bluuebunny/crossref_metadata_2025_split huggingface dataset:
Young-onset colorectal cancer patients disproportionately diagnosed with advanced disease: Patient self-reported journey of symptom duration and misdiagnosis.
Authors: Yarden Ronit , Newcomer Kim Lynn ,   Never2Young
Published: May 2019

3567 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related death among males and females in the US. Despite a decrease in overall incidence and mortality, there has been an alarming increase of CRC diagnosis among young adults (20-49 years old). The Colorectal Cancer Alliance launched a comprehensive survey for young-onset CRC patients and survivors via social media to track the self-reported clinical, psychosocial, financial and quality of life experiences of this often overlooked, group. Methods: The survey was completed by 1195 living patients and survivors. The majority of participants (57%) were diagnosed between the ages of 40 and 49, 33% of patients/survivors were diagnosed between the ages 30-39 and about 10% were diagnosed before the age of 30. Only 8% of the respondents were diagnosed with Lynch syndrome although about 28% reported some family history. Results: Our survey revealed a higher proportion of the young-onset patients and survivors (71%), diagnosed with advanced stage tumors, compared with ACS report for overall CRC patients (60%). The late stage diagnosis subjected young patients to aggressive therapies and a substantial decrease in quality of life including neuropathy, anxiety, clinical depression, and sexual dysfunctions. Most respondents (63%) waited 3-12 months before visiting a doctor, with higher proportion of females waited more than 12 months compared with males (22% vs. 15% p = 0.02). Moreover, even when visited their doctors, most patients indicated that they were initially misdiagnosed. The majority of the respondents (67%) saw at least 2 physicians, and some more than 4 physicians, prior to their diagnosis. Patients that saw 3 or more physicians prior to diagnosis were more likely to be diagnosed with advanced disease. Interestingly, half of the patients that were seen by one physician also claimed they were initially misdiagnosed. Conclusions: Our survey indicates that medical professionals and young adults need to be aware of the increasing incidence of young-onset CRC, and the importance of timely screening when signs and symptoms are present, regardless of age. Yet, 50% of physicians did not explain to the patients’ family members about their elevated risk of the disease and their need for screening.
Germline multigene panel testing in colorectal cancer: Precision therapy and clinical management implications.
Authors: Esplin Edward D. , Yang Shan , Michalski Scott T. , Pineda Alvarez Daniel Esteban , Lincoln Stephen E , Nussbaum Robert L. 
Published: May 2019

3582 Background: Recent studies suggest that the prevalence of abnormalities in homologous recombination deficiency (HRD) genes and other cancer genes not traditionally associated with colorectal cancer (CRC) may be more common in patients with CRC than previously appreciated. Herein, we investigate the efficacy of comprehensive multigene panels in patients with CRC to identify candidates for precision therapies. Methods: DNA sequencing and exon-level copy number analysis were performed in over 9000 patients (pts) referred because of personal history of colon cancer between 2013 and 2018 at a commercial diagnostic laboratory. The genes requisitioned varied but consistently included 14 genes on a hereditary CRC panel; the patient data were de-identified and further analyzed for all 83 genes on a large hereditary cancer syndrome panel under an IRB-approved protocol. Results: Pathogenic/likely pathogenic (P/LP) findings were identified in 2101 of 9669 pts (21%), 1838 (19%) pts when MUTYH heterozygotes are excluded. When restricted to five Lynch syndrome (LS) genes, only 9% of patients had a P/LP finding, which increased to 15% of patients when 19 guidelines-based CRC genes were assessed. 137 pts (1.4%) had two or more P/LP variants. P/LP variants were in MLH1, MSH2, MSH6, PMS2, CHEK2, APC, MUTYH, BRCA2, ATM, BRCA1, PALB2, RAD50, BRIP1, TP53, EPCAM, among others, of which 1.4% were BRCA1/2. When a comprehensive multigene panel was utilized P/LP variants in genes with known therapeutic implications, such as in HRD and mismatch repair deficiency (MMRD), were detected in 1408 (14%) of patients, and 1670 (17%) had P/LP variants in genes with established clinical management guidelines. Conclusions: This study suggests that 1 in 5 patients with CRC harbor actionable germline variants, up to one-half of which remain undetected when only LS genes are tested. Comprehensive panel testing identified candidates for precision treatment and established management recommendations, and have clinical implications for both pts and their at risk family members.
Influence of WNT and DNA damage response pathway alterations on outcomes in patients with unresectable metastatic colorectal cancer.
Authors: Mondaca Sebastian , Walch Henry S , Nandakumar Subhiksha , Chatila Walid K. , Hechtman Jaclyn Frances , Cercek Andrea , Diaz Luis A. , Sanchez-Vega Francisco , Kemeny Nancy E. , Segal Neil Howard , Stadler Zsofia Kinga , Varghese Anna M. , Vakiani Efsevia , Ladanyi Marc , Berger Michael F. , Solit David B. , Shia Jinru , Saltz Leonard B. , Schultz Nikolaus D , Yaeger Rona 
Published: May 2019

