Arielle Elkrief, Igor Odintsov, Roger S Smith, Morana Vojnic, Takuo Hayashi, Inna Khodos, Vladimir Markov, Zebing Liu, Allan J W Lui, Jamie L Bloom, Michael D Offin, Charles M Rudin, Elisa de Stanchina, Gregory J Riely, Romel Somwar, Marc Ladanyi
Purpose: MDM2, a negative regulator of the TP53 tumor suppressor, is oncogenic when amplified. MDM2 amplification (MDM2amp) is mutually exclusive with TP53 mutation and is seen in 6% of patients with lung adenocarcinoma (LUAD), with significant enrichment in subsets with receptor tyrosine kinase (RTK) driver alterations. Recent studies have shown synergistic activity of MDM2 and MEK inhibition in patient-derived LUAD models with MDM2amp and RTK driver alterations. However, the combination of MDM2 and RTK inhibitors in LUAD has not been studied.
Methods: We evaluated the combination of MDM2 and RTK inhibition in patient-derived models of LUAD.
Results: In a RET-fusion LUAD patient-derived model with MDM2amp, MDM2 inhibition with either milademetan or AMG232 combined with selpercatinib resulted in long-term in vivo tumor control markedly superior to either agent alone. Similarly, in an EGFR-mutated model with MDM2amp, combining either milademetan or AMG232 with osimertinib resulted in long-term in vivo tumor control, which was strikingly superior to either agent alone.
Conclusion: These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach.
{"title":"Combination of MDM2 and Targeted Kinase Inhibitors Results in Prolonged Tumor Control in Lung Adenocarcinomas With Oncogenic Tyrosine Kinase Drivers and <i>MDM2</i> Amplification.","authors":"Arielle Elkrief, Igor Odintsov, Roger S Smith, Morana Vojnic, Takuo Hayashi, Inna Khodos, Vladimir Markov, Zebing Liu, Allan J W Lui, Jamie L Bloom, Michael D Offin, Charles M Rudin, Elisa de Stanchina, Gregory J Riely, Romel Somwar, Marc Ladanyi","doi":"10.1200/PO.24.00241","DOIUrl":"https://doi.org/10.1200/PO.24.00241","url":null,"abstract":"<p><strong>Purpose: </strong>MDM2, a negative regulator of the TP53 tumor suppressor, is oncogenic when amplified. <i>MDM2</i> amplification (MDM2amp) is mutually exclusive with <i>TP53</i> mutation and is seen in 6% of patients with lung adenocarcinoma (LUAD), with significant enrichment in subsets with receptor tyrosine kinase (RTK) driver alterations. Recent studies have shown synergistic activity of MDM2 and MEK inhibition in patient-derived LUAD models with MDM2amp and RTK driver alterations. However, the combination of MDM2 and RTK inhibitors in LUAD has not been studied.</p><p><strong>Methods: </strong>We evaluated the combination of MDM2 and RTK inhibition in patient-derived models of LUAD.</p><p><strong>Results: </strong>In a RET-fusion LUAD patient-derived model with MDM2amp, MDM2 inhibition with either milademetan or AMG232 combined with selpercatinib resulted in long-term in vivo tumor control markedly superior to either agent alone. Similarly, in an EGFR-mutated model with MDM2amp, combining either milademetan or AMG232 with osimertinib resulted in long-term in vivo tumor control, which was strikingly superior to either agent alone.</p><p><strong>Conclusion: </strong>These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach.</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/PMC11404768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142287718","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}
Margaret E Macy, Rajen Mody, Joel M Reid, Jin Piao, Lauren Saguilig, Todd A Alonzo, Stacey L Berg, Elizabeth Fox, Brenda J Weigel, Douglas S Hawkins, Margaret M Mooney, P Mickey Williams, David R Patton, Brent D Coffey, Sinchita Roy-Chowdhuri, Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, D Williams Parsons
Purpose: The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice trial assigned patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with tumors that harbored prespecified genomic alterations in the cyclinD-CDK4/6-INK4a-Rb pathway with intact Rb expression were assigned and treated with the cdk4/6 inhibitor palbociclib.
Methods: Patients received palbociclib orally once daily for 21 days of 28-day cycles until disease progression, intolerable toxicity, or up to 2 years. The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival.
Results: Twenty-three patients (median age, 15 years; range, 8-21) were enrolled; 20 received protocol therapy and were evaluable for toxicity and response. Of the evaluable patients, the most common diagnoses were osteosarcoma (n = 9) and rhabdomyosarcoma (n = 6). A single actionable gene amplification was found in 19 tumors (CDK4, n = 11, CDK6, n = 2, CCND3, n = 6), with one tumor harboring two amplifications (CDK4 and CCND2). Hematologic toxicities were the most common treatment-related events. No objective responses were seen. Two patients with tumors harboring CDK4 amplifications (neuroblastoma and sarcoma) had best response of stable disease for six and three cycles. Six-month progression was 10% (95% CI, 1.7 to 27.2).
