bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiomics analysis of pediatric solid tumors within the INFORM precision oncology study: From functional drug profiling to biomarker identification.
Authors: ElHarouni Dina , Peterziel Heike , Schramm Kathrin , Milde Till , Oppermann Sina , Oehme Ina , Witt Olaf , Schlesner Matthias , Jäger Natalie
Published: June 2022

10036

Background: Within the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) registry over 1200 childhood malignancies were molecularly profiled using next generation sequencing to identify therapeutic targets. Nevertheless, high evidence targets were only detected in 5% of cases and only 50% of the patients were identified with druggable pathways, while the remaining cases lacked druggable alterations. Thus, an ex-vivo functional drug response profiling platform for pediatric solid tumors has been established within the INFORM program to identify novel biomarkers and unravel molecular mechanisms associated with drug response profiles for clinical translation. Methods: Solid tumors from 97 paediatric patients were screened against a library of 76 drugs. A quality control classification decision tree was designed to select the samples for further analysis. Whole exome sequencing, low-coverage whole genome sequencing, and RNA-seq were used to analyze the molecular profiles of the samples. Molecular features were filtered to retain oncogenic and druggable events. Five data feature views (mutations, mRNA, gene fusions, CNVs, and drug responses) were used to train a Multi-Omics Factor Analysis (MOFA) model to identify prominent latent factors. Results: 81 samples passed the quality control inclusion criteria of which 76 samples had available omics data profiles. Quantitative drug profiling measurements were reported using the selective asymmetric drug sensitivity score.The multi-omics analysis captured five entity-specific omics signatures of Ewing sarcoma, Wilms tumor, BCOR sarcoma, neuroblastoma and ependymoma. Moreover, the analysis revealed sensitivity to navitoclax in neuroblastoma samples with PHOX2B-GATA3 overexpression, and an association between MEK inhibitor sensitivity and an expression signature in Wilms tumors. Conclusions: The combination of functional drug and multi-omics profiling enabled the identification of novel biomarkers for drug sensitivities in pediatric solid tumors. As we continue to expand the number of patient samples evaluated with our drug sensitivity platform, this dataset will provide insights for novel drug targets, and could unravel key molecular events and mechanisms acting towards personalized therapies.
Associations between global longitudinal strain (GLS), N-terminal-prohormone brain natriuretic peptide (NT-proBNP) and subsequent cardiomyopathy (CM) in a clinically assessed cohort of childhood cancer survivors exposed to cardiotoxic therapy.
Authors: Ehrhardt Matthew J. , Liu Qi , Jefferies John L. , Mulrooney Daniel A. , Sapkota Yadav , Goldberg Jason , Dixon Stephanie B , Lucas John Thomas , Ness Kirsten K. , Srivastava Deo Kumar , Mazur Wojciech , Plana Gomez Juan Carlos , Robison Leslie L. , Yasui Yutaka , Hudson Melissa M. , Armstrong Gregory T.
Published: June 2022

10052

Background: Among survivors exposed to anthracycline or chest radiation (RT) who have an ejection fraction (EF) of ≥50%, the utility of GLS and NT-proBNP to identify survivors who are at highest risk for future CM is unknown. Methods: Survivors participating in the St. Jude Lifetime Cohort, ≥5 years from cancer diagnosis and at risk for CM per the International Guideline Harmonization Group (IGHG), underwent baseline surveillance echocardiography. A baseline GLS and NT-proBNP was also performed for survivors with an EF ≥50%. Multivariable Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of CM (graded per modified Common Terminology Criteria for Adverse Events v4.0) based on abnormal baseline GLS (≥ -18) and/or NT-proBNP (>age-sex-specific 97.5th percentiles) adjusted for age at baseline assessment, age at diagnosis, sex, race, hypertension, diabetes, obesity, and IGHG risk group (Table footnote). Results: Among 1598 at-risk survivors (median age 35.1, range 9.4-68.8 years), all had GLS and 1110 NT-proBNP at baseline. 165 (10.3%) developed CM ≥ grade 2 at a median follow-up of 5.2 (0.7-10.0) years. IGHG moderate- and high-risk survivors exposed to anthracyclines were at increased risk of CM at follow-up if both baseline GLS and NT-proBNP were abnormal (HR=3.4, 95% CI: 1.9-5.8; Table) or GLS was abnormal and NT-proBNP not assessed (HR=3.8, 95% CI: 2.0-7.2), or when GLS was normal and NT-proBNP was abnormal (HR=1.9, 95% CI: 1.1-3.4). Abnormal GLS and/or NT-proBNP were not associated with increased risk of CM in IGHG low-risk survivors or in those defined as moderate- to high-risk due to chest RT only. Conclusions: Among long-term survivors of childhood cancer exposed to >100 mg/m2 anthracycline, abnormal GLS and NT-proBNP identified those survivors at increased risk of future CM despite an EF ≥50% on surveillance echocardiography. Conditional surveillance strategies utilizing GLS and NT-proBNP may benefit moderate- to high-risk survivors. [Table: see text]
Prevalence of incidental pathogenic germline variants detected in cfDNA in patients with oncogene-driven non-small cell lung cancer.
Authors: Mezquita Laura , Bucheit Leslie A. , Laguna Juan Carlos , Pastor Belen , Teixido Cristina , Gorria Teresa , Albarran-Artahona Victor , Garcia de Herreros Marta , Reyes Roxana , Reguart Noemi , Vinolas Nuria , Arcocha Ainara , Puig-Butillé Joan Anton , Drusbosky Leylah , Faull Iris , Castro Elena , Patel Jyoti D. , Prat Aleix , Besse Benjamin
Published: June 2022