3585 Background: We assembled a large series of consecutive patients with unresectable metastatic colorectal cancer (mCRC) to identify genomic biomarkers of response and survival. Methods: Patients with unresectable mCRC treated at Memorial Sloan Kettering with genomic tumor profiling between 2014 and 2017 were included. Patients who underwent upfront metastasectomy or received neoadjuvant/conversion chemotherapy were excluded. Clinical information was retrieved from electronic medical records, and we evaluated associations between genomic profiles with progression free survival (PFS) on first-line chemotherapy and overall survival (OS). Categorical data were analyzed by Fisher exact test and time-to-event data were analyzed by Cox proportional hazards models. Results: Of 1453 mCRCs profiled in this period, 471 patients met the study criteria. Median age was 59 years (range, 18 to 95), and 73% of patients were stage IV at diagnosis. Most tumors (91%) were microsatellite stable (MSS). The most frequent first-line regimen was FOLFOX +/- bevacizumab (66%). Among MSS patients treated with oxaliplatin-containing regimens (n = 305), 7% harbored alterations in genes associated with DNA damage response (DDR) (BRCA1, BRCA2, ATM, PALB2). DDR gene alterations were not associated with PFS (P = 0.94) nor were different quartiles of large-state transitions (P = 0.54). Genomic alterations that significantly varied by duration of response included BRAF (16%, 10%, and 5% for PFS < 6 months, 6-12 months, and > 12 months, respectively) and APC (62%, 74%, and 80% for PFS < 6 months, 6-12 months, and > 12 months, respectively). APC mutation, single or dual, was associated with significantly longer PFS (HR 0.67) and OS (HR 0.59) in multivariate analysis versus no WNT pathway alteration or alterations in other WNT pathway genes (RNF43, AXIN2, CTNNB1). Conclusions: In unresectable mCRC patients, mutations in APC were associated with better outcomes; absence of an APC alteration or the occurrence of other WNT pathway alterations was associated with shorter survival. Somatic alterations in DDR genes were not associated with outcomes in mCRC patients receiving oxaliplatin-containing regimen.
Immune-related gene signature in predicting prognosis of early-stage colorectal cancer patients.
Authors: Ke Jia , Liu Xuanhui , Jiang Xiaofeng , Chen Yufeng , Cai Zerong , Lan Ping , Wu Xiaojian , Gao Feng 
Published: May 2019

3586 Background: Immune-related genes (IRGs) were found to be associated with the prognosis of colorectal cancer (CRC) patients. The aim of this study was to evaluate the impact of IRGs in predicting prognosis of early-stage CRC patients. Methods: According to the CIT microarray data set, 309 early-stage CRC patients were selected for generation of immune-related gene signature (IRGS). 5 independent data sets included 1587 CRC patients with complete prognostic information were divided into a training cohort (566 patients) and two validation cohorts (624 patients in validation-1 and 397 patients in meta-validation). Prognostic analysis were performed to test the predictive value of IRGS. Results: Of 309 early-stage CRC patients, a prognostic immune signature included 23 immune-related genes was constructed. In the training cohort, when considering patients with early tumor stage (I or II), IRGS significantly stratified patients into immune low- vs high-risk groups in terms of disease-free survival (HR = 5.03, 95%CI = 2.94-8.62, P < 0.001). Similarly, higher IRGS was correlated with significantly worse prognosis of early-stage CRC patients in validation-1 (HR = 2.71, 95%CI = 1.44-5.08, P = 0.001) and meta-validation cohort (HR = 3.10, 95%CI = 1.60-6.00, P < 0.001). When compared with Oncotype DX, we found IRGS achieved an improved survival correlation in the training cohort (mean C-index, 0.85 vs 0.65) and the validation-1 cohort (mean C-index, 0.72 vs 0.61). After integrated with clinical characteristics, IRGS remained as an independent prognostic factor after adjusting for T stage and TNM stage of tumor in multivariate analysis (HR = 2.02, 95%CI = 1.61-2.53, P < 0.001). Furthermore, IRGS stratified immune low-risk group patients with adjuvant chemotherapy showed even worse disease-free survival when compared with those without adjuvant chemotherapy (HR = 5.66, 95%CI = 3.153-10.16, P < 0.001 in the training cohort and HR = 3.21, 95%CI = 1.74-5.92, P < 0.001 in the validation-1 cohort). IRGS identified immune high-risk group obtained a significantly higher immune and stromal infiltration (P < 0.001). Particularly, the percentages of Macrophages M2 and CD8+ T cells infiltration were significantly different between these two groups. Conclusions: The proposed prognostic IRGS is a promising system for estimating DFS of colorectal cancer patients, especially those in early-stage. Further studies are needed to evaluate the clinical utility of this system in predicting prognosis of colorectal cancer patients.
Differences in pathology and mutational status among colorectal cancer (CRC) patients pre-, post-, and during screening age.
Authors: Fernandes Gustavo Dos Santos , Pereira Allan Andresson Lima , Braga Gabriella Pereira , Gumz Brenda Pires , Crosara Alves Texeira Marcela , Mascarenhas Cintia do Couto , Girardi Daniel da Motta , Barrichello Adriana Paula de Castro , Seidler Heinrich 
Published: May 2019

