Pub Date : 2024-09-17DOI: 10.1158/1078-0432.ccr-24-0803
Jeffrey L. Jensen, Olivia Bobek, Irenaeus C. C. Chan, Brian C. Miller, David W. Hillman, Glenn Heller, Todd Druley, Andrew J. Armstrong, Michael J. Morris, Matthew I. Milowsky, Himisha Beltran, Kelly L. Bolton, Catherine C. Coombs
Purpose: Mutations in hematopoietic progenitor cells accumulate with age leading to clonal expansion, termed clonal hematopoiesis (CH). CH in the general population is associated with hematopoietic neoplasms and reduced overall survival (OS), predominantly through cardiovascular adverse events (CVAE). Because androgen receptor pathway inhibitors (ARPI) used in metastatic castration-resistant prostate cancer (mCRPC) are also associated with CVAEs and because CH negatively impacted survival in an advanced solid tumor cohort, we hypothesized that CH in mCRPC may be associated with increased CVAEs and inferior survival. Experimental Design: A targeted DNA sequencing panel captured common CH mutations in pretreatment blood samples from 957 patients enrolled in Alliance A031201: a randomized trial of enzalutamide ± abiraterone/prednisone in the first-line mCRPC setting. The primary outcome was the impact of CH on OS; the secondary outcomes were progression-free survival (PFS) and CVAEs. Results: Baseline comorbidities were similar by CH status. No differences in OS/progression-free survival were detected regardless of treatment arm or the variant allele frequency threshold used to define CH [primary: 2% (normal-CH, N-CH); exploratory: 0.5% (low-CH) and 10% (high-CH, H-CH)]. Patients with H-CH (7.2%) and TET2-mutated N-CH (6.0%) had greater odds of any CVAE (14.5% vs. 4.0%; P = 0.0004 and 12.3% vs. 4.2%; P = 0.010, respectively). More major CVAEs were observed in patients with H-CH (5.8% vs. 1.9%; P = 0.042) and N-CH (3.4% vs. 1.8%; P = 0.147). Conclusions: CH did not affect survival in patients with mCRPC treated with ARPIs in A031201. H-CH and TET2-mutated CH were associated with more CVAEs. These findings inform the risk/benefit discussion about ARPIs in mCRPC.
目的：造血祖细胞中的突变会随着年龄的增长而累积，导致克隆扩增，即克隆性造血（CH）。一般人群中的克隆性造血与造血肿瘤和总生存率（OS）降低有关，主要是通过心血管不良事件（CVAE）引起的。由于转移性去势抵抗性前列腺癌（mCRPC）中使用的雄激素受体通路抑制剂（ARPI）也与CVAE有关，而且CH对晚期实体瘤队列的生存有负面影响，因此我们假设mCRPC中的CH可能与CVAE增加和生存率降低有关。实验设计：一个靶向DNA测序面板捕获了957名参加A031201联盟的患者的预处理血液样本中常见的CH突变：这是一项在一线mCRPC治疗中使用恩杂鲁胺±阿比特龙/泼尼松的随机试验。主要结果是CH对OS的影响；次要结果是无进展生存期（PFS）和CVAEs。研究结果不同CH状态下的基线合并症相似。无论采用哪种治疗方法或用于定义CH的变异等位基因频率阈值[主要：2%（正常-CH，N-CH）；探索性：0.5%（低-CH）]，均未发现OS/无进展生存期的差异：0.5%（低CH）和10%（高CH，H-CH）]。H-CH（7.2%）和TET2突变的N-CH（6.0%）患者发生任何CVAE的几率更高（分别为14.5% vs. 4.0%; P = 0.0004和12.3% vs. 4.2%; P = 0.010）。在 H-CH 患者（5.8% 对 1.9%；P = 0.042）和 N-CH 患者（3.4% 对 1.8%；P = 0.147）中观察到更多的主要 CVAE。结论在A031201中，CH不会影响接受ARPIs治疗的mCRPC患者的生存率。H-CH和TET2突变的CH与更多的CVAE相关。这些发现为有关 ARPIs 治疗 mCRPC 的风险/效益讨论提供了参考。
{"title":"Clonal Hematopoiesis and Clinical Outcomes in Metastatic Castration-Resistant Prostate Cancer Patients Given Androgen Receptor Pathway Inhibitors (Alliance A031201)","authors":"Jeffrey L. Jensen, Olivia Bobek, Irenaeus C. C. Chan, Brian C. Miller, David W. Hillman, Glenn Heller, Todd Druley, Andrew J. Armstrong, Michael J. Morris, Matthew I. Milowsky, Himisha Beltran, Kelly L. Bolton, Catherine C. Coombs","doi":"10.1158/1078-0432.ccr-24-0803","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-0803","url":null,"abstract":"Purpose: Mutations in hematopoietic progenitor cells accumulate with age leading to clonal expansion, termed clonal hematopoiesis (CH). CH in the general population is associated with hematopoietic neoplasms and reduced overall survival (OS), predominantly through cardiovascular adverse events (CVAE). Because androgen receptor pathway inhibitors (ARPI) used in metastatic castration-resistant prostate cancer (mCRPC) are also associated with CVAEs and because CH negatively impacted survival in an advanced solid tumor cohort, we hypothesized that CH in mCRPC may be associated with increased CVAEs and inferior survival. Experimental Design: A targeted DNA sequencing panel captured common CH mutations in pretreatment blood samples from 957 patients enrolled in Alliance A031201: a randomized trial of enzalutamide ± abiraterone/prednisone in the first-line mCRPC setting. The primary outcome was the impact of CH on OS; the secondary outcomes were progression-free survival (PFS) and CVAEs. Results: Baseline comorbidities were similar by CH status. No differences in OS/progression-free survival were detected regardless of treatment arm or the variant allele frequency threshold used to define CH [primary: 2% (normal-CH, N-CH); exploratory: 0.5% (low-CH) and 10% (high-CH, H-CH)]. Patients with H-CH (7.2%) and TET2-mutated N-CH (6.0%) had greater odds of any CVAE (14.5% vs. 4.0%; P = 0.0004 and 12.3% vs. 4.2%; P = 0.010, respectively). More major CVAEs were observed in patients with H-CH (5.8% vs. 1.9%; P = 0.042) and N-CH (3.4% vs. 1.8%; P = 0.147). Conclusions: CH did not affect survival in patients with mCRPC treated with ARPIs in A031201. H-CH and TET2-mutated CH were associated with more CVAEs. These findings inform the risk/benefit discussion about ARPIs in mCRPC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236200","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 : 2024-09-17DOI: 10.1158/1078-0432.ccr-24-1928
