bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of clinical RNA-sequencing in the detection of actionable fusions compared to DNA-sequencing alone.
Authors: Michuda Jackson , Park Ben Ho , Cummings Amy Lauren , Devarakonda Siddhartha , O'Neil Bert , Islam Sumaiya , Parsons Jerod , Ben-Shachar Rotem , Breschi Alessandra , Blackwell Kimberly L. , Chen James Lin , Dudley Joel , Stumpe Martin , Guinney Justin , Cohen Ezra E.W.
Published: June 2022

3077

Background: While targeted DNA-seq can detect clinically actionable fusions in tumor tissue samples, technical and analytical challenges may give rise to false negatives. RNA-based, whole-exome sequencing provides a complementary method for fusion detection, and may improve the identification of actionable variants. In this study, we quantify this benefit using a large, real-world clinical dataset to assess actionable fusions detected from RNA in conjunction with DNA profiling. Methods: Using the Tempus Research Database, we retrospectively analyzed a de-identified dataset of ̃80K samples (77.4K patients) profiled with the Tempus xT assay (both DNA-seq with fusion detection in 21 genes and whole exome capture RNA-seq). Only patients that had successful RNA- and DNA-seq were included. Fusions were detected using the Tempus bioinformatic and clinical workflow. Candidate fusions were filtered based on read support thresholds, fusion annotation ( i.e., breakpoints, reading frame, conserved domains), and manual review. OncoKB was used to select fusion alterations in levels 1 and 2 and to identify those indication-matched to targeted therapies. Results: We identified 2118 level 1 and 2 fusion events across 1945 patients across 20 different cancer types. Most fusions were observed in non-small cell lung cancer (NSCLC) (25%) and biliary cancer (9%) samples. Of the 2118 fusion events, 29.1% (616) were detected only through RNA-seq while 4.8% (101) of the events were identifiable only through DNA-seq. Notably, 69.4% of fusions in low-grade glioma and 58.2% in sarcomas were detected only by RNA-seq. When evaluating specific gene fusion events, RNA-seq consistently improved the detection of fusions compared to DNA-seq alone (Table) across all cancer types. A total of 1106 fusions were classified as targetable by OncoKB indication-matched therapies with 19% (214) of these identifiable through RNA-seq alone, 5% (54) by DNA-seq alone, and 76% (838) identifiable through RNA- and DNA-seq. Overall, fusions identified through RNA-seq alone led to a 24% increase in the number of patients who were eligible to receive matched therapies (214 / 892). This included imatinib for patients with CML/BLCL (69.8%), crizotinib for NSCLC (40.3%) and entrectinib for NTRK and ROS1 fusions (32.5%). Conclusions: The addition of RNA-seq to DNA-seq significantly increased the detection of fusion events and ability to match patients to targeted therapies. Results support consideration of combined RNA-DNA-seq for standard-of-care fusion calling. [Table: see text]
Comprehensive genomic profiling to identify gene alterations in DNA repair pathway across solid tumors.
Authors: McDonnell Kevin , Basu Gargi D. , Hoag Jess W. , Hall David W. , Alyaqoub Fadel S. , Dombrowski Susan M. , Noel Pawan , Szelinger Szabolcs , Udhane Sameer S. , Wang Min , LoBello Janine R. , Thakkar Snehal Govind , Baehner Frederick L. , Hong Christine , Park Wai , Idos Gregory , Gray Stacy W. , Gruber Stephen B.
Published: June 2022

3124

Background: Deleterious events in DNA damage response (DDR) are hallmarks of cancer associated with sensitivity to PARP inhibitors (PARPi) and immune checkpoint inhibitors (CPI). This study investigated DDR pathway alterations across solid tumors. Methods: Samples were sequenced with the Oncomap ExTra assay using tumor-normal paired whole-exome DNA sequencing to detect single base substitutions, indels, and copy number alterations that were clinically actionable, defined as associated with FDA approved drugs or clinical trial enrollment. Here, we report the frequency of MSI-high and TMB-high (>10 mutations/Mb), and clinically-actionable alterations for the following 49 DDR genes: ARID1A, ATM, ATR, ATRX, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CDK12, CHEK1/2, EPCAM, ERCC1/2/3/4/5, FANCA/C/D2/E/F/G/I/L/M, MLH1, MRE11A, MSH2/6, MUTYH, NBN, PALB2, PMS2, PPP2R2A, PTEN, RAD21/50/51/51B/51C/51D/52/54L, XRCC1/2/3. Results: Of the 6055 patient samples profiled, 1633 (27.0%) had clinically actionable alterations in DDR genes; DDR alterations varied from 0-64.3% across tumor types. For the 5657 samples with TMB/MSI data, 429 (7.6%) had high TMB and 193 (3.4%) were MSI-high; MSI-high samples were usually TMB-high (n = 180; 93.2%). The percent of cancers that were TMB-high or MSI-high varied from 0-64.8% and 0-20.8% respectively. Actionable BRCA1/2 gene alterations were present in 319 patients (5.3%, range 0-15.3%). Three cancers (biliary, brain and liver) had BRCA1/2 alterations in less than 2% of patients but across the 49 DDR genes alterations were present in more than 20% of patients, representing a greater than 10-fold difference. Across solid tumors, this analysis identifies a group of 1314 patients (21.7%) who harbor a DDR gene alteration other than BRCA1/2. Conclusions: Defective DNA repair as detected by deleterious alterations in DDR genes along with TMB/MSI status has the potential to guide clinicians to FDA-approved therapy or clinical trial enrollment in a large percentage of patients across solid tumor types.[Table: see text]
Molecular and immune landscape of FH-mutated cancers.
Authors: Al-Share Bayan A , Wu Sharon , Alloghbi Abdurahman , Alkassis Samer , Guastella Anthony , Helmstetter Anthony , Nabhan Chadi , Nazha Bassel , Barata Pedro C. , Ryan Charles J. , McKay Rana R. , Heath Elisabeth I.
Published: June 2022

