Pub Date : 2024-09-03DOI: 10.1158/1078-0432.CCR-24-0901
Thijs van der Vaart, Maarten M J Wijnenga, Karin van Garderen, Hendrikus J Dubbink, Pim J French, Marion Smits, Clemens M F Dirven, Johan M Kros, Arnaud J P E Vincent, Martin J van den Bent
Purpose: IDH-mutant glioma is classified as oligodendroglioma or astrocytoma based on 1p19q-codeletion. Whether prognostic factors are similar between these tumor types is not well understood.
Experimental design: Retrospective cohort study. Molecular characterization was performed with targeted next-generation sequencing. Tumor volumes were calculated using semiautomatic 3D segmentation on all pre- and post-operative MRI scans. Overall survival was assessed with the Cox-proportional hazards model.
Results: A total of 383 patients with newly diagnosed IDH-mutant glioma were followed up for a median of 7.2 years. Grades 3 and 4 patients had significantly lower Karnofsky performance, with tumors having more contrast enhancement. Patients also received more aggressive postsurgery treatment. Postoperative tumor volume is significantly and independently associated with survival (HR, per cm3 1.19; 95% CI, 1.03-1.39) in IDH-mutant glioma. A separate analysis of oligodendroglioma and astrocytoma showed a significant association of postoperative tumor volume in astrocytoma but not in oligodendroglioma. Higher age and histologic tumor grade were associated with worse survival in patients with oligodendroglioma but not with astrocytoma.
Conclusions: Our data support an initial strategy of extensive resection in patients with oligodendroglioma and astrocytoma. Other important prognostic factors differ between these tumor types, urging researchers and clinicians to keep treating these tumors as separate entities.
{"title":"Differences in the Prognostic Role of Age, Extent of Resection, and Tumor Grade between Astrocytoma IDHmt and Oligodendroglioma: A Single-Center Cohort Study.","authors":"Thijs van der Vaart, Maarten M J Wijnenga, Karin van Garderen, Hendrikus J Dubbink, Pim J French, Marion Smits, Clemens M F Dirven, Johan M Kros, Arnaud J P E Vincent, Martin J van den Bent","doi":"10.1158/1078-0432.CCR-24-0901","DOIUrl":"10.1158/1078-0432.CCR-24-0901","url":null,"abstract":"<p><strong>Purpose: </strong>IDH-mutant glioma is classified as oligodendroglioma or astrocytoma based on 1p19q-codeletion. Whether prognostic factors are similar between these tumor types is not well understood.</p><p><strong>Experimental design: </strong>Retrospective cohort study. Molecular characterization was performed with targeted next-generation sequencing. Tumor volumes were calculated using semiautomatic 3D segmentation on all pre- and post-operative MRI scans. Overall survival was assessed with the Cox-proportional hazards model.</p><p><strong>Results: </strong>A total of 383 patients with newly diagnosed IDH-mutant glioma were followed up for a median of 7.2 years. Grades 3 and 4 patients had significantly lower Karnofsky performance, with tumors having more contrast enhancement. Patients also received more aggressive postsurgery treatment. Postoperative tumor volume is significantly and independently associated with survival (HR, per cm3 1.19; 95% CI, 1.03-1.39) in IDH-mutant glioma. A separate analysis of oligodendroglioma and astrocytoma showed a significant association of postoperative tumor volume in astrocytoma but not in oligodendroglioma. Higher age and histologic tumor grade were associated with worse survival in patients with oligodendroglioma but not with astrocytoma.</p><p><strong>Conclusions: </strong>Our data support an initial strategy of extensive resection in patients with oligodendroglioma and astrocytoma. Other important prognostic factors differ between these tumor types, urging researchers and clinicians to keep treating these tumors as separate entities.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1158/1078-0432.CCR-24-0693
Rachel Elias, Alise Blake, Lori Dean, Jessica S Flynn, Leila Sachner, Lynn Harrison, Rose B McGee, Kim E Nichols, Katianne M Howard Sharp
Purpose: Cancer predisposition syndrome (CPS) surveillance allows for the early detection and treatment of neoplasms; however, the psychosocial impact of tumor surveillance is poorly understood for cancer-affected adolescents with CPS and their parents. To gain further insight, we qualitatively characterized the affective and cognitive experience of adolescents undergoing tumor surveillance.
Experimental design: Adolescents with a history of cancer and their parents independently completed semistructured interviews querying their experience with the adolescent's tumor surveillance. Interviews were coded using emotion coding and content analysis before developing themes using thematic analysis.
Results: Eight adolescents and 11 parents (seven mothers, four fathers) completed interviews. Parent themes included maternal anxiety, relief following surveillance, fathers' positive expectations and emotions surrounding surveillance results, coping strategies, and perception of going through surveillance together with their child. Adolescent themes included normalization of surveillance, indifference about surveillance but excitement to return to the hospital, focus on physical and logistic aspects, relief focused on being done with scans, and belief that outcomes would be good. Past scans/surveillance experiences influencing surveillance feelings were a theme across both parents and adolescents.
Conclusions: Our findings suggest that tumor surveillance is not causing marked emotional distress for cancer-affected adolescents with CPS. In contrast, mothers of cancer-affected adolescents undergoing surveillance may present with anxiety leading up to tumor surveillance and, for a subset, in between surveillance appointments. These observations highlight a need for ongoing psychosocial screening for families of children with CPS and a role for psychosocial providers in the multidisciplinary management of CPS.
