Sharad K Verma, Keren L Witkin, Anu Sharman, Malcolm A Smith
Fusion oncoproteins are associated with childhood cancers and have proven challenging to target, aside from those that include kinases. As part of its efforts for targeting childhood cancers, the National Cancer Institute recently conducted a series on ‘Novel Chemical Approaches for Targeting Fusion Oncoproteins’. Key learnings on leading platforms and technologies which can be utilized to advance the development of molecular therapeutics that target fusion oncoproteins in childhood cancers are described. Recent breakthroughs in medicinal chemistry and chemical biology provide new ground and creative strategies to exploit for the development of targeted agents for improving outcomes against these recalcitrant cancers.
{"title":"Targeting fusion oncoproteins in childhood cancers: Challenges and future opportunities for developing therapeutics","authors":"Sharad K Verma, Keren L Witkin, Anu Sharman, Malcolm A Smith","doi":"10.1093/jnci/djae075","DOIUrl":"https://doi.org/10.1093/jnci/djae075","url":null,"abstract":"Fusion oncoproteins are associated with childhood cancers and have proven challenging to target, aside from those that include kinases. As part of its efforts for targeting childhood cancers, the National Cancer Institute recently conducted a series on ‘Novel Chemical Approaches for Targeting Fusion Oncoproteins’. Key learnings on leading platforms and technologies which can be utilized to advance the development of molecular therapeutics that target fusion oncoproteins in childhood cancers are described. Recent breakthroughs in medicinal chemistry and chemical biology provide new ground and creative strategies to exploit for the development of targeted agents for improving outcomes against these recalcitrant cancers.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140349152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R. Sandoval, M. Bottosso, Tianyu Li, Natália Polidorio, Brittany L. Bychkovsky, B. Verret, A. Gennari, Sophie Cahill, M. Achatz, O. Caron, Marion Imbert-Bouteille, Catherine Noguès, Kara N Mawell, Cristina Fortuno, A. Spurdle, N. Tayob, Fabrice Andre, Judy E Garber
BACKGROUND A large well-annotated recent international cohort of Li-Fraumeni (LFS) patients with early-stage breast cancer (BC) was examined for shared features. METHODS This multicentre cohort study included females with a germline TP53 pathogenic or likely pathogenic variant and nonmetastatic BC diagnosed between 2002-2022. Clinical and genetic data were obtained from institutional registries and clinical charts. Descriptive statistics were utilized to summarize proportions and differences were assessed by Chi square or Wilcoxon rank sum tests. Metachronous contralateral breast cancer (CBC) risk, radiation-induced sarcoma risk, and recurrence-free survival (RFS) were analyzed by Kaplan-Meier methodology. RESULTS Among 227 females who met study criteria, the median age of first BC diagnosis was 37 years (range 21-71), 11.9% presented with bilateral synchronous BC and 18.1% had ductal carcinoma in situ (DCIS) only. In total, 166 (73.1%) underwent mastectomies including 67 bilateral mastectomies as first BC surgery. Among those with retained breast tissue, CBC rate was 25.3% at 5-years. Among 186 invasive tumors, 72.1% were stages I-II, 48.9% node-negative, and the most common subtypes were HR+/HER2- (40.9%) and HR+/HER2 + (34.4%). At a median follow-up of 69.9 months (IQR 32.6-125.9), invasive HR+/HER2- disease had the highest recurrence risk among the subtypes (5-year RFS 61.1%, p = .0012). Among those who received radiation therapy (n = 79), the 5-year radiation-induced sarcoma rate was 4.8%. CONCLUSION We observed high rates of DCIS, HR+ and HER2+ breast cancers, with a worse outcome in the HR+/HER2- luminal tumors despite appropriate treatment. Confirmation of these findings in further studies could have implications for BC care in LFS.
{"title":"TP53-associated early breast cancer: new observations from a large cohort.","authors":"R. Sandoval, M. Bottosso, Tianyu Li, Natália Polidorio, Brittany L. Bychkovsky, B. Verret, A. Gennari, Sophie Cahill, M. Achatz, O. Caron, Marion Imbert-Bouteille, Catherine Noguès, Kara N Mawell, Cristina Fortuno, A. Spurdle, N. Tayob, Fabrice Andre, Judy E Garber","doi":"10.1093/jnci/djae074","DOIUrl":"https://doi.org/10.1093/jnci/djae074","url":null,"abstract":"BACKGROUND\u0000A large well-annotated recent international cohort of Li-Fraumeni (LFS) patients with early-stage breast cancer (BC) was examined for shared features.\u0000\u0000\u0000METHODS\u0000This multicentre cohort study included females with a germline TP53 pathogenic or likely pathogenic variant and nonmetastatic BC diagnosed between 2002-2022. Clinical and genetic data were obtained from institutional registries and clinical charts. Descriptive statistics were utilized to summarize proportions and differences were assessed by Chi square or Wilcoxon rank sum tests. Metachronous contralateral breast cancer (CBC) risk, radiation-induced sarcoma risk, and recurrence-free survival (RFS) were analyzed by Kaplan-Meier methodology.