tbuckley/cabot-search huggingface dataset:
Phase II trial, multicenter, first line paclitaxel-avelumab treatment for inoperable angiosarcoma.
Authors: Hye Ryeon Kim, Miso Kim, Jeong Eun Kim, Hyojeong Kim, Yu Jung Kim, Myoung Joo Kang, Kwonoh Park, Woo Kyun Bae, Jung Yong Hong, Sung Yong Oh
Journal: Journal of Clinical Oncology (2024)

11512 Background: Angiosarcomas are very rare tumors of vascular or lymphatic origin characterized by a clinical heterogeneity in terms of presentation and behavior. It can occur in any site of body but most commonly originate in the skin of head and neck and in breast area. Many patients could not receive surgical resection due to its location and/or rapid progression, even who had localized disease. Moreover, conventional cytotoxic chemotherapy has shown limited effect in angiosarcoma. Here, we conduct a prospective, phase II study to evaluate the efficacy and toxicities of paclitaxel plus avelumab as the first line therapy for unresectable angiosarcoma. Methods: Patients with unresectable locally advanced or metastatic angiosarcoma, who had not received systemic treatment, were enrolled. Paclitaxel (80 mg/m 2 ) was intravenously infused on days 1, 8, and 15 of every 28-days cycle, and avelumab (10mg/kg) was intravenously infused biweekly. The treatment was continued until disease progression or unacceptable toxicity, or withdrawal of consent, whichever occurred first. The primary endpoint was the objective response rate (ORR), and the secondary endpoint was overall survival (OS), progression free survival (PFS), and safety profiles. Results: A total 32 patients (21 male, 11 female) were finally enrolled, and the median age was 63.5 (range, 27 to 82). The ORR was 50.0% (n = 16), including one complete response. Median OS and PFS were 14.5 (95% CI, 9.4 to 24.6) and 6.0 (95% CI, 5.4 to 9.5) months, respectively. Among patients who received at least one dose of treatment (n = 33), adverse events (AEs) of any grade were reported in 90.9% (n = 30), and severe AEs were in 12.1% (n = 4), including one death. The most common hematologic/non-hematologic AEs were neutropenia (n = 13, 39.4%) and pain (n = 12, 36.4%), respectively. Febrile neutropenia, neutropenia, and aspiration were reported in two patients (6.1%) each. Conclusions: Avelumab plus paclitaxel for patients with inoperable angiosarcoma, was effective and has tolerable safety profile. Additional translation studies and phase III studies are needed to clearly identify effectiveness and safety. Clinical trial information: NCT03512834 . [Table: see text]
Novel models for the functional characterization of SDHA germline variants to predict cancer risk.
Authors: Jason Kent, Michael C. Heinrich
Journal: Journal of Clinical Oncology (2024)

11532 Background: SDHA mutations are the most common cause of SDH-deficient GIST. More than 80% of SDHA-mutant GIST are associated with heterozygous germline mutations. Enhanced cancer surveillance of individuals carrying a known pathogenic germline SDHA mutation has the potential to detect early-stage tumors, allowing for curative surgery. However, of the &gt; 1000 SDHA missense variants listed in ClinVar, &gt; 95% are VUS. We must improve our ability to interpret the significance of SDHA variants before genetic sequencing can be utilized to its fullest potential for assessing cancer risk. Methods: We generated a novel clonal SDHA knock out (SDHA KO ) human cell line with complete loss of SDHA expression and enzymatic activity. We next generated a clonal cell line harboring one copy of a landing pad cassette, allowing for site-specific integration of transfected expression cassettes mediated by Bxb1 recombinase. We validated that wild-type SDHA cDNA restored SDHA expression and enzymatic activity to levels equivalent to the parental HAP1 cells. We then selected 17 known benign variants (B,LB) and 21 known cancer missense variants (P, LP). In addition, we selected six missense variants associated with primary mitochondrial disease rather than cancer. Lastly, we selected 22 missense VUS. We created a mutant cell line in our KO landing pad cell line for each SDHA variant, as well as a control nonsense variant (SDHA R31X ). Cell lines were analyzed for normalized SDH activity measurements (SDHA WT activity score = 1) Results: As expected, benign variants were collectively WT-like, with a mean Activity Score of 0.917. However, there was substantial variability amongst individual variants, with SDHA Y55H having the lowest score at 0.215. Although known PMD variants (mean Activity Score = 0.358) were associated with lower functionality than that of benign variants, the extent of SDH dysfunction corresponding to cancer variants (mean Activity Score = 0.007) was substantially lower. Notably, all but one cancer variant could be described as functionally amorphic, as their Activity Scores were not significantly different from that of a control null variant, SDHA R31X , whose mean Activity Score was 0.004. We used the Activity Scores of these clinical control variants to establish thresholds to classify "cancer-like" or "benign-like" variants, which meet ACMG/AMP criteria for PS3_strong and BS_3 strong evidence according to an OddsPath calculation. We biochemically profiled 22 cell lines expressing a SDHA VUS. Using functional data and ACMG criteria, 3 variants could be reclassified as "Likely Benign", 14 could be reclassified as "Likely Pathogenic", and 5 remained a VUS (77% successfully reclassified). Conclusions: Functional characterization of SDHA germline missense variants has the potential to identify individuals who will benefit from genetic counseling and enhanced cancer screening procedures.
