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":"8 ","pages":"e2400138"},"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":"8 ","pages":"e2300649"},"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}
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":"8 ","pages":"e2400135"},"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}
Brandon A Mahal, Matthew Margolis, Earl Hubbell, Cheng Chen, Jeffrey M Venstrom, John Abran, Jordan J Kartlitz, Alexander W Wyatt, Eric A Klein
Purpose: Indolent prostate cancer (PCa) is prevalent in the intended use population (adults age 50-79 years) for blood-based multicancer early detection (MCED) tests. We examined the detectability of PCa by a clinically validated, targeted methylation-based MCED test.
Methods: Detectability by Gleason grade group (GG), clinical stage, association of detection status with tumor methylated fraction (TMeF), and overall survival (OS) were assessed in substudy 3 of Circulating Cell-Free Genome Atlas (CCGA; ClinicalTrials.gov identifier: NCT02889978) and PATHFINDER (ClinicalTrials.gov identifier: NCT04241796) studies.
Results: Test sensitivity for PCa in substudy 3 of CCGA was 11.2% (47/420). The test detected 0 (0%) of 58 low-grade (GG1), 3 (1.9%) of 157 favorable intermediate-grade (GG2), 4 (5.1%) of 78 unfavorable intermediate-grade (GG3), and 36 (31.9%) of 113 high-grade (GG4 and 5) cancers and 3 (3.2%) of 95 stage I, 11 (4.7%) of 235 stage II, 7 (14.9%) of 47 stage III, and 22 (81.5%) of 27 stage IV cases. The median TMeF was higher for detected than nondetected cases (2,106.0 parts per million [PPM]; IQR, 349.8-24,376.3 v 24.4 PPM; IQR, 17.8-38.5; P < .05). Nondetected cases had better OS (P < .05; hazard ratio [HR], 0.263 [95% CI, 0.104 to 0.533]) and detected cases had similar survival (P = .2; HR, 0.672 [95% CI, 0.323 to 1.21]) compared with SEER adjusted for age, GG, and stage. Performance was similar in PATHFINDER, with no detected GG1/2 (0/13) or stage I/II (0/16) cases.
Conclusion: This MCED test preferentially detects high-grade, clinically significant PCa. Use in population-based screening programs in addition to standard-of-care screening is unlikely to exacerbate overdiagnosis of indolent PCa.
{"title":"A Targeted Methylation-Based Multicancer Early Detection Blood Test Preferentially Detects High-Grade Prostate Cancer While Minimizing Overdiagnosis of Indolent Disease.","authors":"Brandon A Mahal, Matthew Margolis, Earl Hubbell, Cheng Chen, Jeffrey M Venstrom, John Abran, Jordan J Kartlitz, Alexander W Wyatt, Eric A Klein","doi":"10.1200/PO.24.00269","DOIUrl":"10.1200/PO.24.00269","url":null,"abstract":"<p><strong>Purpose: </strong>Indolent prostate cancer (PCa) is prevalent in the intended use population (adults age 50-79 years) for blood-based multicancer early detection (MCED) tests. We examined the detectability of PCa by a clinically validated, targeted methylation-based MCED test.</p><p><strong>Methods: </strong>Detectability by Gleason grade group (GG), clinical stage, association of detection status with tumor methylated fraction (TMeF), and overall survival (OS) were assessed in substudy 3 of Circulating Cell-Free Genome Atlas (CCGA; ClinicalTrials.gov identifier: NCT02889978) and PATHFINDER (ClinicalTrials.gov identifier: NCT04241796) studies.