bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic analysis of recurrent early stage and de novo metastatic colorectal cancer among veterans.
Authors: Essegian Derek , DiNatale Tia , Lee Kyung Min , Lynch Julie Ann , Becker Daniel Jacob 
Published: June 2024

e15593 Background: The Veterans Health Administration (VHA) diagnoses approximately 4,000 cases of colon cancer each year and conducts Next Generation Sequencing (NGS) on recurrent and metastatic cases. The molecular profile of cancers resected for cure that recur is poorly characterized and holds promise to clarify both the risk and mechanisms of recurrence. We sought to characterize these genetic differences. Methods: A national database from the VHA consisting of colon cancer patients was analyzed for those with recurrent disease who have received NGS testing from 2015-2021. Data was analyzed by stage and presence of DNA mismatch repair (MMR) (MLH1, MSH2, PMS2, MSH6) and DNA damage repair (DDR) abnormalities (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D) in addition to receipt of chemotherapy and overall survival with univariate and multivariate cox proportional hazards analyses and multivariate logistic regression analyses. Chi squared analyses were also performed comparing presence of DNA abnormalities between early recurrent and stage IV cancers. Results: From309,318 cases with colon cancer codes, we identified 2,366 colon cancer patients who had NGS and had recurrent or de novo metastatic disease. 1,072 patients had initial staging annotated (I n = 89, II n = 194, III n = 320 , IV n = 453). The average age was 69.41 years; 70.5% white, 21.5% Black and 7.8% other. Among all patients, DNA MMR abnormalities (n = 117) were associated with better overall survival, after controlling for age and race (HR 0.6, 95% CI 0.42-0.85, p < 0.005). Among recurrent early stage (I-III) and stage IV patients, MMR (n = 55 and n = 21, respectively) is associated with improved survival in multivariable models (HR 0.39, 95% CI 0.33-0.46, p < 0.001) . Among the 4 DNA MMR genes, MSH2 mutations had the strongest association with survival (univariate HR 0.31, 0.15-0.62, p < 0.001). Among patients with MMR abnormalities, those who received either only capecitabine or only fluorouracil (without irinotecan or oxaliplatin) had worse overall survival (HR 2.6, 1.34 -5.04, p < 0.005). This effect was more pronounced in early stage recurrent patients versus patients with de novo metastatic disease (HR 5.1, 1.87 – 13.9, p < 0.001). Finally, we also found that early stage patients with recurrent disease are more likely to have MMR abnormalities compared to de novo metastatic (8.8% vs 4.6%, p < 0.01) and confirmed this finding after controlling for race and age. (OR 2.13, p < 0.005). Conclusions: Among Veteranswith colon cancer, resected recurrent colon cancer is more likely to have DNA MMR abnormalities than de novo metastatic disease. Veterans with recurrent and or metastatic disease with DNA MMR have better outcomes regardless of stage at diagnosis. These findings suggest different pathogenesis for those with recurrent disease after curative resection, and for those with de novo metastatic disease.
Predictors of receiving targeted treatment among eligible patients with metastatic colorectal cancer.
Authors: Woodward Alexa , Bazan-Williamson Jean Lucia , Mohanty Pallavi , Brenton Ashley 
Published: June 2024

e15594 Background: Colorectal cancer is among the most frequently diagnosed cancers and ranks as the third leading cause of cancer-related mortality globally with increasing prevalence among younger patients and high mortality. While targeted therapies have revolutionized treatment and tripled the median survival over the past two decades, many eligible patients fail to receive them. This study sought to identify factors associated with receiving targeted treatment among eligible patients. Methods: We identified a cohort of patients with metastatic colorectal cancer diagnosed between 2007 and 2023 (n = 521,074) in Optum’s clinicogenomic database. Eligible patients were identified based on clinical and treatment history, broad-panel next-gen sequencing (NGS) results and the drug indications for targeted treatments available at time of diagnosis (n = 8,533), including MSI/MMR status, RAS WT status, presence of BRAF V600E, and other biomarkers. In total, we considered tucatinib, encorafenib, pembrolizumab, nivolumab, ipilimumab, panitumumab, cetuximab, and regorafenib. Most patients did not receive targeted treatment; we applied a synthetic minority oversampling technique to correct this class imbalance. We assessed how factors including sex, race, and receipt of genetic counseling services influenced the likelihood of receiving targeted treatment using logistic regression. Results: In the fully adjusted multivariable logistic regression analysis, all variables were significant with p < 0.05. Notably, patients receiving genetic counseling had 68% greater odds of receiving targeted treatment (OR, 1.68 [95% CI, 1.20-2.36]). African American (OR, 0.37 [95% CI, 0.27-0.50]) and Asian patients (OR, 0.10 [95% CI, 0.04-0.24]) had lower odds of receiving targeted treatment compared to Whites. Similarly, patients treated in community settings had 86% lower odds compared to patients in academic settings (OR, 0.14, [95% CI, 0.11-0.18]) as did male patients (OR, 0.39, [95% CI, 0.33-0.44]). Conclusions: This study underscores the challenges in receiving targeted treatments despite clinical eligibility. Our findings highlight the significance of genetic counseling in facilitating access to targeted therapies, and the stark gap in uptake among minority patients. These results can inform strategies to increase access to these treatments. Future research will attempt to better understand the mechanisms underlying receipt of targeted treatment.
