JCO precision oncology最新文献

{"title":"Identification of a Suitable Subgroup for Radiation Dose Escalation in Definitive Concurrent Chemoradiation Therapy for Nonmetastatic Esophageal Squamous Cell Carcinoma.","authors":"Po-Chien Shen, Wei-Kai Chuang, Yang-Hong Dai, Cheng-Hsiang Lo, Yu-Fu Su, Jen-Fu Yang, Wen-Yen Huang, Chun-Shu Lin, Chia-Feng Lu","doi":"10.1200/PO-24-00555","DOIUrl":"https://doi.org/10.1200/PO-24-00555","url":null,"abstract":"<p><strong>Purpose: </strong>Dose escalation may only be suitable for some patients with esophageal cancer (EC) undergoing concurrent chemoradiotherapy (CCRT). This study aimed to identify specific subgroups of patients for whom dose escalation was most beneficial.</p><p><strong>Materials and methods: </strong>Between January 2008 and December 2022, 187 patients with EC underwent CCRT; 94 patients received high-dose (HD) radiotherapy (RT; >64.8 Gy), and 93 patients received low-dose (LD) RT. We developed a model on the basis of clinical and radiomic features to compare the predicted survival probabilities of patients with EC receiving HD- and LD-RT. Patients suitable for HD-RT could be identified. We validated our findings of a suitable HD subgroup by evaluating the actual overall survival (OS) across different subgroups in the testing set.</p><p><strong>Results: </strong>Our model comprised HD and LD submodels, each predicting patient survival under their respective RT doses. The HD and LD submodels achieved concordance indexes of 0.78 and 0.75 in their respective testing sets. The average areas under the receiver operating characteristic curve over years 1-3 were 0.890 and 0.807 in the HD and LD testing sets, respectively. By comparing patients' predicted survival under HD- and LD-RT in the model, we classified the patients in the testing set into the HD-suitable (HDS) subgroup and the HD-unsuitable subgroup. In the subgroup analysis, HD-RT led to a better OS benefit for the identified HDS subgroup compared with LD-RT (<i>P</i> = .014). Among the HD-treated patients, the HDS subgroup showed better OS than did patients identified as unsuitable (<i>P</i> < .001).</p><p><strong>Conclusion: </strong>We identified a suitable subgroup of patients with EC who might benefit from HD-RT. This model could aid clinicians in prescribing RT doses.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400555"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785555","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}

{"title":"Influence of Epithelial-Mesenchymal Transition on Risk of Relapse and Outcome to Eribulin or Cyclin-Dependent Kinase Inhibitors in Metastatic Breast Cancer.","authors":"Arlene Chan, Jespal Gill, HuiJun Chih, Sarah Christine Elisabeth Wright, Natali Vasilevski, Pieter Johan Adam Eichhorn","doi":"10.1200/PO.24.00274","DOIUrl":"10.1200/PO.24.00274","url":null,"abstract":"<p><strong>Purpose: </strong>The presence of epithelial-mesenchymal transition (EMT) in breast cancer (BC) cells has been linked to worse prognosis and may influence response to systemic treatment. We explored the effect of EMT in tumor samples of patients with metastatic BC on disease-free interval and overall survival in those patients receiving eribulin or cyclin-dependent kinase 4/6 inhibitors (CDK4/6i).</p><p><strong>Materials and methods: </strong>Key inclusion criteria included available archived primary BC tissue and, where available, matched metastatic biopsy. Patients received eribulin and/or a CDK4/6i in the metastatic setting. Specimens were assessed for biomarkers by immunohistochemistry (CDH1, AE1/3, VIM, CDH2, ZEB1, pSMAD2, and SMAD4) and gene expression by droplet digital polymerase chain reaction (<i>CDH1</i>, <i>CDH2</i>, <i>SNAI1</i> & <i>2</i>, <i>TWIST1</i>, <i>VIM</i>, <i>PTEN</i>, and <i>ZEB1</i> & <i>2</i>).</p><p><strong>Results: </strong>Between 2002 and 2020, 127 patients were included (95 early-stage disease at diagnosis with metastatic relapse, 32 de novo metastatic disease). In metastatic samples, presence of ZEB1 overexpression was associated with shorter time to recurrence (48.1 months shorter; <i>P</i> = .003), with pSMAD2 overexpression suggesting clinical significance of 52.0 months shorter; <i>P</i> = .01. High gene expression levels for SNAIL1, <i>TWIST1</i>, and <i>PTEN</i> in the primary BC were associated with significantly longer survival in patients who received eribulin (<i>P</i> < .05); high <i>VIM</i> was associated with a clinically relevant trend toward shorter survival after a CDK4/6i (<i>P</i> = .013).</p><p><strong>Conclusion: </strong>We demonstrate in our exploratory study that biomarkers involved in the process of EMT could have a prognostic impact in a cohort of patients with BC uniformly treated and with long-term follow-up. Genes known to be involved in EMT were associated with improved eribulin efficacy, while suggesting a poorer outcome with CDK4/6i.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400274"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11634087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789468","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}

