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Pembrolizumab ± paricalcitol in metastatic pancreatic cancer postmaximal cytoreduction.
IF 4.8 2区 医学 Q1 ONCOLOGY Pub Date : 2025-01-17 DOI: 10.1093/oncolo/oyae323
Vincent Chung, Angela Alistar, Carlos Becerra, Anup Kasi, Erkut Borazanci, Gayle S Jameson, Denise J Roe, Betsy C Wertheim, Derek Cridebring, Morgan Truitt, Michael Downes, Michael T Barrett, Ron Korn, Keehoon Lee, Haiyong Han, Ronald Evans, Daniel D Von Hoff

Lessons learned: Intravenous paricalcitol did not improve the efficacy of pembrolizumab, likely related to the short half-life.

Background: Immunotherapy has limited benefit in the treatment of advanced pancreatic cancer with the tumor microenvironment playing a key role in immune resistance. In preclinical studies, vitamin D receptor (VDR) agonists have been shown to sensitize pancreatic tumors to PD-1 blockade.

Methods: This was a randomized, double-blinded, placebo-controlled, phase II trial to evaluate pembrolizumab with or without paricalcitol as maintenance therapy for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Participants were ≥18 years; histologically or cytologically confirmed metastatic PDAC showing no disease progression after frontline systemic therapy, and achieving maximal cytoreduction (eg, with no further antitumor effect), Eastern Cooperative Oncology Group (ECOG) status of 0 or 1; adequate organ function. Study treatment included: pembrolizumab 200 mg IV every 3 weeks and either paricalcitol 25 mcg IV 3 times per week or placebo. The primary objective was to evaluate 6-month progression free survival (PFS). Secondary objectives include evaluating the toxicity of the combination and overall survival (OS).

Results: There was no significant difference in 6-month PFS, median PFS, median OS, nor treatment-related AEs between the 2 arms.

Conclusions and relevance: Paricalcitol did not improve the efficacy of pembrolizumab likely related to its short half-life of only 5-7 hours. Microbiome analysis revealed significant difference between long-term (>12 weeks) and short-term (<12 weeks) survival groups across treatment arms. Modulation of the tumor microenvironment will likely require more sustained VDR activity.

Trial registration: Clinicaltrials.gov, ID: NCT03331562.

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引用次数: 0
Anaplastic Lymphoma Kinase (ALK) Inhibitors Show Activity in Colorectal Cancer With ALK Rearrangements: Case Series and Literature Review. 无性淋巴瘤激酶(ALK)抑制剂在ALK重排的结直肠癌中显示出活性:病例系列和文献综述。
IF 4.8 2区 医学 Q1 ONCOLOGY Pub Date : 2025-01-17 DOI: 10.1093/oncolo/oyae020
Tingting Hu, Jinbo Zhan, Li Li, Yan He, Yun Lin, Jingru Wang, Haiming Yu, Jianping Xiong, Ziling Fang, Jun Deng, Shanshan Huang, Xiaojun Xiang

Anaplastic lymphoma kinase (ALK) rearrangement is a well-known driver oncogene detected in approximately 5% of non-small cell lung cancer. However, ALK rearrangement is much less frequent in other solid tumors outside the lungs, such as colorectal cancer (CRC); thus, the optimal management of CRC with ALK rearrangements has yet to be established. In this report, we describe 2 cases of ALK-positive CRC, both of which benefited from ALK tyrosine kinase inhibitor (ALK-TKI) therapy. Case 1 was a postoperative patient with poorly differentiated colon adenocarcinoma, who was diagnosed with metastatic relapse shortly after surgery. Both fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and bevacizumab combined with 5-fluorouracil, l-leucovorin, and irinotecan (FOLFIRI) proved ineffective against the disease. The patient was then treated with ensartinib, as the CAD-ALK fusion gene was detected by genomic analysis. The patient was initially treated with ensartinib monotherapy for 9 months, then with ensartinib combined with local radiotherapy and fruquintinib for another 4 months for isolated hilar hepatic lymph node metastasis. The patient experienced disease progression with an acquired ALK G1202R resistance mutation that responded well to lorlatinib. Case 2 involved a 72-year-old man with advanced colon cancer (pT4bN2aM1b, stage IV) harboring an EML4-ALK fusion. The patient underwent resection of the right colon tumor due to intestinal obstruction, but the disease continued to progress after 12 courses of FOLFIRI and bevacizumab chemotherapy. However, the patient responded remarkably well to alectinib. Our report emphasizes the importance of gene detection in the treatment of malignant tumors, and the significance of ALK mutations in CRC.

