JCO precision oncology最新文献

{"title":"Clinical and Preclinical Activity of EGFR Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer Harboring <i>BRAF</i> Class 3 Mutations.","authors":"Alessandro Di Federico, Stefania Angelicola, Mariateresa Frascino, Irene Siracusa, Beatrice Bisanti, Francesca Ruzzi, Maria Sofia Semprini, Hugo De Jonge, Andrea De Giglio, Francesca Sperandi, Stefano Brocchi, Barbara Melotti, Francesca Giunchi, Elisa Gruppioni, Annalisa Altimari, Pier-Luigi Lollini, Andrea Ardizzoni, Arianna Palladini, Francesco Gelsomino","doi":"10.1200/PO.24.00240","DOIUrl":"10.1200/PO.24.00240","url":null,"abstract":"<p><strong>Purpose: </strong>Patients with tumors harboring <i>BRAF</i> class 3 mutations lack targeted therapies. These mutations are characterized by low/absent BRAF kinase domain activation and are believed to amplify already active RAS signaling, potentially triggered by receptor tyrosine kinases like EGFR.</p><p><strong>Materials and methods: </strong>Two patients with <i>BRAF</i> class 3-mutated metastatic non-small-cell lung cancer (NSCLC) were treated with erlotinib at our Institution after failure of standard therapies. Two cell lines were established from patients with <i>BRAF</i> class 3-mutated NSCLC, and their sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs) was assessed using <i>EGFR-</i>mutated, <i>BRAF</i> class 1 and 2-mutated, and <i>KRAS</i>-mutated NSCLC cell lines as controls.</p><p><strong>Results: </strong>Patient 1, a 60-year-old male with BRAF^D594N-mutated NSCLC, achieved complete response to erlotinib after progression on first- and second-line chemotherapy. Patient 2, a 60-year-old female with BRAF^D594G-mutated NSCLC, achieved partial response to erlotinib after progression on first-line chemoimmunotherapy. High baseline phosphorylated EGFR values and reduced EGFR activation following erlotinib were observed in <i>BRAF</i> class 3-mutated and <i>EGFR</i>-mutated cell lines, but not in <i>BRAF</i> class 1-mutated, <i>BRAF</i> class 2-mutated, or <i>KRAS</i>-mutated lines. Erlotinib inhibited 2-dimensional growth in <i>BRAF</i> class 3-mutated cell lines (IC₅₀ 6.33 and 7.11 µM) and in the <i>BRAF</i> class 2-mutated cell line (IC₅₀ 5.51 µM), albeit at higher concentrations than in <i>EGFR</i>-mutated lines, whereas it showed no effect on <i>BRAF</i> class 1-mutated (IC₅₀, >25 µM) or <i>KRAS</i>-mutated (IC₅₀, >25 µM) lines. These findings were corroborated by 3-dimensional and sphere formation assays. In the Cancer Cell Line Encyclopedia, <i>BRAF</i> class 3-mutated NSCLC cell lines showed greater sensitivity to EGFR-TKIs compared with <i>BRAF</i> class 2-mutated and <i>KRAS</i>-mutated lines.</p><p><strong>Conclusion: </strong><i>BRAF</i> class 3 mutations in NSCLC may identify a novel targetable population sensitive to EGFR-TKIs.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400240"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785532","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":"Cancer-Control Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer With <i>BRCA</i> Gene or Tumor Suppressor Mutations Undergoing 177-Lutetium Prostate-Specific Membrane Antigen Radioligand Therapy.","authors":"Mike Wenzel, Florestan Koll, Benedikt Hoeh, Clara Humke, Henning Reis, Peter Wild, Thomas Steuber, Markus Graefen, Derya Tilki, Amir Sabet, Daniel Gröner, Felix K H Chun, Philipp Mandel","doi":"10.1200/PO-24-00645","DOIUrl":"https://doi.org/10.1200/PO-24-00645","url":null,"abstract":"<p><strong>Purpose: </strong>Several tumor gene mutations are known for metastatic castration-resistant prostate cancer (mCRPC). The individual response to 177-lutetium prostate specific membrane antigen radioligand therapy (Lu-PSMA) is under current investigation regarding the genomic profile of patients with mCRPC.</p><p><strong>Materials and methods: </strong>We relied on the FRAMCAP database and compared progression-free survival (PFS) and overall survival (OS) rates of patients with mCRPC with breast cancer-related antigen (<i>BRCA</i>) or tumor suppressor gene mutations (<i>TP53</i>, <i>PTEN</i>, <i>RB1</i>). Specifically, subgroup analyses were performed for patients with Lu-PSMA-treated mCRPC.