Jonas Windrich, Gina M. Ney, Philip S. Rosenberg, Jung Kim, Martin Zenker, Douglas R. Stewart, Christian P. Kratz
Purpose: To determine the cancer risk and spectrum in patients with multi-lineage mosaic RASopathies with pathogenic variants (PV) in HRAS or KRAS. Methods: We conducted a systematic literature review to identify multi-lineage mosaic RASopathy cases with a PV in HRAS or KRAS to create a retrospective cohort. We calculated cumulative incidence, cancer-free survival and hazard rates (HR) for cancer and standardized incidence rates (SIR). Results: This study identified 69 patients. Seventeen percent had cancer, including rhabdomyosarcoma located in the urogenital region (n=7), skin cancer (n=3), Wilms tumor (n=1), and bladder cancer (n=1). Cumulative cancer incidence by age 20 was 20% (95% CI, 4 to 37%). The annual cancer HR peaked at 14% within the first two years of life. The highest SIR was found for rhabdomyosarcoma (SIR = 800, 95% CI, 300 to 1648). Conclusions: This is the first investigation of cancer risk in KRAS or HRAS PV-positive mosaic RASopathies to date. The high incidence and SIR values found highlight the need for rigorous rhabdomyosarcoma surveillance in young children and skin cancer surveillance in adults with this high-risk condition.
{"title":"Cancer in multi-lineage mosaic RASopathies due to pathogenic variants in HRAS or KRAS: a systematic review and meta-analysis","authors":"Jonas Windrich, Gina M. Ney, Philip S. Rosenberg, Jung Kim, Martin Zenker, Douglas R. Stewart, Christian P. Kratz","doi":"10.1158/1078-0432.ccr-24-1928","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1928","url":null,"abstract":"Purpose: To determine the cancer risk and spectrum in patients with multi-lineage mosaic RASopathies with pathogenic variants (PV) in HRAS or KRAS. Methods: We conducted a systematic literature review to identify multi-lineage mosaic RASopathy cases with a PV in HRAS or KRAS to create a retrospective cohort. We calculated cumulative incidence, cancer-free survival and hazard rates (HR) for cancer and standardized incidence rates (SIR). Results: This study identified 69 patients. Seventeen percent had cancer, including rhabdomyosarcoma located in the urogenital region (n=7), skin cancer (n=3), Wilms tumor (n=1), and bladder cancer (n=1). Cumulative cancer incidence by age 20 was 20% (95% CI, 4 to 37%). The annual cancer HR peaked at 14% within the first two years of life. The highest SIR was found for rhabdomyosarcoma (SIR = 800, 95% CI, 300 to 1648). Conclusions: This is the first investigation of cancer risk in KRAS or HRAS PV-positive mosaic RASopathies to date. The high incidence and SIR values found highlight the need for rigorous rhabdomyosarcoma surveillance in young children and skin cancer surveillance in adults with this high-risk condition.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236161","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 : 2024-09-17DOI: 10.1158/1078-0432.ccr-24-1374
Mary-Louise C. Greer, Lisa J. States, David Malkin, Stephan D. Voss, Andrea S. Doria
Whole-body MRI (WBMRI) is an integral part of screening infants, children and adolescents for pre-symptomatic neoplasms in certain cancer predisposition syndromes (CPS). This includes Li-Fraumeni and Constitutional Mismatch Repair Deficiency syndromes, among others. The list of syndromes where WBMRI adds value, as part of a comprehensive surveillance protocol, continues to evolve in response to new evidence, growing experience and more widespread adoption of WBMRI. In July 2023, the American Association of Cancer Research (AACR) reconvened an international, multidisciplinary panel to revise and update recommendations stemming from the 2016 AACR Special Workshop on Childhood Cancer Predisposition. That initial meeting resulted in a series of publications in Clinical Cancer Research in 2017, including “Pediatric Cancer Predisposition Imaging: Focus on Whole Body MRI”. This 2024 review of WBMRI in CPS updates the 2017 WBMRI publication, the revised recommendations derived from the 2023 AACR Childhood Cancer Predisposition Workshop based on available data, societal guidelines and expert opinion. Different aspects of acquiring and interpreting WBMRI including diagnostic accuracy are discussed. Application of WBMRI in resource poor environments, as well as integration of whole-body imaging techniques with emerging technologies such as cell-free DNA, or liquid biopsies, and artificial intelligence/machine learning are also considered.
