bluuebunny/crossref_metadata_2025 huggingface dataset:
Histopathological response (HR) after neoadjuvant chemotherapy (ChT) for high-risk soft tissue sarcomas (STS): A planned analysis of the ISG-STS-1001 trial.
Authors: Pasquali Sandro , Collini Paola , Romagosa Cleofe , Coindre Jean Michel , Pizzamiglio Sara , Verderio Paolo , Barisella Marta , Palmerini Emanuela , Quagliuolo Vittorio , Martin Broto Javier , Lopez-Pousa Antonio , Grignani Giovanni , Blay Jean-Yves , Lugowska Iwona A. , Fontana Valeria , Sbaraglia Marta , Bague Silvia , De Tos Paolo , Casali Paolo G , Gronchi Alessandro
Published: June 2023

11511

Background: HR after neoadjuvant ChT for high-risk STS has not been prospectively characterized and the prognostic implications remain unclear. This planned analysis of the ISG-STS-1001 trial, which compared neoadjuvant anthracycline plus ifosfamide (AI) and a histology-tailored (HT) ChT, was aimed at characterizing HR after neoadjuvant ChT and investigating association with the risk of recurrence. Methods: Patients registered in the ISG-STS-1001 study (ID: NCT01710176) were included if they had the per-protocol assessment of HR in surgical specimens. The following morphological post-treatment changes were considered: residual stainable tumor cells, necrosis, hemorrhage, sclerosis, sclerohyalinosis, and fibrohistiocytic reaction with haemosiderin. Pathologists at each study site analyzed and expressed each of these changes as a rate within each tumor. Disease-free survival (DFS), which was the trial primary end-point, was the outcome variable. Results: HR was assessed in 201 of 287 randomized patients (47 had re-excision, 7 did not have surgery, and 32 were not evaluable after wide excision), who were followed up for a median of 89 months (IQR 75-102 months). Presence (>1%) of stainable tumor cells (N=194, 96%) was not associated with DFS (HR=1.47, 95%CI 0.36–5.98, P= 0.591). Conversely, presence (≥1%) of necrosis (N=169, 84%) was associated with shorter DFS (HR=3.11, 95%CI 1.36–7.14, P=0.007) and sclerohyalinosis >20% (N=42, 21%) was associated with a lower risk of recurrence (HR=0.51, 95%CI 0.28–0.94, P=0.031). These findings were confirmed when patients who had preoperative radiotherapy (N=32) were excluded. In patients randomized to AI with tumors evaluable for HR (N=98), sclerohyalinosis >20% (N=24, 24.5%) maintained the association with a lower risk of recurrence (HR=0.24, 95%CI 0.09 – 0.67, P=0.007). Finally, the prognostic value of necrosis and sclerohyalinosis for DFS held also when patients registered in the study (187/361 evaluable for HR) were selected in addition to randomized patients. Conclusions: This is the first study that prospectively evaluated HR after neoadjuvant ChT in high-risk STS. Previous classifications of HR were based on expert consensus and had limited prognostic relevance. In this study residual stainable tumor cells, which is often considered the most relevant post-treatment change, did not stratify patient risk, while sclerohyalinosis (>20%) singled out patients with the best outcome after neoadjuvant ChT. Clinical trial information: NCT01710176 .
Impact of pregnancy in women with desmoid fibromatosis: An international retrospective observational study.
Authors: Fiore Marco , Bonvalot Sylvie , Personeni Giulia , Raut Chandrajit P , Mercier Kelly , Gladdy Rebecca , Ljevar Silva , Tzanis Dimitrios , Rossi Enrica , Sulciner Megan , Suraweera Harini , Colombo Chiara , Rabih Mikhael , Coppola Marianna , Sarre-Lazcano Catherine , Iadecola Sara , Figura Costanza , Salvatore Daniela , Gronchi Alessandro
Published: June 2023

11513

Background: Desmoid fibromatosis (DF) often occurs during pregnancy/peripartum. Guidance for planning new pregnancies during active surveillance or following DF resection has been limited. Thus, we sought to evaluate outcomes and decision making in the peripartum. Methods: Women of child-bearing age with DF diagnosed between 2000 and 2020 were interviewed about procreation decisions, in a multicenter retrospective observational study (NCT05284305). Pregnancies simultaneous or after diagnosis were analyzed. Primary outcome was DF progression/recurrence within 1 yr postpartum. Secondary outcomes were spontaneous regression, switch to active treatment, and obstetric risks. To estimate probability of progression, a random intercept logistic model was fit to account for correlation of progression in multiple pregnancies in the same patient. Results: Of 483 pts interviewed, 120 (24.8%) postponed, 32 (6.6%) interrupted, and/or 232 (48%) avoided pregnancy (in 93.3%, 50%, and 72.9% of cases because of DF), respectively. 147 pregnancies in 131 pts were concurrent with or after diagnosis: 26 (17.7%, Group A) concurrent with diagnosis, 48 (32.7%, B) after DF resection, and 73 (49.7%, C) with DF on surveillance. Estimated probability of progression was 12.0% (CI 2.0 – 48.4) during pregnancy and 15.8% (5.6 – 37.5) postpartum; for pregnancies after diagnosis (Groups B and C), these rates were 5.1% (0.4 – 40.0) and 9.0% (1.8 – 35.0). On multivariate analysis, age at pregnancy and size of primary DF were significant risk factors for progression (Table). Estimated probability of spontaneous regression was 3.6% (CI 0.2-40.7) during pregnancy and 7.1% (CI 0.3 – 67.2) postpartum. 7/38 (18.4%) spontaneously regressed after pregnancy-related PD, 4/23 (17.4%) in Groups B and C. Treatment for progression was needed in 9/79 (11.4%) postpartum, in 4/63 (6.3%) in Groups B and C. Obstetric complications were comparable to population data in developed countries. Conclusions: After DF diagnosis, pregnancy is safe with a risk of progression of 5% during pregnancy and 9% postpartum. Treatment is needed in only 6%. Spontaneous regression is less common but occurs even after initial progression. Patients decision making about procreation appeared to be influenced by their DF diagnosis. This study supports counseling that fertility options should be fully explored with expert guidance as intervention rates are low. [Table: see text]
Tumor volume and T2 hyperintensity changes from DeFi: A phase 3, randomized, controlled trial of nirogacestat in patients with desmoid tumors.
Authors: Alcindor Thierry , Kasper Bernd , Gounder Mrinal M. , Ratan Ravin , Van Der Graaf Winette T.A. , Wilky Breelyn A. , Riedel Richard F. , Federman Noah , Peruzzi Agnese , Moody Stephanie , Lim Allison , Tumminello Brad , Kummar Shivaani , Schöffski Patrick
Published: June 2023