Extracorporeal irradiation and reimplantation for bone sarcomas: Medium- and long-term oncologic and functional outcomes.
Authors: Biplab Mishra, Mandip C Shah, Kinjal Jani
Journal: Journal of Clinical Oncology (2024)

11524 Background: Extracorporeal irradiation is an effective and established method for limb salvage in the management of malignant bone tumours.We analyzed the oncological and functional outcomes of extracorporeal radiotherapy (ECRT) and reimplantation done for bone sarcomas. Methods: 67 patients (29 osteosarcoma, 27 Ewing’s sarcoma, 11 others; mean age 16 years) were treated with ECRT between 2010 and 2022. Femur was commonest bone (33) followed by tibia (11) and humerus (11). 48 had a metadiaphyseal while 19 had osteoarticular resections. A single dose of 50 Gy was delivered to the resected bone segments. The irradiated bones were reimplanted immediately as a biological graft. Construct was stabilized with long locking plates. Osteoarticular ECRT was coupled with joint replacement. Patients were treated with chemotherapy as per standard protocol. Functional outcome was assessed by Musculoskeletal Tumor Society (MSTS) scoring system. Results: The mean resected length of bone was 17 cm (9 to 26). All 67 patients were available at a mean follow-up of 66 months (22 to 166). The mean time to union for all osteotomy sites was 6 months (2 to 17): metaphyseal osteotomy sites united quicker than diaphyseal osteotomy sites (3.8 months (3 to 6) versus 9.5 months (4 to 17)). 2 deep infections necessitated removal of the ECRT segment. There were 2 local recurrences in soft-tissue needing amputation. 6 of the remaining 113 (5.3%) junctions remained ununited which needed additional bone grafting. 5/6 junctions united after bone grafting. 1 remained ununited needing cementation across the segment. At the time of final follow-up, 47 patients were free of disease, one was alive with disease and 19 had died of disease. The mean Musculoskeletal Tumor Society Score at the last follow-up was 26 (18 to 30). Conclusions: The radiated bone acts as a size-matched allograft and has very good union rates. The complication rates are very low. Extracorporeal irradiation is an oncologically safe and biological reconstruction technique for limb salvage in sarcomas and has good functional results. It should be recommended to all suitable patients.
Efficacy and safety of lurbinectedin (LUR) with irinotecan (IRI) in a phase 2 expansion cohort of patients (Pts) with synovial sarcoma (SS).