全身核磁共振成像（WBMRI）是筛查婴儿、儿童和青少年是否患有某些癌症易感综合征（CPS）的症状前肿瘤的重要组成部分。其中包括 Li-Fraumeni 和体质错配修复缺陷综合征等。作为综合监测方案的一部分，WBMRI 可增加价值的综合征列表将随着新证据的出现、经验的积累和 WBMRI 的更广泛应用而不断发展。2023 年 7 月，美国癌症研究协会 (AACR) 重新召集了一个国际多学科小组，对 2016 年 AACR 儿童癌症易感性特别研讨会提出的建议进行修订和更新。首次会议的成果是 2017 年在《临床癌症研究》（Clinical Cancer Research）上发表的一系列文章，包括《儿童癌症易感性成像》（Pediatric Cancer Predisposition Imaging）：聚焦全身核磁共振成像》。这篇2024年CPS上的WBMRI综述更新了2017年的WBMRI出版物，以及2023年AACR儿童癌症易感性研讨会根据现有数据、社会指南和专家意见得出的修订建议。讨论了获取和解释 WBMRI 的各个方面，包括诊断准确性。还考虑了 WBMRI 在资源匮乏环境中的应用，以及全身成像技术与无细胞 DNA 或液体活检和人工智能/机器学习等新兴技术的整合。
{"title":"Update on Whole-body MRI Surveillance for Pediatric Cancer Predisposition Syndromes","authors":"Mary-Louise C. Greer, Lisa J. States, David Malkin, Stephan D. Voss, Andrea S. Doria","doi":"10.1158/1078-0432.ccr-24-1374","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1374","url":null,"abstract":"Whole-body MRI (WBMRI) is an integral part of screening infants, children and adolescents for pre-symptomatic neoplasms in certain cancer predisposition syndromes (CPS). This includes Li-Fraumeni and Constitutional Mismatch Repair Deficiency syndromes, among others. The list of syndromes where WBMRI adds value, as part of a comprehensive surveillance protocol, continues to evolve in response to new evidence, growing experience and more widespread adoption of WBMRI. In July 2023, the American Association of Cancer Research (AACR) reconvened an international, multidisciplinary panel to revise and update recommendations stemming from the 2016 AACR Special Workshop on Childhood Cancer Predisposition. That initial meeting resulted in a series of publications in Clinical Cancer Research in 2017, including “Pediatric Cancer Predisposition Imaging: Focus on Whole Body MRI”. This 2024 review of WBMRI in CPS updates the 2017 WBMRI publication, the revised recommendations derived from the 2023 AACR Childhood Cancer Predisposition Workshop based on available data, societal guidelines and expert opinion. Different aspects of acquiring and interpreting WBMRI including diagnostic accuracy are discussed. Application of WBMRI in resource poor environments, as well as integration of whole-body imaging techniques with emerging technologies such as cell-free DNA, or liquid biopsies, and artificial intelligence/machine learning are also considered.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236202","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 : 2024-09-17DOI: 10.1158/1078-0432.ccr-24-1547
Daniel Morgensztern, Neal Ready, Melissa L. Johnson, Afshin Dowlati, Noura Choudhury, David P. Carbone, Eric Schaefer, Susanne M. Arnold, Sonam Puri, Zofia Piotrowska, Aparna Hegde, Anne C. Chiang, Wade Iams, Anthony Tolcher, Kaname Nosaki, Toshiyuki Kozuki, Tianhong Li, Rafael Santana-Davila, Hiroaki Akamatsu, Haruyasu Murakami, Hiroshi Yokouchi, Song Wang, Jiuhong Zha, Rui Li, Randy R. Robinson, Pooja Hingorani, Edwin E. Jeng, Muhammad Furqan
Purpose: Seizure-related homolog protein 6 (SEZ6) is a novel target expressed in small cell lung cancer (SCLC). ABBV-011, a SEZ6-targeted antibody conjugated to calicheamicin, was evaluated in a phase I study (NCT03639194) in patients with relapsed/refractory SCLC. We report initial outcomes of ABBV-011 monotherapy. Patients and Methods: ABBV-011 was administered intravenously once every 3 weeks (Q3W) during dose escalation (0.3–2 mg/kg) and expansion. Patients with SEZ6-positive tumors (≥25% of tumor cells with ≥1+ staining intensity by immunohistochemistry) were preselected for expansion. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated. Results: As of August 2022, 99 patients received ABBV-011 monotherapy (dose escalation, n=36; Japanese dose evaluation, n=3; dose expansion, n=60 [1 mg/kg, n=40]); median age was 63 years (range, 41–79). Thirty-two percent, 41%, and 26% of patients received 1, 2, and ≥3 prior therapies, respectively. The maximum tolerated dose was not reached through 2.0 mg/kg. Most common treatment-emergent adverse events (TEAEs) were fatigue (50%), nausea (42%), and thrombocytopenia (41%). Most common hepatic TEAEs were increased aspartate aminotransferase (22%), increased g-glutamyltransferase (21%), and hyperbilirubinemia (17%); 2 patients experienced veno-occlusive liver disease. Objective response rate (ORR) was 19% (19/98). In the 1-mg/kg dose-expansion cohort (n=40), ORR was 25%; median response duration was 4.2 months (95% CI, 2.6–6.7) and median progression-free survival was 3.5 months (95% CI, 1.5–4.2). Conclusions: ABBV-011 1.0 mg/kg Q3W monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated patients with relapsed/refractory SCLC. SEZ6 is a promising novel SCLC target and warrants further investigation.