无性淋巴瘤激酶(ALK)重排是一种众所周知的驱动性癌基因,在大约5%的非小细胞肺癌中被检测到。然而,ALK重排在肺部以外的其他实体瘤(如结直肠癌)中的发生率要低得多;因此,ALK重排的结直肠癌的最佳治疗方法尚未确定。在本报告中,我们描述了两例ALK阳性的CRC,这两例患者均受益于ALK酪氨酸激酶抑制剂(ALK-TKI)的治疗。病例 1 是一名分化较差的结肠腺癌术后患者,术后不久被诊断为转移性复发。事实证明,氟尿嘧啶、亮霉素和奥沙利铂(FOLFOX)以及贝伐单抗联合 5-氟尿嘧啶、l-亮霉素和伊立替康(FOLFIRI)均对该病无效。由于通过基因组分析发现了 CAD-ALK 融合基因,患者随后接受了恩沙替尼治疗。患者最初接受了为期9个月的恩沙替尼单药治疗,之后又接受了为期4个月的恩沙替尼联合局部放疗和弗罗替尼治疗,以治疗孤立的肝门肝淋巴结转移。该患者的疾病进展伴有获得性 ALK G1202R 耐药突变,对洛拉替尼(lorlatinib)反应良好。病例 2 涉及一名 72 岁的男性晚期结肠癌患者(pT4bN2aM1b,IV 期),携带 EML4-ALK 融合基因。患者因肠梗阻接受了右侧结肠肿瘤切除术,但在接受了 12 个疗程的 FOLFIRI 和贝伐单抗化疗后,病情仍在继续发展。然而,患者对阿来替尼的反应非常好。我们的报告强调了基因检测在恶性肿瘤治疗中的重要性,以及 ALK 突变在 CRC 中的重要意义。
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引用次数: 0
Association of opioid use with survival in patients with cancer treated with immune checkpoint inhibitors: it is time for evidence-based behaviors. 接受免疫检查点抑制剂治疗的癌症患者使用阿片类药物与生存的关系:现在是采取循证行为的时候了。
IF 4.8 2区 医学 Q1 ONCOLOGY Pub Date : 2025-01-17 DOI: 10.1093/oncolo/oyae081
Raffaele Giusti, Giampiero Porzio, Marco Maltoni, Marco Filetti, Arturo Cuomo, Elena Bandieri, Dario Trapani, Eduardo Bruera

Cancer is a leading cause of morbidity and mortality worldwide, with pain experienced by most patients undergoing cancer treatment. Opioids are the recommended treatment for cancer pain management, but recent studies suggest a negative association between opioid use and survival rates among patients undergoing immunotherapy. However, conclusions cannot be drawn regarding causality from these observational data. Immunotherapy, which boosts the body's immune system to fight cancer cells, has emerged as a promising treatment option for all types of cancer. Immune checkpoint inhibitors (ICIs) can activate the anticancer function of exhausted T cells and have shown remarkable survival benefits in patients with multiple malignancies. However, a recent systematic review and meta-analysis suggested that the use of opioids during ICI treatment has an adverse effect on patient prognosis, while the use of NSAIDs is not significantly associated with the prognosis in patients treated with ICIs. These reviews have major limitations due to the retrospective nature of the studies and the multiple factors that can influence the phenomenon. Therefore, caution is required when interpreting results from retrospective data on drug interactions. The findings of this study are alarming and potentially harmful to patients with cancer suffering from pain or other symptoms requiring opioid drugs.

癌症是全球发病率和死亡率的主要原因,大多数接受癌症治疗的患者都会感到疼痛。阿片类药物是治疗癌症疼痛的推荐疗法,但最近的研究表明,在接受免疫疗法的患者中,阿片类药物的使用与存活率之间存在负相关。然而,从这些观察数据中并不能得出因果关系的结论。免疫疗法可增强人体的免疫系统来对抗癌细胞,已成为所有类型癌症的一种很有前景的治疗方法。免疫检查点抑制剂(ICIs)可激活衰竭T细胞的抗癌功能,并在多种恶性肿瘤患者中显示出显著的生存优势。然而,最近的一项系统综述和荟萃分析表明,在 ICI 治疗期间使用阿片类药物会对患者的预后产生不利影响,而使用非甾体抗炎药与接受 ICIs 治疗的患者的预后并无明显关联。这些综述存在很大的局限性,因为这些研究都是回顾性的,而且有多种因素会影响这一现象。因此,在解释药物相互作用回顾性数据的结果时需要谨慎。这项研究的结果令人震惊,可能会对因疼痛或其他症状而需要阿片类药物的癌症患者造成危害。
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引用次数: 0
Next-generation sequencing-based evaluation of the actionable landscape of genomic alterations in solid tumors: the "MOZART" prospective observational study. 基于新一代测序的实体瘤基因组改变可操作性评估:"MOZART "前瞻性观察研究。
IF 4.8 2区 医学 Q1 ONCOLOGY Pub Date : 2025-01-17 DOI: 10.1093/oncolo/oyae206
Francesco Schettini, Marianna Sirico, Marco Loddo, Gareth H Williams, Keeda-Marie Hardisty, Paul Scorer, Robert Thatcher, Pablo Rivera, Manuela Milani, Carla Strina, Giuseppina Ferrero, Marco Ungari, Cristina Bottin, Fabrizio Zanconati, Nicolò de Manzini, Sergio Aguggini, Richard Tancredi, Elena Fiorio, Antonio Fioravanti, Maurizio Scaltriti, Daniele Generali

Background: The identification of the most appropriate targeted therapies for advanced cancers is challenging. We performed a molecular profiling of metastatic solid tumors utilizing a comprehensive next-generation sequencing (NGS) assay to determine genomic alterations' type, frequency, actionability, and potential correlations with PD-L1 expression.