10569

Background: Preliminary data has highlighted inherited predisposition to lung cancer (LC) related to certain pathogenic germline variant (PGV) in cancer predisposing genes, including patients (pts) with tumors harboring somatic driver oncogene alterations (alt); however, the frequency of PGV in LC is unknown. Liquid biopsy assays may be able to identify incidental PGV (iPGV) in pts with solid tumors at scale. Here, we report the prevalence of iPGV in genes predisposing to cancer in pts with advanced non-small cell LC (aNSCLC) relative to driver alt status. Methods: Genomic results were retrospectively queried from 31126 pts with aNSCLC who had Guardant360 testing as part of routine clinical care from 10/2020-12/2021. iPGVs were defined as being non-synonymous, non-VUS alt in selected genes known to increase lifetime cancer risk (Table) with variant allele frequency (VAF) >30% and pathogenicity defined by a proprietary bioinformatics pipeline. Clinical factors such as age, gender, histology, and diagnosis status (new/progressing) were extracted from test requisition forms. The driver group included guideline-recommended and emerging somatic mutations (m) in EGFR/KRAS/BRAF/MET/HER2, fusions (f) in ALK/ROS1/RET/NTRK1-3 and amplifications (a) in HER2/MET. Results: Out of 31126, 720 (2.3%) of pts had predicted iPGV, of whom 54% were female, with a median age of 64 (22-100); most pts were newly diagnosed (66%). Among them, 92% of pts had iPGVs identified in the homologous recombination and repair (HRR) pathway, 3% in mismatch repair (MMR) pathway and 5% EGFR iPGVs. A total of 335 (47%) pts with iPGVs had somatic driver alt (Table): 20% of pts with iPGV had KRASm (n=144/720; 67 G12C), 12% EGFRm (n=87; 28 ex19del, 35 ex21(L858R)), 2.5% BRAFm (n=18), 2.5% METm ex14 skip (n=18), 0.1% HER2m (n=1), 0.8% ALKf (n=6), 0.1% ROS1f (n=1), 0.1% RETf (n=1), 0.1% HER2a (n=1), and 0.4% METa (n=3). ATM iPGVs were enriched in pts with driver alt. (45% driver vs 27% non-driver, p<0.0001) while BRCA1 iPGVs were more frequently observed in pts without driver alt. (17% vs 8%, p<0.0001). Distribution of other iPGVs was similar across driver/non-driver groups. Conclusions: In this large cohort, 2.3% of pts with aNSCLC were iPGV-carriers; 47% of pts had oncogene-driven tumors, particularly with KRAS, EGFR, BRAF and MET alt. iPGV and lung carcinogenesis need further evaluation to define the role of genetic predisposition in LC risk and to determine the highest risk individuals to explore screening and therapeutic strategies, such as in pts with other solid tumors. [Table: see text]
Co-occurrence of germline pathogenic variants in Chinese patients with solid tumors.
Authors: Zhang Yan , Han Tiantian , Guo Didi , Luo Ningning , Lu Guanghua , Bu Fanfeng
Published: June 2022

10579

Background: Germline mutations play an important role in cancer risk and susceptibility. With the growing implementation of next generation sequence of multiple gene panel, an increasing number of cases that carry two or more inherited cancer-predisposing alleles in the same individual are being described. However, understanding the impact of these combined mutations on the patient's phenotype can be particularly challenging. To further understand these combined mutations, we analyze the genetic susceptibility mutations of Chinese solid tumor patients to explore the characteristics of multiple germline variants. Methods: Genetic mutations were reviewed in cancer patients who underwent hybridization capture based next-generation sequencing (NGS). The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines, and only pathogenic and likely pathogenic variants were included in this study. Results: Germline variants were identified in 1267 individuals, including 1244 patients harbored one germline mutations and 23 patients carried ≥2 germline mutations, and there was no age difference in the two groups (57 vs 55, p = 0.62). In the ≥2 germline mutations group, genes most frequently involved were BRCA1/2 (12/47, 25.5%), CHEK2 (4/47, 5,1%), TP53(4/47, 5,1%) and MUTYH (4/47, 5,1%). Most of these variants affected DNA damage repair pathways [57% homologous recombination repair (HR), 15% mismatch repair (MMR)]. Besides, double variants in HR and HR pathway were found in 8 patients, HR and MMR pathway were found in 5 patients. Surprisingly, the 50-year-old man with colorectal cancer with three pathogenic variants of the [ FH - BRCA2- FANCD2] genes showed a high aggregation of tumors associated with leiomyomatosis and renal cell cancer and HBOC. Conclusions: We found over 56.5% patients with multiple pathogenic variants in DNA damage repair pathways, which may have important implications for the treatment strategy for these patients. Next-generation sequencing technologies now provide the opportunity to perform simultaneous parallel testing of large numbers of inherited cancer genes, which could guide the clinician as to what the effect of each combination of mutations might be.
Implementation of universal, pan-cancer germline genetic testing in patients with cancer in Jordan.
Authors: Abdel-Razeq Hikmat , Tbakhi Abdelghani , Abuhijlih Ramiz , Abujamous Lama , Al Masri Mahmoud , Abukhashabeh Razan , Mitchell Asia , Heald Brandie , Nielsen Sarah M. , Nussbaum Robert Luke , Esplin Edward D.
Published: June 2022