3125

Background: Fumarate Hydratase (FH) encodes an essential enzyme in the TCA cycle. Inactivating germline mutations in FH lead to hereditary leiomyomatosis and renal cell cancer syndrome with risk of development of certain cancers. Sporadic FH mutations have been described in different cancers but implications of somatic mutations on cancer outcomes and survival are not well described. Here, we characterize the molecular landscape of FH-mutant cancers. Methods: Tumors analyzed using NGS (NextSeq, 592 genes; NovaSeq, WES), IHC, and WTS (NovaSeq) (Caris Life Sciences, Phoenix, AZ). PD-L1 tested by 22c3, 28-8 (Agilent) and SP-142 (Spring Biosciences) IHC (>1%). MSI tested by FA, IHC, and NGS. TMB measured by totaling somatic mutations per tumor (TMB-h > 10 mutations/MB). Real-world overall survival was extracted from insurance claims data and calculated from first treatment to last contact using K-M survival curves for molecularly defined cohorts. Statistical significance was determined using chi-square and Wilcoxon rank-sum test, adjusted for multiple comparisons (q<0.05). Results: 3239 FH mutations were seen in 45 tumor types in 3149 FH-mutated tumors. NSCLC, colorectal and endometrial cancers harbored the most mutations. There were 839 pathogenic (P) or likely pathogenic (LP) and 2400 variants of unknown significance (VUS). Some tumors had multiple mutations. The most common mutations: R233H (P; 37), K477dup (LP; 555), and A41V (VUS; 70). VUS had increased TMB-H (40.4% vs 29.8%, q=0.004) and CREBBP mutations (5.1% vs 1.6%, q=0.012) compared to P+LP. A41V-mt tumors had significantly lower TMB-H than other VUS (8.8% vs 41.5%, q=0.002) and lower MSI-H (3.13% vs 3.69% vs 29.4%, q=0.003) and DICER1, PRKDC, FBXW7 mutations (q<0.05) compared to K477dup and R233. The A41V-mt patients had worse survival compared to patients with P+LP (HR: 1.4, 95% CI: 1.0-2.0, p = 0.049) and a trend toward worse survival compared to K477dup and R233H. In patients treated with chemotherapy, A41 was associated with worse survival compared to P+LP (HR: 4.6, 95% CI: 2.0-10.3, p<0.0001) and compared to K477dup and R233 (p<0.01). There was a trend towards worse survival after IO of A41-mt compared to P+LP (HR: 1.99, 95% CI: 0.88-4.5, p = 0.093). Conclusions: FH alterations are found in multiple cancers. A41V was the most common VUS mutation and is associated with a distinct molecular profile compared to K477dup-mt and R233-mt tumors; it was associated with worse survival in all-comers and after chemotherapy compared to P+LP mutations. This highlights the significance of this mutation and the need for further investigation into how this specific and other FH mutations contribute to cancer progression and treatment outcomes.
Molecular correlates of MAEA expression in colorectal cancer (CRC).
Authors: Soni Shivani , Battaglin Francesca , Baca Yasmine , Xiu Joanne , Brodskiy Pavel , Lo Jae Ho , Algaze Sandra , Jayachandran Priya , Arai Hiroyuki , Zhang Wu , Weinberg Benjamin Adam , Lou Emil , Gulhati Pat , Khushman Mohd , Shields Anthony Frank , Goldberg Richard M. , Marshall John , Korn Wolfgang Michael , Lenz Heinz-Josef
Published: June 2022

3128

Background: Macrophage Erythroblast Attacher (MAEA) plays an important role in actin cytoskeleton rearrangement in macrophages and erythroid cells. We previously reported that MAEA suppresses migration, invasion and enhances chemosensitivity in CRC cell lines. Here we aimed to characterize the molecular features associated with MAEA gene expression in CRC. Methods: 14416 CRC were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes or WES) and RNA (WTS). Top quartile transcripts per million (TPM) for MAEA expression were considered high (Q4) while bottom quartile low (Q1). Consensus molecular subtypes (CMS) were assessed using RNAseq. Cell infiltration (CI) in the tumor microenvironment (TME) was estimated by QuantiSEQ. X2 and Fisher-Exact tests were used and significance was determined as P-value adjusted for multiple comparisons ( Q < 0.05). Results: MAEA expression was highest in rectal tumors (13.6 median TPM) followed by transverse and right-sided tumors (13.0 and 12.8, respectively) and lowest in left-sided tumors (12.5). Overall, MAEA TPM were associated with higher tumor mutational burden (≥ 10 Mut/Mb) (11.8% vs. 8.2%) and dMMR/MSI-H (8.7% vs. 5.1%) ( Q < 0.0001); however, the association with TMB was not observed in MSS tumors. In the MSS cohort, MAEA expression was the highest in CMS4 (14.9 median TPM) followed by CMS1 (12.5), CMS2 (11.9), and the lowest in CMS3 (10.3, all intergroup Q < 0.05). MAEA high was associated with lower mutation rates of APC and amplification of FLT1/ FLT3 while higher mutation rates of ASXL1, KMT2A/C/D, SMARCA4, FBXW7, PTEN, RNF43, BRCA2, HNF1A in the overall cohort ( Q < 0.05). In the MSS cohort, FBXW7 mutation significance with MAEA high expression held true ( Q < 0.05) while MAEA high expression trended to associate with higher mutation rates of KMT2D, SMARCA4, PTEN, BRCA2 mutations, and a lower frequency of FLT1/ FLT3 CNA ( P < 0.05 but Q > 0.05). High MAEA was associated with higher immune CI in the TME, including B cells, macrophages (M1 and M2), neutrophils, NK cells, Tregs, CD4+ T cells and myeloid dendritic cells both in the overall cohort and in MSS tumors (fold change: 1.11-1.33, all Q < 0.001). Conclusions: Our data show a strong association between MAEA gene expression and distinct molecular features (including CMS and immune biomarkers) and TME cell infiltration in CRC. These findings suggest that targeting MAEA may have relevant clinical applications in selected CRC subgroups and MAEA may be an important player in determining the composition of the TME.
Rapid access to biomarker data in a community setting: Integration of next-generation sequencing into routine pathologic workflow.
Authors: Perdrizet Kirstin , Cheema Parneet Kaur , Beharry Andrea , Diep Joanne , Iafolla Marco , Raskin William , Dudani Shaan , Brett Mary Anne , Starova Blerta , Olsen Brian , Sheffield Brandon
Published: June 2022