11514

Background: MRI tumor volume or T2 signal intensity changes may represent novel imaging techniques that could have a prognostic or predictive value for assessing response in desmoid tumors (DT). For example, hyperintense areas on T2-weighted images have been associated with active fibroblastic proliferation and ≥90% hyperintensity is associated with DT disease progression, whereas iso- or hypo-intense areas are associated with inactive sites of disease. In DeFi (NCT03785964), the novel gamma secretase inhibitor nirogacestat (n=70 patients) significantly improved the primary endpoint of PFS compared with placebo (n=72 patients; hazard ratio, 0.29 [95% CI, 0.15, 0.55; P<0.001]) and significantly improved the secondary endpoint of ORR per blinded, independent central review (41% vs 8%; P<0.001). Complete responses were achieved in 7% with nirogacestat and 0% with placebo. Here, we present an exploratory analysis of MRI tumor volume and T2 signal intensity changes in DeFi. Methods: Eligible adults had histologically confirmed DT that had progressed ≥20% per RECIST v1.1 within 12 months of screening. Patients were randomized 1:1 to receive nirogacestat 150 mg or placebo twice daily taken continuously in 28-day cycles. Volumetric MRI and T2 hyperintensity of the largest target tumor were evaluated at screening and every 6 cycles during the double-blind phase. MRI T2 signal intensity is represented as the ratio of hyperintensity in total tumor volume to muscle background. A blinded, independent, central radiologist reviewed all MRI scans. Results: Nirogacestat treatment led to more substantial reductions versus placebo in tumor volume and T2 hyperintensity ratio (Table). At baseline, similar proportions of patients in each arm had a T2 hyperintensity ratio ≥90% (95% vs 97%). This ratio changed from ≥90% at baseline to <90% at any time after baseline in 34% of patients in the nirogacestat arm and 15% of those on placebo. Conclusions: In DeFi, nirogacestat demonstrated substantial reduction of tumor volume and T2 hyperintensity of the largest target tumors by MRI compared with placebo in adults with DT. These results are consistent with the significant improvement in ORR achieved with nirogacestat. These data suggest that volumetric MRI and T2 hyperintensity might provide additional information in the evaluation of treatment response in DT. The prognostic or predictive value of these imaging techniques in DT should be further studied. Clinical trial information: NCT03785964 . [Table: see text]
SARC037: Results of phase I study of trabectedin given as a 1-hour (h) infusion in combination with low dose irinotecan in relapsed/refractory Ewing sarcoma (ES).
Authors: Grohar Patrick , Ballman Karla V. , Heise Rachel , Glod John , Wedekind Mary Frances , Mascarenhas Leo , Gedminas Jenna Marie , DuBois Steven G. , Maki Robert G. , Crompton Brian D. , Hayashi Masanori , Peer Cody J. , Figg William Douglas , Lindenberg Maria Liza , Mena Gonzalez Esther , Bagatell Rochelle , Laetsch Theodore Willis , Widemann Brigitte C. , Reinke Denise K. , Chugh Rashmi
Published: June 2023

11519

Background: Recurrent ES carries a poor prognosis, and systemic therapies have limited efficacy. Preclinical models suggested that trabectedin (T) could achieve serum concentrations high enough to suppress the dominant oncogene of ES (i.e. EWS::FLI1 transcription factor), and that this effect is sustained by subsequent administration of low dose irinotecan (I). We conducted a phase I study of T+I in patients (pts) with ES. Methods: This multicenter dose escalation study employed a standard 3+3 design. T was given as a 1-h infusion on day (D)1 with low dose I intravenously on D2 and 4 of a 21D cycle. Dose limiting toxicities (DLTs) were evaluated in cycle one. Eligibility required confirmed EWS::FLI1 fusion transcript, age ≥10 years, ECOG performance status ≤2, adequate organ function and willing to have a research biopsy if safely accessible. Primary objectives were to determine the recommended dose (RD) and safety of T+I. Secondary objectives comprised efficacy of T+I and avidity of ES for 3'-Deoxy-3'-18F Fluorothymidine (18F-FLT) PET. Results: 20 pts enrolled from 1/2021-12/2022 across 5 sites, 5F/15M, median age 18 years (range 10-59). Pts had received a median of 4 (range 2-9) prior therapy lines including irinotecan in 60% of pts. Grade (G) 3/4 treatment-emergent adverse events (TEAEs) occurring in ≥10% of pts were: elevated ALT/AST, elevated creatinine phosphokinase, febrile neutropenia, anemia, lymphopenia, neutropenia, and thrombocytopenia. There were 2 G5 respiratory TEAEs. 18F-FLT PET scans were obtained in 5 pts. ES tumors were 18F-FLT PET avid. Dose level (DL)2 was the RD. At DL 2 and above, there were 4 PRs, 6 SD in 14 evaluable pts (Table). Conclusions: T+I can be safely administered to heavily pretreated pts with ES, demonstrating activity at the RD with 3 PRs (n=5 evaluable). The 18F-FLT PET may be useful to understand patterns of disease progression in ES. Correlative studies will be critical to understanding the mechanism of drug activity. Given the clinical benefit seen with T+I at RD, a phase II portion in pts with ES ≥6 years old is actively accruing. Clinical trial information: NCT04067115 . [Table: see text]
Camrelizumab in combination with doxorubicin, cisplatin, ifosfamide, and methotrexate as neoadjuvant therapy for osteosarcoma: A single-arm, exploratory phase II trial.
Authors: Tang Qinglian , Zhu Xiaojun , Song Guohui , Lu Jinchang , Wu Hao , Xu Huaiyuan , Zhang Xin-ke , Ai Fei , Zhang Yingchun , Wang Jin
Published: June 2023