Conclusion: The CDK4/6 inhibitor palbociclib at 75 mg/m2 orally daily was tolerable in this heavily pretreated cohort. No objective responses were observed in this histology-agnostic biomarker-selected population with treatment-refractory solid tumors, demonstrating that pathway alteration alone is insufficient in pediatric cancers to generate a response to palbociclib monotherapy.
{"title":"Palbociclib in Solid Tumor Patients With Genomic Alterations in the cyclinD-cdk4/6-INK4a-Rb Pathway: Results From National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice Trial Arm I (APEC1621I).","authors":"Margaret E Macy, Rajen Mody, Joel M Reid, Jin Piao, Lauren Saguilig, Todd A Alonzo, Stacey L Berg, Elizabeth Fox, Brenda J Weigel, Douglas S Hawkins, Margaret M Mooney, P Mickey Williams, David R Patton, Brent D Coffey, Sinchita Roy-Chowdhuri, Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, D Williams Parsons","doi":"10.1200/PO-24-00418","DOIUrl":"10.1200/PO-24-00418","url":null,"abstract":"<p><strong>Purpose: </strong>The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice trial assigned patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with tumors that harbored prespecified genomic alterations in the cyclinD-CDK4/6-INK4a-Rb pathway with intact Rb expression were assigned and treated with the cdk4/6 inhibitor palbociclib.</p><p><strong>Methods: </strong>Patients received palbociclib orally once daily for 21 days of 28-day cycles until disease progression, intolerable toxicity, or up to 2 years. The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival.</p><p><strong>Results: </strong>Twenty-three patients (median age, 15 years; range, 8-21) were enrolled; 20 received protocol therapy and were evaluable for toxicity and response. Of the evaluable patients, the most common diagnoses were osteosarcoma (n = 9) and rhabdomyosarcoma (n = 6). A single actionable gene amplification was found in 19 tumors (<i>CDK4</i>, n = 11, <i>CDK6</i>, n = 2, <i>CCND3</i>, n = 6), with one tumor harboring two amplifications (<i>CDK4</i> and <i>CCND2</i>). Hematologic toxicities were the most common treatment-related events. No objective responses were seen. Two patients with tumors harboring <i>CDK4</i> amplifications (neuroblastoma and sarcoma) had best response of stable disease for six and three cycles. Six-month progression was 10% (95% CI, 1.7 to 27.2).</p><p><strong>Conclusion: </strong>The CDK4/6 inhibitor palbociclib at 75 mg/m<sup>2</sup> orally daily was tolerable in this heavily pretreated cohort. No objective responses were observed in this histology-agnostic biomarker-selected population with treatment-refractory solid tumors, demonstrating that pathway alteration alone is insufficient in pediatric cancers to generate a response to palbociclib monotherapy.</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/PMC11488755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142287722","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 : 2024-09-01Epub Date: 2024-09-30DOI: 10.1200/PO.24.00281
Reuben Ben-David, Parissa Alerasool, Hitasha Kalola, Neeraja Tillu, Mohammed Almoflihi, Che-Kai Tsao, Matthew D Galsky, John P Sfakianos, Peter Wiklund, Nikhil Waingankar, Reza Mehrazin
Purpose: Understanding the specific tumor characteristics associated with detectable circulating tumor DNA (ctDNA) in patients with renal cell carcinoma (RCC) is critical for informing future studies aiming to establish the clinical utility of such testing. We characterized the pathologic and clinical features associated with preoperatively detectable ctDNA in patients with renal masses suspicious for RCC.
Methods: Consecutive patients who underwent partial or radical nephrectomy for nonmetastatic suspected RCC (cT1b-T3) during 2022-2023 had prospectively collected tumor-informed ctDNA analyses conducted preoperatively and postoperatively. Descriptive statistics and univariate analyses were used to describe the study findings.
Results: Sixty-nine patients with a median age of 62 years (IQR, 51-70) and a median follow-up time of 7 months (IQR, 3-11) had 205 ctDNA samples collected for analysis. Thirty-nine (61%) had preoperative detectable ctDNA of 64 patients. Postoperative ctDNA status was available for 47 patients, and three (6%) had detectable ctDNA. Two had inferior vena cava (IVC) involvement, and one developed metastatic disease. Subgroup analysis of solely malignant RCC (n = 65) revealed that patients with preoperative detectable ctDNA had a higher pathologic stage (P = .001), larger tumors (7 v 4.5 cm; P = .001), higher tumor complexity (P = .022), and increased rates of tumor grades 3-4 (P = .038). All patients with gross renal vein or IVC involvement (n = 9) and those with lymphovascular invasion (n = 6) on pathology had detectable preoperative ctDNA. On univariate analysis, high tumor complexity, larger tumors, and tumor grades 3-4 were found to be predictors of preoperatively detectable ctDNA status.