3143

Background: Biomarker data in the form of next generation sequencing (NGS) are critical to the delivery of precision cancer care. Onsite testing is often limited to large academic centers, requiring smaller community centers to rely on samples send outs. Turnaround time for biomarkers can be lengthy and can adversely affect the delivery of optimal therapy in many tumor types. This study aims to evaluate the feasibility of rapidly delivered comprehensive NGS in a community center using a novel workflow in the laboratory by integrating NGS into the routine immunohistochemistry (IHC) service. Methods: An automated NGS workflow utilizing the Genexus integrated sequencer with the Oncomine precision assay GX (OPA, Thermofisher Scientific), was validated for clinical use and integrated into the routine diagnostic IHC service. During the study period (Oct 2020 – Oct 2021), NGS biomarker data was generated and reported alongside IHC biomarkers where applicable. A retrospective chart review was performed to assess the early experience and performance characteristics of this novel approach to biomarker testing. Results: A total of 578 solid tumor samples underwent genomic profiling. Median turnaround time for biomarker results was 3 business days (IQR 2-5). The majority (n = 481, 83%) of cases were resulted in fewer than 5 business days. Tumor types included lung cancer (n = 310, 54%), melanoma (n = 97, 17%), and colorectal cancer (n = 68, 12%). Specimen types included surgical resections (n = 104, 18%), core biopsies (n = 411, 71%), and cytology specimens (n = 63, 11%). NGS testing detected key driver alterations at expected prevalence rates in respective tumor types; lung EGFR (16%), ALK (3%), RET (1%), melanoma BRAF (43%), colorectal RAS/RAFwild-type (33%), among others. Conclusions: This is the first study demonstrating the clinical feasibility and turnaround time statistics of automated comprehensive NGS performed and interpreted in parallel with diagnostic histopathology and immunohistochemistry in a community setting. This novel approach of integrating biomarkers, IHC, and morphology offers rapid turnaround by removing the need for outsourcing biomarker data. This model could be adopted by other community centers to improve rapid access to biomarker data and therapeutic decision making.
Nivolumab (NIVO) ± ipilimumab (IPI) in patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Five-year follow-up from CheckMate 142.
Authors: Overman Michael J. , Lenz Heinz-Josef , Andre Thierry , Aglietta Massimo , Wong Mark Ka , Luppi Gabriele , Van Cutsem Eric , McDermott Raymond S. , Hendlisz Alain , Cardin Dana Backlund , Morse Michael , Neyns Bart , Hill Andrew Graham , Limon M. Luisa , Garcia-Alfonso Pilar , Krishnamurthy Anuradha , Chen Franklin , Abdullaev Sandzhar , Soleymani Samira , Lonardi Sara
Published: June 2022

3510

Background: NIVO ± IPI is approved in previously treated pts with MSI-H/dMMR mCRC in the US, EU, and Japan, based on findings from the phase 2 CheckMate 142 study (NCT02060188). NCCN guidelines include NIVO + IPI as an initial therapy option for pts with MSI-H/dMMR mCRC. Results from a ~5-year follow-up from CheckMate 142 cohorts 1–3 (C1–3) are reported here. Methods: In this non-randomized, multicohort study, pts with MSI-H/dMMR mCRC were treated as follows: C1 (2L+; NIVO 3 mg/kg Q2W), C2 (2L+; NIVO 3 mg/kg + IPI 1 mg/kg Q3W [4 doses], followed by NIVO 3 mg/kg Q2W) and C3 (1L; NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W), until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by investigator assessment (INV) per RECIST v1.1. Other key endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), all by INV and blinded independent central review; overall survival (OS), and safety. Results: In C1 (N = 74), C2 (N = 119), and C3 (N = 45), median (range) follow-up (time from first dose to data cutoff) was 70.0 (66.2–88.7), 64.0 (60.0–75.8), and 52.4 (47.6–57.1) months (mo), respectively. ORR (95% CI) by INV was 39% (28–51), 65% (55–73), and 71% (56–84; Table) and progressive disease (PD) rates were 26%, 12%, and 16% in C1, C2, and C3, respectively. Median DOR was not reached in the 3 cohorts. The 48-mo PFS rates were 36%, 54%, and 51% and 48-mo OS rates were 49%, 71%, and 72% in C1, C2, and C3, respectively (Table). PFS and OS rates with up to 60 mo of follow-up will be presented. Safety data are shown in the table. Conclusions: With extended follow-up of ~5 years, NIVO ± IPI continued to demonstrate durable OS and PFS benefit, with no new safety signals. These updated data further support current treatment recommendations for 2L+ NIVO ± IPI and 1L NIVO + IPI for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]
Mucinous adenocarcinoma of the anal canal: Clinical characteristics and outcomes of 767 patients from National Cancer Database.
Authors: Melamed Sam , Lee Jin Sun , Onyshchenko Mykola
Published: June 2022

