bluuebunny/crossref_metadata_2025 huggingface dataset:
Retrospective study to estimate the prevalence of HER2-low breast cancer (BC) and describe its clinicopathological characteristics.
Authors: Viale Giuseppe , Niikura Naoki , Tokunaga Eriko , Aleynikova Olga , Hayashi Naoki , Sohn Joohyuk , O'Brien Ciara , Higgins Gavin , Varghese Della , James Gareth D , Moh Akira , Scotto Nana
Published: June 2022

1087

Background: Approximately 50% of BCs traditionally categorized as HER2 negative (HER2-neg) express low levels of HER2 (IHC 1+ or IHC 2+/ISH-; Miglietta, NPJ Breast Cancer 2021). HER2-targeted therapies for HER2-low metastatic BC (mBC) are under investigation (eg, T-DXd in the phase 3 DESTINY-Breast04 study; NCT03734029), but HER2 assays currently used to select patients (pts) for approved anti-HER2 therapies are optimized for high HER2 expression and are not validated for HER2-low detection. A recent study found relatively poor agreement (<70% interrater agreement) in evaluation of IHC scores of 0 and 1+ using current HER2 assays (Fernandez, JAMA Oncol 2022). Our objectives were to assess the prevalence of HER2-low among HER2-neg based on rescored HER2 IHC slides after training on low-end expression scoring and to describe pt characteristics of HER2-low vs HER2 IHC 0 mBC. Preliminary results are reported for 233 of 1000 planned pts. Methods: This multicenter, retrospective study (NCT04807595) included pts with confirmed HER2-neg unresectable/mBC diagnosed between 2015 and 2017. Local laboratories, blinded to historical HER2 scores, rescored HER2 IHC-stained slides. HER2 was assessed using Ventana 4B5 and other assays. BCs were categorized as HER2-low or HER2 IHC 0. The prevalence of HER2-low BC among pts originally scored as HER2-neg was measured. Demographics (eg, age, country, race) and clinicopathological characteristics were examined via medical charts/electronic health records. Concordance between historical HER2 scores and rescores was assessed. Results: HER2 rescores were obtained for 233 pts (mean age, 54 y). HER2-low prevalence was 63.2% overall and numerically greater in hormone receptor (HR)–positive vs HR-negative subgroups (66.1% vs 54.8%; Table). No notable differences in prevalence were seen among different HER2 assays or in demographic/baseline disease characteristics between the HER2-low and HER2 IHC 0 groups. Concordance rate between historical and rescored slides for HER2-status classification was 82.3%. The presentation will include an expanded data set (≈400 pts) with additional results. Conclusions: Data on HER2-low prevalence in BC is limited. Preliminary data from this study of mBC samples suggest a somewhat higher prevalence estimate (≈63%) than a previous study of primary BC samples (≈50%). Concordance was 82%; ongoing analyses with updated data will clarify the concordance between rescored and historical HER2 slides. These data can support development of best practices for identifying pts with HER2-low expression who may benefit from HER2-targeted therapies. Clinical trial information: NCT04807595. [Table: see text]
Eribulin mesylate versus eribulin plus anlotinib in patients with advanced or metastatic breast cancer: Results of a phase II study.
Authors: Liu Liping , Hu Zhe-Yu , Xie Ning , Yang Xiaohong , Xiao Huawu , Li Jing , Tian Can , Wu Hui , Lu Jun , Gao Jianxiang , Hu Xuming , Cao Min , Shui Zhengrong , Liu Bingliang , Ouyang Quchang
Published: June 2022

1094

Background: Eribulin mesylate is a structurally simplified, synthetic, macrocyclic ketone analogue of Halichondrin B. We investigated the efficacy and safety of eribulin monotherapy versus eribulin plus the oral anti-angiogenesis inhibitor anlotinib in patients with advanced or metastatic breast cancer. Methods: This Phase II study included adult Chinese patients with locally advanced or metastatic breast cancer previously treated with at least two chemotherapy regimens, including both anthracycline- and taxane-based therapy (NCT05206656). Patients were randomized (1:1) to receive eribulin (1.4 mg/m2, intravenously, on days 1−8), alone or in combination with anlotinib (12 mg orally once daily), in 21-day cycles. The primary endpoint was investigator-assessed disease control rate (DCR), per RECIST version 1.1. Key secondary endpoints included objective response rate (ORR), progression-free survival (PFS) and safety. Results: Between February 12, 2020, and July 22, 2021, 56 patients were randomized to eribulin (n=32) or eribulin plus anlotinib (n=24) (Table). Sites of metastasis were: bone (60.7%), lung (52.7%), liver (53.6%), lymph nodes (73.2%) and soft tissue (7.1%). Among all patients, the DCR was 66.7% versus 100% (treatment difference, 33.3%; P=0.007), the ORR was 37.0% versus 38.9%, and the median PFS was 3.7 months versus 9.7 months (adjusted hazard ratio, 0.20; 95% CI, 0.04 to 0.91; P=0.04) for patients receiving eribulin versus eribulin plus anlotinib, respectively. Among 36 (64.3%) patients with triple-negative breast cancer, the DCR was 55.6% versus 72.2% (treatment difference, 16.7%; P=0.300) and the median PFS was 3.6 months versus 9.7 months (log rank P=0.030) with eribulin alone versus eribulin plus anlotinib, respectively. The most frequent grade 3-4 adverse events in the eribulin and eribulin plus anlotinib groups were decreased neutrophil count (25.0% [n=8] vs. 29.2% [n=7]) elevated transaminase (6.3% [n=2] vs. 0.0%) and decreased thrombocyte count (3.1% [n=1] vs. 0.0%), respectively. Conclusions: Eribulin plus anlotinib was associated with a significantly better DCR, ORR and PFS than eribulin monotherapy in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. Clinical trial information: NCT05206656. [Table: see text]
Quality and content of online cancer information: An analysis of NCI-designated cancer center YouTube videos.
Authors: Kim Luke , Trejo Evelin , Idossa Dame , Duma Narjust , Velazquez Manana Ana I.
Published: June 2022