Methods: A total of 304 adult patients with heavily pretreated metastatic cancers treated between January 2019 and March 2021 were recruited. The CLIA-/UKAS-accredit Oncofocus assay targeting 505 genes was used on newly obtained or archived biopsies. Chi-square, Kruskal-Wallis, and Wilcoxon rank-sum tests were used where appropriate. Results were significant for P < .05.

Results: A total of 237 tumors (78%) harbored potentially actionable genomic alterations. Tumors were positive for PD-L1 in 68.9% of cases. The median number of mutant genes/tumor was 2.0 (IQR: 1.0-3.0). Only 34.5% were actionable ESCAT Tier I-II with different prevalence according to cancer type. The DNA damage repair (14%), the PI3K/AKT/mTOR (14%), and the RAS/RAF/MAPK (12%) pathways were the most frequently altered. No association was found among PD-L1, ESCAT, age, sex, and tumor mutational status. Overall, 62 patients underwent targeted treatment, with 37.1% obtaining objective responses. The same molecular-driven treatment for different cancer types could be associated with opposite clinical outcomes.

Conclusions: We highlight the clinical value of molecular profiling in metastatic solid tumors using comprehensive NGS-based panels to improve treatment algorithms in situations of uncertainty and facilitate clinical trial recruitment. However, interpreting genomic alterations in a tumor type-specific manner is critical.

背景:为晚期癌症确定最合适的靶向疗法具有挑战性。我们利用全面的下一代测序(NGS)分析方法对转移性实体瘤进行了分子谱分析,以确定基因组改变的类型、频率、可操作性以及与 PD-L1 表达的潜在相关性:共招募了 304 名在 2019 年 1 月至 2021 年 3 月期间接受过重度预处理的转移性癌症成年患者。针对 505 个基因的 CLIA/UKAS 认证 Oncofocus 检测被用于新获得或存档的活组织切片。在适当情况下使用了卡方检验、Kruskal-Wallis 检验和 Wilcoxon 秩和检验。结果对 P 有显著影响:共有 237 例肿瘤(78%)存在潜在的可操作基因组改变。68.9%的肿瘤PD-L1呈阳性。突变基因/肿瘤的中位数为 2.0(IQR:1.0-3.0)。只有34.5%的病例属于可采取行动的ESCAT I-II级,不同癌症类型的发病率不同。DNA损伤修复(14%)、PI3K/AKT/mTOR(14%)和RAS/RAF/MAPK(12%)通路是最常发生改变的通路。PD-L1、ESCAT、年龄、性别和肿瘤突变状态之间没有关联。共有62名患者接受了靶向治疗,其中37.1%的患者获得了客观反应。针对不同癌症类型的相同分子驱动治疗可能会产生相反的临床结果:我们强调了使用基于 NGS 的综合面板对转移性实体瘤进行分子图谱分析的临床价值,以改进不确定情况下的治疗算法并促进临床试验招募。然而,以肿瘤类型特异性的方式解释基因组改变至关重要。
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引用次数: 0
Precision medicine: an intrahepatic cholangiocarcinoma with a novel RBPMS-MET fusion sensitive to crizotinib. 精准医学:一种新型RBPMS-MET融合对克唑替尼敏感的肝内胆管癌。
IF 4.8 2区 医学 Q1 ONCOLOGY Pub Date : 2025-01-17 DOI: 10.1093/oncolo/oyae340
Wei Wan, Xueqin Liu, Yamin Zhang, Rui Shen, Weihu Xia, Shuangni Li, Yuan Tan, Qianqian Duan, Jinpeng Liu, Wuping Wang

Background: Intrahepatic cholangiocarcinoma is a malignant tumor that starts from the epithelium of the bile duct and has a poor prognosis. They are characterized by poor response to chemotherapy and lack of effective targeted therapies; thus, therapeutic options are limited.

Case presentation: A 59-year-old man was admitted to the hospital for a workup of abnormal CA19-9 levels. He was diagnosed with ICC, underwent surgery and was found to have pT1bNx disease. He developed rapid disease recurrence on adjuvant gemcitabine + capecitabine. Following recurrence, he received first-line systemic pembrolizumab + lenvatinib and second-line pembrolizumab + lenvatinib + chemotherapy and had mild tumor regression followed by progression. Next-generation sequencing was performed on the baseline surgical sample. This revealed a novel RBPMS-MET fusion, and based on the literature, crizotinib 250 mg twice a day was administered. After 3 months of crizotinib treatment, magnetic resonance imaging revealed a significant reduction in liver lesions, and 4 months after initiating treatment, scans demonstrated a partial response.

Conclusion: Our case report strengthens the evidence that crizotinib may be a viable treatment option for patients with ICC with a c-MET tyrosine kinase fusion, necessitating additional clinical investigation.

