Pub Date : 2024-10-01Epub Date: 2024-10-02DOI: 10.1200/PO.24.00209
Karin Holmsten, Gottfrid Sjödahl, Johan Abrahamsson, Carina Bernardo, Pontus Eriksson, Mattias Höglund, Fredrik Liedberg, Anders Ullén
Purpose: Cisplatin-based combination chemotherapy (CHT) is standard of care in metastatic urothelial cancer (mUC); however, no predictive molecular biomarkers are available for clinical use. The aim of this study was to investigate the impact of molecular subtypes in relation to treatment response and survival in patients with mUC treated with first-line CHT.
Patients and methods: Molecular subtype classification according to the Lund Taxonomy (LundTax) was performed by tumor transcriptomic profiling and immunostaining in a retrospective cohort. Molecular subtypes were investigated in relation to the primary end point overall response rate (ORR) and secondary end points progression-free survival (PFS) and overall survival (OS). Differential gene expression and association to treatment response were explored.
Results: Ninety-five patients with mUC were classified into urothelial-like (Uro, 43%), genomically unstable (GU, 26%), basal squamous-like (Ba/Sq, 20%), mesenchymal-like (Mes-like, 8%), and small cell neuroendocrine-like (Sc/NE, 3%) subtypes. Patients with Mes-like tumors had lower ORR (14%) compared with Uro (70%), GU (77%), Ba/Sq (75%), and Sc/NE (67%; odds ratio, 0.06 [95% CI, 0.01 to 0.54], P = .012). Furthermore, patients with Mes-like tumors had significantly shorter PFS (hazard ratio [HR], 5.18 [95% CI, 2.28 to 11.76], P < .001) and OS (HR, 3.19 [95% CI, 1.45 to 7.03], P = .004). Patients with Uro and GU showed the longest survival. In responders, an enrichment of downregulated stromal- and immune-related genes was seen. Downregulation of interferon-induced transmembrane protein 2 was associated with increased ORR and improved OS.
Conclusion: This study identifies different CHT responses by LundTax molecular subtypes in patients with mUC, where the Mes-like subtype was associated with lower response rate and shorter survival.
{"title":"Molecular Subtypes Are Associated With Clinical Benefit in Cisplatin-Treated Metastatic Urothelial Cancer Patients.","authors":"Karin Holmsten, Gottfrid Sjödahl, Johan Abrahamsson, Carina Bernardo, Pontus Eriksson, Mattias Höglund, Fredrik Liedberg, Anders Ullén","doi":"10.1200/PO.24.00209","DOIUrl":"10.1200/PO.24.00209","url":null,"abstract":"<p><strong>Purpose: </strong>Cisplatin-based combination chemotherapy (CHT) is standard of care in metastatic urothelial cancer (mUC); however, no predictive molecular biomarkers are available for clinical use. The aim of this study was to investigate the impact of molecular subtypes in relation to treatment response and survival in patients with mUC treated with first-line CHT.</p><p><strong>Patients and methods: </strong>Molecular subtype classification according to the Lund Taxonomy (LundTax) was performed by tumor transcriptomic profiling and immunostaining in a retrospective cohort. Molecular subtypes were investigated in relation to the primary end point overall response rate (ORR) and secondary end points progression-free survival (PFS) and overall survival (OS). Differential gene expression and association to treatment response were explored.</p><p><strong>Results: </strong>Ninety-five patients with mUC were classified into urothelial-like (Uro, 43%), genomically unstable (GU, 26%), basal squamous-like (Ba/Sq, 20%), mesenchymal-like (Mes-like, 8%), and small cell neuroendocrine-like (Sc/NE, 3%) subtypes. Patients with Mes-like tumors had lower ORR (14%) compared with Uro (70%), GU (77%), Ba/Sq (75%), and Sc/NE (67%; odds ratio, 0.06 [95% CI, 0.01 to 0.54], <i>P</i> = .012). Furthermore, patients with Mes-like tumors had significantly shorter PFS (hazard ratio [HR], 5.18 [95% CI, 2.28 to 11.76], <i>P</i> < .001) and OS (HR, 3.19 [95% CI, 1.45 to 7.03], <i>P</i> = .004). Patients with Uro and GU showed the longest survival. In responders, an enrichment of downregulated stromal- and immune-related genes was seen. Downregulation of interferon-induced transmembrane protein 2 was associated with increased ORR and improved OS.</p><p><strong>Conclusion: </strong>This study identifies different CHT responses by LundTax molecular subtypes in patients with mUC, where the Mes-like subtype was associated with lower response rate and shorter survival.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142347062","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}
Purpose: The clinical and research FPG500 program (ClinicalTrials.gov identifier: NCT06020625) is currently ongoing at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS to tailor matched targeted therapies (MTTs) according to biomarkers predictive of response identified by comprehensive genome profiling (CGP).
