bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of short-term death and long-term survival in advanced hepatocellular carcinoma (HCC) treated with contemporary tyrosine kinase inhibitors (TKI) or immunotherapy: A multicenter analysis from the HCC-CHORD consortium.
Authors: Dibajnia Pooya , Freeman Mark , Krishnan Tharani , LEE Cha Len , Ramjeesingh Ravi , Solar Vasconcelos Joao Paulo , Lyubetska Hanna , Provost Esther , Li Jessica , Ding Philip Q. , Lim Howard J , Knox Jennifer J. , Gordon Vallerie Lynn , Cheung Winson Y. , Tam Vincent C. , Meyers Brandon M.
Published: June 2024

4098

Background: Advances in systemic therapy for HCC have increased treatment options, including TKIs and immunotherapy combinations. Variables that predict patient outcomes may be helpful in personalizing treatment decisions. The aim of this study was to identify predictors of short-term death (STD) and long-term survival (LTS) for HCC patients. Methods: Retrospective review of patients with advanced HCC who received a TKI or immunotherapy combinations was conducted between Aug 2018 to Aug 2022 in the Canadian provinces of British Columbia, Alberta, Nova Scotia, Manitoba, as well as from select institutions in Ontario (n = 2). Prior locoregional therapies were permitted. Variables examined were: Barcelona Clinic Liver Cancer (BCLC) stage, Child-Pugh class, albumin-bilirubin (ALBI) grade, alpha fetoprotein (AFP) level, microvascular invasion (MVI), and distant metastases. Multivariate logistic regression was used to determine independent predictors of STD (patient survival < 6 months vs others) and LTS (patient survival > 18 months vs others). Results: 520 patients with the following baseline characteristics were included: median age 66, 84.6% male, 87.4% ECOG performance status 0-1, 69.7% BCLC stage C, and 88.7% Child-Pugh A. First-line treatments were primarily: lenvatinib 57.3%, sorafenib 8.1%, and atezolizumab/bevacizumab 31.7%. Median progression-free survival was 7.4 months (95% CI: 6.2 to 8.4), and overall survival was 17.1 months (95% CI:, 15.1 to 18.8). Independent predictors of STD were (odds ratio): ALBI grade (2.26), MVI (2.13), and distant metastases (2.14). These three factors were also predictive for LTS: ALBI grade (0.45), MVI (0.49), and distant metastases (0.36). Child-Pugh class, AFP, and BCLC stage were not predictive of STD nor LTS (Table). Conclusions: This study supports higher ALBI grade, MVI and distant metastases as predictors of STD, while lower ALBI grade, absence of MVI and lack of distant metastases were predictive of LTS in HCC patients treated with contemporary TKIs or immunotherapy combination regimens. These predictors may help guide treatment decisions in patient populations underrepresented in clinical trials, including patients with Child-Pugh B7 score who are often excluded. [Table: see text]
OPTIMIZE-1 primary analysis: Safety, efficacy and biomarker results of a phase 1b/2 study combining CD40 agonist mitazalimab with mFOLFIRINOX in previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Van Laethem Jean-Luc , Borbath Ivan , Geboes Karen Paula , Cassier Philippe Alexandre , Lambert Aurélien , Mitry Emmanuel , Prenen Hans , Pilla Lorenzo , Blanc Jean-Frédéric , Gallego Jiménez Inmaculada , Pazo Cid Roberto A. , Rodríguez Garrote Mercedes , Feliú Jaime , Nordbladh Karin , Enell Smith Karin , Gomez Jimenez David , Ellmark Peter , Pico de Coaña Yago , Ambarkhane Sumeet Vijay , Macarulla Teresa
Published: June 2024

