Pub Date : 2024-11-19DOI: 10.1158/1078-0432.ccr-24-2599
Nicolas Coudray, Michael A. Occidental, Jose G. Mantilla, Adalberto Claudio Quiros, Ke Yuan, Jan Balko, Aristotelis Tsirigos, George Jour
Purpose: Necrosis quantification in the neoadjuvant setting using pathology slide review is the most important validated prognostic marker in conventional osteosarcoma. Herein, we explored three deep learning strategies on histology samples to predict outcome for OSA in the neoadjuvant setting. Experimental Design: Our study relies on a training cohort from New York University (New York, NY) and an external cohort from Charles university (Prague, Czechia). We trained and validated the performance of a supervised approach that integrates neural network predictions of necrosis/tumor content, and compared predicted overall survival (OS) using Kaplan-Meier curves. Furthermore, we explored morphology-based supervised and self-supervised approaches to determine whether intrinsic histomorphological features could serve as a potential marker for OS in the setting of neoadjuvant. Results: Excellent correlation between the trained network and the pathologists was obtained for the quantification of necrosis content (R2=0.899, r=0.949, p < 0.0001). OS prediction cutoffs were consistent between pathologists and the neural network (22% and 30% of necrosis, respectively). Morphology-based supervised approach predicted OS with p-value=0.0028, HR=2.43 [1.10-5.38]. The self-supervised approach corroborated the findings with clusters enriched in necrosis, fibroblastic stroma, and osteoblastic morphology associating with better OS (lg2HR; -2.366; -1.164; -1.175; 95% CI=[-2.996; -0.514]). Viable/partially viable tumor and fat necrosis were associated with worse OS (lg2HR;1.287;0.822;0.828; 95% CI=[0.38-1.974]). Conclusions: Neural networks can be used to automatically estimate the necrosis to tumor ratio, a quantitative metric predictive of survival. Furthermore, we identified alternate histomorphological biomarkers specific to the necrotic and tumor regions themselves which can be used as predictors.
目的：在新辅助治疗中使用病理切片审查进行坏死量化是传统骨肉瘤最重要的有效预后标志。在此，我们探索了三种针对组织学样本的深度学习策略，以预测新辅助治疗中骨肉瘤的预后。实验设计：我们的研究依赖于纽约大学（纽约州纽约市）的训练队列和查尔斯大学（捷克布拉格）的外部队列。我们训练并验证了一种监督方法的性能，该方法整合了神经网络对坏死/肿瘤内容的预测，并使用 Kaplan-Meier 曲线比较了预测的总生存期（OS）。此外，我们还探索了基于形态学的监督和自我监督方法，以确定内在组织形态学特征是否可作为新辅助治疗情况下OS的潜在标记。结果：训练有素的网络与病理学家对坏死含量的量化结果具有极好的相关性（R2=0.899，r=0.949，p < 0.0001）。病理学家和神经网络的 OS 预测临界值一致（坏死率分别为 22% 和 30%）。基于形态学的监督方法预测 OS 的 p 值=0.0028，HR=2.43 [1.10-5.38]。自我监督方法证实了这一发现，坏死、成纤维基质和成骨细胞形态丰富的簇与较好的OS相关（lg2HR；-2.366；-1.164；-1.175；95% CI=[-2.996；-0.514]）。存活/部分存活的肿瘤和脂肪坏死与较差的 OS 有关（lg2HR; 1.287;0.822;0.828; 95% CI=[0.38-1.974]）。结论神经网络可用于自动估算坏死与肿瘤的比率，这是一个预测生存率的定量指标。此外，我们还发现了坏死区和肿瘤区本身特异的替代组织形态学生物标志物，可用作预测指标。
{"title":"Quantitative and Morphology-Based Deep Convolutional Neural Network Approaches for Osteosarcoma Survival Prediction in the Neoadjuvant and Metastatic Setting.","authors":"Nicolas Coudray, Michael A. Occidental, Jose G. Mantilla, Adalberto Claudio Quiros, Ke Yuan, Jan Balko, Aristotelis Tsirigos, George Jour","doi":"10.1158/1078-0432.ccr-24-2599","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2599","url":null,"abstract":"Purpose: Necrosis quantification in the neoadjuvant setting using pathology slide review is the most important validated prognostic marker in conventional osteosarcoma. Herein, we explored three deep learning strategies on histology samples to predict outcome for OSA in the neoadjuvant setting. Experimental Design: Our study relies on a training cohort from New York University (New York, NY) and an external cohort from Charles university (Prague, Czechia). We trained and validated the performance of a supervised approach that integrates neural network predictions of necrosis/tumor content, and compared predicted overall survival (OS) using Kaplan-Meier curves. Furthermore, we explored morphology-based supervised and self-supervised approaches to determine whether intrinsic histomorphological features could serve as a potential marker for OS in the setting of neoadjuvant. Results: Excellent correlation between the trained network and the pathologists was obtained for the quantification of necrosis content (R2=0.899, r=0.949, p &lt; 0.0001). OS prediction cutoffs were consistent between pathologists and the neural network (22% and 30% of necrosis, respectively). Morphology-based supervised approach predicted OS with p-value=0.0028, HR=2.43 [1.10-5.38]. The self-supervised approach corroborated the findings with clusters enriched in necrosis, fibroblastic stroma, and osteoblastic morphology associating with better OS (lg2HR; -2.366; -1.164; -1.175; 95% CI=[-2.996; -0.514]). Viable/partially viable tumor and fat necrosis were associated with worse OS (lg2HR;1.287;0.822;0.828; 95% CI=[0.38-1.974]). Conclusions: Neural networks can be used to automatically estimate the necrosis to tumor ratio, a quantitative metric predictive of survival. Furthermore, we identified alternate histomorphological biomarkers specific to the necrotic and tumor regions themselves which can be used as predictors.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"5 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-19DOI: 10.1158/1078-0432.ccr-24-1957
Young Kwang Chae, Lucy Corthell, Sandip Pravin. Patel, Robert Edwards, Jennifer M. Scalici, Hye Sung Kim, Liam IL-Young Chung, Megan Othus, Christine M. McLeod, Helen X. Chen, Elad Sharon, Howard Streicher, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock
Background: Dual PD-1/CTLA-4 inhibition shows promise in various malignancies. The SWOG S1609 DART trial presents initial results of ipilimumab/nivolumab in vulvar cancers. Methods: DART is a prospective/open-label/multicenter (1,016 US sites)/multi-cohort phase II clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint was objective response rate [ORR, confirmed complete and partial responses (CR and PR, respectively)] per RECISTv1.1; progression-free survival (PFS), overall survival (OS), clinical benefit rate [CBR; overall response plus stable disease (SD) ≥6 months], and toxicity are secondary endpoints. Results: Sixteen evaluable patients (median age, 55.5 years; 0-6 prior therapies; no prior immunotherapy) were analyzed, all of whom had squamous cell carcinoma histology. ORR was 18.8% (3/16), CBR was 25% (4/16), and CBR plus unconfirmed PR rate was 31% (5/16); PFS was 34.1, 16.7. 15.5, 7.2 and 7.0 months for these five patients. The median PFS and OS were 2.2 and 7.6 months. The most common adverse events were diarrhea, fatigue, pruritus, anorexia, and nausea (25%, n=4 each). Grade 3-4 adverse events occurred in 25% of patients (n=4). There was 1 grade 1-2 adverse event (6.7%) that led to discontinuation, and 1 (6.7%) grade 5 death adverse event. Conclusion: Ipilimumab plus nivolumab in vulvar cancers resulted in an objective response in three out of 16 patients, all of whom had durable responses lasting over one year. Notably, two additional patients experienced durable SD and unconfirmed PR. Correlative studies to determine response and resistance markers are ongoing.
{"title":"A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609: Vulvar Cancers","authors":"Young Kwang Chae, Lucy Corthell, Sandip Pravin. Patel, Robert Edwards, Jennifer M. Scalici, Hye Sung Kim, Liam IL-Young Chung, Megan Othus, Christine M. McLeod, Helen X. Chen, Elad Sharon, Howard Streicher, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock","doi":"10.1158/1078-0432.ccr-24-1957","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1957","url":null,"abstract":"Background: Dual PD-1/CTLA-4 inhibition shows promise in various malignancies. The SWOG S1609 DART trial presents initial results of ipilimumab/nivolumab in vulvar cancers. Methods: DART is a prospective/open-label/multicenter (1,016 US sites)/multi-cohort phase II clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint was objective response rate [ORR, confirmed complete and partial responses (CR and PR, respectively)] per RECISTv1.1; progression-free survival (PFS), overall survival (OS), clinical benefit rate [CBR; overall response plus stable disease (SD) ≥6 months], and toxicity are secondary endpoints. Results: Sixteen evaluable patients (median age, 55.5 years; 0-6 prior therapies; no prior immunotherapy) were analyzed, all of whom had squamous cell carcinoma histology. ORR was 18.8% (3/16), CBR was 25% (4/16), and CBR plus unconfirmed PR rate was 31% (5/16); PFS was 34.1, 16.7. 15.5, 7.2 and 7.0 months for these five patients. The median PFS and OS were 2.2 and 7.6 months. The most common adverse events were diarrhea, fatigue, pruritus, anorexia, and nausea (25%, n=4 each). Grade 3-4 adverse events occurred in 25% of patients (n=4). There was 1 grade 1-2 adverse event (6.7%) that led to discontinuation, and 1 (6.7%) grade 5 death adverse event. Conclusion: Ipilimumab plus nivolumab in vulvar cancers resulted in an objective response in three out of 16 patients, all of whom had durable responses lasting over one year. Notably, two additional patients experienced durable SD and unconfirmed PR. Correlative studies to determine response and resistance markers are ongoing.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"108 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-19DOI: 10.1158/1078-0432.ccr-24-1553
Alejandro Rios-Hoyo, Kaitlyn Xiong, Jiawei Dai, Christina Yau, Michal Marczyk, Rolando Garcia-Milian, Denise M. Wolf, Laura A. Huppert, Rita Nanda, Gillian L. Hirst, Erin F. Cobain, Laura J. van 't Veer, Laura J. Esserman, Lajos Pusztai
Purpose: The MammaPrint prognostic assay categorizes breast cancers into high- and low-risk subgroups, and the high-risk group can be further subdivided into high 1 (MP-H1), and very high-risk high-2 (MP/H-2). The aim of this analysis was to assess clinical and molecular differences between the hormone receptor positive/HER2-negative (HR+) MP-H1, -H2, and triple negative (TN) MP-H1 and -H2 cancers. Experimental design: Pre-treatment gene expression data from 742 HER2 negative breast cancers enrolled in the I-SPY2 neoadjuvant trial was used. Prognostic risk categories were assigned using the MammaPrint assay. Transcriptional similarities across the 4 receptor and prognostic groups were assessed using principal component analyses and by identifying differentially expressed genes. We also examined pathologic complete response (pCR) rates and event-free survivals (EFS) by risk group. Results: Principal component analysis showed that HR+/MP-H2 tumors clustered with TN/MP-H2 cancers. Only 125 genes showed differential expression between the HR+/MP-H2 and TN/MP-H2 cancers while 1,465 genes were differentially expressed between HR+/MP-H2 and -H1. Gene set analysis revealed similarly high expression of cell cycle, DNA repair, and immune-infiltration related pathways in HR+/MP-H2 and TN/MP-H2 cancers. HR+/MP-H2 cancers also showed low estrogen receptor (ER)-related gene expression. pCR rates were similarly high in TN/MP-H2 and HR+/MP-H2 cancers (42% vs 30.5%, p=0.11), and MP-H2 cancers with residual cancer had similarly poor EFS regardless of ER status. Conclusions: In conclusion, HR+/MP-H2 cancers closely resemble TN breast cancers in transcriptional and clinical features and benefit from similar treatment strategies.