Materials and methods: The non-small cell lung cancer (NSCLC) cohort results from the FPG500 program are outlined. CGP was performed by TruSight Oncology 500 High Throughput (TSO500HT) assay or Oncomine Focus Assay plus Archer's FusionPlex Lung Panel according to tumor cell content and DNA/RNA quantity. Relevant issues for Molecular Tumor Board (MTB) evaluation included uncommon genomic findings, evaluation for off-label therapies, uncertain result confirmation, and variants of suspect germline origin requiring genetic counseling. Progression-free survival (PFS) and overall survival (OS) for the enrolled patients were assessed using Kaplan-Meier analysis.
Results: In 2022, 283 patients with NSCLC were considered for sequencing, with 93% meeting eligibility criteria. TSO500HT sequencing was conducted in 76% of patients. Follow-up data were obtained for 187 patients, among whom 81% received treatment. Potential driver alterations were identified in 59% of patients, with 41% receiving MTT: 25% were prescribed approved MTTs, whereas 16% gained access to experimental drugs post-MTB evaluation; of note, 18% did not receive any MTT because the regimen was not yet reimbursed in our country. Median PFS and OS varied among treatment groups, with standard chemotherapy/immunotherapy at 7.7 and 10.7 months, approved tyrosine kinase inhibitors at 18.8 and 23.9 months, and MTT post-MTB discussion at 14 and 23.4 months, respectively.
Conclusion: The early data of the FPG program (NSCLC cohort) support the implementation of CGP and MTB in clinical practice to grant access to patients harboring actionable molecular alterations to the most effective and individualized available treatment options, thus improving their survival outcomes.
{"title":"Impact of Comprehensive Genome Profiling on the Management of Advanced Non-Small Cell Lung Cancer: Preliminary Results From the Lung Cancer Cohort of the FPG500 Program.","authors":"Antonio Vitale, Luca Mastrantoni, Jacopo Russo, Flavia Giacomini, Diana Giannarelli, Simona Duranti, Emanuele Vita, Camilla Nero, Ettore D'Argento, Tina Pasciuto, Luciano Giacò, Mariantonietta Di Salvatore, Arianna Panfili, Alessio Stefani, Alessandra Cancellieri, Filippo Lococo, Elisa De Paolis, Vanina Livi, Gennaro Daniele, Rocco Trisolini, Angelo Minucci, Stefano Margaritora, Domenica Lorusso, Nicola Normanno, Giovanni Scambia, Giampaolo Tortora, Emilio Bria","doi":"10.1200/PO.24.00297","DOIUrl":"https://doi.org/10.1200/PO.24.00297","url":null,"abstract":"<p><strong>Purpose: </strong>The clinical and research FPG500 program (ClinicalTrials.gov identifier: NCT06020625) is currently ongoing at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS to tailor matched targeted therapies (MTTs) according to biomarkers predictive of response identified by comprehensive genome profiling (CGP).</p><p><strong>Materials and methods: </strong>The non-small cell lung cancer (NSCLC) cohort results from the FPG500 program are outlined. CGP was performed by TruSight Oncology 500 High Throughput (TSO500HT) assay or Oncomine Focus Assay plus Archer's FusionPlex Lung Panel according to tumor cell content and DNA/RNA quantity. Relevant issues for Molecular Tumor Board (MTB) evaluation included uncommon genomic findings, evaluation for off-label therapies, uncertain result confirmation, and variants of suspect germline origin requiring genetic counseling. Progression-free survival (PFS) and overall survival (OS) for the enrolled patients were assessed using Kaplan-Meier analysis.</p><p><strong>Results: </strong>In 2022, 283 patients with NSCLC were considered for sequencing, with 93% meeting eligibility criteria. TSO500HT sequencing was conducted in 76% of patients. Follow-up data were obtained for 187 patients, among whom 81% received treatment. Potential driver alterations were identified in 59% of patients, with 41% receiving MTT: 25% were prescribed approved MTTs, whereas 16% gained access to experimental drugs post-MTB evaluation; of note, 18% did not receive any MTT because the regimen was not yet reimbursed in our country. Median PFS and OS varied among treatment groups, with standard chemotherapy/immunotherapy at 7.7 and 10.7 months, approved tyrosine kinase inhibitors at 18.8 and 23.9 months, and MTT post-MTB discussion at 14 and 23.4 months, respectively.</p><p><strong>Conclusion: </strong>The early data of the FPG program (NSCLC cohort) support the implementation of CGP and MTB in clinical practice to grant access to patients harboring actionable molecular alterations to the most effective and individualized available treatment options, thus improving their survival outcomes.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390683","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}
