JCO precision oncology最新文献

{"title":"Phase II Study of Sunitinib in Tumors With <i>c-KIT</i> Mutations: Results From the NCI MATCH ECOG-ACRIN Trial (EAY131) Subprotocol V.","authors":"Lilian T Gien, Zihe Song, Andrew Poklepovic, Eric A Collisson, James A Zwiebel, Robert J Gray, Victoria Wang, Lisa M McShane, Larry V Rubinstein, David R Patton, P Mickey Williams, Stanley R Hamilton, 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-24-00514","DOIUrl":"10.1200/PO-24-00514","url":null,"abstract":"<p><strong>Purpose: </strong>The NCI-MATCH study is a tumor-agnostic platform trial enrolling patients to targeted therapies on the basis of genomic alterations. Subprotocol V investigated sunitinib in patients with tumors harboring <i>c</i>-<i>KIT</i> mutations.</p><p><strong>Methods: </strong>EAY131-V, is an open-label, single-arm, phase II study. Eligible patients had malignancies containing somatic <i>c-KIT</i> mutation on exons 9, 11, 13, or 14. Exclusions were mutations on exons 17 and 18, gastrointestinal stromal tumors, renal cell carcinoma, and pancreatic neuroendocrine tumors. Patients received sunitinib 50 mg orally once daily for 4 weeks with 2-week rest per cycle, until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR); secondary end points were progression-free survival (PFS) at 6 months, PFS, overall survival, and toxicities.</p><p><strong>Results: </strong>Between November 1, 2016, and May 21, 2020, 10 patients were enrolled and nine were eligible and started treatment. The median age was 62 years (range, 30-76), 77.8% received two previous lines of systemic therapy, and 22.2% received >3 lines. The most common histology was melanoma (44%) and then squamous cell carcinoma of the lung or thymus (33%). There were two partial responses with an ORR of 22.2% (90% CI, 4.1 to 55) and stable disease in 44%. All patients demonstrated tumor shrinkage of target lesions. The estimated 6-month PFS was 33.3% (90% CI, 15.4 to 72.4). Grade 3-4 toxicities occurred in five patients (55.6%). This arm was closed in 2022 on the basis of low accrual. Prevalence of eligible <i>c-KIT</i> mutations after screening 5,540 patients was 0.45%.</p><p><strong>Conclusion: </strong>Sunitinib for <i>c-KIT</i> mutations did not meet the primary end point, but in this small sample size, a potential signal cannot be ruled out. Rate of eligible <i>c-KIT</i> mutations was low, affecting accrual to this arm.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400514"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818111","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":"Nectin-4 Positivity in Genitourinary Malignancies: A Systematic Review.","authors":"Emanuele Crupi, Tiago Costa de Padua, Laura Marandino, Giuseppe Fallara, Filippo Pederzoli, Alessia Cimadamore, Emanuele C Goetz, Antonio Cigliola, Damiano A Patané, Chiara Mercinelli, Valentina Tateo, Andrea Salonia, Alberto Briganti, Francesco Montorsi, Joshua J Meeks, Philippe E Spiess, Omar Alhalabi, Jianjun Gao, Ashish M Kamat, Petros Grivas, Andrea Necchi, Daniele Raggi","doi":"10.1200/PO-24-00470","DOIUrl":"https://doi.org/10.1200/PO-24-00470","url":null,"abstract":"<p><strong>Purpose: </strong>Aberrant expression of nectin-4 (N4) has been observed in several malignancies emerging as new target for antibody-drug conjugates, especially in urothelial carcinoma of the bladder (UBC). Limited data on N4 positivity in nonurothelial genitourinary (GU) cancers are available. This systematic-review aimed to investigate N4 positivity among GU malignancies.</p><p><strong>Methods: </strong>A systematic literature review was performed on March 2023 using PubMed, MEDLINE, and Embase databases according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Protocol was amended to incorporate a new updated search on March 2024.</p><p><strong>Results: </strong>Twenty-five studies evaluating N4 positivity in GU tumors were included, 14 on UBC, three on upper tract urothelial carcinoma (UTUC), six on histologic subtypes (HS) and divergent histology of the bladder, one on papillary renal cell carcinoma (pRCC), one in chromophobe RCC (chRCC), two on penile cancer, one in prostate cancer (PCa). Among UBC, stratifying per stage N4 positivity was higher in metastatic (weighted mean [WM], 90.8; range, 59.6-100) and in non-muscle-invasive (WM, 87.4; range, 86.7-88.3) than in muscle-invasive UC (WM, 83.1; range, 68.2-100). The N4 positivity of UBC was higher than UTUC (WM, 62.9; range, 44.4-65.7). Immunohistochemistry N4 positivity was reported to be lower in non-UC malignancies, including pRCC (WM, 44.1; range, 44.1-44.1), HS (WM, 63.5; range, 0-100), PCa (WM0; range, 0-0), chRCC (WM, 18.5; range, 18.5-18.5), and penile cancer (WM, 86.5; range, 61.4-98.3), compared with UBC overall (WM, 87.1; range, 59.6-100).</p><p><strong>Conclusion: </strong>Non-UC malignancies seem to have a lower N4 positivity rate than UC. N4 positivity in bladder cancer appears to vary according to stage and presence of HS. The predictive and prognostic role of N4 must be further characterized in larger and prospective studies.