{"title":"Hormone Receptor Positive HER2-negative/MammaPrint High-2 Breast Cancers Closely Resemble Triple Negative Breast Cancers","authors":"Alejandro Rios-Hoyo, Kaitlyn Xiong, Jiawei Dai, Christina Yau, Michal Marczyk, Rolando Garcia-Milian, Denise M. Wolf, Laura A. Huppert, Rita Nanda, Gillian L. Hirst, Erin F. Cobain, Laura J. van 't Veer, Laura J. Esserman, Lajos Pusztai","doi":"10.1158/1078-0432.ccr-24-1553","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1553","url":null,"abstract":"Purpose: The MammaPrint prognostic assay categorizes breast cancers into high- and low-risk subgroups, and the high-risk group can be further subdivided into high 1 (MP-H1), and very high-risk high-2 (MP/H-2). The aim of this analysis was to assess clinical and molecular differences between the hormone receptor positive/HER2-negative (HR+) MP-H1, -H2, and triple negative (TN) MP-H1 and -H2 cancers. Experimental design: Pre-treatment gene expression data from 742 HER2 negative breast cancers enrolled in the I-SPY2 neoadjuvant trial was used. Prognostic risk categories were assigned using the MammaPrint assay. Transcriptional similarities across the 4 receptor and prognostic groups were assessed using principal component analyses and by identifying differentially expressed genes. We also examined pathologic complete response (pCR) rates and event-free survivals (EFS) by risk group. Results: Principal component analysis showed that HR+/MP-H2 tumors clustered with TN/MP-H2 cancers. Only 125 genes showed differential expression between the HR+/MP-H2 and TN/MP-H2 cancers while 1,465 genes were differentially expressed between HR+/MP-H2 and -H1. Gene set analysis revealed similarly high expression of cell cycle, DNA repair, and immune-infiltration related pathways in HR+/MP-H2 and TN/MP-H2 cancers. HR+/MP-H2 cancers also showed low estrogen receptor (ER)-related gene expression. pCR rates were similarly high in TN/MP-H2 and HR+/MP-H2 cancers (42% vs 30.5%, p=0.11), and MP-H2 cancers with residual cancer had similarly poor EFS regardless of ER status. Conclusions: In conclusion, HR+/MP-H2 cancers closely resemble TN breast cancers in transcriptional and clinical features and benefit from similar treatment strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"14 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-19DOI: 10.1158/1078-0432.ccr-24-1999
Angela K. Green, Qin Zhou, Alexia Iasonos, William A. Zammarrelli, Britta Weigelt, Lora H. Ellenson, Rashmi Chhetri-Long, Pooja Shah, Jade Loh, Vania Hom, Pier Selenica, Joseph Erinjeri, Iva Petkovska, Sarat Chandarlapaty, Seth Cohen, Rachel Grisham, Jason Konner, Maria M. Rubinstein, William Tew, Tiffany Troso-Sandoval, Carol Aghajanian, Vicky Makker
Purpose: Inhibition of the cyclin D-cyclin dependent kinase (CDK)4/6-INK4-retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Responses to endocrine monotherapy in advanced endometrial cancer (EC) are suboptimal, perhaps due to genomic alterations that promote estrogen receptor (ER)-independent cyclin D1-CDK4/6 activation. We hypothesized that addition of abemaciclib, a CDK4/6 kinase inhibitor, to antiestrogen therapy with fulvestrant will be an effective therapeutic strategy in patients with advanced or recurrent EC. Methods: In this phase II study, patients with advanced or recurrent EC received 150 mg of abemaciclib orally twice daily with 500 mg of fulvestrant intramuscularly monthly with a 2-week loading dose. Eligibility included ER or progesterone receptor expression ³1% by immunohistochemistry, measurable disease, £2 prior lines of chemotherapy, and £1 prior line of hormonal therapy. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Results: Twenty-seven patients initiated therapy and 25 were evaluable for efficacy. Eleven patients achieved partial response; 10 responses (91%) were in copy number-low/no specific molecular profile tumors, 1 (9%) was in a microsatellite instability-high tumor, and no responses were observed in copy number-high/TP53abnormal tumors. The ORR was 44% (90% CI, 27.0%-62.1%). Median duration of response was 15.6 months. Median progression-free survival was 9.0 months (90% CI: 1.8-20.4). The most common grade ³3 treatment-related adverse events were neutropenia (26%) and anemia (19%); no new safety signals were identified. Conclusions: The combination of abemaciclib and fulvestrant has promising activity with durable responses in advanced or recurrent EC; a randomized trial is planned.