3596 Background: Screening protocols for CRC are broadly recommended and effective in reducing mortality. However, populations from different age groups can harbor distinct pathological and molecular profiles that can also be influenced by screening and polyp resection, especially in older ages. Methods: We retrospectively analyzed tumors from stage IV CRC patients from a central pathology laboratory in Brazil that is a reference for mutational profiling countrywide. Patients were classified into age groups as the following: pre-screening (PrSA; <45yo), screening(SA; 45-75yo) and post-screening age (PoSA; >75yo). Every tumor has been centrally reviewed by the pathologist. Groups were compared regarding clinicopathologic features and presence of RAS and BRAF mutations. Results: We included 1244 pts (164 PrSA, 919 SA and 161 PoSA). There were no difference among groups regarding sidedness(p= .68)and KRASmutations (p=.0.97). Stage IV at diagnose (p =.001), presence of signet-ring cell component (p< .001) along with poorly differentiated tumors (p= .006) were most found on young patients, while BRAFand NRASmutations where significantly more common among PosSA (table). Conclusions: PosSA and PreSA CRCs seem to present a distinct profile from SA populations, including differences in the molecular and pathologic aspects. This could impact the frequency of screening tests among different age groups. [Table: see text]
Gene mutations of SWI/SNF complex and molecular profile in colorectal cancer.
Authors: Tokunaga Ryuma , Xiu Joanne , Goldberg Richard M. , Philip Philip Agop , Seeber Andreas , Battaglin Francesca , Arai Hiroyuki , Lo Jae Ho , Puccini Alberto , Naseem Madiha , Berger Martin D. , Soni Shivani , Zhang Wu , Chen Wangjuh Sting , Hwang Jimmy J. , Shields Anthony Frank , Marshall John , Baba Hideo , Korn W. Michael , Lenz Heinz-Josef 
Published: May 2019

3600 Background: The SWI/SNF complex includes proteins produced by 29 genes that regulate chromatin structure remodeling through effects upon transcription, replication, and repair. Understanding how SWI/SNF gene mutations interact to affect cancer progression could lead to new treatment strategies. Methods: We analyzed 7,370 colorectal cancer (CRC) samples with immunohistochemical stains (IHC) and Next-Generation Sequencing (NGS) using a 592-gene panel to examine the association between gene mutations of the SWI/SNF complex ( ARID1A, ARID2, PBRM1, SMARCA4, SMARCB1, SMARCE1, BCL11A, BCL11B, BCL7A, SS18, and SS18L1) and molecular features. Results: The overall mutation rate of the SWI/SNF complex genes was 11.3% ( ARID1A: 7.7% , ARID2: 1.7% , SMARCA4: 1.3% , PBRM1: 1.2% , BCL11A: 1.0% , SMARCB1: 0.5% , BCL11B: 0.5% , SMARCE1: 0.3% , SS18: 0.3% , BCL7A: 0.1% , SS18L1: 0.1%). When compared to tumors with SWI/SNF wild-type genes, those tumors with SWI/SNF gene mutations showed significantly higher rates of microsatellite instability (MSI)-high (40.9% vs 2.4%, P < 0.001), tumor mutational burden (TMB)-high (>= 10mut/MB) (56.8% vs 21.6%, P < 0.001) and PD-L1 positivity (17.9% vs 5.5%, P < 0.001). Tumors with each gene mutant also had strong association with the immune profile (MSI-high, TMB-high, and PD-L1 positivity) (Table). Furthermore, even SWI/SNF gene mutant samples with microsatellite stable status were significantly associated with TMB-high (28.2%, P < 0.001) and PD-L1 positivity (10.0%, P < 0.001). Conclusions: Gene mutations of the SWI/SNF complex exhibit findings that suggest that this subgroup of CRCs may have a higher likelihood of response to PD-1 and PD-L1 targeting monoclonal antibodies. If validated in other data sets, these findings can be used to justify clinical trials with eligibility based upon the presence of mutations within the SWI/SNF complex. [Table: see text]
Randomized phase II study of second-line modified FOLFIRI with PARP inhibitor ABT-888 (Veliparib) (NSC-737664) versus FOLFIRI in metastatic pancreatic cancer (mPC): SWOG S1513.
Authors: Chiorean E. Gabriela , Guthrie Katherine A , Philip Philip Agop , Swisher Elizabeth M. , Jalikis Florencia , Pishvaian Michael J. , Berlin Jordan , Noel Marcus Smith , Suga Jennifer Marie , Garrido-Laguna Ignacio , Cardin Dana Backlund , Lew Danika L. , Lowy Andrew M. , Hochster Howard S. 
Published: May 2019