</p><p><strong>Results: </strong>Test sensitivity for PCa in substudy 3 of CCGA was 11.2% (47/420). The test detected 0 (0%) of 58 low-grade (GG1), 3 (1.9%) of 157 favorable intermediate-grade (GG2), 4 (5.1%) of 78 unfavorable intermediate-grade (GG3), and 36 (31.9%) of 113 high-grade (GG4 and 5) cancers and 3 (3.2%) of 95 stage I, 11 (4.7%) of 235 stage II, 7 (14.9%) of 47 stage III, and 22 (81.5%) of 27 stage IV cases. The median TMeF was higher for detected than nondetected cases (2,106.0 parts per million [PPM]; IQR, 349.8-24,376.3 <i>v</i> 24.4 PPM; IQR, 17.8-38.5; <i>P</i> < .05). Nondetected cases had better OS (<i>P</i> < .05; hazard ratio [HR], 0.263 [95% CI, 0.104 to 0.533]) and detected cases had similar survival (<i>P</i> = .2; HR, 0.672 [95% CI, 0.323 to 1.21]) compared with SEER adjusted for age, GG, and stage. Performance was similar in PATHFINDER, with no detected GG1/2 (0/13) or stage I/II (0/16) cases.</p><p><strong>Conclusion: </strong>This MCED test preferentially detects high-grade, clinically significant PCa. Use in population-based screening programs in addition to standard-of-care screening is unlikely to exacerbate overdiagnosis of indolent PCa.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400269"},"PeriodicalIF":5.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107583","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}
Jaleh Fallah, Jianjin Xu, Hee-Koung Joeng, Chana Weinstock, Brian L Heiss, William F Maguire, Xin Gao, Joyce Cheng, Elaine Chang, Sundeep Agrawal, Mallorie H Fiero, Richard Pazdur, Paul G Kluetz, Laleh Amiri-Kordestani, Daniel L Suzman
False-positive ctDNA results do not explain lack of efficacy for PARPi in patients with ATMm and CHEK2m CRPC.
ctDNA假阳性结果并不能解释PARPi对ATMm和CHEK2m CRPC患者缺乏疗效。
{"title":"False-Positive Circulating Tumor DNA Results Do Not Explain Lack of Efficacy for PARP Inhibitors in Patients With Castration-Resistant Prostate Cancer Harboring <i>ATM</i> and <i>CHEK2</i> Mutations.","authors":"Jaleh Fallah, Jianjin Xu, Hee-Koung Joeng, Chana Weinstock, Brian L Heiss, William F Maguire, Xin Gao, Joyce Cheng, Elaine Chang, Sundeep Agrawal, Mallorie H Fiero, Richard Pazdur, Paul G Kluetz, Laleh Amiri-Kordestani, Daniel L Suzman","doi":"10.1200/PO.24.00354","DOIUrl":"10.1200/PO.24.00354","url":null,"abstract":"<p><p>False-positive ctDNA results do not explain lack of efficacy for PARPi in patients with ATMm and CHEK2m CRPC.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400354"},"PeriodicalIF":5.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107584","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}
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":"8 ","pages":"e2300520"},"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}
Antibody-drug conjugates (ADCs) are fusions of therapeutic drugs and antibodies conjugated by a linker, designed to deliver a therapeutic payload to cells expressing the target antigen. By delivering the highly cytotoxic agent directly to cancer cells, ADCs are designed to enhance safety and broaden the therapeutic window. Recently, ADCs have demonstrated promising efficacy in various solid tumors and are rapidly expanding their indications. The prognosis of patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor, with no new therapeutics since the advent of anti-PD-1 antibodies in 2016, highlighting a critical need for innovative therapies. Recent preliminary results suggest that ADCs could be promising treatment options for HNSCC as they explore a variety of target antigens, payloads, and linkers. However, for successful adaptation of ADCs in the treatment of HNSCC, addressing key challenges such as payload toxicities, antigen heterogeneity, and adaptive resistance will be essential. Current research focused on new ADC structures, including multispecific antibodies and noncytotoxic payloads, and diverse combination approaches, show promise for future advancements.