</p><p><strong>Results: </strong>Of 194 patients with mCRPC, 22% was <i>BRCA1/2</i> versus 14% <i>PTEN/TP53/RB1</i> versus 63% without one of these mutations. Patients with no mutation harbored a significantly lower Gleason score of 8-10, relative to <i>BRCA</i> and <i>PTEN/TP53/RB1</i> patients. In PFS analyses of first-line mCRPC, no difference between all three groups was observed, whereas the median OS differed significantly with 46.3 versus 48.7 versus 95.4 months for <i>BRCA</i> versus <i>PTEN/TP53/RB1</i> versus no mutated patients (<i>P</i> < .05). In univariable Cox regression models, BRCA-mutated patients were at higher risk of death (hazard ratio, 2.57; <i>P</i> < .01), whereas <i>PTEN/TP53/RB1</i> patients were not (<i>P</i> = .4). Of 87 patients with Lu-PSMA-treated mCRPC, significant differences in PFS and OS were observed (both <i>P</i> ≤ .02). In univariable and multivariable Cox regression models, BRCA-mutated Lu-PSMA patients were at higher risk of death, whereas <i>PTEN/TP53/RB1</i> patients had similar outcomes as no mutated patients.</p><p><strong>Conclusion: </strong>In real-world setting, substantially lower OS in mCRPC is observed for <i>BRCA</i>- and <i>PTEN/TP53/RB1</i>-mutated patients, whereas no difference in first-line PFS could be computed. In Lu-PSMA-treated patients, worst outcomes were observed for <i>BRCA</i> patients.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400645"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789465","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":"Anti-KRAS G12C and Anti-EGFR Rechallenge in Chemotherapy-Refractory <i>KRAS</i> G12C-Mutated Colorectal Cancer: A Case Report.","authors":"Linda Morris, Leontios Pappas, Aditya Pandey, Harshabad Singh, Samuel Klempner, Bennett Caughey","doi":"10.1200/PO-24-00547","DOIUrl":"https://doi.org/10.1200/PO-24-00547","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400547"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853339","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":"Longitudinal Testing of Circulating Tumor DNA in Patients With Metastatic Renal Cell Carcinoma.","authors":"Arnab Basu, Cherry Au, Ajitha Kommalapati, Hyndavi Kandala, Sumedha Sudhaman, Tamara Mahmood, Carcia Carson, Natalia Pajak, Punashi Dutta, Mark Calhoun, Meenakshi Malhotra, Adam C ElNaggar, Minetta C Liu, James Ferguson Iii, Charles Peyton, Soroush Rais-Bahrami, Alan Tan","doi":"10.1200/PO-24-00667","DOIUrl":"10.1200/PO-24-00667","url":null,"abstract":"<p><strong>Purpose: </strong>Tumor-informed circulating tumor DNA (ctDNA) has shown promise as a biomarker for treatment response monitoring (TRM) in a variety of tumor types, with the potential to improve clinical outcomes. We evaluated ctDNA status and dynamics during surveillance and as part of TRM with clinical outcomes in both patients with clear cell renal cell carcinoma (ccRCC) and non-clear cell renal cell carcinoma (nccRCC) treated with standard-of-care immunotherapy or targeted therapy regimens.</p><p><strong>Methods: </strong>This was a multicenter retrospective analysis of real-world data obtained from commercial ctDNA testing (Signatera, Natera, Inc) in patients with metastatic RCC. Clinical data were collected on International Metastatic RCC Database Consortium (IMDC) risk category, pathologic subtype, and grade.</p><p><strong>Results: </strong>The cohort comprised 92 patients (490 plasma samples) including both clear cell and non-clear cell histological subtypes (ccRCC: 79.3%; nccRCC: 14.1%; unclassified: 6.5%). Most of the patients belonged to the IMDC intermediate-risk category (75%, 69/92). Median follow-up was 10 months (range, 4.2-25.8). ctDNA dynamics were assessed in 56 patients on treatment, and ctDNA status was analyzed in the surveillance cohort (n = 32 patients). Serial ctDNA negativity or clearance correlated with improved progression-free survival (PFS) compared with those who became or were persistently ctDNA positive on therapy (hazard ratio [HR], 3.2; <i>P</i> = .012). In the surveillance cohort, patients with positive ctDNA longitudinally experienced significantly inferior PFS (HR, 18; <i>P</i> = .00026) compared with those who were serially negative.