Distinctive clinical and molecular aberrations of colorectal cancer patients with ovarian metastases.
Authors: Lenyo Alexandria , Eng Cathy , Magge Deepa , Ciombor Kristen Keon 
Published: June 2024

e15595 Background: Ovarian metastases (OM) from colorectal cancer (CRC) are a rare phenomenon. There are limited data detailing outcomes from surgical interventions on OM. However, there is a lack of studies integrating genetic aberrations identified in these patients with clinical characteristics. Methods: We conducted a retrospective review of CRC patients with OM. Demographic variables of interest included age and stage at diagnosis, time from diagnosis to discovery of OM, laterality of OM, primary tumor sidedness, and choice of chemotherapy. Next Generation Sequencing was utilized to collect solid tumor DNA sequencing, in addition to cell-free DNA (cfDNA). Results: A cohort of 12 MSI-S patients was identified between December 2023 and January 2024. Median age of diagnosis was 42.5 y/o. Demographics noted: Primary tumor sidedness included descending colon [58%; 86% of these sigmoid] and ascending colon (42%). AJCC T4 (50%) with OM at presentation (83%); unilateral (58%); 57% in the left ovary. 67% of patients underwent bilateral salpingo-oophorectomy (BSO), 25% unilateral resection, and 8.3% had no resection. 9 patients continue to receive treatment; 3 patients are deceased. Tissue NGS data was available for 75% of patients. The most common mutations were p53 (100%), APC (88%), KRAS (G12A, G12C and G12D; 38%), and PIK3CA (25%). cfDNA data was available for 58% of patients; common mutations were APC (86%), p53 (71%), KRAS [G12C (2); G12D; 43%), PMS2 (29%), BRAF V600E (14%) and BRAF amplification (14%). Conclusions: In our cohort, CRC patients with OM were of early age onset with sigmoid > ascending colon cancer with similar molecular alterations by tissue and cfDNA noting increased KRAS aberrations. Hence, NGS should be completed in all CRC as an opportunity to further characterize potentially actionable mutations in patients with OM, expanding precision oncology availability to this select patient population.
The impact of COVID-19 and missed diagnosis of colorectal cancer.
