JCO precision oncology最新文献

{"title":"Prevalence and Distribution of Unexpected Actionable Germline Pathogenic Variants Identified on Broad-Based Multigene Panel Testing Among Patients With Cancer.","authors":"Kara K Landry, Michael J DeSarno, Lindsay Kipnis, Farid Barquet Ramos, Katelyn M Breen, Kaleigh Patton, Audrey Morrissette, Ryan M Buehler, Chinedu Ukaegbu, Mersedeh Rohanizadegan, Matthew B Yurgelun, Sapna Syngal, Huma Q Rana, Judy E Garber","doi":"10.1200/PO-24-00553","DOIUrl":"https://doi.org/10.1200/PO-24-00553","url":null,"abstract":"<p><strong>Purpose: </strong>In patients with a variety of malignancies undergoing multigene panel testing (MGPT), we examined the frequency of a pathogenic/likely pathogenic variant (PV) that would not have been predicted on the basis of the patient's personal and family history of cancer.</p><p><strong>Methods: </strong>This is a retrospective review of patients with cancer ascertained from a single academic cancer center who underwent broad-based MGPT of ≥20 cancer predisposition genes not selected on the basis of personal or family cancer history from 2015 to 2021. Low-penetrance variants and recessive inheritance genes were excluded. Deidentified pedigrees were analyzed to determine clinical suspicion of PV.</p><p><strong>Results: </strong>MGPT was performed on 10,975 patients with cancer: 1,134 (10.3%) were found to have ≥1 PV in a moderate or highly penetrant cancer susceptibility gene. Three hundred seven (2.8%) of the PVs were not predicted on the basis of patient's personal cancer history alone, and 192 (1.7%) remained unsuspected after patient's cancer diagnosis and review of family cancer histories were considered. Unexpected PVs accounted for 16.9% of the 1,134 patients with a moderate- or high-penetrance PV. Most frequent unexpected variants were <i>MITF</i> (n = 18), <i>PMS2</i> (n = 18), <i>ATM</i> (n = 17), <i>BRIP1</i> (n = 17), <i>HOXB13</i> (n = 14), <i>SDHA</i> (n = 12), <i>CHEK2</i> (n = 11), <i>BRCA2</i> (n = 7), <i>MSH6</i> (n = 7), <i>SDHC</i> (n = 7), <i>PALB2</i> (n = 6), and <i>TP53</i> (n = 6). Low-penetrance or recessive variants were found in 519 (4.7%) patients. Variants of uncertain significance were found in 3,775 (34.4%).</p><p><strong>Conclusion: </strong>In patients with cancer, MGPT identified a rate of 1.7% PV in unexpected actionable cancer predisposition genes. Findings were more often unexpected (2.8%) when considering only the patient cancer history. These findings may justify consideration of broader MGPT panels in patients with cancer, given implications for subsequent surveillance, cascade testing, and treatment options dependent on specific findings.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400553"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Utility of a Circulating Tumor Cell-Based Cerebrospinal Fluid Assay in the Diagnosis and Molecular Analysis of Leptomeningeal Disease in Patients With Advanced Non-Small Cell Lung Cancer.","authors":"Jyoti Malhotra, Ramya Muddasani, Jeremy Fricke, Isa Mambetsariev, Amanda Reyes, Razmig Babikian, Shaira Therese Dingal, Pauline Kim, Erminia Massarelli, Lisa Feldman, Mike Chen, Michelle Afkhami, Ravi Salgia","doi":"10.1200/PO-24-00373","DOIUrl":"https://doi.org/10.1200/PO-24-00373","url":null,"abstract":"<p><strong>Purpose: </strong>Leptomeningeal disease (LMD) is associated with significant morbidity and mortality for metastatic non-small cell lung cancer (NSCLC). We describe our clinical experience in evaluating the use of cerebrospinal fluid (CSF)-derived circulating tumor cells (CTCs) for the diagnosis of LMD and the detection of genomic alterations in CSF cell-free DNA (cfDNA).</p><p><strong>Methods: </strong>Patients with NSCLC who had CSF collection as part of routine clinical care for suspected LMD were included in the study. CSF was evaluated for CTCs and cfDNA using a commercial assay (CNSide; Biocept, San Diego, CA), and molecular profiling was performed. Molecular testing results from sequencing of tumor tissue and plasma circulating tumor DNA were collected. cMET and human epidermal growth factor receptor 2 (HER2) expression analysis was performed using fluorescence in situ hybridization (FISH).