ASPSCR1-TFE3融合突变的腺泡软组织肉瘤的治疗策略

患者是位腺泡软组织肉瘤的小姑娘，6月份的时候她父亲请我帮忙解读她的基因检测报告。基因报告比较简单，就检测出了ASPSCR1-TFE3的融合突变这个标志性突变。
一、靶向治疗
ASPSCR1-TFE3的融合突变，按照6月份当时的可查资料，一般可以考虑两个治疗策略：
1、抑制MET
《Correlation of Immunological and Molecular Profiles with Response to Crizotinib in Alveolar Soft Part Sarcoma: An Exploratory Study Related to the EORTC 90101 "CREATE" Trial》
Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma characterized by an unbalanced translocation, resulting in ASPSCR1-TFE3 fusion that transcriptionally upregulates MET expression. The European Organization for Research and Treatment of Cancer (EORTC) 90101 "CREATE" phase II trial evaluated the MET inhibitor crizotinib in ASPS patients, achieving only limited antitumor activity. We performed a comprehensive molecular analysis of ASPS tissue samples collected in this trial to identify potential biomarkers correlating with treatment outcome. A tissue microarray containing 47 ASPS cases was used for the characterization of the tumor microenvironment using multiplex immunofluorescence. DNA isolated from 34 available tumor samples was analyzed to detect recurrent gene copy number alterations (CNAs) and mutations by low-coverage whole-genome sequencing and whole-exome sequencing. Pathway enrichment analysis was used to identify diseased-associated pathways in ASPS sarcomagenesis. Kaplan-Meier estimates, Cox regression, and the Fisher's exact test were used to correlate histopathological and molecular findings with clinical data related to crizotinib treatment, aiming to identify potential factors associated with patient outcome. Tumor microenvironment characterization showed the presence of PD-L1 and CTLA-4 in 10 and 2 tumors, respectively, and the absence of PD-1 in all specimens. Apart from CD68, other immunological markers were rarely expressed, suggesting a low level of tumor-infiltrating lymphocytes in ASPS. By CNA analysis, we detected a number of broad and focal alterations. The most common alteration was the loss of chromosomal region 1p36.32 in 44% of cases. The loss of chromosomal regions 1p36.32, 1p33, 1p22.2, and 8p was associated with shorter progression-free survival. Using whole-exome sequencing, 13 cancer-associated genes were found to be mutated in at least three cases. Pathway enrichment analysis identified genetic alterations in NOTCH signaling, chromatin organization, and SUMOylation pathways. NOTCH4 intracellular domain dysregulation was associated with poor outcome, while inactivation of the beta-catenin/TCF complex correlated with improved outcome in patients receiving crizotinib. ASPS is characterized by molecular heterogeneity. We identify genetic aberrations potentially predictive of treatment outcome during crizotinib therapy and provide additional insights into the biology of ASPS, paving the way to improve treatment approaches for this extremely rare malignancy.
但是很可惜患者的MET免疫组化结果是阴性。所以有原则就有例外，有一般就有特殊。群体数据只能参考，不能直接套到个体头上；个体一定要做精准检测，这是精准治疗的前提和基础。

2、抑制MTOR+抗血管生成
《Everolimus in combination with vandetanib in children, adolescents, and young adults: a phase I study》
Patients and methods: We designed a phase 1 trial to test the drug combination of a multikinase VEGF receptor 2 inhibitor, vandetanib, and an mTOR inhibitor, everolimus, in a pediatric and young adult patient cohort with advanced cancers. Exceptional responders were probed for tumor mutational profile to explore possible molecular mechanisms of response.
Results: Among 21 enrolled patients, clinical benefit was observed in 38% (one patient with partial response and eight patients with stable disease) with a median progression-free survival of 3.3 months. The most common treatment-related adverse event was rash (n = 13). Other treatment-related toxicities included diarrhea, fatigue, hypertension, QT prolongation, hypertriglyceridemia/hypercholesterolemia, transaminitis, thrombocytopenia, and weight loss. None of the patients experienced dose-limiting toxicities. Three exceptional responders were analyzed and were found to harbor genetic alterations including kinase insert domain receptor (KDR) Q472H mutation, EWSR1-CREB3L1, CDKN2A/B loss, and ASPL/ASPSCR1-TFE3 fusion.