4133

Background: With a 5 year overall survival (OS) rate <5%, PDAC is a leading cause of cancer related mortality. Currently available systemic therapies are not curative and new therapeutic options are needed. Mitazalimab is a human CD40 agonistic IgG1antibody that reduces immune suppression, sensitizes the tumor to chemotherapy, and induces long lasting anti-tumor T cell responses. OPTIMIZE-1 (NCT04888312) is a Phase 1b/2, open label, multicenter study assessing mitazalimab's safety and efficacy combined with mFOLFIRINOX (mFFX) in chemotherapy naïve mPDAC patients (pts). Methods: In the first 21 day cycle, mitazalimab was administered on day 1 and 10 and mFFX infusion started on day 8. In subsequent cycles, treatment followed a 14 day cycle with mitazalimab given 2 days after mFFX. The primary endpoint is objective response rate (ORR) compared to 30% ORR for FFX (Conroy, 2011) (80% power; α (1-sided) =0.10). Secondary and exploratory endpoints include Duration of Response (DoR), progression free survival (PFS), OS, safety, PK and PD biomarker assessments. Results: Seventy pts with mPDAC were treated with mFFX + mitazalimab (safety set: 5 at 450 µg/kg and 65 at 900 µg/kg). 57 patients at 900 µg/kg received ≥2 treatment cycles and were efficacy evaluable. The most common grade ≥3 AEs were neutropenia (25.7%), anemia (11.4%), hypokalemia (15.7%) and thrombocytopenia (11.4%), consistent with FFX safety profile. Two pts discontinued treatment due to AEs. Confirmed ORs were observed in 23 pts (40.4%), including 1 complete responder (CR). Median OS, PFS and duration of Response (DoR) were 14.3 months (mo), 7.4 mo and 12.5 mo respectively, with a median follow up of 12.7 mo. 29 pts (51%) remain in the study (32% on treatment, 19% in survival follow up). Efficacy results including correlation with detected KRAS G12 mutations are summarized (Table). Conclusions: Mitazalimab in combination with mFFX is a feasible regimen with a manageable safety profile. The primary endpoint was met; KRAS G12 V and R mutations were associated with better efficacy. Given the promising DoR linked with survival benefit in previously untreated mPDAC, these results merit continued development of mitazalimab in a confirmatory phase 3 study. Clinical trial information: NCT04888312 . [Table: see text]
Penpulimab combined with anlotinib and nab-paclitaxel plus gemcitabine (PAAG) as first-line treatment for metastatic pancreatic cancer: A prospective, multicenter, single-arm, phase 2 study.
Authors: Du Juan , Tong Fan , Sha Hui-zi , Sun Yi , Zhu Yahui , Qi Liang , Li Xiaoqin , Li Wei , Yang Yan , Li Zeqing , Xu Caihua , Ni Jiayao , Gu Qing , Zhang Xing , Zhu Chan , Wang Xiaoxuan , Liu Baorui
Published: June 2024