11041

Background: The internet and social media have become a common source of medical information. Previous analyses have found that YouTube videos disseminate biased cancer related information of low to moderate quality. We analyzed online information disseminated by NCI-designated Cancer Centers (CC) through their YouTube pages. Methods: We searched CC websites and online search engines to identify CC-specific YouTube pages. Our sample included each CC’s top 20 most-viewed videos uploaded during 2019, which were < 5 minutes long, and available in English or Spanish. We examined video content themes and speaker demographics. For patient education videos, we evaluated content understandability and quality of information using validated measures [i.e., Patient Education Materials Assessment Tool (PEMAT) and DISCERN]. Data was summarized using descriptive statistics. Results: A total of 31 of 64 clinical NCI-designated CC had dedicated YouTube pages. Only 6 (19%) CC had videos in languages other than English. A total of 402 videos were examined for content themes and demographic characteristics. 43% focused on patient education (n = 175), 36% research (n = 139), 24% survivorship (n = 95), and 13% clinical trials (n = 52). 32% (n = 119) of speakers were doctors and 18% (n = 65) patients. Perceived speakers’ ethnicity was 57% White (n = 229), followed by Asian (15%, n = 60), Black or African American (8%, n = 32), and Latinx (4%, n = 16). Perceived gender of speakers was 49% women (n = 197) and 51% men (n = 203). Most videos were understandable (91%, n = 159), but only 21% (n = 36) provided high quality information. Videos discussing treatments lacked discussion of risks, alternate options, and effects on quality of life. Conclusions: Most patient education videos uploaded to NCI-designated CC YouTube pages have low to moderate quality information and limited ethnic diversity of speakers. With ongoing trends of increasing misinformation spreading through social media, CC have an opportunity to create and disseminate high-quality, reliable, and comprehensive educational videos that meet the informational needs of patients with cancer and their caregivers.[Table: see text]
Female representation in oncology leadership in Africa: Analysis of trends in the African organization for cancer research and training in cancer (AORTIC).
Authors: Mutebi Miriam Claire , Aryeetey Naa Adorkor , Carson Laura M. , Alemu Haimanot Kasahun , Vanderpuye Verna D. , Hammad Nazik
Published: June 2022

11052

Background: Board membership in oncology organizations and invitation to speak at major oncology conferences is an established indicator of gender disparities in oncology leadership. Recent studies note an upward trend in female board membership and female speakers at oncology conferences in European and American contexts. However, little is known about trends of female representation in board membership and at oncology conferences in Africa. AORTIC is the premier African cancer organization and hosts a biennial conference, during which its council members are elected for a two-year term. The conference hosts over 1000 participants and is highly regarded internationally. As the largest gathering of African oncologists, the conference presents a unique opportunity for insight into workforce disparities and trends. This study presents an analysis of female council membership and speaker participation at the 2015, 2017, 2019 and 2021 AORTIC conferences. Methods: AORTIC conference programmes and AORTIC elections for council membership in 2015, 2017, 2019 and 2021 were analyzed for gender representation. Speakers were divided into categories including keynote speakers, facilitators, session speakers, panelists, and oral abstract presenters. For each AORTIC session, data was collected on speaker name, gender, and affiliated country. Participants who presented multiple times were counted multiple times, as their role often varied between sessions. Personal data and country affiliation was determined through online biographies of speakers and/or visual confirmation of professional photographs. A simple descriptive analysis of the data and trends is presented here. Results: Since 2015, the proportion of female speakers and council members at AORTIC has increased. In 2015, females accounted for 44% of speakers, in contrast to 55% in 2021. In 2021, females made up over 50% of all speaker categories except keynote. The proportion of female council members also increased, from 42% in 2015 to 69% in 2021. Trends in geographic representation of speakers were also analyzed for gender, revealing an increase in female speakers residing in Africa. (Table) Conclusions: The proportion of female speakers and council members at Africa’s largest cancer conference has increased significantly since 2015. Female speaker participation was higher than in North America and Europe in 2017 and surpassed 50 % in 2021. In addition, female council membership in AORTIC has surpassed 50%, up to 69% in 2021. These trends suggest a rise in female leadership in cancer research and training on the continent, indicating that strengthening local platforms in LMIC may be associated with improved gender assimilation. [Table: see text]
Gender and early career faculty disparities in hematology and medical oncology board review lectures series.
Authors: Al-Kraimeen Leen Mohammad , Syaj Sebawe , Akhdar Marah , Abushukair Hassan Mohammed , Mohty Razan , Al Hadidi Samer
Published: June 2022