Conclusion: Preoperative ctDNA was detectable in 61% of patients with nonmetastatic RCC, and it correlated with clinically relevant features. Clinical trials should consider incorporating both preoperative and postoperative ctDNA analyses to augment prediction of disease recurrence and to refine treatment decision making.
{"title":"Tumor Characteristics Associated With Preoperatively Detectable Tumor-Informed Circulating Tumor DNA in Patients With Renal Masses Suspicious for Renal Cell Carcinoma.","authors":"Reuben Ben-David, Parissa Alerasool, Hitasha Kalola, Neeraja Tillu, Mohammed Almoflihi, Che-Kai Tsao, Matthew D Galsky, John P Sfakianos, Peter Wiklund, Nikhil Waingankar, Reza Mehrazin","doi":"10.1200/PO.24.00281","DOIUrl":"10.1200/PO.24.00281","url":null,"abstract":"<p><strong>Purpose: </strong>Understanding the specific tumor characteristics associated with detectable circulating tumor DNA (ctDNA) in patients with renal cell carcinoma (RCC) is critical for informing future studies aiming to establish the clinical utility of such testing. We characterized the pathologic and clinical features associated with preoperatively detectable ctDNA in patients with renal masses suspicious for RCC.</p><p><strong>Methods: </strong>Consecutive patients who underwent partial or radical nephrectomy for nonmetastatic suspected RCC (cT1b-T3) during 2022-2023 had prospectively collected tumor-informed ctDNA analyses conducted preoperatively and postoperatively. Descriptive statistics and univariate analyses were used to describe the study findings.</p><p><strong>Results: </strong>Sixty-nine patients with a median age of 62 years (IQR, 51-70) and a median follow-up time of 7 months (IQR, 3-11) had 205 ctDNA samples collected for analysis. Thirty-nine (61%) had preoperative detectable ctDNA of 64 patients. Postoperative ctDNA status was available for 47 patients, and three (6%) had detectable ctDNA. Two had inferior vena cava (IVC) involvement, and one developed metastatic disease. Subgroup analysis of solely malignant RCC (n = 65) revealed that patients with preoperative detectable ctDNA had a higher pathologic stage (<i>P</i> = .001), larger tumors (7 <i>v</i> 4.5 cm; <i>P</i> = .001), higher tumor complexity (<i>P</i> = .022), and increased rates of tumor grades 3-4 (<i>P</i> = .038). All patients with gross renal vein or IVC involvement (n = 9) and those with lymphovascular invasion (n = 6) on pathology had detectable preoperative ctDNA. On univariate analysis, high tumor complexity, larger tumors, and tumor grades 3-4 were found to be predictors of preoperatively detectable ctDNA status.</p><p><strong>Conclusion: </strong>Preoperative ctDNA was detectable in 61% of patients with nonmetastatic RCC, and it correlated with clinically relevant features. Clinical trials should consider incorporating both preoperative and postoperative ctDNA analyses to augment prediction of disease recurrence and to refine treatment decision making.</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":"142347064","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}
Pancreatic neuroendocrine tumors (pNETs) are the second most prevalent neoplasms of the pancreas with variable prognosis and clinical course. Our knowledge of the genetic alterations in patients with pNETs has expanded in the past decade with the availability of whole-genome sequencing and germline testing. This review will focus on potential clinical applications of the genetic testing in patients with pNETs. For somatic testing, we discuss the commonly prevalent somatic mutations and their impact on prognosis and treatment of patients with pNET. We also highlight the relevant genomic biomarkers that predict response to specific treatments. Previously, germline testing was only recommended for high-risk patients with syndromic features (MEN1, VHL, TSC, and NF1), we review the evolving paradigm of germline testing in pNETs as recent studies have now shown that sporadic-appearing pNETs can also harbor germline variants.
{"title":"Genomic Landscape of Pancreatic Neuroendocrine Tumors and Implications for Clinical Practice.","authors":"Ana De Jesus-Acosta, Chirayu Mohindroo","doi":"10.1200/PO.24.00221","DOIUrl":"https://doi.org/10.1200/PO.24.00221","url":null,"abstract":"<p><p>Pancreatic neuroendocrine tumors (pNETs) are the second most prevalent neoplasms of the pancreas with variable prognosis and clinical course. Our knowledge of the genetic alterations in patients with pNETs has expanded in the past decade with the availability of whole-genome sequencing and germline testing. This review will focus on potential clinical applications of the genetic testing in patients with pNETs. For somatic testing, we discuss the commonly prevalent somatic mutations and their impact on prognosis and treatment of patients with pNET. We also highlight the relevant genomic biomarkers that predict response to specific treatments. Previously, germline testing was only recommended for high-risk patients with syndromic features (<i>MEN1</i>, <i>VHL</i>, <i>TSC</i>, and <i>NF1</i>), we review the evolving paradigm of germline testing in pNETs as recent studies have now shown that sporadic-appearing pNETs can also harbor germline variants.</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":"142132748","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}
David G Su, Ankit Dhiman, Varun V Bansal, Yuanyuan Zha, Ardaman Shergill, Blasé Polite, Lindsay Alpert, Kiran K Turaga, Oliver S Eng
Purpose: High-grade appendiceal adenocarcinomas (HGAA) with peritoneal metastases (PMs) are associated with poor survival. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a novel treatment approach for unresectable HGAA-PM. However, its influence on immunogenomic profiles has not yet been fully explored.