\u0000\u0000\u0000RESULTS\u0000Among 227 females who met study criteria, the median age of first BC diagnosis was 37 years (range 21-71), 11.9% presented with bilateral synchronous BC and 18.1% had ductal carcinoma in situ (DCIS) only. In total, 166 (73.1%) underwent mastectomies including 67 bilateral mastectomies as first BC surgery. Among those with retained breast tissue, CBC rate was 25.3% at 5-years. Among 186 invasive tumors, 72.1% were stages I-II, 48.9% node-negative, and the most common subtypes were HR+/HER2- (40.9%) and HR+/HER2 + (34.4%). At a median follow-up of 69.9 months (IQR 32.6-125.9), invasive HR+/HER2- disease had the highest recurrence risk among the subtypes (5-year RFS 61.1%, p = .0012). Among those who received radiation therapy (n = 79), the 5-year radiation-induced sarcoma rate was 4.8%.\u0000\u0000\u0000CONCLUSION\u0000We observed high rates of DCIS, HR+ and HER2+ breast cancers, with a worse outcome in the HR+/HER2- luminal tumors despite appropriate treatment. Confirmation of these findings in further studies could have implications for BC care in LFS.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"628 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140749398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
James L Li, Julian C McClellan, Haoyu Zhang, Guimin Gao, Dezheng Huo
Background Although genome-wide association studies (GWAS) of breast cancer (BC) identified common variants which differ between intrinsic subtypes, genes through which these variants act to impact BC risk have not been fully established. Transcriptome-wide association studies (TWAS) have identified genes associated with overall BC risk, but subtype-specific differences are largely unknown. Methods We performed two multi-tissue TWASs for each BC intrinsic subtype including an expression-based approach that collated TWAS signals from expression quantitative trait loci (eQTLs) across multiple tissues and a novel splicing-based approach that collated signals from splicing QTLs (sQTLs) across intron clusters and subsequently across tissues. We utilized summary statistics for five intrinsic subtypes including Luminal A-like, Luminal B-like, Luminal B/HER2-negative-like, HER2-enriched-like, and Triple-negative BC, generated from 106,278 BC cases and 91,477 controls in the Breast Cancer Association Consortium. Results Overall, we identified 235 genes in 88 loci across were associated with at least one of the five intrinsic subtypes. Most genes were subtype-specific, and many have not been reported in previous TWAS. We discovered common variants that modulate expression of CHEK2 confer increased risk to Luminal-A-like BC, in contrast to the viewpoint that CHEK2 primarily harbors rare, penetrant mutations. Additionally, our splicing-based TWAS provided population-level support for MDM4 splice variants that increased triple-negative BC risk. Conclusion Our comprehensive, multi-tissue TWAS corroborated previous GWAS loci for overall BC risk and intrinsic subtypes, while underscoring how common variation which impacts expression and splicing of genes in multiple tissue types can be used to further elucidate the etiology of BC.
背景 尽管乳腺癌（BC）的全基因组关联研究（GWAS）发现了不同内在亚型之间的常见变异，但这些变异通过哪些基因对乳腺癌风险产生影响尚未完全确定。全转录组关联研究（TWAS）发现了与乳腺癌总体风险相关的基因，但亚型特异性差异在很大程度上还不为人所知。方法 我们为每种 BC 固有亚型进行了两项多组织 TWAS，包括一种基于表达的方法，该方法整理了多个组织中来自表达定量性状位点 (eQTL) 的 TWAS 信号；以及一种基于剪接的新方法，该方法整理了各内含子群中来自剪接 QTL (sQTL) 的信号，并随后整理了各组织中的信号。我们利用乳腺癌协会联盟（Breast Cancer Association Consortium）中 106,278 例 BC 病例和 91,477 例对照中产生的五种固有亚型的汇总统计数据，包括 Luminal A-like、Luminal B-like、Luminal B/HER2-negative-like、HER2-enriched-like 和 Triple-negative BC。结果 总体而言，我们在 88 个位点上发现了 235 个基因，这些基因至少与五种内在亚型中的一种相关。大多数基因是亚型特异性的，许多基因在以前的 TWAS 中没有报道过。我们发现，调节 CHEK2 表达的常见变异会增加患 Luminal-A 类 BC 的风险，这与认为 CHEK2 主要存在罕见、穿透性突变的观点截然不同。此外，我们基于剪接的 TWAS 为增加三阴性 BC 风险的 MDM4 剪接变异提供了人群水平的支持。结论 我们的综合、多组织 TWAS 证实了以前关于 BC 整体风险和内在亚型的 GWAS 基因位点，同时强调了影响多种组织类型中基因表达和剪接的常见变异可用于进一步阐明 BC 的病因学。
{"title":"Multi-tissue transcriptome-wide association studies identified 235 genes for intrinsic subtypes of breast cancer","authors":"James L Li, Julian C McClellan, Haoyu Zhang, Guimin Gao, Dezheng Huo","doi":"10.1093/jnci/djae041","DOIUrl":"https://doi.org/10.1093/jnci/djae041","url":null,"abstract":"Background Although genome-wide association studies (GWAS) of breast cancer (BC) identified common variants which differ between intrinsic subtypes, genes through which these variants act to impact BC risk have not been fully established. Transcriptome-wide association studies (TWAS) have identified genes associated with overall BC risk, but subtype-specific differences are largely unknown. Methods We performed two multi-tissue TWASs for each BC intrinsic subtype including an expression-based approach that collated TWAS signals from expression quantitative trait loci (eQTLs) across multiple tissues and a novel splicing-based approach that collated signals from splicing QTLs (sQTLs) across intron clusters and subsequently across tissues. We utilized summary statistics for five intrinsic subtypes including Luminal A-like, Luminal B-like, Luminal B/HER2-negative-like, HER2-enriched-like, and Triple-negative BC, generated from 106,278 BC cases and 91,477 controls in the Breast Cancer Association Consortium. Results Overall, we identified 235 genes in 88 loci across were associated with at least one of the five intrinsic subtypes. Most genes were subtype-specific, and many have not been reported in previous TWAS. We discovered common variants that modulate expression of CHEK2 confer increased risk to Luminal-A-like BC, in contrast to the viewpoint that CHEK2 primarily harbors rare, penetrant mutations. Additionally, our splicing-based TWAS provided population-level support for MDM4 splice variants that increased triple-negative BC risk. Conclusion Our comprehensive, multi-tissue TWAS corroborated previous GWAS loci for overall BC risk and intrinsic subtypes, while underscoring how common variation which impacts expression and splicing of genes in multiple tissue types can be used to further elucidate the etiology of BC.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"88 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139943281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hua-Ren R Cherng, Melody Qu, Zafar Zafari, Søren Bentzen, Terri S Armstrong, Vinai Gondi, Paul D Brown, Minesh Mehta, Mark V Mishra
