bluuebunny/crossref_metadata_2025_split huggingface dataset:
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]