{"title":"Playing Russian Roulette: Parent and Adolescent Perspectives on Tumor Surveillance for Adolescents with Cancer Predisposition Syndromes.","authors":"Rachel Elias, Alise Blake, Lori Dean, Jessica S Flynn, Leila Sachner, Lynn Harrison, Rose B McGee, Kim E Nichols, Katianne M Howard Sharp","doi":"10.1158/1078-0432.CCR-24-0693","DOIUrl":"10.1158/1078-0432.CCR-24-0693","url":null,"abstract":"<p><strong>Purpose: </strong>Cancer predisposition syndrome (CPS) surveillance allows for the early detection and treatment of neoplasms; however, the psychosocial impact of tumor surveillance is poorly understood for cancer-affected adolescents with CPS and their parents. To gain further insight, we qualitatively characterized the affective and cognitive experience of adolescents undergoing tumor surveillance.</p><p><strong>Experimental design: </strong>Adolescents with a history of cancer and their parents independently completed semistructured interviews querying their experience with the adolescent's tumor surveillance. Interviews were coded using emotion coding and content analysis before developing themes using thematic analysis.</p><p><strong>Results: </strong>Eight adolescents and 11 parents (seven mothers, four fathers) completed interviews. Parent themes included maternal anxiety, relief following surveillance, fathers' positive expectations and emotions surrounding surveillance results, coping strategies, and perception of going through surveillance together with their child. Adolescent themes included normalization of surveillance, indifference about surveillance but excitement to return to the hospital, focus on physical and logistic aspects, relief focused on being done with scans, and belief that outcomes would be good. Past scans/surveillance experiences influencing surveillance feelings were a theme across both parents and adolescents.</p><p><strong>Conclusions: </strong>Our findings suggest that tumor surveillance is not causing marked emotional distress for cancer-affected adolescents with CPS. In contrast, mothers of cancer-affected adolescents undergoing surveillance may present with anxiety leading up to tumor surveillance and, for a subset, in between surveillance appointments. These observations highlight a need for ongoing psychosocial screening for families of children with CPS and a role for psychosocial providers in the multidisciplinary management of CPS.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1158/1078-0432.CCR-24-0090
Robert W Lentz, Tyler J Friedrich, Patrick J Blatchford, Kimberly R Jordan, Todd M Pitts, Hannah R Robinson, S Lindsey Davis, Sunnie S Kim, Alexis D Leal, Mathew R Lee, Meredith R N Waring, Anne C Martin, Adrian T A Dominguez, Stacey M Bagby, Sarah J Hartman, S Gail Eckhardt, Wells A Messersmith, Christopher H Lieu
Purpose: In this single-institution phase II investigator-initiated study, we assessed the ability of MAPK and VEGF pathway blockade to overcome resistance to immunotherapy in microsatellite-stable metastatic colorectal cancer (MSS mCRC).
Patients and methods: Patients with MSS, BRAF wild-type mCRC who progressed on ≥2 prior lines of therapy received pembrolizumab, binimetinib, and bevacizumab until disease progression or unacceptable toxicity. After a safety run-in, patients were randomized to a 7-day run-in of binimetinib or simultaneous initiation of all study drugs, to explore whether MEK inhibition may increase tumor immunogenicity. The primary endpoint was objective response rate (ORR) in all patients combined (by Response Evaluation Criteria in Solid Tumors v1.1).
Results: Fifty patients received study drug treatment; 54% were male with a median age of 55 years (range, 31-79). The primary endpoint, ORR, was 12.0% [95% confidence interval (CI) 4.5%-24.3%], which was not statistically different than the historical control data of 5% (P = 0.038, exceeding prespecified threshold of 0.025). The disease control rate was 70.0% (95% CI, 55.4%-82.1%), the median progression-free survival 5.9 months (95% CI, 4.2-8.7 months), and the median overall survival 9.3 months (95% CI, 6.7-12.2 months). No difference in efficacy was observed between the randomized cohorts. Grade 3 and 4 adverse events were observed in 56% and 8% of patients, respectively; the most common were rash (12%) and increased aspartate aminotransferase (12%).
Conclusions: Pembrolizumab, binimetinib, and bevacizumab failed to meet its primary endpoint of higher ORR compared with historical control data, demonstrated a high disease control rate, and demonstrated acceptable tolerability in refractory MSS mCRC.