11526

Background: Tumor necrosis rate after neoadjuvant therapy is one of the strongest predictors of long-term outcome for patients with osteosarcoma. Patients with good response (tumor necrosis rate ≥90%) have a substantially better survival than those with poor response (tumor necrosis rate < 90%), with 5-year overall survival of 75-80% and 55-65%, respectively. However, treatments for osteosarcoma have not yet shown much progress since the introduction of perioperative chemotherapy in 1970s. New neoadjuvant combinations are required to explored for osteosarcoma. Methods: In this phase II trial (NCT04294511), patients aged 14-65 years with histopathologically confirmed osteosarcoma and Eastern Cooperative Oncology Group performance status of 0-1 received three 21-day cycles of neoadjuvant regimen (camrelizumab 200 mg on day 1 of each cycle; doxorubicin 37.5 mg/m2 or liposomal doxorubicin 25 mg/m2 on days 1-2 of cycles 1 and 3; cisplatin 100 mg/m2 on day 2 of cycles 1 and 3; methotrexate 8-12 g/m2 on day 12 of cycle 1; and ifosfamide 3 g/m2 on days 1-4 of cycle 2). Surgery was scheduled 12-14 days after neoadjuvant therapy. Two weeks after surgery, patients received 6 cycles of adjuvant therapy (camrelizumab 200 mg on day 1 of each cycle; doxorubicin 37.5 mg/m2 or liposomal doxorubicin 25 mg/m2 on days 9-10 of cycles 1, 3, and 5; cisplatin 100 mg/m2 on day 10 of cycles 1, 3, and 5; methotrexate 8-12 g/m2 on day 2 of cycles 1, 3, and 5; and ifosfamide 3 g/m2 on days 1-4 of cycles 2, 4, and 6). The primary endpoint was good response (tumor necrosis rate ≥90%) rate after neoadjuvant therapy. Results: A total of 86 patients were screened and 75 patients signed informed consent from December 2019 to June 2022. By the data cutoff date on December, 2022, 8 patients did not complete neoadjuvant therapy and 2 patients refused surgery. 65 patients completed neoadjuvant therapy, one patient had disease progression before surgery, 64 received surgical resection and adjuvant therapy, and 44 completed adjuvant therapy. Thirty-one (48.4%, 95%CI: 36.6%-60.4%) of 64 patients showed good response. The most common grade 3-4 adverse events were decreased platelet count (44.0%), decreased white blood cell (37.3%), decreased neutrophil count (29.3%), oral mucositis (14.7%), increased alanine aminotransferase (12.0%), and increased aspartate aminotransferase (10.7%). Conclusions: Camrelizumab combined with doxorubicin, cisplatin, methotrexate and ifosfamide in the perioperative treatment of osteosarcoma patients were safe and tolerable. Postoperative good response rate was similar to previously reported results. Survival follow-up is still ongoing to analyze the effect of perioperative immunotherapy combined with chemotherapy on long-term outcomes of patients with osteosarcoma. Clinical trial information: NCT04294511 .
Variations in the approach to lung metastases in osteosarcoma among pediatric and adult patients.
Authors: Wytiaz Victoria A , Rice John , Rao Rama , Schuetze Scott , Chang Andrew C. , Reddy Rishindra M , Angeles Christina Vadala , Chugh Rashmi
Published: June 2023