Authors: Gregory Michael Cote, Javier Martin Broto, Sant P. Chawla, Bruno Bockorny, Alejandro Falcon Gonzalez, Antonio López Pousa, Luis G. Paz-Ares, Benjamin Verret, Sara Martinez, Sonia Extremera, Martin Cullell-Young, Salvador Fudio, Carmen Maria Kahatt, Ali Hassan Zeaiter, Axel Le Cesne
Journal: Journal of Clinical Oncology (2024)

11560 Background: LUR has shown activity in several solid malignancies. Preclinical studies found synergism for LUR combined with IRI (Galmarini C. Cancer Res 2013; 73: Abst 5499). The phase 1b/2 study PM1183-A-014-15 (NCT02611024) evaluated the LUR/IRI combination in pretreated pts with advanced solid tumors. The recommended dose was defined at LUR 2.0 mg/m 2 on Day (D) 1 + IRI 75 mg/m 2 on D1, D8 q3wk with primary G-CSF prophylaxis. After observing 3 partial responses in SS pts during the phase 1b part, a phase 2 expansion cohort was implemented to explore this activity further. Methods: This cohort included pts with SS progressing after up to 2 prior cytotoxic-containing lines for advanced disease. The primary endpoint was overall response rate (ORR) per independent review committee (IRC)/investigator. Results: Thirty pts were enrolled and treated. Baseline characteristics were median age 41 y (range, 19-73), 57% males, 53% ECOG PS=1. Primary tumor location was mostly in the extremities (53%). Most common tumor metastatic sites at study entry were lung (83%), pleura (37%) and lymph nodes (23%). 60% had at least one lesion &gt;50mm. The median number of prior lines was 2 (range, 1-5), and the median number of prior chemotherapy lines for advanced disease was 1 (range, 0-3). The median time from diagnosis was 32 mo (range, 2-160 mo). The best response to first-line therapy was stable disease in 50% of pts and progressive disease in 8%. Efficacy results are summarized (Table). Most common G3/4 events/abnormalities were neutropenia (60%), anemia (27%), thrombocytopenia (17%), diarrhea (10%), fatigue (10%) and febrile neutropenia (10%). 20% had treatment-related SAEs. No treatment-related discontinuations or deaths occurred. No evidence of drug-drug interaction was observed in the PK analysis. Conclusions: The LUR/IRI combination showed activity in pretreated SS with manageable toxicity. These results reinforce the rationale for assessing the activity of LUR combined with IRI in SS and other tumor types. Clinical trial information: NCT02611024 .[Table: see text]
Transcriptomic analysis of novel tumor suppressor gene fusions in bone sarcomas.
Authors: Dmitrii Grachev, Danil Ivanov, Vladimir Kushnarev, Sheila T. Yong, Nikita Kotlov, Konstantin Chernyshov, Alexander Bagaev, Nathan Hale Fowler, Anthony Paul Conley, Gregory Michael Cote, Sant P. Chawla
Journal: Journal of Clinical Oncology (2024)

11523 Background: Despite the evolution of therapeutic strategies for sarcomas in the past four decades, survival in the metastatic setting remains poor. This underscores the urgent need to explore new diagnostic and treatment avenues to improve patient outcomes. Harnessing the capability of RNA sequencing (RNA-seq) to detect gene fusions de-novo, we analyzed treated bone sarcoma samples with the aim to uncover gene fusions and breakpoints that are potentially relevant as clinical biomarkers and treatment targets. Methods: We analyzed 83 formalin-fixed, paraffin-embedded tumor samples of treated bone sarcomas, including osteosarcomas, chondrosarcomas, chordomas, and Ewing sarcomas. These samples were subject to in-depth whole exome analysis and bulk RNA-seq. RNA-seq was employed to identify gene fusions, with STAR-fusion utilized for sequence calling. Quality control of all NGS samples was performed using FastQC, FastQ Screen, RSeQC, and MultiQC. Tumor purity was assessed via pathological and bioinformatics examination with the threshold set at 20%. Fusions involving tumor suppressor genes listed in the OncoKB database were investigated further. A comprehensive literature search on PubMed and Google Scholar as well as analysis of the FusionGDB and COSMIC databases were performed to verify candidates of novel gene fusions. We also compared our samples with those in the publicly available MSK sarcoma cohort and 11 osteosarcoma cell line datasets. Results: We detected 238 gene fusions in all samples analyzed. Among these fusions, 18 (16 previously unknown, 2 previously reported) involving known tumor suppressor genes were present in 14 samples (17%). Among the 16 previously unknown fusions, 8 were indicative of potential loss-of-function variants of tumor suppressors: TP53-NF1, TP53-CEMIP, CTNNBL1-RB1, PRPF40A-FBXW7, VAMP2-MSH3, and ETV6-ATM in osteosarcoma; BRD4-TP53 in unspecified bone sarcoma; and FBXW7-ZNF770 in Ewing sarcoma. Furthermore, we also uncovered a novel breakpoint combination in EWSR1-ETV4 in Ewing sarcoma that links exon 9 of EWSR1to exon 9 of ETV4. Conclusions: Our comprehensive transcriptomic analysis of treated sarcoma samples uncovered previously unknown gene fusions involving tumor suppressor genes and a unique breakpoint combination in an oncogene. These findings emphasize the crucial role of RNA-seq not only in advancing genomic research of sarcomas, but also in identifying potential biomarkers/targets and devising new treatment strategies for this rare cancer.