11060

Background: Studies show that women and early career faculty members have less access to career development opportunities and leadership positions. These disparities slow the process of change and may affect leadership roles, promotions, and career advancements in academic medicine. Here, we provide the first analysis of speakers’ gender and early faculty disparities in hematology and medical oncology board review series. Methods: We performed a cross-sectional analysis of speakers at all major hematology and/or oncology board review series meetings, which were held in the United States between January 2017 and December 2021. Six major board review series were involved: Baylor/M.D. Anderson Cancer Center, the Brigham and Dana-Farber, George Washington School of Medicine and Health Sciences, Memorial Sloan Kettering Cancer Center, Seattle Cancer Care Alliance, and the American Society of Hematology. Details of the lectures were acquired via accessing brochures available on the institutions’ official websites. Data on board certification and maintenance of certificate (MOC) were obtained from the American Board of Internal Medicine (ABIM) website. We extracted the number of publications from the PubMed website (MEDLINE). Results: Our analysis included 1224 board review lectures presented by 386 speakers. Of which, 315 (81.6%) were American Board of Internal Medicine (ABIM) certified, and MOC was active in 56.1% of speakers. Females accounted for 37.7% of all speakers, with a representation of less than 50% in 5 out of 6 board review series. The least proportion of female participation was among lectures discussing malignant hematology topics (24.8%), followed by solid tumors (38.9%), and benign hematology topics (44.1%). Faculty members with more than 15 years of experience since initial certification presented more than half of the lectures. The median time from initial hematology or medical oncology certification to lecture presentation was 12.5 years and 14 years, respectively, which varied significantly among different series (p < 0.001). Speakers’ median number of publications was 84. We also investigated how frequently the same speaker gave lectures. Thirteen male speakers conducted more than or equal to 10 lectures across all board review series, compared to only two female speakers who did the same. An upward trend of improvement in females participation was found at all board review conference meetings across the years. Conclusions: Our data suggest that women and early career faculty members are underrepresented in hematology and oncology board review series. Therefore, efforts should be made to ensure equal participation of them in such important activities needed to advance academic careers.
GALLANT: A phase 2 study using metronomic gemcitabine, doxorubicin, nivolumab, and docetaxel as second/third-line therapy for advanced sarcoma (NCT04535713).
Authors: Adnan Noufil , Sekhon Simranjit , Chawla Sant P. , Kim Ted T. , Chua-Alcala Victoria S. , Fernando Mitchel , Ahari Amir , Feske William , Quon Doris V. , Gordon Erlinda Maria
Published: June 2022

11518

Background: In our experience, combinatorial therapy with lower doses of doxorubicin, gemcitabine, and docetaxel has been effective with a manageable toxicity profile in patients with advanced soft tissue sarcomas. Hypothesis: The addition of nivolumab will have synergistic effects and improve treatment outcomes. Methods: Primary objective: To assess progression-free survival; Secondary objectives: (1) To evaluate best overall response during treatment period confirmed in a 6-week follow-up, (2) PFS rate at 6 and 9 months, (3) Overall survival rate at 6, 12 months, and (4) Incidence of treatment-related adverse events (TRAEs). Inclusion criteria: Previously treated male and female subjects, > 18 years of age, pathologically confirmed diagnosis of locally advanced, unresectable, or metastatic sarcoma, measurable disease by RECIST v1.1, and acceptable hematologic and organ functions. Exclusion Criteria: History of autoimmune disorder. Treatment schedule: Metronomic doses of gemcitabine (600 mg/m2 max:1000 mg), doxorubicin (18 mg/m2; max: 32 mg), docetaxel (25 mg/m2; max:42 mg) on Day 1 and Day 8, and nivolumab (240 mg) on Day 1 only. Repeat treatment cycles may be given every three weeks if toxicity grade is <1. Results: This is an Interim Report on the modified Intent-to-treat population (n = 43). This population completed at least one treatment cycle and had a follow-up CT or MRI scan at week 6. The most common histological subtypes in this group include leiomyosarcoma (n = 15), pleomorphic sarcoma (n = 4), synovial sarcoma (n = 4), liposarcoma (n = 3), osteosarcoma (n = 3) and other (n = 10). Best Overall Response = 2 CR (surgical CR), 6 PR, 30 SD, 5 PD. The disease control rate (CR+PR+SD) was 88.4%. Median PFS was > 4.6 (range: 1-27) months; 4 month PFS rate 60%. Median OS 6.2 months, with 4-month OS 74%. Historically, the median PFS on preceding lines of therapy was 2 (range: 1-14) months. There were no unexpected side effects noted in this study. The most common grade 3/4 TRAEs include Fatigue (n = 13), Nausea (n = 9), Neutropenia (n = 8), thrombocytopenia (n = 6), Anemia (n = 6). Conclusions: The GALLANT protocol using metronomic Gemcitabine, Doxorubicin (Adriamycin), Nivolumab, and Docetaxel (Taxotere) (1) is an effective regimen as second/third-line therapy for advanced sarcoma with no unexpected side effects, and (2) may have synergistic activity when this metronomic chemotherapy is combined with an immune checkpoint inhibitor. Clinical trial information: NCT04535713.
Extended progression-free survival and long-term safety of nirogacestat in patients with desmoid tumors.
Authors: O'Sullivan Coyne Geraldine Helen , Kummar Shivaani , Steinberg Seth M. , Hogu Murielle , Takebe Naoko , Shah Amisha , Doroshow James H. , Chen Alice P.
Published: June 2022

11545

Background: Desmoid tumors are rare, locally invasive, soft-tissue neoplasms that can cause significant morbidity and frequently recur despite surgery or radiation. The ongoing phase II trial of nirogacestat, a gamma-secretase inhibitor, in patients (pts) with recurrent, refractory desmoid tumors (NCT01981551), has reported disease stabilization and multiple partial responses as assessed by RECIST criteria (Kummar JCO 2017). Herein, we report long-term outcomes, tolerability, and safety of this study. Methods: A total of 17 pts enrolled in this open label, single arm, phase II study, completing accrual in 2014. Pts received 150 mg nirogacestat orally twice a day in continuous 3-week cycles. Objective treatment response was defined by RECIST 1.1 at cycle 1 and every 6 cycles thereafter using CT (affected area) per the primary study objective; optional MRI assessment was concurrently performed. Yearly CT scans of the chest, abdomen, and pelvis were performed on pts starting in 2016. Results: As of Dec. 31, 2021, 4/17 (23%) pts remain on nirogacestat treatment for over 7 years. The objective response rate has not changed since the 2017 publication [31.25% (5/16 evaluable patients), with an exact two-sided Clopper-Pearson 95% confidence interval of 11.0-58.7%], but the observed extended progression-free survival (PFS) is notable; no RECIST disease progression has been observed for any of the 16 evaluable patients at any point on study. Median time on treatment was 4.14 years (range: 0.17-7.99 years). Most common adverse events remain hypophosphatemia (13/17, 76%; 8 grade 3 [gr3], 5 gr2), diarrhea (13/17, 76%; 1 gr3, 4 gr2, 8 gr1), nausea (11/17, 65%; 11 gr1), AST increase (11/17, 65%; 1 gr2, 10 gr1), and lymphopenia (11/17, 65%; 2 gr2, 9 gr1); no pts required a dose reduction after the second year of therapy. Bone fractures (fx) were reported in 4 pts (3 female/1 male) during the first 4 years of treatment (1 hip fx, 1 rib fx, 2 metatarsal stress fxs). Two of these 4 pts experienced a further fx approximately 1 year later (contralateral metatarsal; hip). Both pts with hip fx were > 10 years post-menopausal. Given median age at enrollment (34 years; range: 20-69 years) and reported fx events, bone health was evaluated with findings in keeping with expected range for age. No secondary malignancies have been identified to date. Conclusions: No patients receiving nirogacestat have progressed after a median of more than 4 years of treatment. The long duration of responses and lack of tumor progressions observed in this trial has informed the design of a phase III trial in pts with progressing desmoid tumors (NCT03785964) that is currently underway. Clinical trial information: NCT01981551.
Efficacy of liposomal doxorubicin in patients with intra- and extra-abdominal desmoid fibromatosis.
Authors: Dorand Rodney Dixon , Cohen Sean , Keedy Vicki Leigh , Borinstein Scott C. , Chugh Rashmi , Davis Elizabeth J.
Published: June 2022