10580

Background: Detection of pathogenic germline variants (PGVs) has a significant and growing impact on the management of patients with many types of cancer. Most research to date evaluated individuals of European background, which can result in skewed genetic testing criteria and variant interpretation. Additional data are needed from diverse populations. This study aimed to investigate a universal germline testing strategy and the pattern and frequency of PGVs among all newly diagnosed cancer patients at a single center in Jordan. Methods: In this prospective, observational study, consecutive patients newly diagnosed with cancer were classified as meeting or not meeting National Comprehensive Cancer Network (NCCN) germline genetic testing criteria. All patients underwent an 84-gene panel test, independent of age, stage or family history. Demographics and clinical history were collected and analyzed from information provided by the clinicians on the test requisition form. Descriptive statistics were employed, and statistical significance was determined by two-tailed Fisher’s exact test and unpaired t test. Results: In total, 1377 cancer patients of Arabic background were enrolled, of which 831 (60.3%) met NCCN criteria (Table). PGVs were identified in 210 (15.3%). Excluding the 29 patients who were carriers for autosomal recessive conditions, 192 PGVs were identified in 181 (13.1%) patients. PGVs were most commonly identified in APC (p.I1307K variant, 55, 28.6%), BRCA2 (35, 18.2%), BRCA1 (21, 10.9%), and TP53 (12, 6.3%). While patients who met NCCN testing criteria were more likely to have a PGV (p<0.0001), 44 (24.30%) patients with PGVs did not meet criteria. Among those with PGVs, 177 (97.8%) were potentially eligible for increased screening per NCCN/expert opinion guidelines, 69 (38.1%) targeted therapies, and 89 (49.2%) clinical trials; this included 41 (22.7%), 6 (3.3%), and 14 (7.7%) patients, respectively, that did not meet NCCN testing criteria. 1445 variants of uncertain significance (VUS) were identified in 833 (57.7%) patients, but no difference in VUS rate was observed between those meeting and not meeting criteria (p=0.7354). Conclusions: Overall PGV rate among cancer patients from one center in Jordan was similar to that reported in the literature. While the VUS rate was high, similar rates were observed in those meeting and not meeting criteria. Testing restricted to guidelines could have missed approximately a quarter of patients with PGVs, >95% of whom might qualify for increased screening, targeted therapies, and/or clinical trials. [Table: see text]
Dalpiciclib in combination with letrozole/anastrozole or fulvestrant in HR+/HER2- advanced breast cancer: A phase Ib study.
Authors: Zhang Qingyuan , Zhang Pin , Yan Min , Yan Xi , Wang Xian , Gu Yuanting , Qu Xiujuan , Li Shaorong , Xu Guoying , Yang Wenhui , Zhu Xiaoyu , Zhang Xiaojing , Xu Binghe
Published: June 2022

1066

Background: Dalpiciclib (Dalp; SHR6390) is a novel cyclin-dependent kinase 4/6 inhibitor which showed tolerability and preliminary clinical activity as monotherapy for pretreated advanced breast cancer (ABC). Here we conducted a multicenter, phase 1b trial to further assess the safety, pharmacokinetics and efficacy of Dalp in combination with endocrine therapy (ET) in HR+/HER2- ABC. Methods: 5 cohorts of patients with HR+/HER2- locally recurrent or metastatic BC and any menopausal status were enrolled (~15 patients/combination regimen). Patients without prior treatment for ABC (cohort1/2) were given Dalp (125 or 150 mg po qd, d1-21, q4w) plus letrozole (LTZ; 2.5 mg po qd) or anastrozole (ATZ; 1 mg po qd); patients who progressed after ET (cohort 3-5) were given Dalp (125, 150, or 175 mg po qd, d1-21, q4w) plus fulvestrant (Fulv; 500 mg im, cycle 1 d1, d15, then d1 q4w). The primary endpoint was safety. The data cutoff date was Sep. 20, 2021. Results: 58 patients received Dalp plus LTZ/ATZ and 46 received Dalp plus Fulv. No maximum tolerated dose of Dalp was reached with LTZ/ATZ or Fulv. Across all cohorts, 75.0%-93.8% of patients had a grade ≥3 treatment-related adverse event (TRAE), with the most common being neutropenia (grade 3, 40.0%-87.5%; grade 4, 4.2%-46.7%) and leukopenia (grade 3, 33.3%-80.0%; grade 4, 0%; Table). Treatment-related serious AEs occurred in 2 (3.4%) patients with Dalp plus LTZ/ATZ and none with Dalp plus Fulv. At the tested dose levels, steady-state areas under the concentration curve and peak concentration of Dalp increased with dose in combination with LTZ/ATZ or Fulv. Dalp 150 mg was associated with a numerically higher objective response rate in both ET-untreated (67.6%, 95% CI 49.5-82.6) and ET-pretreated (53.3%, 95% CI 26.6-78.7) patients per investigator. The median progression-free survival with Dalp 150 mg was 20.3 mo (95% CI 16.9-not reached [NR]) and 16.7 mo (95% CI 1.9-24.1) in ET-untreated and ET-pretreated patients respectively. Conclusions: Dalpiciclib plus letrozole/anastrozole or fulvestrant showed an acceptable safety profile, with hematological toxicities as the most common TRAEs. The recommended phase 3 dose of dalpiciclib was 150 mg. Together with the promising anti-tumor activity observed with the combination therapy in HR+/HER2- ABC, further trials are warranted. Clinical trial information: NCT03481998. [Table: see text]
Effect of transition from inpatient oncology service to oncology consult service on fellow burn out and training.
Authors: Tariq Anosha , Aijaz Talha , Katiyar Vatsala , Rojan Adam
Published: June 2022