目的:在这项由研究者发起的单机构II期研究中,我们评估了MAPK和血管内皮生长因子通路阻断克服微卫星稳定型转移性结直肠癌(MSS mCRC)免疫疗法耐药性的能力:接受pembrolizumab、binimetinib和贝伐珠单抗治疗,直到疾病进展或出现不可接受的毒性。在安全性试运行后,患者被随机分配接受为期7天的比尼替尼试运行或同时开始接受所有研究药物,以探索MEK抑制是否会增加肿瘤免疫原性。主要终点是所有患者的客观反应率(ORR,根据 RECIST v1.1):50名患者接受了研究药物治疗;54%为男性,中位年龄为55岁(31-79岁)。主要终点ORR为12.0%(95%置信区间[CI] 4.5-24.3%),与历史对照数据5%相比无统计学差异(P=0.038,超过预先指定的阈值0.025)。疾病控制率为 70.0%(95% CI 55.4-82.1%),中位无进展生存期为 5.9 个月(95% CI 4.2-8.7 个月),中位总生存期为 9.3 个月(95% CI 6.7-12.2 个月)。随机分组之间未发现疗效差异。分别有56%和8%的患者出现3级和4级不良反应;最常见的不良反应是皮疹(12%)和天冬氨酸氨基转移酶升高(12%):结论:与历史对照数据相比,Pembrolizumab、binimetinib和贝伐珠单抗未能达到较高ORR的主要终点,但在难治性MSS mCRC中表现出较高的疾病控制率和可接受的耐受性。
{"title":"A Phase II Study of Potentiation of Pembrolizumab with Binimetinib and Bevacizumab in Refractory Microsatellite-Stable Colorectal Cancer.","authors":"Robert W Lentz, Tyler J Friedrich, Patrick J Blatchford, Kimberly R Jordan, Todd M Pitts, Hannah R Robinson, S Lindsey Davis, Sunnie S Kim, Alexis D Leal, Mathew R Lee, Meredith R N Waring, Anne C Martin, Adrian T A Dominguez, Stacey M Bagby, Sarah J Hartman, S Gail Eckhardt, Wells A Messersmith, Christopher H Lieu","doi":"10.1158/1078-0432.CCR-24-0090","DOIUrl":"10.1158/1078-0432.CCR-24-0090","url":null,"abstract":"<p><strong>Purpose: </strong>In this single-institution phase II investigator-initiated study, we assessed the ability of MAPK and VEGF pathway blockade to overcome resistance to immunotherapy in microsatellite-stable metastatic colorectal cancer (MSS mCRC).</p><p><strong>Patients and methods: </strong>Patients with MSS, BRAF wild-type mCRC who progressed on ≥2 prior lines of therapy received pembrolizumab, binimetinib, and bevacizumab until disease progression or unacceptable toxicity. After a safety run-in, patients were randomized to a 7-day run-in of binimetinib or simultaneous initiation of all study drugs, to explore whether MEK inhibition may increase tumor immunogenicity. The primary endpoint was objective response rate (ORR) in all patients combined (by Response Evaluation Criteria in Solid Tumors v1.1).</p><p><strong>Results: </strong>Fifty patients received study drug treatment; 54% were male with a median age of 55 years (range, 31-79). The primary endpoint, ORR, was 12.0% [95% confidence interval (CI) 4.5%-24.3%], which was not statistically different than the historical control data of 5% (P = 0.038, exceeding prespecified threshold of 0.025). The disease control rate was 70.0% (95% CI, 55.4%-82.1%), the median progression-free survival 5.9 months (95% CI, 4.2-8.7 months), and the median overall survival 9.3 months (95% CI, 6.7-12.2 months). No difference in efficacy was observed between the randomized cohorts. Grade 3 and 4 adverse events were observed in 56% and 8% of patients, respectively; the most common were rash (12%) and increased aspartate aminotransferase (12%).</p><p><strong>Conclusions: </strong>Pembrolizumab, binimetinib, and bevacizumab failed to meet its primary endpoint of higher ORR compared with historical control data, demonstrated a high disease control rate, and demonstrated acceptable tolerability in refractory MSS mCRC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1158/1078-0432.CCR-23-3917
Jade M van Berge Henegouwen, Laurien J Zeverijn, Birgit S Geurts, Louisa R Hoes, Hanneke van der Wijngaart, Vincent van der Noort, Alwin D R Huitema, Filip Y F de Vos, Katrien Grünberg, Haiko J Bloemendal, Henk M W Verheul, Emile E Voest, Hans Gelderblom
Purpose: Although eligibility criteria are essential in trial design, overly restrictive criteria contribute to low accrual and limited generalizability. To enhance trial inclusivity, there has been growing interest in broadening eligibility criteria, especially for patients with advanced or treatment-refractory disease. Yet, the impact on patient safety remains uncertain. In the Drug Rediscovery Protocol (DRUP), protocol exceptions are frequently requested and occasionally granted. Here we describe the impact of these waivers on treatment safety and efficacy.
Experimental design: DRUP is a multicenter, nonrandomized clinical basket trial treating patients with therapy-refractory cancer with molecularly targeted and immunotherapies outside their registered indications (NCT02925234). Here, all granted waivers were revised, analyzed in terms of safety and efficacy outcome, and comparedwithoutcomes of includedpatientswho didnot receive awaiver.
Results: Between September 1, 2016, and September 1, 2021, protocol waivers were granted for 82 patients (8%) of 1,019 included patients in DRUP. Most waivers (45%) were granted for general- or drug-related eligibility criteria; other categories were out-of-window testing, treatment, and testing exceptions. Serious adverse event rate was similar between patients who received a waiver (pW) and patients who did not (pNW): 39% vs. 41%, respectively (P = 0.81). The clinical benefit (either objective response or stable disease ≥ 16 weeks) rate of pW was 40% versus 33% in pNW (P = 0.43).
Conclusions: Safety and clinical benefit were preserved in patients for whom a waiver was granted. These data support a more personalized approach in assessing eligibility criteria, especially in trials with widely used and approved drugs accruing patients without other treatment options. See related commentary by Waqar and Govindan, p. 3655.