Pub Date : 2024-10-01Epub Date: 2024-10-11DOI: 10.1200/PO.24.00176
Pieterjan Perremans, Filip Van Herpe, Gertjan Rasschaert, Johan Van Ongeval, Jochen Decaestecker, Baki Topal, Gabriele Bislenghi, Albert Wolthuis, Halit Topal, Christophe Deroose, Eric Van Cutsem, Jeroen Dekervel
Case series describing excellent outcomes for patients with dMMR GI cancer after resection of a single progressive lesion under immunotherapy.
系列病例描述了 dMMR 消化道癌症患者在免疫疗法下切除单个进展性病变后的良好疗效。
{"title":"Salvage Surgery for Unifocal Progressive Metastatic Mismatch Repair-Deficient GI Cancer Responding to Immune Checkpoint Inhibition.","authors":"Pieterjan Perremans, Filip Van Herpe, Gertjan Rasschaert, Johan Van Ongeval, Jochen Decaestecker, Baki Topal, Gabriele Bislenghi, Albert Wolthuis, Halit Topal, Christophe Deroose, Eric Van Cutsem, Jeroen Dekervel","doi":"10.1200/PO.24.00176","DOIUrl":"https://doi.org/10.1200/PO.24.00176","url":null,"abstract":"<p><p>Case series describing excellent outcomes for patients with dMMR GI cancer after resection of a single progressive lesion under immunotherapy.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406410","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}
Pub Date : 2024-10-01Epub Date: 2024-10-11DOI: 10.1200/PO.24.00254
Maria Fatteh, Jaime Wehr, Katerina Karaindrou, Rena R Xian, Christopher Gocke, Ming-Tseh Lin, Dana Petry, Kala Visvanathan, Rima Couzi, Cesar Santa Maria, Vered Stearns, Jessica J Tao, Valsamo Anagnostou, Jenna V Canzoniero
Polyclonal convergent evolution to PARPi resistance in a patient with metastatic breast cancer with gPALB2.
一名患有 gPALB2 的转移性乳腺癌患者对 PARPi 耐药性的多克隆趋同进化。
{"title":"Poly (ADP-ribose) Polymerase Inhibitor Resistance Driven by Emergence of Polyclonal Mutations With Convergent Evolution: A Molecular Tumor Board Discussion.","authors":"Maria Fatteh, Jaime Wehr, Katerina Karaindrou, Rena R Xian, Christopher Gocke, Ming-Tseh Lin, Dana Petry, Kala Visvanathan, Rima Couzi, Cesar Santa Maria, Vered Stearns, Jessica J Tao, Valsamo Anagnostou, Jenna V Canzoniero","doi":"10.1200/PO.24.00254","DOIUrl":"10.1200/PO.24.00254","url":null,"abstract":"<p><p>Polyclonal convergent evolution to PARPi resistance in a patient with metastatic breast cancer with gPALB2.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11485209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406409","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}
Pub Date : 2024-10-01Epub Date: 2024-10-21DOI: 10.1200/PO-24-00585
Vrutangkumar Shah, Daniel Muzyka, Carolyn Guidarelli, Kristen Sowlasky, Fay Horak, Kerri Winters-Stone
{"title":"Reply to E. Shash.","authors":"Vrutangkumar Shah, Daniel Muzyka, Carolyn Guidarelli, Kristen Sowlasky, Fay Horak, Kerri Winters-Stone","doi":"10.1200/PO-24-00585","DOIUrl":"https://doi.org/10.1200/PO-24-00585","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142465973","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}
Pub Date : 2024-10-01Epub Date: 2024-10-16DOI: 10.1200/PO-24-00676
{"title":"Erratum: Pharmacodynamic Activity of [<sup>18</sup>F]-Fluorthanatrace Poly(ADP-ribose) Polymerase Positron Emission Tomography in Patients With BRCA<i>1</i>/<i>2</i>-Mutated Breast Cancer Receiving Talazoparib.","authors":"","doi":"10.1200/PO-24-00676","DOIUrl":"https://doi.org/10.1200/PO-24-00676","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142465970","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}
Purpose: Robotic-assisted proctectomy (RAP) has emerged as the predominant surgical approach for patients with rectal cancer in recent years; although good postoperative patient recovery with accurate prediction is a guarantee of adaptive surveillance management, there is still a lack of easy-to-use prognostic tools and risk scores designed specifically for those patients undergoing RAP.