{"title":"Assessing Nectin-4 as a Predictive Biomarker in Urothelial Carcinoma and Other Genitourinary Malignancies.","authors":"Zeynep Irem Ozay, Chadi Hage Chehade, Neeraj Agarwal, Umang Swami","doi":"10.1200/PO-24-00766","DOIUrl":"https://doi.org/10.1200/PO-24-00766","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400766"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853342","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}

{"title":"Erratum: Tumor Characteristics Associated With Preoperatively Detectable Tumor-Informed Circulating Tumor DNA in Patients With Renal Masses Suspicious for Renal Cell Carcinoma.","authors":"","doi":"10.1200/PO-24-00733","DOIUrl":"https://doi.org/10.1200/PO-24-00733","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400733"},"PeriodicalIF":5.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582370","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}

{"title":"Updated Survival Follow-Up for Phase Ib Trial of the Histone Deacetylase Inhibitor Abexinostat With Pazopanib in Patients With Solid Tumor Malignancies.","authors":"Erica S Tsang, Rahul R Aggarwal, Emily K Bergsland, Susan Calabrese, Alexandrine Rozie, Sibapriya Chaudhuri, Mallika S Dhawan, Nela Pawlowska, Jennifer Grabowsky, Scott Thomas, Pamela N Munster","doi":"10.1200/PO.24.00328","DOIUrl":"10.1200/PO.24.00328","url":null,"abstract":"<p><strong>Purpose: </strong>Histone deacetylase (HDAC) inhibition downregulates hypoxia-inducible factor-1α and modulates multiple metabolomic pathways relevant in cancer. Here we report a potential novel biomarker to predict exceptional responders (>3 years) in patients receiving HDAC and vascular endothelial growth factor (VEGF) inhibition.</p><p><strong>Patients and methods: </strong>Patients with solid tumor malignancies were enrolled in this phase Ib trial of abexinostat (4/7 ×21 days) and pazopanib (28/28 days), with a dose expansion in renal cell carcinoma (RCC). Plasma was analyzed for metabolomics and peripheral blood mononuclear cells (PBMCs) for VEGF and HDAC2 expression levels.</p><p><strong>Results: </strong>Fifty-one patients were enrolled: n = 36 patients in dose escalation and n = 15 in dose expansion. After the initial report in 2017, six patients had remained on study: four with RCC and one each with medullary thyroid and thymic neuroendocrine carcinoma. One patient with RCC remains on treatment for >11 years after progression on five systemic therapies. Overall, the median duration of therapy measured 5.6 (1-133) months. The median duration of therapy in exceptional responders measured 44.1 (39.8-133+) months. The median overall survival in patients with high PBMC HDAC2 expression versus low HDAC2 was 32.3 versus 9.2 months (<i>P</i> = .004) for all patients and 43.3 versus 25.1 months for patients with RCC (<i>P</i> = .09). Exceptional responders had lower kynurenine levels both pre- and post-treatment (<i>P</i> = .002, <i>P</i> < .001, respectively). HDAC2 and kynurenine expression levels were inversely correlated (<i>P</i> = .02).</p><p><strong>Conclusion: </strong>Abexinostat added to pazopanib shows extended tolerability and long-term responses and survival. PBMC HDAC2 levels, the abexinostat target, are relevant predictors of response. In addition, metabolomic assessment points to kynurenine as a predictor for exceptional response to combined VEGF plus HDAC inhibition.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400328"},"PeriodicalIF":5.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604540","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}