Safety and toxicity evaluation of the combination of selinexor with atezolizumab in patients with soft tissue sarcomas.
Authors: Jibran Ahmed, Geraldine Helen O'Sullivan Coyne, Nancy Moore, Jared C. Foster, Steven Gore, Helen X. Chen, Lamin Juwara, Barry C. Johnson, James H. Doroshow, Alice P. Chen
Journal: Journal of Clinical Oncology (2024)

11557 Background: The U.S. Food and Drug Administration (FDA) recently approved the anti-PD-L1 antibody atezolizumab for alveolar soft part sarcoma (ASPS). Selinexor, a selective XPO1 inhibitor, demonstrated cytotoxic activity in ASPS-KY and ASPS-1 cell lines of ASPS and other sarcoma cell lines; it has been approved as a part of regimens to treat multiple myeloma and diffuse large B-cell lymphoma. Preliminary clinical data demonstrate acceptable safety profiles in patients with melanoma who received selinexor in combination with an anti-PD-1 antibody. Methods: We designed a randomized phase 2 study to evaluate atezolizumab with or without selinexor in adult patients with ASPS that included a safety run-in (SR) open to patients with soft tissue sarcoma (NCT05333458). Prior immune checkpoint inhibitor therapy was not allowed. During the SR, patients received selinexor (60 mg PO) on days 1, 8, and 15 of the 28-day cycle and atezolizumab (1200 mg flat dose IV) on day 8 at the Developmental Therapeutics Clinic. Protocol-defined treatment-related adverse events (TRAEs) occurring during cycle 1 would either expand accrual to the SR or close the study. Safety data were evaluated by the principal investigator and NCI CTEP (National Cancer Institute Cancer Therapy Evaluation Program). Results: Six patients were enrolled in the SR and were evaluated weekly during the first cycle of study treatment. All patients were female with a median age of 47 years (range: 22-71 years). Diagnoses included sclerosing epithelioid fibrosarcoma (n=2), dedifferentiated liposarcoma (n=1), metastatic leiomyosarcoma (n=1), metastatic angiosarcoma (n=1), and ASPS (n=1). No patients were removed from the SR due to AEs. Two patients experienced grade 3 TRAEs, including one instance each of neutropenia and lymphopenia (Table). Beyond cycle 1, there was 1 occurrence of grade 3 lymphopenia. No grade 4 or 5 AEs have occurred during the SR. Fatigue and nausea were the most prevalent TRAEs, but only one patient experienced grade 2 nausea; all other occurrences of nausea and fatigue were at grade 1. Conclusions: The safety run-in completed without any occurrences of protocol-defined treatment-related toxicity during cycle 1. The treatment was well tolerated. Based on these data, the randomized part of this study began accruing patients with ASPS across the ETCTN (Experimental Therapeutics Clinical Trials Network). Clinical trial information: NCT05333458 . [Table: see text]
Predictive gene signature for trabectedin efficacy in advanced soft‐tissue sarcoma: A Spanish group for research in sarcoma (GEIS) study.