{"title":"Maximizing Treatment Opportunities: Assessing Protocol Waivers' Impact on Safety and Outcome in the Drug Rediscovery Protocol.","authors":"Jade M van Berge Henegouwen, Laurien J Zeverijn, Birgit S Geurts, Louisa R Hoes, Hanneke van der Wijngaart, Vincent van der Noort, Alwin D R Huitema, Filip Y F de Vos, Katrien Grünberg, Haiko J Bloemendal, Henk M W Verheul, Emile E Voest, Hans Gelderblom","doi":"10.1158/1078-0432.CCR-23-3917","DOIUrl":"10.1158/1078-0432.CCR-23-3917","url":null,"abstract":"<p><strong>Purpose: </strong>Although eligibility criteria are essential in trial design, overly restrictive criteria contribute to low accrual and limited generalizability. To enhance trial inclusivity, there has been growing interest in broadening eligibility criteria, especially for patients with advanced or treatment-refractory disease. Yet, the impact on patient safety remains uncertain. In the Drug Rediscovery Protocol (DRUP), protocol exceptions are frequently requested and occasionally granted. Here we describe the impact of these waivers on treatment safety and efficacy.</p><p><strong>Experimental design: </strong>DRUP is a multicenter, nonrandomized clinical basket trial treating patients with therapy-refractory cancer with molecularly targeted and immunotherapies outside their registered indications (NCT02925234). Here, all granted waivers were revised, analyzed in terms of safety and efficacy outcome, and comparedwithoutcomes of includedpatientswho didnot receive awaiver.</p><p><strong>Results: </strong>Between September 1, 2016, and September 1, 2021, protocol waivers were granted for 82 patients (8%) of 1,019 included patients in DRUP. Most waivers (45%) were granted for general- or drug-related eligibility criteria; other categories were out-of-window testing, treatment, and testing exceptions. Serious adverse event rate was similar between patients who received a waiver (pW) and patients who did not (pNW): 39% vs. 41%, respectively (P = 0.81). The clinical benefit (either objective response or stable disease ≥ 16 weeks) rate of pW was 40% versus 33% in pNW (P = 0.43).</p><p><strong>Conclusions: </strong>Safety and clinical benefit were preserved in patients for whom a waiver was granted. These data support a more personalized approach in assessing eligibility criteria, especially in trials with widely used and approved drugs accruing patients without other treatment options. See related commentary by Waqar and Govindan, p. 3655.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141455682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1158/1078-0432.CCR-23-3403
Andrew T Lenis, Vignesh Ravichandran, Samantha Brown, Syed M Alam, Andrew Katims, Hong Truong, Peter A Reisz, Samantha Vasselman, Barbara Nweji, Karen A Autio, Michael J Morris, Susan F Slovin, Dana Rathkopf, Daniel Danila, Sungmin Woo, Hebert A Vargas, Vincent P Laudone, Behfar Ehdaie, Victor Reuter, Maria Arcila, Michael F Berger, Agnes Viale, Howard I Scher, Nikolaus Schultz, Anuradha Gopalan, Mark T A Donoghue, Irina Ostrovnaya, Konrad H Stopsack, David B Solit, Wassim Abida
Purpose: Patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab. We define the genomic features, clinical course, and response to immune checkpoint blockade (ICB) in patients with MSI-H/dMMR and TMB-H prostate cancers without MSI [TMB-H/microsatellite stable (MSS)].
Experimental design: We sequenced 3,244 tumors from 2,257 patients with prostate cancer. MSI-H/dMMR prostate cancer was defined as an MSIsensor score ≥10 or MSIsensor score ≥3 and <10 with a deleterious MMR alteration. TMB-H was defined as ≥10 mutations/megabase. PSA50 and RECIST responses were assigned. Overall survival and radiographic progression-free survival (rPFS) were compared using log-rank test.
Results: Sixty-three (2.8%) men had MSI-H/dMMR, and 33 (1.5%) had TMB-H/MSS prostate cancers. Patients with MSI-H/dMMR and TMB-H/MSS tumors more commonly presented with grade group 5 and metastatic disease at diagnosis. MSI-H/dMMR tumors had higher TMB, indel, and neoantigen burden compared with TMB-H/MSS. Twenty-seven patients with MSI-H/dMMR and 8 patients with TMB-H/MSS tumors received ICB, none of whom harbored polymerase epsilon (polE) catalytic subunit mutations. About 45% of patients with MSI-H/dMMR had a RECIST response, and 65% had a PSA50 response. No patient with TMB-H/MSS had a RECIST response, and 50% had a PSA50 response. rPFS tended to be longer in patients with MSI-H/dMMR than in patients with TMB-H/MSS who received immunotherapy. Pronounced differences in genomics, TMB, or MSIsensor score were not detected between MSI-H/dMMR responders and nonresponders.
Conclusions: MSI-H/dMMR prostate cancers have greater TMB, indel, and neoantigen burden than TMB-H/MSS prostate cancers, and these differences may contribute to profound and durable responses to ICB.