</p><p><strong>Conclusion: </strong>Collectively, we show that serial ctDNA monitoring provides prognostic information for patients undergoing treatment or surveillance, and our findings demonstrate high concordance between ctDNA status/dynamics and subsequent clinical outcomes.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400667"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853431","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":"Phase II Study of Defactinib (VS6063) in Patients With Tumors With <i>NF2</i> Loss: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol U.","authors":"Marjorie G Zauderer, Opeyemi Jegede, David M Jackman, James A Zwiebel, Robert J Gray, Victoria Wang, Lisa M McShane, Larry V Rubinstein, David R Patton, P Mickey Williams, Stanley R Hamilton, Naoko Takebe, Raymond Huang, Jose A Carrillo, Andrew J Brenner, James V Tricoli, Barbara A Conley, Carlos L Arteaga, Lyndsay N Harris, Peter J O'Dwyer, Alice P Chen, Keith T Flaherty","doi":"10.1200/PO.24.00327","DOIUrl":"10.1200/PO.24.00327","url":null,"abstract":"<p><strong>Purpose: </strong>The NCI-MATCH trial assigned patients with solid tumors, lymphomas, or multiple myeloma to targeted therapies on the basis of identified genetic alterations from tumor biopsies. In preclinical models, <i>neurofibromatosis 2</i> (<i>NF2</i>)-inactivated tumors display sensitivity to focal adhesion kinase (FAK) inhibition. The EAY131-U subprotocol evaluated the efficacy of defactinib, a FAK inhibitor, in patients with <i>NF2</i>-altered tumors.</p><p><strong>Methods: </strong>Patients whose tumors harbored an inactivating <i>NF2</i> mutation on next-generation sequencing were assigned to subprotocol U. Defactinib 400 mg was given orally twice a day until progression or intolerable toxicity. The primary end point was objective response rate (ORR), secondary end points included toxicity, progression-free survival (PFS), and 6-month PFS.</p><p><strong>Results: </strong>Of 5,548 patients with sufficient tissue for genomic analysis, 57 patients were found to have <i>NF2</i> alterations. Thirty-five patients ultimately enrolled and 33 were treated, with one not having central confirmation and two ineligible for outcome analysis. All patients had received previous treatment, with 52% having received three or more previous lines of therapy. The most common treatment-related toxicities were fatigue (36%), nausea (33%), and hyperbilirubinemia (27%), with 27% of patients having grade 3 toxicities. Median follow-up was 35.9 months with an ORR of 3% from one partial response in a patient with choroid meningioma. Among the 12 patients (40%) with a best response of stable disease, eight demonstrated some tumor shrinkage. Median PFS was 1.9 months, and six patients achieved a PFS >5.5 months. No correlation was identified between clinical outcomes and tumor histology or specific <i>NF2</i> genotype.</p><p><strong>Conclusion: </strong>This protocol did not meet its prespecified primary end point. Defactinib monotherapy had limited clinical activity in this cohort of previously treated patients with solid tumors exhibiting <i>NF2</i> loss.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400327"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853435","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":"<i>KRAS</i> Variants Are Associated With Survival Outcomes and Genomic Alterations in Biliary Tract Cancers.","authors":"Rebecca Gelfer, Aiste Gulla, Hannah L Kalvin, Yi Song, James Harding, Ghassan K Abou-Alfa, Eileen M O'Reilly, Wungki Park, Rohit Chandwani, Alice Wei, Peter Kingham, Jeffrey Drebin, Vinod Balachandran, Michael D'Angelica, Kevin Soares, Mithat Gonen, William R Jarnagin","doi":"10.1200/PO.24.00263","DOIUrl":"10.1200/PO.24.00263","url":null,"abstract":"<p><strong>Purpose: </strong><i>KRAS</i> variants are associated with poor outcomes in biliary tract cancers (BTCs). This study assesses the prevalence of <i>KRAS</i> variants and their association with survival and recurrence in patients with intrahepatic cholangiocarcinoma (IHC), extrahepatic cholangiocarcinoma (EHC), and gallbladder adenocarcinoma (GB).