4135

Background: Chemotherapy currently serves as the cornerstone for treating metastatic pancreatic cancer (mPC). Nevertheless, the survival of patients with mPC remains poor. Besides, the efficacy of single-agent immune checkpoint inhibitors or antiangiogenesis in the treatment of mPC is not satisfying. Therefore, it is important to explore combination therapy options for patients with mPC. This trial was conducted to evaluate the effectiveness and safety of penpulimab combined with anlotinib and nab-paclitaxel plus gemcitabine (PAAG) for mPC. Methods: This was a prospective, multicenter, single-arm phase II trial. Eligible pts were those who aged over 18 years, histologically or cytologically confirmed PC, have not received treatment before and radiographically showed distant metastases and measurable lesions. Patients received penpulimab (200mg, IV, D1) and Anlotinib (12mg, P.O, QD, D1-14), in addition to nab-paclitaxel (125mg/m2, I.V, D1,8) and gemcitabine (1.0g/m2, I.V, D1,8), administered over a 21-day treatment cycle. The primary endpoint was objective response rate (ORR) and disease control rate (DCR). Secondary end points included Progression-free Survival (PFS), overall survival (OS) and safety. Immune microenvironmental features of baseline were analyzed as exploratory results (NCT05493995). Results: 66 pts were enrolled and received PAAG therapy, and the last follow-up time was December 31, 2023. All pts were eligible for response evaluation. The ORR was recorded at 50% (33/66) (95% CI, 37.4%-62.6%), with 33 pts achieving partial response. The DCR was 95.5% (63/66) (95% CI, 87.3%-99.1%). With median follow-up duration of 12.8 months, median PFS was 8.8 months (95% CI, 8.1–11.3) and median OS was 13.7 months (95% CI, 12.4-not reached). The most common TRAEs were anaemia, leukocytopenia, fatigue and rash. Grade 3 TRAEs were reported in 36.4% pts (24/66). In exploratory analysis, higher T cell recruiting score and lower baseline serum CA72-4 level were detected in PR pts compared with SD/PD pts. Furthermore, the B cell, NK CD56dim cell and Th9 cell scores were up-regulated in PFS-long pts. Conclusions: PAAG regimen as first-line treatment was demonstrated to be tolerable, with promising anti-tumor activity in mPC. The identified biomolecular markers revealed potential to guide precision treatment of PAAG for mPC. Clinical trial information: NCT05493995 .
NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Updated overall survival analysis with 29-month follow-up of NAPOLI 3.
Authors: Hussein Maen A. , Khan Gazala , Chandana Sreenivasa R , Pazo Cid Roberto A. , Kiss Igor , Gallego Javier , Macarulla Teresa , De La Fouchardiere Christelle , Goetze Thorsten , Dean Andrew Peter , O'Reilly Eileen M. , Wainberg Zev A. , Lee Woo Jin , Van Cutsem Eric , Hubner Richard , Paulson Andrew Scott , Bekaii-Saab Tanios S. , Pant Shubham , Maxwell Fiona , Melisi Davide
Published: June 2024

4136

Background: NAPOLI 3 (NCT04083235, N = 770), a global, randomized, open-label phase 3 study, demonstrated that NALIRIFOX significantly improved overall survival (OS, primary endpoint) and progression-free survival compared with nab-paclitaxel and gemcitabine in patients with untreated mPDAC. Here, we report an updated analysis of OS. Methods: Eligible patients with histopathologically/cytologically confirmed untreated mPDAC were randomized (1:1) to receive liposomal irinotecan 50 mg/m2 + oxaliplatin 60 mg/m2 + leucovorin 400 mg/m2 + 5-fluorouracil 2400 mg/m2 (NALIRIFOX, n = 383) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 (Gem+NabP, n = 387) on days 1, 8 and 15 of a 28-day cycle. Randomization was stratified by ECOG performance status, geographic region and presence/absence of liver metastases. An updated OS analysis (data cutoff: 3 October 2023) was conducted. Kaplan–Meier methods were used to estimate median (95% confidence interval [CI]) OS and hazard ratios (HRs [95% CI]) were estimated using stratified Cox proportional hazard models. The difference between groups was tested using a stratified log-rank test. Results: The median follow-up for OS was 28.7 months in the NALIRIFOX arm and 29.7 months in the Gem+NabP arm. At data cutoff, 11 patients were still receiving study treatment, all of whom were in the NALIRIFOX arm. With a total of 673 OS events (NALIRIFOX, n = 328; Gem+NabP, n = 345), median OS was 11.1 months (95% CI 10.0–12.1) in the NALIRIFOX arm compared with 9.2 months (8.3–10.6) in the Gem+NabP arm (HR 0.84 [95% CI 0.72–0.98]; nominal p = 0.026). At 12 months and 18 months, survival rates were 45.6% (95% CI 40.5–50.5) and 26.6% (22.2–31.1), respectively, in the NALIRIFOX arm and 39.6% (34.7–44.5) and 20.0% (16.1–24.1), respectively, in the Gem+NabP arm. Conclusions: In this 29-month follow-up of NAPOLI 3, NALIRIFOX continued to demonstrate improved OS compared with Gem+NabP, with 11 patients still receiving the NALIRIFOX regimen. These data confirm NALIRIFOX as a new possible standard of care and reference regimen for the first-line treatment of patients with mPDAC. Clinical trial information: NCT04083235 .
Primary prophylaxis with pegylated-granulocyte colony-stimulating factor for patients with unresectable pancreatic cancer treated with modified-FOLFIRINOX: A randomized phase II trial.
Authors: Lee Choong-kun , Kim Il-Hwan , Kim Chang Gon , Choi Hye Jin
Published: June 2024