{"title":"A Phase II Study of Fulvestrant plus Abemaciclib in Hormone Receptor-Positive Advanced or Recurrent Endometrial Cancer","authors":"Angela K. Green, Qin Zhou, Alexia Iasonos, William A. Zammarrelli, Britta Weigelt, Lora H. Ellenson, Rashmi Chhetri-Long, Pooja Shah, Jade Loh, Vania Hom, Pier Selenica, Joseph Erinjeri, Iva Petkovska, Sarat Chandarlapaty, Seth Cohen, Rachel Grisham, Jason Konner, Maria M. Rubinstein, William Tew, Tiffany Troso-Sandoval, Carol Aghajanian, Vicky Makker","doi":"10.1158/1078-0432.ccr-24-1999","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1999","url":null,"abstract":"Purpose: Inhibition of the cyclin D-cyclin dependent kinase (CDK)4/6-INK4-retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Responses to endocrine monotherapy in advanced endometrial cancer (EC) are suboptimal, perhaps due to genomic alterations that promote estrogen receptor (ER)-independent cyclin D1-CDK4/6 activation. We hypothesized that addition of abemaciclib, a CDK4/6 kinase inhibitor, to antiestrogen therapy with fulvestrant will be an effective therapeutic strategy in patients with advanced or recurrent EC. Methods: In this phase II study, patients with advanced or recurrent EC received 150 mg of abemaciclib orally twice daily with 500 mg of fulvestrant intramuscularly monthly with a 2-week loading dose. Eligibility included ER or progesterone receptor expression ³1% by immunohistochemistry, measurable disease, £2 prior lines of chemotherapy, and £1 prior line of hormonal therapy. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Results: Twenty-seven patients initiated therapy and 25 were evaluable for efficacy. Eleven patients achieved partial response; 10 responses (91%) were in copy number-low/no specific molecular profile tumors, 1 (9%) was in a microsatellite instability-high tumor, and no responses were observed in copy number-high/TP53abnormal tumors. The ORR was 44% (90% CI, 27.0%-62.1%). Median duration of response was 15.6 months. Median progression-free survival was 9.0 months (90% CI: 1.8-20.4). The most common grade ³3 treatment-related adverse events were neutropenia (26%) and anemia (19%); no new safety signals were identified. Conclusions: The combination of abemaciclib and fulvestrant has promising activity with durable responses in advanced or recurrent EC; a randomized trial is planned.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"251 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-19DOI: 10.1158/1078-0432.ccr-24-1583
Michael B. Foote, James Robert. White, Walid K. Chatila, Guillem Argilés, Steve Lu, Benoit Rousseau, Oliver Artz, Paul Johannet, Henry Walch, Mitesh Patel, Michelle F. Lamendola-Essel, David Casadevall, Somer Abdelfattah, Shrey Patel, Rona Yaeger, Andrea Cercek, Clara Montagut, Michael Berger, Nikolaus Schultz, Luis A. Diaz
Purpose: Mutational data from multiple solid and liquid biospecimens of a single patient is often integrated to track cancer evolution. However, there is no accepted framework to resolve if individual samples from the same individual share variants due to common identity versus coincidence. Experimental Design: Utilizing 8,000 patient tumors from The Cancer Genome Atlas (TCGA) across 33 cancer types, we estimated background rates of co-occurrence rates of mutations between discrete pairs of samples across cancers and by cancer type. We developed a mutational profile similarity score (MPS) that uses a large background database to produce confidence estimates that two tumors share a unique, related molecular profile. The MPS algorithm was applied to randomly paired tumor profiles, including patients who underwent repeat solid tumor biopsies sequenced with MSK-IMPACT (n=53,113). We also evaluated the MPS in sample pairs from single patients with multiple cancers (n=2,012), as well as patients with plasma and solid-tumor variant profiles (n=884 patients). Results: In unrelated tumors, nucleotide-specific variants are shared in 1.3% (cancer-type agnostic) and in 10-13% (cancer-type specific) of cases. The mutational profile similarity (MPS) method contextualized shared variants to specify whether patients had a single cancer versus multiple distinct cancers. When multiple tumors were compared from the same patient, and an initial clinicopathologic diagnosis was discordant with molecular findings, the MPS anticipated future diagnosis changes in 28% of examined cases. Conclusions: Use of a novel shared variant framework can provide information to clarify the molecular relationship between compared biospecimens with minimal required input.
{"title":"Analysis of shared variants between cancer biospecimens","authors":"Michael B. Foote, James Robert. White, Walid K. Chatila, Guillem Argilés, Steve Lu, Benoit Rousseau, Oliver Artz, Paul Johannet, Henry Walch, Mitesh Patel, Michelle F. Lamendola-Essel, David Casadevall, Somer Abdelfattah, Shrey Patel, Rona Yaeger, Andrea Cercek, Clara Montagut, Michael Berger, Nikolaus Schultz, Luis A. Diaz","doi":"10.1158/1078-0432.ccr-24-1583","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1583","url":null,"abstract":"Purpose: Mutational data from multiple solid and liquid biospecimens of a single patient is often integrated to track cancer evolution. However, there is no accepted framework to resolve if individual samples from the same individual share variants due to common identity versus coincidence. Experimental Design: Utilizing 8,000 patient tumors from The Cancer Genome Atlas (TCGA) across 33 cancer types, we estimated background rates of co-occurrence rates of mutations between discrete pairs of samples across cancers and by cancer type. We developed a mutational profile similarity score (MPS) that uses a large background database to produce confidence estimates that two tumors share a unique, related molecular profile. The MPS algorithm was applied to randomly paired tumor profiles, including patients who underwent repeat solid tumor biopsies sequenced with MSK-IMPACT (n=53,113). We also evaluated the MPS in sample pairs from single patients with multiple cancers (n=2,012), as well as patients with plasma and solid-tumor variant profiles (n=884 patients). Results: In unrelated tumors, nucleotide-specific variants are shared in 1.3% (cancer-type agnostic) and in 10-13% (cancer-type specific) of cases. The mutational profile similarity (MPS) method contextualized shared variants to specify whether patients had a single cancer versus multiple distinct cancers. When multiple tumors were compared from the same patient, and an initial clinicopathologic diagnosis was discordant with molecular findings, the MPS anticipated future diagnosis changes in 28% of examined cases. Conclusions: Use of a novel shared variant framework can provide information to clarify the molecular relationship between compared biospecimens with minimal required input.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"11 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-18DOI: 10.1158/1078-0432.CCR-24-2247
Kendra K Radtke, Brendan C Bender, Zao Li, David C Turner, Sumedha Roy, Anton Belousov, Chi-Chung Li
Cytokine release syndrome (CRS) is a common acute toxicity in T-cell therapies, including T-cell engaging bispecific antibodies (T-BiSp). Effective CRS management and prevention is crucial in T-BiSp development. Required hospitalization for 7 of the 9 approved T-BiSp and the need for clinical intervention in severe cases highlight the importance of mitigation strategies to reduce healthcare burden and improve patient outcome. In this review, we discuss the emerging evidence on CRS mitigation, management, and prediction. We cover different strategies for dose optimization, current and emerging (pre)treatment strategies, quantitative pharmacology tools employed during drug development, and biomarkers and predictive factors. Insights are gleaned on step-up dosing and formulation effects on CRS and CRS relationships with cytokine dynamics and drug levels gathered through review of T-BiSp licensing applications and emerging data from conferences and publications.