4014 Background: PC is characterized by DNA Damage Repair (DDR) deficiencies, including in BRCA1/2, ATM, and FANC genes. Given preclinical synergism between veliparib with irinotecan, safety and preliminary efficacy, we designed a randomized phase II study of mFOLFIRI (no 5-FU bolus) + veliparib vs FOLFIRI alone for 2nd line mPC patients (pts). Methods: Eligible pts had mPC, adequate organ function, ECOG PS 0-1, and 1 prior non-irinotecan systemic therapy.143 pts were to be randomized (1:1) to veliparib vs control. Primary endpoint was overall survival (OS). All pts had blood and tumor biopsies at baseline to assess germline and somatic BRCA1/2 mutations (integrated), and homologous recombination (HR) or DDR biomarkers (exploratory). Results: 123 pts were accrued between 09/2016 to 12/2017, and 108 were included in this analysis. 117 pts were biomarker evaluable: 109 blood/106 tumors. 11 cancers (9%) had HR deficiency (HRD), including 4 germline ( BRCA1, BRCA2, ATM) and 7 somatic mutations ( BRCA2, PALB2, ATM, CDK12). Additional 24 cancers (20%) had germline (n = 11, e.g., FANC, BLM, SLX4, CHEK2) or somatic mutations (n = 13, e.g., FANC, BLM, POLD1, RIF1, MSH2, MSH6) in other DNA repair genes, not classified as HRD. A planned interim futility analysis at 35% of expected PFS events determined the veliparib arm was unlikely to be superior to control. Most common grade 3/4 treatment related toxicities were neutropenia (33% vs 20%), fatigue (19% vs 4%), and nausea (11% vs 4%), for veliparib vs control. Treatment exposure was similar for veliparib vs control: median 4 cycles (range 1-31 vs 1-32). Median OS was 5.1 vs 5.9 mos (HR 1.3, 95%CI 0.9-2.0, p = 0.21), and median PFS was 2.1 vs 2.9 mos (HR 1.5, 95%CI 1.0-2.2, p = 0.05) for veliparib vs control arms, respectively. Correlations of gene mutations and signatures with efficacy outcomes will be presented. Conclusions: Nearly 30% of mPC pts had DNA repair gene abnormalities, including 9% with HRD. Veliparib increased toxicity and did not improve OS when added to mFOLFIRI in biomarker unselected pts. BRCA1/2 and DDR biomarkers will be correlated with efficacy to inform patient selection for future PARP inhibitor clinical trials. Clinical trial information: NCT02890355.
Final report of a phase I/II study of veliparib (Vel) in combination with 5-FU and oxaliplatin (FOLFOX) in patients (pts) with metastatic pancreatic cancer (mPDAC).
Authors: Pishvaian Michael J. , Wang Hongkun , Parenti Sarah , He Aiwu Ruth , Hwang Jimmy J. , Ley Lisa , Difebo Holly , Smaglo Brandon George , Kim Sunnie S. , Weinberg Benjamin Adam , Weiner Louis M. , Marshall John , Brody Jonathan Robert 
Published: May 2019