4145

Background: Pancreatic cancer patients treated with FOLFIRINOX often suffer from severe neutropenia leading to dose reductions and sometimes fatal outcomes. However, there is no high-level evidence for primary prophylaxis of peg-GCSF for those patients. We report the result of a multi-institutional, open-label, randomized phase II trial of the peg-GCSF for unresectable pancreatic cancer patients treated with first-line modified-FOLFIRINOX. Methods: Treatment-naïve patients with histologically confirmed locally advanced or metastatic pancreatic cancer from two Korean cancer centers were enrolled. Patients received oxaliplatin 85mg/m2 D1 + leucovorin 400mg/m2 D1 + irinotecan 150mg/m2 D1 + 5-FU 2,400mg/m2 46h continuous infusion, every other week. After 1:1 randomization, peg-GCSF (pegteograstim 6 mg, GC Biopharma Corp.) was administered on day 4 for initial 8 cycles for primary prophylaxis group, where no G-CSF was given for control group. Crossover to administer peg-GCSF was permitted if patients in control group developed grade 3-4 neutropenia during initial 8 cycles. Co-primary endpoints were grade 3-4 neutropenia or febrile neutropenia during initial 8 cycles of mFOLFIRINOX. Secondary endpoints included relative dose intensity (RDI), patient reported quality of life, bone pain, and survival. Results: Between Feb 2022 and Jan 2024, 38 patients were randomized to peg-GCSF primary prophylaxis group and 39 patients were randomized to control group. Peg-GCSF group patients had significantly less grade 3-4 neutropenia during initial 8 cycles of mFOLFIRINOX, compared to the control (1/38, 2.6% vs 15/39, 38.5%, P=0.0001). None of peg-GCSF group patients experienced febrile neutropenia, where 5 patients (12.8%) experienced febrile neutropenia in control group. Cumulative RDIs of mFOLFIRINOX until progression or 8th cycles were similar between two groups with 93%. Although this trial was not powered for survival comparison, median PFS (9.0 vs 7.3 months) was numerically longer for peg-GCSF group compared to control. OS was not reached for both arms, but hazard ratio was 0.48 for peg-GCSF group. Conclusions: Primary prophylaxis with peg-GCSF significantly reduced grade 3-4 neutropenia and febrile neutropenia in patients with locally advanced or metastatic pancreatic cancer treated with mFOLFIRINOX events. Considering the study design of permitting the crossover, cumulative RDI was similar. Further follow-up of survival and quality of life results will be presented. Clinical trial information: KCT0006536 .
The function of KRAS4B isoform in pancreatic cancer.
Authors: Wang Kexin , Sangüesa Laura Beltran , Kalla Daniela , Pauli Theresa , Schnieke Angelika , Flisikowska Tatiana , Flisikowski Krzysztof
Published: June 2024