背景:肝内胆管癌是一种起源于胆管上皮的恶性肿瘤,预后较差。它们的特点是对化疗反应差,缺乏有效的靶向治疗;因此,治疗的选择是有限的。病例介绍:一名59岁男性因CA19-9水平异常入院。他被诊断为ICC,接受了手术,并被发现患有pT1bNx疾病。辅助使用吉西他滨+卡培他滨后病情迅速复发。复发后,患者接受了一线全身派姆单抗+ lenvatinib和二线派姆单抗+ lenvatinib化疗,肿瘤轻度消退,随后进展。对基线手术样本进行新一代测序。这揭示了一种新的RBPMS-MET融合,根据文献,克唑替尼250毫克,每天两次。克唑替尼治疗3个月后,磁共振成像显示肝脏病变显著减少,开始治疗4个月后,扫描显示部分反应。结论:我们的病例报告加强了克唑替尼可能是c-MET酪氨酸激酶融合的ICC患者的可行治疗选择的证据,需要额外的临床研究。
{"title":"Precision medicine: an intrahepatic cholangiocarcinoma with a novel RBPMS-MET fusion sensitive to crizotinib.","authors":"Wei Wan, Xueqin Liu, Yamin Zhang, Rui Shen, Weihu Xia, Shuangni Li, Yuan Tan, Qianqian Duan, Jinpeng Liu, Wuping Wang","doi":"10.1093/oncolo/oyae340","DOIUrl":"10.1093/oncolo/oyae340","url":null,"abstract":"<p><strong>Background: </strong>Intrahepatic cholangiocarcinoma is a malignant tumor that starts from the epithelium of the bile duct and has a poor prognosis. They are characterized by poor response to chemotherapy and lack of effective targeted therapies; thus, therapeutic options are limited.</p><p><strong>Case presentation: </strong>A 59-year-old man was admitted to the hospital for a workup of abnormal CA19-9 levels. He was diagnosed with ICC, underwent surgery and was found to have pT1bNx disease. He developed rapid disease recurrence on adjuvant gemcitabine + capecitabine. Following recurrence, he received first-line systemic pembrolizumab + lenvatinib and second-line pembrolizumab + lenvatinib + chemotherapy and had mild tumor regression followed by progression. Next-generation sequencing was performed on the baseline surgical sample. This revealed a novel RBPMS-MET fusion, and based on the literature, crizotinib 250 mg twice a day was administered. After 3 months of crizotinib treatment, magnetic resonance imaging revealed a significant reduction in liver lesions, and 4 months after initiating treatment, scans demonstrated a partial response.</p><p><strong>Conclusion: </strong>Our case report strengthens the evidence that crizotinib may be a viable treatment option for patients with ICC with a c-MET tyrosine kinase fusion, necessitating additional clinical investigation.</p>","PeriodicalId":54686,"journal":{"name":"Oncologist","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142808695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Molecular tumor board: molecularly adjusted therapy upon identification and functional validation of a novel ALK resistance mutation in a case of lung adenocarcinoma. 肿瘤分子委员会:在一例肺腺癌中发现新型 ALK 抗性突变并进行功能验证后,对治疗进行分子调整。
IF 4.8 2区 医学 Q1 ONCOLOGY Pub Date : 2025-01-17 DOI: 10.1093/oncolo/oyae143
Annette Arndt, Christian Neumann, Armin Riecke, Arthur Bauer, Matthias Müller, Manuela Wölfle-Guter, Michael Grunert, Hauke Busch, Axel Künstner, Nikolas von Bubnoff, Stephanie Fliedner, Dina Greinert, Jasmin Osius, Kumar Nagarathinam, Konrad Steinestel, Sivahari Prasad Gorantla, Niklas Gebauer, Hanno M Witte

We report a case of a long-term surviving patient with EML4/ALK translocated non-small cell adenocarcinoma of the lung in UICC8 stage IVA. During recurrence under continuous crizotinib therapy, a hitherto insufficiently characterized missense mutation in the ALK gene (Arg1181His) was identified through targeted sequencing. The aforementioned EML4/ALK translocation could still be detected in this situation. Employing a 3D reconstruction of the ALK tertiary structure, considering its interaction with various ALK inhibitors at the molecular binding site, our analysis indicated the presence of a mutation associated with crizotinib resistance. To validate the biological relevance of this previously unknown mutation, we carried out an in vitro validation approach in cell culture in addition to the molecular diagnostics accompanied by the molecular tumor board. The tumor scenario was mimicked through retroviral transfection. Our comparative in vitro treatment regimen paired with the clinical trajectory of the patient, corroborated our initial clinical and biochemical suspicions. Our approach demonstrates preclinical, in silico, and clinical evidence of a novel crizotinib resistance mutation in ALK as well as sensitivity toward brigatinib and potentially lorlatinib. In future cases, this procedure represents an important contribution to functional diagnostics in the context of molecular tumor boards.