</p><p><strong>Results: </strong>Twenty-two patients were included (77% female; median age 60 years). Sixty-four percent had sensitizing <i>EGFR</i> mutations, and 32% had an atypical <i>EGFR</i> mutation. Thirteen of the 22 patients (59%) were diagnosed with LMD using the CSF CTC assay. Five of these 13 patients (38%) had negative CSF cytology for LMD, and two patients (15%) had normal magnetic resonance imaging brain imaging. Seven of the 13 patients (54%) had sufficient CTCs to perform molecular profiling. The concordance with tissue next-generation sequencing was 100%, and the driver mutation was identified in all seven patients with the CSF cfDNA assay. cMET expression and HER2 expression via FISH were noted in 11 patients (50%) and four patients (18%) respectively.</p><p><strong>Conclusion: </strong>We detected higher sensitivity to diagnose LMD using CSF CTC-based assay; 38% of LMD cases identified using this assay were missed by standard CSF cytology. CSF molecular testing using CSF cfDNA demonstrated high concordance with tissue-based molecular testing.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400373"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolution of Rapid Clonal Dynamics and Non-Cross-Resistance in Response to Alternating Targeted Therapy and Chemotherapy in BRAF-V600E-Mutant Colon Cancer.","authors":"Srilatha Simhadri, Jillian N Carrick, Susan Murphy, Om A Kothari, Husam Al-Hraishami, Atul Kulkarni, Nahed Jalloul, Katarina Stefanik, Manisha Bandari, Kavya Chettur, Ming Yao, Vasudeva Ginjala, Roman Groisberg, Howard Hochster, Janice Mehnert, Gregory Riedlinger, Hossein Khiabanian, Michael P Verzi, Kevin Tong, Shridar Ganesan","doi":"10.1200/PO.23.00260","DOIUrl":"10.1200/PO.23.00260","url":null,"abstract":"<p><strong>Purpose: </strong>Combined BRAF, MEK, and EGFR inhibition can induce clinical responses in BRAF-V600E-mutant colon cancer, but rapid resistance often occurs.</p><p><strong>Methods: </strong>We use serial monitoring of circulating tumor DNA cell-free plasma DNA (cfDNA) in a patient case study in addition to organoids derived from mouse models of BRAF-V600E-mutant intestinal cancer, which emulated the patient's mutational profile to assess drug treatment efficacy.</p><p><strong>Results: </strong>We demonstrate dynamic evolution of resistance to combined EGFR/BRAF/MEK inhibition in a pediatric patient with metastatic BRAF-V600E-mutant, mismatch repair-stable colon cancer. Initial resistance to targeted therapy was associated with development of MET amplification. Sequential treatment with chemotherapy and targeted therapy resulted in clearing of the resistant MET-amplified clone. Rechallenge with combined BRAF/EGFR inhibition resulted in clinical and radiographic response, demonstrating these treatments may be non-cross-resistant. Tumor organoids were used to model clinical findings and demonstrated effectiveness of combined targeted therapy and chemotherapy.</p><p><strong>Conclusion: </strong>These findings suggest rational strategies for combining sequential chemotherapy and BRAF-/EGFR-directed therapy in BRAF-V600E-mutant colon cancer to prevent resistance and improve outcome. The data demonstrate rapid clonal dynamics in response to effective therapies in BRAF-V600E-mutant colon cancer that can be monitored by serial cfDNA analysis. Moreover, in mismatch repair-proficient BRAF-V600E-mutant colon cancers, combined EGFR and BRAF/MEK therapy is not cross-resistant with standard chemotherapy, suggesting new rational combination treatment strategies.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2300260"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11627326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parents' Experiences With and Preferences for Receiving Information About Tumor Genomic Sequencing: Findings From a Qualitative Study and Implications for Practice.","authors":"Brittany L Greene, Krysta S Barton, Emily Bonkowski, Shannon M Stasi, Natalie Waligorski, Jonathan M Marron, Abby R Rosenberg","doi":"10.1200/PO-24-00543","DOIUrl":"https://doi.org/10.1200/PO-24-00543","url":null,"abstract":"<p><strong>Purpose: </strong>The use of up-front tumor genomic sequencing (TGS) is becoming increasingly common in pediatric oncology. Despite this, little is known about how parents receive information about TGS at the time of their child's cancer diagnosis. We aimed to describe parents' experiences with and preferences for receiving information about TGS and to use these findings to inform practical guidance for pediatric oncology clinicians.