11023

Background: The hematology-oncology inpatient service at the University of Louisville underwent a major change in July 2021 from a medical oncology service run by hematology/oncology fellows and attendings to a hospitalist-run service with hematology/oncology fellows and attendings sharing patient care responsibility as a consulting service. We planned this study because, to date, no published work has studied the effect of transitioning from an inpatient to consult service on fellow burnout, education, and training. Methods: A survey was distributed in July 2021, and a follow-up survey was sent in January 2022. The survey had 38 questions regarding the impact of the workload on time for study, research, personal and professional life, which were scored from 1 to 5. Two tail paired t-test was used to compare the difference in means. The survey also contained questions from the Mayo Clinic Resident Well-Being Index (RSWBI). This index has been validated to identify distress among fellows and allows for the comparison of local results with national data from RSWBI. In RSWBI, scores range from 0-7, with 0 being the lowest risk and 7 being the highest risk of burnout. A cut-off of a score ≥ 5 identifies individuals with a high degree of distress, is associated with an increased risk of error, suicidal ideation, and burnout, and has been validated in more than 1700 residents/fellows. Results: We distributed the survey to 2nd and 3rd-year fellows. 5/6 fellows completed the survey. 3 of them were male and 2 females. Change in inpatient service structure did not impact time for study, research, patient encounter, or ability to handle the volume of work. Improvement in adequate time preparing for clinic was statistically significant (P=0.03), and other improvements were also noted in concentration, time for family, and better personal and professional relationships (Table). RSWBI median score before the transition was 3.6, which improved to 2.0 after the transition to consulting service, which was similar to the national average where the median score was 2.0 among 8237 residents/fellows. 2 fellows (40%) were at high risk of distress before the transition. 1 fellow (20%) was at high risk of distress after the transition, which was comparable to the national average where 19.4% resident/fellows scored ≥5. Conclusions: These results show increased levels of distress in fellows that improved to the national average following transition from a primary inpatient medical oncology service to a consult service.[Table: see text]
The need to develop the career pathway in oncology as an opportunity to improve the satisfaction of young oncologists in Spain: A national survey by the Spanish Society of Medical Oncology (SEOM) + mir section.
Authors: Jiménez Labaig Pablo , Sánchez Domingo Antonio , Sesma Andrea , Quilez Alicia , Pacheco Barcia Vilma , Obispo Berta , Paez David , Quintanar Maria Teresa , Sánchez-Cánovas Manuel , Tarazona Noelia , Fernandez Montes Ana , Felip Enriqueta , Rodriguez-Lescure Alvaro , Elez Elena
Published: June 2022

11038

Background: A long-term planning of the oncologists’ career path is essential to approach the continuous changes in the oncology field given the need of further subspecialization after the training period. Our aim is to evaluate the current professional development of young medical oncologists in Spain and seek improvement strategies to enhance their careers in order to guarantee commitment with research and improve in patient care and outcomes. Methods: The SEOM +MIR Section launched a national online survey in May 2021 aimed at young medical oncology consultants (<6 years of experience) and last year medical oncology residents. Spanish professionals were invited to participate via email through the SEOM database. A descriptive analysis was performed using R software v4.1.2. Results: A total of 162 responses were eligible. 103 (64%) were women. 129 (80%) were consultants and 33 (20%) were residents. 92 (68%) performed standard clinical care and 11 (7%) research activity. 118 (73%) were subspecialized in a main area of interest and almost half of them, 70 (59%), chose it because it was the only option available after finishing residency. 87 (54%) had considered different employment opportunities other than standard clinical care and 38 (23%) showed an interest in enhancing their research activity. 141 (87%) showed relevant concern about their employment stability (table attached). 82 (51%) had considered working abroad: 33 (44%) outside European Union. The main reasons were: 132 (81%) believed the professional standing in Spain was worse than other countries, 41 (25%) thought it might increase their professional development and 33 (20%) argued for better salary conditions abroad. Among them, 21 (13%) had signed at least 4 contracts and 66 (41%) had ≥5 employment contracts in the last 5 years. 27% of respondents indicated that the figure of the boss had been the most contributing professional in their professional career. The mentor (20%) and the tutor (18%) also stand out as relevant figures in terms of professional development. Up to 27% of the sample refers not to have obtained any help from the figures mentioned. Conclusions: An absence of engagement in the long-term career paths of young medical oncologists in Spain was observed. Research is not defined in the current early professional life. Furthermore, there is a lack of contractual quality and planning for the entry into the labour market of newly trained oncologists. The lack of such a career pathway has consequences that encourage the search for employment opportunities different from clinical care and in other countries. [Table: see text]
A novel oral paclitaxel and HM10381 (oraxel)-treated metastatic breast cancer: A phase I study (KX-ORAX-CN-007).
Authors: Qin Tao , Lai Xiuping , Wang Ying , Wang Jing , Chen Junyi , Zhang Yiwen , Wu Junyan , Song Erwei , Yao Herui
Published: June 2022

1104

Background: This phase I study assessed the pharmacokinetics, safety, antitumor activity of oral paclitaxel and HM10381 (Oraxel) in patients with metastatic breast cancer. Methods: Oraxol (oral paclitaxel 205 mg/m2 plus HM30181A 15 mg) daily for 3 consecutive days weekly for up to 16 weeks was administered to patients. The primary objective endpoint was pharmacokinetic analysis. The secondary endpoint were objective response rate (ORR) and safety. For pharmacokinetic analysis, timed blood samples were collected. Results: Twenty-four female patients were enrolled from Apr 2019 to Aug 2019. The median age was 53 years (range: 35 to 70 years). The mean lines and median line of treatment were 2.5 and 2, respectively. Previous breast cancer treatments included chemotherapy in 23 (96%) patients, hormonal therapy in 20 (83%) patients. Prior taxanes therapy was reported in 20 (83%) patients. There were 15 patients in efficacy dataset. The best ORR (Investigator) was PR in 40%, SD in 53%, and PD in 7%. The best overall response rate (ICRRC) was PR in 36%, SD in 57%, and PD in 7% of patients. There were no hypersensitivity-type reactions. Adverse events of interest neutropenia, neurotoxicity, and diarrhea were reported as 20 (83%)，7 (29%) and 11 (46%), retrospectively. A total of 15 (63%) patients experienced Grade ≥3 TEAEs, including neutrophil count decreased in 11 (46%) patients, WBC count decreased in 8 (33%) patients. Treatment related SAE was reported in 1 (4.17%) patient experienced febrile neutropenia, pneumonia, and septic shock. The PK data indicated that the efficacy response is not associated with oral paclitaxel exposure parameters AUC or Cmax. Conclusions: The study showed that Oraxol as novel oral chemotherapy agent shows promising antitumor activity in patients with metastatic breast cancer, manageable toxicity, and no hypersensitivity-type reactions. Clinical trial information: NCT04993040.
Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: Results of the expanded cohort of myxoid liposarcoma of the randomized clinical trial from the Italian Sarcoma Group (ISG), the Spanish Sarcoma Group (GEIS), the French Sarcoma Group (FSG), and the Polish Sarcoma Group (PSG).
Authors: Gronchi Alessandro , Palmerini Emanuela , Quagliuolo Vittorio , Martin Broto Javier , Lopez-Pousa Antonio , Grignani Giovanni , Brunello Antonella , Blay Jean-Yves , Diaz Beveridge Robert , Ferraresi Virginia , Lugowska Iwona , Pizzamiglio Sara , Verderio Paolo , Fontana Valeria , Donati Davide Maria , Palassini Elena , Stacchiotti Silvia , Miceli Rosalba , Dei Tos Angelo Paolo , Casali Paolo Giovanni
Published: June 2022