{"title":"Current Landscape of Antibody-Drug Conjugate Development in Head and Neck Cancer.","authors":"Jong Chul Park, Donghoon Shin","doi":"10.1200/PO.24.00179","DOIUrl":"https://doi.org/10.1200/PO.24.00179","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) are fusions of therapeutic drugs and antibodies conjugated by a linker, designed to deliver a therapeutic payload to cells expressing the target antigen. By delivering the highly cytotoxic agent directly to cancer cells, ADCs are designed to enhance safety and broaden the therapeutic window. Recently, ADCs have demonstrated promising efficacy in various solid tumors and are rapidly expanding their indications. The prognosis of patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor, with no new therapeutics since the advent of anti-PD-1 antibodies in 2016, highlighting a critical need for innovative therapies. Recent preliminary results suggest that ADCs could be promising treatment options for HNSCC as they explore a variety of target antigens, payloads, and linkers. However, for successful adaptation of ADCs in the treatment of HNSCC, addressing key challenges such as payload toxicities, antigen heterogeneity, and adaptive resistance will be essential. Current research focused on new ADC structures, including multispecific antibodies and noncytotoxic payloads, and diverse combination approaches, show promise for future advancements.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400179"},"PeriodicalIF":5.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992320","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}
Imran Safder, Henkel Valentine, Nicole Uzzo, John Sfakianos, Robert Uzzo, Shilpa Gupta, Jason Brown, Daniel Ranti, Elizabeth Plimack, George Haber, Christopher Weight, Alexander Kutikov, Philip Abbosh, Laura Bukavina
Purpose: The purpose of this study was to elucidate the relationship between the tumor microenvironment (TME) and cellular diversity in bladder cancer (BLCA) progression, leveraging single-cell RNA sequencing (scRNA-seq) data to identify potential prognostic biomarkers and construct a prognostic model for BLCA.
Methods: We analyzed scRNA-seq data of normal and tumor bladder cells from the Gene Expression Omnibus (GEO) database to uncover crucial markers within the bladder TME. The study compared gene expression in normal versus tumor bladder cells, identifying differentially expressed genes. These genes were subsequently assessed for their prognostic significance using patient follow-up data from The Cancer Genome Atlas. Prognostic models were constructed using Least Absolute Shrinkage and Selection Operator and multivariate Cox regression analyses, focusing on eight genes of interest. The predictive performance of the model was also tested against additional GEO data sets (GSE31684, GSE13507, and GSE32894).
Results: The prognostic model demonstrated reliable prediction of patient outcomes. Validation through gene set enrichment analysis and immune cell infiltration assessment supported the model's efficacy. The results from both the univariate and multivariate analyses suggest that the risk score is an independent prognostic factor with a hazard ratio of 2.97 (95% CI, 2.28 to 3.9, P < .001). In the validation cohort, the AUC at 1, 2, and 3 years is 0.74, 0.74, and 0.72, respectively.
Conclusion: Our findings proposed biomarkers with prognostic potential, laying the groundwork for future in vitro validation and therapeutic exploration. This contributes to a deeper understanding of the genes associated with bladder TME and may improve prognostic precision in BLCA management.