11581

Background: Desmoid tumors (DT) or aggressive fibromatosis are rare growths of fibroblastic connective tissue that can be locally aggressive but without metastatic potential. Most cases are sporadic, but 5-20% of cases are associated with Familial adenomatous polyposis (FAP). Despite numerous systemic options, optimal choice is unclear, and there is a paucity of studies comparing efficacy based on tumor site. Liposomal doxorubicin (LD) can be an appealing option for DT patients (pts) given its favorable schedule and toxicity profile. In this study, we compared outcomes in pts with intra-abdominal (IA) and extra-abdominal (EA) DT who received LD. Methods: We identified pts with DT who were treated with LD between 1/2010 - and 2/2022 at two sarcoma centers. Tumor and pt characteristics and outcomes were clinically (symptom improvement) and radiologically (RECIST 1.1) assessed. Results: 40 pts with DT treated with LD were identified; 58% female and 42% male. Pt characteristics and outcomes are summarized in Table 1. Primary tumor site was IA in 21 (53%) pts. FAP was present more commonly in pts with IA vs EA DT, 8/21 (43%) and 4/19 (21%), respectively. In the IA cohort, LD was given as first (15/21, 71%), second (10%) or third (19%) line therapy. LD was used more commonly as a later line in the EA cohort with 16%, 52%, 16%, and 16% receiving it in first, second, third, and fourth lines, respectively. 37 pts were evaluable for response. Response rate in the IA cohort treated in first-line was 50% (8 of 16) and 10 of 12 evaluable pts had symptomatic improvement. No first-line responses were seen in the EA cohort. As later lines of therapy, 7/12 pts had disease control in the second line, 6/8 pts in the third line, and 1/2 pts in the fourth line with LD in the IA cohort. 1 patient had fourth line response to LD in the EA cohort. Disease control rate with LD was 72.5% across all pts. Reasons for early discontinuation of LD included progression or lack of symptom improvement (20%), allergic reaction (12.5%), adverse effects (7.5%), or infection (2.5%). No acute or long-term cardiotoxicity was reported. 2 pts had no signs of recurrence or symptoms at follow-up, 33 pts were alive with symptomatic DT, 1 patient died from disease, and 3 were lost to follow-up. Conclusions: In our study, LD provided tumor response, disease control, and symptomatic improvement regardless of location or prior therapy, with responses most frequently seen in IA DT in first line setting. Further studies should include comparison of efficacy, adverse effects, and patient-reported outcomes while accounting for tumor location and line of therapy. [Table: see text]
Interim analysis of a single-center, single-arm, prospective phase 2 study to evaluate the efficacy and safety of benralizumab for alpelisib rash in metastatic PIK3CA-mutant, hormone receptor–positive breast cancer.
Authors: Lacouture Mario E. , Pan Alexander , Dranitsaris George , Harris Ucalene , Chandarlapaty Sarat , Dang Chau T. , Gajria Devika , Gordon Allison , Iyengar Neil M. , Robson Mark E. , Razavi Pedram , Rosen Ezra , Wong Serena Tsan-Lai , Jain Manu , Moy Andrea , Markova Alina
Published: June 2022