3522

Background: Mucinous adenocarcinoma of the anal canal (MAAC) is a relatively rare disease, constituting less than 10% of anal cancers. It carries a relatively poor 5-year survival rate of between 50-60%. MAAC rarity and proximity to rectal mucosa can present a diagnostic challenge as it can be misidentified as adenocarcinoma of the lower rectum. Because of its rarity, the bulk of knowledge of the disease is derived from individual case studies or small institutional reviews. Thus, there remains no clear standard of treatment for AAC. While abdominal perineal resection is the main management approach, the role of systemic therapy and radiation on clinical outcomes remains ill-defined. The lack of national guidelines, variability in institutional approaches and in access to tertiary cancer centers may contribute to differences in patient outcomes and raise the question of healthcare disparities. In this study, we analyzed the data from 767 patients with MAAC from the National Cancer Database (NCDB). Methods: We obtained clinicopathological demographic, socioeconomic data and survival outcomes from 767 patients with MAAC that were registered in the NCDB from 2004 to 2017. The treatment patterns and prognostic factors were analyzed. Results: The majority of patients, 85%, were older than 50. White patients comprised 75.6%, Black 18.8% and Asians 3.3%. Only 3.9% were Hispanics. Among 647 patients who had survival data, the majority received the following therapies: 311 received surgery and chemoradiation, 131 only surgery and 131 only chemoradiation. White and Black patients had similar survival odds, whereas Asian patients had significantly higher overall survival (OS) (HR 0.42). Patients treated at academic facilities had significantly better OS than patients treated at non-academic facilities (HR 1.41-1.57), and patients with private insurance (HR 0.37) had significantly better survival when compared to patients with other insurance types. Patients with only Stage II exhibited significant survival differences when given both surgery and chemoradiation, compared being given either treatment modality alone (HR 0.56); interestingly, male patients in this group did not benefit from adding chemoradiation to surgery while female patients did (p = 0.1, p = 0.011). Conclusions: Surgical resection seems to be the most important treatment modality in MACC, while for patients with stage II addition of chemoradiation statistically significantly improves survival. Access to tertiary cancer centers and therapy costs contribute to differences in survival outcomes, which brings the question of healthcare disparities and the need for national guidelines for MACC management.
Effect of primary tumor sidedness on the association of tumor-infiltrating lymphocytes with survival of patients with stage III colon cancer (NCCTG N0147) [alliance].
Authors: Saberzadeh Ardestani Bahar , Foster Nathan R. , Lee Hee Eun , Shi Qian , Alberts Steven R , Smyrk Thomas C. , Sinicrope Frank A.
Published: June 2022

3525

Background: Tumor-infiltrating lymphocytes (TILs) are significantly associated with clinical outcomes in patients with colon cancer. However, the potential for a differential effect of TILs on prognosis based on primary tumor sidedness has not been studied. We determined the interaction between TILs and tumor sidedness in relationship to disease-free survival (DFS). Methods: We analyzed data on TIL densities by primary tumor sidedness in 1532 stage III colon carcinomas from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy (NCCTG N0147). TIL densities were dichotomized as low or high (≤3 /HPF) based on an optimized cutoff previously identified for DFS in this cohort. Right-sided tumors were defined as proximal to the splenic flexure. Analysis of TILs and sidedness with DFS were examined using Kaplan-Meier methodology and multivariable Cox regression. Results: Overall, tumors with high vs low TILs had the best DFS [HRadj: 0.58 (95%CI: 0.45-0.74); Padj <0.0001]. The association of TIL densities with 5-yr DFS differed significantly by primary tumor sidedness ( Pinteraction (adj) = 0.045). Among right-sided tumors, high vs low TILs were significantly associated with improved DFS ( Padj <0.0001)[Table]. Among left-sided tumors, however, DFS did not differ significantly for high vs low TILs ( Padj =0.173)[Table]. Similar results for TILs and DFS by sidedness were found for pMMR cancers. We then analyzed our data in low risk (T1-3, N1) and high risk (T4 and/or N2) tumors. Among low risk tumors, high vs low TILs was significantly associated with improved 5-yr DFS only in right-sided tumors ( Padj =0.006) [Table]. Among high risk tumors, high vs low TILs were significantly associated with better DFS in both right-sided ( Padj<0.001) and left-sided ( Padj =0.024) tumors. Conclusions: Overall, tumors with high TIL densities had significantly better DFS in right-sided but not left-sided cancers. Among low risk patients, the association of high TILs with better DFS was limited to right-sided tumors. These findings suggest that TILs should be interpreted by sidedness for prognostication. ClinicalTrials.gov Identifier: NCT00079274 . [Table: see text]
A secondary data analysis of colorectal cancer screening among males assigned at birth: Differences by sexual orientation and race/ethnicity.
Authors: Xie Hui , Li Yannan , Le Haoxin , Wang Qian , Theodoropoulos Nicholas , Wen Chi
Published: June 2022

3529

Background: We have limited information on CRC screening disparities in people of color (POC) with sexual minority identity. Methods: We analyzed the Behavioral Risk Factor Surveillance Survey (BRFSS) data of males assigned at birth age 50-75 years for up-to-date CRC screening. Descriptive analyses in demographics, socioeconomics, healthy behaviors, and CRC screening were conducted by race/ethnicity, followed by multivariable regressions to identify predictors of CRC screening stratified by race/ethnicity. Results: About 67.70% of eligible males reported having an up-to-date CRC screening that met the USPSTF guideline, with the highest rate among gay men (74.92%) and the lowest among bisexual men (65.35%; p = 0.0024). Non-Hispanic Whites had the higher rates of receiving CRC screening across all groups (p < 0.010). In the adjusted multivariable logistic models for NH-White males, gay men (1.52, 95% CI: 1.20-1.91), non-current smokers (1.56, 95% CI: 1.44-1.69), being overweight/obese (1.15, 95%CI: 1.07-1.23), and being physically active (1.08, 95%CI: 1.00-1.16) had greater odds of having CRC screening. Similar patterns were not found in Hispanic and non-Hispanic Black males. Gay men (3.88, 95% CI: 1.51-9.98) had greater odds of CRC screening in Hispanics, whereas being a non-current smoker (1.42, 95%CI: 1.13-1.79) was a significant factor in NH-Blacks. Health insurance coverage was a significant factor across all racial/ethnic groups. Conclusions: CRC screening disparities were most pronounced among racial/ethnic minority males. Future work on developing tailored CRC screening programs for racial/ethnic subgroups using an intersectional framework is warranted to elucidate observed heterogeneity across race/ethnicity and sexual orientation.
Survival outcomes following colorectal cancer surgery in low- and middle-income countries: A systematic review.
Authors: Diehl Tom M. , Khan Adel H. , Mughal Nabiha Akhlaq , Schroeder Daniel T. , Pourdashti Sheida , Christensen Leslie , Khan Sadaf , Zafar Syed Nabeel
Published: June 2022

