Comprehensive Genomic Profiling of Rare Tumors: Routes to Targeted Therapies

Wang, Shuhang; Chen, Rongrong; Tang, Yu; Yu, Yue; Fang, Yuan; Huang, Huiyao; Wu, Dawei; Fang, Hong; Bai, Ying; Sun, Chao; Yu, An; Fan, Qi; Gu, Dejian; Yi, Xin; Li, Ning

doi:10.3389/fonc.2020.00536

Cited by 19 publications

(25 citation statements)

References 23 publications

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“…According to the definition and update of rare tumors published/established by the China National Cancer Center ( 3 ), we collected and retrospectively analyzed data on immunotherapy-related indicators from a total of 852 rare tumors patients in the Geneplus database, including 136 reports of PD-L1 expression, 821 reports of TMB, 705 of MSI and 355 of HLA-I heterozygosity.…”

Section: Methodsmentioning

confidence: 99%

“…We found that the incidence of therapeutic targets in rare tumors in the Chinese population was significantly higher than in the general population (53.43% vs. 20.40% respectively). Moreover, in the Chinese population, prevalence of targetable genomic alterations within those rare tumors (ALK, BRAF, BRCA2, CDKN2A, EGFR, HER2, KIT, MET, ROS1) was 32.4%, which is more than 3 times that which is found in the general population according to cBioPortal ( 3 ).…”

Section: Introductionmentioning

confidence: 91%

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Comprehensive Genomic Profiling of Rare Tumors in China: Routes to Immunotherapy

et al. 2021

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Treatment options for rare tumors are limited, and comprehensive genomic profiling may provide useful information for novel treatment strategies and improving outcomes. The aim of this study is to explore the treatment opportunities of patients with rare tumors using immune checkpoint inhibitors (ICIs) that have already been approved for routine treatment of common tumors. We collected immunotherapy-related indicators data from a total of 852 rare tumor patients from across China, including 136 programmed cell death ligand-1 (PD-L1) expression, 821 tumors mutational burden (TMB), 705 microsatellite instability (MSI) and 355 human leukocyte antigen class I (HLA-I) heterozygosity reports. We calculated the positive rates of these indicators and analyzed the consistency relationship between TMB and PD-L1, TMB and MSI, and HLA-I and PD-L1. The prevalence of PD-L1 positive, TMB-H, MSI-, and HLA-I -heterozygous was 47.8%, 15.5%, 7.4%, and 78.9%, respectively. The consistency ratio of TMB and PD-L1, TMB and MSI, and HLA-I and PD-L1 was 54.8% (78/135), 87.3% (598/685), and 47.4% (54/114), respectively. The prevalence of the four indicators varied widely across tumors systems and subtypes. The probability that neuroendocrine tumors (NETs) and biliary tumors may benefit from immunotherapy is high, since the proportion of TMB-H is as high as 50% and 25.4% respectively. The rates of PD-L1 positivity, TMB-H and MSI-H in carcinoma of unknown primary (CUP) were relatively high, while the rates of TMB-H and MSI-H in soft tissue tumors were both relatively low. Our study revealed the distribution of immunotherapeutic indicators in patients with rare tumors in China. Comprehensive genomic profiling may offer novel therapeutic modalities for patients with rare tumors to solve the dilemma of limited treatment options.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

Comprehensive Genomic Profiling of Rare Tumors in China: Routes to Immunotherapy

et al. 2021

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“…The incidence of actionable gene alterations covered by the current protocol was 32.4% among the 63 pathological subtypes, which suggests that studying these mutations in rare tumours in the Chinese patient population might help greatly improve patient outcomes. 4 Limited exploration of targeted therapy of rare solid tumours with promising efficacy Of the 133 s pathological subtypes of rare solid tumours, clinical investigations of targeted therapy cover only 11.9% (16/135) of rare solid tumours (except for all solid tumours similar to MSI-H/dMMR approved for treatment with pembrolizumab). However, notably, the ORR and disease control rate (DCR) of targeted therapy are superior to those of standard treatment in rare tumours with actionable alterations.…”

Section: High Incidence Of Actionable Gene Alterations In Rare Tumoursmentioning

confidence: 99%

Platform study of genotyping-guided precision medicine for rare solid tumours: a study protocol for a phase II, non-randomised, 18-month, open-label, multiarm, single-centre clinical trial testing the safety and efficacy of multiple Chinese-approved targeted drugs and PD-1 inhibitors in the treatment of metastatic rare tumours

Wang

Huang

et al. 2021

BMJ Open

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IntroductionLimited clinical studies have been conducted on rare solid tumours, and there are few guidelines on the diagnosis and treatment, including experiences with targeted therapy and immunotherapy, of rare solid tumours in China, resulting in limited treatment options and poor outcomes. This study first proposes a definition of rare tumours and is designed to test the preliminary efficacy of targeted and immunotherapy drugs for the treatment of rare tumours.Methods and analysisThis is a phase II, open-label, non-randomised, multiarm, single-centre clinical trial in patients with advanced rare solid tumours who failed standard treatment; the study aims to evaluate the safety and efficacy of targeted drugs in patients with advanced rare solid tumours with corresponding actionable alterations, as well as the safety and efficacy of immune checkpoint (programmed death receptor inhibitor 1, PD-1) inhibitors in patients with advanced rare solid tumours without actionable alterations. Patients with advanced rare tumours who fail standardised treatment and carry actionable alterations (Epidermal growth factor receptor (EGFR) mutations, ALK gene fusions, ROS-1 gene fusions, C-MET gene amplifications/mutations, BRAF mutations, CDKN2A mutations, BRCA1/2 mutations, HER-2 mutations/overexpressions/amplifications or C-KIT mutations) will be enrolled in the targeted therapy arm and be given the corresponding targeted drugs. Patients without actionable alterations will be enrolled in the PD-1 inhibitor arm and be treated with sintilimab. After the patients treated with vemurafenib, niraparib and palbociclib acquire resistance, they will receive combination treatment with sintilimab or atezolizumab. With the use of Simon’s two-stage Minimax design, and the sample size was estimated to be 770. The primary endpoint of this study is the objective response rate. The secondary endpoints are progression-free survival in the targeted treatment group and single-agent immunotherapy group; the duration of response in the targeted therapy and single-agent immunotherapy groups; durable clinical benefit in the single-agent immunotherapy group; and the incidence of adverse events.Ethics and disseminationEthics approval was obtained from the Chinese Academy of Medical Sciences (ID: 20/132-2328). The results from this study will be actively disseminated through manuscript publications and conference presentations.Trial registration numbersNCT04423185; ChiCTR2000039310.

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“…Rearrangements include EML4-ALK translocation in non-small cell lung cancer, which can be targeted by drugs such as crizotinib. Now there is testing for biomarkers related to PD-L1 expression in various tumours that can be targeted by checkpoint inhibitors such as atezolizumab.Molecular profiling that allows matching treatments for cancers to their targets has resulted in a boost for new drug development in rare cancers by using drugs targeted to molecular biomarkers that they have in common with more common cancers, in basket trials 15. Limitations of gene expression profiling and IHC can be illustrated in diffuse large B-cell lymphoma (DLBCL) as summarized by Ofori et al in this issue of the Journal 16.…”

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confidence: 99%

“…Molecular profiling that allows matching treatments for cancers to their targets has resulted in a boost for new drug development in rare cancers by using drugs targeted to molecular biomarkers that they have in common with more common cancers, in basket trials 15 …”

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confidence: 99%