4147

Background: Pancreatic ductal adenocarcinoma (PDAC) remains a significant challenge in the field of oncology, demanding the creation of models that faithfully replicate the human condition to aid in early diagnosis and the discovery of effective treatments. To address this need, we have developed the genetically engineered pig PDAC model. The model closely recapitulates the pathophysiological aspects of the human disease, including disease progression, histopathological subtypes of tumors, and the occurrence of metastasis. Alternative splicing variants have been proven to be novel targets in PDAC. KRAS undergoes mutations in PDAC more often than any other oncogene. The distinction between the two KRAS isoforms arises from the alternative splicing of exon 4 within the KRAS locus, resulting in the expression of major KRAS4A and minor KRAS4B splice isoforms, with KRAS4B is understudied, and functions in cancer are unknown. Based on this strong rationale, we initiated a study to functionally validate the role of the KRAS4B isoform in PDAC. Methods: qPCR was carried out to determine the expression level of KRAS4A and KRAS 4B in PDAC tumors and cell lines as well as in different tissues. To investigate the function of KRAS4B, we generated two pancreatic cancer cell lines harboring the genetic signature of PdxCre/KrasG12D/p53R167H mutation (KPC) or PdxCre/KrasG12D mutation (KC). Using CRISPR/Cas9 technology to knockout KRAS4B isoform. Additionally, we designed a vector for investigating the overexpression of KRAS4B. Results: At the molecular level, we revealed a differential expression of KRAS isoforms 4A and 4B in PDAC tumors and cell lines. Notably, the KRAS4B isoform was exclusively expressed in the advanced stages of PDAC. At the cellular level, we successfully disrupted the KRAS4B isoform in both cell lines. The overexpression vector of KRAS4B has been successfully constructed for further analysis. Subsequent functional assays will encompass analyses of mRNA and protein expression levels, along with assessments of key cellular behaviors, including proliferation, invasion, migration, and morphological alterations. Moreover, we will discern changes in tumor subtypes by examining the distinct expression patterns of epithelial and mesenchymal markers. Conclusions: Therefore, we engineered KRAS4B knockout and overexpression vectors to investigate its role in PDAC, utilizing our cell lines derived from our genetically engineered pig model. This approach offers a robust platform that enhances the bridge between translational and preclinical research in studying PDAC.
Investigating racial, gender, and socioeconomic disparities in early-onset versus late-onset colorectal cancer: An analysis using the NIH All of Us database.
Authors: Eun Yong , Olusoji Rahman Adesoji , Osei Noah , Omore Ibrahim , Ahluwalia Meena
Published: June 2024

e15520

Background: Colorectal cancer (CRC) is a significant public health concern, with disparities based on race, gender, and socioeconomic status increasingly recognized. The incidence of early-onset CRC (EOCRC) is rising, highlighting the need for detailed examination of disparities in EOCRC compared to late-onset CRC (LOCRC). This study utilizes the NIH All of Us database to explore these disparities. Methods: We conducted a cross-sectional analysis of 266,520 participants from the NIH All of Us Registered Tier Dataset v7. CRC cases were identified based on at least two recorded diagnoses in electronic health records. Participants were categorized into EOCRC if diagnosed before age 50 and LOCRC if diagnosed at age 50 or above. We compared demographic and socioeconomic variables, including gender, race/ethnicity, income, education, and smoking status, between the groups, using questionnaire responses. Statistical analyses were performed using R. Results: The average age at diagnosis was 42.1 years for EOCRC patients and 63.7 years for LOCRC patients. The EOCRC group had a higher proportion of females (57.8%) compared to the LOCRC group (49.2%, p = 0.006). Whites constituted the majority in both categories, but Hispanics were significantly more represented in the EOCRC group (21.1%) compared to the LOCRC group (11.1%, p < 0.001). Individuals with a higher income (more than $100,000 per year) were more prevalent in the EOCRC group (29.9%) than in the LOCRC group (17.7%, p < 0.001). There was no significant difference in education levels between the two groups (p = 0.52). A history of smoking 100 or more cigarettes was less common in EOCRC patients (32.8%) than LOCRC patients (48.1%, p < 0.001). Conclusions: This analysis highlights significant disparities in racial and gender representation as well as income level. Despite observed differences between the two groups, Hispanics, females, and higher income alone may not explain the only influencing factors as other cofounders, like insurance level, may have impacted the result. Cigarette exposure was more prevalent in the LOCRC group, which may represent a stronger environmental influence on CRC within this group. These findings highlight the need for further research to understand the underlying causes of these disparities and to develop targeted interventions. By addressing these disparities, we can move towards more equitable outcomes across all populations. [Table: see text]
Racial differences in genomic profiles and clinical outcomes of patients with colorectal carcinoma: A single institution retrospective study.
Authors: Titus Abraham , Lund Alexander , Sharma Gaurav , Escobar Daisy E , Abdalla Ahmed
Published: June 2024