{"title":"A Phase I First-in-Human Study of ABBV-011, a Seizure-Related Homolog Protein 6-Targeting Antibody-Drug Conjugate, in Patients With Small Cell Lung Cancer","authors":"Daniel Morgensztern, Neal Ready, Melissa L. Johnson, Afshin Dowlati, Noura Choudhury, David P. Carbone, Eric Schaefer, Susanne M. Arnold, Sonam Puri, Zofia Piotrowska, Aparna Hegde, Anne C. Chiang, Wade Iams, Anthony Tolcher, Kaname Nosaki, Toshiyuki Kozuki, Tianhong Li, Rafael Santana-Davila, Hiroaki Akamatsu, Haruyasu Murakami, Hiroshi Yokouchi, Song Wang, Jiuhong Zha, Rui Li, Randy R. Robinson, Pooja Hingorani, Edwin E. Jeng, Muhammad Furqan","doi":"10.1158/1078-0432.ccr-24-1547","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1547","url":null,"abstract":"Purpose: Seizure-related homolog protein 6 (SEZ6) is a novel target expressed in small cell lung cancer (SCLC). ABBV-011, a SEZ6-targeted antibody conjugated to calicheamicin, was evaluated in a phase I study (NCT03639194) in patients with relapsed/refractory SCLC. We report initial outcomes of ABBV-011 monotherapy. Patients and Methods: ABBV-011 was administered intravenously once every 3 weeks (Q3W) during dose escalation (0.3–2 mg/kg) and expansion. Patients with SEZ6-positive tumors (≥25% of tumor cells with ≥1+ staining intensity by immunohistochemistry) were preselected for expansion. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated. Results: As of August 2022, 99 patients received ABBV-011 monotherapy (dose escalation, n=36; Japanese dose evaluation, n=3; dose expansion, n=60 [1 mg/kg, n=40]); median age was 63 years (range, 41–79). Thirty-two percent, 41%, and 26% of patients received 1, 2, and ≥3 prior therapies, respectively. The maximum tolerated dose was not reached through 2.0 mg/kg. Most common treatment-emergent adverse events (TEAEs) were fatigue (50%), nausea (42%), and thrombocytopenia (41%). Most common hepatic TEAEs were increased aspartate aminotransferase (22%), increased g-glutamyltransferase (21%), and hyperbilirubinemia (17%); 2 patients experienced veno-occlusive liver disease. Objective response rate (ORR) was 19% (19/98). In the 1-mg/kg dose-expansion cohort (n=40), ORR was 25%; median response duration was 4.2 months (95% CI, 2.6–6.7) and median progression-free survival was 3.5 months (95% CI, 1.5–4.2). Conclusions: ABBV-011 1.0 mg/kg Q3W monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated patients with relapsed/refractory SCLC. SEZ6 is a promising novel SCLC target and warrants further investigation.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236197","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 : 2024-09-17DOI: 10.1158/1078-0432.ccr-24-1327
Gabriel J. Starrett, Brittany C. Baikie, Benjamin K. Stoff, Hans E. Grossniklaus, Inga Van Buren, Elizabeth G. Berry, Roberto A. Novoa, Kerri E. Rieger, Kavita Y. Sarin, Charles F. Lynch, Michael C. Royer, Mary L. Piaskowski, Isaac Brownell, Emily Y. Chu, Rama Godse, Suephy C. Chen, Kelly J. Yu, Alisa M. Goldstein, Eric A. Engels, Michael R. Sargen
Purpose: Sebaceous carcinoma is the third most common nonkeratinocyte skin cancer in the United States with 1,000 cases per year. The clinicopathologic features of sebaceous carcinoma and benign sebaceous neoplasms (adenomas, sebaceomas) can overlap, highlighting the need for molecular biomarkers to improve classification. This study describes the genomic and transcriptomic landscape of sebaceous neoplasms in order to understand tumor etiology and biomarkers relevant for diagnosis and treatment. Experimental Design: We performed whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS) of sebaceous neoplasms from six academic and two federal healthcare facilities in the United States diagnosed between January 1, 1999, and December 31, 2021. Results: We evaluated 98 sebaceous neoplasms: 64 tumors (32 adenomas, 2 sebaceomas, 5 atypical sebaceous neoplasms, 25 carcinomas) had sufficient material for WGS, 96 tumors (42 adenomas, 11 sebaceomas, 8 atypical sebaceous neoplasms, 35 carcinomas) had sufficient material for WTS, and 62 tumors (31 adenomas, 2 sebaceomas, 5 atypical sebaceous neoplasms, 24 carcinomas) had sufficient material for combined WGS and WTS. Overall, we found decreased cholesterol biosynthesis and increased TP53 mutations, copy number gains (chromosome 6, 8q, and/or 18), and tumor mutation burden-high (>10 mutations/MB) in carcinomas compared to adenomas. Although diminished compared to adenomas, most carcinomas still had higher cholesterol biosynthesis than nonmalignant skin. Multiomics profiling also supported a precancerous model of tumor evolution with sebaceomas and atypical sebaceous neoplasms being likely intermediate lesions. Conclusions: The study findings highlight key diagnostic biomarkers for sebaceous carcinoma and suggest that immunotherapy and modulation of cholesterol biosynthesis could be effective treatment strategies.
