Pub Date : 2024-11-15DOI: 10.1016/j.ygyno.2024.11.003
Wafa Khadraoui , Jennifer A. Sinnott , Caitlin E. Meade , Jesse Plascak , Autumn Carey , Floor J. Backes , Robert L. Dood , Britton Trabert , Ashley S. Felix
Objective
Among gynecologic cancer patients, it is unclear whether participation in clinical trials impacts survival outcomes. In addition, given the known racial and ethnic disparities in gynecologic cancer trial enrollment, it is important to assess whether clinical trial enrollment is similarly related to overall survival among racial and ethnic minorities. Therefore, we examined associations between clinical trial enrollment and overall survival and potential effect modification by race/ethnicity and cancer site among gynecologic cancer patients.
Methods
We used the National Cancer Database to identify women diagnosed with a cervical, ovarian, or uterine cancer from 2004 to 2020 (N = 861,817). Race/ethnicity categories included American Indian/Alaska Native, Asian, Black, Hispanic (any race), Native Hawaiian/Pacific Islander, and White. We used stratified Cox proportional hazards regression to estimate univariable and multivariable-adjusted hazard ratios and 95% confidence intervals for associations of clinical trial enrollment and overall survival. Effect modification by race/ethnicity and cancer site was assessed with multiplicative interaction terms in separate models.
Results
Median follow-up was 56.0 months (range 0.03–229.4 months). Clinical trial enrollment was related to improved overall survival among gynecologic cancer patients in the overall study population (hazard ratio = 0.90, 95% confidence interval = 0.82–0.99). Neither race/ethnicity (p = 0.34) nor cancer site (p = 0.09) modified the association.
Conclusion
Clinical trial enrollment was associated with improved outcomes for gynecologic cancer patients. These findings are important in demonstrating that participation in clinical trials, regardless of therapeutic treatment assignment, is related to better outcomes.
{"title":"Clinical trial enrollment during first course of gynecologic cancer treatment and survival","authors":"Wafa Khadraoui , Jennifer A. Sinnott , Caitlin E. Meade , Jesse Plascak , Autumn Carey , Floor J. Backes , Robert L. Dood , Britton Trabert , Ashley S. Felix","doi":"10.1016/j.ygyno.2024.11.003","DOIUrl":"10.1016/j.ygyno.2024.11.003","url":null,"abstract":"<div><h3>Objective</h3><div>Among gynecologic cancer patients, it is unclear whether participation in clinical trials impacts survival outcomes. In addition, given the known racial and ethnic disparities in gynecologic cancer trial enrollment, it is important to assess whether clinical trial enrollment is similarly related to overall survival among racial and ethnic minorities. Therefore, we examined associations between clinical trial enrollment and overall survival and potential effect modification by race/ethnicity and cancer site among gynecologic cancer patients.</div></div><div><h3>Methods</h3><div>We used the National Cancer Database to identify women diagnosed with a cervical, ovarian, or uterine cancer from 2004 to 2020 (<em>N</em> = 861,817). Race/ethnicity categories included American Indian/Alaska Native, Asian, Black, Hispanic (any race), Native Hawaiian/Pacific Islander, and White. We used stratified Cox proportional hazards regression to estimate univariable and multivariable-adjusted hazard ratios and 95% confidence intervals for associations of clinical trial enrollment and overall survival. Effect modification by race/ethnicity and cancer site was assessed with multiplicative interaction terms in separate models.</div></div><div><h3>Results</h3><div>Median follow-up was 56.0 months (range 0.03–229.4 months). Clinical trial enrollment was related to improved overall survival among gynecologic cancer patients in the overall study population (hazard ratio = 0.90, 95% confidence interval = 0.82–0.99). Neither race/ethnicity (<em>p</em> = 0.34) nor cancer site (<em>p</em> = 0.09) modified the association.</div></div><div><h3>Conclusion</h3><div>Clinical trial enrollment was associated with improved outcomes for gynecologic cancer patients. These findings are important in demonstrating that participation in clinical trials, regardless of therapeutic treatment assignment, is related to better outcomes.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"192 ","pages":"Pages 59-64"},"PeriodicalIF":4.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-14DOI: 10.1016/j.ygyno.2024.10.032
Catherine C. Classen , Meredith L. Chivers , Lori A. Brotto , Lisa Barbera , Jeanne Carter , John Koval , John W. Robinson , Sarah E. Ferguson
Objective
To assess whether a 12-week, professionally facilitated, asynchronous online support group would reduce sexual distress (primary outcome) and improve sexual function, body image, depression symptoms, relationship satisfaction, and social support (secondary outcomes) in women treated for gynecologic cancer.