{"title":"Clinical Pharmacology of Cytokine Release Syndrome with T-cell Engaging Bispecific Antibodies: Current Insights and Drug Development Strategies.","authors":"Kendra K Radtke, Brendan C Bender, Zao Li, David C Turner, Sumedha Roy, Anton Belousov, Chi-Chung Li","doi":"10.1158/1078-0432.CCR-24-2247","DOIUrl":"10.1158/1078-0432.CCR-24-2247","url":null,"abstract":"<p><p>Cytokine release syndrome (CRS) is a common acute toxicity in T-cell therapies, including T-cell engaging bispecific antibodies (T-BiSp). Effective CRS management and prevention is crucial in T-BiSp development. Required hospitalization for 7 of the 9 approved T-BiSp and the need for clinical intervention in severe cases highlight the importance of mitigation strategies to reduce healthcare burden and improve patient outcome. In this review, we discuss the emerging evidence on CRS mitigation, management, and prediction. We cover different strategies for dose optimization, current and emerging (pre)treatment strategies, quantitative pharmacology tools employed during drug development, and biomarkers and predictive factors. Insights are gleaned on step-up dosing and formulation effects on CRS and CRS relationships with cytokine dynamics and drug levels gathered through review of T-BiSp licensing applications and emerging data from conferences and publications.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1158/1078-0432.CCR-23-3991
Silvia Stacchiotti, Silvia Martini, Sandro Pasquali, Anna M Frezza, Alessia Beretta, Stefano Percio, Mara Lecchi, Monica Tortoreto, Marta Barisella, Paola Collini, Gian Paolo Dagrada, Alessandra Merlini, Paul H Huang, Andrew Jenks, Robin L Jones, William D Tap, Matilde Ingrosso, Carlo Morosi, Silvia Brich, Claudia Giani, Paolo Verderio, Paolo G Casali, Hugh Leonard, Alessandro Gronchi, Valentina Zuco, Nadia Zaffaroni
Purpose: Epithelioid hemangioendothelioma (EHE), an ultra-rare sarcoma, poses therapeutic challenges because of limited efficacy of conventional chemotherapy in advanced cases, necessitating exploration of new treatment avenues and identification of novel aggressive biomarkers. This study aimed at (i) utilizing a patient-derived xenograft model of EHE and its associated cell line to assess the efficacy of sirolimus and (ii) analyzing two distinct patient cohorts to pinpoint circulating biomarkers of EHE aggressiveness.
Experimental design: A patient-derived xenograft model and corresponding cell line were established from a patient with advanced EHE, demonstrating consistency with the original tumor in terms of histomorphology, WWTR1::CAMTA1 fusion presence, and genomic and transcriptomic profiles. Two independent patient series were employed to investigate the association between growth/differentiation factor 15 (GDF-15) serum levels and EHE aggressiveness.
Results: ELISA analyses on EHE cell culture medium and blood from EHE-carrying mice revealed the release of GDF-15 by EHE cells. Sirolimus exhibited markedly higher antitumor activity compared with doxorubicin, concurrently reducing GDF-15 expression/release both in vivo and in vitro. This reduction was attributed to the drug-induced inhibition of phosphorylation/activation of 4E-BP1 and subsequent downregulation of the GDF-15 transcription factors ATF4 and ATF5. Blood sample analyses from two independent patient series showed a significant correlation between GDF-15 and EHE aggressiveness.
Conclusions: This study identifies GDF-15 as a novel biomarker of EHE aggressiveness and underscores the superior efficacy of sirolimus compared with doxorubicin in our experimental models. The observed inhibition of GDF-15 release by sirolimus suggests its potential as a biomarker for monitoring the drug's activity in patients.
{"title":"GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression.","authors":"Silvia Stacchiotti, Silvia Martini, Sandro Pasquali, Anna M Frezza, Alessia Beretta, Stefano Percio, Mara Lecchi, Monica Tortoreto, Marta Barisella, Paola Collini, Gian Paolo Dagrada, Alessandra Merlini, Paul H Huang, Andrew Jenks, Robin L Jones, William D Tap, Matilde Ingrosso, Carlo Morosi, Silvia Brich, Claudia Giani, Paolo Verderio, Paolo G Casali, Hugh Leonard, Alessandro Gronchi, Valentina Zuco, Nadia Zaffaroni","doi":"10.1158/1078-0432.CCR-23-3991","DOIUrl":"10.1158/1078-0432.CCR-23-3991","url":null,"abstract":"<p><strong>Purpose: </strong>Epithelioid hemangioendothelioma (EHE), an ultra-rare sarcoma, poses therapeutic challenges because of limited efficacy of conventional chemotherapy in advanced cases, necessitating exploration of new treatment avenues and identification of novel aggressive biomarkers. This study aimed at (i) utilizing a patient-derived xenograft model of EHE and its associated cell line to assess the efficacy of sirolimus and (ii) analyzing two distinct patient cohorts to pinpoint circulating biomarkers of EHE aggressiveness.</p><p><strong>Experimental design: </strong>A patient-derived xenograft model and corresponding cell line were established from a patient with advanced EHE, demonstrating consistency with the original tumor in terms of histomorphology, WWTR1::CAMTA1 fusion presence, and genomic and transcriptomic profiles. Two independent patient series were employed to investigate the association between growth/differentiation factor 15 (GDF-15) serum levels and EHE aggressiveness.</p><p><strong>Results: </strong>ELISA analyses on EHE cell culture medium and blood from EHE-carrying mice revealed the release of GDF-15 by EHE cells. Sirolimus exhibited markedly higher antitumor activity compared with doxorubicin, concurrently reducing GDF-15 expression/release both in vivo and in vitro. This reduction was attributed to the drug-induced inhibition of phosphorylation/activation of 4E-BP1 and subsequent downregulation of the GDF-15 transcription factors ATF4 and ATF5. Blood sample analyses from two independent patient series showed a significant correlation between GDF-15 and EHE aggressiveness.</p><p><strong>Conclusions: </strong>This study identifies GDF-15 as a novel biomarker of EHE aggressiveness and underscores the superior efficacy of sirolimus compared with doxorubicin in our experimental models. The observed inhibition of GDF-15 release by sirolimus suggests its potential as a biomarker for monitoring the drug's activity in patients.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5122-5137"},"PeriodicalIF":12.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11565171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1158/1078-0432.CCR-24-0362
Mikayla B Bowen, Brenda Melendez, Qian Zhang, Richard K Yang, Bryan M Fellman, Barrett C Lawson, Naomi N Adjei, Joseph Celestino, Khalida M Wani, Bhavana Singh, Diana L Urbauer, Alexander J Lazar, Karen H Lu, Jennifer A Wargo, Shannon N Westin, Melinda S Yates
Purpose: Nonsurgical treatment options are increasingly needed for endometrial atypical hyperplasia (AH) and endometrioid endometrial cancer (EEC). Despite promising initial response rates, prospective long-term data and determinants for relapse are limited.