BACKGROUND EuroQoL EQ-5D is a commonly used measure of health-related quality of life (HRQOL) in clinical trials given the use of its index score as a measure of health utilities. It is unclear whether EQ-5D is sensitive to changes in neurocognitive function and progression that occur following brain radiation. This study sought to evaluate the sensitivity of EQ-5D-5L in reflecting these changes. PATIENTS and METHODS A secondary analysis of NRG Oncology CC001 was performed. Mean EQ-5D-5L index and visual analog scale (VAS) score changes from baseline between groups of patients stratified by neurocognitive function and intracranial progression status were assessed. MD Anderson Symptom Inventory for brain tumor (MDASI-BT) symptom and interference items were also analyzed between groups. RESULTS EQ-5D-5L index and VAS score changes between patients who had cognitive failure and those that had preserved cognition showed no significant differences at any time point. In contrast, VAS changes at 4 (1.61 vs -5.13, P = .05) and 6 months (8.17 vs -0.14, P = .04) were significantly improved in the patients who survived without intracranial progression. MDASI-BT cognitive factor scores were significantly improved in the cohort of patients with preserved neurocognitive function at 2 (1.68 vs 2.08, P = .05) and 4 months (1.35 vs 1.83, P = .04). MDASI-BT symptom interference was significantly associated with intracranial progression at 4 months, but not with neurocognitive status. CONCLUSION EQ-5D-5L index and VAS scores were not sensitive to neurocognitive changes that patients experienced, but VAS scores were sensitive to progression. This study challenges the routine use of EQ-5D as a QoL metric in brain metastases clinical trials that are focused on preventing neurocognitive dysfunction. Trial Registration NCT# 02360215
背景 欧洲生活质量指数（EuroQoL EQ-5D）是临床试验中常用的健康相关生活质量（HRQOL）测量指标，其指数得分可作为健康效用的测量指标。目前还不清楚 EQ-5D 是否对脑放射后神经认知功能的变化和发展敏感。本研究旨在评估 EQ-5D-5L 在反映这些变化方面的敏感性。患者和方法 对 NRG Oncology CC001 进行了二次分析。评估了按神经认知功能和颅内进展状态分层的患者组间的平均 EQ-5D-5L 指数和视觉模拟量表 (VAS) 评分与基线相比的变化。此外，还分析了不同组间的 MD 安德森脑肿瘤症状量表（MDASI-BT）症状和干扰项目。结果 在任何时间点，认知功能衰竭患者与认知功能保留患者之间的 EQ-5D-5L 指数和 VAS 评分变化均无显著差异。相比之下，未出现颅内病变的存活患者在 4 个月（1.61 vs -5.13，P = .05）和 6 个月（8.17 vs -0.14，P = .04）时的 VAS 变化明显改善。在神经认知功能得到保留的患者队列中，MDASI-BT认知因子评分在2个月（1.68 vs 2.08，P = .05）和4个月（1.35 vs 1.83，P = .04）时均有明显改善。MDASI-BT 症状干扰与 4 个月时的颅内病变进展有显著相关性，但与神经认知状态无关。结论 EQ-5D-5L 指数和 VAS 评分对患者的神经认知变化不敏感，但 VAS 评分对病情进展敏感。这项研究对在脑转移临床试验中常规使用EQ-5D作为QoL指标提出了质疑，因为脑转移临床试验的重点是预防神经认知功能障碍。试验注册 NCT# 02360215
{"title":"Evaluating the sensitivity of EQ-5D-5L in patients with brain metastases: a secondary analysis of NRG CC001","authors":"Hua-Ren R Cherng, Melody Qu, Zafar Zafari, Søren Bentzen, Terri S Armstrong, Vinai Gondi, Paul D Brown, Minesh Mehta, Mark V Mishra","doi":"10.1093/jnci/djae020","DOIUrl":"https://doi.org/10.1093/jnci/djae020","url":null,"abstract":"BACKGROUND EuroQoL EQ-5D is a commonly used measure of health-related quality of life (HRQOL) in clinical trials given the use of its index score as a measure of health utilities. It is unclear whether EQ-5D is sensitive to changes in neurocognitive function and progression that occur following brain radiation. This study sought to evaluate the sensitivity of EQ-5D-5L in reflecting these changes. PATIENTS and METHODS A secondary analysis of NRG Oncology CC001 was performed. Mean EQ-5D-5L index and visual analog scale (VAS) score changes from baseline between groups of patients stratified by neurocognitive function and intracranial progression status were assessed. MD Anderson Symptom Inventory for brain tumor (MDASI-BT) symptom and interference items were also analyzed between groups. RESULTS EQ-5D-5L index and VAS score changes between patients who had cognitive failure and those that had preserved cognition showed no significant differences at any time point. In contrast, VAS changes at 4 (1.61 vs -5.13, P = .05) and 6 months (8.17 vs -0.14, P = .04) were significantly improved in the patients who survived without intracranial progression. MDASI-BT cognitive factor scores were significantly improved in the cohort of patients with preserved neurocognitive function at 2 (1.68 vs 2.08, P = .05) and 4 months (1.35 vs 1.83, P = .04). MDASI-BT symptom interference was significantly associated with intracranial progression at 4 months, but not with neurocognitive status. CONCLUSION EQ-5D-5L index and VAS scores were not sensitive to neurocognitive changes that patients experienced, but VAS scores were sensitive to progression. This study challenges the routine use of EQ-5D as a QoL metric in brain metastases clinical trials that are focused on preventing neurocognitive dysfunction. Trial Registration NCT# 02360215","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139568351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Juan Yanguela, Bradford E Jackson, Katherine E Reeder-Hayes, Mya L Roberson, Gabrielle B Rocque, Tzy-Mey Kuo, Matthew R LeBlanc, Christopher Baggett, Laura Green, Erin Laurie-Zehr, Stephanie B Wheeler