11508

Background: An ISG, GEIS, FSG and PSG randomized trial on 3 cycles of neoadjuvant epirubicine+ifosfamide (EI) versus a histology-tailored (HT) regimen in selected localized high-risk STS showed some superiority of EI in all histologies with the exception of Myxoid Liposarcoma (MLPS) where EI and HT regimens seemed equivalent (J Clin Oncol 2020; 38:2178-86). This MLPS cohort was expanded with the aim to assess the non-inferiority of the HT regimen compared to EI. Methods: This was a multicenter European randomized trial comparing EI versus a HT regimen. Patients (pts) had localized high-risk (grade = 3; size >5 cm; deeply seated) undifferentiated pleomorphic sarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, synovial sarcoma or MLPS of extremities or trunk wall. Primary end-point was Disease Free Survival (DFS). Secondary end-point was Overall Survival (OS). The MLPS cohort was expanded after the results of the 3rd interim analysis (Lancet Oncol 2017; 18:812-22) in order to reject the hypothesis that HT regimen trabectedin is associated with a HR of relapse = 1.25 with a non-inferiority design. To this aim, a Bayesian monitoring approach was used until the probability that the true HR is higher than 1.25 was greater than 80% or smaller than 5%. Results: From May 2011 to June 2020, 101 pts affected by high-risk MLPS were randomized, 56 to EI and 45 to HT regimen. The median follow-up was 66 months (IQ range 37-89). Median size was 107 mm (IQ range 84-143), 108 mm (IQ range 86-150) in the EI and 106 mm (IQ range75-135) in the HT arm. The DFS and OS probabilities at 60 months were 0.86 and 0.73 (HR:0.60; 95%CI: 0.24-1.46; log rank p = 0.26 for DFS) and 0.88 and 0.90 (HR:1.20; 95%CI:0.37-3.93; log rank p = 0.77 for OS), in the HT and EI arm, respectively. 5-yr observed and Sarculator-predicted OS were 0.89 (95% CI 0.82-0.97) and 0.80 in all patients (p = 0.020), 0.90 (95% CI 0.81-1.00) and 0.79 in the EI arm (p = 0.049) and 0.88 (95% CI 0.77-1.00) and 0.81 in the HT arm (p = 0.204) respectively. Conclusions: In the expanded cohort of MLPS, the HT neoadjuvant therapy trabectedin was not inferior to EI. While survival in both arms was better than predicted by Sarculator, it is left to understand whether this patient population, who had on average a lower Sarculator-predicted risk of death compared with the rest of the trial population, may benefit from a neoadjuvant therapy. Clinical trial information: NCT01710176.
Platelet derived growth factor receptor alpha (PDGFRA) mutant gastrointestinal stromal tumours (GISTs): Clinicopathological characteristics and outcomes from a regional centre in the United Kingdom.
Authors: Favara David M , Wong Han Hsi , Harrington Jennifer , Giger Olivier , Bulusu Venkata Ramesh
Published: June 2022

11534

Background: GISTs are the most common mesenchymal tumours of the gastrointestinal tract with an annual incidence of 10-15 per million. 10% of GISTS have activating mutations in the PDGFRA gene. We report our 13 year experience of all the PDGFRA-mutated GISTs in our regional centre in Cambridge. Methods: PDGFRA-mutant GISTs were identified from the Cambridge GIST database. Demographics, clinical and histopathological features, survival and response to tyrosine kinase inhibitors of all the patients from 2008-2021 were reviewed. Results: n = 50 (male:female 1.5:1) Median age 68 years (range 19-87). 8% of patients were under the age of 40 years. Tumour size ranged from 1-26 cm with a median of 5 cm. Mitotic index ranged from 1-51 with a median of 1 mitosis/5mm2. 52% of GISTs were located in the gastric body. Histological subtypes: 44% epithelioid, 36% mixed and 20% spindle cell. 38% of cases had high KIT expression (immunohistochemistry), whilst 48% had patchy expression and 14% were negative. Most were DOG1-positive (94%). 76% had radical surgery, 60% had laparoscopic resection. 24% were assessed as being high risk GISTs using the modified AFIP model contrasted to 13% being high risk with prognostic contour mapping. 13% developed metastatic disease with liver being the most common metastatic site. The table shows PDGFRA mutational analysis results: 58% had a D842V mutation. None had a KIT mutation. With a median follow up of 55.1 months, 82% were alive. 6 patients died from metastatic GIST and 3 from other causes. Median time to metastatic disease in resected GISTs was 30.1 months and median time from metastatic diagnosis to death was 18.5 months. Patients who presented with metastatic disease had poor survival compared with patients with localised disease ( p=0.001). 8 patients were treated with tyrosine kinase inhibitors including imatinib, sunitinib and regorafenib prior to 2020 with no objective responses. 3 patients were treated with Avapritinib since 2020 within the compassionate use programme. All 3 patients had partial responses and 2 patients are continuing Avapritinib with no grade 3 adverse events. Conclusions: We report the largest single centre PDGFRA-mutant GIST cohort from Europe. Male preponderance and exclusive gastric location were observed. KIT expression was patchy to negative in the majority of patients. 58% had PDGFRA D842V mutations for which Avapritinib has been recently approved. No objective responses were seen with imatinib, sunitinib or regorafenib. Our early experience with Avapritinib is promising.[Table: see text]
Clinical markers of immunotherapy outcomes in sarcoma.
Authors: Husain Marium , Liebner David A. , Kim Hangil , Xu Menglin , Chen James Lin , Tinoco Gabriel
Published: June 2022

