse OS when treated with anti-EGFR mAb (HR 1.8; 95% CI 1.0-3.1; p= 0.05), whereas pts with LPT appeared to have a favorable outcome when treated with an anti-EGFR mAb containing regimen (HR 0.4; 95% CI 0.2-0.7; p< 0.01). Conclusions: This exploratory analysis of five studies suggests that PTL has limited prognostic impact in BRAFmt mCRC but might carry predictive information regarding anti-EGFR mAb efficacy in a 1st-line treatment setting. Further prospective studies are needed to validate these results and to grasp the differences in the heterogeneous group of BRAFmt pts. Clinical trial information: FIRE-1 was before mandatory registration, NCT00254137, NCT00433927, NCT01249638, NCT01328171.
Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer (mCRC).
Authors: Arai Hiroyuki , Yang Yan , Millstein Joshua , Denda Tadamichi , Ou Fang-Shu , Innocenti Federico , Takeda Hiroyuki , Doi Ayako , Horie Yoshiki , Umemoto Kumiko , Izawa Naoki , Wang Jingyuan , Battaglin Francesca , Kawanishi Natsuko , Jayachandran Priya , Soni Shivani , Wu Zhang , Venook Alan P. , Sunakawa Yu , Lenz Heinz-Josef 
Published: June 2022

3586 Background: HSP90 mediated chaperoning is a well-conserved biological mechanism for stabilization and activation of kinases. More than 60% of human kinases including VEGFR, CRAF, CSF1R, and FGFR are target of HSP90 (client kinases), whereas EGFR is non-client. CDC37 is a specific co-chaperone determining selectivity of client kinases recognized by HSP90. We hypothesized that gene expression levels of CDC37 have predictive values for anti-angiogenic therapies in mCRC. Methods: The subjects of this study were mCRC patients treated with regorafenib (REGO, Japanese retrospective cohort) and those treated with bevacizumab (BEV) or cetuximab (CET) in combination with first-line chemotherapy (CALGB/SWOG 80405 trial cohort). CDC37 expression levels were measured using RNA isolated from FFPE samples by nCounter gene expression profiling (Nanostring) and HiSeq 2500 (Illumina) in the Japanese and CALGB/SWOG 80405 cohorts, respectively. Overall survival (OS) and progression-free survival (PFS) were compared between patients with high CDC37 expression ( CDC37-H) and those with low expression ( CDC37-L), grouped by median cutoff value in each cohort. Results: In total, 484 patients were included (50 treated with REGO, 227 treated with BEV, and 207 treated with CET). In REGO-treated patients, CDC37-H showed significantly better OS (median 11.3 vs 6.0 months, adjusted hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.11-0.54, p <0.01) and PFS (median 3.5 vs 1.9 months, adjusted HR 0.51, 95% CI 0.28-0.94, p = 0.03) compared to CDC37-L. Similarly, in BEV-treated patients, CDC37-H showed significantly better PFS (median 13.5 vs 9.6 months, adjusted HR 0.59, 95% CI 0.43-0.79, p <0.01) and numerically better OS (median 34.1 vs 29.4 months, adjusted HR 0.81, 95% CI 0.60-1.11, p = 0.20) compared to CDC37-L. However, in CET-treated patients, CDC37-H and CDC37-L patients showed similar OS (median 33.7 vs 26.1 months, adjusted HR 1.00, 95% CI 0.73-1.38, p = 0.98) and PFS (median 11.3 vs 11.0 months, adjusted HR 1.08, 95% CI 0.81-1.45, p = 0.60). Significant interaction was observed between CDC37 expression and treatment in terms of PFS in the CALGB/SWOG 80405 cohort ( p = 0.01). Conclusions: Our results suggest patients with CDC37-dependent ( CDC37-H) tumors may derive more benefit from REGO and BEV both of which target HSP90 client kinases or signaling pathways, but not from CET which target HSP90 non-client kinase. Further validation studies are warranted to develop a novel personalized approach for targeted therapies based on CDC37 expression in mCRC patients. Support: U10CA180821, U10CA180888; Pfizer, Genentech; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT00265850.
Using cell-free circulating tumor DNA (cfDNA) to identify guideline-relevant biomarkers for therapy selection in 14,000 patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Kasi Pashtoon Murtaza , Tan Benjamin R. , Nguyen Timmy Q. , Starr Jason S. , Bucheit Leslie A. , Drusbosky Leylah , Weipert Caroline 
Published: June 2022

