Whole-genome and Transcriptome Sequencing Identified <i>NOTCH2</i> and <i>HES1</i> as Potential Markers of Response to Imatinib in Desmoid Tumor (Aggressive Fibromatosis): A Phase II Trial Study

9515 Background: Aggressive fibromatosis (desmoid tumors, AF) are uncommon, locally aggressive, connective tissue neoplasms. Existing literature on systemic treatment of AF is sparse and consists mostly of case reports and small case-series. Based on previous observation of regression of AF treated with IM and tumoral expression of IM targets, SARC (Sarcoma Alliance for Research through Collaboration) included the treatment of AF onto a multi-institution phase II trial of IM in sarcoma. Here we report early clinical and laboratory results of the AF group. Methods: Eligible patients had histologically proven AF, unresectable or difficult to resect without considerable functional impairment. Patients were treated with IM 300 mg po BID (BSA≥1.5m2). The primary endpoint was complete (CR) or partial response(PR) at two months or stable disease (SD) or better at four months. Tumor DNA was extracted from available formalin fixed paraffin embedded tissue specimens and analyzed via allelic PCR and genomic DNA sequence analysis for specific point mutations in PDGFRα exons 12/14/18, PDGFRβ exons 12/18, KIT exons 9/11/13/17, and bRAF. Results: 51 patients were enrolled from 10/02 to 12/05 at 5 institutions, with 45 patients currently evaluable. The median age is 37 (range 14–67), and median number of prior therapies is 1 (range 0–3). 36 patients (80%) reached the primary endpoint of CR/PR at 2 months or SD or better at 4 months. The median time to treatment failure is 6.8 months (95% C.I. 5.8–17.1). Thus far, the maximum change in the largest dimension of the tumor ranged from a 21% increase to a 45% decrease. In 22 available tumor specimens, deletions within PDGFRαE12 and E18 were noted in 1 and 3 patients, respectively, while a wildtype genotype was found in other regions. Conclusions: IM has activity in AF, the mechanism of which remains unclear. While this is the largest reported phase II trial of AF, further improvement in evaluating clinical efficacy in this disease is clearly necessary. We plan an analysis of the maximum change in largest tumor dimension for each patient, which will be particularly beneficial in AF as responses often occur late. We have not as yet identified a laboratory predictor of clinical benefit. Further investigation of other potential targets in fresh tissue is warranted. [Table: see text]

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Whole-Genome and Transcriptome Sequencing Identified NOTCH2 and HES1 As Potential Markers of Response to Imatinib in Desmoid Tumor (Aggressive Fibromatosis): A Phase II Trial Study

10.21203/rs.3.rs-993539/v1 ◽

2021 ◽

Author(s):

Joonha Kwon ◽

Jun Hyeong Lee ◽

Young Han Lee ◽

Jeeyun Lee ◽

Jin-Hee Ahn ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Clinical Response ◽

Rna Sequencing ◽

Genome Sequencing ◽

Desmoid Tumor ◽

Large Scale ◽

Genetic Interaction ◽

Statistical Significance ◽

Aggressive Fibromatosis ◽

Whole Genome

Abstract Background: Desmoid tumor, also known as aggressive fibromatosis, is well-characterized by abnormal Wnt/β-catenin signaling. Various therapeutic options, including imatinib, are available to efficiently treat desmoid tumor. However, molecular mechanism of why imatinib works remains poorly understood. Here, we describe the potential roles of NOTCH2 and HES1 in association with clinical response to imatinib as in genome and transcriptome levels. Methods: We identified all somatic mutations in coding and non-coding regions via whole genome sequencing using desmoid tumor samples. To validate the genetic interaction with expression level in desmoid-tumor condition, we utilized large-scale Whole-genome sequencing (WGS) and transcriptome datasets from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. RNA-sequencing was performed using prospective and retrospective cohort samples to evaluate the expressional relevance with clinical response. Results: Among 20 patients, 4 (20%) had a partial response and 14 (66.7%) had stable disease, 11 of which continued for ≥1 year. With gene-wise functional analyses, we detected significant correlation between recurrent NOTCH2 noncoding mutations and clinical response to imatinib. Based on PCAWG data analyses, NOTCH2 mutations affect its expression levels particularly in the presence of CTNNB1 missense mutations. By analyzing RNA-sequencing with additional desmoid tumor samples, we found that NOTCH2 expression was significantly correlated with HES1 expression. Interestingly, NOTCH2 had no statistical power to discriminate responders and non-responders. Instead, HES1 was differentially expressed with statistical significance between responders and non-responders Conclusions: Imatinib was effective and well tolerated for advanced desmoid tumor treatment. Our results show that HES1, regulated by NOTCH2, as an indicator of sensitivity to imatinib, which provides an important therapeutic consideration for desmoid tumor. Trial Registration: ClinicalTrials.gov, NCT02495519, Registered July 13, 2015- Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT02495519