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400470"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769019","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":"Genomic Landscape of Malignant Phyllodes Tumors Identifies Subsets for Targeted Therapy.","authors":"Rani Bansal, Tolulope Adeyelu, Andrew Elliott, Antoinette R Tan, Jennifer R Ribeiro, Jane Meisel, Matthew J Oberley, Stephanie L Graff, George W Sledge, Juneko E Grilley-Olson, Sarah L Sammons, Laura H Rosenberger","doi":"10.1200/PO.24.00289","DOIUrl":"10.1200/PO.24.00289","url":null,"abstract":"<p><strong>Purpose: </strong>Malignant phyllodes tumors (MPTs) are rare fibroepithelial tumors of the breast with aggressive biologic behavior and high recurrence rates. Surgery remains the primary treatment modality for these tumors; however, initial investigations suggest a potential for targeted therapies in managing this disease. Therefore, we aimed to assess the molecular landscape of MPTs to reveal possible treatment opportunities.</p><p><strong>Methods: </strong>MPTs (n = 57) from primary and metastatic sites underwent genomic sequencing (592-gene panel or whole exome), whole-transcriptome sequencing, and immunohistochemistry (PD-L1, human epidermal growth factor receptor 2 [HER2]) at Caris Life Sciences (Phoenix, AZ). Immune cell fractions in the tumor microenvironment were estimated using quanTIseq. Mann-Whitney <i>U</i>, chi-square, and Fisher's exact tests were used to determine significance (<i>P</i> < .05).</p><p><strong>Results: </strong>MPTs had low <i>ERBB2</i> expression, comparable with the HER2-negative subset of a large cohort of breast adenocarcinoma samples (N = 9,926). Frequent alterations included <i>TERT</i> promoter; <i>MED12</i>, <i>TP53</i>, and <i>NF1</i> mutations; and less frequently <i>EGFR</i>, <i>PIK3CA</i>, and <i>BRAF</i>. Differences in mutation prevalences were observed between primary sites, lung metastases, and nonlung metastases. One MPT specimen harbored a pathogenic <i>TPM4:NTRK1</i> fusion, and treatment with larotrectinib for over 16 months suggested a clinical response to therapy. PD-L1+ status was observed in 15.2% of MPTs overall, with similar prevalence in primary sites and lung metastases. B cells, M2 macrophages, neutrophils, and natural killer cells had the highest median cell fractions in MPTs.</p><p><strong>Conclusion: </strong>Considering the occurrence of several actionable alterations including a <i>TPM4:NTRK1</i> fusion reported herein, these results support the use of next-generation sequencing (NGS) including RNA analysis for fusion detection to identify such alterations in patients with MPTs. These findings highlight the importance of comprehensive NGS in MPT research to uncover potential targeted treatment options for these patients.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400289"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11634179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785550","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":"Clinical Utility of Genomic Sequencing for Hereditary Cancer Syndromes: An Observational Cohort Study.","authors":"Salma Shickh, Chloe Mighton, Marc Clausen, Jordan Sam, Daena Hirjikaka, Emma Reble, Tracy Graham, Seema Panchal, Andrea Eisen, Christine Elser, Kasmintan A Schrader, Nancy N Baxter, Andreas Laupacis, Jordan Lerner-Ellis, Raymond H Kim, Yvonne Bombard","doi":"10.1200/PO-24-00407","DOIUrl":"10.1200/PO-24-00407","url":null,"abstract":"<p><strong>Purpose: </strong>Genomic sequencing (GS) is increasingly used to improve diagnoses and inform targeted therapies. GS can also be used to identify the 10% of cancer patients with an underlying hereditary cancer syndrome (HCS), who can benefit from surveillance and preventive surgery that reduce morbidity/mortality. However, the evidence on clinical utility of GS for HCS is limited: we aimed to fill this gap by assessing yield of all cancer results and associated recommendations for patients undergoing GS for HCS.</p><p><strong>Materials and methods: </strong>An observational chart review and survey were conducted for cancer patients with previous uninformative cancer gene panel results, who received GS as part of the Incidental Genomics Trial (ClinicalTrials.gov identifier: NCT03597165). Descriptive statistics were used to describe demographics and clinical history. Proportions were calculated to compare frequencies of result types and recommendations made and followed.</p><p><strong>Results: </strong>A total of 276 patients were eligible and included. Participants were mostly female (n = 240), European (n = 158), and with breast cancer history (n = 168). Yield: 25 patients (9.1%) received ≥1 pathogenic/likely pathogenic variant, 246 (89%) received ≥1 variant of uncertain significance (VUS), and 27 (10%) were negative. Most pathogenic variants (20/26) were in low/moderate cancer risk genes. The mean number of VUS was 2.7/patient and higher in non-Europeans versus Europeans (3.5 <i>v</i> 2.5, <i>P</i> < .05). Recommendations: Pathogenic variants triggered 100 recommendations in 21/25 patients; most were for genetic counseling, communication to relatives, and cascade testing.</p><p><strong>Conclusion: </strong>GS provided a modest increase in utility after first-tier cancer gene panels, at the cost of a high frequency of uncertain results. Furthermore, most positives were low/moderate cancer risk results that did not have corresponding evidence-based, management guidelines.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400407"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818101","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 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}