3544

Background: Colorectal cancer (CRC) is a surgical disease that ranks among leading causes of global deaths, but little is known about survival outcomes following CRC surgery in low- and middle-income countries (LMICs). In this study, we sought to review all published literature on long-term outcomes following CRC resections in LMICs. Methods: We completed a systematic review of original research articles presenting survival outcomes after CRC resection with curative intent in LMICs. Databases searched included PubMed, Web of Science, Embase, and Global Index Medicus. Country income groupings were determined by 2020 World Bank data. We excluded articles involving pediatric populations (<18 years), non-primary colorectal cancers, benign disease, and endoscopic/transanal resection only. Articles published before 2005 or without English full text were also excluded. Abstracts and full texts were assessed for eligibility by two independent reviewers; conflicts were resolved by a third reviewer. Data from China dominated the published literature and were excluded from final analysis. Survival data were extracted for 5-year disease free survival (DFS) and overall survival (OS). Results: Our search returned 29,134 articles. After automated and manual deduplication, 18,849 abstracts were assessed for eligibility. Following abstract and full-text review, 583 articles met the inclusion criteria for the study. Table 1 shows the most-represented countries and their associated income levels. In total, 1/27 low-income countries, 11/55 lower-middle income countries, and 16/55 upper-middle income countries were represented, which accounted for 0.3%, 12.9% and 86.8% of all included articles, respectively. The majority of articles were from China (379/583; 65%). Excluding data from China, 5-year disease DFS and OS varied significantly across included studies: Stage I = 64-100% DFS and 70-100% OS; Stage II = 75-94% DFS and 50-94% OS; Stage III = 34-87% DFS and 20-93% OS; Stages I-III combined = 53-86% DFS and 29-97% OS. Conclusions: There is a dearth of data on long-term outcomes following CRC operations in LMICs, especially among low-income countries. OS ranges markedly by country income group highlighting global disparities in cancer care. Our review emphasizes a dire need for cancer research capacity building in LMICs. [Table: see text]
Impact of consensus molecular subtyping (CMS) on survival in the CO.26 trial of durvalumab plus tremelimumab versus best supportive care (BSC) in metastatic colorectal cancer (mCRC).
Authors: Loree Jonathan M. , Topham James T. , Kennecke Hagen Fritz , Feilotter Harriet , Lee Young S , Virk Shakeel , Kopetz Scott , Duose Dzifa Yawa , Manyam Ganiraju C. , Morris Jeffrey S , Maru Dipen M. , Renouf Daniel , Jonker Derek J. , Tu Dongsheng , O'Callaghan Christopher J. , Chen Eric Xueyu
Published: June 2022

3551

Background: CO.26 was a phase 2 trial (2-sided α=0.1 and 80% power) that randomized 180 patients with refractory mCRC 2:1 to durvalumab + tremelimumab vs BSC with improved overall survival (OS) (HR 0.73, 90%CI 0.55-0.97, P=0.07). A Nanostring assay validated for use with FFPE was used to determine CMS for correlation with outcome. Methods: Archival FFPE from 163/180 (91%) of patients (pts) underwent RNA extraction and CMS subtyping. Cox proportional hazard models evaluated the prognostic and predictive impact of CMS on overall survival. Results: CMS distribution was skewed towards CMS4 (76%), with lower prevalence of CMS1 (2%), CMS2 (16%) and CMS3 (2%). There were 7/163 cases of indeterminate CMS (4%). Subgroup analysis was restricted to CMS2 and CMS4 based on sample size. With BSC alone, CMS2 showed trends to worse OS compared to all other patients pooled (HR 1.93, 90% CI 1.03-3.61, P=0.085), while CMS4 did not (HR 0.86, 90% CI 0.50-1.48, P=0.64). OS but not progression free survival (PFS) was improved with durvalumab + tremelimumab in the overall population. OS was improved with durvalumab + tremelimumab among patients with CMS2 tumors (HR 0.39, 90% CI 0.19-0.82, P=0.035) but not in patients with CMS4 tumors (HR 0.73, 90% CI 0.52-1.02, P=0.12) compared to BSC. Neither CMS2 (P-interaction=0.37) nor CMS4 (P-interaction=0.91) were predictive of OS benefit from durvalumab + tremelimumab compared to BSC. Disease control rate (DCR) trended to being better among CMS4 (24/85) than CMS2 cancers (1/15, OR 5.51, 90% CI 1.10-29.88, P=0.11) or CMS4 vs all non CMS4 cancers (1/21, OR 7.87, 90% CI 1.65-41.98, P=0.023) for patients on durvalumab + tremelimumab. PFS was not improved with durvalumab + tremelimumab in CMS2 (P=0.19) or CMS4 (P=0.29) cancers relative to BSC. Conclusions: In this trial of refractory colorectal cancer, we saw a shift in CMS subtype with more CMS4 than expected. Compared to CMS4, CMS2 showed stronger signals towards improved OS with durvalumab + tremelimumab but had a lower disease control rate. Differences in immune signaling by CMS may be important determinants of which component of immune regulation needs to be targeted in mCRC to improve outcomes. Clinical trial information: NCT02870920. [Table: see text]
Impact of age and gender on the efficacy and safety of panitumumab plus fluorouracil and folinic acid versus fluorouracil and folinic acid alone as maintenance therapy in RAS WT metastatic colorectal cancer (mCRC): Subgroup analysis of the PANAMA-study (AIO-KRK-0212).
Authors: Heinrich Kathrin , Karthaus Meinolf , Fruehauf Stefan , Graeven Ullrich , Müller Lothar , Koenig Alexander , von Weikersthal Ludwig , Caca Karel , Kretzschmar Albrecht , Goekkurt Eray , Haas Siegfried , Alig Annabel Helga Sophie , Kurreck Annika , Stahler Arndt , Held Swantje , Reinacher-Schick Anke C. , Heinemann Volker , Stintzing Sebastian , Trarbach Tanja , Modest Dominik Paul
Published: June 2022