我们报告了一例长期存活的 EML4/ALK 易位非小细胞肺腺癌 UICC8 IVA 期患者。在持续接受克唑替尼治疗的复发过程中,通过靶向测序发现了 ALK 基因中一个迄今特征尚不充分的错义突变(Arg1181His)。在这种情况下仍能检测到上述的EML4/ALK易位。通过对 ALK 三级结构进行三维重建,并考虑到其在分子结合位点与各种 ALK 抑制剂的相互作用,我们的分析表明存在与克唑替尼耐药相关的突变。为了验证这一先前未知突变的生物学相关性,除了分子诊断和分子肿瘤板之外,我们还在细胞培养中进行了体外验证。我们通过逆转录病毒转染模拟了肿瘤情景。我们的体外治疗方案与患者的临床轨迹相比较,证实了我们最初的临床和生化猜测。我们的方法证明了 ALK 中新型克唑替尼耐药突变的临床前、硅学和临床证据,以及对瑞加替尼(brigatinib)和潜在的洛拉替尼(lorlatinib)的敏感性。在未来的病例中,这种方法将为肿瘤分子板的功能诊断做出重要贡献。
{"title":"Molecular tumor board: molecularly adjusted therapy upon identification and functional validation of a novel ALK resistance mutation in a case of lung adenocarcinoma.","authors":"Annette Arndt, Christian Neumann, Armin Riecke, Arthur Bauer, Matthias Müller, Manuela Wölfle-Guter, Michael Grunert, Hauke Busch, Axel Künstner, Nikolas von Bubnoff, Stephanie Fliedner, Dina Greinert, Jasmin Osius, Kumar Nagarathinam, Konrad Steinestel, Sivahari Prasad Gorantla, Niklas Gebauer, Hanno M Witte","doi":"10.1093/oncolo/oyae143","DOIUrl":"10.1093/oncolo/oyae143","url":null,"abstract":"<p><p>We report a case of a long-term surviving patient with EML4/ALK translocated non-small cell adenocarcinoma of the lung in UICC8 stage IVA. During recurrence under continuous crizotinib therapy, a hitherto insufficiently characterized missense mutation in the ALK gene (Arg1181His) was identified through targeted sequencing. The aforementioned EML4/ALK translocation could still be detected in this situation. Employing a 3D reconstruction of the ALK tertiary structure, considering its interaction with various ALK inhibitors at the molecular binding site, our analysis indicated the presence of a mutation associated with crizotinib resistance. To validate the biological relevance of this previously unknown mutation, we carried out an in vitro validation approach in cell culture in addition to the molecular diagnostics accompanied by the molecular tumor board. The tumor scenario was mimicked through retroviral transfection. Our comparative in vitro treatment regimen paired with the clinical trajectory of the patient, corroborated our initial clinical and biochemical suspicions. Our approach demonstrates preclinical, in silico, and clinical evidence of a novel crizotinib resistance mutation in ALK as well as sensitivity toward brigatinib and potentially lorlatinib. In future cases, this procedure represents an important contribution to functional diagnostics in the context of molecular tumor boards.</p>","PeriodicalId":54686,"journal":{"name":"Oncologist","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Impact of HER2-targeted PET/CT imaging in patients with breast cancer and therapeutic response monitoring. HER2 靶向 PET/CT 成像对乳腺癌患者的影响以及治疗反应监测。
IF 4.8 2区 医学 Q1 ONCOLOGY Pub Date : 2025-01-17 DOI: 10.1093/oncolo/oyae188
Xinyu Gui, Xu Liang, Xiaoyi Guo, Zhi Yang, Guohong Song

Background: Patients with breast cancer exhibit heterogeneity in the expression of the human epithelial growth factor receptor 2 (HER2). Clinically, re-biopsying recurrent or metastatic lesions presents substantial challenges. This study aimed to evaluate the efficacy of HER2-targeted PET/CT imaging in identifying HER2 expression in breast cancer lesions and monitoring therapeutic responses.

Patients and methods: This exploratory analysis used data from a prospective study that included adult patients with breast cancer who underwent both Al18F-NOTA-HER2-BCH and 18F-FDG PET/CT imaging at Beijing Cancer Hospital between June 2020 and July 2023 (NCT04547309).

Results: Fifty-nine participants, with a median age of 55 years, were analyzed. Lesions imaged with HER2-targeted PET/CT before anti-HER2 therapy exhibited higher SUVmax values than after therapy in HER2 immunohistochemistry (IHC) 3 + lesions (19.9, 95% CI: 15.7-25.3 vs 9.8, 95% CI: 5.6-14.7; P = .006). A significant positive correlation was observed between SUVmax on HER2-targeted PET/CT and IHC before therapy (P = .034), with higher SUVmax values noted in lesions with positive HER2 pathology compared to those with negative HER2 status (17.9 ± 13.2 vs 1.1 ± 0.3; P = .007). HER2 expression heterogeneity was confirmed both between primary and metastatic lesions (22.9%) and among different metastatic sites (26.7%) as assessed by HER2-targeted PET/CT. A superior therapeutic response correlated with higher pretreatment SUVmax values. The HER2-targeted PET/CT procedure was well-tolerated by all patients.

Conclusion: HER2-targeted PET/CT imaging offers a practical, non-invasive, and quantitative approach for assessing HER2 status in breast cancer patients, facilitating the optimization and personalization of therapeutic strategies by oncologists.