</p><p><strong>Methods: </strong>We conducted semistructured interviews with English-speaking parents (older than 18 years) of patients (younger than 18 years) who had TGS for a new diagnosis of cancer. We analyzed the interviews thematically. Participants also completed a short demographic survey, and we obtained medical information about participants' children via chart review.</p><p><strong>Results: </strong>We interviewed 20 parents (14 mothers; median age, 38 years) of children who underwent TGS for a newly diagnosed cancer (10 leukemias/lymphomas, three CNS tumors, seven other solid tumors). Children were 6 months to 17 years at diagnosis (median, 6 years). Fifteen parents and their children were White, two of whom were Hispanic and four of whose children were Hispanic. No participants identified themselves or their child as Black. We identified the following themes regarding information delivery about genomic testing from the interviews: (1) those in the parent role have some universal information needs; (2) information delivery preferences vary among parents, even within one family; and (3) parents desire standard yet tailored information delivery.</p><p><strong>Conclusion: </strong>Parents made suggestions consistent with elements of established high-quality communication in pediatric oncology. As genomic testing is more standardly incorporated into childhood cancer care, communication with parents may need to adapt to reflect this. Our findings highlight potential opportunities to support parents in receiving information about genomic testing.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400543"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase II Trial of the PARP Inhibitor, Niraparib, in BAP1 and Other DNA Damage Response Pathway-Deficient Neoplasms.","authors":"Thomas J George, Ji-Hyun Lee, David L DeRemer, Peter J Hosein, Steven Staal, Merry Jennifer Markham, Dennie Jones, Karen C Daily, Jonathan A Chatzkel, Brian H Ramnaraign, Julia L Close, Nkiruka Ezenwajiaku, Martina C Murphy, Carmen J Allegra, Sherise Rogers, Zhongyue Zhang, Derek Li, Gayathri Srinivasan, Montaser Shaheen, Robert Hromas","doi":"10.1200/PO-24-00406","DOIUrl":"10.1200/PO-24-00406","url":null,"abstract":"<p><strong>Purpose: </strong>BRCA1-associated protein 1 (BAP1) is a critical cell cycle and DNA damage response (DDR) regulator with mutations (mBAP1) causing a functional protein loss. PARP inhibitors (PARPis) demonstrate synthetic lethality in mBAP1 preclinical models, independent of underlying BRCA status. This study aimed to explore the clinical activity of niraparib in patients with advanced tumors likely to harbor mBAP1.</p><p><strong>Methods: </strong>This was a phase II multicenter trial in which refractory solid tumor patients were assigned to cohort A (histology-specific tumors likely to harbor mBAP1) or cohort B (histology-agnostic tumors with other known non-BRCA-confirmed DDR mutations). All patients received niraparib 300 mg orally once daily on a 28-day cycle. The primary end point was objective response rate, and secondary end points included progression-free survival (PFS) and overall survival.</p><p><strong>Results: </strong>From August 2018 through December 2021, 37 patients were enrolled with 31 evaluable for response (cohort A, n = 18; cohort B, n = 13). In cohort A, the best response was one partial response (PR; 6%), eight stable disease (SD; 44%), and nine progressive disease (PD; 50%). This cohort stopped at the first stage following the prespecified Simon's design. mBAP1 was confirmed in 7/9 patients (78%) with PR or SD but in only 3/9 (33%) in those with PD. The median PFS in patients with mBAP1 (n = 10) was 6.7 months (95% CI, 1.0 to 9.2) versus 1.8 months (95% CI, 0.9 to 4.5) for wild-type (n = 8; <i>P</i> = .020). In cohort B, the best response was six SD (46%) and seven PD (54%), with SD in those with <i>ATM</i>, <i>CHEK2</i>, <i>PTEN</i>, <i>RAD50</i>, and <i>ARID1A</i> mutations.</p><p><strong>Conclusion: </strong>Niraparib failed to meet the prespecified efficacy end point for response. However, clinical benefit was suggested in a proportion of patients who had a confirmed mBAP1, supporting further investigation.