</p><p><strong>Methods: </strong>In this cross-sectional, single-institution study at Memorial Sloan Kettering, tumors from 985 patients treated between 2004 and 2022 with IHC, EHC, and GB who underwent either curative-intent resection or were treated with chemotherapy for unresectable disease were used for targeted sequencing.</p><p><strong>Results: </strong>Of the 985 patients sequenced, 15% had a <i>KRAS</i> mutation. Five hundred and seventy-two had unresectable disease (n = 395 IHC, n = 71 EHC, n = 106 GB) and 413 were treated with curative-intent resection (n = 175 IHC, n = 119 EHC, and n = 119 GB). Median follow-up time was 18 months (IQR, 11-31). <i>KRAS G12D</i> mutations were most common in IHC (38%) and EHC (37%) tumors. Mutations in <i>SF3B1</i> co-occurred with mutant <i>KRAS</i> in IHC and EHC, with comutant resectable patients having worse survival after adjusting for tumor type (hazard ratio [HR], 4.04 [95% CI, 1.45 to 11.2]; <i>P</i> = .007). <i>KRAS G12</i> mutations were associated with worse survival in patients with IHC compared with wild-type (WT) or other <i>KRAS</i> mutations, regardless of resection status (unresectable <i>P</i> < .001, resectable <i>P</i> = .011). After adjusting for clinical covariates, <i>KRAS</i> G12 mutations remained a prognostic indicator for patients with IHC compared with WT (HR, 1.99 [95% CI, 1.41 to 2.80]; <i>P</i> < .001).</p><p><strong>Conclusion: </strong>The adverse impact of <i>KRAS</i> mutations in BTC is driven by G12 alterations in patients with IHC regardless of resection status, which was not observed in GB or EHC. There are unique comutational partners in distinct BTC subsets. These differences have important clinical implications in the era of KRAS-targeted therapeutics.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400263"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789437","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":"Prevalence and Distribution of Unexpected Actionable Germline Pathogenic Variants Identified on Broad-Based Multigene Panel Testing Among Patients With Cancer.","authors":"Kara K Landry, Michael J DeSarno, Lindsay Kipnis, Farid Barquet Ramos, Katelyn M Breen, Kaleigh Patton, Audrey Morrissette, Ryan M Buehler, Chinedu Ukaegbu, Mersedeh Rohanizadegan, Matthew B Yurgelun, Sapna Syngal, Huma Q Rana, Judy E Garber","doi":"10.1200/PO-24-00553","DOIUrl":"https://doi.org/10.1200/PO-24-00553","url":null,"abstract":"<p><strong>Purpose: </strong>In patients with a variety of malignancies undergoing multigene panel testing (MGPT), we examined the frequency of a pathogenic/likely pathogenic variant (PV) that would not have been predicted on the basis of the patient's personal and family history of cancer.</p><p><strong>Methods: </strong>This is a retrospective review of patients with cancer ascertained from a single academic cancer center who underwent broad-based MGPT of ≥20 cancer predisposition genes not selected on the basis of personal or family cancer history from 2015 to 2021. Low-penetrance variants and recessive inheritance genes were excluded. Deidentified pedigrees were analyzed to determine clinical suspicion of PV.</p><p><strong>Results: </strong>MGPT was performed on 10,975 patients with cancer: 1,134 (10.3%) were found to have ≥1 PV in a moderate or highly penetrant cancer susceptibility gene. Three hundred seven (2.8%) of the PVs were not predicted on the basis of patient's personal cancer history alone, and 192 (1.7%) remained unsuspected after patient's cancer diagnosis and review of family cancer histories were considered. Unexpected PVs accounted for 16.9% of the 1,134 patients with a moderate- or high-penetrance PV. Most frequent unexpected variants were <i>MITF</i> (n = 18), <i>PMS2</i> (n = 18), <i>ATM</i> (n = 17), <i>BRIP1</i> (n = 17), <i>HOXB13</i> (n = 14), <i>SDHA</i> (n = 12), <i>CHEK2</i> (n = 11), <i>BRCA2</i> (n = 7), <i>MSH6</i> (n = 7), <i>SDHC</i> (n = 7), <i>PALB2</i> (n = 6), and <i>TP53</i> (n = 6). Low-penetrance or recessive variants were found in 519 (4.7%) patients. Variants of uncertain significance were found in 3,775 (34.4%).