背景:乳腺癌患者的人类上皮生长因子受体 2(HER2)表达具有异质性。在临床上,对复发或转移病灶进行再次活检是一项巨大的挑战。本研究旨在评估HER2靶向PET/CT成像在确定乳腺癌病灶中HER2表达和监测治疗反应方面的疗效:该前瞻性研究纳入了2020年6月至2023年7月期间在北京肿瘤医院接受Al18F-NOTA-HER2-BCH和18F-FDG PET/CT成像的成年乳腺癌患者(NCT04547309):分析了59名参与者,中位年龄为55岁。在抗HER2治疗前使用HER2靶向PET/CT成像的病灶的SUVmax值高于治疗后HER2免疫组化(IHC)3 +病灶的SUVmax值(19.9,95% CI:15.7-25.3 vs 9.8,95% CI:5.6-14.7;P = .006)。治疗前,HER2靶向PET/CT和IHC的SUVmax之间存在明显的正相关性(P = .034),HER2病理阳性病灶的SUVmax值高于HER2阴性病灶(17.9 ± 13.2 vs 1.1 ± 0.3;P = .007)。根据HER2靶向PET/CT评估,原发病灶和转移病灶之间(22.9%)以及不同转移部位之间(26.7%)的HER2表达异质性均得到证实。较好的治疗反应与较高的治疗前 SUVmax 值相关。所有患者都能很好地耐受HER2靶向PET/CT检查:HER2靶向PET/CT成像为评估乳腺癌患者的HER2状态提供了一种实用、无创和定量的方法,有助于肿瘤专家优化和个性化治疗策略。
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引用次数: 0
Dramatic response to crizotinib through MET phosphorylation inhibition in rare TFG-MET fusion advanced squamous cell lung cancer. 罕见的 TFG-MET 融合晚期鳞状细胞肺癌通过抑制 MET 磷酸化对克唑替尼产生了显著反应。
IF 4.8 2区 医学 Q1 ONCOLOGY Pub Date : 2025-01-17 DOI: 10.1093/oncolo/oyae166
Wanwan Cheng, Ting Xu, Lu Yang, Naimeng Yan, Jie Yang, Shencun Fang

With the widespread use of next-generation sequencing (NGS) for solid tumors, mesenchymal-to-epithelial transition factor (MET) rearrangement/fusion has been confirmed in multiple cancer types. MET amplification and MET exon 14 skipping mutations induce protein autophosphorylation; however, the pathogenic mechanism and drug sensitivity of MET fusion remain unclear. The following report describes the clinical case of a patient diagnosed with squamous lung cancer bearing a TFG-MET gene fusion. In vitro assays demonstrated MET phosphorylation and oncogenic capacity due to the TFG-MET rearrangement, both of which were inhibited by crizotinib treatment. The patient was treated with crizotinib, which resulted in sustained partial remission for more than 17 months. Collectively, cellular analyses and our case report emphasize the potential of MET fusion as a predictive biomarker for personalized target therapy for solid tumors.

随着下一代测序技术(NGS)在实体瘤中的广泛应用,间质-上皮转化因子(MET)重排/融合已在多种癌症类型中得到证实。MET 扩增和 MET 第 14 号外显子跳越突变可诱导蛋白质自磷酸化;然而,MET 融合的致病机制和药物敏感性仍不清楚。以下报告描述了一名被诊断为鳞状肺癌的患者的临床病例,该患者带有 TFG-MET 基因融合。体外检测显示,TFG-MET重排导致MET磷酸化和致癌能力,而克唑替尼治疗可抑制这两种情况。患者接受克唑替尼治疗后,部分病情得到了持续超过 17 个月的缓解。细胞分析和我们的病例报告共同强调了MET融合作为实体瘤个性化靶向治疗的预测性生物标志物的潜力。
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引用次数: 0
COMPOSIT study: evaluating osimertinib combination with targeted therapies in EGFR-mutated non-small cell lung cancer. 复合研究:评价奥西替尼联合靶向治疗egfr突变的非小细胞肺癌。
IF 4.8 2区 医学 Q1 ONCOLOGY Pub Date : 2024-12-26 DOI: 10.1093/oncolo/oyae312
Camille Mehlman, Aurelie Swalduz, Isabelle Monnet, Clara Morin, Marie Wislez, Florian Guisier, Hubert Curcio, Pauline Du Rusquec, Alexis B Cortot, Valerie Gounant, Baptiste Abbar, Boris Duchemann, Etienne Giroux-Leprieur, Thomas Pierret, Fleur-Marie Quilot, Jacques Cadranel, Vincent Fallet

Introduction: The emergence of diverse resistance mechanisms after osimertinib therapy, including on-target epidermal growth factor receptor (EGFR) mutations and off-target alterations, warrants investigation of novel therapeutics to overcome these challenges and improve patient outcomes.

Methods: COMPOSIT was a French, retrospective, multicenter, cohort study of the effectiveness and tolerability of osimertinib in combination with other targeted therapies in patients with advanced EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC) who harbored other oncogenic drivers as primary or acquired resistance mechanisms. Real-world progression-free survival (rwPFS), overall survival (OS), and objective response rate (ORR) were the primary endpoints.

Results: The study included 61 patients (63.9% women; median age, 61 years). Chemotherapy was administered to 26 patients (42.6%) before the combinations. The most frequently targeted resistance mechanisms were MET amplification (n = 40) and BRAF alterations (n = 11). Sixteen combinations of osimertinib with other targeted therapies were reported. Overall (except for 10 patients in clinical trials), median rwPFS and OS were 3.9 (95% CI, 2.9-5.2) and 9.8 months (95% CI, 6.8-14.8). Best ORR (n = 54) was 50% (95% CI, 33.0-72.8). In patients with MET amplification (n = 29), median rwPFS and OS were 4.9 (95% CI, 2.9-7.2) and 8.6 months (95% CI, 5.3-21.6). Grade ≥3 adverse events occurred in 15 patients (24.6%). No deaths were related to treatment.