{"title":"Multiomics Profiling Distinguishes Sebaceous Carcinoma from Benign Sebaceous Neoplasms and Provides Insight into the Genetic Evolution of Sebaceous Carcinogenesis","authors":"Gabriel J. Starrett, Brittany C. Baikie, Benjamin K. Stoff, Hans E. Grossniklaus, Inga Van Buren, Elizabeth G. Berry, Roberto A. Novoa, Kerri E. Rieger, Kavita Y. Sarin, Charles F. Lynch, Michael C. Royer, Mary L. Piaskowski, Isaac Brownell, Emily Y. Chu, Rama Godse, Suephy C. Chen, Kelly J. Yu, Alisa M. Goldstein, Eric A. Engels, Michael R. Sargen","doi":"10.1158/1078-0432.ccr-24-1327","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1327","url":null,"abstract":"Purpose: Sebaceous carcinoma is the third most common nonkeratinocyte skin cancer in the United States with 1,000 cases per year. The clinicopathologic features of sebaceous carcinoma and benign sebaceous neoplasms (adenomas, sebaceomas) can overlap, highlighting the need for molecular biomarkers to improve classification. This study describes the genomic and transcriptomic landscape of sebaceous neoplasms in order to understand tumor etiology and biomarkers relevant for diagnosis and treatment. Experimental Design: We performed whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS) of sebaceous neoplasms from six academic and two federal healthcare facilities in the United States diagnosed between January 1, 1999, and December 31, 2021. Results: We evaluated 98 sebaceous neoplasms: 64 tumors (32 adenomas, 2 sebaceomas, 5 atypical sebaceous neoplasms, 25 carcinomas) had sufficient material for WGS, 96 tumors (42 adenomas, 11 sebaceomas, 8 atypical sebaceous neoplasms, 35 carcinomas) had sufficient material for WTS, and 62 tumors (31 adenomas, 2 sebaceomas, 5 atypical sebaceous neoplasms, 24 carcinomas) had sufficient material for combined WGS and WTS. Overall, we found decreased cholesterol biosynthesis and increased TP53 mutations, copy number gains (chromosome 6, 8q, and/or 18), and tumor mutation burden-high (>10 mutations/MB) in carcinomas compared to adenomas. Although diminished compared to adenomas, most carcinomas still had higher cholesterol biosynthesis than nonmalignant skin. Multiomics profiling also supported a precancerous model of tumor evolution with sebaceomas and atypical sebaceous neoplasms being likely intermediate lesions. Conclusions: The study findings highlight key diagnostic biomarkers for sebaceous carcinoma and suggest that immunotherapy and modulation of cholesterol biosynthesis could be effective treatment strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236255","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 : 2024-09-13DOI: 10.1158/1078-0432.ccr-24-1883
Alexander W. Wyatt, Saskia Litière, Francois-Clement Bidard, Luc Cabel, Lars Dyrskjøt, Chris A. Karlovich, Klaus Pantel, Joan Petrie, Reena Philip, Hillary S. Andrews, Paz J. Vellanki, Sofie H. Tolmeijer, Xenia Villalobos Alberu, Christian Alfano, Jan Bogaerts, Emiliano Calvo, Alice P. Chen, Rodrigo A. Toledo, Elisabeth G. E. de Vries, Lesley Seymour, Scott A. Laurie, Elena Garralda
Early indicators of metastatic cancer response to therapy are important for evaluating new drugs and stopping ineffective treatment. The Response Evaluation Criteria in Solid Tumors (RECIST) based on repeat cancer imaging are widely adopted in clinical trials, are used to identify active regimens that may change practice, and contribute to regulatory approvals. However, these criteria do not provide insight before 6 – 12 weeks of treatment and typically require that patients have measurable disease. Recent data suggests that measuring on-treatment changes in the amount or proportion of circulating tumor DNA (ctDNA) in peripheral blood plasma may accurately identify responding and non-responding cancers at earlier time points. Over the past year, the RECIST working group has evaluated current evidence for plasma ctDNA kinetics as a treatment response biomarker in metastatic cancers and early endpoint in clinical trials, to identify areas of focus for future research and validation. Here, we outline the requirement for large standardized trial datasets, greater scrutiny of optimal ctDNA collection time points and assay thresholds, and consideration of regulatory body guidelines and patient opinions. In particular, clinically-meaningful changes in plasma ctDNA abundance are likely to differ by cancer type and therapy class, and must be assessed before ctDNA can be considered as a potential pan-cancer response evaluation biomarker. Despite the need for additional data, minimally-invasive on-treatment ctDNA measurements hold promise to build upon existing response assessments such as RECIST, and offer opportunities for developing novel early endpoints for modern clinical trials.
