Taylor A Rives, James Collard, Ning Li, Donglin Yan, Charles S Dietrich, Rachel W Miller, Frederick R Ueland, Justine Pickarski, Jill M Kolesar
Purpose: Tumor next-generation sequencing (NGS) testing identifies possible germline pathogenic variants (PGPVs), creating a dilemma for appropriate recognition, triage, and management. The objective of this study was to determine the clinical utility of an institutional molecular tumor board (MTB) in assessing tumor NGS reports for PGPVs.
Methods: Our institutional MTB reviews all NGS reports to provide treatment and further testing recommendations, including genetic counseling referral and consideration of genetic testing (GC/GT). We studied the patients reviewed by the MTB who were recommended for GC/GT to determine the frequency of referral to a GC, germline test completion, rate of pathogenic germline variants (PGVs), factors related to PGVs, and germline conversion rate (GCR).
Results: Of the 2,355 patients reviewed by the MTB during the study period, 609 (25.9%) had a recommendation for GC/GT. Of the 609 with a GC/GT recommendation, only 181 (29.7%) were referred for GC/GT by their treating physicians, and only 107 (17.6%) completed GT. Of the 107 patients completing GT, 29 (26%) had a confirmed PGV. The only factors significantly associated with PGVs were testing due to a PGPV and higher mean variant allele fraction on the tumor NGS. Only 40 patients with a GC/GT recommendation (14.3%) due to a PGPV completed GT; however, the GCR was 42.5% (n = 17/40).
Conclusion: The MTB review of PGPV is clinically valuable, identifying PGPV in 12% of patients undergoing tumor NGS and a GCR of 42.5%. Rates of GC/GT completion were relatively low due to under-referral by treating physicians. Given the high GCR, the authors encourage institutional algorithms to help increase GC/GT rates for patients found to have PGPV following tumor NGS testing.
{"title":"Clinical Utility of Molecular Tumor Board Review for Identification of Possible Germline Pathogenic Variants on Tumor Next-Generation Sequencing Reports.","authors":"Taylor A Rives, James Collard, Ning Li, Donglin Yan, Charles S Dietrich, Rachel W Miller, Frederick R Ueland, Justine Pickarski, Jill M Kolesar","doi":"10.1200/PO.24.00301","DOIUrl":"https://doi.org/10.1200/PO.24.00301","url":null,"abstract":"<p><strong>Purpose: </strong>Tumor next-generation sequencing (NGS) testing identifies possible germline pathogenic variants (PGPVs), creating a dilemma for appropriate recognition, triage, and management. The objective of this study was to determine the clinical utility of an institutional molecular tumor board (MTB) in assessing tumor NGS reports for PGPVs.</p><p><strong>Methods: </strong>Our institutional MTB reviews all NGS reports to provide treatment and further testing recommendations, including genetic counseling referral and consideration of genetic testing (GC/GT). We studied the patients reviewed by the MTB who were recommended for GC/GT to determine the frequency of referral to a GC, germline test completion, rate of pathogenic germline variants (PGVs), factors related to PGVs, and germline conversion rate (GCR).</p><p><strong>Results: </strong>Of the 2,355 patients reviewed by the MTB during the study period, 609 (25.9%) had a recommendation for GC/GT. Of the 609 with a GC/GT recommendation, only 181 (29.7%) were referred for GC/GT by their treating physicians, and only 107 (17.6%) completed GT. Of the 107 patients completing GT, 29 (26%) had a confirmed PGV. The only factors significantly associated with PGVs were testing due to a PGPV and higher mean variant allele fraction on the tumor NGS. Only 40 patients with a GC/GT recommendation (14.3%) due to a PGPV completed GT; however, the GCR was 42.5% (n = 17/40).</p><p><strong>Conclusion: </strong>The MTB review of PGPV is clinically valuable, identifying PGPV in 12% of patients undergoing tumor NGS and a GCR of 42.5%. Rates of GC/GT completion were relatively low due to under-referral by treating physicians. Given the high GCR, the authors encourage institutional algorithms to help increase GC/GT rates for patients found to have PGPV following tumor NGS testing.</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/PMC11404756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142287717","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-24-00434
Jeremy L Davis, Amber F Gallanis
Total gastrectomy should be performed less often in germline CDH1 variant carriers based on mounting clinical evidence.