Methods: This study used the electronic health records of 506 RAP participants, including a National Specialist Center for da Vinci Robotic Colorectal Surgery (NSCVRCS) meta cohort, and an independent external validation Sun Yat-sen Memorial Hospital cohort. In the NSCVRCS meta cohort, patients were divided into a discovery cohort (70%, n = 268), where the best-fit model was applied to model our prediction system, RAP-AIscore. Subsequently, an internal validation process for RAP-AIscore was conducted using a replication cohort (30%, n = 116). The study designed and implemented a large-scale artificial intelligence (AI) hybrid framework to identify the best strategy for building a survival assessment system, the RAP-AIscore, from 132 potential modeling scenarios through a combination of iterative cross-validation, Monte Carlo cross-validation, and bootstrap resampling. The 10 variables most relevant to clinical interpretability were identified on the basis of the AI hybrid optimal model values, which helps provide reliable prognostic survival guidance for new patients.
Results: The consistent evaluation of discrimination, calibration, generalization, and prognostic value across cohorts reaffirmed the accuracy and robust extrapolation capability of this system. The 10 feature variables most associated with clinical interpretability on the basis of Shapley values were identified, facilitating reliable prognostic survival guidance for new patients.
Conclusion: This study introduces a promising and informative tool, the RAP-AIscore, which can be explained through nomograms for interpreting clinical outcomes. It facilitates postoperative risk stratification management and enhances clinical management of prognosis for RAP patients.
{"title":"Artificial Intelligence Hybrid Survival Assessment System for Robot-Assisted Proctectomy: A Retrospective Cohort Study.","authors":"Shiqian Zhang, Ge Zhang, Ming Wang, Song-Bin Guo, Fuqi Wang, Yun Li, Kaisaierjiang Kadier, Zhaokai Zhou, Pengpeng Zhang, Hao Chi, Chuchu Zhang, Quanbo Zhou, Pin Lyu, Shuaiya Zhao, Shuaixi Yang, Weitang Yuan","doi":"10.1200/PO.24.00089","DOIUrl":"https://doi.org/10.1200/PO.24.00089","url":null,"abstract":"<p><strong>Purpose: </strong>Robotic-assisted proctectomy (RAP) has emerged as the predominant surgical approach for patients with rectal cancer in recent years; although good postoperative patient recovery with accurate prediction is a guarantee of adaptive surveillance management, there is still a lack of easy-to-use prognostic tools and risk scores designed specifically for those patients undergoing RAP.</p><p><strong>Methods: </strong>This study used the electronic health records of 506 RAP participants, including a National Specialist Center for da Vinci Robotic Colorectal Surgery (NSCVRCS) meta cohort, and an independent external validation Sun Yat-sen Memorial Hospital cohort. In the NSCVRCS meta cohort, patients were divided into a discovery cohort (70%, n = 268), where the best-fit model was applied to model our prediction system, RAP-AIscore. Subsequently, an internal validation process for RAP-AIscore was conducted using a replication cohort (30%, n = 116). The study designed and implemented a large-scale artificial intelligence (AI) hybrid framework to identify the best strategy for building a survival assessment system, the RAP-AIscore, from 132 potential modeling scenarios through a combination of iterative cross-validation, Monte Carlo cross-validation, and bootstrap resampling. The 10 variables most relevant to clinical interpretability were identified on the basis of the AI hybrid optimal model values, which helps provide reliable prognostic survival guidance for new patients.</p><p><strong>Results: </strong>The consistent evaluation of discrimination, calibration, generalization, and prognostic value across cohorts reaffirmed the accuracy and robust extrapolation capability of this system. The 10 feature variables most associated with clinical interpretability on the basis of Shapley values were identified, facilitating reliable prognostic survival guidance for new patients.</p><p><strong>Conclusion: </strong>This study introduces a promising and informative tool, the RAP-AIscore, which can be explained through nomograms for interpreting clinical outcomes. It facilitates postoperative risk stratification management and enhances clinical management of prognosis for RAP patients.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142465968","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}