Background Inequities in guideline-concordant treatment receipt contribute to worse survival in Black breast cancer (BCa) patients. Inequity-reduction interventions (eg, navigation, bias training, tracking dashboards) can close such treatment gaps. We simulated the population-level impact of statewide implementation of inequity-reduction interventions on racial BCa inequities in North Carolina. Methods Using registry-linked multi-payer claims data, we calculated Black/White inequities in endocrine (ET; n = 12,033) and chemotherapy (CTx; n = 1,819) receipt. We then built cohort- (ET and CTx), and race-stratified Markov models to simulate the potential increase in the proportion of patients receiving ET or CTx and subsequent improvements in BCa outcomes if inequity-reducing intervention were implemented statewide. We report uncertainty bounds representing 95% of simulation results. Results 75.6% and 72.1% of Black patients received ET and CTx over the 2006-2015 and 2004-2015 periods (vs 79.3 and 78.9% of White patients, respectively). Inequity-reduction interventions could increase ET and CTx receipt among Black patients to 89.9% (85.3, 94.6%) and 85.7% (80.7, 90.9%). Such interventions could also decrease 5-and 10-year BCa mortality gaps from 3.4 to 3.2 (3.0, 3.3) and from 6.7 to 6.1 (5.9, 6.4) percentage points in the ET cohorts and from 8.6 to 8.1 (7.7, 8.4) and from 8.2 to 7.8 (7.3, 8.1) percentage points in the CTx cohorts. Conclusions Inequity-focused interventions could improve cancer outcomes for Black patients. However, they would not fully close the racial BCa mortality gap. Addressing other inequities along cancer continuum (eg, screening, pre-and post-diagnosis risk factors) is required to achieve full equity in BCa outcomes.
{"title":"Simulating the population impact of interventions to reduce racial gaps in breast cancer treatment","authors":"Juan Yanguela, Bradford E Jackson, Katherine E Reeder-Hayes, Mya L Roberson, Gabrielle B Rocque, Tzy-Mey Kuo, Matthew R LeBlanc, Christopher Baggett, Laura Green, Erin Laurie-Zehr, Stephanie B Wheeler","doi":"10.1093/jnci/djae019","DOIUrl":"https://doi.org/10.1093/jnci/djae019","url":null,"abstract":"Background Inequities in guideline-concordant treatment receipt contribute to worse survival in Black breast cancer (BCa) patients. Inequity-reduction interventions (eg, navigation, bias training, tracking dashboards) can close such treatment gaps. We simulated the population-level impact of statewide implementation of inequity-reduction interventions on racial BCa inequities in North Carolina. Methods Using registry-linked multi-payer claims data, we calculated Black/White inequities in endocrine (ET; n = 12,033) and chemotherapy (CTx; n = 1,819) receipt. We then built cohort- (ET and CTx), and race-stratified Markov models to simulate the potential increase in the proportion of patients receiving ET or CTx and subsequent improvements in BCa outcomes if inequity-reducing intervention were implemented statewide. We report uncertainty bounds representing 95% of simulation results. Results 75.6% and 72.1% of Black patients received ET and CTx over the 2006-2015 and 2004-2015 periods (vs 79.3 and 78.9% of White patients, respectively). Inequity-reduction interventions could increase ET and CTx receipt among Black patients to 89.9% (85.3, 94.6%) and 85.7% (80.7, 90.9%). Such interventions could also decrease 5-and 10-year BCa mortality gaps from 3.4 to 3.2 (3.0, 3.3) and from 6.7 to 6.1 (5.9, 6.4) percentage points in the ET cohorts and from 8.6 to 8.1 (7.7, 8.4) and from 8.2 to 7.8 (7.3, 8.1) percentage points in the CTx cohorts. Conclusions Inequity-focused interventions could improve cancer outcomes for Black patients. However, they would not fully close the racial BCa mortality gap. Addressing other inequities along cancer continuum (eg, screening, pre-and post-diagnosis risk factors) is required to achieve full equity in BCa outcomes.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"166 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139568340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Danielle R Trakimas, Wojtek Mydlarz, Leila J Mady, Wayne Koch, Harry Quon, Nyall R London, Carole Fakhry
Background Studies have shown lower overall survival for patients with head and neck cancer treated at low-volume or community cancer centers. As the incidence of human papillomavirus (HPV)–related oropharyngeal squamous cell carcinoma steadily rises in the United States, we hypothesized that a greater proportion of patients with HPV-related oropharyngeal squamous cell carcinoma is being treated at community cancer centers, with a shift toward primary nonsurgical treatment. Methods This cohort study included patients from the US National Cancer Database who received a diagnosis of HPV-related oropharyngeal squamous cell carcinoma from 2010 to 2019 and underwent treatment at a community cancer center or academic cancer center. The proportion of patients with HPV-related oropharyngeal squamous cell carcinoma treated at community cancer centers and receiving primary nonsurgical treatment was analyzed over time. Four-year overall survival was compared between community cancer centers and academic cancer centers. Results The majority (67.4%) of 20 298 patients were treated at an academic cancer center, yet the proportion of patients treated at community cancer centers increased by 10% from 2010 to 2019 (P < .01 for trend). The proportion of patients undergoing primary nonsurgical treatment increased from 62.1% to 73.7% from 2010 to 2019 (P < .01 for trend), and patients were statistically significantly more likely to