12100

Background: Rash associated with increased peripheral eosinophils develops in approximately 50% of metastatic breast cancer patients receiving alpelisib. Antihistamines and corticosteroids have limited benefit. Refractory rash may lead to decreased dose intensity and affect clinical outcome. Benralizumab is an anti-IL-5Rα chimeric monoclonal antibody that depletes peripheral eosinophils and has demonstrated benefit in eosinophilic asthma and hypereosinophilic syndrome. We investigate the efficacy and safety of benralizumab for the treatment of alpelisib rash. Methods: We performed a single-center, single-arm, prospective phase 2 study to evaluate the efficacy and safety of benralizumab in cancer patients who developed CTCAE grade 2/3 skin events resulting from immunotherapy or targeted therapies with absolute blood eosinophil counts of ≥300/mcl. While remaining on culprit drugs, patients were treated with benralizumab 30mg once every 4 weeks for the first 3 doses followed by once every 8 weeks for 3 additional doses (approved dosing for eosinophilic asthma). Primary endpoint was clinical response measured as reduction in CTCAE grade 2/3 skin event to grade ≤1 by week 4. Secondary endpoints were patient quality of life (QoL) measured by skindex16, safety data, need for supportive oral corticosteroids, and changes in cytokines and eosinophil biomarkers. This interim analysis focuses on patients with PIK3CA-mutant metastatic breast cancer receiving alpelisib. Results: Between September 16th 2020 and January 1st 2022, we enrolled 10 metastatic breast cancer patients with grade 2/3 rash attributed to alpelisib (5 pts with G3). All patients had a reduction of rash to grade ≤1 (n = 10, p < 0.0001), and a decrease in peripheral absolute eosinophils (mean 500/mcl to 0, p < 0.0001). Of these, 6 patients had been on prophylactic oral antihistamines and 2 had oral steroid coadministration. QoL significantly improved (Skindex16 mean score 58 to 16, p = 0.0001) and eosinophils in skin histology decreased per HPF (mean 6.25 to 0.25, n = 8, p = 0.2) by week 4. An increase in IL-5 > 600% and reduction IL-6 and TNF-α > 50% were reported by week 4 and 8. Grade 1/2 mucositis in 4 patients were reported as adverse events. Conclusions: Our findings suggest that benralizumab is safe and effective for the treatment of grade 2/3 rash with eosinophilia related to alpelisib in patients with breast cancer. A reduction in rash severity was evidenced in all patients, along with improved QoL. Larger controlled studies are in development to evaluate the efficacy of benralizumab for the prevention of alpelisib rash. Clinical trial information: NCT04552288.
Evaluation of outcomes in patients (pts) with stage 4 non-small cell lung cancer (NSCLC 4) harboring actionable oncogenic drivers (AOD) when treated prior to report of mutation without tyrosine kinase inhibitors (TKI): An Integra Connect Database (ICD) retrospective observational study.
Authors: Smith Robert E. , Johnson Melissa Lynne , Gordan Lucio N. , Xue Mei , Varughese Prateesh , Dorrow Natalie A. , Wang Brandon , Vaidya Varun , Gart Mike , Gierman Hinco J. , Scott Jeffrey A.
Published: June 2022

1530

Background: In a prior analysis, we identified 525 pts with newly diagnosed NSCLC 4 harboring AOD in the ICD. Of these, 141 were treated prior to the reporting of AOD with chemotherapy (C), immune checkpoint inhibitor (ICI), or both. This report details the clinical outcomes of these 141 compared to the 384 treated after AOD reported. Methods: Real world data (RWD) were obtained from a curated ICD for pts with NSCLC 4 diagnosed 1/1/2018-12/31/2020 with cutoff of data 3/31/2021. Pts with EGFR, ALK, ROS1, BRAF, MET, RET, HER2, and NTRK were included if their treatment record were captured. Also included were demographics, ECOG score, date of first report of AOD and dates of initiations of first and any second line of therapy and date of apparent death (AD). Outcome measures were time to next treatment or apparent death (TTNT) and apparent survival (AS) (ICD model does not allow date of death per HIPAA de-identified Expert Determination). Descriptive statistics were used with Kaplan-Meier (K-M) estimates and Hazard Ratios (HR) by Cox regression. 3 cohorts were defined: Group (Gr) A with 384 pts treated after AOD reported and used as the comparator; the 141 pts treated before AOD with C, ICI or both were divided into Gr B (n = 51) who subsequently switched to TKI within 35 days and Gr C (n = 90) who did not switch. Results: As shown in data table, AS was significantly worse in Gr B and Gr C, TTNT was significantly worse in Gr C and with worsening trend in Gr B. Two potential confounders were identified: higher ECOG scores might indicate more urgency to assign treatment, but pts with ECOG ≥ 2 were similar in all 3 groups; also, difference in proportion of EGFRm by Group (Gr A 62%, Gr B 57%, and Gr C 29%), but separating cohorts by EGFR mutation status did not alter results. Conclusions: While subject to the limitations of a retrospective observational RWD study, this study strongly suggests outcomes are significantly compromised in pts harboring AOD but who are treated initially with C, ICI or both, even in pts quickly switched to TKI. Since a prospective clinical trial is not ethically feasible, these findings may stimulate review of current guidelines, fuel optimization of universal testing in NSCLC 4, and encourage utilization of liquid or ultra-fast NGS with their rapid turnaround times in order to improve survival in this setting. [Table: see text]
Multiparametric analysis in GBM plasma extracellular vesicles (Evs) and surface marker expression profile.
Authors: Aibaidula Abudumijiti(Zack) , Fain Cori E. , Cumba Garcia Luz , Jung Miyeon , Johnson Aaron J. , Parney Ian F.
Published: June 2022

2038

Background: Glioblastoma (GBM) is the most common malignant brain tumor with poor clinical prognosis. Management of GBM is hampered by the lack of an accurate test that can be used for differential diagnosis of tumor progression from inflammatory pseudoprogression. Plasma extracellular vesicles (EVs) has been shown to be a promising source for biomarker identification. In this project, we aimed to identify GBM plasma EV markers that could serve as the basis of a liquid biopsy. Methods: Sample preparation, assay controls and instrument calibration were performed following MIFlowCyt-EV guideline. Plasma samples were subjected to 2-step centrifugations to remove cell debris and platelets. 10ul of plasma sample was diluted with 90ul filtered PBS, then stained for EV surface markers including CD9, CD31, CD45, CD41a and CD11b, as well as actin phalloidin. Stained plasma samples were purified using IZON qEV1/70nm column, then EV fractions were analyzed using full spectrum Cytek Aurora flow cytometer. Clustering analysis was performed on EV events (CD9 +/ actin phalloidin -) using t-SNE and FlowSOM extensions from FlowJo plugins. Results: Compared to normal donors, GBM plasma EVs were bigger in size (higher SSC value) and expressed higher levels of CD9, CD31, CD45 and CD11b while ND plasma EVs had higher CD41a expression. t-SNE and FlowSOM analysis demonstrated that GBM plasma EVs had a unique surface marker expression profile compared to ND EVs. It also showed 10 EV sub-populations that differed in size as well as various surface marker expression levels. Four of these subpopulations were enriched in GBM EVs, while three of these were enriched in ND EVs. Conclusions: This multiparametric analysis revealed that GBM plasma EVs had a unique surface marker expression profile compared to ND plasma EVs. Further separation and molecular profiling analysis based on each sub population could reveal EV biomarkers that are unique to each sample population.
Prevalence of high tumor mutational burden (TMB-H) and microsatellite instability-high (MSI-H) status in neuroendocrine neoplasms.
Authors: Padda Sukhmani Kaur , Aggarwal Rahul Raj , Ashok Arya , Mauer Elizabeth , Shirazi Maryam , Bergsland Emily K.
Published: June 2022