根据越来越多的临床证据,应减少对 CDH1 基因变异携带者实施全胃切除术。
{"title":"A Decreased Appetite for Prophylactic Total Gastrectomy.","authors":"Jeremy L Davis, Amber F Gallanis","doi":"10.1200/PO-24-00434","DOIUrl":"10.1200/PO-24-00434","url":null,"abstract":"<p><p>Total gastrectomy should be performed less often in germline CDH1 variant carriers based on mounting clinical evidence.</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/PMC11444520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142347058","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}
Mwanasha H Merrill, Sophie R Cahill, Hannah W Pepprock, Robert Redd, Huma Q Rana, Katherine E Economy, Judy E Garber, Ann S LaCasce
{"title":"Detection of Maternal Malignancy After Abnormal Noninvasive Prenatal Testing: A Single-Center Case Series.","authors":"Mwanasha H Merrill, Sophie R Cahill, Hannah W Pepprock, Robert Redd, Huma Q Rana, Katherine E Economy, Judy E Garber, Ann S LaCasce","doi":"10.1200/PO.24.00058","DOIUrl":"https://doi.org/10.1200/PO.24.00058","url":null,"abstract":"","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":"142287720","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}
Ann Ayzman, Russell K Pachynski, Melissa A Reimers
{"title":"Progress and Promise for Multicancer Early Detection Testing in Prostate Cancer.","authors":"Ann Ayzman, Russell K Pachynski, Melissa A Reimers","doi":"10.1200/PO-24-00565","DOIUrl":"https://doi.org/10.1200/PO-24-00565","url":null,"abstract":"","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":"142287724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-09-30DOI: 10.1200/PO.24.00280
Hailey Seibert, Hanna Kakish, Jeremy S Bordeaux, Luke D Rothermel, Richard S Hoehn
Socioeconomic factors influence the survival of patients with early stage melanoma and thus should be accounted for in prognostication tools.
社会经济因素会影响早期黑色素瘤患者的存活率,因此应在预后工具中加以考虑。
{"title":"Accounting for Socioeconomic Factors and Selection Bias That Affect Survival for Patients With Early-Stage Melanoma.","authors":"Hailey Seibert, Hanna Kakish, Jeremy S Bordeaux, Luke D Rothermel, Richard S Hoehn","doi":"10.1200/PO.24.00280","DOIUrl":"https://doi.org/10.1200/PO.24.00280","url":null,"abstract":"<p><p>Socioeconomic factors influence the survival of patients with early stage melanoma and thus should be accounted for in prognostication tools.</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":"142347059","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}
Yonina R Murciano-Goroff, Angela B-Y Hui, Jose A Araujo Filho, Emily G Hamilton, Jacob J Chabon, Everett J Moding, Rene F Bonilla, Emily S Lebow, Daniel Gomez, Andreas Rimner, Michelle S Ginsberg, Michael Offin, Ritika Kundra, Viola Allaj, Larry Norton, Jorge S Reis-Filho, Pedram Razavi, Alexander Drilon, David R Jones, James M Isbell, W Victoria Lai, Charles M Rudin, Ash A Alizadeh, Bob T Li, Maximilian Diehn
Purpose: Small cell lung cancer (SCLC) is characterized by rapid progression after platinum resistance. Circulating tumor (ctDNA) dynamics early in treatment may help determine platinum sensitivity.
Materials and methods: Serial plasma samples were collected from patients receiving platinum-based chemotherapy for SCLC on the first 3 days of cycle one and on the first days of subsequent cycles with paired samples collected both before and again after infusions. Tumor-informed plasma analysis was carried out using CAncer Personalized Profiling by deep Sequencing (CAPP-Seq). The mean variant allele frequency (VAF) of all pretreatment mutations was tracked in subsequent blood draws and correlated with radiologic response.
Results: ctDNA kinetics were assessed in 122 samples from 21 patients. Pretreatment VAF did not differ significantly between patients who did and did not respond to chemotherapy (mean 22.5% v 4.6%, P = .17). A slight increase in ctDNA on cycle 1, day 1 immediately post-treatment was seen in six of the seven patients with available draws (fold change from baseline: 1.01-1.44), half of whom achieved a response. All patients who responded had a >2-fold decrease in mean VAF on cycle 2 day 1 (C2D1). Progression-free survival (PFS) and overall survival (OS) were significantly longer in patients with a >2-fold decrease in mean VAF after one treatment cycle (6.8 v 2.6 months, log-rank P = .0004 and 21.7 v 6.4 months, log rank P = .04, respectively).