Materials and methods: We obtained 79 samples of metastatic peritoneal tumor deposits from patients diagnosed with HGAA and performed whole-exome sequencing, RNA sequencing, and immunoprofiling before and after HIPEC. Tumor biopsies were subjected to immunogenomic profiling to detect mutational signatures and immune populations associated with oncologic outcomes.
Results: Fifteen patients with HGAA-PMs were included in the study. The median progression-free survival (PFS) was 6.7 months (2.7-25.3) and the median overall survival was 11.4 months (4.7-42). Mucin-associated genes (MUC16, MUC3A, and MUC5AC) and titin (TTN) had the highest mutation frequencies. Mutational signatures such as single-base substitution 29 and doublet-base substitution 11 were present in >50% of single-base and double-base mutations. Higher PD-L1 coexpression on CD8+ T cells demonstrated a higher PFS both intratumorally (P = .019) and at the margin (P = .025).
Conclusion: HIPEC-associated mutational signatures were identified in HGAA-PMs. Elevated PD-L1+ cytotoxic T-cell populations after HIPEC had better PFS, offering valuable insights for prognostication in the context of HIPEC treatment.
{"title":"Mutational Features and Tumor Microenvironment Alterations in High-Grade Appendiceal Cancers Treated With Iterative Hyperthermic Intraperitoneal Chemotherapy.","authors":"David G Su, Ankit Dhiman, Varun V Bansal, Yuanyuan Zha, Ardaman Shergill, Blasé Polite, Lindsay Alpert, Kiran K Turaga, Oliver S Eng","doi":"10.1200/PO.24.00149","DOIUrl":"10.1200/PO.24.00149","url":null,"abstract":"<p><strong>Purpose: </strong>High-grade appendiceal adenocarcinomas (HGAA) with peritoneal metastases (PMs) are associated with poor survival. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a novel treatment approach for unresectable HGAA-PM. However, its influence on immunogenomic profiles has not yet been fully explored.</p><p><strong>Materials and methods: </strong>We obtained 79 samples of metastatic peritoneal tumor deposits from patients diagnosed with HGAA and performed whole-exome sequencing, RNA sequencing, and immunoprofiling before and after HIPEC. Tumor biopsies were subjected to immunogenomic profiling to detect mutational signatures and immune populations associated with oncologic outcomes.</p><p><strong>Results: </strong>Fifteen patients with HGAA-PMs were included in the study. The median progression-free survival (PFS) was 6.7 months (2.7-25.3) and the median overall survival was 11.4 months (4.7-42). Mucin-associated genes (<i>MUC16</i>, <i>MUC3A</i>, and <i>MUC5AC</i>) and titin (<i>TTN</i>) had the highest mutation frequencies. Mutational signatures such as single-base substitution 29 and doublet-base substitution 11 were present in >50% of single-base and double-base mutations. Higher PD-L1 coexpression on CD8<sup>+</sup> T cells demonstrated a higher PFS both intratumorally (<i>P</i> = .019) and at the margin (<i>P</i> = .025).</p><p><strong>Conclusion: </strong>HIPEC-associated mutational signatures were identified in HGAA-PMs. Elevated PD-L1+ cytotoxic T-cell populations after HIPEC had better PFS, offering valuable insights for prognostication in the context of HIPEC treatment.</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/PMC11432692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142287721","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}
Thejus Jayakrishnan, Yasmine Baca, Joanne Xiu, Mehrie Patel, Benjamin A Weinberg, Emil Lou, Jashodeep Datta, Moh'd Khushman, Pat Gulhati, Sanjay Goel, Tiago Biachi de Castria, Vaia Florou, Kanika G Nair, Suneel D Kamath, Alok A Khorana
Purpose: Early-onset biliary tract cancer (eoBTC) is among the fast-growing subset of early-onset cancers, yet little is known about its biology. We sought to identify novel molecular characteristics of eoBTC in relation to average-onset BTC (aoBTC) using a real-world multiomics data set.
Methods: The study comprised patients with BTC whose tumors underwent molecular analyses at Caris Life Sciences and were categorized by age (<50 years for eoBTC, ≥50 years for aoBTC). P values were adjusted for multiple testing and considered significant at Q < 0.05 (molecular comparisons) or Q < 0.25 (Gene Set Enrichment Analysis [GSEA]). Insurance claims data were used for survival analysis.