Authors: Rohatgi Atharva , Liao Cheng-I , Johnson Caitlin Ruth , Kapp Daniel Stuart , Chan John K 
Published: June 2024

e15598 Background: To evaluate the impact of COVID-19 pandemic on colorectal cancer diagnosis based on sex, age, race, and regions within the US. Methods: Data on colorectal cancer incidence were obtained from the United States Cancer Statistics (USCS) program from 2001-2020. SEER*Stat 8.4.1.2 and Joinpoint regression program 5.0.2 were used to calculate estimated and actual incidence rates per 100,000 adults. Rates were age-adjusted as appropriate. We compared actual colorectal cancer incidence rates in the year 2020 to estimated rates based on trends from 2001-2019 with sub-analyses for sex, age, race, and region. Results: From 2001 to 2019, there were 2,627,565 identified cases of colorectal cancer in the United States. In 2019, prior to the pandemic, the incidence rate of colorectal cancer was the highest in males at 42.26 per 100,000 compared to 32.18 in females. The overall cancer incidence was 36.87 per 100,000 in both males and females in the US. Based on the data from 2001 to 2019, colorectal cancer decreased by 2.20% per year (p < 0.001). Using these prior trends, it was expected that the incidence of colorectal cancer to be 36.44 per 100,000 adults (115,392 total cases) in 2020. However, the reported incidence was only 32.47 per 100,000 (102,798). Thus, there were 10.9% (12,594) less colorectal cancer cases than expected. The missed diagnosis rate was more pronounced in males compared to females, where 11.90% and 10.84% less colorectal cancer cases were detected compared to expected in 2020, respectively. Based on age, the cases missed were the highest amongst middle aged adults, with 13.56%, 13.49%, and 13.05% cases missed for the age groups between 50-54, 65-69, and 70-74 respectively. Based on racial and ethnic groups, we found that Non-Hispanic Asians and Pacific Islander (NHAPI) had the greatest number of missed cases at 14.38% compared to 11.98%, 11.36%, and 11.27% of Non-Hispanic Black (NHB), Non-Hispanic White (NHW), and Hispanic adults, respectively. The discrepancy between expected and actual number of cases by U.S. region ranged from the highest in the Southern (11.64%) to the lowest in the Western (10.92%) region. An intersectionality analysis showed that 40–44-year-old NHAPI females residing in the Western region had the largest discrepancy at 47.96%. Conclusions: The reported colorectal cancer cases significantly declined during the pandemic. Males, middle age, NHAPI and NHB race and ethnicity, and those residing in the Southern region had the most number of missing cases. Due to the widespread prevalence of colorectal cancers, more mitigating factors are needed to improve the access to care for patients in these at-risk groups to improve diagnosis and detection of colorectal cancer and its associated mortality.
PRIMROSE: A modular phase 1/2a study of AZD3470, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP deficient advanced solid tumors.
Authors: Spira Alexander I. , Lau James , Hattersley Maureen M. , Aronson Boaz E. , Peters Jane , Soo-Hoo Yee , Sawant Aarti , Loizou Joanna , Smith Claire , Dean Emma , Postel-Vinay Sophie , Solomon Benjamin J. 
Published: June 2024

TPS3179 Background: Protein arginine methyltransferase 5 (PRMT5) is an epigenetic enzyme that catalyzes symmetric dimethylation of arginine substrates, regulating multiple cell processes. Deletion of the methylthioadenosine phosphorylase gene MTAP in tumor cells results in accumulation of the metabolite methylthioadenosine (MTA), a partial inhibitor of PRMT5, potentially rendering tumor cells susceptible to further PRMT5 targeting. Clinical activity of first-generation, non-selective PRMT5 inhibitors (PRMT5i) is limited by bone marrow toxicity due to lack of selectivity between normal cells and MTAP-deficient tumor cells. Second-generation PRMT5i, including AZD3470, should selectively target MTAP-deficient tumor cells whilst sparing normal cells. AZD3470 preferentially binds PRMT5 in the presence of MTA in MTAP-deficient tumor cells, inhibiting PRMT5 methylation activity, and is less effective in MTAP-proficient cells. PRIMROSE (NCT06130553) is a first-in-human, Phase 1/2a, open-label, multicenter study of AZD3470 as monotherapy and in combination with anti-cancer agents in patients with MTAP-deficient advanced / metastatic solid tumors. Methods: Eligible patients are aged ≥18 years with MTAP-deficient advanced or refractory solid tumors, ≥1 prior line of treatment in the recurrent / metastatic setting, ≥1 measurable lesion per RECIST v1.1, ECOG performance status 0/1, adequate organ and bone marrow function, and no prior treatment with PRMT5i. Module 1 will evaluate AZD3470 monotherapy. Part A (dose escalation) will enroll up to ~54 patients and follow a modified toxicity probability interval-2 (mTPI-2) design with once-daily dosing in 21-day cycles. Treatment will be given until progression or discontinuation criteria are met. Part B (dose optimization and expansion) will expand specific patient populations and / or tumor types, with up to ~30 patients per cohort; dosing will be based on safety and tolerability data from Part A. Further modules for combination treatments may be added based on emerging supportive data. The primary objectives are to assess safety and tolerability, including dose-limiting toxicities, and to determine the recommended phase 2 dose of AZD3470. The secondary objective is evaluation of efficacy, including objective response rate, duration of response, disease control rate, change in tumor size, progression-free survival, and overall survival. An additional secondary objective in Module 1 is to assess pharmacokinetics. The study is planned to take place in ~20 centers across eight countries. The study was opened to enrollment in December 2023. Clinical trial information: NCT06130553 .