</p><p><strong>Conclusion: </strong>In patients with cancer, MGPT identified a rate of 1.7% PV in unexpected actionable cancer predisposition genes. Findings were more often unexpected (2.8%) when considering only the patient cancer history. These findings may justify consideration of broader MGPT panels in patients with cancer, given implications for subsequent surveillance, cascade testing, and treatment options dependent on specific findings.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400553"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818067","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":"Clinical Utility of a Circulating Tumor Cell-Based Cerebrospinal Fluid Assay in the Diagnosis and Molecular Analysis of Leptomeningeal Disease in Patients With Advanced Non-Small Cell Lung Cancer.","authors":"Jyoti Malhotra, Ramya Muddasani, Jeremy Fricke, Isa Mambetsariev, Amanda Reyes, Razmig Babikian, Shaira Therese Dingal, Pauline Kim, Erminia Massarelli, Lisa Feldman, Mike Chen, Michelle Afkhami, Ravi Salgia","doi":"10.1200/PO-24-00373","DOIUrl":"https://doi.org/10.1200/PO-24-00373","url":null,"abstract":"<p><strong>Purpose: </strong>Leptomeningeal disease (LMD) is associated with significant morbidity and mortality for metastatic non-small cell lung cancer (NSCLC). We describe our clinical experience in evaluating the use of cerebrospinal fluid (CSF)-derived circulating tumor cells (CTCs) for the diagnosis of LMD and the detection of genomic alterations in CSF cell-free DNA (cfDNA).</p><p><strong>Methods: </strong>Patients with NSCLC who had CSF collection as part of routine clinical care for suspected LMD were included in the study. CSF was evaluated for CTCs and cfDNA using a commercial assay (CNSide; Biocept, San Diego, CA), and molecular profiling was performed. Molecular testing results from sequencing of tumor tissue and plasma circulating tumor DNA were collected. cMET and human epidermal growth factor receptor 2 (HER2) expression analysis was performed using fluorescence in situ hybridization (FISH).</p><p><strong>Results: </strong>Twenty-two patients were included (77% female; median age 60 years). Sixty-four percent had sensitizing <i>EGFR</i> mutations, and 32% had an atypical <i>EGFR</i> mutation. Thirteen of the 22 patients (59%) were diagnosed with LMD using the CSF CTC assay. Five of these 13 patients (38%) had negative CSF cytology for LMD, and two patients (15%) had normal magnetic resonance imaging brain imaging. Seven of the 13 patients (54%) had sufficient CTCs to perform molecular profiling. The concordance with tissue next-generation sequencing was 100%, and the driver mutation was identified in all seven patients with the CSF cfDNA assay. cMET expression and HER2 expression via FISH were noted in 11 patients (50%) and four patients (18%) respectively.</p><p><strong>Conclusion: </strong>We detected higher sensitivity to diagnose LMD using CSF CTC-based assay; 38% of LMD cases identified using this assay were missed by standard CSF cytology. CSF molecular testing using CSF cfDNA demonstrated high concordance with tissue-based molecular testing.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400373"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818091","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":"Evolution of Rapid Clonal Dynamics and Non-Cross-Resistance in Response to Alternating Targeted Therapy and Chemotherapy in BRAF-V600E-Mutant Colon Cancer.","authors":"Srilatha Simhadri, Jillian N Carrick, Susan Murphy, Om A Kothari, Husam Al-Hraishami, Atul Kulkarni, Nahed Jalloul, Katarina Stefanik, Manisha Bandari, Kavya Chettur, Ming Yao, Vasudeva Ginjala, Roman Groisberg, Howard Hochster, Janice Mehnert, Gregory Riedlinger, Hossein Khiabanian, Michael P Verzi, Kevin Tong, Shridar Ganesan","doi":"10.1200/PO.23.00260","DOIUrl":"10.1200/PO.23.00260","url":null,"abstract":"<p><strong>Purpose: </strong>Combined BRAF, MEK, and EGFR inhibition can induce clinical responses in BRAF-V600E-mutant colon cancer, but rapid resistance often occurs.</p><p><strong>Methods: </strong>We use serial monitoring of circulating tumor DNA cell-free plasma DNA (cfDNA) in a patient case study in addition to organoids derived from mouse models of BRAF-V600E-mutant intestinal cancer, which emulated the patient's mutational profile to assess drug treatment efficacy.