Materials and methods: Follow-up data from patients in our prospective phase II trial of levonorgestrel intrauterine device (LIUD) for AH/G1EEC were collected from medical records. Spatial transcriptomics (Nanostring GeoMX digital spatial profiling) with in silico cell type deconvolution and pathway analyses were employed on longitudinal biopsy samples from five patients across pre-treatment, on-treatment, and relapse.
Results: Of 43 participants exhibiting initial response to LIUD, 41 had follow-up data. Sixteen (39%) experienced relapse. Clinical factors associated with shorter response duration included younger age, initial diagnosis of G1EEC, lack of response at 6 months, premenopausal status, and Hispanic ethnicity (P < 0.05), but only 6-month response status remained a significant predictor in a multivariate model (P = 0.023). LIUD increased abundance of NK cells (ΔMCP-counter score = 46.13, FDR = 0.004) and cytotoxic lymphocytes (ΔMCP-counter score = 277.67, FDR = 0.004), as well as lymphocyte cytotoxicity markers PRF1 (log2FC = 1.62, FDR = 0.025) and GZMA (log2FC = 2.47, FDR = 0.008). NK cells were reduced at relapse (ΔMCP-counter score = -55.96, FDR = 0.02). Immune-related pathways (IFNα response and TGFβ signaling) were enriched at relapse (FDR < 0.05). IDO1 expression, reflecting immune exhaustion, was upregulated at relapse (FDR < 0.05).
Conclusions: Upfront resistance and relapse after initial response to LIUD for AH/G1EEC impacts nearly half of patients, remaining a major hurdle for nonsurgical treatment of AH/G1EEC. Molecular studies evaluating longitudinal biopsies from a small cohort implicate immune mechanisms at relapse, including reversal of progestin-related immunomodulation and increased immune exhaustion. See related commentary by Johannet and Friedman, p. 5001.
{"title":"Long-Term Follow-up of Levonorgestrel Intrauterine Device for Atypical Hyperplasia and Early Endometrial Cancer Reveals Relapse Characterized by Immune Exhaustion.","authors":"Mikayla B Bowen, Brenda Melendez, Qian Zhang, Richard K Yang, Bryan M Fellman, Barrett C Lawson, Naomi N Adjei, Joseph Celestino, Khalida M Wani, Bhavana Singh, Diana L Urbauer, Alexander J Lazar, Karen H Lu, Jennifer A Wargo, Shannon N Westin, Melinda S Yates","doi":"10.1158/1078-0432.CCR-24-0362","DOIUrl":"10.1158/1078-0432.CCR-24-0362","url":null,"abstract":"<p><strong>Purpose: </strong>Nonsurgical treatment options are increasingly needed for endometrial atypical hyperplasia (AH) and endometrioid endometrial cancer (EEC). Despite promising initial response rates, prospective long-term data and determinants for relapse are limited.</p><p><strong>Materials and methods: </strong>Follow-up data from patients in our prospective phase II trial of levonorgestrel intrauterine device (LIUD) for AH/G1EEC were collected from medical records. Spatial transcriptomics (Nanostring GeoMX digital spatial profiling) with in silico cell type deconvolution and pathway analyses were employed on longitudinal biopsy samples from five patients across pre-treatment, on-treatment, and relapse.</p><p><strong>Results: </strong>Of 43 participants exhibiting initial response to LIUD, 41 had follow-up data. Sixteen (39%) experienced relapse. Clinical factors associated with shorter response duration included younger age, initial diagnosis of G1EEC, lack of response at 6 months, premenopausal status, and Hispanic ethnicity (P < 0.05), but only 6-month response status remained a significant predictor in a multivariate model (P = 0.023). LIUD increased abundance of NK cells (ΔMCP-counter score = 46.13, FDR = 0.004) and cytotoxic lymphocytes (ΔMCP-counter score = 277.67, FDR = 0.004), as well as lymphocyte cytotoxicity markers PRF1 (log2FC = 1.62, FDR = 0.025) and GZMA (log2FC = 2.47, FDR = 0.008). NK cells were reduced at relapse (ΔMCP-counter score = -55.96, FDR = 0.02). Immune-related pathways (IFNα response and TGFβ signaling) were enriched at relapse (FDR < 0.05). IDO1 expression, reflecting immune exhaustion, was upregulated at relapse (FDR < 0.05).</p><p><strong>Conclusions: </strong>Upfront resistance and relapse after initial response to LIUD for AH/G1EEC impacts nearly half of patients, remaining a major hurdle for nonsurgical treatment of AH/G1EEC. Molecular studies evaluating longitudinal biopsies from a small cohort implicate immune mechanisms at relapse, including reversal of progestin-related immunomodulation and increased immune exhaustion. See related commentary by Johannet and Friedman, p. 5001.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5073-5082"},"PeriodicalIF":12.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1158/1078-0432.CCR-24-2983
Samuel Rosner, Sydney Connor, Khaled Sanber, Marianna Zahurak, Tianbei Zhang, Isha Gurumurthy, Zhen Zeng, Brad Presson, Dipika Singh, Roni Rayes, Lavanya Sivapalan, Gavin Pereira, Zhicheng Ji, Rohit Thummalapalli, Joshua E Reuss, Stephen R Broderick, David R Jones, Julie S Deutsch, Tricia R Cottrell, Jamie Chaft, Jonathan Spicer, Janis Taube, Valsamo Anagnostou, Julie R Brahmer, Drew M Pardoll, Hongkai Ji, Patrick M Forde, Kristen A Marrone, Kellie N Smith
Purpose: Co-mutations of the KRAS and STK11 genes in advanced non-small cell lung cancer (NSCLC) are associated with immune checkpoint blockade (ICB) resistance. While neoadjuvant chemoimmunotherapy is now a standard of care treatment for resectable NSCLC, the clinical and immunologic impact of KRAS andSTK11 co-mutations in this setting are unknown.