{"title":"Plasma ctDNA as a treatment response biomarker in metastatic cancers: evaluation by the RECIST working group","authors":"Alexander W. Wyatt, Saskia Litière, Francois-Clement Bidard, Luc Cabel, Lars Dyrskjøt, Chris A. Karlovich, Klaus Pantel, Joan Petrie, Reena Philip, Hillary S. Andrews, Paz J. Vellanki, Sofie H. Tolmeijer, Xenia Villalobos Alberu, Christian Alfano, Jan Bogaerts, Emiliano Calvo, Alice P. Chen, Rodrigo A. Toledo, Elisabeth G. E. de Vries, Lesley Seymour, Scott A. Laurie, Elena Garralda","doi":"10.1158/1078-0432.ccr-24-1883","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1883","url":null,"abstract":"Early indicators of metastatic cancer response to therapy are important for evaluating new drugs and stopping ineffective treatment. The Response Evaluation Criteria in Solid Tumors (RECIST) based on repeat cancer imaging are widely adopted in clinical trials, are used to identify active regimens that may change practice, and contribute to regulatory approvals. However, these criteria do not provide insight before 6 – 12 weeks of treatment and typically require that patients have measurable disease. Recent data suggests that measuring on-treatment changes in the amount or proportion of circulating tumor DNA (ctDNA) in peripheral blood plasma may accurately identify responding and non-responding cancers at earlier time points. Over the past year, the RECIST working group has evaluated current evidence for plasma ctDNA kinetics as a treatment response biomarker in metastatic cancers and early endpoint in clinical trials, to identify areas of focus for future research and validation. Here, we outline the requirement for large standardized trial datasets, greater scrutiny of optimal ctDNA collection time points and assay thresholds, and consideration of regulatory body guidelines and patient opinions. In particular, clinically-meaningful changes in plasma ctDNA abundance are likely to differ by cancer type and therapy class, and must be assessed before ctDNA can be considered as a potential pan-cancer response evaluation biomarker. Despite the need for additional data, minimally-invasive on-treatment ctDNA measurements hold promise to build upon existing response assessments such as RECIST, and offer opportunities for developing novel early endpoints for modern clinical trials.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231300","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 : 2024-09-13DOI: 10.1158/1078-0432.ccr-24-1166
Hey Min Lee, Ajay Kumar. Saw, Van K. Morris, Stefania Napolitano, Christopher Bristow, Sanjana Srinivasan, Michael Peoples, Alexey Sorokin, Preeti Kanikarla Marie, Jonathan Schulz, Anand K. Singh, Christopher Terranova, Oluwadara Coker, Abhinav Jain, Scott Kopetz, Kunal Rai
Purpose: BRAFV600E-mutated colorectal cancer (CRC) exhibits a strong correlation with DNA hypermethylation suggesting this subgroup of tumors presents unique epigenomic phenotypes. Nonetheless, 5-azacitidine, which inhibits DNA methyltransferase activity, is not efficacious in BRAFV600E CRC in vivo. Experimental Design: We randomized and treated mice implanted with patient-derived tumor xenografts harboring BRAFV600E mutation with control, 5-azacitidine, vemurafenib (BRAF inhibitor), or the combination. Comprehensive epigenomic profiling was conducted on control and 5-azacitidine-treated tumor samples, including DNA methylation, histone modifications, chromatin accessibility, and gene expression. Combinations of epigenetic agents were explored in preclinical BRAFV600E CRC models. Results: A profound reduction of DNA methylation levels upon 5-azacitidine treatment was confirmed, however, transcriptional repression was not relieved. This study unbiasedly explored the adaptive engagement of other epigenomic modifications upon 5-azacitidine treatment. A loss of histone acetylation and a gain of histone methylations, including H3K27 and H3K4 trimethylation, were observed around these hypomethylated regions suggesting the involvement of polycomb repressive complex (PRC) activity around the genome with loss of DNA methylation, therefore maintaining the repression of key tumor suppressor genes. Combined inhibition of PRC activity through EZH2 inhibitor with 5-azacitidine treatment additively improved efficacies in BRAFV600E CRC cells. Conclusions: In conclusion, DNA hypomethylation by 5-azacitidine exhibits a close association with H3K27me3 and PRC activity in BRAFV600E CRC, and simultaneous blockade of DNMT and EZH2 holds promise as a potential therapeutic strategy for patients with BRAFV600E-mutated CRC.