{"title":"Microsatellite Instability, Tumor Mutational Burden, and Response to Immune Checkpoint Blockade in Patients with Prostate Cancer.","authors":"Andrew T Lenis, Vignesh Ravichandran, Samantha Brown, Syed M Alam, Andrew Katims, Hong Truong, Peter A Reisz, Samantha Vasselman, Barbara Nweji, Karen A Autio, Michael J Morris, Susan F Slovin, Dana Rathkopf, Daniel Danila, Sungmin Woo, Hebert A Vargas, Vincent P Laudone, Behfar Ehdaie, Victor Reuter, Maria Arcila, Michael F Berger, Agnes Viale, Howard I Scher, Nikolaus Schultz, Anuradha Gopalan, Mark T A Donoghue, Irina Ostrovnaya, Konrad H Stopsack, David B Solit, Wassim Abida","doi":"10.1158/1078-0432.CCR-23-3403","DOIUrl":"10.1158/1078-0432.CCR-23-3403","url":null,"abstract":"<p><strong>Purpose: </strong>Patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab. We define the genomic features, clinical course, and response to immune checkpoint blockade (ICB) in patients with MSI-H/dMMR and TMB-H prostate cancers without MSI [TMB-H/microsatellite stable (MSS)].</p><p><strong>Experimental design: </strong>We sequenced 3,244 tumors from 2,257 patients with prostate cancer. MSI-H/dMMR prostate cancer was defined as an MSIsensor score ≥10 or MSIsensor score ≥3 and <10 with a deleterious MMR alteration. TMB-H was defined as ≥10 mutations/megabase. PSA50 and RECIST responses were assigned. Overall survival and radiographic progression-free survival (rPFS) were compared using log-rank test.</p><p><strong>Results: </strong>Sixty-three (2.8%) men had MSI-H/dMMR, and 33 (1.5%) had TMB-H/MSS prostate cancers. Patients with MSI-H/dMMR and TMB-H/MSS tumors more commonly presented with grade group 5 and metastatic disease at diagnosis. MSI-H/dMMR tumors had higher TMB, indel, and neoantigen burden compared with TMB-H/MSS. Twenty-seven patients with MSI-H/dMMR and 8 patients with TMB-H/MSS tumors received ICB, none of whom harbored polymerase epsilon (polE) catalytic subunit mutations. About 45% of patients with MSI-H/dMMR had a RECIST response, and 65% had a PSA50 response. No patient with TMB-H/MSS had a RECIST response, and 50% had a PSA50 response. rPFS tended to be longer in patients with MSI-H/dMMR than in patients with TMB-H/MSS who received immunotherapy. Pronounced differences in genomics, TMB, or MSIsensor score were not detected between MSI-H/dMMR responders and nonresponders.</p><p><strong>Conclusions: </strong>MSI-H/dMMR prostate cancers have greater TMB, indel, and neoantigen burden than TMB-H/MSS prostate cancers, and these differences may contribute to profound and durable responses to ICB.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1158/1078-0432.CCR-24-0244
Leonard Schmiester, Fara Brasó-Maristany, Blanca González-Farré, Tomás Pascual, Joaquín Gavilá, Xavier Tekpli, Jürgen Geisler, Vessela N Kristensen, Arnoldo Frigessi, Aleix Prat, Alvaro Köhn-Luque
Purpose: Development of a computational biomarker to predict, prior to treatment, the response to CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy in patients with breast cancer.
Experimental design: A mechanistic mathematical model that accounts for protein signaling and drug mechanisms of action was developed and trained on extensive, publicly available data from breast cancer cell lines. The model was built to provide a patient-specific response score based on the expression of six genes (CCND1, CCNE1, ESR1, RB1, MYC, and CDKN1A). The model was validated in five independent cohorts of 148 patients in total with early-stage or advanced breast cancer treated with endocrine therapy and CDK4/6i. Response was measured either by evaluating Ki67 levels and PAM50 risk of relapse (ROR) after neoadjuvant treatment or by evaluating progression-free survival (PFS).
Results: The model showed significant association with patient's outcomes in all five cohorts. The model predicted high Ki67 [area under the curve; AUC (95% confidence interval, CI) of 0.80 (0.64-0.92), 0.81 (0.60-1.00) and 0.80 (0.65-0.93)] and high PAM50 ROR [AUC of 0.78 (0.64-0.89)]. This observation was not obtained in patients treated with chemotherapy. In the other cohorts, patient stratification based on the model prediction was significantly associated with PFS [hazard ratio (HR) = 2.92 (95% CI, 1.08-7.86), P = 0.034 and HR = 2.16 (1.02 4.55), P = 0.043].
Conclusions: A mathematical modeling approach accurately predicts patient outcome following CDK4/6i plus endocrine therapy that marks a step toward more personalized treatments in patients with Luminal B breast cancer.