2625

Background: Neuroendocrine neoplasms (NENs) encompass a rare group of tumors arising in nearly any organ site. Patients with advanced-stage NENs have limited treatment options, and molecular profiling is not routinely performed in NENs. However, given tissue-agnostic FDA approvals for immunotherapy in biomarker-selected solid tumors, we sought to assess the frequency of TMB-H and MSI-H in NENs by organ site and in comparison to non-NEN counterparts. Methods: We retrospectively analyzed de-identified records from the Tempus database of NENs sequenced with the Tempus xT assay (DNA-seq of 595-648 genes at 500x coverage). Patients were included if their primary cancer arose in the lungs, GI tract (esophagus, stomach, small bowel, colon, rectum), pancreas, or prostate. Histologic diagnoses were grouped as NENs (including high grade or low/intermediate grade), and non-NENs (e.g. adenocarcinoma, squamous cell carcinoma) based on data abstracted from pathology reports. TMB-H was defined as ≥ 10 mutations/megabase. MSI-H was calculated as previously published (PMID: 31570899). Statistical comparisons were limited to groups of 10 or larger. Results: We characterized a total of 1,477 NENs from the following anatomic sites: lung (64%, N=951), pancreas (15%, N= 220), GI (15%, N= 224) and prostate (6%, N=82). TMB-H was most common in NENs arising in the lungs (17%, N=155), followed by the pancreas (5.4%, N=11), GI tract (4.8%, N=10), and prostate (3.8%, N=3) (p< 0.001). Overall, TMB-H was more common in high-grade NENs compared to low/int-grade NENs [17% (N=147) vs. 6.2% (N=31), P<0.001]. This was also observed in lung NENs [high-grade 19% (N=135) v low/int grade 10% (N=19), P=0.006], with other organ site analyses limited by sample size (although a similar trend was noted for GI NENs). The majority of patients with TMB-H lung NENs had a current or prior smoking history (94%, N=119). Overall, TMB-H was similar in NENs compared to non-NENs [13% (N=179) vs. 12% (N=3018), P=0.4]. However, in the pancreas, TMB-H was more common in NENs vs. non-NENs [(5.4% (N=11) v 1.6% (N=59), P<0.001] while the reverse was true in lung NENs [17% (N=155) v 22% (N=2006), P=0.001]. MSI-H was observed in only 0.9% (N=12) of NENs overall, including in 0.4% (N=4) of lung, 1.4% (N=3) of pancreas, 1.9% (N=4) of GI, and 1.2% (N=1) of prostate NENs. MSI-H status was less common in NENs compared to non-NENs [0.9% (N=12) vs. 2.5% (N=614), P<0.001]. Conclusions: In this real-world NEN cohort, the actionable molecular alterations of TMB-H (13%) and MSI-H (0.9%) were observed. Taken together, the data suggest that molecular profiling (regardless of grade) may help identify a small but meaningful subset of patients with NENs who may benefit from immunotherapeutic treatment approaches. Furthermore, the identification of MSI-H NENs has important implications related to germline testing.
Inpatient complications of immunotherapy-associated colitis in solid malignancies: Real-world data analysis.
Authors: Pichardo Rayli , Abu Omar Yazan , Wang Ding
Published: June 2022

2657

Background: Immune checkpoint inhibitors (ICPis) and their containing regimens have been proven beneficial for the treatment of multiple malignancies, while immune-related adverse events (IrAEs) have become constant safety challenges in their clinical management through all ICPi therapies. Diarrhea resulted from immune-mediated colitis has been one of the most common IrAEs. The Aim of this study is to evaluate the real-world incidence and factors that contributed to colitis among patients hospitalized for anti-neoplastic immunotherapy using a large nation-wide database. Methods: We performed a retrospective analysis with the National Inpatient Sample (NIS) using ICD10-CM and PCS codes to identify patients with solid tumors hospitalized for immunotherapy between October 2015 and 2018. A comparison analysis was made between patients who developed diarrhea (or colitis) or not during their hospitalizations. Patient characteristics included past medical history, location, charges, length of stay (LOS) and inpatient complications variables, data were compared between the two groups. Results: The data from 5,795 admissions for immunotherapy were included, of which 615 (10.61%) inpatient events were complicated by diarrhea (colitis). Patients with diarrhea tended to be males (60%), slightly older at age 57 years, higher percentage of white patients (78%) though not statistically significant from those who did not have colitis. On the other hand, the length of inpatient stay was statistically longer (7 vs 5 days, p < 0.05), and associated with higher expenses ($214,612 vs $ 134,195, p < 0.05). In addition, inpatient admissions with colitis were more towards larger academic hospitals (80% vs 67%, p = 0.01). ICPi-treated patients with genitourinary (GU) cancers were observed more with colitis among these admissions (27% vs 15%, p < 0.05). Though no difference from mortalities observed, serious complications, such as acute kidney injury (AKI) (44% vs 20%, p < 0.05) and non-septic shock rates were higher (7% vs 2%, p = 0.01) among colitis admissions. Conclusions: This real-world data analysis of inpatient admissions from ICPi-treated cancer patients demonstrated colitis with diarrhea as a common safety concern over ICPi-therapies, a higher risk among patients of GU primaries, higher risk with serious medical complications: acute renal dysfunction and non-septic shock, led to increased length of stays (LOS) and financial burden. Special attention and further study may be placed among ICPi-treated GU cancer patients. [Table: see text]
Increased systemic toxicities from antibody-drug conjugates (ADCs) with cleavable versus non-cleavable linkers: A meta-analysis of commercially available ADCs.
Authors: Wynn Carrie , Patel Ritesh , Hillegass William B. , Tang Shou-Ching
Published: June 2022