undergo nonsurgical treatment at community cancer centers than at academic cancer centers (adjusted odds ratio = 1.20, 95% confidence interval = 1.18 to 1.22). Treatment at community cancer centers was associated with worse survival overall (adjusted hazard ratio = 1.19, 95% confidence interval = 1.09 to 1.31), specifically for patients receiving primary nonsurgical treatment (adjusted hazard ratio = 1.22, 95% confidence interval = 1.11 to 1.34). Conclusions Treatment of HPV-related oropharyngeal squamous cell carcinoma has recently shifted to community cancer centers, with an increase in the proportion of nonsurgical treatment and worse overall survival at these centers compared with academic cancer centers. Concentration of care for HPV-related oropharyngeal squamous cell carcinoma at academic cancer centers and dedicated head and neck cancer centers may increase access to all available treatment modalities and improve survival.
{"title":"Increasing radiation therapy and lower survival for human papillomavirus–related oropharynx cancer associated with a shift to community cancer center care","authors":"Danielle R Trakimas, Wojtek Mydlarz, Leila J Mady, Wayne Koch, Harry Quon, Nyall R London, Carole Fakhry","doi":"10.1093/jnci/djad238","DOIUrl":"https://doi.org/10.1093/jnci/djad238","url":null,"abstract":"Background Studies have shown lower overall survival for patients with head and neck cancer treated at low-volume or community cancer centers. As the incidence of human papillomavirus (HPV)–related oropharyngeal squamous cell carcinoma steadily rises in the United States, we hypothesized that a greater proportion of patients with HPV-related oropharyngeal squamous cell carcinoma is being treated at community cancer centers, with a shift toward primary nonsurgical treatment. Methods This cohort study included patients from the US National Cancer Database who received a diagnosis of HPV-related oropharyngeal squamous cell carcinoma from 2010 to 2019 and underwent treatment at a community cancer center or academic cancer center. The proportion of patients with HPV-related oropharyngeal squamous cell carcinoma treated at community cancer centers and receiving primary nonsurgical treatment was analyzed over time. Four-year overall survival was compared between community cancer centers and academic cancer centers. Results The majority (67.4%) of 20 298 patients were treated at an academic cancer center, yet the proportion of patients treated at community cancer centers increased by 10% from 2010 to 2019 (P &lt; .01 for trend). The proportion of patients undergoing primary nonsurgical treatment increased from 62.1% to 73.7% from 2010 to 2019 (P &lt; .01 for trend), and patients were statistically significantly more likely to undergo nonsurgical treatment at community cancer centers than at academic cancer centers (adjusted odds ratio = 1.20, 95% confidence interval = 1.18 to 1.22). Treatment at community cancer centers was associated with worse survival overall (adjusted hazard ratio = 1.19, 95% confidence interval = 1.09 to 1.31), specifically for patients receiving primary nonsurgical treatment (adjusted hazard ratio = 1.22, 95% confidence interval = 1.11 to 1.34). Conclusions Treatment of HPV-related oropharyngeal squamous cell carcinoma has recently shifted to community cancer centers, with an increase in the proportion of nonsurgical treatment and worse overall survival at these centers compared with academic cancer centers. Concentration of care for HPV-related oropharyngeal squamous cell carcinoma at academic cancer centers and dedicated head and neck cancer centers may increase access to all available treatment modalities and improve survival.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139081707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rengyun Liu, Guangwu Zhu, Jie Tan, Xiaopei Shen, Mingzhao Xing
Background BRAF V600E and TERT promoter mutations are core components in current genetic-based risk assessment for precision management of papillary thyroid cancer (PTC). It remains unknown whether this could be refined to even better precision by a widely recognized prognostic single nucleotide polymorphism (SNP), rs2853669T>C, in the TERT promoter. Methods Genetic status of mutations and SNP were examined by sequencing genomic DNA from PTC in 608 patients (427 women and 181 men) aged 47 years (IQR 37-57), with a median follow-up time of 75 months (IQR 36 to 123), and their relationship with clinical outcomes was analyzed. Luciferase reporter assay was performed to examine TERT promoter activities. Results TERT promoter mutations showed a strong association with PTC recurrence in the presence of genotype TT of rs2853669 (adjusted HR = 2.12, 95% CI 1.10-4.12) but not TC/CC (adjusted HR = 1.17, 95% CI 0.56-2.41). TERT and BRAF mutations commonly coexisted and synergistically promoted PTC recurrence. With this genetic duet, TT of rs2853669 showed a robustly higher disease recurrence compared with TC/CC (adjusted HR = 14.26, 95% CI 2.86-71.25). Patients with the genetic trio of BRAF V600E, TERT mutation and TT of rs2853669 had a recurrence of 76.5% vs recurrence of 8.4% with neither mutation and with TC/CC (HR = 13.48, 95% CI 6.44-28.21). T allele of rs2853669 strongly increased TERT promoter, particularly the mutant promoter. Conclusions SNP rs2853669T>C dramatically refines the prognostic power of BRAF V600E and TERT promoter mutations to a higher precision, suggesting the need for including this SNP in the current genetic-based risk prognostication of PTC.