Results: The study included 5,587 patients with BTC (453 eoBTC, median age = 44 years and 5,134 aoBTC, median age = 68 years). FGFR2 fusion (15.7% in eoBTC v 5.9% in aoBTC) and NIPBL fusion (1.1% v 0%) were significantly more prevalent in eoBTC (both Q < 0.001). The interferon gamma-IFG score (fold change [FC], 1.1; Q = 0.01) and T-cell inflammation score (FC, 17.3; Q = 0.03) were significantly higher in aoBTC. On GSEA, angiogenesis was enriched in eoBTC (normalized enrichment score [NES] = 1.51; Q = 0.16), whereas IFG (NES = -1.58; Q = 0.06) and inflammatory response (NES = -1.46; Q = 0.18) were enriched in aoBTC. The median overall survival (OS) was 16.5 (eoBTC) versus 13.3 months (aoBTC), hazard ratio = 0.86, P = .004. The median OS by FGFR2 fusion (with fusion v without) was 21.7 versus 15.0 months (P = .47) for eoBTC and 18.6 versus 12.2 months (P < .001) for aoBTC.
Conclusion: We identified crucial differences including higher prevalence of FGFR2 fusions in eoBTC and variations in immunotherapy-related markers. Better outcomes in eoBTC were affected by the FGFR2 fusion status. Our findings underscore the need for ensuring access to next-generation sequencing testing, including prompt identification of actionable targets.
{"title":"Molecular Differences With Therapeutic Implications in Early-Onset Compared With Average-Onset Biliary Tract Cancers.","authors":"Thejus Jayakrishnan, Yasmine Baca, Joanne Xiu, Mehrie Patel, Benjamin A Weinberg, Emil Lou, Jashodeep Datta, Moh'd Khushman, Pat Gulhati, Sanjay Goel, Tiago Biachi de Castria, Vaia Florou, Kanika G Nair, Suneel D Kamath, Alok A Khorana","doi":"10.1200/PO.24.00138","DOIUrl":"https://doi.org/10.1200/PO.24.00138","url":null,"abstract":"<p><strong>Purpose: </strong>Early-onset biliary tract cancer (eoBTC) is among the fast-growing subset of early-onset cancers, yet little is known about its biology. We sought to identify novel molecular characteristics of eoBTC in relation to average-onset BTC (aoBTC) using a real-world multiomics data set.</p><p><strong>Methods: </strong>The study comprised patients with BTC whose tumors underwent molecular analyses at Caris Life Sciences and were categorized by age (<50 years for eoBTC, ≥50 years for aoBTC). <i>P</i> values were adjusted for multiple testing and considered significant at <i>Q</i> < 0.05 (molecular comparisons) or <i>Q</i> < 0.25 (Gene Set Enrichment Analysis [GSEA]). Insurance claims data were used for survival analysis.</p><p><strong>Results: </strong>The study included 5,587 patients with BTC (453 eoBTC, median age = 44 years and 5,134 aoBTC, median age = 68 years). <i>FGFR2</i> fusion (15.7% in eoBTC <i>v</i> 5.9% in aoBTC) and <i>NIPBL</i> fusion (1.1% <i>v</i> 0%) were significantly more prevalent in eoBTC (both <i>Q</i> < 0.001). The interferon gamma-IFG score (fold change [FC], 1.1; <i>Q</i> = 0.01) and T-cell inflammation score (FC, 17.3; <i>Q</i> = 0.03) were significantly higher in aoBTC. On GSEA, angiogenesis was enriched in eoBTC (normalized enrichment score [NES] = 1.51; <i>Q</i> = 0.16), whereas IFG (NES = -1.58; <i>Q</i> = 0.06) and inflammatory response (NES = -1.46; <i>Q</i> = 0.18) were enriched in aoBTC. The median overall survival (OS) was 16.5 (eoBTC) versus 13.3 months (aoBTC), hazard ratio = 0.86, <i>P</i> = .004. The median OS by FGFR2 fusion (with fusion <i>v</i> without) was 21.7 versus 15.0 months (<i>P</i> = .47) for eoBTC and 18.6 versus 12.2 months (<i>P</i> < .001) for aoBTC.</p><p><strong>Conclusion: </strong>We identified crucial differences including higher prevalence of <i>FGFR2</i> fusions in eoBTC and variations in immunotherapy-related markers. Better outcomes in eoBTC were affected by the <i>FGFR2</i> fusion status. Our findings underscore the need for ensuring access to next-generation sequencing testing, including prompt identification of actionable targets.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893483","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}
Trametinib, an MEK inhibitor, may offer a new therapeutic option for patients with NF1-related GIST.