4015 Background: 17 – 25% of mPDACs harbor DNA damage response (DDR) mutations, the presence of which can be predictive of a response to platinum and PARP inhibitor-based therapy. The PARP inhibitor, Vel is a potent sensitizing agent for, and has been safely combined with DNA-damaging chemotherapies. Methods: We initiated a Phase I/II trial of Vel + FOLFOX in pts with mPDAC. Pts received standard mFOLFOX6 except without the 5FU bolus, Q2 weeks. For the Phase I portion, a 3+3 dose escalation of Vel identified a recommended Phase II dose of 200mg orally BID, days 1-7, Q2 weeks. For the Phase II portion, we enrolled two cohorts: 1) Untreated pts; 2) Previously treated pts. Also, for Phase II, pts were pre-selected if they had either a pathogenic germline or somatic DDR mutation (e.g. BRCA1/2, PALB2, ATM), and/or a family history suggestive of a breast or ovarian cancer syndrome (labelled FH+). Objective response rate (ORR) was the primary objective of the Phase II cohorts; key secondary endpoints were median progression-free survival (PFS) and overall survival (OS). Results: Between 01-2011 and 12-2018, 64 pts received treatment, 31 in Phase I, and 15 untreated and 18 previously treated in Phase II. The combination was well tolerated, with the main Grade 3/4 AEs being myelosuppression (16%) and nausea/vomiting (6%). Of the 64 pts, 55% were male; median age was 64; 95% had an ECOG PS of 1; 78% were platinum-naïve; 69% were FH+; and 27% had a known DDR mutation. 57 pts were evaluable for response, and the ORR, PFS, and OS for the different pt subgroups are detailed below. The Phase II cohorts achieved the primary endpoint of an ORR ≥ 25%. Most notably, plat-naïve, FH+, and DDR mutation+ pts had an ORR of 58%. Conclusions: The combination of Vel + FOLFOX is safe, well tolerated, and shows promising efficacy particularly in plat-naïve pts who are FH+ and/or harbor DDR mutations. A randomized trial to assess the contribution of Vel to the regimen is warranted. Clinical trial information: NCT01489865. [Table: see text]
Rivaroxaban thromboprohylaxis in ambulatory patients with pancreatic cancer: Results from a prespecified subgroup analysis of the CASSINI study.
Authors: Vadhan-Raj Saroj , McNamara Mairead Geraldine , Venerito Marino , Riess Hanno , O'Reilly Eileen Mary , Overman Michael J. , Zhou Xiao , Vijapurkar Ujjwala , Kaul Simrati , Wildgoose Peter , Khorana Alok A. 
Published: May 2019

4016 Background: Rivaroxaban thromboprophylaxis has been shown to reduce venous thromboembolism (VTE) on-treatment in ambulatory cancer patients in a recent randomized trial. Pancreatic cancer patients are at substantial risk for VTE; value of thromboprophylaxis has not been definitively established. Methods: CASSINI was a double-blind placebo-controlled trial of cancer patients initiating a new regimen, at high risk for VTE (Khorana score ≥2), randomized to rivaroxaban 10 mg daily or placebo up to 180 days. Patients were stratified by presence or absence of pancreatic cancer. Patients had screening ultrasound and blood drawn at baseline and every 8 wks. Primary efficacy endpoint was a composite of symptomatic DVT, asymptomatic proximal DVT, any PE and VTE-related death. Primary safety endpoint was International Society on Thrombosis and Hemostasis (ISTH)-defined major bleeding. Results: Of 1080 patients enrolled, 49 (4.5%) failed screening due to baseline VTE, with even higher rates [24/362 (6.6%)] in patients with pancreatic cancer. Of 841 randomized patients, 273 (32.6%) had pancreatic cancer with median age 66 y; 57% male and 155/273 (57% in each arm) completing the double-blind period. During intervention (on-treatment) period, 5/135 (3.7%) pancreatic cancer patients in the rivaroxaban arm and 14/138 (10.1%) in placebo arm had primary endpoint events [HR 0.35; 95%CI (0.13, 0.97), p = 0.03; number needed to treat, NNT = 16]. Major bleeding was not increased, occurring in 2 (1.5%) patients in rivaroxaban arm and 3 (2.3%) in placebo arm. Further benefit with rivaroxaban was observed when including primary and secondary endpoints (arterial/visceral events): 6/135 (4%) events in rivaroxaban vs 17/138 (12%) in placebo [HR, 0.34; 95%CI (0.14, 0.87), P = 0.02; NNT = 13]. Correlative biomarker studies demonstrated significant decline in D-dimer values over time (weeks 8 and 16) in patients without VTE randomized to rivaroxaban prophylaxis compared to placebo (P < 0.01), supporting clinical findings. Conclusions: Rivaroxaban substantially reduced VTE in pancreatic cancer patients during intervention period. Given no increase in major bleeding, our findings suggest benefit to rivaroxaban thromboprophylaxis in pancreatic cancer patients initiating systemic therapy. Clinical trial information: NCT02555878.