</p><p><strong>Results: </strong>We demonstrate dynamic evolution of resistance to combined EGFR/BRAF/MEK inhibition in a pediatric patient with metastatic BRAF-V600E-mutant, mismatch repair-stable colon cancer. Initial resistance to targeted therapy was associated with development of MET amplification. Sequential treatment with chemotherapy and targeted therapy resulted in clearing of the resistant MET-amplified clone. Rechallenge with combined BRAF/EGFR inhibition resulted in clinical and radiographic response, demonstrating these treatments may be non-cross-resistant. Tumor organoids were used to model clinical findings and demonstrated effectiveness of combined targeted therapy and chemotherapy.</p><p><strong>Conclusion: </strong>These findings suggest rational strategies for combining sequential chemotherapy and BRAF-/EGFR-directed therapy in BRAF-V600E-mutant colon cancer to prevent resistance and improve outcome. The data demonstrate rapid clonal dynamics in response to effective therapies in BRAF-V600E-mutant colon cancer that can be monitored by serial cfDNA analysis. Moreover, in mismatch repair-proficient BRAF-V600E-mutant colon cancers, combined EGFR and BRAF/MEK therapy is not cross-resistant with standard chemotherapy, suggesting new rational combination treatment strategies.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2300260"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11627326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769010","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":"Parents' Experiences With and Preferences for Receiving Information About Tumor Genomic Sequencing: Findings From a Qualitative Study and Implications for Practice.","authors":"Brittany L Greene, Krysta S Barton, Emily Bonkowski, Shannon M Stasi, Natalie Waligorski, Jonathan M Marron, Abby R Rosenberg","doi":"10.1200/PO-24-00543","DOIUrl":"https://doi.org/10.1200/PO-24-00543","url":null,"abstract":"<p><strong>Purpose: </strong>The use of up-front tumor genomic sequencing (TGS) is becoming increasingly common in pediatric oncology. Despite this, little is known about how parents receive information about TGS at the time of their child's cancer diagnosis. We aimed to describe parents' experiences with and preferences for receiving information about TGS and to use these findings to inform practical guidance for pediatric oncology clinicians.</p><p><strong>Methods: </strong>We conducted semistructured interviews with English-speaking parents (older than 18 years) of patients (younger than 18 years) who had TGS for a new diagnosis of cancer. We analyzed the interviews thematically. Participants also completed a short demographic survey, and we obtained medical information about participants' children via chart review.</p><p><strong>Results: </strong>We interviewed 20 parents (14 mothers; median age, 38 years) of children who underwent TGS for a newly diagnosed cancer (10 leukemias/lymphomas, three CNS tumors, seven other solid tumors). Children were 6 months to 17 years at diagnosis (median, 6 years). Fifteen parents and their children were White, two of whom were Hispanic and four of whose children were Hispanic. No participants identified themselves or their child as Black. We identified the following themes regarding information delivery about genomic testing from the interviews: (1) those in the parent role have some universal information needs; (2) information delivery preferences vary among parents, even within one family; and (3) parents desire standard yet tailored information delivery.</p><p><strong>Conclusion: </strong>Parents made suggestions consistent with elements of established high-quality communication in pediatric oncology. As genomic testing is more standardly incorporated into childhood cancer care, communication with parents may need to adapt to reflect this. Our findings highlight potential opportunities to support parents in receiving information about genomic testing.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400543"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769024","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}