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Phase II trial of PF-03084014 in adults with desmoid tumors/aggressive fibromatosis.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.10563 ◽

2015 ◽

Vol 33 (15_suppl) ◽

pp. 10563-10563 ◽

Cited By ~ 2

Author(s):

Shivaani Kummar ◽

Khanh Tu Do ◽

Geraldine Helen O'Sullivan Coyne ◽

Baris Turkbey ◽

Paul S. Meltzer ◽

...

Keyword(s):

Phase Ii ◽

Phase Ii Trial ◽

Aggressive Fibromatosis ◽

Desmoid Tumors

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Imatinib for the treatment of aggressive fibromatosis (desmoid tumors) failing local treatment. A phase II trial of the French Sarcoma Group

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.9516 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 9516-9516 ◽

Cited By ~ 1

Author(s):

N. Penel ◽

A. Le Cesne ◽

B. Bui ◽

M. Tubiana-Hulin ◽

C. Guillemet ◽

...

Keyword(s):

Phase Ii ◽

Phase Ii Trial ◽

Local Treatment ◽

Aggressive Fibromatosis ◽

Cytotoxic Agents ◽

Tumor Control ◽

Desmoid Tumors ◽

Phase Ii Trials ◽

Curative Intent ◽

Systemic Treatments

9516 Background: Background: Aggressive fibromatosis/desmoid tumors (AF/DT) are rare tumors with loco regional spreading. Few options are available when local treatments have failed. Although cytotoxic agents, hormonal treatment have been reported to induced responses and tumor control in some patients, only few prospective phase II trials have been reported in the literature. Recently, antitumor activity of imatinib in AF/DT was reported. We report a phase II trial of imatinib in AF/DT after failure of local treatment options. Methods: Pts ≥ 18 years with advanced AF/DT from all sites in whom neither surgery nor radiotherapy was possible were eligible. The principal inclusion criterias were: disease not amenable to surgery and/or radiation with curative intent, systemic pre-treatments allowed and presence of a measurable lesion with evidence of progression. Imatinib was given at the dose of 400 mg/d and increased to 800 mg/d if progression. Primary endpoint was the rate of progression free at 3 months. A two stages Simon‘s optimal design was used with p0=10%, p1=30%, α=0.05 and 90% power. 18 pts were scheduled to be recruited in the first stage for a total of 35 evaluable pts. Results: Between 09/2004 and 10/2005, 40 pts were included in 15 centers. The median age was 40 years (range 20–72) with 26% males. Primary sites were extra abdominal, mesenteric, abdominal wall in 79, 15, and 6% respectively. 15% patients had not been operated previously and 17% undergone radiotherapy. Prior systemic treatments were: NSAID, hormonal therapy or chemotherapy in 34, 46 and 23%, respectively. Median treatment duration was 4 months (range 0–12). No G4 toxicity was reported. Toxicities (G1–3) were notified for 30 pts including asthenias (70%), nauseas (53%), diarrheas, oedema (40%). G3 toxicities were abdominal pain (10%), rash, nausea, vomiting and asthenia (7%). At 3 months, 22 pts (55%) were evaluable with 1 CR, 17 SD and 4PD. As of December 2005, 7 of the 40 pts had progressed. After progression, dose was stopped in 2 pts and increased to 800mg in 5 pts with 2 tumor control following dose-escalation. Conclusions: Imatinib induces prolonged disease stabilization in the majority of evaluable patients with AF/DT in whom no local treatment option was available. [Table: see text]

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Updated outcome with long-term follow-up of imatinib for the treatment of progressive or recurrent aggressive fibromatosis (desmoid tumor): A FNCLCC/ French Sarcoma Group phase II trial

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.10518 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 10518-10518 ◽

Cited By ~ 1

Author(s):

A. Dufresne ◽

N. Penel ◽

S. Salas ◽

A. Le Cesne ◽

D. Perol ◽

...