11528

Background: Osteosarcoma (OS) is most common in the pediatric (ped) and young adult population but can occur at any age. Amongst other factors, older age confers a worse prognosis, and it is uncertain whether this is due to inherent biologic differences or treatment approaches. Lung-only metastases (mets) is common, and metastasectomy is performed frequently to improve overall survival. Little is known about the differences in lung-only metastatic OS and approaches to metastasectomies between ped and adult populations. Methods: A single-institution retrospective chart review using a free-text search engine and keywords “osteosarcoma, “lung mets” and “pulmonary mets”, generated 206 patients(pts) diagnosed from 2006-2021. Eligible pts had a diagnosis of lung-only metastatic disease, resection performed at the institution and at least one year of follow-up data. Data was analyzed in two cohorts based on age at OS diagnosis: ped (age<18) and adult (age > 18 years), as well as with age as a continuous predictor. Results: Fifty pts (27F/23M) with lung only mets were eligible for analysis with a median follow up of 10.4 years. Median age was 23 yrs (range 6-77); 20 pts (40% were ≤18 years old); 31 pts (16 ped, 15 adult) had an extremity primary site. Rates of metachronous (67% vs 60%) and bilateral (50% vs 40%) lung mets were similar in ped vs. adult pts, respectively. The median number of lung mets was 2 (range 1 to > 25) with 50% of patients (35) having 2-6 metastases (8 ped, 20 adult). The median size of lung metastasis was 1.2 cm (range 0.1-4.0 cm). 15 ped pts (75%) underwent metastasectomy, compared to 19 adult (63.3%) (OR 1.74, p = 0.39). Probability of metastasectomy decreased with age when used as a continuous predictor (p = 0.11). Ped pts were more likely to have an open procedure as compared to thoracoscopic (OR 12.75, p < 0.01). There was no significant difference in relapse-free survival between ped and adult pts who underwent metastatectomy (p = 0.84). Median overall survival following lung metastasis detection was 5.8 years for ped pts compared to 3 years for adult pts (p = 0.15 from Cox model). Conclusions: Multiple tumor and patient-specific factors affect the decision to undergo metastatectomy in lung-only OS. In our single-center study we learned that timing, pattern, and number of lung mets in ped vs. adult pts were similar, but younger pts were more likely to undergo an open procedure. Our data trended towards a lower chance of undergoing metastatectomy with older age. Larger studies are required to further understand decision-making and therapeutic outcome and a randomized study of open vs. thoracoscopic metastatecomy for lung-only OS mets is underway. In this small study, many patients with lung-only metastatic OS had long-term survival. We showed that relapse-free survival post-metastatecomy was similar in ped and adult patients.
Outcomes in patients with advanced gastrointestinal stromal tumor who did not have baseline ctDNA detected in the INTRIGUE study.
Authors: Trent Jonathan C. , Jones Robin Lewis , George Suzanne , Gelderblom Hans , Schöffski Patrick , von Mehren Margaret , Zalcberg John Raymond , Kang Yoon-Koo , Abdul Razak Albiruni Ryan , Attia Steven , Le Cesne Axel , Reichmann William , Sprott Kam , Achour Haroun , Sherman Matthew L. , Ruiz-Soto Rodrigo , Blay Jean-Yves , Heinrich Michael C. , Bauer Sebastian ,   on behalf of the INTRIGUE Investigators
Published: June 2023

11536

Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 kinase inhibitors, including imatinib. Exploratory baseline circulating tumor DNA (ctDNA) next-generation sequencing (NGS) analysis from INTRIGUE showed pts with second-line advanced GIST with primary KIT exon 11 mutations and secondary resistance mutations exclusively in KIT exons 17/18 derived clinical benefit from ripretinib but not sunitinib (Bauer S et al. J Clin Oncol. 2023; Abs 397784). Outcomes in pts with advanced GIST with ctDNA not detected (ctDNA-ND) had not been evaluated. Here, we present exploratory data from INTRIGUE in pts who had baseline ctDNA-ND vs ctDNA detected (ctDNA-D). Methods: INTRIGUE is an open-label, phase 3 study that enrolled pts with advanced GIST who had disease progression on or intolerance to imatinib (NCT03673501). Pts were randomized 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off) and stratified by mutation according to local pathology report. Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA NGS-based assay. Pts with ctDNA-D had ≥1 somatic alteration in the 74 genes analyzed. Results: Pts with ctDNA-ND (82/362, 22.7%) were younger (median: 55.5 vs 62.0 years) and had smaller sums of longest diameters of target lesions (median [range]: 57.6 [11–459] vs 108.8 [15–418] mm) vs ctDNA-D (280/362, 77.3%). Progression-free survival (PFS) was longer in pts with ctDNA-ND vs ctDNA-D and numerically higher with ripretinib vs sunitinib in pts with ctDNA-ND (Table). Pts with ctDNA-ND categorized as not having a KIT exon 9 mutation at randomization ( KIT exon 11, other KIT/PDGFRA, or KIT/PDGFRA wild-type; n = 71) had longer PFS with ripretinib vs sunitinib (median not estimable [NE] vs 11 months; HR = 0.56; 95% CI 0.28 to 1.12). Objective response rate (ORR) and overall survival (OS) were higher with ctDNA-ND vs ctDNA-D. Safety was similar between groups and consistent with the primary analysis. Conclusions: Pts with ctDNA-ND had better efficacy outcomes vs pts with ctDNA-D in both treatment arms; PFS was numerically higher with ripretinib vs sunitinib in pts with ctDNA-ND. Although little is known about the biology driving ctDNA in GIST, these data suggest pts may have improved outcomes and different treatment sensitivity based on ctDNA detectability. Clinical trial information: NCT03673501 . [Table: see text]
Large versus limited molecular profiling panel screening program in patients with metastatic sarcoma: An exploratory subgroup analysis from the ProfiLER 02 trial.
Authors: Brahmi Mehdi , Tredan Olivier , Penel Nicolas , Chevreau Christine , Perrin Christophe , Firmin Nelly , Bompas Emmanuelle , Bertucci Francois , Attignon Valéry , Saintigny Pierre , Treilleux Isabelle , Chabaud Sylvie , Garin Gwenaelle , Pérol David , Blay Jean-Yves , Dufresne Armelle
Published: June 2023