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400406"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11616782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769029","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":"Discovery of Gene Fusions in Driver-Negative Cancer Samples From the National Cancer Institute-Molecular Analysis for Therapy Choice Screening Cohort.","authors":"Stefan T Kaluziak, Elizabeth M Codd, Rashi Purohit, Beatrice Melli, Prinjali Kalyan, Jo Anne Fordham, Grace Kirkpatrick, Lisa M McShane, Ting-Chia Chang, Guangxiao Yang, Jinglan Wang, P Mickey Williams, Chris Karlovich, Jeffrey Sklar, A John Iafrate","doi":"10.1200/PO-24-00493","DOIUrl":"10.1200/PO-24-00493","url":null,"abstract":"<p><strong>Purpose: </strong>The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) trial was implemented to identify actionable genetic alterations across cancer types and enroll patients accordingly onto treatment arms, irrespective of tumor histology. Using multiplex polymerase chain reaction (PCR) next-generation sequencing, NCI-MATCH genotyped 5,540 patients, discovering gene fusions in 202/5,540 tumors (3.65%). This result, substantially lower than the fusion detection prevalence of 8.5% across all patients with cancer screened at Massachusetts General Hospital's (MGH) clinical laboratories, supported reanalysis of NCI-MATCH samples identified as mutations-of-interest (MOI)-negative. The assay used by NCI-MATCH requires previous knowledge of both fusion genes, cannot detect novel fusions, and may underestimate fusion-positive patients. Anchored multiplex PCR (AMP) technology permits fusion detection with knowledge of just one gene of the fusion partners.</p><p><strong>Methods: </strong>Using AMP-based kits, we reprocessed 663 MOI-negative samples. 200 ng of RNA per sample were shipped from the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network biorepository to MGH (n = 319) and Yale University (n = 344), processed, and sequenced on the NextSeq550. Reported fusions were manually reviewed, and novel fusions orthogonally verified via reverse-transcription PCR and Sanger sequencing.</p><p><strong>Results: </strong>AMP identified 148 fusions in 142/663 MOI-negative patients (21% [95% CI, 18 to 25]), of which 28 were covered by the Oncomine Comprehensive Assay (OCA) panel but missed, while 120 were not covered by OCA. Among AMP-identified positive patients, 32 had actionable fusions, 24 contained novel fusions, and six had two fusion events. We identified fusions in 12/34 (35% [95% CI, 20 to 54]) cholangiocarcinomas and 43/109 (39% [95% CI, 30 to 49]) sarcomas.</p><p><strong>Conclusion: </strong>Technology and awareness of actionable fusions have improved since the NCI-MATCH trial. With AMP-based technology, we identified 142 patients with fusions not detected during NCI-MATCH screening, many potentially actionable. These striking data underscore the need to optimize the fusion-detection capabilities of genotyping assays used in precision medicine.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400493"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11634183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785548","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":"Targeted-Agent Continual Reassessment Method: A Novel Bayesian Enrichment Design for Phase I Trials of Molecularly Targeted Therapies.","authors":"Clement Ma, David S Shulman, Hasan Al-Sayegh, Steven G DuBois, Wendy B London","doi":"10.1200/PO.24.00360","DOIUrl":"10.1200/PO.24.00360","url":null,"abstract":"<p><strong>Purpose: </strong>Novel therapies targeting specific genomic alterations are a promising treatment approach for relapsed/refractory cancer. Patients with specific alterations may be more likely to respond. Trial designs should maximize opportunities for such patients to enroll on these trials. Existing designs do not enrich for patients with specific alterations. We developed the adaptive Targeted Agent-Continual Reassessment Method (TARGET-CRM) to optimize dose finding and enrich for patients with specific alterations, and applied it in a pediatric phase I trial.</p><p><strong>Methods: </strong>Patients were stratified to cohort A (unspecified tumors) or cohort B (rare genomic alterations). The TARGET-CRM design permits cohort B patients to immediately enroll at one dose level below the currently evaluated dose level instead of waiting for an open slot at the current dose level. Using simulations, we compared the operating characteristics (accuracy-the proportion of trials in which the true maximum tolerated dose [MTD] was identified/recommended; safety-the dose-limiting toxicity [DLT] rate; the proportion of cohort B patients enrolled) of the TARGET-CRM, standard CRM, and 3 + 3 designs across various scenarios.