Conclusion: A >2-fold decrease in ctDNA concentration was observed by C2D1 in all patients who were sensitive to platinum-based therapy and was associated with longer PFS and OS.
{"title":"Early Circulating Tumor DNA Shedding Kinetics for Prediction of Platinum Sensitivity in Patients With Small Cell Lung Cancer.","authors":"Yonina R Murciano-Goroff, Angela B-Y Hui, Jose A Araujo Filho, Emily G Hamilton, Jacob J Chabon, Everett J Moding, Rene F Bonilla, Emily S Lebow, Daniel Gomez, Andreas Rimner, Michelle S Ginsberg, Michael Offin, Ritika Kundra, Viola Allaj, Larry Norton, Jorge S Reis-Filho, Pedram Razavi, Alexander Drilon, David R Jones, James M Isbell, W Victoria Lai, Charles M Rudin, Ash A Alizadeh, Bob T Li, Maximilian Diehn","doi":"10.1200/PO.24.00216","DOIUrl":"10.1200/PO.24.00216","url":null,"abstract":"<p><strong>Purpose: </strong>Small cell lung cancer (SCLC) is characterized by rapid progression after platinum resistance. Circulating tumor (ctDNA) dynamics early in treatment may help determine platinum sensitivity.</p><p><strong>Materials and methods: </strong>Serial plasma samples were collected from patients receiving platinum-based chemotherapy for SCLC on the first 3 days of cycle one and on the first days of subsequent cycles with paired samples collected both before and again after infusions. Tumor-informed plasma analysis was carried out using CAncer Personalized Profiling by deep Sequencing (CAPP-Seq). The mean variant allele frequency (VAF) of all pretreatment mutations was tracked in subsequent blood draws and correlated with radiologic response.</p><p><strong>Results: </strong>ctDNA kinetics were assessed in 122 samples from 21 patients. Pretreatment VAF did not differ significantly between patients who did and did not respond to chemotherapy (mean 22.5% <i>v</i> 4.6%, <i>P</i> = .17). A slight increase in ctDNA on cycle 1, day 1 immediately post-treatment was seen in six of the seven patients with available draws (fold change from baseline: 1.01-1.44), half of whom achieved a response. All patients who responded had a >2-fold decrease in mean VAF on cycle 2 day 1 (C2D1). Progression-free survival (PFS) and overall survival (OS) were significantly longer in patients with a >2-fold decrease in mean VAF after one treatment cycle (6.8 <i>v</i> 2.6 months, log-rank <i>P</i> = .0004 and 21.7 <i>v</i> 6.4 months, log rank <i>P</i> = .04, respectively).</p><p><strong>Conclusion: </strong>A >2-fold decrease in ctDNA concentration was observed by C2D1 in all patients who were sensitive to platinum-based therapy and was associated with longer PFS and OS.</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/PMC11376985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132747","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}
Lauren R Desrosiers-Battu, Tao Wang, Jacquelyn Reuther, George Miles, Hongzheng Dai, Eunji Jo, Heidi Russell, Robin Raesz-Martinez, Alva Recinos, Stephanie Gutierrez, Amy Thomas, Emily Berenson, Jessica Corredor, Kimberly Nugent, Rachel Wyatt Castillo, Rebecca Althaus, Rebecca Littlejohn, Shawn Gessay, Gail Tomlinson, Jonathan Gill, Juan Carlos Bernini, Kelly Vallance, Timothy Griffin, Sarah Scollon, Frank Y Lin, Christine Eng, Shashikant Kulkarni, Susan G Hilsenbeck, Angshumoy Roy, Amy L McGuire, D Williams Parsons, Sharon E Plon
Purpose: To evaluate the relative diagnostic yield of clinical germline genomic tests in a diverse pediatric cancer population.
Patients and methods: The KidsCanSeq study enrolled pediatric cancer patients across six sites in Texas. Germline analysis included both exome sequencing and a therapy-focused pediatric cancer gene panel. The results were categorized by participants demographics, the presence of pathogenic or likely pathogenic (P/LP) variants, and variants of uncertain significance (VUS) in cancer predisposition genes (CPGs). Pediatric actionable CPGs were defined as those with cancer surveillance recommendations during childhood.
Results: Cancer P/LP variants were reported by at least one platform in 103 of 578 (17.8%) participants of which 76 were dominant cancer genes (13.1%) with no significant differences by self-described race or Hispanic ethnicity. However, the proportion of participants with VUS was greater in Asian and African American participants (P = .0029). Diagnostic yield was 16.6% for exome versus 8.5% for panel (P < .0001) with 42 participants with concordant germline results. Exome-only results included P/LP variants in 30 different CPGs in 54 participants, whereas panel-only results included seven participants with a copy number or structural P/LP variants in CPGs. There was no significant difference in diagnostic yield limited to pediatric actionable CPGs (P = .6171).