Authors: David Silva Moura, Juan A. Cordero Varela, Ramiro Alvarez, Carolina Agra Pujol, Francisco Izquierdo, Rafael Ramos, Luis Ortega, Francisco Martin-Davila, Nieves Hernandez Leon, Cleofe Romagosa, Maria Ángeles Vaz-Salgado, Javier Lavernia, Silvia Bague, Empar Mayodormo-Aranda, Jose Lucinio Mondaza-Hernandez, Marta Renshaw-Calderon, Nadia Hindi, Claudia Valverde Morales, Javier Martínez-Trufero, Javier Martin Broto
Journal: Journal of Clinical Oncology (2024)

11543 Background: Predictive biomarkers of trabectedin represent a clinical unmet need to support the rational selection of this drug in the advanced soft‐tissue sarcomas (STS) setting. A few potential predictive biomarkers of trabectedin had been described in previous studies, including ERCC1, BRCA1, and HMGA1, among others; however, they are based mostly on the analysis of single selected molecular factors. We presented here a predictive transcriptomic-based signature for trabectedin efficacy in STS. Methods: A total of 140 patients with advanced STS (at diagnosis or at any time from then on), with paraffin tumor block available, with at least 2 lines of treatment in advanced disease (one of them trabectedin) were included in this study. Gene expression was evaluated by direct transcriptomics, using HTG EdgeSeq Oncology Biomarkers Panel (HTG Molecular Diagnostics, Inc.; Tucson, AZ, USA). Raw counts were normalized to transcripts per million (TPM). Univariate Cox regression analysis was performed to find genes significantly associated with PFS and only those genes with significantly different curves were further retained (P &lt; 0.05). These remaining genes were used as input to build a gene expression signature, using a multivariate Cox regression applying a Lasso penalty. Risk scores were calculated by multiplying the expression of every gene with its corresponding Cox regression coefficient. Results: A series of 140 patients was studied, with a median age of 51, 54% males, and a median follow-up from diagnostics of 45 months. The most frequent subtypes were L-sarcomas (54%). A twenty-nine-gene predictive signature of trabectedin efficacy was built for advanced STS treatment. This signature included 13 and 16 genes associated with resistance or sensitivity to trabectedin, respectively. Genes associated with low efficacy of trabectedin included HMGA1, NES, FANCA, and FANCB, among others, whereas the high expression of genes such as NTRK2 or CDKN2Awere associated with higher activity of trabectedin. Patients in the high‐risk gene signature group showed a significantly worse PFS compared with patients in the low‐risk group: [2.0 months (95% CI 1.7-2.2) vs. 8.2 months (95% CI 5.1-11.3), p&lt;0.001]. Conclusions: Our study identified a new 29-gene-based signature that significantly predicts trabectedin efficacy in STS patients. Prospective validation of this predictive gene signature is warranted.
Efficacy of nirogacestat in participants with poor prognostic factors for desmoid tumors: Analyses from the randomized phase 3 DeFi study.
Authors: Bruno Vincenzi, Nam Bui, Palma Dileo, Noah Federman, Richard F. Riedel, Brian Andrew Van Tine, Vincent Amoruccio, Allison Lim, Ana B. Oton, Bernd Kasper
Journal: Journal of Clinical Oncology (2024)

11556 Background: Desmoid tumors (DT) are rare, locally aggressive, soft-tissue tumors with a highly unpredictable natural course and substantial patient burden, including pain and functional limitations. Prognosis of DT is potentially dependent on multiple factors, including tumor location, size, patient’s age, mutational status, and presence of pain. Nirogacestat (niro), a targeted gamma secretase inhibitor, is the only treatment approved in the US for adults with progressing DT. In the phase 3 DeFi study, niro demonstrated significant and clinically meaningful improvement vs placebo (pbo) in the primary and key secondary endpoints of progression-free survival (PFS: HR, 0.29 [95% CI: 0.15-0.55]; P&lt;.001), objective response rate (ORR: 41% vs 8%; P&lt;.001), and patient-reported outcomes (pain, DT-specific symptom burden, physical and role functioning, and overall quality of life; P≤0.01, all). The objective of this analysis was to determine the effect of niro in patient subgroups that have been associated with poor prognosis (larger tumor size, younger age, CTNNB1 mutation types, and pain). Methods: DeFi (NCT03785964) was a global, multicenter, double-blind study to determine the efficacy, safety, and tolerability of niro in adults with progressing DT. Patients were randomized 1:1 to niro 150 mg (n=70) or pbo (n=72), taken twice-daily in 28-day cycles. Post hoc analyses of PFS and ORR were conducted in individuals stratified by patient- and tumor-related prognostic factors. Results: PFS and ORR improvement favored niro vs pbo regardless of the patient subgroup, including: baseline tumor size (≤10 cm, &gt;10 cm); age (≤30 y, &gt;30 y); CTNNB1 mutation type (S45F, T41A); and baseline pain (uncontrolled, controlled) (Table). Across the subgroups analyzed, PFS hazard ratio ranged from 0.18 to 0.39, with values &lt;1 favoring niro over pbo. ORR risk difference (niro – pbo) ranged from 18.1% to 56.0%, with values &gt;0 favoring niro. Conclusions: Niro demonstrated consistent improvement in PFS and ORR vs pbo in patients with characteristics implicated as poor prognostic factors for DT—including larger tumor size, younger age, CTNNB1 mutation types, and pain. These results indicate that niro can provide substantial benefit across the subgroups analyzed. Clinical trial information: NCT03785964 . [Table: see text]