Methods
Participants were 398 women recruited from three Canadian provinces and one American cancer center in cohorts of 40. Participants were randomized (50:50 odds) to either the immediate treatment condition (ITC) or the waitlist control condition (WCC). Eligibility included: completed treatment for gynecologic cancer, disease-free for at least 3 months, no more than 5 years post-diagnosis, met criteria for psychosexual distress, willing to discuss sexual concerns, 18 years or older, English speaking, and access to a computer. Participants in the ITC received a 12-week online group along with psychoeducational material each week to stimulate discussion. Two 90-min synchronous sessions were offered in weeks 4 and 8.
Results
Reductions in sexual distress for ITC were not significantly different compared to WCC. Similarly, no treatment effects were observed for body image, depression, relationship satisfaction, or social support. ITC showed statistically significant improvements in sexual functioning compared to WCC, but these gains were not retained at 4-month follow-up.
Conclusion
Treatment effects were modest, although in the expected direction. As this study was underpowered, it offers preliminary evidence that an asynchronous, online psychoeducational support group may confer positive benefits for women's sexual functioning. The efficiency, convenience, and accessibility of online interventions has significant potential to close gaps in women's access to evidence-based sexual health care.
{"title":"A randomized controlled trial of an online support group addressing psychosexual distress among women treated for gynecologic cancer","authors":"Catherine C. Classen , Meredith L. Chivers , Lori A. Brotto , Lisa Barbera , Jeanne Carter , John Koval , John W. Robinson , Sarah E. Ferguson","doi":"10.1016/j.ygyno.2024.10.032","DOIUrl":"10.1016/j.ygyno.2024.10.032","url":null,"abstract":"<div><h3>Objective</h3><div>To assess whether a 12-week, professionally facilitated, asynchronous online support group would reduce sexual distress (primary outcome) and improve sexual function, body image, depression symptoms, relationship satisfaction, and social support (secondary outcomes) in women treated for gynecologic cancer.</div></div><div><h3>Methods</h3><div>Participants were 398 women recruited from three Canadian provinces and one American cancer center in cohorts of 40. Participants were randomized (50:50 odds) to either the immediate treatment condition (ITC) or the waitlist control condition (WCC). Eligibility included: completed treatment for gynecologic cancer, disease-free for at least 3 months, no more than 5 years post-diagnosis, met criteria for psychosexual distress, willing to discuss sexual concerns, 18 years or older, English speaking, and access to a computer. Participants in the ITC received a 12-week online group along with psychoeducational material each week to stimulate discussion. Two 90-min synchronous sessions were offered in weeks 4 and 8.</div></div><div><h3>Results</h3><div>Reductions in sexual distress for ITC were not significantly different compared to WCC. Similarly, no treatment effects were observed for body image, depression, relationship satisfaction, or social support. ITC showed statistically significant improvements in sexual functioning compared to WCC, but these gains were not retained at 4-month follow-up.</div></div><div><h3>Conclusion</h3><div>Treatment effects were modest, although in the expected direction. As this study was underpowered, it offers preliminary evidence that an asynchronous, online psychoeducational support group may confer positive benefits for women's sexual functioning. The efficiency, convenience, and accessibility of online interventions has significant potential to close gaps in women's access to evidence-based sexual health care.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"192 ","pages":"Pages 73-79"},"PeriodicalIF":4.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-14DOI: 10.1016/j.ygyno.2024.11.006
Manoj Sonavane , Jenna Hedlich-Dwyer , Valeria L. Dal Zotto , Min Tang , John Nemunaitis , Laura Stanbery , Adam Walter , Ernest Bognar , Rodney P. Rocconi , Natalie R. Gassman
Objective
Genomic instability has been proposed as a predictive biomarker for immunotherapy in ovarian cancer. We tested a method for measuring DNA damage, a direct measure of genomic instability, in ovarian tumors and its ability to predict immunotherapy response to Vigil (gemogenovatucel-T).
Methods
Eighty-two formalin-fixed paraffin-embedded tumors from the VITAL trial (NCT02346747) underwent DNA damage assessment using Repair Assisted Damage Detection (RADD). VITAL tested maintenance Vigil therapy vs. placebo for stage IIIB-IV newly diagnosed ovarian cancer in clinical complete response. DNA lesion levels determined by RADD were scored and assessed against patient survival outcomes, expression of CD39, and gene expression signatures.
Results
A graduated distribution of RADD scores occurred across all 82 ovarian samples. RADD scores were able to predict HR status (p < 0.001). RADD demonstrated a significant Pearson's correlation with suggested Vigil biomarker CD39 (r = 0.473; p < 0.001), specifically within HRP tumors (r = 0.57; p = 0.002). High RADD scores correlated with worse recurrent free survival (RFS) in the placebo arm of the trial (7.9 vs. 14.7 months, high vs. low; p = 0.066). High RADD scores were also predictive of significant RFS over 39.4 months with Vigil compared to placebo (25.1 vs. 11.7 months, p = 0.005) and improved, but not significantly, OS with 38.8 vs. 31.8 months.