Conclusion: Approximately 18% of a diverse pediatric cancer population had germline diagnostic findings with 50% of P/LP variants reported by only one platform because of CPGs not on the targeted panel and copy number variants (CNVs)/rearrangements not reported by exome. Although diagnostic yields were similar in this diverse population, increases in VUS results were observed in Asian and African American populations. Given the clinical significance of CNVs/rearrangements in this cohort, detection is critical to optimize germline analysis of pediatric cancer populations.
{"title":"Comparing the Diagnostic Yield of Germline Exome Versus Panel Sequencing in the Diverse Population of the Texas KidsCanSeq Pediatric Cancer Study.","authors":"Lauren R Desrosiers-Battu, Tao Wang, Jacquelyn Reuther, George Miles, Hongzheng Dai, Eunji Jo, Heidi Russell, Robin Raesz-Martinez, Alva Recinos, Stephanie Gutierrez, Amy Thomas, Emily Berenson, Jessica Corredor, Kimberly Nugent, Rachel Wyatt Castillo, Rebecca Althaus, Rebecca Littlejohn, Shawn Gessay, Gail Tomlinson, Jonathan Gill, Juan Carlos Bernini, Kelly Vallance, Timothy Griffin, Sarah Scollon, Frank Y Lin, Christine Eng, Shashikant Kulkarni, Susan G Hilsenbeck, Angshumoy Roy, Amy L McGuire, D Williams Parsons, Sharon E Plon","doi":"10.1200/PO.24.00187","DOIUrl":"https://doi.org/10.1200/PO.24.00187","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate the relative diagnostic yield of clinical germline genomic tests in a diverse pediatric cancer population.</p><p><strong>Patients and methods: </strong>The KidsCanSeq study enrolled pediatric cancer patients across six sites in Texas. Germline analysis included both exome sequencing and a therapy-focused pediatric cancer gene panel. The results were categorized by participants demographics, the presence of pathogenic or likely pathogenic (P/LP) variants, and variants of uncertain significance (VUS) in cancer predisposition genes (CPGs). Pediatric actionable CPGs were defined as those with cancer surveillance recommendations during childhood.</p><p><strong>Results: </strong>Cancer P/LP variants were reported by at least one platform in 103 of 578 (17.8%) participants of which 76 were dominant cancer genes (13.1%) with no significant differences by self-described race or Hispanic ethnicity. However, the proportion of participants with VUS was greater in Asian and African American participants (<i>P</i> = .0029). Diagnostic yield was 16.6% for exome versus 8.5% for panel (<i>P</i> < .0001) with 42 participants with concordant germline results. Exome-only results included P/LP variants in 30 different CPGs in 54 participants, whereas panel-only results included seven participants with a copy number or structural P/LP variants in CPGs. There was no significant difference in diagnostic yield limited to pediatric actionable CPGs (<i>P</i> = .6171).</p><p><strong>Conclusion: </strong>Approximately 18% of a diverse pediatric cancer population had germline diagnostic findings with 50% of P/LP variants reported by only one platform because of CPGs not on the targeted panel and copy number variants (CNVs)/rearrangements not reported by exome. Although diagnostic yields were similar in this diverse population, increases in VUS results were observed in Asian and African American populations. Given the clinical significance of CNVs/rearrangements in this cohort, detection is critical to optimize germline analysis of pediatric cancer populations.</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/PMC11392521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142287719","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-24-00405
Christine N Bailey, Brian J Martin, Valentina I Petkov
{"title":"Reply to H. Seibert et al.","authors":"Christine N Bailey, Brian J Martin, Valentina I Petkov","doi":"10.1200/PO-24-00405","DOIUrl":"https://doi.org/10.1200/PO-24-00405","url":null,"abstract":"","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":"142347063","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}
Theodore W Laetsch, Kathleen Ludwig, P Mickey Williams, Sinchita Roy-Chowdhuri, David R Patton, Brent Coffey, Joel M Reid, Jin Piao, Lauren Saguilig, Todd A Alonzo, Stacey L Berg, Joyce Mhlanga, Elizabeth Fox, Brenda J Weigel, Douglas S Hawkins, Margaret M Mooney, Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, Donald Williams Parsons
Purpose: Patients age 1-21 years with relapsed or refractory solid and CNS tumors were assigned to phase II studies of molecularly targeted therapies on the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial. Patients whose tumors harbored predefined genetic alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway and lacked mitogen-activated protein kinase pathway activating alterations were treated with the PI3K/mTOR inhibitor samotolisib.