Phase 1/2 study of FMC-376 an oral KRAS G12C dual inhibitor in participants with locally advanced unresectable or metastatic solid tumors (PROSPER).
Authors: Keating Anne Therese , Papadopoulos Kyriakos P. , Hloros Eleni , Spira Alexander I. , McKean William Bennion , Krivoshik Andrew Peter 
Published: June 2024

TPS3184 Background: FMC-376 is a highly selective, orally bioavailable, dual (ON/OFF) irreversible covalent inhibitor that rapidly and effectively blocks signaling via ON (GTP-bound) mutant KRAS G12C and prevents OFF (GDP-bound) KRAS G12C from being activated. This prevents downstream KRAS G12C signaling without affecting wild-type KRAS protein. Nonclinical pharmacology studies demonstrate that FMC-376 inhibits tumor cell growth and viability in cells harbouring KRAS G12C mutation and results in tumor regression in multiple mouse models including PDX models of NSCLC, PDAC and CRC. FMC-376 demonstrated the ability to overcome mechanisms associated with innate and acquired resistance to the first generation KRASG12C (off) only inhibitors. [1]. Methods: This clinical study is global and is designed to evaluate the safety, tolerability, PK/PD and anti-tumor activity of FMC-376. Phase 1A (Dose Escalation) may enroll ~83 participants, Phase 1B (Dose Expansion) in tumor specific cohorts may enroll ~120 participants to optimize dosing and Phase 2 (Cohort Expansion) may enroll multiple tumor specific cohorts. Phase 1A includes participants who have progressed on or are ineligible for available standard approved therapies including KRAS G12C inhibitors. Participants will be enrolled into 1 of 5 escalating dose levels. BOIN design will be employed with a single Cohort, accelerated titration. Key eligibility criteria include histologically or cytologically confirmed locally advanced/unresectable or metastatic solid tumors with KRAS G12C mutations, ECOG 0-1 and adequate hematologic, hepatic and renal function. Participants with stable treated brain metastases may be eligible, but participants with leptomeningeal disease or carcinomatous meningitis are not eligible. FMC-376 will be administered PO QD for 21-day cycles until PD. Key objectives include establishing doses, based on incidence of DLTs, identifying SAEs/AEs and changes in ECG parameters, characterizing the PK profile and evaluating the clinical activity of FMC-376 via RECIST v1.1. In addition, FMC-376 target engagement and changes in expression of RAS pathway genes will be evaluated. A dose escalation and safety committee will be established to oversee the dose escalation portion of the study. The study is open to enrollment as of February 2024, NCT06244771. 1. AACR 2023 Annual Meeting Discovery of FMC-376 a novel orally bioavailable inhibitor of activated KRASG12C Kevin Webster, April 16, 2023. Clinical trial information: NCT06244771 .
A phase 1/1b first-in-human (FIH) study of JZP898 as monotherapy and in combination with pembrolizumab in adult patients with advanced or metastatic solid tumors.
Authors: McKean Meredith , Hutson Thomas E. , Piha-Paul Sarina A. , Micaily Ida , Liao Mingxiang , Humphreys Robin , Brock Graham , Sahr Natasha , Amber Vian , Spira Alexander I. 