Conclusions: Combinations of osimertinib with other targeted therapies appeared to be feasible and safe and may offer clinical benefit to overcome resistance to osimertinib in EGFRm NSCLC, especially in patients with MET amplification.

奥西替尼治疗后出现多种耐药机制,包括靶向表皮生长因子受体(EGFR)突变和脱靶改变,需要研究新的治疗方法来克服这些挑战并改善患者的预后。方法:COMPOSIT是法国的一项回顾性、多中心、队列研究,研究了奥西替尼联合其他靶向治疗在晚期egfr突变(EGFRm)非小细胞肺癌(NSCLC)患者中的有效性和耐受性,这些患者具有其他致癌驱动因素作为原发性或获得性耐药机制。真实世界无进展生存期(rwPFS)、总生存期(OS)和客观缓解率(ORR)是主要终点。结果:纳入61例患者,其中女性占63.9%;中位年龄61岁)。26例(42.6%)患者在联合用药前接受化疗。最常见的耐药机制是MET扩增(n = 40)和BRAF改变(n = 11)。报道了16例奥西替尼与其他靶向治疗的联合用药。总体而言(临床试验中的10例患者除外),中位rwPFS和OS分别为3.9个月(95% CI, 2.9-5.2)和9.8个月(95% CI, 6.8-14.8)。最佳ORR (n = 54)为50% (95% CI, 33.0-72.8)。在MET扩增的患者中(n = 29),中位rwPFS和OS分别为4.9 (95% CI, 2.9-7.2)和8.6个月(95% CI, 5.3-21.6)。15例患者发生≥3级不良事件(24.6%)。没有与治疗相关的死亡。结论:奥西替尼联合其他靶向治疗似乎是可行和安全的,并可能为克服EGFRm NSCLC对奥西替尼的耐药提供临床益处,特别是在MET扩增患者中。
{"title":"COMPOSIT study: evaluating osimertinib combination with targeted therapies in EGFR-mutated non-small cell lung cancer.","authors":"Camille Mehlman, Aurelie Swalduz, Isabelle Monnet, Clara Morin, Marie Wislez, Florian Guisier, Hubert Curcio, Pauline Du Rusquec, Alexis B Cortot, Valerie Gounant, Baptiste Abbar, Boris Duchemann, Etienne Giroux-Leprieur, Thomas Pierret, Fleur-Marie Quilot, Jacques Cadranel, Vincent Fallet","doi":"10.1093/oncolo/oyae312","DOIUrl":"https://doi.org/10.1093/oncolo/oyae312","url":null,"abstract":"<p><strong>Introduction: </strong>The emergence of diverse resistance mechanisms after osimertinib therapy, including on-target epidermal growth factor receptor (EGFR) mutations and off-target alterations, warrants investigation of novel therapeutics to overcome these challenges and improve patient outcomes.</p><p><strong>Methods: </strong>COMPOSIT was a French, retrospective, multicenter, cohort study of the effectiveness and tolerability of osimertinib in combination with other targeted therapies in patients with advanced EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC) who harbored other oncogenic drivers as primary or acquired resistance mechanisms. Real-world progression-free survival (rwPFS), overall survival (OS), and objective response rate (ORR) were the primary endpoints.</p><p><strong>Results: </strong>The study included 61 patients (63.9% women; median age, 61 years). Chemotherapy was administered to 26 patients (42.6%) before the combinations. The most frequently targeted resistance mechanisms were MET amplification (n = 40) and BRAF alterations (n = 11). Sixteen combinations of osimertinib with other targeted therapies were reported. Overall (except for 10 patients in clinical trials), median rwPFS and OS were 3.9 (95% CI, 2.9-5.2) and 9.8 months (95% CI, 6.8-14.8). Best ORR (n = 54) was 50% (95% CI, 33.0-72.8). In patients with MET amplification (n = 29), median rwPFS and OS were 4.9 (95% CI, 2.9-7.2) and 8.6 months (95% CI, 5.3-21.6). Grade ≥3 adverse events occurred in 15 patients (24.6%). No deaths were related to treatment.</p><p><strong>Conclusions: </strong>Combinations of osimertinib with other targeted therapies appeared to be feasible and safe and may offer clinical benefit to overcome resistance to osimertinib in EGFRm NSCLC, especially in patients with MET amplification.</p>","PeriodicalId":54686,"journal":{"name":"Oncologist","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A phase II trial of larotrectinib in tumors with NTRK fusions or extremes of NTRK mRNA overexpression identified by comprehensive genomic profiling. 一项larorectinib的II期临床试验,通过综合基因组谱鉴定出NTRK融合或NTRK mRNA过表达极端的肿瘤。
IF 4.8 2区 医学 Q1 ONCOLOGY Pub Date : 2024-12-25 DOI: 10.1093/oncolo/oyae339
Subotheni Thavaneswaran, Hao-Wen Sim, John Grady, David Espinoza, Min Li Huang, Frank Lin, Margaret McGrath, Jayesh Desai, Michail Charakidis, Michael Brown, Maya Kansara, John Simes, David Thomas

Background: TRK-inhibitors have demonstrated efficacy across several cancers with NTRK fusions. Their activity in cancers with NTRK overexpression remains unclear.