{"title":"DNA Methylation Classes of Stage II and III Primary Melanomas and Their Clinical and Prognostic Significance.","authors":"Kathleen Conway, Sharon N Edmiston, Amanda Vondras, Allison Reiner, David L Corcoran, Ronglai Shen, Eloise A Parrish, Honglin Hao, Lan Lin, Jessica M Kenney, Gbemisola Ilelaboye, Caroline E Kostrzewa, Pei Fen Kuan, Klaus J Busam, Cecilia Lezcano, Tim K Lee, Eva Hernando, Paul B Googe, David W Ollila, Stergios Moschos, Ivan Gorlov, Christopher I Amos, Marc S Ernstoff, Anne E Cust, James S Wilmott, Richard A Scolyer, Graham J Mann, Ismael A Vergara, Jennifer Ko, Judy R Rees, Shaofeng Yan, Eduardo Nagore, Marcus Bosenberg, Bonnie Gould Rothberg, Iman Osman, Jeffrey E Lee, Yvonne Saenger, Paul Bogner, Cheryl L Thompson, Meg Gerstenblith, Sheri L Holmen, Pauline Funchain, Elise Brunsgaard, Natalie D Depcik-Smith, Li Luo, Tawny Boyce, Irene Orlow, Colin B Begg, Marianne Berwick, Nancy E Thomas","doi":"10.1200/PO-24-00375","DOIUrl":"10.1200/PO-24-00375","url":null,"abstract":"<p><strong>Purpose: </strong>Patients with stage II and III cutaneous primary melanoma vary considerably in their risk of melanoma-related death. We explore the ability of methylation profiling to distinguish primary melanoma methylation classes and their associations with clinicopathologic characteristics and survival.</p><p><strong>Materials and methods: </strong>InterMEL is a retrospective case-control study that assembled primary cutaneous melanomas from American Joint Committee on Cancer (AJCC) 8th edition stage II and III patients diagnosed between 1998 and 2015 in the United States and Australia. Cases are patients who died of melanoma within 5 years from original diagnosis. Controls survived longer than 5 years without evidence of melanoma recurrence or relapse. Methylation classes, distinguished by consensus clustering of 850K methylation data, were evaluated for their clinicopathologic characteristics, 5-year survival status, and differentially methylated gene sets.</p><p><strong>Results: </strong>Among 422 InterMEL melanomas, consensus clustering revealed three primary melanoma methylation classes (MethylClasses): a CpG island methylator phenotype (CIMP) class, an intermediate methylation (IM) class, and a low methylation (LM) class. CIMP and IM were associated with higher AJCC stage (both <i>P</i> = .002), Breslow thickness (CIMP <i>P</i> = .002; IM <i>P</i> = .006), and mitotic index (both <i>P</i> < .001) compared with LM, while IM had higher N stage than CIMP (<i>P</i> = .01) and LM (<i>P</i> = .007). CIMP and IM had a 2-fold higher likelihood of 5-year death from melanoma than LM (CIMP odds ratio [OR], 2.16 [95% CI, 1.18 to 3.96]; IM OR, 2.00 [95% CI, 1.12 to 3.58]) in a multivariable model adjusted for age, sex, log Breslow thickness, ulceration, mitotic index, and N stage. Despite more extensive CpG island hypermethylation in CIMP, CIMP and IM shared similar patterns of differential methylation and gene set enrichment compared with LM.</p><p><strong>Conclusion: </strong>Melanoma MethylClasses may provide clinical value in predicting 5-year death from melanoma among patients with primary melanoma independent of other clinicopathologic factors.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400375"},"PeriodicalIF":5.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11737429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604533","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}

{"title":"Neo-wt-<i>RAS</i> in ctDNA: Is It Worth Using Anti-EGFR Therapies?","authors":"Pasquale F Innominato, Abdoulaye Karaboué, Francis A Lévi","doi":"10.1200/PO-24-00628","DOIUrl":"https://doi.org/10.1200/PO-24-00628","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400628"},"PeriodicalIF":5.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604537","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}