背景 BRAF V600E 和 TERT 启动子突变是目前基于基因的甲状腺乳头状癌（PTC）精准管理风险评估的核心内容。目前仍不清楚的是，TERT启动子中被广泛认可的预后单核苷酸多态性（SNP）rs2853669T>C是否能使这一评估更加精确。方法 通过对 608 名年龄为 47 岁（IQR 37-57）、中位随访时间为 75 个月（IQR 36-123）的 PTC 患者（427 名女性和 181 名男性）的基因组 DNA 进行测序，检查了突变和 SNP 的遗传状态，并分析了它们与临床结果的关系。采用荧光素酶报告分析法检测 TERT 启动子的活性。结果 在rs2853669基因型为TT时，TERT启动子突变与PTC复发密切相关（调整后HR=2.12，95% CI 1.10-4.12），但与TC/CC无关（调整后HR=1.17，95% CI 0.56-2.41）。TERT和BRAF突变通常共存，并协同促进PTC复发。在这种基因二重奏中，rs2853669的TT与TC/CC相比显示出更高的疾病复发率（调整后HR = 14.26，95% CI 2.86-71.25）。BRAF V600E、TERT 突变和 rs2853669 的 TT 三重遗传患者的复发率为 76.5%，而无突变和 TC/CC 患者的复发率为 8.4%（HR = 13.48，95% CI 6.44-28.21）。rs2853669的T等位基因强烈增加了TERT启动子，尤其是突变启动子。结论 SNP rs2853669T>C 显著提高了 BRAF V600E 和 TERT 启动子突变的预后能力，使其精确度更高，这表明有必要将该 SNP 纳入目前基于基因的 PTC 风险预后中。
{"title":"Genetic Trio of BRAF and TERT Mutations and rs2853669TT in Papillary Thyroid Cancer Aggressiveness","authors":"Rengyun Liu, Guangwu Zhu, Jie Tan, Xiaopei Shen, Mingzhao Xing","doi":"10.1093/jnci/djad265","DOIUrl":"https://doi.org/10.1093/jnci/djad265","url":null,"abstract":"Background BRAF V600E and TERT promoter mutations are core components in current genetic-based risk assessment for precision management of papillary thyroid cancer (PTC). It remains unknown whether this could be refined to even better precision by a widely recognized prognostic single nucleotide polymorphism (SNP), rs2853669T&gt;C, in the TERT promoter. Methods Genetic status of mutations and SNP were examined by sequencing genomic DNA from PTC in 608 patients (427 women and 181 men) aged 47 years (IQR 37-57), with a median follow-up time of 75 months (IQR 36 to 123), and their relationship with clinical outcomes was analyzed. Luciferase reporter assay was performed to examine TERT promoter activities. Results TERT promoter mutations showed a strong association with PTC recurrence in the presence of genotype TT of rs2853669 (adjusted HR = 2.12, 95% CI 1.10-4.12) but not TC/CC (adjusted HR = 1.17, 95% CI 0.56-2.41). TERT and BRAF mutations commonly coexisted and synergistically promoted PTC recurrence. With this genetic duet, TT of rs2853669 showed a robustly higher disease recurrence compared with TC/CC (adjusted HR = 14.26, 95% CI 2.86-71.25). Patients with the genetic trio of BRAF V600E, TERT mutation and TT of rs2853669 had a recurrence of 76.5% vs recurrence of 8.4% with neither mutation and with TC/CC (HR = 13.48, 95% CI 6.44-28.21). T allele of rs2853669 strongly increased TERT promoter, particularly the mutant promoter. Conclusions SNP rs2853669T&gt;C dramatically refines the prognostic power of BRAF V600E and TERT promoter mutations to a higher precision, suggesting the need for including this SNP in the current genetic-based risk prognostication of PTC.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138770869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ryan S Huang, Andrew Mihalache, Abdulwadud Nafees, Asad Hasan, Xiang Y Ye, Zhihui Liu, Natasha B Leighl, Srinivas Raman
Background Multidisciplinary cancer conferences (MCCs) are comprised of regular meetings between diverse specialists working together to share clinical decision making in cancer care. The aim of this study is to systematically review and meta-analyze the effect of MCC intervention on overall survival of cancer patients. Methods A systematic literature search was conducted on Ovid MEDLINE, EMBASE and the Cochrane Controlled Register of Trials for studies published up to July 2023. Studies reporting on the impact of MCCs on overall survival of patients were included. A standard random effects model with the inverse-variance weighted approach was used to estimate the pooled hazard ratio of mortality (MCC vs non-MCC) across studies and the heterogeneity was assessed by I2. Publication bias was examined using funnel plot and Egger’s test. Results A total of 134,287 cancer patients from 59 studies were included in our analysis, with 48,467 managed by MCCs and 85,820 in the control arm. Across all cancer types, patients managed by MCCs had an increased overall survival compared to control patients (HR = 0.67, 95%CI = [0.62, 0.71], I2=84%). Median survival time was 30.2 months and 19.0 months in the MCC intervention and control group, respectively. In subgroup analysis, a positive effect of MCC intervention on overall survival was found in breast, colorectal, esophageal, haematological, hepatocellular, lung, pancreatic, and head and neck cancer. Conclusions Overall, our meta-analysis found a significant positive effect of MCCs compared to controls. Further studies are needed to establish nuanced guidelines when optimizing MCC integration for treating diverse cancer patient populations.