MEK抑制剂Trametinib可为NF1相关GIST患者提供一种新的治疗选择。
{"title":"Efficacy of Trametinib in Neurofibromatosis Type 1-Associated Gastrointestinal Stromal Tumors: A Case Report.","authors":"Misao Fukuda, Toru Mukohara, Takeshi Kuwata, Kuniko Sunami, Yoichi Naito","doi":"10.1200/PO.23.00649","DOIUrl":"10.1200/PO.23.00649","url":null,"abstract":"<p><p>Trametinib, an MEK inhibitor, may offer a new therapeutic option for patients with NF1-related GIST.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906690","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}
Carol Cremin, Angela C Bedard, Quan Hong, Sze Wing Mung, Jennifer Nuk, Andrew Wong, Husain Akbar, Eugene Cheung, Daniel Renouf, David Schaeffer, Sophie Sun, Kasmintan A Schrader
Purpose: Approximately 5%-10% of patients with pancreatic ductal adenocarcinoma (PDAC) have an inherited basis, yet uptake of genetic testing remains low and subject to disparities. This study compared two genetic testing pathways available to patients referred to a provincial cancer center, BC Cancer: a traditional hereditary cancer clinic-initiated testing (HCT) pathway and a new oncology clinic-initiated testing (OCT) pathway.
Methods: Study subjects were patients with confirmed PDAC referred for genetic testing through the HCT or OCT pathway between June 1, 2020, and February 1, 2022. Charts were retrospectively reviewed for patient characteristics and testing outcomes.
Results: The study population was 397 patients (HCT, n = 279 and OCT, n = 118). OCT patients were more likely to have non-European ethnicity compared with HCT patients (41.9% v 25.6%, P = .004), to have earlier-stage disease (P = .012), and to have better Eastern Cooperative Oncology Group performance status than the HCT group (P = .001). A total of 306 patients completed testing (77%). OCT patients had higher test completion rates than HCT patients (odds ratio, 3.74 [95% CI, 1.66 to 9.62]). Median time for results was shorter in OCT than in HCT (53 days [IQR, 44-76] v 107 days [IQR, 63.8-158.3]). Pancreatic cancer susceptibility pathogenic gene variants were identified in 8.5% (26/306).
Conclusion: The real-world observations in our study show that oncology clinic-initiated hereditary testing is more effective and faster than testing through hereditary cancer clinic referrals and reaches a more ethnically diverse population. This has important implications for publicly funded environments with limited resources for genetic counseling.
{"title":"Improving Access to Hereditary Testing in Pancreatic Ductal Carcinoma.","authors":"Carol Cremin, Angela C Bedard, Quan Hong, Sze Wing Mung, Jennifer Nuk, Andrew Wong, Husain Akbar, Eugene Cheung, Daniel Renouf, David Schaeffer, Sophie Sun, Kasmintan A Schrader","doi":"10.1200/PO.24.00167","DOIUrl":"10.1200/PO.24.00167","url":null,"abstract":"<p><strong>Purpose: </strong>Approximately 5%-10% of patients with pancreatic ductal adenocarcinoma (PDAC) have an inherited basis, yet uptake of genetic testing remains low and subject to disparities. This study compared two genetic testing pathways available to patients referred to a provincial cancer center, BC Cancer: a traditional hereditary cancer clinic-initiated testing (HCT) pathway and a new oncology clinic-initiated testing (OCT) pathway.</p><p><strong>Methods: </strong>Study subjects were patients with confirmed PDAC referred for genetic testing through the HCT or OCT pathway between June 1, 2020, and February 1, 2022. Charts were retrospectively reviewed for patient characteristics and testing outcomes.</p><p><strong>Results: </strong>The study population was 397 patients (HCT, n = 279 and OCT, n = 118). OCT patients were more likely to have non-European ethnicity compared with HCT patients (41.9% <i>v</i> 25.6%, <i>P</i> = .004), to have earlier-stage disease (<i>P</i> = .012), and to have better Eastern Cooperative Oncology Group performance status than the HCT group (<i>P</i> = .001). A total of 306 patients completed testing (77%). OCT patients had higher test completion rates than HCT patients (odds ratio, 3.74 [95% CI, 1.66 to 9.62]). Median time for results was shorter in OCT than in HCT (53 days [IQR, 44-76] <i>v</i> 107 days [IQR, 63.8-158.3]). Pancreatic cancer susceptibility pathogenic gene variants were identified in 8.5% (26/306).</p><p><strong>Conclusion: </strong>The real-world observations in our study show that oncology clinic-initiated hereditary testing is more effective and faster than testing through hereditary cancer clinic referrals and reaches a more ethnically diverse population. This has important implications for publicly funded environments with limited resources for genetic counseling.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893481","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 prognostic value of lymphocyte infiltration score (LIS) and its nearest neighbor distance to tumor cells (NNDTC) in giant cell tumor of bone (GCTB) is currently not well established. This study aims to characterize LIS and NNDTC and examine their correlation with denosumab treatment responsiveness, clinicopathologic features, and patient prognosis.
Methods: Using multiplexed quantitative immunofluorescence, LIS was evaluated in 253 tumor specimens, whereas NNDTC was computed using HALO software. Subsequently, we analyzed the association of these parameters with patient outcomes (progression-free survival [PFS] and overall survival [OS]), clinicopathologic features, and denosumab treatment responsiveness.