3567

Background: Clinical trials in mCRC are usually conducted irrespective of gender and mostly also irrespective of age. However, gender- and age-associated differences relating to safety and efficacy in the treatment of mCRC are of presently moving into the focus of interest. We investigated the effect of gender and age on efficacy and safety in the PANAMA trial. Methods: PANAMA investigated the efficacy of panitumumab (Pmab) plus fluorouracil and folinic acid (FU/FA) versus FU/FA alone after first-line induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab in patients with RAS wild-type metastatic colorectal cancer. In this post-hoc analysis, the study population was stratified for age (≤ 65 years versus > 65 years) and gender (male versus female). Evaluated efficacy endpoints were progression-free survival (PFS), overall survival (OS) of maintenance therapy and objective response rate (ORR) during maintenance therapy. Safety endpoints were rates of any grade and grade 3/4 adverse events (AEs). Results: In total, 165 male and 83 female patients were randomized and treated. Male patients had a significant benefit from the addition of Pmab to maintenance treatment with regard to PFS (HR 0.63; 95% CI 0.45-0.88; p = 0.006) and demonstrated a strong trend towards better ORR during maintenance therapy (Odds ratio 1.92; 95%CI 1.02-3.70, p = 0.053). In female patients, no difference regarding PFS was seen between treatment arms (HR 0.85; 95% CI 0.53-1.35, p = 0.491), while a trend towards better ORR with Pmab (Odds ratio 2.50; 95% CI 0.99-6.25; p = 0.063) was observed. Gender had no significant impact on OS, nor did age categories affect survival endpoints. Adverse events grade ≥ 3 occurring during maintenance therapy were comparable between male and female patients (12.9% vs 13.5%; p = 0.791) and in different age categories (p = 0.393). Conclusions: In the Panama trial, addition of Pmab to maintenance treatment with FU/FA improved outcome in RAS wild-type mCRC. This effect is irrespective of age and is pronounced in male patients. Our results support the relevance of gender in mCRC. Clinical trial information: NCT01991873. [Table: see text]
Trifluridine/tipiracil plus bevacizumab (FTD/TPI + BEV) and trifluridine/tipiracil (FTD/TPI) monotherapy in metastatic colorectal cancer (mCRC): Results of a meta-analysis.
Authors: Yoshino Takayuki , Taieb Julien , Andre Thierry , Kuboki Yasutoshi , Pfeiffer Per , Kumar Amit , Hochster Howard S.
Published: June 2022

3568

Background: FTD/TPI is approved for patients (pts) with refractory mCRC. FTD/TPI + BEV has been evaluated in refractory mCRC in phase 1 and 2 trials and shown efficacy and tolerability, but few head-to-head studies compare FTD/TPI + BEV with FTD/TPI. We therefore conducted this meta-analysis to evaluate outcomes with FTD/TPI + BEV and FTD/TPI monotherapy in mCRC. Methods: We searched MEDLINE, Embase, and Cochrane Library databases; ASCO, ESMO, and AACR proceedings (past 3 years); Clinicaltrials.gov and UMIN registries; systematic review bibliographies; gray literature; and guidelines through June 2021 for studies involving pts with mCRC treated with FTD/TPI + BEV or FTD/TPI. Only randomized controlled trials (RCTs), non-RCTs, and prospective observational studies of previously treated pts with mCRC were evaluated. Outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), adverse event (AE) rates, and AE-related discontinuation rates. Fixed and random effects models based on inverse-variance weighting were used to estimate relative effects and pooled absolute outcomes for ORR, DCR, AE rates, and AE-related discontinuation rates. PFS and OS were estimated from pooled Kaplan–Meier curves using Guyot’s algorithm. Results: Twenty-nine of 875 screened publications were selected, which included a total of 10,285 pts and reported on 5 RCTs, 11 non-RCTs, and 10 prospective observational studies. In an RCT (n = 93; Pfeiffer et al. Lancet Oncol. 2020), FTD/TPI + BEV was associated with significant reductions in risks for progression and death versus FTD/TPI. Pooled efficacy outcomes were higher with FTD/TPI + BEV than FTD/TPI (Table). Pooled rates for grade ≥3 febrile neutropenia, asthenia/fatigue, diarrhea, nausea, and vomiting were similar with FTD/TPI + BEV and FTD/TPI, although grade ≥3 neutropenia occurred more frequently with FTD/TPI + BEV than FTD/TPI (43% vs 29%). AE-related discontinuation rates were similar (Table). Conclusions: This meta-analysis suggests that FTD/TPI + BEV provides benefits over FTD/TPI in pts with refractory mCRC and has a similar safety profile, but it is associated with a higher rate of grade ≥3 neutropenia. Limitations of the analysis include study design heterogeneity. Data from RCTs (eg, phase 3 SUNLIGHT trial [NCT04737187]) are required to confirm these findings. [Table: see text]
Response to epithelial growth factor receptor inhibitor (EGFRi) treatment in patients with early-onset, treatment-naïve metastatic colorectal cancer (mCRC): An ARCAD database analysis.
Authors: Jin Zhaohui , Dixon Jesse G. , Hubbard Joleen M. , Eng Cathy , Lieu Christopher Hanyoung , Douillard Jean-Yves , Adams Richard , Maughan Timothy S. , Van Cutsem Eric , Venook Alan P. , Lenz Heinz-Josef , Heinemann Volker , Stintzing Sebastian , Kaplan Richard S. , Bokemeyer Carsten , Chibaudel Benoist , Zalcberg John Raymond , Yoshino Takayuki , De Gramont Aimery , Shi Qian
Published: June 2022