{"title":"Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated colorectal cancer.","authors":"Hey Min Lee, Ajay Kumar. Saw, Van K. Morris, Stefania Napolitano, Christopher Bristow, Sanjana Srinivasan, Michael Peoples, Alexey Sorokin, Preeti Kanikarla Marie, Jonathan Schulz, Anand K. Singh, Christopher Terranova, Oluwadara Coker, Abhinav Jain, Scott Kopetz, Kunal Rai","doi":"10.1158/1078-0432.ccr-24-1166","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1166","url":null,"abstract":"Purpose: BRAFV600E-mutated colorectal cancer (CRC) exhibits a strong correlation with DNA hypermethylation suggesting this subgroup of tumors presents unique epigenomic phenotypes. Nonetheless, 5-azacitidine, which inhibits DNA methyltransferase activity, is not efficacious in BRAFV600E CRC in vivo. Experimental Design: We randomized and treated mice implanted with patient-derived tumor xenografts harboring BRAFV600E mutation with control, 5-azacitidine, vemurafenib (BRAF inhibitor), or the combination. Comprehensive epigenomic profiling was conducted on control and 5-azacitidine-treated tumor samples, including DNA methylation, histone modifications, chromatin accessibility, and gene expression. Combinations of epigenetic agents were explored in preclinical BRAFV600E CRC models. Results: A profound reduction of DNA methylation levels upon 5-azacitidine treatment was confirmed, however, transcriptional repression was not relieved. This study unbiasedly explored the adaptive engagement of other epigenomic modifications upon 5-azacitidine treatment. A loss of histone acetylation and a gain of histone methylations, including H3K27 and H3K4 trimethylation, were observed around these hypomethylated regions suggesting the involvement of polycomb repressive complex (PRC) activity around the genome with loss of DNA methylation, therefore maintaining the repression of key tumor suppressor genes. Combined inhibition of PRC activity through EZH2 inhibitor with 5-azacitidine treatment additively improved efficacies in BRAFV600E CRC cells. Conclusions: In conclusion, DNA hypomethylation by 5-azacitidine exhibits a close association with H3K27me3 and PRC activity in BRAFV600E CRC, and simultaneous blockade of DNMT and EZH2 holds promise as a potential therapeutic strategy for patients with BRAFV600E-mutated CRC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231298","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 : 2024-09-13DOI: 10.1158/1078-0432.ccr-24-1750
Miguel A. Miranda-Román, Cindy J. Lee, Eve Fishinevich, Leili Ran, Amish J. Patel, Juan Yan, Makhzuna N. Khudoynazarova, Sarah Warda, Mohini R. Pachai, Yu Chen, Ping Chi
Purpose: Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive subtype of soft tissue sarcoma with a high propensity to metastasize and extremely limited treatment options. Loss of the RAS-GAP NF1 leads to sustained RAF/MEK/ERK signaling in MPNST. However, single-agent MEK inhibitors (MEKi) have failed to elicit a sustained inhibition of the MAPK signaling pathway in MPNST. Experimental Design: We employed pharmacological, biochemical, and genetic perturbations of the receptor tyrosine kinase (RTK) and MAPK signaling pathway regulators to investigate the mechanisms of MEKi resistance and evaluated combination therapeutic strategies in various preclinical MPNST models in vitro and in vivo. Results: Here, we report that MEKi treatment resistance in MPNST involves two adaptive pathways: direct transcriptional upregulation of the receptor tyrosine kinase (RTK) PDGFRβ, and MEKi-induced increase in RAF dimer formation and activation of downstream signaling. While the pharmacological combination of MEKi with a PDGFRβ specific inhibitor was more effective than treatment with MEKi alone, the combination of MEKi and RAF-dimer inhibitors led to a robust inhibition of the MAPK pathway signaling. This combination treatment was effective in vitro and in vivo, as demonstrated by the significant increase in drug synergism and its high effectiveness in decreasing MPNST viability. Conclusions: Our findings suggest that the combination of MEKi and PDGFR and/or RAF dimer inhibitors can overcome MEKi resistance and may serve as a novel targeted therapeutic strategy for NF1-deficient MPNST patients, which in turn could impact future clinical investigations for this patient population.
{"title":"MEK inhibitors lead to PDGFR pathway upregulation and sensitize tumors to RAF dimer inhibitors in NF1-deficient malignant peripheral nerve sheath tumor (MPNST)","authors":"Miguel A. Miranda-Román, Cindy J. Lee, Eve Fishinevich, Leili Ran, Amish J. Patel, Juan Yan, Makhzuna N. Khudoynazarova, Sarah Warda, Mohini R. Pachai, Yu Chen, Ping Chi","doi":"10.1158/1078-0432.ccr-24-1750","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1750","url":null,"abstract":"Purpose: Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive subtype of soft tissue sarcoma with a high propensity to metastasize and extremely limited treatment options. Loss of the RAS-GAP NF1 leads to sustained RAF/MEK/ERK signaling in MPNST. However, single-agent MEK inhibitors (MEKi) have failed to elicit a sustained inhibition of the MAPK signaling pathway in MPNST. Experimental Design: We employed pharmacological, biochemical, and genetic perturbations of the receptor tyrosine kinase (RTK) and MAPK signaling pathway regulators to investigate the mechanisms of MEKi resistance and evaluated combination therapeutic strategies in various preclinical MPNST models in vitro and in vivo. Results: Here, we report that MEKi treatment resistance in MPNST involves two adaptive pathways: direct transcriptional upregulation of the receptor tyrosine kinase (RTK) PDGFRβ, and MEKi-induced increase in RAF dimer formation and activation of downstream signaling. While the pharmacological combination of MEKi with a PDGFRβ specific inhibitor was more effective than treatment with MEKi alone, the combination of MEKi and RAF-dimer inhibitors led to a robust inhibition of the MAPK pathway signaling. This combination treatment was effective in vitro and in vivo, as demonstrated by the significant increase in drug synergism and its high effectiveness in decreasing MPNST viability. Conclusions: Our findings suggest that the combination of MEKi and PDGFR and/or RAF dimer inhibitors can overcome MEKi resistance and may serve as a novel targeted therapeutic strategy for NF1-deficient MPNST patients, which in turn could impact future clinical investigations for this patient population.