3032

Background: Though in theory ADCs should deliver high-dose chemotherapy directly to target cells with few systemic effects, in clinical practice numerous side effects have been observed. We hypothesized that ADCs with cleavable linkers would have more systemic toxicities than those with non-cleavable linkers due to the increased free payload released systemically. To compare their side effect profiles, we conducted a meta-analysis of adverse events (AEs) of commercially available ADCs. Methods: Systematic review yielded 12 phase II/III clinical trials that led to the FDA approval of commercially available ADCs. Polatuzumab vedotin was not included because it was only studied in combination with other agents. Any grade AEs and grade ≥3 AEs occurring in at least 5% of patients in each study were recorded. The estimated inverse variance weighted absolute average risk and 95% confidence interval (CI) were estimated for each AE. Absolute risk differences and 95% CIs were estimated by linker type. Results: Data from 2,417 patients treated with 9 ADCs were pooled. 7 ADCs had cleavable linkers (N = 1,082), and 2 had non-cleavable linkers (N = 1,335). At least half of studies reported thrombocytopenia, neutropenia, anemia, increased AST and ALT, nausea, vomiting, diarrhea, hypokalemia, headache, and fatigue, as well as rates of all grade and grade ≥3 AEs. AEs ≥ grade 3 occurred in 43% of patients overall, 47% in the cleavable linker arms and 34% in the non-cleavable arms. This was significantly different (weighted risk difference -12.9%; 95% CI -17.1% to -8.8%). There was also a significant difference favoring non-cleavable linkers for ≥ grade 3 neutropenia (-9.1%; 95% CI -12% to -6.2%) and ≥ grade 3 anemia (-1.7%; 95% CI -3.3% to -0.1%). Cleavable linkers were significantly associated with increased AST all grade (3.9%; 95% CI 0.3% to 7.5%) and increased ALT all grade (3.7%; 95% CI 0.2% to 7.3%), though notably the CI approached 0 on the low end of difference for each. There was no significant difference in rates of all grade AEs or in rates of discontinuation due to AEs. There was no significant difference in rates of all grade nausea, vomiting, diarrhea, hypokalemia, or headache. Finally, there was no significant difference in rates of grade ≥3 thrombocytopenia, increased AST/ALT, or fatigue. Conclusions: Cleavable linkers appear to have significantly higher rates of ≥ grade 3 AEs and neutropenia within the limitations of this non-randomized comparison and treatment of heterogeneous malignancies. The increased payload in the circulation likely accounts for this; however, it may also make them more efficacious, as suggested by the results of the DESTINY-Breast03 trial. In the final analysis, we will compare the efficacy of cleavable vs non-cleavable ADCs indirectly using the standard of care for each tumor and line of therapy, with the exception of breast cancer.
A cell-free RNA-based next-generation sequencing (NGS) assay for the detection of actionable gene fusions in patients with non–small cell lung cancer (NSCLC).
Authors: Choudhury Yukti , Cher Chae Yin , Ho Jia Min , Chan Claire , Teh Mun Wei , Ngeow Kao Chin , Pek Michelle
Published: June 2022

3040

Background: Gene fusions and alternate RNA splice forms represent clinically actionable driver and resistance-conferring alterations in NSCLC and other cancers. Where tissue samples are inadequate for molecular testing, liquid biopsies could address the gap in detection of clinically relevant gene fusions. Targeted cell-free (cf) DNA-based NGS methods are typically used for non-invasive blood-based testing of gene fusions, but have limited sensitivity if fusion breakpoints involve long intronic regions or repetitive sequences (e.g. NTRKs and NRG1). RNA-based approaches are not affected by introns, can identify expressed fusion genes and can discriminate splicing. We developed an NGS assay optimized for cfRNA analyte for the detection of actionable gene fusions and exon deletion/skipping events in liquid biopsies. Methods: A highly multiplexed molecular-barcoded primer panel was designed for cfRNA-based detection of actionable fusion genes in NSCLC ( ALK, BRAF, FGFR2, FGFR3, MET (including exon 14 skipping), NRG1, NTRK1/2/3, RET and ROS1) covering > 90% of reported driver and partner gene exons in COSMIC database. The panel also targets housekeeping genes as endogenous sample controls. We developed a custom bioinformatics pipeline to call fusions and exon skipping based on split and spanning reads. Results: In initial analytical validation using fragmented RNA from pre-characterized reference material (representing 32 unique fusions at known copy numbers), the assay could detect as low as 10 fusion copies with a sensitivity of 97.6% and a specificity of 100%. For clinical testing, cfRNA co-eluted with cfDNA in nucleic acid extracts from plasma was used. In plasma samples (n = 103) from advanced NSCLC, 76% (15/21) of fusions (5 ALK, 3 RET, 2 ROS1, 5 MET ex14 skipping, 1 FGFR3-TACC3) detected in a clinically validated cfDNA assay (LiquidHALLMARK) were also detected in corresponding cfRNA. In a subset of samples that were driver-negative untreated or tyrosine kinase-inhibitor treated, the cfRNA assay yielded 9 gene fusions or breakpoints (1 CD74-NRG1, 4 BRAF, 2 MET, 2 FGFR3-TACC3 fusions) that could not be detected by the cfDNA assay. This represents an increase of 8.7% (9/103) of actionable alterations (driver or resistance) identified using cfRNA. Together cfRNA and cfDNA resulted in 30 fusion events to be detected compared to 21 by the cfDNA assay alone, representing a 42.8% (9/21) increase in fusion-specific detection of the combined assay. Conclusions: This novel cfRNA assay can detect actionable gene fusions and exon skipping events in liquid biopsies with high sensitivity. Combining cfRNA with more routine cfDNA testing can increase the total actionable diagnostic information from non-invasive testing in NSCLC patients where tissue samples are lacking, especially for gene fusions not amenable to detection in cfDNA.
Cell-free RNA in liquid biopsy and biomarkers profiling of hematologic and solid tumors.
Authors: Albitar Maher , Zhang Hong , Charifa Ahmad , Ip Andrew , De Dios Ivan , Ma Wanlong , McCloskey James , Donato Michele , Siegel David Samuel DiCapua , Waintraub Stanley E. , Gutierrez Martin , Pecora Andrew L , Goy Andre
Published: June 2022