e15582

Background: In the era of precision oncology, there is an immediate need to study the heterogeneity of molecular biology and clinical outcomes in racially diverse colorectal cancer (CRC) patients. Black patients are known to have poorer outcomes compared to their white counterparts. Understanding differences in patients’ molecular and genomic profiles may help explain these racial disparities. Methods: Demographic and clinical outcome data was abstracted from medical records of colorectal cancer patients who were diagnosed between 2008 and 2021 at The University of South Alabama. Tumor only next generation sequencing (NGS) of DNA (592 or WES) and RNA (WTS) was performed at Caris Life Sciences (Phoenix, AZ). Overall survival (OS) was defined as time from diagnosis to death or last contact. Descriptive analyses were performed using t-test and chi-square test, survival analyses were performed using Kaplan-Meier method and Log rank test (GraphPad Prism version 10.1.1). Results: 66 patients with CRC were included, 73% were white and 27% were black. The median age for white patients was 60.5 years and for black patients was 55.5 years (p = 0.049). In the white population, 52.1% of the patients were male and 47.9% were female. In the black population, 33.3% were male and 66.7% were female. The most common sites of malignancy for white patients were rectum (32.6%) and sigmoid (26.1%), whereas for black patients the most common sites were sigmoid (27.8%) and cecum (22.2%). Overall, the most common mutations were TP53 (68.2%), APC (65.2%), KRAS (47%), SMAD4 (16.7%), and FBXW7 (13.6%). The prevalence rates of TP53 (77.8 vs 64.6%), APC (72.2 vs 62.5%), KRAS (66.7 vs 39.6%), and SMAD4 (27.8 vs 14.6%) trended higher in black patients, with KRAS being statistically significant (p = 0.049). FBXW7 trended higher in white patients (14.6 vs 11.1%). Eleven (23%) white patients had a variant of uncertain significance in the ATM gene, which was not observed in black patients. More white patients had stage IV disease compared to black patients (69% vs 50%). No statistically significant difference in OS was found between races (HR 0.68, 95% CI of 0.35 to 1.3, p = 0.2). However, white patients had a median OS of 1334 days compared to 927 days for black patients. Conclusions: White and black CRC patients have unique molecular tumor profiles that may better explain the differences in survival. Our results warrant larger studies with racially and ethnically diverse patient populations to explore these racial disparities and close the gap in colorectal cancer care.
Simultaneous operations in patients with colorectal cancer with liver metastases.
Authors: Islamov Hurshid , Tillyashaykhov Mirzagaleb , Saydullaev Sunnatilla , Ziyaev Yakhyo , Ten Yakov , Sobitov Abdurakhmon , Khudoyorov Sanzhar , Botir Karakhodjaev , Yusupov Adxamjon
Published: June 2024