Experimental design: We evaluated and compared recurrence-free survival of resectable KRAS-mutated NSCLC tumors, with or without co-occuring STK11 mutations, treated with neoadjuvant ICB. Single cell transcriptomics was performed on tumor-infiltrating T cells from 7 KRASmut/STK11wttumors and 6 KRASmut/STK11mut tumors.
Results: Relative to KRASmut/STK11wttumors, KRASmut/STK11mut exhibited significantly higher recurrence risk. Single-cell transcriptomics showed enhanced oxidative phosphorylation with evidence of decreased PGE-2 signaling and increased IL-2 signaling in CD8+ tumor-infiltrating lymphocytes (TIL) from KRASmut/STK11mut tumors, a finding that was mirrored in KRASwt tumors that relapsed. TIL from KRASmut/STK11mut tumors expressed high levels of molecules associated with tumor residence, including CD39 and ZNF683 (HOBIT).
Conclusions: These divergent T cell transcriptional fates suggest T cell maintenance and residence may be detrimental to anti-tumor immunity in the context of neoadjuvant ICB for resectable NSCLC, regardless of KRAS mutation status. Our work provides a basis for future investigations into the mechanisms underpinning PGE-2 and IL-2 signaling as they relate to T cell immunity to cancer and to divergent clinical outcomes in KRASmut/STK11mut NSCLC treated with neoadjuvant ICB.
{"title":"Divergent clinical and immunologic outcomes based on STK11 co-mutation status in resectable KRAS-mutant lung cancers following neoadjuvant immune checkpoint blockade.","authors":"Samuel Rosner, Sydney Connor, Khaled Sanber, Marianna Zahurak, Tianbei Zhang, Isha Gurumurthy, Zhen Zeng, Brad Presson, Dipika Singh, Roni Rayes, Lavanya Sivapalan, Gavin Pereira, Zhicheng Ji, Rohit Thummalapalli, Joshua E Reuss, Stephen R Broderick, David R Jones, Julie S Deutsch, Tricia R Cottrell, Jamie Chaft, Jonathan Spicer, Janis Taube, Valsamo Anagnostou, Julie R Brahmer, Drew M Pardoll, Hongkai Ji, Patrick M Forde, Kristen A Marrone, Kellie N Smith","doi":"10.1158/1078-0432.CCR-24-2983","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2983","url":null,"abstract":"<p><strong>Purpose: </strong>Co-mutations of the KRAS and STK11 genes in advanced non-small cell lung cancer (NSCLC) are associated with immune checkpoint blockade (ICB) resistance. While neoadjuvant chemoimmunotherapy is now a standard of care treatment for resectable NSCLC, the clinical and immunologic impact of KRAS andSTK11 co-mutations in this setting are unknown.</p><p><strong>Experimental design: </strong>We evaluated and compared recurrence-free survival of resectable KRAS-mutated NSCLC tumors, with or without co-occuring STK11 mutations, treated with neoadjuvant ICB. Single cell transcriptomics was performed on tumor-infiltrating T cells from 7 KRASmut/STK11wttumors and 6 KRASmut/STK11mut tumors.</p><p><strong>Results: </strong>Relative to KRASmut/STK11wttumors, KRASmut/STK11mut exhibited significantly higher recurrence risk. Single-cell transcriptomics showed enhanced oxidative phosphorylation with evidence of decreased PGE-2 signaling and increased IL-2 signaling in CD8+ tumor-infiltrating lymphocytes (TIL) from KRASmut/STK11mut tumors, a finding that was mirrored in KRASwt tumors that relapsed. TIL from KRASmut/STK11mut tumors expressed high levels of molecules associated with tumor residence, including CD39 and ZNF683 (HOBIT).</p><p><strong>Conclusions: </strong>These divergent T cell transcriptional fates suggest T cell maintenance and residence may be detrimental to anti-tumor immunity in the context of neoadjuvant ICB for resectable NSCLC, regardless of KRAS mutation status. Our work provides a basis for future investigations into the mechanisms underpinning PGE-2 and IL-2 signaling as they relate to T cell immunity to cancer and to divergent clinical outcomes in KRASmut/STK11mut NSCLC treated with neoadjuvant ICB.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1158/1078-0432.CCR-24-1782
David S Moura, Jesus M Lopez-Marti, Iva Benesova, Carlos de Andrea, Davide di Lernia, Serena Lacerenza, Jose L Mondaza-Hernandez, Marta Martin-Ruiz, Marta Ramirez-Calvo, Giovanni Grignani, Javier Martinez-Trufero, Andres Redondo, Claudia Valverde, Silvia Stacchiotti, Antonio Lopez-Pousa, José A Lopez-Guerrero, Antonio Gutierrez, Victor Encinas-Tobajas, Nadia Hindi, Dario Sangiolo, Jose A Lopez-Martin, Zuzana Ozaniak Strizova, Javier Martin-Broto
Purpose: The IMMUNOSARC trial combined an antiangiogenic agent (sunitinib) with a PD1 inhibitor (nivolumab) in advanced sarcomas. Here, we present the first correlative studies of the soft-tissue sarcoma cohort enrolled in this trial.