11578

Background: Despite immunotherapy’s promise in oncology, its use for sarcoma remains challenging. There are no sarcoma-specific biomarkers for immune checkpoint inhibitors (ICI). Previously, we reported our institutional experience highlighting ICI activity in 29 patients with sarcoma. In this updated study, we further explore responses to ICI based on ICI regimen and other covariates to identify significant clinical factors in sarcoma outcomes. Methods: Patients in the Ohio State University Sarcoma clinics were enrolled in the Sarcoma Retrospective ICI database from January 1, 2015 through November 1, 2021. Data included treatment regimen (single agent ICI or ICI+combination) along with covariates: stage, age, gender, histology, change in neutrophil-to-lymphocyte ratio (NLR), number of cycles of ICI and immune-related adverse events (irAE). ICI+combination was further categorized into ICI+chemotherapy, ICI+radiation, ICI+surgery or ICI+multiple (more than 2 modalities). Statistical analysis included log rank tests and proportional hazard regression. The primary objective was to evaluate overall survival (OS) and progression-free survival (PFS). Results: One hundred and thirty-five patients met inclusion criteria. We demonstrated improved OS in patients treated with ICI+combination (p = 0.014, median 64 weeks), but no effect on PFS (p = 0.471, median 31 weeks). Whether patients had received single agent or combination ICI, those who received more than 3 cycles of ICI had an improved OS and PFS (p < 0.05 for both). Patients who received single-agent ICI and whose change in NLR was less than 5 had an improved OS (p = 0.002); this was not seen in patients who received ICI+combination therapy (p = 0.441). Patients who had a documented irAE of dermatitis had improved OS but only in the ICI+combination cohort (p = 0.021). There were no differences in OS based on age, gender, histology or sub-categories of ICI+combination. This was not the case for PFS; patients who received any ICI regimen and were younger than 70 had a worse PFS (p = 0.036). Patients who developed an irAE, specifically colitis (p = 0.009), hepatitis (p = 0.048) and dermatitis (p = 0.003) had an improved PFS. There were no differences in PFS based on ICI regimen (or sub-categories of ICI+combination), gender, histology, change in NLR or grade of irAE. Our ICI cohort results are consistent with historical data from our previous study. Further, irAEs are similar to historical data. Conclusions: This retrospective study demonstrates that ICI+combination therapy can improve OS in sarcoma. This is consistent with our prior results of ICI in sarcoma. Benefits in OS/PFS were seen in patients who received more than 3 cycles of ICI and developed certain irAE. These results can direct the optimal duration of ICI therapy. Those with decreased change in NLR also had improved OS, demonstrating a potential prognostic biomarker. Further studies are needed to validate our findings.
Rural-urban disparities in Geriatric Assessment (GA) impairments and mortality among older adults with cancer: Results from the Cancer and Aging Resilience Evaluation (CARE) Registry.
Authors: Fowler Mackenzie , Kenzik Kelly , Al-Obaidi Mustafa , Harmon Christian , Giri Smith , Arora Sankalp , Khushman Moh'd M. , Outlaw Darryl Alan , Bhatia Smita , Williams Grant Richard
Published: June 2022

12012

Background: Rural-urban disparities persist in cancer incidence and mortality, despite improvement in cancer screening and treatment. Older adults are at increased risk for cancer, represent the majority of cancer cases, and are more likely to reside in rural areas than younger adults are. GAs are recommended in clinical management of older adults with cancer, in part to identify aging-related impairments predictive of adverse outcomes; few studies have explored rural-urban disparities in GA impairments and mortality among older patients with cancer. Methods: We included 937 older adults (≥60y) from the CARE registry recently diagnosed with cancer who underwent GA at their first pre-chemotherapy visit to the UAB oncology clinic. Rural-urban status using Rural-Urban Commuting Area (RUCA) codes, classified the cohort by residence in metropolitan, micropolitan, and rural/small town areas. We included self-rated performance status (PS) (≥2 on Eastern Cooperative Oncology Group PS), instrumental activities of daily living (IADL) [≥1 impairment], physical and mental health-related quality of life (HRQoL) [t-score < 40 on PROMIS 10-item Global Health], and overall survival as outcomes. Logistic regression evaluated the association between rural-urban status and each outcome (except overall survival, where we used Cox regression analyses). Micropolitan residence was chosen as the reference category due to similar high risk in both rural and urban areas. Results: Median age at study participation was 69.0y (Interquartile range: 64.0-74.0); 12.4% resided in rural, 14.8% in micropolitan and 72.8% in urban areas; 22.5% were diagnosed with colorectal cancer, 19.0% with pancreatic, and 12.4% with hepatobiliary; 74.7% were Stage III/IV. Participants in rural areas were more likely to be white and less educated. After adjustment for age, sex, race, education and cancer type/stage, rural residence was associated with increased odds of impaired PS (OR = 1.93, 95% CI: 1.10-3.40), limitations in IADLs (OR = 1.79, 95% CI: 1.03-3.10), and impaired physical HRQoL (OR = 1.84, 95% CI: 1.05-3.22) compared to micropolitan residence. Urban residence was not significantly associated with any GA outcomes compared to micropolitan residence. Rural residence was associated with higher hazard of death compared to micropolitan residence (HR = 1.88, 95% CI: 1.09-3.24) as well as urban residence (HR = 1.67, 95% CI: 1.13-2.45). Conclusions: Among older adults with newly diagnosed cancer, rural residence was associated with impaired PS, limitations in IADLs, impaired physical HRQoL, and reduced overall survival. Implementation of routine GA among older adults in rural areas may aid in early identification and intervention on GA impairments to improve cancer outcomes.
New strategies for multimodal analgesia in patients with high-risk geriatric cancer in perioperative period.
Authors: Tumanyan Sergey V. , Rozenko Dmitry A. , Oros Oksana V. , Shepelenko Aleksandr V. , Chekmezova Svetlana A. , Popova Natalia N.
Published: June 2022