Results: Low LIS was indicative of both poor PFS and OS (both P < .001). In addition, LIS was significantly associated with sex (P = .046), Enneking staging (P < .001), Ki-67 expression (P = .007), and denosumab treatment responsiveness (P = .005). Lower CD8+ (tumor interior [TI]) NNDTC, and CD3+ (TI) NNDTC were associated with worse PFS (P = .003 and .038, respectively), whereas lower CD8+ (TI) NNDTC was associated with worse OS (P = .001), but CD8+ (tumor infiltrating margin) NNDTC had the opposite effect (P = .002). Moreover, NNDTC showed a correlation with several clinicopathologic features. Importantly, LIS outperformed Enneking and Campanacci staging systems in predicting the clinical outcomes of GCTB.
Conclusion: These findings suggest that LIS is a reliable predictive tool for clinically relevant outcomes and response to denosumab therapy in patients with GCTB. These parameters may prove to be useful in guiding prognostic risk stratification and therapeutic optimization for patients.
{"title":"Lymphocyte Infiltration Score and Spatial Characteristics Refined the Prognosis and Denosumab Treatment Responsiveness Indicators for Giant Cell Tumor of Bone.","authors":"Hai-Lin Wu, Chao Xia, Fu-Sheng Liu, Bo-Yv Zheng, Hua-Qing Niu, Guo-Qiang Zhu, Ming-Xiang Zou, Bo-Wen Zheng","doi":"10.1200/PO.24.00135","DOIUrl":"https://doi.org/10.1200/PO.24.00135","url":null,"abstract":"<p><strong>Purpose: </strong>The prognostic value of lymphocyte infiltration score (LIS) and its nearest neighbor distance to tumor cells (NNDTC) in giant cell tumor of bone (GCTB) is currently not well established. This study aims to characterize LIS and NNDTC and examine their correlation with denosumab treatment responsiveness, clinicopathologic features, and patient prognosis.</p><p><strong>Methods: </strong>Using multiplexed quantitative immunofluorescence, LIS was evaluated in 253 tumor specimens, whereas NNDTC was computed using HALO software. Subsequently, we analyzed the association of these parameters with patient outcomes (progression-free survival [PFS] and overall survival [OS]), clinicopathologic features, and denosumab treatment responsiveness.</p><p><strong>Results: </strong>Low LIS was indicative of both poor PFS and OS (both <i>P</i> < .001). In addition, LIS was significantly associated with sex (<i>P</i> = .046), Enneking staging (<i>P</i> < .001), <i>Ki-67</i> expression (<i>P</i> = .007), and denosumab treatment responsiveness (<i>P</i> = .005). Lower CD8<sup>+</sup> (tumor interior [TI]) NNDTC, and CD3<sup>+</sup> (TI) NNDTC were associated with worse PFS (<i>P</i> = .003 and .038, respectively), whereas lower CD8<sup>+</sup> (TI) NNDTC was associated with worse OS (<i>P</i> = .001), but CD8<sup>+</sup> (tumor infiltrating margin) NNDTC had the opposite effect (<i>P</i> = .002). Moreover, NNDTC showed a correlation with several clinicopathologic features. Importantly, LIS outperformed Enneking and Campanacci staging systems in predicting the clinical outcomes of GCTB.</p><p><strong>Conclusion: </strong>These findings suggest that LIS is a reliable predictive tool for clinically relevant outcomes and response to denosumab therapy in patients with GCTB. These parameters may prove to be useful in guiding prognostic risk stratification and therapeutic optimization for patients.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142043915","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}
Huaying Wang, Lie Lin, Chuqiao Liang, Jiaohui Pang, Jiani C Yin, Junli Zhang, Yang Shao, Chengming Sun, Renhua Guo
Purpose: Next-generation sequencing (NGS) has enabled the detection of concomitant driver alterations in non-small cell lung cancer (NSCLC). However, the magnitude and clinical relevance of concomitant drivers remain to be explored.
Methods: We profiled concomitant driver alterations of EGFR+ NSCLC by using targeted NGS. The associated genomic and clinical features were analyzed and validated in an independent The Cancer Genome Atlas cohort of patients with EGFR+ NSCLC.
Results: Out of the total patient population, 334 patients had EGFR mutations along with concomitant driver mutations, comprising 3.09% of the entire cohort. The most frequent co-occurring mutations with sensitizing EGFR mutations include KRAS at 53.9%, followed by ERBB2 at 24.3%, MET at 16.5%, and BRAF at 3.3%. KRAS mutations in concomitant drivers were frequently hyperexchange mutations (25.6% v 8.2%, P < .001), compared with KRAS single drivers. EGFR/ERBB2 drivers exhibited a higher incidence of ERBB2 amplification (40.7% v 16.5%, P < .001) and p.S310F/Y mutations (44.4% v 4.3%, P < .001) compared with ERBB2 alone. EGFR/MET drivers had a higher frequency of MET amplification (71.4% v 43.3%) than MET single drivers. At the genomic level, the median number of additional concurrent mutations was four, with TSC2 (4%), CD274 (1%), and TP53 (63%) being the most frequently coaltered genes in concomitant driver tumors. Interestingly, clonality analysis indicated that EGFR mutations were more likely to occur as clonal events, whereas the codrivers were more often subclonal. Patients with concomitant drivers or with concomitant MET amplification exhibited worse prognosis.