{"title":"KRASG12D-Mutated Metastatic Colorectal Cancer: Clinical, Molecular, Immunologic, and Prognostic Features of a New Emerging Targeted Alteration.","authors":"Roberto Moretto, Daniele Rossini, Sabina Murgioni, Paolo Ciracì, Vincenzo Nasca, Marco Maria Germani, Maria Alessandra Calegari, Guglielmo Vetere, Rossana Intini, Ada Taravella, Vittorio Studiale, Chiara Boccaccio, Alessandro Passardi, Emiliano Tamburini, Alberto Zaniboni, Lisa Salvatore, Filippo Pietrantonio, Sara Lonardi, Gianluca Masi, Chiara Cremolini","doi":"10.1200/PO.24.00329","DOIUrl":"https://doi.org/10.1200/PO.24.00329","url":null,"abstract":"<p><strong>Purpose: </strong>KRASG12D mutation (mut) occurs in about 10%-12% of metastatic colorectal cancer (mCRC). Recently, novel KRASG12D inhibitors have been developed and are currently under investigation in phase I/II clinical trials in solid tumors including mCRC. We aimed at performing a comprehensive characterization of clinical, molecular, immunologic, and prognostic features of KRASG12D-mutated mCRC to inform the design and the interpretation of future trials.</p><p><strong>Methods: </strong>We performed a pooled analysis of phase III TRIBE and TRIBE2 studies comparing 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/bevacizumab (bev) to doublets (5-fluorouracil, leucovorin, and oxaliplatin or 5-fluorouracil, leucovorin, and irinotecan)/bev.</p><p><strong>Results: </strong>One hundred and thirty-six (16%) of 854 patients with available KRASG12D mutational status were KRASG12D mutated. KRASG12D-mutated patients had more frequently right-sided primary tumor and were less likely to present liver-only metastases with respect to other RAS mutated and all-wild-type (wt) patients. Compared with the BRAFV600E-mutated group, KRASG12D-mutated patients had more frequently left-sided primary tumor, resected primary tumor at the time of diagnosis, and Eastern Cooperative Oncology Group performance status 0. KRASG12D-mutated patients had better prognosis than BRAFV600E-mutated and worse prognosis than all wt patients. No prognostic difference was evident between KRASG12D mut and other <i>RAS</i> mut patients overall or according to other specific <i>KRAS</i> or <i>NRAS</i> hotspot mutations. No interaction effect was observed between KRASG12D mut and the benefit provided by FOLFOXIRI/bev compared with doublets/bev. <i>PIK3CA</i> mut were reported more frequently among KRASG12D-mutated tumors compared with both other <i>RAS</i> mut and all wt.</p><p><strong>Conclusion: </strong>A detail estimation of KRASG12D mut mCRC patients' characteristics and expected outcomes may be useful when planning future studies in this subgroup. The high prevalence of PI3K/PTEN/Akt pathway activating alterations may affect the efficacy of targeted strategies.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400329"},"PeriodicalIF":5.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604534","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}