12046

Background: Perioperative pain (POP) in high-risk geriatric patients with cancer (HRGCP) is an important issue. The purpose of this study was to optimize perioperative analgesia in HRGCP. Methods: This randomized study of the quality and effectiveness of perioperative analgesics included 115 HRGCP aged 64-88 years who underwent surgeries on the organs of the chest, abdomen and pelvis for various cancers. The patients were divided into 2 groups. Group 1 (n = 52): patient-controlled analgesia with morphine and nonsteroidal anti-inflammatory drugs (NSAIDs); group 2 (n = 63): ultrasound-guided bilateral transversus abdominis plane (TAP) block with ropivacaine. Intraoperative and perioperative analgesia was maintained with a continuous infusion of lidocaine, magnesium sulphate, microdoses of fentanyl and NSAIDs. Results and pain syndrome were assessed by monitoring the Efficacy Safety Score (ESS), personal and reactive anxiety, stress response (cortisol, insulin, lactate, glucose), rates of functional activity recovery, the need for opioid analgesics, frequency of postoperative nausea and vomiting (PONV). Results: Patients in group 2 showed a significant decrease in the perioperative need for opioid analgesics and significantly decreased POP. Analysis of variance of mean values revealed statistically lower scores of ESS, visual analogue scale and POP (p < 0.05) during the first 24 hours of perioperative period in group 2 compared with group 1. Patient-controlled analgesia showed analgesic effect in 88.5% (p < 0.05) cases. However, the effect was less pronounced, compared to multimodal analgesia, and did not reduce cognitive disorders. In group 2, opioid-sparing analgesic effect was 95.3% (p < 0.05). Multimodal analgesia reduced the stress response (p < 0.05) in perioperative period and did not cause cognitive dysfunction while reducing PONV episodes, unlike morphine. Despite the minimal doses of narcotic analgesics in group 2, multimodal analgesia provided safe analgesia and functional activity recovery in perioperative period with minimum negative effects of opioids. Conclusions: The strategy of multimodal analgesia based on a combination of intraoperative TAP block and infusions of lidocaine and microdoses of fentanyl can significantly improve the quality of analgesia in perioperative period.
Association of polypharmacy and potential drug-drug interactions with adverse outcomes in older adults with advanced cancer receiving systemic treatment.
Authors: Mohamed Mostafa Refaat , Mohile Supriya Gupta , Juba Katherine , Awad Hala , Wells Megan , Loh Kah Poh , Flannery Marie Anne , Culakova Eva , Tylock Rachael , Desai Nisarg , Bradley Thomas Paul , Onitilo Adedayo A. , Ramsdale Erika E.
Published: June 2022

12053

Background: Polypharmacy (PP) is common in older adults starting cancer treatment and associated with increased risk of potential drug-drug interactions (PDI). PP and PDI may affect treatment-related outcomes in older patients. This study evaluates the association of PP and PDI with systemic treatment adverse outcomes in older adults with advanced cancer. Methods: This secondary analysis of prospectively collected data from the GAP 70+ Trial (NCT02054741; PI: Mohile) enrolled patients aged 70+ with advanced (i.e. incurable) cancer; had ≥1 geriatric assessment domain impairment; and planned to start a new chemotherapy regimen or another regimen with high risk of toxicity. PP was assessed prior to initiation of treatment and defined as concurrent use of ≥8 medications (meds). PDI among all drugs were reviewed prior to initiation of treatment using Lexi-Interact® Online with category D and X considered “major PDI”. Study outcomes were assessed within 3 months of treatment initiation and included: 1) total number of Grade ≥2 toxicities according to National Cancer Institute Common Toxicity Criteria; 2) total number of Grade ≥3 toxicities; and 3) early treatment discontinuation due to toxicity. Multivariable linear and logistic regression models were used to examine the association of PP and PDI with treatment adverse-outcomes adjusted for age, gender, cancer type, comorbidity, physical function, social support, and study arm. Results: Among 718 participants, the mean age was 77 (range 70-96); 43% were females; and 57% had lung or gastrointestinal cancers. The median number of meds was 5 (range 0-24); 28% received ≥8 concurrent meds; and 25% had ≥1 major PDI. The mean number of Grade ≥2 toxicities for patients with PP was 9.8 versus 7.7 in patients without PP (adjusted β=1.87, standard error [SE]=0.71, P<0.01). The mean number of Grade ≥3 toxicities for patients with PP was 2.9 versus 2.2 in patients without PP (adjusted β=0.59, SE=0.29, P=0.04). Patients with ≥1 major PDI had 59% higher odds of early treatment discontinuation versus those without major PDI (adjusted odds ratio 1.59, 95% confidence interval=1.03-2.46, P=0.03). There was no significant association between PP and early treatment discontinuation. Major PDI were not significantly associated with toxicity (Ps>0.05). Conclusions: In a cohort of vulnerable older adults with advanced cancer, PP and PDI are associated with increased risk of systemic treatment adverse outcomes. Providing meaningful screening and interventional tools to optimize medication use may improve treatment outcomes in these patients. Funding:UG1CA18996, U01CA233167.
Prevalence of frailty for middle-aged and older adults starting a new line of systemic cancer treatment: Is age just a number?
Authors: Pergolotti Mackenzi , Wood Kelley C , Hidde Mary , Kendig Tiffany , Williams Grant Richard , Giri Smith , Ronnen Ellen A. , Carroll Rachel
Published: June 2022