Pub Date : 2024-10-01Epub Date: 2024-10-30DOI: 10.1200/PO-24-00478
Jacqueline Lammert, Tobias Dreyer, Sonja Mathes, Leonid Kuligin, Kai J Borm, Ulrich A Schatz, Marion Kiechle, Alisa M Lörsch, Johannes Jung, Sebastian Lange, Nicole Pfarr, Anna Durner, Kristina Schwamborn, Christof Winter, Dyke Ferber, Jakob Nikolas Kather, Carolin Mogler, Anna L Illert, Maximilian Tschochohei
Purpose: Rapidly expanding medical literature challenges oncologists seeking targeted cancer therapies. General-purpose large language models (LLMs) lack domain-specific knowledge, limiting their clinical utility. This study introduces the LLM system Medical Evidence Retrieval and Data Integration for Tailored Healthcare (MEREDITH), designed to support treatment recommendations in precision oncology. Built on Google's Gemini Pro LLM, MEREDITH uses retrieval-augmented generation and chain of thought.
Methods: We evaluated MEREDITH on 10 publicly available fictional oncology cases with iterative feedback from a molecular tumor board (MTB) at a major German cancer center. Initially limited to PubMed-indexed literature (draft system), MEREDITH was enhanced to incorporate clinical studies on drug response within the specific tumor type, trial databases, drug approval status, and oncologic guidelines. The MTB provided a benchmark with manually curated treatment recommendations and assessed the clinical relevance of LLM-generated options (qualitative assessment). We measured semantic cosine similarity between LLM suggestions and clinician responses (quantitative assessment).
Results: MEREDITH identified a broader range of treatment options (median 4) compared with MTB experts (median 2). These options included therapies on the basis of preclinical data and combination treatments, expanding the treatment possibilities for consideration by the MTB. This broader approach was achieved by incorporating a curated medical data set that contextualized molecular targetability. Mirroring the approach MTB experts use to evaluate MTB cases improved the LLM's ability to generate relevant suggestions. This is supported by high concordance between LLM suggestions and expert recommendations (94.7% for the enhanced system) and a significant increase in semantic similarity from the draft to the enhanced system (from 0.71 to 0.76, P = .01).
Conclusion: Expert feedback and domain-specific data augment LLM performance. Future research should investigate responsible LLM integration into real-world clinical workflows.
{"title":"Expert-Guided Large Language Models for Clinical Decision Support in Precision Oncology.","authors":"Jacqueline Lammert, Tobias Dreyer, Sonja Mathes, Leonid Kuligin, Kai J Borm, Ulrich A Schatz, Marion Kiechle, Alisa M Lörsch, Johannes Jung, Sebastian Lange, Nicole Pfarr, Anna Durner, Kristina Schwamborn, Christof Winter, Dyke Ferber, Jakob Nikolas Kather, Carolin Mogler, Anna L Illert, Maximilian Tschochohei","doi":"10.1200/PO-24-00478","DOIUrl":"https://doi.org/10.1200/PO-24-00478","url":null,"abstract":"<p><strong>Purpose: </strong>Rapidly expanding medical literature challenges oncologists seeking targeted cancer therapies. General-purpose large language models (LLMs) lack domain-specific knowledge, limiting their clinical utility. This study introduces the LLM system Medical Evidence Retrieval and Data Integration for Tailored Healthcare (MEREDITH), designed to support treatment recommendations in precision oncology. Built on <i>Google's Gemini Pro</i> LLM, MEREDITH uses <i>retrieval-augmented generation</i> and <i>chain of thought</i>.</p><p><strong>Methods: </strong>We evaluated MEREDITH on 10 publicly available fictional oncology cases with iterative feedback from a molecular tumor board (MTB) at a major German cancer center. Initially limited to <i>PubMed</i>-indexed literature (draft system), MEREDITH was enhanced to incorporate clinical studies on drug response within the specific tumor type, trial databases, drug approval status, and oncologic guidelines. The MTB provided a benchmark with manually curated treatment recommendations and assessed the clinical relevance of LLM-generated options (qualitative assessment). We measured semantic cosine similarity between LLM suggestions and clinician responses (quantitative assessment).