Conclusions
RADD revealed DNA repair proficiency without mutation signatures or expression profiling. High DNA damage levels show improved survival for Vigil maintenance therapies and are correlated with immune evasion proteins. The persistence of DNA lesions in the genomic DNA offers a new biomarker for immunotherapy patient stratification.
目的：有人提出将基因组不稳定性作为卵巢癌免疫疗法的预测性生物标志物。我们测试了一种测量卵巢肿瘤中 DNA 损伤（基因组不稳定性的直接测量指标）的方法及其预测 Vigil（gemogenovatucel-T）免疫治疗反应的能力：来自VITAL试验（NCT02346747）的82颗福尔马林固定石蜡包埋肿瘤采用修复辅助损伤检测（RADD）技术进行了DNA损伤评估。VITAL 对临床完全反应的 IIIB-IV 期新诊断卵巢癌患者进行了维吉疗法与安慰剂的对比试验。通过 RADD 确定的 DNA 损伤水平与患者的生存结果、CD39 的表达和基因表达特征进行了评分和评估：结果：在所有82份卵巢样本中，RADD评分呈梯度分布。RADD评分能够预测HR状态（p 结论：RADD显示了DNA修复能力：RADD显示了DNA修复能力，而无需突变特征或表达谱分析。高DNA损伤水平显示Vigil维持疗法的生存率有所提高，并与免疫逃避蛋白相关。基因组 DNA 中 DNA 损伤的持续存在为免疫疗法患者分层提供了新的生物标志物。
{"title":"Repair Assisted Damage Detection (RADD) as a predictive biomarker for immunotherapy response in ovarian cancer","authors":"Manoj Sonavane , Jenna Hedlich-Dwyer , Valeria L. Dal Zotto , Min Tang , John Nemunaitis , Laura Stanbery , Adam Walter , Ernest Bognar , Rodney P. Rocconi , Natalie R. Gassman","doi":"10.1016/j.ygyno.2024.11.006","DOIUrl":"10.1016/j.ygyno.2024.11.006","url":null,"abstract":"<div><h3>Objective</h3><div>Genomic instability has been proposed as a predictive biomarker for immunotherapy in ovarian cancer. We tested a method for measuring DNA damage, a direct measure of genomic instability, in ovarian tumors and its ability to predict immunotherapy response to Vigil (gemogenovatucel-T).</div></div><div><h3>Methods</h3><div>Eighty-two formalin-fixed paraffin-embedded tumors from the VITAL trial (<span><span>NCT02346747</span><svg><path></path></svg></span>) underwent DNA damage assessment using Repair Assisted Damage Detection (RADD). VITAL tested maintenance Vigil therapy vs. placebo for stage IIIB-IV newly diagnosed ovarian cancer in clinical complete response. DNA lesion levels determined by RADD were scored and assessed against patient survival outcomes, expression of CD39, and gene expression signatures.</div></div><div><h3>Results</h3><div>A graduated distribution of RADD scores occurred across all 82 ovarian samples. RADD scores were able to predict HR status (<em>p</em> < 0.001). RADD demonstrated a significant Pearson's correlation with suggested Vigil biomarker CD39 (<em>r</em> = 0.473; p < 0.001), specifically within HRP tumors (<em>r</em> = 0.57; <em>p</em> = 0.002). High RADD scores correlated with worse recurrent free survival (RFS) in the placebo arm of the trial (7.9 vs. 14.7 months, high vs. low; <em>p</em> = 0.066). High RADD scores were also predictive of significant RFS over 39.4 months with Vigil compared to placebo (25.1 vs. 11.7 months, <em>p</em> = 0.005) and improved, but not significantly, OS with 38.8 vs. 31.8 months.</div></div><div><h3>Conclusions</h3><div>RADD revealed DNA repair proficiency without mutation signatures or expression profiling. High DNA damage levels show improved survival for Vigil maintenance therapies and are correlated with immune evasion proteins. The persistence of DNA lesions in the genomic DNA offers a new biomarker for immunotherapy patient stratification.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"192 ","pages":"Pages 65-72"},"PeriodicalIF":4.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.ygyno.2024.11.001
Lakeisha Mulugeta-Gordon , Anna Jo Bodurtha Smith
In the United Sates, over 115,000 individuals are diagnosed with a gynecologic cancer annually with access to a gynecologic oncologist and evidence-based treatment remaining a persistent challenge. Coverage decisions by private and public insurance, including Medicaid and Medicare, play key roles in access to care, impacting oncologic outcomes. The expansion of Medicaid insurance under the Affordable Care Act improved early diagnosis, treatment, and survival in gynecologic cancers, but disparities remain for individuals in non-Medicaid expansion states. For individuals with Medicare or private insurance, coverage gaps and high out-of-pocket costs are barriers to cancer care, particularly for novel therapeutic treatments. Efforts to streamline care access, expand clinical trial participation, and reduce administrative burdens continue. Addressing these disparities require improving insurance literacy in patients and clinicians, coordination, and community partnerships to support equitable and comprehensive gynecologic cancer care.