3572

Background: Early onset colorectal cancer (eoCRC: disease diagnosed < 50) has been increasing over the past 2 decades. Currently, standard treatment recommendations for eoCRC patients (pts) with metastatic disease does not differ from late-onset CRC (loCRC) pts although outcomes data in eoCRC pts is limited. Methods: Individual patient data on 5,761 treatment-naive metastatic eoCRC pts was pooled from 8 phase II and III randomized EGFRi studies (2000 - 2012) from the ARCAD mCRC database. The distribution of demographics, clinicopathological features, and biomarkers were summarized by age groups. Progression-free survival (PFS) was compared between age groups by stratified Cox models, adjusting for potential confounders. Predictive value of age group was evaluated by testing interaction effect between treatment and age variables based on a subset of trials with concurrent randomizations between regimens with and without EGFRi Results: eoCRC (n=756) were more evenly distributed between gender, had improved performance status (PS), increased likelihood of metastatic resection, and distant lymph node metastasis, but were less likely to have lung metastasis or KRAS mutation compared to loCRC (n=5,005, table 1). eoCRC and loCRC patients had similar distribution of primary tumor sidedness, primary resection, liver and/or peritoneal involvement, number of metastatic sites involved, and BRAF mutations (MT). No difference in PFS for eoCRC versus loCRC pts was noted (7.8 vs. 7.9 months [M], adjusted hazard ratio [HRadj], 1.02, 95% confidence interval [CI], 0.93-1.11). Among pts with KRAS wild type (WT) and left sided primary tumors, univariable analysis of EGFRi demonstrated improved mPFS in loCRC (9.9 vs 8.5M, HR = 0.74, p<0.001), but this benefit was not seen in eoCRC (8.3 vs 8.9 months, HR 1.20, p=0.36). The same pattern was observed upon multivariable analysis (Table). Conclusions: In our pooled analysis, EGFRi + chemotherapy significantly improved PFS in treatment-naïve loCRC patients but not in left sided, KRAS WT, eoCRC patients. Further validation in an independent cohort is warranted. [Table: see text]
Predictive and prognostic value of carcinoembryonic antigen (CEA) on maintenance therapy with 5-fluoruracil/leucovorin plus panitumumab or 5-fluoruracil/leucovorin alone in RAS wildtype metastatic colorectal cancer: Evaluation of the phase II PanaMa trial (AIO KRK 0212).
Authors: Kurreck Annika , Karthaus Meinolf , Fruehauf Stefan , Graeven Ullrich , Mueller Lothar , Koenig Alexander , von Weikersthal Ludwig , Goekkurt Eray , Haas Siegfried , Stahler Arndt , Heinemann Volker , Held Swantje , Alig Annabel Helga Sophie , Hoppe Beeke , Kind Andreas Jay , Kasper Stefan , Stintzing Sebastian , Trarbach Tanja , Modest Dominik Paul
Published: June 2022

3587

Background: Carcinoembryonic antigen (CEA) may reflect response to antitumor treatment in metastatic colorectal cancer (mCRC). The predictive value of CEA has not yet been proven for subsequent maintenance therapy. This analysis aims to evaluate the predictive and prognostic value of pre- and post-induction treatment CEA on maintenance with 5-fluoruracil/leucovorin (FU/FA) plus panitumumab (pmab) [arm A] or FU/FA alone [arm B] in RAS wildtype mCRC patients treated within the PanaMa trial. Methods: Patients with CEA measurements (pre- and post-induction therapy) were grouped as normal (both measurements ≤5 ug/l), stable (between +25% and -25%), decreasing (<-25%), and increasing (>+25%) CEA. Survival parameters (overall survival (OS), progression-free survival (PFS) from initiation of maintenance therapy) were expressed by the Kaplan-Meier method and compared by log-rank testing, and Cox regression. The objective response (OR) to maintenance therapy was analyzed by chi-square testing. Results: Out of 248 patients in the in the full analysis set, 245 patients were eligible for CEA analysis. Normal CEA occurred in 58 (23.7%), stable CEA in 16 (6.5%), decreasing CEA in 161 (65.7%), and increasing CEA in 10 (4.1%) patients. In the subgroup of decreasing CEA, there was a significant difference in the prediction of OR between both treatment arms with a better positive predictive value for the pmab-containing maintenance (44.0% vs. 27.5%, p=0.032). Increasing compared to decreasing CEA was associated with unfavourable survival outcome of maintenance irrespective of treatment arm (Table). Conclusions: CEA kinetics during induction therapy appears to have a predictive value for subsequent maintenance, notably pmab-based. Besides that, CEA levels had a significant impact on survival parameters of maintenance irrespective of the addition of pmab to FU/FA. This analysis is limited by the small number of patients in the subgroup of increasing CEA. Clinical trial information: NCT01991873. [Table: see text]
Metastasis patterns and racial disparities in gastrointestinal cancers: A SEER database population study 2010–2018.
Authors: Al Armashi Abdul Rahman , Hammad Faris , Elantably Dina , Patell Kanchi , Somoza-Cano Francisco , Al Zubaidi Anas , Ravakhah Keyvan , Alkrekshi Akram
Published: June 2022