Published: June 2024

TPS3190 Background: JZP898 is a conditionally activated prodrug of interferon alpha (IFNα) that can preferentially deliver IFNα to the tumor microenvironment while potentially minimizing systemic IFNα therapy-associated toxicity. Antitumor activity of IFNα is well-established, but concerns regarding systemic toxicity restrict its use in clinical practice. JZP898, in combination with a checkpoint inhibitor such as pembrolizumab, may provide lasting and potent antitumor activity with minimal additive toxicity attributed to conventional or pegylated IFNα. This phase 1 FIH study will determine a maximum tolerated dose (MTD)/recommended dose (RD) and investigate safety, tolerability, pharmacokinetics (PK), immunogenicity, and preliminary antitumor activity of JZP898 monotherapy and JZP898 combined with pembrolizumab in adult patients with advanced or metastatic solid tumors. Methods: This phase 1, FIH, open-label, multicenter study (NCT06108050) is investigating JZP898 intravenous infusion in adult patients (≥18 years old) with histological or cytological diagnosis of advanced or metastatic solid tumors, European Cooperative Oncology Group performance status ≤1, and measurable disease per RECIST v1.1 criteria. The study consists of a dose finding phase (JZP898 as monotherapy and in combination with pembrolizumab; Part A) and a combination dose expansion phase (JZP898 in combination with pembrolizumab; Part B). In Part A (dose finding), the JZP898 MTD and/or monotherapy RD will be determined using Bayesian optimal interval (BOIN) design based on the incidence of dose-limiting toxicities (DLTs) and all available safety and PK data; the combination recommended phase 2 dose (RP2D) will be determined using BOIN criteria and all available safety, PK/PD, immunogenicity, and preliminary signal of antitumor activity data. Patients will be treated until disease progression, death, unacceptable toxicity, or withdrawal from the study. All patients will be followed for survival until 18 months after the last patient starts study intervention. Primary endpoints include: the incidence and nature of DLTs (Part A); investigator-assessed objective response rate (ORR) per RECIST v1.1 (Part B); the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events; changes in laboratory values or vital signs; and the incidence of dose modifications or discontinuations due to TEAEs. Secondary endpoints include: PK parameters; incidence of antidrug antibodies; investigator-assessed duration of response; progression-free survival; disease control rate; investigator-assessed ORR (Part A); and overall survival (Part B). The study is actively enrolling patients with a planned enrollment of up to 177 patients. Clinical trial information: NCT06108050 .
SWOG S2107: Randomized phase II trial of encorafenib and cetuximab with or without nivolumab for patients with previously treated, microsatellite stable, BRAFV600E metastatic and/or unresectable colorectal cancer.
Authors: Morris Van K. , Guthrie Katherine A. , Kopetz Scott , Breakstone Rimini , Karasic Thomas Benjamin , Hu Zishuo Ian , Colby Sarah , Fakih Marwan , Gholami Sepideh , Gold Philip Jordan , Chiorean E. Gabriela , Philip Philip A. 
Published: June 2024

TPS3640 Background: Patients with microsatellite stable (MSS), BRAFV600E metastatic colorectal cancer (mCRC) experience poor survival outcomes. Second-line treatment with the BRAF inhibitor encorafenib (E) and anti-EGFR antibody cetuximab (C) is an approved treatment combination, with overall response rate (ORR) of 20% and median progression-free survival (PFS) of 4.1 months. Anti-PD-1 antibodies like nivolumab (N) are ineffective as monotherapy for patients with MSS, BRAFV600E mCRC. In preclinical models of MSS, BRAFV600E CRC, inhibition of BRAF and EGFR induces loss of expression of mismatch repairs genes and promotes a microsatellite instability-high phenotype, which may prime these tumors for response to immunotherapy. In support of these findings, a single-institution clinical trial of E + C + N for 26 patients with MSS, BRAFV600E mCRC reported an ORR of 50% and median PFS of 7.2 months. We hypothesize that the addition of N to E + C will improve median PFS for patients with MSS, BRAFV600E mCRC. Methods: In this prospective phase II clinical trial (N=84), patients with previously treated MSS, BRAFV600E mCRC are randomized 2:1 into 2 arms, respectively: experimental treatment (E + C + N) or standard treatment (E + C). No prior BRAF, EGFR, or immunotherapy agents are allowed. All patients receive E (300 mg PO daily) and C (500 mg/m2 IV every 14 days), and patients in the experimental arm receive N (480 mg IV every 28 days). The primary endpoint is PFS. Secondary endpoints include overall survival, best overall response, duration of response, and safety/tolerability. Using a one-sided α= .10 and power 80%, we target an improvement in median PFS from 4.2 to 7.3 months (hazard ratio 0.57). Additional patient specimens will be collected for exploratory correlative research. As of 2/2024, 50 of 84 planned participants have been enrolled. Clinical trial information: NCT05308446 .