{"title":"Computational Model Predicts Patient Outcomes in Luminal B Breast Cancer Treated with Endocrine Therapy and CDK4/6 Inhibition.","authors":"Leonard Schmiester, Fara Brasó-Maristany, Blanca González-Farré, Tomás Pascual, Joaquín Gavilá, Xavier Tekpli, Jürgen Geisler, Vessela N Kristensen, Arnoldo Frigessi, Aleix Prat, Alvaro Köhn-Luque","doi":"10.1158/1078-0432.CCR-24-0244","DOIUrl":"10.1158/1078-0432.CCR-24-0244","url":null,"abstract":"<p><strong>Purpose: </strong>Development of a computational biomarker to predict, prior to treatment, the response to CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy in patients with breast cancer.</p><p><strong>Experimental design: </strong>A mechanistic mathematical model that accounts for protein signaling and drug mechanisms of action was developed and trained on extensive, publicly available data from breast cancer cell lines. The model was built to provide a patient-specific response score based on the expression of six genes (CCND1, CCNE1, ESR1, RB1, MYC, and CDKN1A). The model was validated in five independent cohorts of 148 patients in total with early-stage or advanced breast cancer treated with endocrine therapy and CDK4/6i. Response was measured either by evaluating Ki67 levels and PAM50 risk of relapse (ROR) after neoadjuvant treatment or by evaluating progression-free survival (PFS).</p><p><strong>Results: </strong>The model showed significant association with patient's outcomes in all five cohorts. The model predicted high Ki67 [area under the curve; AUC (95% confidence interval, CI) of 0.80 (0.64-0.92), 0.81 (0.60-1.00) and 0.80 (0.65-0.93)] and high PAM50 ROR [AUC of 0.78 (0.64-0.89)]. This observation was not obtained in patients treated with chemotherapy. In the other cohorts, patient stratification based on the model prediction was significantly associated with PFS [hazard ratio (HR) = 2.92 (95% CI, 1.08-7.86), P = 0.034 and HR = 2.16 (1.02 4.55), P = 0.043].</p><p><strong>Conclusions: </strong>A mathematical modeling approach accurately predicts patient outcome following CDK4/6i plus endocrine therapy that marks a step toward more personalized treatments in patients with Luminal B breast cancer.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1158/1078-0432.ccr-24-1152
Lorena Heinst, Kwang Seok Lee, Ruth Berthold, Ilka Isfort, Svenja Wosnig, Anna Kuntze, Susanne Hafner, Bianca Altvater, Claudia Rössig, Pierre Åman, Eva Wardelmann, Claudia Scholl, Wolfgang Hartmann, Stefan Fröhling, Marcel Trautmann
Purpose: The pathognomonic FUS::DDIT3 fusion protein drives myxoid liposarcoma (MLS) tumorigenesis via aberrant transcriptional activation of oncogenic signaling. Since FUS::DDIT3 has so far not been pharmacologically tractable to selectively target MLS cells, this study investigated the functional role of the cell cycle regulator WEE1 as novel FUS::DDIT3‑dependent therapeutic vulnerability in MLS. Experimental Design: Immunohistochemical evaluation of the cell cycle regulator WEE1 was performed in a large cohort of MLS specimens. FUS::DDIT3 dependency and biological function of the G1/S cell cycle checkpoint were analyzed in a mesenchymal stem cell model and liposarcoma cell lines in vitro. WEE1 activity was modulated by RNAi‑mediated knockdown and the small molecule inhibitor MK-1775 (Adavosertib). An established MLS cell line-based chicken chorioallantoic membrane model was employed for in vivo confirmation. Results: We demonstrate that enhanced WEE1 pathway activity represents a hallmark of FUS::DDIT3‑expressing cell lines as well as MLS tissue specimens and that WEE1 is required for MLS cellular survival in vitro and in vivo. Pharmacologic inhibition of WEE1 activity results in DNA damage accumulation and cell cycle progression forcing cells to undergo apoptotic cell death. In addition, our results uncover FUS::DDIT3-dependent WEE1 expression as an oncogenic survival mechanism to tolerate high proliferation and resulting replication stress in MLS. Fusion protein-driven G1/S cell cycle checkpoint deregulation via overactive Cyclin E/CDK2 complexes thereby contributes to enhanced WEE1 inhibitor sensitivity in MLS. Conclusions: Our preclinical study identifies WEE1-mediated replication stress tolerance as molecular vulnerability in FUS::DDIT3-driven MLS tumorigenesis that could represent a novel target for therapeutic intervention.
{"title":"Exploiting WEE1 kinase activity as FUS::DDIT3-dependent therapeutic vulnerability in myxoid liposarcoma","authors":"Lorena Heinst, Kwang Seok Lee, Ruth Berthold, Ilka Isfort, Svenja Wosnig, Anna Kuntze, Susanne Hafner, Bianca Altvater, Claudia Rössig, Pierre Åman, Eva Wardelmann, Claudia Scholl, Wolfgang Hartmann, Stefan Fröhling, Marcel Trautmann","doi":"10.1158/1078-0432.ccr-24-1152","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1152","url":null,"abstract":"Purpose: The pathognomonic FUS::DDIT3 fusion protein drives myxoid liposarcoma (MLS) tumorigenesis via aberrant transcriptional activation of oncogenic signaling. Since FUS::DDIT3 has so far not been pharmacologically tractable to selectively target MLS cells, this study investigated the functional role of the cell cycle regulator WEE1 as novel FUS::DDIT3‑dependent therapeutic vulnerability in MLS. Experimental Design: Immunohistochemical evaluation of the cell cycle regulator WEE1 was performed in a large cohort of MLS specimens. FUS::DDIT3 dependency and biological function of the G1/S cell cycle checkpoint were analyzed in a mesenchymal stem cell model and liposarcoma cell lines in vitro. WEE1 activity was modulated by RNAi‑mediated knockdown and the small molecule inhibitor MK-1775 (Adavosertib). An established MLS cell line-based chicken chorioallantoic membrane model was employed for in vivo confirmation. Results: We demonstrate that enhanced WEE1 pathway activity represents a hallmark of FUS::DDIT3‑expressing cell lines as well as MLS tissue specimens and that WEE1 is required for MLS cellular survival in vitro and in vivo. Pharmacologic inhibition of WEE1 activity results in DNA damage accumulation and cell cycle progression forcing cells to undergo apoptotic cell death. In addition, our results uncover FUS::DDIT3-dependent WEE1 expression as an oncogenic survival mechanism to tolerate high proliferation and resulting replication stress in MLS. Fusion protein-driven G1/S cell cycle checkpoint deregulation via overactive Cyclin E/CDK2 complexes thereby contributes to enhanced WEE1 inhibitor sensitivity in MLS. Conclusions: Our preclinical study identifies WEE1-mediated replication stress tolerance as molecular vulnerability in FUS::DDIT3-driven MLS tumorigenesis that could represent a novel target for therapeutic intervention.