3047

Background: Expressed RNA can capture mutations, changes in expression levels due to methylation, and provide information on cell of origin, growth, and proliferation status. We developed an approach to isolate fragmented RNA from peripheral blood plasma and explored its potential to be used in liquid biopsy. Methods: Peripheral blood cfRNA was extracted from patients with neoplasms in B-cell (#105), T-cell (#16), Myeloid (#73), and from solid tumors (#44), Normal individuals (#51), and reactive post-transplant (#137). RNA was sequenced using a 1459-gene panel. Expression profile was generated using Cufflinks. Results: cfRNA levels of various solid tumor biomarkers (CA-125, CA-15-3, CEA 8, Keratin19, Keratin6A...) were significantly higher (P < 0.0001) in samples from solid tumors as compared with normal control. Similarly, cfRNA lymphoid markers (CD19, CD22, CD79A, and CD79B...) and cfRNA myeloid markers (CD33, CD14, CD117, CD56...) were all higher in B-cell lymphoid neoplasms and myeloid neoplasms, respectively (P < 0.0001), as compared with control. In evaluating the host immune system, cfRNA CD4:CD8B and CD3D:CD19 ratios in normal controls were as expected (median: 5.92 and 6.87, respectively) and were significantly lower in solid tumors (median 3.40 and 2.23, respectively, P < 0.0002). Solid tumor cfRNA showed CTLA4:CD8B ratio significantly higher in tumors than in normal (median 0.74 vs 0.19, P = 0.0001), while there was no difference in cfRNA PD-L1:CD8B ratio (median 1.45 vs 1.77, P = 0.96). Similar distinct patterns are noted for various cytokine and chemokines. cfRNA was highly predictive of diagnosis (AUC > 0.98) of solid tumors, B-cell lymphoid neoplasms, T-cell lymphoid neoplasms, and myeloid neoplasms as compared with normal control. When a specific neoplastic disease was considered against all cases including control and other neoplasms, the AUC varied between 0.77 and 0.949. Conclusions: This data shows that liquid biopsy using targeted sequencing of cfRNA in patients with various types of cancer provides comprehensive and reliable information on the neoplastic disease as well as the host. [Table: see text]
Serum concentrations of oncometabolite, 2-hydroxyglutarate (2HG), as biomarkers for isocitrate dehydrogenase (IDH1/2) mutations in cholangiocarcinoma (ICCA).
Authors: Lee Cha Len , Mason Warren P. , O'Kane Grainne M. , Grant Robert C. , Knox Jennifer J. , Cruz Candice , Zhang Wenjiang , Zadeh Gelareh , Chen Eric Xueyu
Published: June 2022

3049

Background: Mutations in IDH1/2 genes are common in low-grade glioma (GM) and occur in approximately 20% of intrahepatic cholangiocarcinoma (ICCA). Mutant IDHs leads to preferential accumulation of the R-relative (R2HG) to the S-enantiomer (S2HG) of 2HG. We investigated the utility of circulating R2HG, total R2HG+S2HG (tRS) and ratio of R2HG/S2HG (rRS) as biomarkers in GM and ICCA patients (pts). Methods: Blood and tumor tissues samples were obtained from pts with IDH1/2-mutant GM and ICCA. IDH mutation was confirmed by either immunohistochemistry (GM pts) or next generation sequencing (ICCA pts). Samples were analyzed for S2HG and R2HG using a validated HPLC tandem mass spectrometry method. Tissue and serum R2HG, tRS and rRS were compared with paired t-tests for GM pts. Serum S2HG, R2HG, tRS and rRS were compared with unpaired t-tests between GM and ICCA pts. A p<0.05 was considered statistically significant. Results: Blood and tumor samples were collected from 21 pts (GM = 11, ICCA=10). Tumor tissues were insufficient for analysis in 1 GM and 8 ICCA pts. Tissue S2HG, R2HG, tRS, and rRS were 0.72±0.68 ng/g, 48.92±58.92 ng/g, 66.87±80.35 ng/g and 55.77±36.23 for GM pts. There were no differences in R2HG and tRS between tissue and serum samples, while S2HG was significantly higher in serum samples ( p = 0.001) and rRS was significantly higher in tissue samples for GM pts ( p = 0.001). rRS were 144.8 and 244.9 respectively in 2 ICCA pts with sufficient tissues. There was no difference in serum S2HG between GM and ICCA pts. However, serum R2HG, tRS and rRS were significantly higher in ICCA pts. Conclusions: In IDH1/2 mutant GM and ICCA pts, R2HG was increased relative to S2HG in tumor tissues. In GM pts, the accumulation of R2HG in tumor tissues was not reflected in blood, likely due to the inability of 2HG to diffuse across the blood-brain barrier. Serum R2HG, tRS and rRS were significantly elevated in ICCA pts. These biomarkers have no clinical utilities in GM pts. However, they can potentially be used to identify IDH mutations in ICCA pts, especially given the inability to obtain tumor tissue in some ICCA pts. Clinical trial information: NCT03991832. [Table: see text]