11545

Background: Profiler 02 (NCT03163732) is a multicentre, randomized molecular screening clinical trial aiming to evaluate the feasibility and the benefit of a large NGS (Next-generation sequencing) panel (FoundationOne Medicine NGS panel or FOne, 324 cancer-related genes) compared to a limited one (Control panel or CTRL, 87 cancer-related genes) in terms of clinical, quality of life and health economic outcomes. We present here the results of the patients with advanced/metastatic sarcoma included in the Profiler 02 trial. Methods: Patients (pts) were enrolled during their first-line of standard therapy for an advanced sarcoma. All sarcomas diagnosIs were performed within the RRePS network (French pathology network of reference for sarcomas) and a central pathological review confirmed if quality and quantity of material were acceptable for molecular analysis. Patients were randomized within the two study arms (FOne versus CTRL) and DNA was analysed using both panels. The primary objective of the study was to compare the proportion of patients for whom a genomically driven recommended therapy (RT) could be initiated based on the FOne versus CTRL panels. A dedicated Molecular Tumour Board (MTB) reviewed tumour genomics data of both panels independently to propose a RT. Results: From January 2018 to July 2019, 39 pts with sarcoma (20F, 19M), with a median age of 54 years [21-81], were randomized between FOne Arm (17 pts) and CTRL Arm (22 pts). Pathological subtypes per arm are presented in the the table. Overall, 19 pts (49%) had at least one genomically driven RT, 11 according to both panels and 8 according to FOne panel exclusively (McNemar’s test, p=0.01). Main RT were CDK4/6 inhibitors ( n=5), PI3K/AKT/mTOR inhibitors ( n=4), and immunotherapy ( n=4). After the MBT, a RT was initiated for seven patients, four according to FOne panel only and three according to both panels. Importantly, a complete response was observed for a metastatic MPNST (Malignant Peripheral Nerve Sheath Tumor) with a high tumour mutational burden (TMB) detected by the FOne panel (37 mutations per megabase) and treated with durvalumab (anti-PDL1) + tremelimumab (anti-CTLA4). Conclusions: Although from an exploratory subgroup analysis, these results suggest that a large molecular profiling panel including TMB (FOne panel) might increase the number of RT and the number of sarcoma patients treated. Studies of precision medicine in rare cancers such as sarcomas are feasible,this approach could benefit to patients. Clinical trial information: NCT03163732 . [Table: see text]
Aristolochic acid (AA) exposure and telomere maintenance mechanism in liver angiosarcoma (AS).
Authors: Chen Tom Wei-Wu , Hsu Chia-Lang , Wu Yu-Ching , Ou Da-Liang , Su Yung-Yeh , Cheng Ann-Lii , Hsu Chiun
Published: June 2023

11551

Background: Liver AS has a grave prognosis and our previous study (Chen TW et al. Cancer 2022) showed that the incidence of liver AS is higher in Asia. We aimed to investigate the etiology of liver AS and its molecular characteristics. Methods: We performed whole exome (WES) and transcriptome sequencing (RNA-seq) of AS (liver 10, scalp 5, breast 2, trunk 1, heart 1) and hepatocellular carcinoma (HCC, 9) from National Taiwan University Hospital (NTUH) and re-analyzed WES & RNA-seq of AS from the Count Me In Project (CMI, 46). Somatic mutations and copy number alternation were called by Mutect2 and Sequenza from tumor-normal matched WES. Non-negative matrix factorization was used to determine mutational signature profiles and the contributions of each signature to each sample. Telomere length was estimated using TelSeq. Results: We identified four single-base-substitution (SBS) signatures using somatic mutations from 74 (AS/HCC 65/9) WES data. The dominated signature in liver AS had exceptionally high cosine similarity (93.08%) with COSMIC SBS22 (ver 3.2), which is related to AA exposure. The AA-mutation signature contributed significantly (adjusted p < 0.01) to the DNA mutations in 70% (7/10), 0% (0/9), 7% (3/46), and 56% (5/9) of liver AS (NTUH), nonliver AS (NTUH), CMI AS, and HCC (NTUH), respectively. TP53 (60% vs 22% vs 32%) and ATRX (40% vs 0% vs 11%) mutations were more common in liver than nonliver AS (NTUH) or CMI, while KDR mutation rates were similar (30% vs 44% vs 22%). Among TP53 mutations from liver AS with AA signature, 86% (6/7) showed the typical A:T > T:A mutation caused explicitly by AA-induced DNA damage. In liver vs nonliver AS, the median number of mutations and neoantigen burdens were 6.55 vs 0.98 (p = 0.0076) and 1572 vs 544 (p = 0.095), respectively. Although liver AS and HCC were highly associated with AA-mutation signature, liver AS had significantly longer telomeres in terms of tumor/normal telomere ratio (median 1.27 vs 1.16, p = 0.0009) but a significantly lower telomerase enzyme activity (p = 0.016). We did not find an association between ATRX mutation, or its mRNA expression level, with the extended telomere length in liver AS. Compared to nonliver AS, the activity of the telomere replication molecule BUB1 was significantly higher in liver AS (p = 0.0029). Conclusions: Our study is the first to connect AA exposure to the etiology of liver AS. The high mutation rate and distinct telomere maintenance mechanism of liver AS provides insights into future treatments.
Efficacy and safety of anlotinib combined with anthracycline and ifosfamide followed by anlotinib maintenance in advanced soft tissue sarcoma: A single-arm, phase 2 trial.
Authors: Liu Zengjun , Liu Mengyao , Xu Jing , Hu Wenyu , Zhu Dongyuan , Tao Rongjie , Xu Ni , Zhang Hui , Li Minghuan
Published: June 2023