12054

Background: Frailty is associated with adverse outcomes and increased risk of mortality for older adults (>60 years) with cancer. Geriatric assessment (GA) has gained popularity in routine cancer care as a clinical tool to screen for frailty in older adults starting a new line of cancer treatment, and to guide clinical decision making during systemic therapy. Emerging research indicates GA may also be useful to identify frailty in middle-aged adults (40-60 years) with cancer, but more research is needed. In this study, we used GA data to compare the prevalence of frailty between middle-aged and older adults starting a new line of systemic cancer treatment. Methods: Participants included adult patients with cancer due to begin a new line of systemic therapy at a multi-office community-based oncology private practice and enrolled in a clinical trial (NCT04852575). At baseline, participants completed an online version of the Cancer and Aging Resilience Evaluation (CARE) — a patient-reported GA adapted from the Cancer and Aging Research Group. Frailty score was constructed using a 44-item deficit accumulation method and categorized as frail (>0.35), pre-frail (0.2-0.35) or robust (0-0.2) using published cutoffs. We grouped participants by age, middle-aged (40-60 years) or older-aged (>60 years), then used independent t-test and chi-squared statistic to compare frailty scores (continuous) prevalence of frailty (categorical) between groups. Hypothesis testing was two sided and the level of significance was 0.05. Results: Participants ( n=96) were predominantly female (62%), Caucasian (68%) and beginning first line systemic therapy (69%) for either newly diagnosed cancer or new recurrence of disease; median time since diagnosis was 1 month. Common cancer types included: breast (34%), gastrointestinal (23%), hematologic (15%) and lung (12%). Disease stage was predominantly stage 3 (28%) or stage 4 (38%). When comparing middle-aged ( n=31, Mage = 54.74 ± 4.79, range = 41.23 – 59.98 years) vs. older adult -groups ( n=65, Mage = 70.27 ± 5.91, range = 60.64 – 84.29 years), there was no significant difference in mean frailty score ( p = 0.22) or the proportion categorized as frail vs. pre-frail vs. robust ( p = 0.32); see Table. Stage of disease and prevalence of common cancer types was similar between age groups (p>.05). Conclusions: In our cohort, middle and older aged patients who completed patient-report GA had similar prevalence of frailty before starting systemic therapy. Using the GA as a functional-age assessment to detect frailty for adults of varied ages could allow for earlier intervention aimed at impacting tolerance to therapy. Clinical trial information: NCT04852575. [Table: see text]
Retrospective analysis of healthcare disparities in Philadelphia chromosome-positive ALL: A single-institution experience of a large metropolitan area.
Authors: Bouligny Ian Michael , Tran Valerie , Zacholski Kyle , Venn Chad Michael , Alnimer Yanal Mufeed , Ho Thuy , Maher Keri Renee
Published: June 2022

12067

Background: Philadelphia chromosome-positive (Ph+) ALL is an aggressive hematological neoplasm with a dismal prognosis. Hematopoietic stem cell transplant (HSCT) remains the standard of care for those reaching complete remission due to high relapse rates with conventional therapy alone. We have previously demonstrated findings concerning for imbalanced outcomes among racial groups in AML. In the era of TKIs targeting BCR-ABL1 in combination with conventional therapy, it is unclear whether trends noted in AML are also seen in Ph+ ALL. Thus, the purpose of this study was to investigate the impact of healthcare disparities on outcomes in Ph+ ALL with regards to access to care, response rates, toxicities, and overall outcomes. Methods: We retrospectively analyzed 59 patients with Ph+ B-ALL treated at our institution with TKIs +/- chemoimmunotherapy during January 2015 to January 2021. Baseline patient demographics were obtained, including insurance type, performance status at diagnosis, cytogenetic and molecular profiling, dates and doses of induction, toxicity, response, MRD analysis, and HSCT access and outcomes. Race was determined by patient self-report as recorded in the electronic medical record. Results: We divided 58 patients (one excluded as race was unknown) into two cohorts: 23 (39.7%) patients that identified as minorities, including African American, Hispanic/Latino, and Asian, and 35 (60.3%) identifying as White. There were no differences in baseline characteristics including age (p =.367), sex (p =.788), ECOG at diagnosis (p =.438), Charlson Comorbidity Index scores (p =.551), or presence of additional poor-prognostic mutations (p >.999). Despite this, minorities were significantly more likely to be treated with lower-intensity regimens compared to non-minorities (p =.022). Achievement of CR by MRD was approaching statistical significance favoring the non-minority cohort (60.0% versus 27.3%, p =.055). Receipt of HSCT numerically favored the non-minority cohort, approaching statistical significance (54.3% versus 26.1%, p =.056). At a median follow-up time of 3.3 y., the median OS was not reached between the two groups and there was no difference in survival between the two groups (p =.662). Conclusions: Despite similar patient-related characteristics, minority populations are more likely to be treated with lower-intensity strategies, concerning for bias in regimen selection. Achievement of CR by MRD and receipt of HSCT appeared to be numerically lower in the minority cohort. While there appeared to be no difference between the two cohorts with regards to survival during the follow-up period, it is unclear if this would be maintained with longer follow-up. These findings highlight the need for ongoing vigilance regarding physician biases and increasing the need for improving access to curative treatment for all patients.