{"title":"Identification and Validation of Prognostic Model for Tumor Microenvironment-Associated Genes in Bladder Cancer Based on Single-Cell RNA Sequencing Data Sets.","authors":"Imran Safder, Henkel Valentine, Nicole Uzzo, John Sfakianos, Robert Uzzo, Shilpa Gupta, Jason Brown, Daniel Ranti, Elizabeth Plimack, George Haber, Christopher Weight, Alexander Kutikov, Philip Abbosh, Laura Bukavina","doi":"10.1200/PO.23.00661","DOIUrl":"10.1200/PO.23.00661","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to elucidate the relationship between the tumor microenvironment (TME) and cellular diversity in bladder cancer (BLCA) progression, leveraging single-cell RNA sequencing (scRNA-seq) data to identify potential prognostic biomarkers and construct a prognostic model for BLCA.</p><p><strong>Methods: </strong>We analyzed scRNA-seq data of normal and tumor bladder cells from the Gene Expression Omnibus (GEO) database to uncover crucial markers within the bladder TME. The study compared gene expression in normal versus tumor bladder cells, identifying differentially expressed genes. These genes were subsequently assessed for their prognostic significance using patient follow-up data from The Cancer Genome Atlas. Prognostic models were constructed using Least Absolute Shrinkage and Selection Operator and multivariate Cox regression analyses, focusing on eight genes of interest. The predictive performance of the model was also tested against additional GEO data sets (GSE31684, GSE13507, and GSE32894).</p><p><strong>Results: </strong>The prognostic model demonstrated reliable prediction of patient outcomes. Validation through gene set enrichment analysis and immune cell infiltration assessment supported the model's efficacy. The results from both the univariate and multivariate analyses suggest that the risk score is an independent prognostic factor with a hazard ratio of 2.97 (95% CI, 2.28 to 3.9, <i>P</i> < .001). In the validation cohort, the AUC at 1, 2, and 3 years is 0.74, 0.74, and 0.72, respectively.</p><p><strong>Conclusion: </strong>Our findings proposed biomarkers with prognostic potential, laying the groundwork for future in vitro validation and therapeutic exploration. This contributes to a deeper understanding of the genes associated with bladder TME and may improve prognostic precision in BLCA management.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2300661"},"PeriodicalIF":5.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992321","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}
Florence T H Wu, James T Topham, Chris J O'Callaghan, Harriet Feilotter, Hagen F Kennecke, Leylah Drusbosky, Daniel J Renouf, Derek J Jonker, Dongsheng Tu, Eric X Chen, Jonathan M Loree
Purpose: In metastatic colorectal cancer (mCRC), RAS mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether RAS mutations ever become clonally undetectable.
Methods: CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. RAS mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression.
Results: Among the 95 patients with KRAS/NRAS mutations in their archival tumor tissue, 6.3% (6/95) had undetectable RAS mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to RAS-wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo-RAS-WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent RAS mutations (75%), P = .046. The likelihood of synchronous metastases at cancer diagnosis (33% v 63%; P = .15) or liver metastases at trial baseline (50% v 68.5%; P = .17) was not significantly different between patients with disappearing versus persistent RAS mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; P = .52) was not significantly different between those with disappearing versus persistent RAS mutations. The disappearance of RAS mutations was not associated with primary tumor sidedness (P = .41), archival BRAF/MEK/ERK-mutant status (P = .16/1.00/.09), nor baseline ctDNA HER2 amplifications (P = 1.00).
Conclusion: We identified a 3.2%-6.3% prevalence of the neo-RAS-WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.