11553

Background: Anthracycline plus ifosfamide is the standard first line treatment regime for advanced soft tissue sarcoma (STS). Anlotinib, a multikinase angiogenesis inhibitor, has evolved as a standard second line treatment option in Chinese advanced STS patients. This study was performed to evaluate the efficacy and safety of anlotinib combined with anthracycline and ifosfamide followed by anlotinib maintenance in the first line treatment of patients with advanced STS. Methods: This prospective, open-label, single-arm, phase 2 trial was conducted in Shandong Cancer Hospital and Institute (ChiCTR2100054711). The key inclusion criteria included: (a) age was 18-70 years; (b) ECOG performance state of 0-1; (c) histologically confirmed high-grade STS; (d) unresectable or metastatic STS; (e) previously untreated, and sensitive to chemotherapy; (f) having measurable lesions according to RECIST 1.1. All patients received up to 6 cycles of anlotinib (12 mg QD on day1-14, 21 days per cycle) combined with anthracycline (epirubicin 40mg/m2/d on day 1-2, 21 days per cycle; or liposomal doxorubicin 30mg/m2/d on day 1, 21 days per cycle) and ifosfamide (2g/m2/d on day 1-3, 21 days per cycle) followed by anlotinib maintenance until disease progression, unacceptable toxicity or death. Pegylated recombinant human granulocyte colony-stimulating factor was administered following chemotherapy. The primary endpoint was objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse effect (AE). Results: From December 2021 to December 2022, 31 patients (median [range] age, 53 [18-69] years; 20 [64.5%] male) were enrolled. 29 were evaluable for objective response, and the ORR and DCR were 31.03% (95%CI, 17.28-49.23%) and 82.76% (95%CI, 65.45-92.4%), respectively. With a median follow-up duration of 6.3 months (range, 0.8–14.0), the median PFS for all 31 patients was 6.9 months (95% CI, 2.62-11.17). The median OS was not reached. Treatment-related AEs of any grade occurred in all patients. The most common AEs included nausea/vomiting (88.46%), anemia (23.08%), leukopenia (19.23%), venous thrombosis (15.38%), hand-foot syndrome (11.54%) and elevated alanine aminotransferase or aspartate aminotransferase (11.54%). The most frequent ≥ grade 3 AEs were leukopenia (11.54%) and thrombocytopenia (7.69%). 2 serious AEs (1 left heart failure and 1 intestinal obstruction) were recorded. No treatment-related death occurred. Conclusions: This study suggested that anlotinib combined with anthracycline and ifosfamide followed by anlotinib maintenance demonstrated encouraging efficacy with a manageable safety profile in the first line treatment of patients with advanced STS. Clinical trial information: ChiCTR2100054711 .
Novel MRI scoring system to assess osseous malignancy in patients with soft tissue sarcoma following radiotherapy.
Authors: Vijayakumar Gayathri , Jones Conor M. , Supple Stephen , Meyer John R. , Blank Alan T.
Published: June 2023

11561

Background: Although radiotherapy is an important component of STS management, radiation induced changes such as radiation osteitis are commonly identified on magnetic resonance imaging (MRI). These imaging findings may be concerning for malignancy and sometimes require biopsy for investigation. This study proposes a novel MRI scoring system to assess osseous lesions and predict potential for malignancy based on MRI score in STS patients who received radiotherapy. Methods: The MRI score consisted of 3 parameters: morphology, signal intensity, and progression. Interobserver reliability between the total score of MRI examinations scored by two senior musculoskeletal radiologists were analyzed with Cohen’s kappa coefficient. Receiver operating curve (ROC) analysis was performed to determine a predictive MRI score for malignancy. Results: 156 MRI’s from 30 STS patients who received radiotherapy were retrospectively reviewed. Two (6.7%) patients developed regional osseous metastasis identified on MRI. The kappa coefficient of the scoring system was 0.785 demonstrating substantial interobserver agreement (p<0.001). ROC analysis demonstrated that the optimal cut-off value for malignant lesion on MRI was 5.5 (area under the curve 0.998 (95% CI 0.993-1.000) p<0.001). Conclusions: This novel MRI scoring system recommends lesions with a score of six and above to be biopsied to distinguish if malignancy is present. We believe this scoring system can be utilized by multidisciplinary care teams to guide clinical recommendations for patients with STS and MRI findings concerning for malignancy versus radiation induced changes.[Table: see text]
The SPEARHEAD-1 trial of afamitresgene autoleucel (afami-cel [formerly ADP-A2M4]): Analysis of overall survival in advanced synovial sarcoma.
Authors: Van Tine Brian Andrew , Ganjoo Kristen N. , Blay Jean-Yves , Valverde Claudia , Araujo Dejka M. , Abdul Razak Albiruni Ryan , Le Cesne Axel , Schuetze Scott , Wagner Michael J , Attia Steven , Forcade Edouard , Druta Mihaela , Pollack Seth , Bai Jane , Bayer Paige , Van Winkle Erin , Norry Elliot , McAlpine Cheryl , Williams Dennis , D'Angelo Sandra P.
Published: June 2023

11563

Background: Afami-cel is an autologous, T-cell receptor (TCR) T-cell therapy to treat human leukocyte antigen (HLA) A*02–eligible patients (pts) with advanced solid tumors positive for the cancer testis antigen melanoma-associated antigen A4 (MAGE-A4). The efficacy and safety of afami-cel in pretreated pts with advanced/metastatic synovial sarcoma or myxoid/round cell liposarcoma are being evaluated in the Phase 2, two-cohort, open-label, SPEARHEAD-1 (NCT04044768) trial. Here we report interim overall survival (OS) data in the pts with advanced synovial sarcoma in Cohort 1. Methods: Pts who were HLA-A*02 positive with advanced synovial sarcoma (with evidence of clinical/radiological progression) positive for MAGE-A4 received afami-cel after lymphodepleting chemotherapy containing fludarabine and cyclophosphamide. The primary endpoint was overall response rate per RECIST v1.1 by independent review. Secondary endpoints included OS and progression-free survival (PFS), estimated utilizing the Kaplan-Meier method. Results: As of August 29, 2022, 44 pts with synovial sarcoma received afami-cel (2.68–9.99×109 transduced T-cells) in Cohort 1. The median age was 41 years (range: 19–73 years), 50% of pts were female, 89% of pts were white, 96% of pts were typed as HLA-A*02:01P, and median tumor MAGE-A4 expression H-score was 257 (132–300). Pts were heavily pre-treated with a median of 3 prior lines of therapy (range: 1–12). The median follow-up time at the data cut-off was 20.8 months. Median PFS was 3.8 months (95% CI: 2.8, 5.8) and 4.1 months (95% CI: 2.8, 6.9) by independent and investigator review, respectively. Median OS by independent review was 15.4 months (95% CI: 10.9, not estimable) with 52% of pts censored at the data cut-off. The 12-month OS probability was 60% and 24-month OS probability was 40%. Twenty-one pts received additional therapy during long term follow up (systemic therapy, n = 20; radiation, n = 6; other, n = 4). In the 17 pts who had a RECIST response by independent review, the median OS was not reached, the 12-month OS probability was 90%, and 24-month OS probability was 60%. Conclusions: Pts with advanced synovial sarcoma treated with afami-cel in SPEARHEAD-1 had encouraging survival, especially those pts with a RECIST response. Clinical trial information: NCT04044768 .
A phase II clinical trial of chidamide in combination with toripalimab in patients with advanced soft tissue sarcoma.
Authors: Zhang Xing , Peng Ruiqing , Pan Qiuzhong , Xu Bushu , Hong Dongchun , Que Yi
Published: June 2023