Methods: Patients received samotolisib twice daily in 28-day cycles until disease progression or unacceptable toxicity. A rolling 6 limited dose escalation was performed as, to our knowledge, this was the first pediatric study of samotolisib. The primary end point was the objective response rate; secondary end points included progression-free survival (PFS) and the recommended phase II dose and toxicity of samotolisib in children.
Results: A total of 3.4% (41/1,206) of centrally tested patients were matched to this arm. Seventeen patients were treated. Among treated patients, the most common diagnoses included osteosarcoma (n = 6) and high-grade glioma (n = 5) harboring alterations in phosphatase and tensin homolog (n = 6), PIK3CA (n = 5), and tuberous sclerosis complex 2 (n = 3). No objective responses or prolonged stable disease were observed. Three-month PFS was 12% (95% CI, 2 to 31). Two patients experienced dose-limiting toxicities (mucositis and pneumonitis). Dose level 2 (115 mg/m2/dose twice daily) was determined to be the recommended phase II dose of samotolisib in children.
Conclusion: This nationwide study was successful at identifying patients and evaluating the efficacy of molecularly targeted therapy for rare molecular subgroups of patients in a histology-agnostic fashion. Unfortunately, there was no activity of samotolisib against tumors with PI3K/mTOR pathway alterations. Prospective trials such as the NCI-COG Pediatric MATCH are necessary to evaluate the efficacy of molecularly targeted therapies given their increasing use in clinical practice.
{"title":"Phase II Study of Samotolisib in Children and Young Adults With Tumors Harboring Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Pathway Alterations: Pediatric MATCH APEC1621D.","authors":"Theodore W Laetsch, Kathleen Ludwig, P Mickey Williams, Sinchita Roy-Chowdhuri, David R Patton, Brent Coffey, Joel M Reid, Jin Piao, Lauren Saguilig, Todd A Alonzo, Stacey L Berg, Joyce Mhlanga, Elizabeth Fox, Brenda J Weigel, Douglas S Hawkins, Margaret M Mooney, Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, Donald Williams Parsons","doi":"10.1200/PO.24.00258","DOIUrl":"10.1200/PO.24.00258","url":null,"abstract":"<p><strong>Purpose: </strong>Patients age 1-21 years with relapsed or refractory solid and CNS tumors were assigned to phase II studies of molecularly targeted therapies on the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial. Patients whose tumors harbored predefined genetic alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway and lacked mitogen-activated protein kinase pathway activating alterations were treated with the PI3K/mTOR inhibitor samotolisib.</p><p><strong>Methods: </strong>Patients received samotolisib twice daily in 28-day cycles until disease progression or unacceptable toxicity. A rolling 6 limited dose escalation was performed as, to our knowledge, this was the first pediatric study of samotolisib. The primary end point was the objective response rate; secondary end points included progression-free survival (PFS) and the recommended phase II dose and toxicity of samotolisib in children.</p><p><strong>Results: </strong>A total of 3.4% (41/1,206) of centrally tested patients were matched to this arm. Seventeen patients were treated. Among treated patients, the most common diagnoses included osteosarcoma (n = 6) and high-grade glioma (n = 5) harboring alterations in phosphatase and tensin homolog (n = 6), <i>PIK3CA</i> (n = 5), and tuberous sclerosis complex 2 (n = 3). No objective responses or prolonged stable disease were observed. Three-month PFS was 12% (95% CI, 2 to 31). Two patients experienced dose-limiting toxicities (mucositis and pneumonitis). Dose level 2 (115 mg/m<sup>2</sup>/dose twice daily) was determined to be the recommended phase II dose of samotolisib in children.</p><p><strong>Conclusion: </strong>This nationwide study was successful at identifying patients and evaluating the efficacy of molecularly targeted therapy for rare molecular subgroups of patients in a histology-agnostic fashion. Unfortunately, there was no activity of samotolisib against tumors with PI3K/mTOR pathway alterations. Prospective trials such as the NCI-COG Pediatric MATCH are necessary to evaluate the efficacy of molecularly targeted therapies given their increasing use in clinical practice.</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":"142287723","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}