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1158/1078-0432.CCR-24-1611
Melissa R Perrino, Anirban Das, Sarah R Scollon, Sarah G Mitchell, Mary-Louise C Greer, Marielle E Yohe, Jordan R Hansford, Jennifer M Kalish, Kris Ann P Schultz, Suzanne P MacFarland, Wendy K Kohlmann, Philip J Lupo, Kara N Maxwell, Stefan M Pfister, Rosanna Weksberg, Orli Michaeli, Marjolijn C J Jongmans, Gail E Tomlinson, Jack Brzezinski, Uri Tabori, Gina M Ney, Karen W Gripp, Andrea M Gross, Brigitte C Widemann, Douglas R Stewart, Emma R Woodward, Christian P Kratz
Neurofibromatosis type 1 (NF1), Noonan syndrome and related syndromes, grouped as the RASopathies, result from dysregulation of the RAS-MAPK pathway and demonstrate varied multisystemic clinical phenotypes. Together the RASopathies are among the more prevalent genetic cancer predisposition syndromes and require nuanced clinical management. When compared to the general population, children with RASopathies are at significantly increased risk of benign and malignant neoplasms. In the last decade, clinical trials have shown that targeted therapies can improve outcomes for low-grade and benign neoplastic lesions but have their own challenges, highlighting the multi-disciplinary care needed for such individuals, specifically those with NF1. This perspective, which originated from the 2023 AACR Childhood Cancer Predisposition Workshop, serves to update pediatric oncologists, neurologists, geneticists, counselors, and other healthcare professionals on revised diagnostic criteria, review previously published surveillance guidelines, and harmonize updated surveillance recommendations for patients with NF1 or RASopathies.
{"title":"Update on Pediatric Cancer Surveillance Recommendations for Patients with Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related RASopathies.","authors":"Melissa R Perrino, Anirban Das, Sarah R Scollon, Sarah G Mitchell, Mary-Louise C Greer, Marielle E Yohe, Jordan R Hansford, Jennifer M Kalish, Kris Ann P Schultz, Suzanne P MacFarland, Wendy K Kohlmann, Philip J Lupo, Kara N Maxwell, Stefan M Pfister, Rosanna Weksberg, Orli Michaeli, Marjolijn C J Jongmans, Gail E Tomlinson, Jack Brzezinski, Uri Tabori, Gina M Ney, Karen W Gripp, Andrea M Gross, Brigitte C Widemann, Douglas R Stewart, Emma R Woodward, Christian P Kratz","doi":"10.1158/1078-0432.CCR-24-1611","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1611","url":null,"abstract":"<p><p>Neurofibromatosis type 1 (NF1), Noonan syndrome and related syndromes, grouped as the RASopathies, result from dysregulation of the RAS-MAPK pathway and demonstrate varied multisystemic clinical phenotypes. Together the RASopathies are among the more prevalent genetic cancer predisposition syndromes and require nuanced clinical management. When compared to the general population, children with RASopathies are at significantly increased risk of benign and malignant neoplasms. In the last decade, clinical trials have shown that targeted therapies can improve outcomes for low-grade and benign neoplastic lesions but have their own challenges, highlighting the multi-disciplinary care needed for such individuals, specifically those with NF1. This perspective, which originated from the 2023 AACR Childhood Cancer Predisposition Workshop, serves to update pediatric oncologists, neurologists, geneticists, counselors, and other healthcare professionals on revised diagnostic criteria, review previously published surveillance guidelines, and harmonize updated surveillance recommendations for patients with NF1 or RASopathies.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1158/1078-0432.CCR-24-0953
Suzanne P MacFarland, Kerri Becktell, Kami Wolfe Schneider, Roland P Kuiper, Harry Lesmana, Julia Meade, Kim E Nichols, Christopher C Porter, Sharon A Savage, Kris Ann Schultz, Hamish Scott, Lisa States, Uri Tabori, Chieko Tamura, Gail Tomlinson, Kristin Zelley, Carol Durno, Andrew Bauer, Sharon E Plon
Gastrointestinal (GI) polyposis and cancer in pediatric patients is frequently due to an underlying hereditary cancer risk syndrome requiring ongoing cancer screening. Identification of at-risk patients through family history, clinical features of syndrome, or symptom onset ensures appropriate cancer risk assessment and management in childhood and beyond. In this 2024 perspective, we outline updates to the hereditary GI cancer screening guidelines first published by the American Association of Cancer Research Pediatric Cancer Predisposition Workshop in 2017.1 These guidelines consider existing recommendations by pediatric and adult gastroenterology consortia to ensure alignment with gastroenterology practices in managing polyposis conditions. We specifically address the recommendations for pediatric screening in familial adenomatous polyposis, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. Further, we emphasize the importance of multidisciplinary care and partnership with gastroenterology, as it is crucial in management of children and families with these conditions.