{"title":"Kinetic Profiling of <i>RAS</i> Mutations With Circulating Tumor DNA in the Canadian Cancer Trials Group CO.26 Trial Suggests the Loss of <i>RAS</i> Mutations in Neo-<i>RAS</i>-Wildtype Metastatic Colorectal Cancer Is Transient.","authors":"Florence T H Wu, James T Topham, Chris J O'Callaghan, Harriet Feilotter, Hagen F Kennecke, Leylah Drusbosky, Daniel J Renouf, Derek J Jonker, Dongsheng Tu, Eric X Chen, Jonathan M Loree","doi":"10.1200/PO.24.00031","DOIUrl":"10.1200/PO.24.00031","url":null,"abstract":"<p><strong>Purpose: </strong>In metastatic colorectal cancer (mCRC), <i>RAS</i> mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether <i>RAS</i> mutations ever become clonally undetectable.</p><p><strong>Methods: </strong>CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. <i>RAS</i> mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression.</p><p><strong>Results: </strong>Among the 95 patients with <i>KRAS/NRAS</i> mutations in their archival tumor tissue, 6.3% (6/95) had undetectable <i>RAS</i> mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to <i>RAS</i>-wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo-<i>RAS</i>-WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent <i>RAS</i> mutations (75%), <i>P</i> = .046. The likelihood of synchronous metastases at cancer diagnosis (33% <i>v</i> 63%; <i>P</i> = .15) or liver metastases at trial baseline (50% <i>v</i> 68.5%; <i>P</i> = .17) was not significantly different between patients with disappearing versus persistent <i>RAS</i> mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; <i>P</i> = .52) was not significantly different between those with disappearing versus persistent <i>RAS</i> mutations. The disappearance of <i>RAS</i> mutations was not associated with primary tumor sidedness (<i>P</i> = .41), archival <i>BRAF/MEK/ERK</i>-mutant status (<i>P</i> = .16/1.00/.09), nor baseline ctDNA <i>HER2</i> amplifications (<i>P</i> = 1.00).</p><p><strong>Conclusion: </strong>We identified a 3.2%-6.3% prevalence of the neo-<i>RAS</i>-WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400031"},"PeriodicalIF":5.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142043914","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}
Antonio Cigliola, Alina Basnet, Joseph M Jacob, Chiara Mercinelli, Valentina Tateo, Damiano Alfio Patanè, Gennady Bratslavsky, Liang Cheng, Petros Grivas, Ashish M Kamat, Philippe E Spiess, Dean C Pavlick, Douglas I Lin, Jeffrey S Ross, Andrea Necchi
Purpose: Although both urachal (U) and nonurachal (NU) bladder adenocarcinomas (adenoCas) share several histologic similarities, they differ in location and sometimes in therapeutic options. We analyzed the differences in genomic alterations (GAs) between these tumor entities, with the aim of identifying potential therapeutic targets for clinical trials.
Materials and methods: Overall, 133 U and 328 NU adenoCas were analyzed. Hybrid capture-based comprehensive genomic profiling (CGP) was performed to evaluate all classes of GA. Germline status of GA was predicted using a validated somatic-germline computational method. CGP was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc).
Results: The most frequent GA in both U and NU cohorts included TP53 (86.5% v 81.1%) and KRAS (34.6% v 27.7%). GAs characteristic of colorectal adenoCa, such as SMAD4 (P = .069) and GNAS (P = .071), were more common in U versus NU. Conversely, TERT (P < .01) and RB1 (P = .071) were more prevalent in NU adenoCa. Notably, both U and NU adenoCas exhibited possibly targetable GA in PIK3CA (7.5% v 7.9%) and ERBB2 (6.8% v 7.6%). Biomarkers associated with potential benefit from anti-PD-1/L1 were infrequent. Median tumor mutational burden was 2.6 and 3.5 mutations per megabase for U and NU, respectively, and PD-L1 expression >1% was rare. Genomic ancestry and genomic signature distribution were similar in both tumor types. GAs were most commonly of somatic nature. Limitations include lack of clinical data, tumor heterogeneity, and retrospective nature.
Conclusion: U and NU adenoCAs revealed differences in GA, with PIK3CA and ERBB2 being identified as putative therapeutic targets. Biomarkers of response to anti-PD-(L)1 were uncommon. Results highlight the potential of CGP to personalize treatment options of bladder adenoCa and inform clinical trial designs.