我对小孩、年轻患者都是很同情的；不需要她们说，我也会经常翻出她们的基因检测报告、蛋白检测报告，去查查有没有什么新的研究成果，看能不能找到什么救她们的办法。
8月6号，我查到了7月15号发表的关于ASPSCR1-TFE3融合突变驱动的肉瘤的最新研究论文：
《ASPSCR1::TFE3 Drives Alveolar Soft Part Sarcoma by Inducing Targetable Transcriptional Programs》
Alveolar soft part sarcoma (ASPS) is a rare mesenchymal malignancy driven by the ASPSCR1::TFE3 fusion. A better understanding of the mechanisms by which this oncogenic transcriptional regulator drives cancer growth is needed to help identify potential therapeutic targets. In this study, we characterized the transcriptional and chromatin landscapes of ASPS tumors and preclinical models, identifying the essential role of ASPSCR1::TFE3 in tumor cell viability by regulating core transcriptional programs involved in cell proliferation, angiogenesis, and mitochondrial biology. ASPSCR1::TFE3 directly interacted with key epigenetic regulators at enhancers and promoters to support ASPS-associated transcription. Among the effector programs driven by ASPSCR1::TFE3, cell proliferation was driven by high levels of cyclin D1 expression. Disruption of cyclin D1/CDK4 signaling led to a loss of ASPS proliferative capacity, and combined inhibition of CDK4/6 and angiogenesis halted tumor growth in xenografts. These results define the ASPS oncogenic program, reveal mechanisms by which ASPSCR1::TFE3 controls tumor biology, and identify a strategy for therapeutically targeting tumor cell-intrinsic vulnerabilities. Significance: The ASPSCR1::TFE3 fusion propels the growth of alveolar soft part sarcoma by activating transcriptional programs that regulate proliferation, angiogenesis, mitochondrial biogenesis, and differentiation and can be therapeutically targeted to improve
ASPSCR1-TFE3融合突变驱动的肉瘤，ccnd1表达高，cdk4表达高，血管密度大；因为ccnd1目前没有专门靶向药，目前治疗策略是用cdk4/6抑制剂来治疗，所以论文建议用cdk4/6抑制剂+抗血管生成药物的治疗策略。
几乎同期发表的另外一篇论文也印证了这个观点。
《Alveolar Soft Part Sarcoma-The Angiogenic Mechanism Regulated by a Fusion Gene Product》
Alveolar soft part sarcoma(ASPS)is a rare malignant tumor whose origin is unidentified, arising from deep soft tissue and affecting adolescents and young adults. ASPS is characterized by its abundant vascular network forming alveolar structures, and demonstrates frequent hematogenous metastasis. An ASPSCR1-TFE3 fusion gene derived from t(X;17)chromosome translocation is detected as a disease gene in all cases, and the ASPSCR1-TFE3 protein causes abnormal transcriptional regulation. We generated a mouse model for ASPS by introducing ASPSCR1-TFE3 into mouse embryonic mesenchymal cells. In the model, tumor angiogenesis and alveolar structures of human ASPS were reproduced, revealing pericyte-rich blood vessels and metastatic processes with pericytic encapsulation of tumor cell nests. ASPSCR1-TFE3 is frequently associated with active enhancers and super-enhancers, and angiogenesis-related enhancers were significantly diminished by the loss of ASPSCR1- TFE3. Angiogenesis-associated enhancers and important target genes, Rab27a, Sytl2, Pdgfb and Vwf were identified by epigenetic CRISPR screening. Rab27a and Sytl2 facilitates trafficking of cytoplasmic vesicles containing angiogenic factors such as Pdgfb and Vwf, resulting in pericyte-rich vascular structures in ASPS. These studies highlight the importance of the Rab27/Sytl axis as a novel drug target in cancer.
ASPSCR1-TFE3融合突变驱动的肉瘤血管丰富，用抗血管生成药物获益可能性大。

抗血管生成药物的选择上，根据《Diagnosis, Prognosis, and Treatment of Alveolar Soft-Part Sarcoma: A Review》这篇综述论文，西地尼布、帕唑帕尼、舒尼替尼等抗血管生成药物对ASPSCR1-TFE3的TFE3有治疗作用。

二、ICB免疫治疗
1、ccnd1表达高，cdk4表达高，血管密度大，这都是ICB免疫治疗的不利因素；用ICB免疫治疗或者单用ICB免疫治疗是不合适的。
《CCND1 Amplification Contributes to Immunosuppression and Is Associated With a Poor Prognosis to Immune Checkpoint Inhibitors in Solid Tumors》
Cyclin D1 (CCND1) amplification relevant to malignant biological behavior exists in solid tumors. The prevalence and utility of CCND1 amplification as a biomarker for the clinical response to treatment with immune checkpoint inhibitors (ICIs) are unknown. Our study is a preliminary investigation mainly focused on the predictive function of CCND1 amplification in the tumor microenvironment (TME) in the aspect of genome and transcriptome. We examined the prevalence of CCND1 amplification and its potential as a biomarker for the efficacy of ICI therapy for solid tumors using a local database (n = 6,536), The Cancer Genome Atlas (TCGA) database (n = 10,606), and the Memorial Sloan Kettering Cancer Center (MSKCC) database (n = 10,109). Comprehensive profiling was performed to determine the prevalence of CCND1 amplification and the correlation with the prognosis and the response to ICIs. A CCND1 amplification occurs in many cancer types and correlates with shorter overall survival and inferior outcomes with ICI therapy. Transcriptomic analysis showed various degrees of immune cell exclusion, including cytotoxic cells, T cells, CD8+ T cells, dendritic cells (DCs), and B cells in the TME in a TCGA CCND1 amplification population. The gene set enrichment analysis suggested that CCND1 amplification correlates with multiple aggressive, immunosuppressive hallmarks including epithelial-mesenchymal transition, transforming growth factor (TGF)-β signaling, KRAS signaling, phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling, p53 pathway, and hypoxia signaling in solid tumors. These findings indicate that CCND1 amplification may be a key point related to immunosuppression in TME and multiple malignancy hallmarks, and it hinders not only the natural host immune responses but also the efficacy of ICIs.
2、患者3月份手术，此后医院给她ICB单药维持；到了9月份，肺部就发现了1.2厘米的转移灶了。这个治疗结果也充分的反映了这点（我怀疑超进展了）。
如果一定要ICB免疫治疗的话，也应该是联合CDK4/6抑制剂和抗血管生成药物；不过这种联合也没什么意义。CDK4/6抑制剂+抗血管生成药物本来就足够控制她的肿瘤，也根本无从判断ICB免疫治疗是否起效。