e15586

Background: Metastatic colorectal cancer (CRC) treatment is a complex process involving surgical oncologists, chemotherapy specialists, and radiation oncologists. Objective: To assess the long-term outcomes of treating patients with metastatic CRC who has gone through simultaneous liver operations. Methods: Data and medical records of 61 patients with primary metastatic CRC treated at the Republican Specialized Scientific-Practical Center of Oncology and Radiology of the Republic of Uzbekistan between 2016 and 2020 were reviewed. Disease diagnosis and treatment were conducted following the current recommendations of the Ministry of Health of the Republic of Uzbekistan. The median follow-up period was 35 months. Results: The mean age of the patients included in the study was 59.1 years (ranging from 36 to 81 years). Of them, 32 male and 29 female patients. Metastatic cancer of the rectum was diagnosed in 18 patients (29.5%), rectosigmoid junction in 9 (14.8%), and colon in 34 (55.7%). Among the patients, 3 had low-grade tumor differentiation, 24 had medium-grade, and 34 had high-grade. According to the "T" criterion, 65.6% of the tumors were categorized as T3, 29.5% as T4, and 4.9% as T2. Different types of surgeries were performed for primary tumor localization, including abdominoperineal resection of the rectum (2 patients), right hemicolectomy (10 patients), rectal resection (5 patients), rectosigmoid junction resection (4 patients), colon resection (6 patients), left hemicolectomy (5 patients), and transabdominal rectal resection (4 patients). Postoperative complications were observed in 16 patients (bile leakage from drainage, wound suppuration, pneumonia, bladder atony). Anastomotic complications were detected in 2 patients. There were no deaths in the early postoperative period. The median overall survival was 36 months. The one-year overall survival rate in the overall group was 91.7% ± 3.7%, two-year - 76.2% ± 5.6%, three-year - 51.9% ± 7.5%. For colon cancer, the three-year overall survival was 62.7% ± 9.3%, rectosigmoid junction - 43.2% ± 20.8%, rectal cancer - 36.8% ± 13.7 (p = 0.974). Conclusions: Simultaneous operations for CRC and liver metastases combined with combination therapy contribute to stabilizing the tumor process and increasing overall survival rates.
A single-sample gene-expression classifier for the intrinsic consensus molecular subtypes in colorectal cancer.
Authors: Tsantoulis Petros , Hong Yourae , Wirapati Pratyaksha , Pu Ting , Peddle Allyson , McKee Thomas , Tejpar Sabine
Published: June 2024

e15587

Background: An analysis of colorectal cancer epithelial cells showed two intrinsic subtypes called iCMS2 and iCMS3, in addition to the bulk consensus subtypes (CMS1-4). The intrinsic subtypes are prognostically important. We present a robust method for calculating the iCMS subtypes in individual samples, as opposed to batches, applicable in a clinical setting. Methods: We selected the subset of iCMS genes (N = 201) with the strongest epithelial expression in colorectal cancer, aiming to reduce the signal from other cell types. We then calculated gene expression centroids by taking the per-gene mean expression of 8 random samples from three non-batch corrected datasets (1779 samples total) that were previously used to derive the iCMS subtypes. Thirty-two centroids were calculated per dataset and per iCMS, for a total of 192 centroids. The single sample classifier (SSC) calculates the most likely iCMS class based on the class of the nearest centroid by non-parametric correlation distance. A confident call is made when the correlation is at least 0.1 and distance from the nearest centroid of the opposite iCMS class is greater than 0.05. Results: The SSC achieved 98.3% agreement with the reference calls in training data. The SSC was applied to unseen data for validation, by classifying non-batch corrected samples one at a time. The same data were clustered with the reference published iCMS public dataset and the reference iCMS was estimated at the batch level by proximity to reference samples in the hierarchical tree structure. Concordance between reference and SSC calls was 91.4% in non-batch corrected data and only modestly improved to 93.9% when batch correction was applied, showing the robustness of this approach. Concordance remained acceptable even when non-confident SSC calls were included (86.9%). The proportion of calls that were judged confident with the SSC was 77.9%, slightly lower than the proportion of confident reference calls (87.6%). In addition, the SSC was applied to data from the VELOUR trial, for which reference iCMS calls were also available. The SSC iCMS was prognostic (HR 0.601 for OS in iCMS2 vs iCMS3, P < 0.00001) and performed at least as well as the reference iCMS (HR 0.669, P = 0.0004). Conclusions: The SSC reproduces the iCMS classification and appears robust to batch effect. The SSC calls are prognostic in clinical trial data. The SSC R package is available for download (https://github.com/CRCrepository/iCMS.SSC). [Table: see text]
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 .