{"title":"The Impact of Multidisciplinary Cancer Conferences on Overall Survival: A Meta-Analysis","authors":"Ryan S Huang, Andrew Mihalache, Abdulwadud Nafees, Asad Hasan, Xiang Y Ye, Zhihui Liu, Natasha B Leighl, Srinivas Raman","doi":"10.1093/jnci/djad268","DOIUrl":"https://doi.org/10.1093/jnci/djad268","url":null,"abstract":"Background Multidisciplinary cancer conferences (MCCs) are comprised of regular meetings between diverse specialists working together to share clinical decision making in cancer care. The aim of this study is to systematically review and meta-analyze the effect of MCC intervention on overall survival of cancer patients. Methods A systematic literature search was conducted on Ovid MEDLINE, EMBASE and the Cochrane Controlled Register of Trials for studies published up to July 2023. Studies reporting on the impact of MCCs on overall survival of patients were included. A standard random effects model with the inverse-variance weighted approach was used to estimate the pooled hazard ratio of mortality (MCC vs non-MCC) across studies and the heterogeneity was assessed by I2. Publication bias was examined using funnel plot and Egger’s test. Results A total of 134,287 cancer patients from 59 studies were included in our analysis, with 48,467 managed by MCCs and 85,820 in the control arm. Across all cancer types, patients managed by MCCs had an increased overall survival compared to control patients (HR = 0.67, 95%CI = [0.62, 0.71], I2=84%). Median survival time was 30.2 months and 19.0 months in the MCC intervention and control group, respectively. In subgroup analysis, a positive effect of MCC intervention on overall survival was found in breast, colorectal, esophageal, haematological, hepatocellular, lung, pancreatic, and head and neck cancer. Conclusions Overall, our meta-analysis found a significant positive effect of MCCs compared to controls. Further studies are needed to establish nuanced guidelines when optimizing MCC integration for treating diverse cancer patient populations.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"203 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138822903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
When diagnosed with cancer or any other life-threatening condition, people must negotiate two once-separate but now integrated realms—a medical care industrial complex and an everyday life now lived in conscious awareness of mortality—a state of being subject to death. Life becomes a series of challenges and disruptions to relationships, body image and integrity, autonomy and independence, life goals, hopes, and dreams for the future. Whether one physically, emotionally, or spiritually survives, thrives, or succumbs to cancer is dependent upon a treatment plan that accounts for the multiple and varied ways in which people experience dual citizenship in the realms of the well and the sick. A theory of cancer survivorship that integrates both medical and patient perspectives into a cogent and coherent framework has the potential to enhance the quality of cancer care and the patient experience.
{"title":"Cancer Survivorship—A Framework for Quality Cancer Care","authors":"Bradley Zebrack","doi":"10.1093/jnci/djad266","DOIUrl":"https://doi.org/10.1093/jnci/djad266","url":null,"abstract":"When diagnosed with cancer or any other life-threatening condition, people must negotiate two once-separate but now integrated realms—a medical care industrial complex and an everyday life now lived in conscious awareness of mortality—a state of being subject to death. Life becomes a series of challenges and disruptions to relationships, body image and integrity, autonomy and independence, life goals, hopes, and dreams for the future. Whether one physically, emotionally, or spiritually survives, thrives, or succumbs to cancer is dependent upon a treatment plan that accounts for the multiple and varied ways in which people experience dual citizenship in the realms of the well and the sick. A theory of cancer survivorship that integrates both medical and patient perspectives into a cogent and coherent framework has the potential to enhance the quality of cancer care and the patient experience.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"35 6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138770699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rena R Jones, Jessica M Madrigal, Rebecca Troisi, Heljä-Marja Surcel, Hanna Öhman, Juha Kivelä, Hannu Kiviranta, Panu Rantakokko, Jani Koponen, Danielle N Medgyesi, Katherine A McGlynn, Joshua Sampson, Paul S Albert, Mary H Ward
Background Per- and polyfluoroalkyl substances (PFAS) are widespread and environmentally persistent chemicals with immunotoxic properties. Children are prenatally exposed through maternal transfer of PFAS to cord blood, but no studies have investigated the relationship with childhood leukemia. Methods We measured maternal serum levels of 19 PFAS in first-trimester samples collected in 1986-2010 and evaluated associations with acute lymphoblastic leukemia (ALL) in full-term offspring (<15 years) for 400 cases and 400 controls in the Finnish Maternity Cohort, matched on sample year, mother’s age, gestational age, birth order, and child’s sex. We analyzed continuous and categorical exposures, estimating odds ratios (OR) and 95% confidence intervals (CI) via conditional logistic regression adjusted for maternal smoking and correlated PFAS (ρ ≥ ±0.3). We also stratified by calendar period, mean diagnosis age, and the child’s sex. Results N‑methyl‑perfluorooctane sulfonamidoacetic acid (MeFOSAA) was associated with ALL in continuous models (per each doubling in levels: ORperlog2=1.22, CI = 1.07-1.39), with a positive exposure-response across categories (OR>90th percentile=2.52, CI = 1.33-4.78; p-trend = 0.01). While we found no relationship with perfluorooctane sulfonic acid (PFOS) overall, an association was observed in samples collected 1986-1995, when levels were highest (median = 17.9 µg/L; ORperlog2=4.01, CI = 1.62-9.93). A positive association with perfluorononanoic acid was suggested among first births (p-interaction = 0.06). The MeFOSAA association was mainly limited to children diagnosed before age 5 (p-interaction = 0.02). We found no consistent patterns of association with other PFAS, nor differences by sex. Conclusions These novel data offer evidence of a relationship between some PFAS and risk of the most common childhood cancer worldwide, including associations with the highest levels of PFOS and with a precursor, MeFOSAA.