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231299","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 : 2024-09-13DOI: 10.1158/1078-0432.ccr-24-0060
Matthew C. Dallos, Aleksandar Z. Obradovic, Patrick McCann, Nivedita Chowdhury, Aditya Pratapa, David H. Aggen, Christopher Gaffney, Karen A. Autio, Renu K. Virk, Angelo M. De Marzo, Emmanuel S. Antonarakis, Howard I. Scher, Charles G. Drake, Dana E. Rathkopf
Purpose: Androgen deprivation therapy (ADT) remains the backbone of prostate cancer treatment. Beyond suppression of testosterone and tumor cell growth, emerging evidence suggests ADT also modulates the immune tumor microenvironment (TME). However, a more precise understanding of the timing and intricacies of these immunological shifts is needed. Experimental Design: Here we analyzed 49 primary prostate cancers, comparing those surgically removed either without treatment or following treatment with degarelix at 4, 7, and 14 days pre-surgery. Utilizing next-generation DNA and RNA sequencing, and multiplexed immunofluorescence, we examined alterations in immune phenotypes in the presence or absence of ADT. Results: Our findings reveal that ADT rapidly transforms the typically bland prostate TME into an inflamed environment within days. Notably, we observed an increase in activated CD8 T-cells along with an increase in suppressive regulatory T-cells (Tregs). We also found an expansion of the myeloid compartment, particularly pro-inflammatory M1-like tumor-associated macrophages. Intriguingly, discernable changes which have not previously been described also occurred in tumor cells, including upregulation of antigen presentation by MHC class I and II and, unexpectedly, a decrease in the “don’t eat me” signal CD47. Conclusions: These observations underscore the critical role of timing and disease context in order to optimize the therapeutic efficacy of immune modulators combined with androgen ablation, for which the presurgical neoadjuvant setting may be ideal. Our findings warrant future prospective validation, which is currently underway.
目的：雄激素剥夺疗法（ADT）仍是治疗前列腺癌的主要手段。除了抑制睾酮和肿瘤细胞生长外，新的证据表明 ADT 还能调节免疫肿瘤微环境 (TME)。然而，我们需要更精确地了解这些免疫学变化的时间和复杂性。实验设计：在此，我们分析了 49 例原发性前列腺癌，比较了未经治疗或手术前 4、7 和 14 天使用地加瑞克治疗后手术切除的前列腺癌。利用新一代 DNA 和 RNA 测序以及多重免疫荧光技术，我们研究了 ADT 存在或不存在时免疫表型的变化。结果：我们的研究结果表明，ADT 能在数天内迅速将典型的平和前列腺 TME 转变为炎症环境。值得注意的是，我们观察到活化的 CD8 T 细胞增加，同时抑制性调节 T 细胞（Tregs）增加。我们还发现髓系细胞群，尤其是促炎性 M1 类肿瘤相关巨噬细胞出现扩张。耐人寻味的是，肿瘤细胞也发生了以前从未描述过的明显变化，包括 MHC I 类和 II 类抗原呈递的上调，以及 "别吃我 "信号 CD47 的意外减少。结论：这些观察结果表明，为了优化免疫调节剂联合雄激素消融的疗效，时机和疾病背景起着至关重要的作用。我们的研究结果值得今后进行前瞻性验证，目前这项工作正在进行中。
{"title":"Androgen Deprivation Therapy Drives a Distinct Immune Phenotype in Localized Prostate Cancer","authors":"Matthew C. Dallos, Aleksandar Z. Obradovic, Patrick McCann, Nivedita Chowdhury, Aditya Pratapa, David H. Aggen, Christopher Gaffney, Karen A. Autio, Renu K. Virk, Angelo M. De Marzo, Emmanuel S. Antonarakis, Howard I. Scher, Charles G. Drake, Dana E. Rathkopf","doi":"10.1158/1078-0432.ccr-24-0060","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-0060","url":null,"abstract":"Purpose: Androgen deprivation therapy (ADT) remains the backbone of prostate cancer treatment. Beyond suppression of testosterone and tumor cell growth, emerging evidence suggests ADT also modulates the immune tumor microenvironment (TME). However, a more precise understanding of the timing and intricacies of these immunological shifts is needed. Experimental Design: Here we analyzed 49 primary prostate cancers, comparing those surgically removed either without treatment or following treatment with degarelix at 4, 7, and 14 days pre-surgery. Utilizing next-generation DNA and RNA sequencing, and multiplexed immunofluorescence, we examined alterations in immune phenotypes in the presence or absence of ADT. Results: Our findings reveal that ADT rapidly transforms the typically bland prostate TME into an inflamed environment within days. Notably, we observed an increase in activated CD8 T-cells along with an increase in suppressive regulatory T-cells (Tregs). We also found an expansion of the myeloid compartment, particularly pro-inflammatory M1-like tumor-associated macrophages. Intriguingly, discernable changes which have not previously been described also occurred in tumor cells, including upregulation of antigen presentation by MHC class I and II and, unexpectedly, a decrease in the “don’t eat me” signal CD47. Conclusions: These observations underscore the critical role of timing and disease context in order to optimize the therapeutic efficacy of immune modulators combined with androgen ablation, for which the presurgical neoadjuvant setting may be ideal. Our findings warrant future prospective validation, which is currently underway.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231301","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}
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