3601 Background: Two cfDNA assays are FDA-approved for use in advanced cancer pts across solid tumors. While several NCCN guidelines recommend cfDNA as a valid and useful method for molecular testing, the utility varies by cancer type. Despite the growing number of molecular alterations pertinent to first-line treatment in mCRC, current guidelines offer little guidance on the use of cfDNA in mCRC. Here we assess the ability of cfDNA to detect guideline-relevant actionable biomarkers informative for first-line therapy selection and beyond in patients with mCRC. Methods: We queried consecutive samples from advanced cancer pts with a diagnosis of CRC who underwent testing via a commercially available cfDNA assay (Guardant360) from September 2018 to January 2022. Validation and content of this assay has been previously described. To enrich for less heavily treated pts, we limited analysis to those whose first cfDNA test was done during the study period and only included the pt’s first test. The maximum variant allele fraction (maxVAF) for each test was used as a proxy for tumor shed and was compared between cancers with a Mann-Whitney test. The frequency of suspected germline alterations was assessed only in pts who received testing via a panel version with expanded mismatch repair (MMR) gene coverage. Tissue frequencies for select biomarkers were obtained from the MSK-IMPACT Clinical Sequencing Cohort in cBioPortal. Results: In total, 14,345 pts with mCRC received their first cfDNA test during the study period, with 92% of pts (13,190) having >1 cfDNA alteration detected. Median age was 62 and 44% of pts were female. The frequencies of key biomarkers are listed in Table 1. The median maxVAF was 5.6%, compared to 2.5% and 1.8% for pts with advanced gastric and NSCLC, respectively (p = < 0.0001 for both). The average turnaround time (TAT) for tests was 7 calendar days. Conclusions: cfDNA results from pts with mCRC demonstrated detection of biomarkers essential to first-line treatment decisions at a frequency comparable to what has been reported via tissue genotyping. mCRC pts had significantly higher tumor shed compared to other cancer types with guidelines that recommend cfDNA as an option for molecular testing, suggesting a potential gap in coverage. Tissue availability in mCRC does not guarantee comprehensive testing is completed quickly (compared to the 7-day TAT seen for cfDNA here), making it an attractive alternative strategy for first-line therapy selection in mCRC. [Table: see text]
Computerized features of tumor diversity on pre-chemoradiation MRI are associated with pathologic complete response in rectal cancers: A multi-institutional study.
Authors: Singh Sneha , DeSilvio Thomas , Purysko Andrei , Paspulati Raj M , Friedman Ken , Liska David , Stein Sharon , Krishnamurthi Smitha S. , Viswanath Satish Easwar 
Published: June 2022

3608 Background: Neoadjuvant chemoradiotherapy (nCRT) prior to total mesorectal excision (TME) reduces the risk of local recurrence and is a standard-of-care treatment for patients with locally advanced rectal cancer. Previous studies have indicated up to 30% of patients who undergo TME demonstrate a pathologic complete response (pCR) to nCRT [2], but current serum markers and clinical evaluation have limited utility in predicting benefit from nCRT. In this study, we evaluated if tumor diversity features on baseline pre-treatment MRI were predictive of pCR in rectal cancers. Methods: Pre-nCRT T2-weighted MRIs from 126 patients who later underwent nCRT and TME (without neoadjuvant chemotherapy) were retrospectively collected from 2 institutions. 69 patients (14 pCR, Institution 1) formed the training cohort D1, while 57 patients (10 pCR, Institution 2) formed the independent holdout validation cohort D2. Response groupings were based on AJCC tumor regression grade (TRG) evaluation where pCR corresponded to no residual tumor cells in excised histopathologic specimens after nCRT (i.e. TRG0) and non/partial response otherwise (TRG1-3). Computerized tumor diversity algorithms extracted measurements of fractal dimensions, surface topology, and persistent homology from annotated tumor regions on MRI to quantify visual patterns, spatial geometry, and prolonged structural similarity. Top tumor diversity features identified via Wilcoxon rank-sum testing were used to train a random forest (RF) machine learning classifier to predict the likelihood of pCR using D1 and then independently evaluated for predicting pCR in D2. Results: Machine learning analysis identified 5 tumor diversity measurements associated with pCR on pre-nCRT MRI. The associated RF classifier for pCR achieved an AUC of 0.98 (95% CI, 0.9808-0.9949) in D1 and an AUC of 0.9117 in hold-out validation on D2. This corresponded to predicting 100% of non/partial response prior to nCRT as well as 80% of pCR patients via tumor diversity features on pre-nCRT MRI. Conclusions: Computerized tumor diversity features on pre-nCRT MRI can predict pathologic complete response to nCRT in rectal cancers. These findings need to be validated in larger multi-institutional cohorts to establish independent predictive utility of MRI-based biomarkers, which could aid in the selection of patients who will see maximal response from neoadjuvant therapy and avoid unnecessary surgery.