Experimental design: Formalin-fixed paraffin-embedded and peripheral blood samples were collected at baseline and week 13. Formalin-fixed paraffin-embedded samples were used for transcriptomics and multiplex immunofluorescence, whereas peripheral blood samples were used for multiplexed immunoassays. Flow cytometry and Luminex assays were performed to validate translational findings in tumor-isolated cells and peripheral blood mononuclear cells derived from patients.
Results: The density of intratumoral CD8+ T cells, measured by multiplexed immunophenotyping, was significantly increased after treatment. This augment was accompanied by the dynamic significant increase in the gene expressions of CD86, CHI3L1, CXCL10, CXCL9, LAG3, and VCAM1 and the decrease in the expression levels of NR4A1. In peripheral blood, 12 proteins were significantly modulated by treatment at week 13. A score integrating the dynamic expression of the 7 genes and the 12 soluble factors separated 2 groups with distinct progression-free survival (PFS): 4.1 months [95% confidence interval, 3.5-not reached (NR)] versus 17 months (95% confidence interval, 12.0-NR), P = 0.014. This molecular score was predictive of PFS when applied to the normalized data determined in the baseline samples.
Conclusions: Treatment with sunitinib and nivolumab inflamed the sarcoma microenvironment, increasing CD8+ T-cell density and the expression of several genes/proteins with relevance in the response to PD1 inhibitors. A molecular signature identified two groups of patients with distinct PFS for the combination of antiangiogenics plus PD1 inhibitor therapy.
目的：IMMUNOSARC 试验将抗血管生成药物（舒尼替尼）与 PD-1 抑制剂（尼维单抗）联合用于晚期肉瘤。在此，我们介绍了对参与该试验的STS队列进行的首次相关研究：实验设计：在基线和第 13 周收集福尔马林固定石蜡包埋样本（FFPE）和外周血样本。FFPE用于转录组学和多重免疫荧光，外周血样本用于多重免疫测定。流式细胞术和 Luminex 检测用于验证肿瘤分离细胞和患者外周血单核细胞的转化结果：结果：通过多重免疫分型法测定，瘤内 CD8+ T 细胞的密度在治疗后显著增加。伴随这种增加的是 CD86、CHI3L1、CXCL10、CXCL9、LAG3 和 VCAM1 基因表达的动态显著增加，以及 NR4A1 表达水平的下降。在外周血中，有 12 种蛋白质在 W13 期受到治疗的显著调节。综合 7 个基因和 12 个可溶性因子的动态表达的评分将无进展生存期（PFS）不同的两组患者区分开来：4.1个月（95% CI 3.5-NR） vs 17个月（95% CI 12.0 - NR），P=0.014。当应用基线样本中确定的归一化数据时，该分子评分可预测PFS：结论：舒尼替尼和尼维单抗的治疗会使肉瘤微环境发炎，增加CD8+ T细胞密度以及与PD-1抑制剂反应相关的几种基因/蛋白的表达。分子特征识别出了两组患者，他们在联合使用抗血管生成药和PD-1抑制剂后的PFS各不相同。
{"title":"Predictive and Dynamic Signature for Antiangiogenics in Combination with a PD1 Inhibitor in Soft-Tissue Sarcoma: Correlative Studies Linked to the IMMUNOSARC Trial.","authors":"David S Moura, Jesus M Lopez-Marti, Iva Benesova, Carlos de Andrea, Davide di Lernia, Serena Lacerenza, Jose L Mondaza-Hernandez, Marta Martin-Ruiz, Marta Ramirez-Calvo, Giovanni Grignani, Javier Martinez-Trufero, Andres Redondo, Claudia Valverde, Silvia Stacchiotti, Antonio Lopez-Pousa, José A Lopez-Guerrero, Antonio Gutierrez, Victor Encinas-Tobajas, Nadia Hindi, Dario Sangiolo, Jose A Lopez-Martin, Zuzana Ozaniak Strizova, Javier Martin-Broto","doi":"10.1158/1078-0432.CCR-24-1782","DOIUrl":"10.1158/1078-0432.CCR-24-1782","url":null,"abstract":"<p><strong>Purpose: </strong>The IMMUNOSARC trial combined an antiangiogenic agent (sunitinib) with a PD1 inhibitor (nivolumab) in advanced sarcomas. Here, we present the first correlative studies of the soft-tissue sarcoma cohort enrolled in this trial.</p><p><strong>Experimental design: </strong>Formalin-fixed paraffin-embedded and peripheral blood samples were collected at baseline and week 13. Formalin-fixed paraffin-embedded samples were used for transcriptomics and multiplex immunofluorescence, whereas peripheral blood samples were used for multiplexed immunoassays. Flow cytometry and Luminex assays were performed to validate translational findings in tumor-isolated cells and peripheral blood mononuclear cells derived from patients.</p><p><strong>Results: </strong>The density of intratumoral CD8+ T cells, measured by multiplexed immunophenotyping, was significantly increased after treatment. This augment was accompanied by the dynamic significant increase in the gene expressions of CD86, CHI3L1, CXCL10, CXCL9, LAG3, and VCAM1 and the decrease in the expression levels of NR4A1. In peripheral blood, 12 proteins were significantly modulated by treatment at week 13. A score integrating the dynamic expression of the 7 genes and the 12 soluble factors separated 2 groups with distinct progression-free survival (PFS): 4.1 months [95% confidence interval, 3.5-not reached (NR)] versus 17 months (95% confidence interval, 12.0-NR), P = 0.014. This molecular score was predictive of PFS when applied to the normalized data determined in the baseline samples.</p><p><strong>Conclusions: </strong>Treatment with sunitinib and nivolumab inflamed the sarcoma microenvironment, increasing CD8+ T-cell density and the expression of several genes/proteins with relevance in the response to PD1 inhibitors. A molecular signature identified two groups of patients with distinct PFS for the combination of antiangiogenics plus PD1 inhibitor therapy.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5192-5206"},"PeriodicalIF":10.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：