3597

Background: Metastatic disease at the time of diagnosis of gastrointestinal (GI) malignancies is a strong predictor of poor outcomes. Differences in metastatic patterns among Caucasians (C) and African-Americans (AA) needs further elucidation. In this study, we analyzed the patterns of metastasis in C and AA in colorectal cancer (CRC), pancreatic cancer (PC), gastric cancer (GC), and liver cancer (LC). Methods: We identified patients with CRC, PC, GC, and LC from the Surveillance, Epidemiology, and End Results Program (SEER) database from 2010-2018. We obtained metastasis data to lungs, liver, bone, and brain at the time of diagnosis. We calculated the relative risk (RR), confidence interval (CI), and standard error with the use of SPSS software, 28.0 (IBM). Results: The most common metastasis site was the liver being highest at 39% in AA with PC. Brain metastasis was the least common. Significant racial disparities were noted. In CRC, AA had a 35-37% increased risk of metastasis to the liver, lung, or bone. AA had a higher risk of liver metastasis in PC and GC, whereas C had a higher risk of lung metastasis. Table 1 summarizes the data findings. Conclusions: This study illustrates the disparities of metastasis from GI cancers among AA and C. While a delay in screening, earlier onset of CRC in AA and socioeconomic factors may explain the disparities witnessed in CRC. However, these factors will fail to explain the difference in metastasis pattern in PC and GC in that AA had a higher risk of liver metastasis, and C had a higher risk of lung metastasis. Moreover, In GC, the brain metastasis rate in C was double that of AA. Further studies of possible biological and other risk factors are needed. [Table: see text]
Using T stage to predict outcomes of adjuvant oxaliplatin (OX)-based chemotherapy (CT) in stage III colon cancer (CC): An ACCENT pooled analysis.
Authors: Cohen Romain , Raeisi Morteza , Yothers Greg , Schmoll Hans-Joachim , Haller Daniel G. , Bachet Jean-Baptiste , Chibaudel Benoist , Wolmark Norman , Yoshino Takayuki , Goldberg Richard M. , Kerr Rachel , Lonardi Sara , George Thomas J. , Shmueli Einat Shacham , Sharara Lama , Andre Thierry , Shi Qian , De Gramont Aimery
Published: June 2022

3606

Background: Standard adjuvant CT for stage III CC are FOLFOX and CAPOX. Recently, IDEA study separated stage III patients (pts) into low risk (T1 to 3, N1) and high risk (T4 or N2). We recently confirmed benefit of OX in both risk groups. However, we observed a difference in the two high-risk subgroups, with benefit in N2 but not in T4 (Margalit O et al; Clin Colorectal Cancer 2021). This prompted us to compare outcomes (OS/TTR) between treatment with OX vs. without OX within sub-stage III CC groups defined by T and N. Methods: We pooled 4941 stage III CC pts from the three studies evaluating 6 months of CT with fluoropyrimidine (FP) ± OX: MOSAIC, C-07 and XELOXA. Baseline characteristics were compared using χ2 and t-test. OS was compared between OX and no OX in T and N subgroups. Kaplan-Meier analyses, adjusted and unadjusted Cox models stratified by study were used. Sub-groups classification was done according to OX benefit and verified by interaction test (Int) considered as significant with a P<0.1. We considered for recommendation of using OX-based adjuvant CT, 1) significant benefit in OS, 2) significant Int between substage and adjuvant therapy, and 3) the three individual trials showing similar results (benefit or non-benefit of OX). Results: In stage III population, T3 pts were 74.9%, T1-2 12.4%, T4 13.1%, while N stage was N1 64.7% and N2 35.3%. Population was well balanced according to treatment allocation in most subgroups. A significant benefit of OX was only observed in T3N1 and T3N2 (OS HR 0.76). Whatever N stage, there was no significant benefit of OX in the T1-2 and T4 subgroups. The effect of OX+FP vs FP alone in OS of the three studies differed between T3 and T1-2 subgroups (P = 0.047). Interaction was borderline between T3 and T4 subgroups (P = 0.10) but there was no interaction between T1-2 and T4 subgroups (P = 0.429). A benefit of OX in TTR remained in the T4 population. Discrepancy between advantage in time to relapse (TTR) and no advantage in OS was not explained by survival post relapse. Conclusions: Our analysis suggested that pts with T1-2N1-2 and T4N1-2 disease had no OS benefit of addition of OX to FP. The good survival achieved with FP alone in T1-2N1-2 pts (5-yr OS 89%) question the addition of OX. In the T4 population our results suggested that benefit of OX was limited and that further studies should assess this issue or at least stratify pts on T stage in the future adjuvant trials in CC. [Table: see text]
Genetic ancestry differences in tumor mutation in early and average-onset colorectal cancer.
Authors: Rhead Brooke , Hein David , Pouliot Yannick , Guinney Justin , De La Vega Francisco , Sanford Nina Niu
Published: June 2022

3620

Background: The incidence and mortality of early onset colorectal cancer (EOCRC), defined as CRC diagnosed prior to age 50, are rising, in contrast to declining rates of average onset CRC (AOCRC). Epidemiologic trends for CRC appear to differ by race/ethnicity, which could be related in part to underlying differences in tumor mutation and gene expression. Previous research has used self-reported race/ethnicity categories, which has been shown to be missing or inaccurate, particularly in highly admixed groups such as Black and Hispanic patients. Hence, we examined tumor profiles of EOCRC and AOCRC using genetic ancestry. Methods: Genetic ancestry was inferred from de-identified data of 1,443 and 3,315 patients with EOCRC and AOCRC, respectively, who underwent tumor profiling with the Tempus xT NGS 648-gene panel and targeted RNAseq. Ancestry informative markers were used to estimate likelihoods for the five continental groups defined in the 1000 Genomes Project: Africa (AFR), Americas (AMR), East Asia (EAS), Europe (EUR), and South Asia (SAS). We assessed the association of genetic ancestry proportions (per 10% increase in each ancestry proportion) with presence of protein altering somatic mutations in key driver genes in CRC. We also assessed interactions between onset age (EOCRC vs. AOCRC) and genetic ancestry in somatic mutations. Results: Across all ages, African ancestry was associated with higher odds of mutations in APC and KRAS and lower odds of BRAF mutations (Table). East Asian ancestry was associated with higher odds of mutations in NTRK3 and TP53. For EOCRC, the association between KRAS and African ancestry remained significant (OR 1.07, p=0.04). Furthermore, there was an interaction (p=0.031) between onset age and race/ethnicity such that the association between African ancestry and APC mutation was significant in AOCRC (OR=1.09) but not EOCRC (OR=1.00). Conclusions: The use of genetic ancestry instead of categorical race/ethnicity provides a more quantitative and precise profile of shared genetic background that can underlie biological race differences in CRC cancer etiology and outcomes. [Table: see text]