11566

Background: Chidamide is an oral subtype-selective histone deacetylase inhibitor which is effective on the patients with hematological tumors and reported to enhance the efficacy of checkpoint blockade therapies and regulate the host immune response. Here, we report preliminary results of Chidamide in combination with Toripalimab in soft tissue sarcoma (STS) patients. Methods: An open, single arm, phase II study of Chidamide with Toripalimab in patients with advanced soft tissue sarcoma after failure of standard treatment was conducted. Eligible patients could have any number of prior therapies, excluding HDAC inhibitors and immune checkpoint inhibitors treatment. All patients received Chidamide orally at 30mg twice weekly in combination with intravenous Toripalimab 240mg every 21 days until progression or unaccepted toxicity. The primary endpoint was RECIST1.1 objective response rate (ORR). The secondary endpoint included progression free survival (PFS), overall survival (OS), disease control rate(DCR) and safety. Results: Forty-six patients with advanced soft tissue sarcoma were enrolled. The median age of the patients was 47 years and the median prior lines of therapy were 3. The main subtypes included leiomyosarcoma (30.4%), well/dedifferentiated liposarcoma (30%), myxoid/round cell liposarcoma (7%), undifferentiated sarcoma(9%), and osteosarcoma (7%). Treatment was well tolerated with the most common adverse events mainly in grade Ⅰ and grade Ⅱ, including thrombocytopenia (43.5%), nausea(28.3%), neutropenia(23.9%), fatigue (17.4%) and hypothyroidism(15.2%). Among 46 efficacy-evaluable patients, the overall response rate and disease control rate were 23.9% and 80.4%, respectively. The median time to an initial response was 3 months (range, 2 to 14), and the 3-mon and 6-mon progression-free survival rate were 92.7% and 58.9%, respectively. Conclusions: Chidamide with Toripalimab every 21 days was well tolerated and showed promising efficacy in patients with advanced STS. Clinical trial information: NCT04025931 .
Efficacy of eribulin administered in combination with an immune checkpoint inhibitor (ICI) and anlotinib as salvage treatment for patients (pts) with advanced adult soft tissue sarcoma (STS).
Authors: Guo Xi , Zhou Yuhong , Zhuang Rongyuan , Zhang Chenlu , You Yang , Li Wei , Wang Zhiming
Published: June 2023

11572

Background: Eribulin combined with a multi-targeted antiangiogenic tyrosine kinase inhibitor has shown efficacy in STS. ICIs have also exhibited improved survival in some STS subtypes. We investigated the efficacy and safety of triple combination therapy with eribulin, an ICI and anlotinib in the treatment of advanced STS in an adult Chinese population. Methods: This study retrospectively analyzed data from patients diagnosed with advanced STS who received combination therapy with eribulin, an ICI and anlotinib at the Department of Oncology, Zhongshan Hospital affiliated to Fudan University. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) by RECIST v1.1, disease control rate (DCR), and treatment-related adverse events (TRAEs) by CTCAE v5.0. Results: Medical records from 32 pts treated between August 15, 2020 and January 31, 2023 were included; the median age was 56 years, 71.8% (23/32) were female, 75.0% (24/32) had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and 25.0% (8/32) had an ECOG PS of 2. Pts had received a median of 2 (range 0-6) prior regimens and the median follow-up was 4.1 months. Among the patients, 50.0% (16/32) had liposarcomas (including 1 with pleomorphic liposarcoma and 15 with dedifferentiated liposarcoma [DDLPS]), 31.3% (10/32) had leiomyosarcomas (LMS), 3 had undifferentiated pleomorphic sarcoma (UPS), and 1 each had angiosarcoma, rhabdomyosarcoma and desmoplastic small round cell tumor. In a preliminary analysis, 29 pts were evaluable for clinical activity; partial responses (PRs) were achieved in 3 pts (2 DDLPS, 1 UPS), the ORR and DCR were 10.3% (3/29) and 62.1% (18/29) respectively, and the median PFS was 5.7 months (95% CI 2.7-9.8). Of the 15 pts with DDLPS (median 1 prior line of therapy; median follow-up 6.3 months), 13 were evaluable for clinical activity; a PR was achieved by 15.4% (2/13), the DCR was 61.5% (8/13), the median PFS was 9.8 months (95% CI 1.8-28.5) and treatment was ongoing in 46.7% of pts (n = 7). Among the 9 evaluable pts with LMS, 0 achieved a PR, the DCR was 44.4% (4/9), median PFS was 3.9 months and 3 pts were still receiving treatment. In the overall cohort (n = 32), TRAEs of any grade occurred in 56.3% of pts (n = 18), the most common were myelosuppression (28.1%), fatigue (15.6%), fever (12.5%) and rash (12.5%). Grade 3/4 TRAEs occurred in 12.5% of pts, with no grade 5 events. Conclusions: This study demonstrates the potential efficacy of combination therapy with eribulin, an ICI and anlotinib in patients with advanced STS, especially in those with the DDLPS subtype. Our data suggest that this combination has good tolerability and a prospective trial is warranted. Clinical trial information: ChiCTR2100053594.
Reduced symptom burden after implementation of an electronic symptom management program.
Authors: Bian Jessica J , Ahrens Paige , Tramontano Angela , Cronin Christine , Wong Sandra L. , Osarogiagbon Raymond U. , Hazard-Jenkins Hannah W. , Dizon Don S. , Paudel Roshan , Schrag Deborah , Hassett Michael J.
Published: June 2023