{"title":"DNA Damage Response Alterations Predict for Neoadjuvant Chemotherapy Sensitivity in Muscle-Invasive Bladder Cancer: A Correlative Analysis of the SWOG S1314 Trial.","authors":"Gopa Iyer, Catherine M Tangen, Michal Sarfaty, Ashley M Regazzi, I-Ling Lee, Megan Fong, Woonyoung Choi, Colin P N Dinney, Thomas W Flaig, Ian M Thompson, Seth P Lerner, David J McConkey, Jonathan E Rosenberg","doi":"10.1200/PO.24.00287","DOIUrl":"https://doi.org/10.1200/PO.24.00287","url":null,"abstract":"<p><strong>Purpose: </strong>Alterations in DNA damage response (DDR) genes, including <i>ERCC2</i>, have been correlated with response to neoadjuvant cisplatin-based chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC). The SWOG 1314 (S1314) trial enrolled patients with MIBC who received one of two NAC regimens followed by radical cystectomy. We examined the prevalence of DDR alterations in NAC responders versus nonresponders and correlated DDR alteration status with response.</p><p><strong>Methods: </strong>Pretreatment tumor specimens from 179 evaluable patients underwent next-generation sequencing (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets assay). Associations were determined between any or only deleterious alterations within nine predefined DDR genes, or any alterations in <i>ERCC2</i>, and progression-free survival (PFS) and overall survival using Cox regression, and, in a subset of evaluable patients, pathologic response (complete response, pT0, or downstaging to <pT2) using logistic regression, adjusting for clinical stage and performance status.</p><p><strong>Results: </strong>Deleterious DDR alterations were detected in 41 (23%) of 179 patients. Of the 151 patients evaluable for pathologic response, patients with deleterious DDR alterations (n = 39) demonstrated a higher pathologic response rate than those without (odds ratio [OR], 3.24 [95% CI, 1.51 to 6.94]; <i>P</i> = .003). In 24 <i>ERCC2</i>-mutant patients, the OR for pT0 was 3.33 (95% CI, 1.35 to 8.22; <i>P</i> = .009) and for <pT2 was 2.33 (95% CI, 0.92 to 5.89; <i>P</i> = .073). The association between deleterious DDR alterations and PFS provided an estimate of hazard ratio, 0.54 (95% CI, 0.29 to 1.01; <i>P</i> = .053).</p><p><strong>Conclusion: </strong>Deleterious DDR alterations were associated with pathologic response following NAC in S1314. Functional validation of <i>ERCC2</i> and other DDR alterations is underway to help refine such alterations as biomarkers of NAC in patients with bladder cancer.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400287"},"PeriodicalIF":5.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582365","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}

{"title":"Personalized Medicine in Histiocytic Disorders: Novel Targets in Patients Without MAPK Alterations.","authors":"Katherine E R Smith, Aldo A Acosta-Medina, Surendra Dasari, Wasantha Ranatunga, Karen L Rech, Aishwarya Ravindran, Jason R Young, Patrick W McGarrah, Gordon J Ruan, Saurabh S Zanwar, Jenny J Li, Julio C Sartori-Valinotti, Jessica N Snider, Thomas E Witzig, Gaurav Goyal, Ronald S Go, Jithma P Abeykoon","doi":"10.1200/PO-24-00471","DOIUrl":"10.1200/PO-24-00471","url":null,"abstract":"<p><strong>Purpose: </strong>BRAF and MEK inhibitors are standard treatments in histiocytic disorders, such as Erdheim-Chester disease (ECD). Some patients lack MAPK-pathway alterations, making these treatments less effective.</p><p><strong>Methods: </strong>We describe three patients with histiocytic disorders who have novel non-MAPK pathway alterations. These alterations were studied through genomic and in silico analyses when applicable, then treated with off-label medications rationally selected on the basis of genomic alterations.</p><p><strong>Results: </strong>Patient 1 had rapidly progressive ECD involving the CNS. A CSF1R in-frame deletion (p.S560_P566del) was identified, and in silico modeling predicted a gain-of-function mutation. This alteration was targeted with pexidartinib, which led to a clinical complete response (CR) within 2 months, and a partial response (PR) on imaging after 3 months. After 15 months, the disease became resistant to pexidartinib and transformed to histiocytic sarcoma. Patient 2 has skin-only involvement of a xanthogranuloma disorder. A KIF5B-FGFR1 fusion was identified on RNA sequencing and targeted with pemigatinib. At 24 months of follow-up, she remains in a clinical PR. Patient 3 has ECD involving the bone marrow, gastrointestinal tract, and subcutaneous tissues. A MEF2C-FLT3 fusion was identified and targeted with sorafenib. He achieved a clinical CR and radiographic PR within 3 months, which has continued for 30 months.</p><p><strong>Conclusion: </strong>We report three patients with histiocytic disorders harboring novel alterations who had sustained responses to off-label kinase inhibitors specific to their histiocytic disorder. Pathogenic variants outside of the MAPK pathway, including variants of unknown significant, may be targeted with readily available small molecules.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400471"},"PeriodicalIF":5.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693018","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}