全氟烷基和多氟烷基物质(PFAS)是广泛存在的具有免疫毒性的环境持久性化学品。儿童在产前通过母体将PFAS转移到脐带血中暴露，但没有研究调查PFAS与儿童白血病的关系。方法:我们测量了1986-2010年收集的孕早期样本中19种PFAS的血清水平，并评估了芬兰产妇队列中400例和400例对照的足月子代(15岁)急性淋巴细胞白血病(ALL)的相关性，这些样本的年份、母亲年龄、胎龄、出生顺序和儿童性别相匹配。我们分析了连续暴露和分类暴露，通过调整母亲吸烟和相关PFAS (ρ≥±0.3)的条件logistic回归估计优势比(OR)和95%置信区间(CI)。我们还按日历期、平均诊断年龄和儿童性别进行分层。结果:在连续模型中，N -甲基全氟辛烷磺酰胺乙酸(MeFOSAA)与ALL相关(水平每增加一倍:ORperlog2=1.22, CI = 1.07-1.39)，跨类别的暴露反应为正(OR>第90百分位数=2.52,CI = 1.33-4.78;P-trend = 0.01)。虽然我们总体上没有发现与全氟辛烷磺酸(PFOS)的关系，但在1986-1995年收集的样品中观察到一种关联，当时水平最高(中位数= 17.9微克/升;ORperlog2=4.01, CI = 1.62-9.93)。第一胎与全氟壬烷酸呈正相关(p-相互作用= 0.06)。MeFOSAA相关性主要局限于5岁前诊断的儿童(p交互作用= 0.02)。我们没有发现与其他PFAS相关的一致模式，也没有性别差异。这些新数据为全氟辛烷磺酸与世界范围内最常见的儿童癌症风险之间的关系提供了证据，包括与全氟辛烷磺酸最高水平和前体MeFOSAA的关联。
{"title":"Maternal serum concentrations of per- and polyfluoroalkyl substances and childhood acute lymphoblastic leukemia","authors":"Rena R Jones, Jessica M Madrigal, Rebecca Troisi, Heljä-Marja Surcel, Hanna Öhman, Juha Kivelä, Hannu Kiviranta, Panu Rantakokko, Jani Koponen, Danielle N Medgyesi, Katherine A McGlynn, Joshua Sampson, Paul S Albert, Mary H Ward","doi":"10.1093/jnci/djad261","DOIUrl":"https://doi.org/10.1093/jnci/djad261","url":null,"abstract":"Background Per- and polyfluoroalkyl substances (PFAS) are widespread and environmentally persistent chemicals with immunotoxic properties. Children are prenatally exposed through maternal transfer of PFAS to cord blood, but no studies have investigated the relationship with childhood leukemia. Methods We measured maternal serum levels of 19 PFAS in first-trimester samples collected in 1986-2010 and evaluated associations with acute lymphoblastic leukemia (ALL) in full-term offspring (&lt;15 years) for 400 cases and 400 controls in the Finnish Maternity Cohort, matched on sample year, mother’s age, gestational age, birth order, and child’s sex. We analyzed continuous and categorical exposures, estimating odds ratios (OR) and 95% confidence intervals (CI) via conditional logistic regression adjusted for maternal smoking and correlated PFAS (ρ ≥ ±0.3). We also stratified by calendar period, mean diagnosis age, and the child’s sex. Results N‑methyl‑perfluorooctane sulfonamidoacetic acid (MeFOSAA) was associated with ALL in continuous models (per each doubling in levels: ORperlog2=1.22, CI = 1.07-1.39), with a positive exposure-response across categories (OR&gt;90th percentile=2.52, CI = 1.33-4.78; p-trend = 0.01). While we found no relationship with perfluorooctane sulfonic acid (PFOS) overall, an association was observed in samples collected 1986-1995, when levels were highest (median = 17.9 µg/L; ORperlog2=4.01, CI = 1.62-9.93). A positive association with perfluorononanoic acid was suggested among first births (p-interaction = 0.06). The MeFOSAA association was mainly limited to children diagnosed before age 5 (p-interaction = 0.02). We found no consistent patterns of association with other PFAS, nor differences by sex. Conclusions These novel data offer evidence of a relationship between some PFAS and risk of the most common childhood cancer worldwide, including associations with the highest levels of PFOS and with a precursor, MeFOSAA.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138679263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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