目的:虽然尿道(U)膀胱腺癌(adenoCas)和非尿道(NU)膀胱腺癌(adenoCas)在组织学上有一些相似之处,但它们的位置不同,有时治疗方案也不同。我们分析了这些肿瘤实体之间基因组改变(GAs)的差异,目的是为临床试验确定潜在的治疗靶点:总共分析了 133 例 U 型腺癌和 328 例 NU 型腺癌。进行了基于混合捕获的综合基因组图谱分析(CGP),以评估所有类别的GA。使用经过验证的体细胞-种系计算方法预测 GA 的种系状态。CGP使用FoundationOne和FoundationOne CDx测定(Foundation Medicine, Inc)进行:结果:在 U 和 NU 队列中,最常见的 GA 包括 TP53(86.5% 对 81.1%)和 KRAS(34.6% 对 27.7%)。具有结直肠腺癌特征的GA,如SMAD4(P = .069)和GNAS(P = .071),在U组和NU组中更为常见。相反,TERT(P < .01)和 RB1(P = .071)在 NU 腺癌中更为常见。值得注意的是,U腺癌和NU腺癌中的PIK3CA(7.5% v 7.9%)和ERBB2(6.8% v 7.6%)都表现出可能的靶向性GA。与抗 PD-1/L1 潜在获益相关的生物标志物并不常见。U和NU的中位肿瘤突变负荷分别为2.6和3.5个突变/兆碱基,PD-L1表达>1%的情况很少见。两种肿瘤类型的基因组祖先和基因组特征分布相似。体细胞基因组特征最常见。不足之处包括缺乏临床数据、肿瘤异质性和回顾性:结论:U腺癌和NU腺癌显示出GA的差异,PIK3CA和ERBB2被确定为潜在的治疗靶点。对抗PD-(L)1反应的生物标志物并不常见。研究结果凸显了CGP在个性化膀胱腺癌治疗方案和临床试验设计方面的潜力。
{"title":"Urachal and Nonurachal Adenocarcinomas of the Urinary Bladder: A Comprehensive Genomic Profiling Study.","authors":"Antonio Cigliola, Alina Basnet, Joseph M Jacob, Chiara Mercinelli, Valentina Tateo, Damiano Alfio Patanè, Gennady Bratslavsky, Liang Cheng, Petros Grivas, Ashish M Kamat, Philippe E Spiess, Dean C Pavlick, Douglas I Lin, Jeffrey S Ross, Andrea Necchi","doi":"10.1200/PO.24.00200","DOIUrl":"https://doi.org/10.1200/PO.24.00200","url":null,"abstract":"<p><strong>Purpose: </strong>Although both urachal (U) and nonurachal (NU) bladder adenocarcinomas (adenoCas) share several histologic similarities, they differ in location and sometimes in therapeutic options. We analyzed the differences in genomic alterations (GAs) between these tumor entities, with the aim of identifying potential therapeutic targets for clinical trials.</p><p><strong>Materials and methods: </strong>Overall, 133 U and 328 NU adenoCas were analyzed. Hybrid capture-based comprehensive genomic profiling (CGP) was performed to evaluate all classes of GA. Germline status of GA was predicted using a validated somatic-germline computational method. CGP was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc).</p><p><strong>Results: </strong>The most frequent GA in both U and NU cohorts included <i>TP53</i> (86.5% <i>v</i> 81.1%) and <i>KRAS</i> (34.6% <i>v</i> 27.7%). GAs characteristic of colorectal adenoCa, such as <i>SMAD4</i> (<i>P</i> = .069) and <i>GNAS</i> (<i>P</i> = .071), were more common in U versus NU. Conversely, <i>TERT</i> (<i>P</i> < .01) and <i>RB1</i> (<i>P</i> = .071) were more prevalent in NU adenoCa. Notably, both U and NU adenoCas exhibited possibly targetable GA in <i>PIK3CA</i> (7.5% <i>v</i> 7.9%) and <i>ERBB2</i> (6.8% <i>v</i> 7.6%). Biomarkers associated with potential benefit from anti-PD-1/L1 were infrequent. Median tumor mutational burden was 2.6 and 3.5 mutations per megabase for U and NU, respectively, and PD-L1 expression >1% was rare. Genomic ancestry and genomic signature distribution were similar in both tumor types. GAs were most commonly of somatic nature. Limitations include lack of clinical data, tumor heterogeneity, and retrospective nature.</p><p><strong>Conclusion: </strong>U and NU adenoCAs revealed differences in GA, with <i>PIK3CA</i> and <i>ERBB2</i> being identified as putative therapeutic targets. Biomarkers of response to anti-PD-(L)1 were uncommon. Results highlight the potential of CGP to personalize treatment options of bladder adenoCa and inform clinical trial designs.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400200"},"PeriodicalIF":5.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992322","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}