</p><p><strong>Results: </strong>MEREDITH identified a broader range of treatment options (median 4) compared with MTB experts (median 2). These options included therapies on the basis of preclinical data and combination treatments, expanding the treatment possibilities for consideration by the MTB. This broader approach was achieved by incorporating a curated medical data set that contextualized molecular targetability. Mirroring the approach MTB experts use to evaluate MTB cases improved the LLM's ability to generate relevant suggestions. This is supported by high concordance between LLM suggestions and expert recommendations (94.7% for the enhanced system) and a significant increase in semantic similarity from the draft to the enhanced system (from 0.71 to 0.76, <i>P</i> = .01).</p><p><strong>Conclusion: </strong>Expert feedback and domain-specific data augment LLM performance. Future research should investigate responsible LLM integration into real-world clinical workflows.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545621","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}
Imatinib may be a useful targeted agent for patients with advanced gastric adenocarcinoma who have KIT mutations.
伊马替尼可能是一种有效的靶向药物,可用于KIT突变的晚期胃腺癌患者。
{"title":"Response to Imatinib in a Patient With Gastric Adenocarcinoma With <i>KIT</i> Q556_K558 In-Frame Deletion: A Case Report.","authors":"Kiichiro Ninomiya, Daisuke Ennishi, Kunio Okamoto, Midori Ando, Satoko Nakamura, Shuta Tomida, Yoshiyuki Ayada, Go Makimoto, Eiki Ichihara, Natsuko Okita, Shinichi Toyooka, Yoshinobu Maeda, Masahiro Tabata","doi":"10.1200/PO.24.00228","DOIUrl":"10.1200/PO.24.00228","url":null,"abstract":"<p><p>Imatinib may be a useful targeted agent for patients with advanced gastric adenocarcinoma who have KIT mutations.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142287725","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}
Harry E Fuentes Bayne, Pashtoon M Kasi, Li Ma, Lowell L Hart, Jenna Wong, David R Spigel, Catherine A Schnabel, James A Reeves, Thorvardur R Halfdanarson, Kai Treuner, F Anthony Greco
Purpose: Cancer of unknown primary (CUP) is a syndrome comprising metastatic cancers without a clinically identified primary site. Although patients with CUP have an unfavorable prognosis, treatment with site-specific therapies guided by clinical features, standard pathology, and molecular assays can improve overall survival. The 92-gene assay (CancerTYPE ID) is a gene expression-based classifier that helps identify the tissue of origin for metastatic cancers with unknown or uncertain diagnoses. This study reports the frequency of selected molecular aberrations of oncogenes, including KRAS, IDH1/2, BRCA1/2, and BRAF, in patients with CUP in the MOSAIC database to highlight potential treatment options.
Methods: MOSAIC is a database of patients with CUP submitted for CancerTYPE ID testing and NeoTYPE biomarker testing. Tumor biopsy samples were analyzed by CancerTYPE ID for tumor type identification and further tested for molecular aberrations of oncogenes, including KRAS, IDH1/2, BRCA1/2, and BRAF.
Results: CancerTYPE ID identified a specific tumor type in 92.5% (2,929 of 3,168) of CUP cases in the MOSAIC database. The most commonly identified histological type was adenocarcinoma (75.4%), with pancreaticobiliary being the most common molecularly diagnosed cancer (24.9%). Aberrations in KRAS, IDH1/2, BRCA, and BRAF genes were identified in 18.8% (n = 597) of biopsies. A cancer-specific US Food and Drug Administration (FDA)-approved or investigational targeted therapy was potentially available for 24.6% (n = 147) of these patients.
Conclusion: This retrospective analysis supports incorporating CancerTYPE ID into the evaluation for patients with CUP to help determine the tissue of origin and identify actionable genetic alterations. This approach may allow more patients with CUP to benefit from site-specific FDA-approved targeted therapies or enrollment into clinical trials.