{"title":"Pediatric cancer screening in hereditary gastrointestinal cancer risk syndromes: An update from the AACR Childhood Cancer Predisposition Working Group.","authors":"Suzanne P MacFarland, Kerri Becktell, Kami Wolfe Schneider, Roland P Kuiper, Harry Lesmana, Julia Meade, Kim E Nichols, Christopher C Porter, Sharon A Savage, Kris Ann Schultz, Hamish Scott, Lisa States, Uri Tabori, Chieko Tamura, Gail Tomlinson, Kristin Zelley, Carol Durno, Andrew Bauer, Sharon E Plon","doi":"10.1158/1078-0432.CCR-24-0953","DOIUrl":"10.1158/1078-0432.CCR-24-0953","url":null,"abstract":"<p><p>Gastrointestinal (GI) polyposis and cancer in pediatric patients is frequently due to an underlying hereditary cancer risk syndrome requiring ongoing cancer screening. Identification of at-risk patients through family history, clinical features of syndrome, or symptom onset ensures appropriate cancer risk assessment and management in childhood and beyond. In this 2024 perspective, we outline updates to the hereditary GI cancer screening guidelines first published by the American Association of Cancer Research Pediatric Cancer Predisposition Workshop in 2017.1 These guidelines consider existing recommendations by pediatric and adult gastroenterology consortia to ensure alignment with gastroenterology practices in managing polyposis conditions. We specifically address the recommendations for pediatric screening in familial adenomatous polyposis, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. Further, we emphasize the importance of multidisciplinary care and partnership with gastroenterology, as it is crucial in management of children and families with these conditions.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-23DOI: 10.1158/1078-0432.CCR-24-1238
Jack Freeland, Maria Muñoz, Edmond O'Donnell, Justin Langerman, Morgan Darrow, Jessica Bergonio, Julissa Suarez-Navarro, Steven Thorpe, Robert Canter, R Lor Randall, Kathrin Plath, Kermit L Carraway, Owen N Witte, Thomas G Graeber, Janai R Carr-Ascher
Purpose: High-grade complex karyotype sarcomas are a heterogeneous group of tumors with a uniformly poor prognosis. Within complex karyotype sarcomas, there are innumerable genetic changes but identifying those that are clinically relevant has been challenging.
Experimental design: To address this, we utilized a pooled genetic screening approach, informed by TCGA data, to identify key drivers and modifiers of sarcoma development that were validated in vivo.
Results: YAP1 and wildtype KRAS were validated as drivers and transformed human mesenchymal stem cells into two distinct sarcoma subtypes, undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma (MFS), respectively. A subset of tumors driven by CDK4 and PIK3CA reflected leiomyosarcoma (LMS) and osteosarcoma (OS) demonstrating the plasticity of this approach and the potential to investigate sarcoma subtype heterogeneity. All generated tumors histologically reflected human sarcomas and had increased aneuploidy as compared to simple karyotype sarcomas. Comparing differential gene expression of TCGA samples to model data identified increased oxidative phosphorylation signaling in YAP1 tumors. Treatment of a panel of soft tissue sarcomas with a combination of YAP1 and oxidative phosphorylation inhibitors led to significantly decreased viability.
Conclusions: Transcriptional co-analysis of TCGA patient samples to YAP1 and KRAS model tumors support that these sarcoma subtypes lie along a spectrum of disease and adds guidance for further transcriptome-based refinement of sarcoma subtyping. This approach can be used to begin to understand pathways and mechanisms driving human sarcoma development, the relationship between sarcoma subtypes and to identify and validate new therapeutic vulnerabilities for this aggressive and heterogeneous disease.
{"title":"Genetic Screen in a Pre-Clinical Model of Sarcoma Development Defines Drivers and Therapeutic Vulnerabilities.","authors":"Jack Freeland, Maria Muñoz, Edmond O'Donnell, Justin Langerman, Morgan Darrow, Jessica Bergonio, Julissa Suarez-Navarro, Steven Thorpe, Robert Canter, R Lor Randall, Kathrin Plath, Kermit L Carraway, Owen N Witte, Thomas G Graeber, Janai R Carr-Ascher","doi":"10.1158/1078-0432.CCR-24-1238","DOIUrl":"10.1158/1078-0432.CCR-24-1238","url":null,"abstract":"<p><strong>Purpose: </strong>High-grade complex karyotype sarcomas are a heterogeneous group of tumors with a uniformly poor prognosis. Within complex karyotype sarcomas, there are innumerable genetic changes but identifying those that are clinically relevant has been challenging.</p><p><strong>Experimental design: </strong>To address this, we utilized a pooled genetic screening approach, informed by TCGA data, to identify key drivers and modifiers of sarcoma development that were validated in vivo.</p><p><strong>Results: </strong>YAP1 and wildtype KRAS were validated as drivers and transformed human mesenchymal stem cells into two distinct sarcoma subtypes, undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma (MFS), respectively. A subset of tumors driven by CDK4 and PIK3CA reflected leiomyosarcoma (LMS) and osteosarcoma (OS) demonstrating the plasticity of this approach and the potential to investigate sarcoma subtype heterogeneity. All generated tumors histologically reflected human sarcomas and had increased aneuploidy as compared to simple karyotype sarcomas. Comparing differential gene expression of TCGA samples to model data identified increased oxidative phosphorylation signaling in YAP1 tumors. Treatment of a panel of soft tissue sarcomas with a combination of YAP1 and oxidative phosphorylation inhibitors led to significantly decreased viability.</p><p><strong>Conclusions: </strong>Transcriptional co-analysis of TCGA patient samples to YAP1 and KRAS model tumors support that these sarcoma subtypes lie along a spectrum of disease and adds guidance for further transcriptome-based refinement of sarcoma subtyping. This approach can be used to begin to understand pathways and mechanisms driving human sarcoma development, the relationship between sarcoma subtypes and to identify and validate new therapeutic vulnerabilities for this aggressive and heterogeneous disease.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}