</p><p><strong>Results: </strong>The proportion of enrolled patients who were cohort B was higher for TARGET-CRM (90%-100%) compared with CRM (approximately 85%) and 3 + 3 (approximately 79%). The DLT rate and rate the true MTD was recommended were similar for TARGET-CRM and CRM, differing by only 0%-4% and 0%-4%, respectively. Results were similar regardless of trial sample size and proportion of cohort B patients in the population.</p><p><strong>Conclusion: </strong>In phase I dose-finding trials of targeted agents, the Bayesian adaptive TARGET-CRM design maximizes enrollment of patients hypothesized as most likely to benefit from the targeted agent, while maintaining similar or superior accuracy and safety as the CRM and 3 + 3 designs.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400360"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882013","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":"Multigene Copy Number Alteration Risk Score Biomarker-Based Enrichment Study Designs in Metastatic Castrate-Resistant Prostate Cancer.","authors":"Yeonjung Jo, Jonathan J Chipman, Benjamin Haaland, Tom Greene, Manish Kohli","doi":"10.1200/PO-24-00399","DOIUrl":"10.1200/PO-24-00399","url":null,"abstract":"<p><strong>Purpose: </strong>A composite multigene risk score derived from tumor-biology alterations specific to metastatic castrate-resistant prostate cancer (mCRPC) state was evaluated as a classifier to design biomarker-based enrichment clinical trials.</p><p><strong>Methods: </strong>A plasma cell-free DNA copy number alteration risk score based on alterations in 24 genes was simulated to develop a biomarker classifier-based clinical trial design enriched for high-risk patients to detect a survival advantage of a novel treatment (hazard ratio of 0.70 with 80% power). We determined the design trade-offs between the number of patients screened and enrolled when varying the type of patients to enrich and the extent of enrichment needed.</p><p><strong>Results: </strong>For a 2-year overall survival end point in mCRPC state, fully enriching patients with mCRPC having a high-risk score of 3 or more (the 95th percentile of a range of risk scores in patients with mCRPC) was determined to require screening to a maximum of 4,149 patients to enroll 259 patients for the targeted effect size. A nonenriched trial was determined to require enrolling 689 patients to be equivalently powered. We identified a pragmatic alternative, which is to enrich patients with mCRPC with a risk score of 1 or more (the 67th percentile) and an enrichment fraction of 0.25. This would require screening 658 patients to enroll 584 patients, and it maximizes the ability to detect a difference in treatment effect by risk score.</p><p><strong>Conclusion: </strong>A plasma multi-CNA risk score classifier can feasibly be leveraged to design an enrichment trial in mCRPC. Enriching 25% of patients screened with a risk score >1 was observed to be optimal for obtaining an adequately powered, biomarker-based mCRPC-enriched clinical trial.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400399"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11627311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769014","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":"Circulating Tumor DNA as a Prognostic Biomarker for Recurrence in Patients With Locoregional Esophagogastric Cancers With a Pathologic Complete Response.","authors":"Eric Michael Lander, Vasily N Aushev, Brandon M Huffman, Diana Hanna, Punashi Dutta, Jenifer Ferguson, Shruti Sharma, Adham Jurdi, Minetta C Liu, Cathy Eng, Samuel J Klempner, Michael K Gibson","doi":"10.1200/PO.24.00288","DOIUrl":"10.1200/PO.24.00288","url":null,"abstract":"<p><strong>Purpose: </strong>After neoadjuvant therapy (NAT) and surgery, up to one third and one half of patients with esophagogastric adenocarcinoma with a pathologic complete response (pCR; tumor regression grade 0 [TRG-0]) and near-pCR (TRG-1) will recur, respectively. Our study aims to evaluate postoperative circulating tumor DNA (ctDNA) as a predictor of recurrence in patients with pCR or near-pCR after curative-intent neoadjuvant chemotherapy or neoadjuvant chemoradiation and surgery.