Methods: This trial enrolled patients with advanced cancers harboring NTRK fusions or extreme mRNA overexpression, defined as NTRK1/2/3 expression by RNA profiling >5 SDs for a given cancer type. The primary endpoint was objective response rate (ORR), with secondary endpoints including time-to-progression (TTP) ratio [TTP on study to TTP on previous systemic therapy (TTP1)], progression-free survival (PFS), and overall survival (OS). Initially planned for 2 non-comparator groups: primary central nervous system (CNS) and non-CNS tumours with NTRK fusions, the protocol was amended to permit NTRK overexpression.

Results: Seventeen patients were treated with larotrectinib: one glioblastoma with a SPECC1L::NTRK2 fusion (group 1), and a peripheral nerve sheath tumor with a TPM3::NTRK1 fusion and 15 patients with overexpression (group 2). The ORR was 6%. An additional 3 of 12 (25%) TTP1-evaluable patients achieved a TTP ratio ≥1.3 and 2 of 5 without an evaluable TTP1 had a PFS >6 months. Median PFS and OS were 3.5 (95% CI, 1.4-6.0) and 15.9 months (95% CI, 6.4-NR), respectively.

Conclusion: Unlike its efficacy in NTRK-fusion positive cancers, larotrectinib did not demonstrate a signal of efficacy among tumors with NTRK overexpression.

背景:trk抑制剂已经证明对几种NTRK融合的癌症有效。它们在NTRK过表达的癌症中的活性尚不清楚。方法:该试验招募了具有NTRK融合或mRNA极度过表达的晚期癌症患者,通过RNA谱分析bbb5 SDs定义为特定癌症类型的NTRK1/2/3表达。主要终点是客观缓解率(ORR),次要终点包括进展时间(TTP)比[研究时的TTP与既往全身治疗时的TTP (TTP1)]、无进展生存期(PFS)和总生存期(OS)。最初计划用于2个非比较组:原发性中枢神经系统(CNS)和NTRK融合的非中枢神经系统肿瘤,修改方案以允许NTRK过表达。结果:larorectinib治疗17例患者,1例胶质母细胞瘤伴spec1l::NTRK2融合(1组),1例外周神经鞘肿瘤伴TPM3::NTRK1融合,15例过表达(2组),ORR为6%。另外,12例可评估TTP1的患者中有3例(25%)TTP比率≥1.3,5例没有可评估TTP1的患者中有2例在6个月后出现PFS。中位PFS和OS分别为3.5个月(95% CI, 1.4-6.0)和15.9个月(95% CI, 6.4-NR)。结论:与对NTRK融合阳性肿瘤的疗效不同,larorectinib对NTRK过表达的肿瘤没有显示出疗效信号。
{"title":"A phase II trial of larotrectinib in tumors with NTRK fusions or extremes of NTRK mRNA overexpression identified by comprehensive genomic profiling.","authors":"Subotheni Thavaneswaran, Hao-Wen Sim, John Grady, David Espinoza, Min Li Huang, Frank Lin, Margaret McGrath, Jayesh Desai, Michail Charakidis, Michael Brown, Maya Kansara, John Simes, David Thomas","doi":"10.1093/oncolo/oyae339","DOIUrl":"https://doi.org/10.1093/oncolo/oyae339","url":null,"abstract":"<p><strong>Background: </strong>TRK-inhibitors have demonstrated efficacy across several cancers with NTRK fusions. Their activity in cancers with NTRK overexpression remains unclear.</p><p><strong>Methods: </strong>This trial enrolled patients with advanced cancers harboring NTRK fusions or extreme mRNA overexpression, defined as NTRK1/2/3 expression by RNA profiling >5 SDs for a given cancer type. The primary endpoint was objective response rate (ORR), with secondary endpoints including time-to-progression (TTP) ratio [TTP on study to TTP on previous systemic therapy (TTP1)], progression-free survival (PFS), and overall survival (OS). Initially planned for 2 non-comparator groups: primary central nervous system (CNS) and non-CNS tumours with NTRK fusions, the protocol was amended to permit NTRK overexpression.</p><p><strong>Results: </strong>Seventeen patients were treated with larotrectinib: one glioblastoma with a SPECC1L::NTRK2 fusion (group 1), and a peripheral nerve sheath tumor with a TPM3::NTRK1 fusion and 15 patients with overexpression (group 2). The ORR was 6%. An additional 3 of 12 (25%) TTP1-evaluable patients achieved a TTP ratio ≥1.3 and 2 of 5 without an evaluable TTP1 had a PFS >6 months. Median PFS and OS were 3.5 (95% CI, 1.4-6.0) and 15.9 months (95% CI, 6.4-NR), respectively.</p><p><strong>Conclusion: </strong>Unlike its efficacy in NTRK-fusion positive cancers, larotrectinib did not demonstrate a signal of efficacy among tumors with NTRK overexpression.</p>","PeriodicalId":54686,"journal":{"name":"Oncologist","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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