目的:原发性不明癌症(CUP)是一种由转移性癌症组成的综合征,临床上无法确定其原发部位。虽然 CUP 患者预后不良,但在临床特征、标准病理学和分子检测的指导下采用特定部位疗法可提高总生存率。92 个基因检测(CancerTYPE ID)是一种基于基因表达的分类器,有助于确定诊断不明或不确定的转移性癌症的原发组织。本研究报告了MOSAIC数据库中CUP患者的部分癌基因分子畸变频率,包括KRAS、IDH1/2、BRCA1/2和BRAF,以突出潜在的治疗方案:MOSAIC是一个CUP患者数据库,这些患者已提交CancerTYPE ID检测和NeoTYPE生物标记物检测。通过CancerTYPE ID分析肿瘤活检样本以确定肿瘤类型,并进一步检测KRAS、IDH1/2、BRCA1/2和BRAF等癌基因的分子畸变:CancerTYPE ID 在 MOSAIC 数据库中 92.5% 的 CUP 病例(3168 例中的 2929 例)中识别出了特定的肿瘤类型。最常见的组织学类型是腺癌(75.4%),胰胆管癌是最常见的分子诊断癌症(24.9%)。在18.8%(n = 597)的活检中发现了KRAS、IDH1/2、BRCA和BRAF基因的畸变。这些患者中有 24.6%(n = 147)可能接受了美国食品药品管理局(FDA)批准的癌症特异性靶向治疗或研究性靶向治疗:这项回顾性分析支持将 CancerTYPE ID 纳入 CUP 患者的评估中,以帮助确定原发组织并识别可操作的基因改变。这种方法可以让更多的 CUP 患者从 FDA 批准的特定部位靶向疗法或临床试验中获益。
{"title":"Personalized Therapy Selection by Integration of Molecular Cancer Classification by the 92-Gene Assay and Tumor Profiling in Patients With Cancer of Unknown Primary.","authors":"Harry E Fuentes Bayne, Pashtoon M Kasi, Li Ma, Lowell L Hart, Jenna Wong, David R Spigel, Catherine A Schnabel, James A Reeves, Thorvardur R Halfdanarson, Kai Treuner, F Anthony Greco","doi":"10.1200/PO.24.00191","DOIUrl":"10.1200/PO.24.00191","url":null,"abstract":"<p><strong>Purpose: </strong>Cancer of unknown primary (CUP) is a syndrome comprising metastatic cancers without a clinically identified primary site. Although patients with CUP have an unfavorable prognosis, treatment with site-specific therapies guided by clinical features, standard pathology, and molecular assays can improve overall survival. The 92-gene assay (CancerTYPE ID) is a gene expression-based classifier that helps identify the tissue of origin for metastatic cancers with unknown or uncertain diagnoses. This study reports the frequency of selected molecular aberrations of oncogenes, including <i>KRAS</i>, <i>IDH1/2</i>, <i>BRCA1/2</i>, and <i>BRAF</i>, in patients with CUP in the MOSAIC database to highlight potential treatment options.</p><p><strong>Methods: </strong>MOSAIC is a database of patients with CUP submitted for CancerTYPE ID testing and NeoTYPE biomarker testing. Tumor biopsy samples were analyzed by CancerTYPE ID for tumor type identification and further tested for molecular aberrations of oncogenes, including <i>KRAS</i>, <i>IDH1/2</i>, <i>BRCA1/2</i>, and <i>BRAF</i>.</p><p><strong>Results: </strong>CancerTYPE ID identified a specific tumor type in 92.5% (2,929 of 3,168) of CUP cases in the MOSAIC database. The most commonly identified histological type was adenocarcinoma (75.4%), with pancreaticobiliary being the most common molecularly diagnosed cancer (24.9%). Aberrations in <i>KRAS</i>, <i>IDH1/2</i>, <i>BRCA</i>, and <i>BRAF</i> genes were identified in 18.8% (n = 597) of biopsies. A cancer-specific US Food and Drug Administration (FDA)-approved or investigational targeted therapy was potentially available for 24.6% (n = 147) of these patients.</p><p><strong>Conclusion: </strong>This retrospective analysis supports incorporating CancerTYPE ID into the evaluation for patients with CUP to help determine the tissue of origin and identify actionable genetic alterations. This approach may allow more patients with CUP to benefit from site-specific FDA-approved targeted therapies or enrollment into clinical trials.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11382827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132749","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}