Keyword(s):

Overall Survival ◽

Phase Ii ◽

Progressive Disease ◽

Phase Ii Trial ◽

Progression Free Survival ◽

Aggressive Fibromatosis ◽

Disease Rate ◽

Free Survival ◽

Number Of Patients

10518 Background: We present updated results from a previously reported phase II trial assessing clinical efficacy of imatinib in progressive or recurrent aggressive fibromatosis (Fayette et al. ASCO 2007) Methods: Patients with aggressive fibromatosis not amenable to radiotherapy or non-mutilating surgery were eligible and received imatinib 400mg daily (increased to 800mg daily in case of progression) up to 1 year then stopped. The primary end point was non-progressive disease rate at 3 months. Independent radiological committee reviewed responses. The number of patients was calculated according to a optimal 2-stages design. Results: Forty patients were included between September 2004 and October 2005 in 15 centers. The median follow up is 33 months [95% CI: 32–35]. Toxicity of imatinib is similar to that previously reported. At 3 months, the nonprogression rate was 91% [95% CI: 77–96] with 1 (2%) complete and 3 (8%) partial confirmed responses observed. The non progression rates at 6, 9, and 12 months were 80%, 69% and 66% respectively. The median time to progression was 9.5 months. The 2-year progression-free survival (PFS) was 55%. No plateau was observed. The 2-year-overall survival was 95%. Two patients with mesenteric aggressive fibromatosis died from progressive disease. In multivariate analysis including clinical factors, only previous radiotherapy was associated with reduced progression free survival. None of the biological factors tested using IHC on TMA (PDGFR α, PDGFR β, β catenin, c-kit, E cadherine, MCSFR, cycline D1 and Erk) were found correlated to response, progression free or overall survival. Conclusions: With a 2.8 years median follow up, this is the largest study which confirms the high efficacy of imatinib (400 mg daily) in patients presenting with aggressive fibromatosis failing local treatment and with documented evidence of progressive disease before imatinib treatment. [Table: see text]

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Multi-Center Phase II Study of Sunitinib in Patients with Advanced Aggressive Fibromatosis (Desmoid Tumor)

Annals of Oncology ◽

10.1016/s0923-7534(20)34042-4 ◽

2012 ◽

Vol 23 ◽

pp. ix479

Author(s):

J. Jo ◽

K. Kim ◽

Y.S. Hong ◽

J. Lee ◽

...

Keyword(s):

Phase Ii ◽

Desmoid Tumor ◽

Phase Ii Study ◽

Aggressive Fibromatosis

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Toripalimab plus chemotherapy as second-line treatment in previously EGFR-TKI treated patients with EGFR-mutant-advanced NSCLC: a multicenter phase-II trial

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00751-9 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Tao Jiang ◽

Pingyang Wang ◽

Jie Zhang ◽

Yanqiu Zhao ◽

Jianying Zhou ◽

...

Keyword(s):

Phase Ii ◽

Transcriptome Sequencing ◽

Advanced Nsclc ◽

Phase Ii Trial ◽

Phase Iii ◽

Line Treatment ◽

Second Line ◽

Multicenter Phase ◽

Whole Exome ◽

Biomarker Analysis

AbstractThis multicenter phase-II trial aimed to investigate the efficacy, safety, and predictive biomarkers of toripalimab plus chemotherapy as second-line treatment in patients with EGFR-mutant-advanced NSCLC. Patients who failed from first-line EGFR-TKIs and did not harbor T790M mutation were enrolled. Toripalimab plus carboplatin and pemetrexed were administrated every three weeks for up to six cycles, followed by the maintenance of toripalimab and pemetrexed. The primary endpoint was objective-response rate (ORR). Integrated biomarker analysis of PD-L1 expression, tumor mutational burden (TMB), CD8 + tumor-infiltrating lymphocyte (TIL) density, whole-exome, and transcriptome sequencing on tumor biopsies were also conducted. Forty patients were enrolled with an overall ORR of 50.0% and disease-control rate (DCR) of 87.5%. The median progression free survival (PFS) and overall survival were 7.0 and 23.5 months, respectively. The most common treatment-related adverse effects were leukopenia, neutropenia, anemia, ALT/AST elevation, and nausea. Biomarker analysis showed that none of PD-L1 expression, TMB level, and CD8 + TIL density could serve as a predictive biomarker. Integrated analysis of whole-exome and transcriptome sequencing data revealed that patients with DSPP mutation had a decreased M2 macrophage infiltration and associated with longer PFS than those of wild type. Toripalimab plus chemotherapy showed a promising anti-tumor activity with acceptable safety profiles as the second-line setting in patients with EGFR-mutant NSCLC. DSPP mutation might serve as a potential biomarker for this combination. A phase-III trial to compare toripalimab versus placebo in combination with chemotherapy in this setting is ongoing (NCT03924050).

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