12006

Background: The SIMPRO consortium implemented an electronic patient reported outcomes (ePRO) symptom management program as part of routine clinical care for patients (pts) receiving systemic cancer therapy or surgery across six health systems including rural and community cancer centers. To evaluate impact of the Epic-integrated electronic symptom management (eSyM) program on quality of life, pre- and post-implementation surveys were sent to a subset of gastrointestinal, thoracic, and gynecologic medical oncology (MO) and surgical (Surg) patients at all sites. Methods: A survey assessing symptom burden, health literacy, and self-efficacy was administered to separate groups of MO and Surg pts before (Pre-Implementation) and after (Post-Implementation) eSyM deployment. A waiver of documentation of consent was obtained for participation. Questions were derived from validated instruments including PROMIS, a standardized measurement tool for patient-reported symptoms. Surveys were completed 30-90 days after surgery or start of systemic therapy. PROMIS item responses were scored individually then translated into standardized T-scores with a mean of 50 based on an established reference population. Mean T-scores for PROMIS depression, anxiety, fatigue, and pain interference were calculated. Higher T-score correlated with greater symptom burden. Comparison between groups utilized non-parametric Kruskal-Wallis testing. Results: The number of survey responses were 498 MO Pre-Implementation, 518 MO Post-Implementation, 566 Surg Pre-Implementation, and 507 Surg Post-Implementation. MO pts reported significantly lower PROMIS mean T-scores for depression, anxiety, fatigue, and pain interference after eSyM compared to a similar group of MO pts prior to eSyM. Surg pts reported lower T-scores for depression, anxiety, fatigue, and pain interference after eSyM compared to a similar group of Surg pts prior to eSyM, although reduction in pain interference was not statistically significant. Conclusions: eSyM deployment in MO was associated with a significant reduction in patient reported depression, anxiety, fatigue, and pain interference. Surgical pts after eSyM deployment reported significantly lower rates of depression, anxiety, and fatigue. External validation with PROMIS based surveys demonstrated small but meaningful benefits of ePRO symptom monitoring as part of routine clinical care across six diverse health systems. Clinical trial information: NCT03850912 . [Table: see text]
Fertility post immune checkpoint blockade.
Authors: Ogle Martinique , Harrold Emily , O'Brien Erin , Weiss Jill A. , Yaqubie Amin , Sinopoli Jenna Cohen , Postow Michael A. , Cercek Andrea
Published: June 2023

12014

Background: Immune checkpoint blockade (ICB) is radically altering the treatment paradigm for a wide range of malignancies. Consequently, the proportion of ICB exposed pts will expand and the impact of ICB on fertility is of increasing importance. We sought to evaluate fertility outcomes post ICB exposure at our institution. Methods: Pts < 45 years old post ≥ 1 cycles of ICB at MSK who consented to the MSK-IMPACT protocol (NCT01775072) were screened for eligibility (n = 537). Pts in receipt of prior cytotoxic chemotherapy or tyrosine kinase, BRAF or MEK inhibitors were excluded. 96 eligible pts were emailed a 28-question survey; 65% were followed up by phone. Results: 50/96 pts responded to the survey, male to female ratio was 27:23. 5 pts were excluded from final analysis due to additional systemic agent use pre-conception. Median age at ICB exposure was 35 (range 19-44). 53% (25/45) of pts received ICB in the metastatic setting. 40% (17/42) of pts received fertility counseling pre-ICB use. There was no statistically significant difference between rates of fertility counseling in metastatic vs non-metastatic settings (p = 0.14). 7 pts (14%) conceived and 2 pts (4%) are currently trying to conceive children post ICB. 4 pts (3 female, 1 male) conceived children with reproductive technology. 3/4 pts used sperm or embryos frozen prior to ICB and IVF leading to successful pregnancies, 2 of which are currently ongoing. One patient froze embryos 6 months after 2 years of PD1 inhibitor (PD1i) monotherapy and embryo implantation led to a currently ongoing pregnancy. Notably this pt developed hypothyroidism with ICB use, controlled with levothyroxine, and has remained euthyroid during pregnancy to date. 3 pts (2 female, 1 male) receiving single agent PD1i in the localized setting conceived naturally at 2 yrs, 9 months and 2 months respectively post ICB. 4/8 pregnancies are currently ongoing without reported immunological complications. 3 deliveries have resulted in 4 children (including 1 set of twins). 1 of these pts had a 1st trimester miscarriage of unclear cause followed by successful pregnancy complicated by gestational diabetes. First pregnancies occurred a median of 1 year post ICB (range 2-24 months). No autoimmune conditions in progeny were reported. Conclusions: Successful conception occurred both naturally and with reproductive assistance technologies post ICB. Most pts did not receive fertility counseling pre-ICB use, possibly reflective of nascent appreciation of complete and durable ICB responses. There were no definite adverse immunological complications reported in pregnancy or progeny of these pts. As ICB indications expand prospective evaluation of ICB impact on fertility in pts desirous of a family is critical and consequently we are integrating longitudinal fertility analysis in neoadjuvant ICB protocols. [Table: see text]