Conclusion: These findings might aid in the selection of effective therapeutic regimens and facilitate the development of combination therapies.
目的:下一代测序(NGS)能够检测非小细胞肺癌(NSCLC)中的并发驱动基因改变。然而,并发驱动基因的程度和临床相关性仍有待探索:方法:我们利用靶向 NGS 分析了表皮生长因子受体(EGFR)+ NSCLC 的伴随驱动基因改变。我们在癌症基因组图谱(The Cancer Genome Atlas)的一个独立的表皮生长因子受体(EGFR)+ NSCLC 患者队列中分析并验证了相关的基因组和临床特征:结果:在所有患者中,有334名患者的表皮生长因子受体突变同时伴有驱动基因突变,占整个队列的3.09%。最常与致敏表皮生长因子受体突变同时发生的突变包括KRAS突变(53.9%)、ERBB2突变(24.3%)、MET突变(16.5%)和BRAF突变(3.3%)。与 KRAS 单个驱动因子相比,并发驱动因子中的 KRAS 基因突变经常是低变异突变(25.6% 对 8.2%,P < .001)。与ERBB2单独驱动相比,EGFR/ERBB2驱动表现出更高的ERBB2扩增发生率(40.7% v 16.5%,P < .001)和p.S310F/Y突变发生率(44.4% v 4.3%,P < .001)。表皮生长因子受体/MET驱动者的MET扩增频率(71.4% v 43.3%)高于MET单一驱动者。在基因组水平上,额外并发突变的中位数为 4 个,TSC2(4%)、CD274(1%)和 TP53(63%)是并发驱动肿瘤中最常见的变异基因。有趣的是,克隆性分析表明,表皮生长因子受体突变更有可能作为克隆事件发生,而同源基因突变则更常见于亚克隆。伴有驱动基因或伴有MET扩增的患者预后较差:这些发现可能有助于选择有效的治疗方案,并促进联合疗法的开发。
{"title":"Landscape of Concomitant Driver Alterations in Classical <i>EGFR</i>-Mutated Non-Small Cell Lung Cancer.","authors":"Huaying Wang, Lie Lin, Chuqiao Liang, Jiaohui Pang, Jiani C Yin, Junli Zhang, Yang Shao, Chengming Sun, Renhua Guo","doi":"10.1200/PO.23.00520","DOIUrl":"https://doi.org/10.1200/PO.23.00520","url":null,"abstract":"<p><strong>Purpose: </strong>Next-generation sequencing (NGS) has enabled the detection of concomitant driver alterations in non-small cell lung cancer (NSCLC). However, the magnitude and clinical relevance of concomitant drivers remain to be explored.</p><p><strong>Methods: </strong>We profiled concomitant driver alterations of <i>EGFR</i>+ NSCLC by using targeted NGS. The associated genomic and clinical features were analyzed and validated in an independent The Cancer Genome Atlas cohort of patients with <i>EGFR</i>+ NSCLC.</p><p><strong>Results: </strong>Out of the total patient population, 334 patients had <i>EGFR</i> mutations along with concomitant driver mutations, comprising 3.09% of the entire cohort. The most frequent co-occurring mutations with sensitizing <i>EGFR</i> mutations include <i>KRAS</i> at 53.9%, followed by <i>ERBB2</i> at 24.3%, <i>MET</i> at 16.5%, and <i>BRAF</i> at 3.3%. <i>KRAS</i> mutations in concomitant drivers were frequently hyperexchange mutations (25.6% <i>v</i> 8.2%, <i>P</i> < .001), compared with <i>KRAS</i> single drivers. <i>EGFR</i>/<i>ERBB2</i> drivers exhibited a higher incidence of <i>ERBB2</i> amplification (40.7% <i>v</i> 16.5%, <i>P</i> < .001) and p.S310F/Y mutations (44.4% <i>v</i> 4.3%, <i>P</i> < .001) compared with <i>ERBB2</i> alone. <i>EGFR</i>/<i>MET</i> drivers had a higher frequency of <i>MET</i> amplification (71.4% <i>v</i> 43.3%) than <i>MET</i> single drivers. At the genomic level, the median number of additional concurrent mutations was four, with <i>TSC2</i> (4%), <i>CD274</i> (1%), and <i>TP53</i> (63%) being the most frequently coaltered genes in concomitant driver tumors. Interestingly, clonality analysis indicated that <i>EGFR</i> mutations were more likely to occur as clonal events, whereas the codrivers were more often subclonal. Patients with concomitant drivers or with concomitant <i>MET</i> amplification exhibited worse prognosis.</p><p><strong>Conclusion: </strong>These findings might aid in the selection of effective therapeutic regimens and facilitate the development of combination therapies.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893482","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}