</p><p><strong>Methods: </strong>We retrospectively identified patients from 11 institutions with stages I-IV esophagogastric cancers (EGCs) who completed NAT and had TRG-0/1 scores at the time of curative-intent surgery. Postoperative plasma samples were collected for ctDNA analysis within a 16-week molecular residual disease (MRD) window after definitive surgery, and during surveillance from January 7, 2020, to November 9, 2023, at the provider's discretion. ctDNA was assessed using a clinically validated, personalized, tumor-informed ctDNA assay (Signatera, Natera, Inc). The primary outcome was recurrence-free survival (RFS).</p><p><strong>Results: </strong>We obtained 309 blood samples from 42 patients with esophagogastric adenocarcinoma with a pCR after neoadjuvant treatment over a median follow-up time of 28.5 months (range, 0.2-81.7). Detectable ctDNA in the 16-week MRD window (N = 23) correlated with higher rates of recurrence (67%; 2/3) compared with undetectable ctDNA (15%; 3/20). Detectable ctDNA within the MRD window was associated with a significantly shorter RFS (hazard ratio [HR], 6.2; <i>P</i> = .049). Among 32 patients who had ctDNA analyzed in the surveillance setting, the recurrence rate was 100% (5/5) in the ctDNA-positive cohort compared with 7.4% (2/27) in ctDNA-negative patients and was associated with shorter RFS (HR, 37.6; <i>P</i> < .001).</p><p><strong>Conclusion: </strong>Within the subgroup of patients with EGC and favorable pathologic responses (TRG 0-1) after NAT, the presence of postoperative ctDNA identified patients with elevated recurrence risk.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400288"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11634147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789466","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":"Identification of a Suitable Subgroup for Radiation Dose Escalation in Definitive Concurrent Chemoradiation Therapy for Nonmetastatic Esophageal Squamous Cell Carcinoma.","authors":"Po-Chien Shen, Wei-Kai Chuang, Yang-Hong Dai, Cheng-Hsiang Lo, Yu-Fu Su, Jen-Fu Yang, Wen-Yen Huang, Chun-Shu Lin, Chia-Feng Lu","doi":"10.1200/PO-24-00555","DOIUrl":"https://doi.org/10.1200/PO-24-00555","url":null,"abstract":"<p><strong>Purpose: </strong>Dose escalation may only be suitable for some patients with esophageal cancer (EC) undergoing concurrent chemoradiotherapy (CCRT). This study aimed to identify specific subgroups of patients for whom dose escalation was most beneficial.</p><p><strong>Materials and methods: </strong>Between January 2008 and December 2022, 187 patients with EC underwent CCRT; 94 patients received high-dose (HD) radiotherapy (RT; >64.8 Gy), and 93 patients received low-dose (LD) RT. We developed a model on the basis of clinical and radiomic features to compare the predicted survival probabilities of patients with EC receiving HD- and LD-RT. Patients suitable for HD-RT could be identified. We validated our findings of a suitable HD subgroup by evaluating the actual overall survival (OS) across different subgroups in the testing set.</p><p><strong>Results: </strong>Our model comprised HD and LD submodels, each predicting patient survival under their respective RT doses. The HD and LD submodels achieved concordance indexes of 0.78 and 0.75 in their respective testing sets. The average areas under the receiver operating characteristic curve over years 1-3 were 0.890 and 0.807 in the HD and LD testing sets, respectively. By comparing patients' predicted survival under HD- and LD-RT in the model, we classified the patients in the testing set into the HD-suitable (HDS) subgroup and the HD-unsuitable subgroup. In the subgroup analysis, HD-RT led to a better OS benefit for the identified HDS subgroup compared with LD-RT (<i>P</i> = .014). Among the HD-treated patients, the HDS subgroup showed better OS than did patients identified as unsuitable (<i>P</i> < .001).</p><p><strong>Conclusion: </strong>We identified a suitable subgroup of patients with EC who might benefit from HD-RT. This model could aid clinicians in prescribing RT doses.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400555"},"PeriodicalIF":5.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}