在美国，每年有超过 115,000 人被诊断出患有妇科癌症，而获得妇科肿瘤专家的诊治和循证治疗仍然是一项长期的挑战。私人和公共保险（包括医疗补助计划和医疗保险计划）的承保决定在获得医疗服务方面起着关键作用，影响着肿瘤治疗效果。平价医疗法案》（Affordable Care Act）扩大了医疗补助保险的覆盖范围，改善了妇科癌症的早期诊断、治疗和存活率，但在未扩大医疗补助保险覆盖范围的州，个人之间的差距依然存在。对于拥有医疗保险或私人保险的人来说，保险缺口和高昂的自付费用是癌症治疗的障碍，尤其是新型治疗方法。简化治疗途径、扩大临床试验参与和减少行政负担的努力仍在继续。要解决这些差异问题，需要提高患者和临床医生的保险知识水平、加强协调和社区合作，以支持公平、全面的妇科癌症治疗。
{"title":"Insurance coverage and access to gynecologic oncology: Where are we now","authors":"Lakeisha Mulugeta-Gordon , Anna Jo Bodurtha Smith","doi":"10.1016/j.ygyno.2024.11.001","DOIUrl":"10.1016/j.ygyno.2024.11.001","url":null,"abstract":"<div><div>In the United Sates, over 115,000 individuals are diagnosed with a gynecologic cancer annually with access to a gynecologic oncologist and evidence-based treatment remaining a persistent challenge. Coverage decisions by private and public insurance, including Medicaid and Medicare, play key roles in access to care, impacting oncologic outcomes. The expansion of Medicaid insurance under the Affordable Care Act improved early diagnosis, treatment, and survival in gynecologic cancers, but disparities remain for individuals in non-Medicaid expansion states. For individuals with Medicare or private insurance, coverage gaps and high out-of-pocket costs are barriers to cancer care, particularly for novel therapeutic treatments. Efforts to streamline care access, expand clinical trial participation, and reduce administrative burdens continue. Addressing these disparities require improving insurance literacy in patients and clinicians, coordination, and community partnerships to support equitable and comprehensive gynecologic cancer care.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"192 ","pages":"Pages 56-58"},"PeriodicalIF":4.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-12DOI: 10.1016/j.ygyno.2024.11.004
Katherine Elizabeth Francis , Sandy Simon , Val Gebski , Florence Joly , Jonathan A. Ledermann , Richard T. Penson , Amit M. Oza , Jacob Korach , Nuria Lainez , Sabrina Chiara Cecere , Giulia Tasca , Martina Gropp-Meier , Keiichi Fujiwara , Elizabeth S. Lowe , Michael Friedlander , Eric Pujade-Lauraine , Chee Khoon Lee
Background
In women with platinum sensitive recurrent ovarian cancer (PSROC) undergoing maintenance treatment, adverse events (AEs) not attributable to the current treatment are not well understood. We used data from SOLO2/ENGOT-Ov21 to evaluate AEs reported in the placebo arm and to explore their longitudinal trajectories.
Methods
SOLO2/ENGOT-Ov21 (NCT01874353) randomly assigned 295 PSROC participants with a BRCA1/2 mutation to maintenance olaparib tablets (N = 196) or matching placebo (N = 99). For those assigned to placebo, we analyzed the AE (CTCAE v4.0) data including type, grade, time of onset and resolution, and attribution by investigator.
Results
Amongst 99 participants who received placebo 788 AEs were reported (95 % reporting ≥1 AE). Twenty-two percent of participants reported at least one grade ≥ 3 AE. Grade ≥ 2 AEs that persisted for over 100 days affected 21 % of participants. Recurring grade ≥ 1 AEs were experienced by 44 % of participants. Study investigators attributed 25 % of all AEs to the placebo treatment, with neutropenia (88 %), nausea (52 %) and thrombocytopenia (50 %) most attributed. Three percent of participants had a dose reduction, 19 % had treatment delays, and 2 % had permanent treatment discontinuation, due to AEs attributed to placebo.
Conclusion
Virtually all PSROC participants in the SOLO2/ENGOT-Ov21 experienced one or more AE whilst on placebo. Furthermore, study investigators attributed one quarter of AEs to be related to placebo therapy and dose alterations and treatment changes were made based on these AE. Further work is needed to improve measurement and categorization of AEs in trials of maintenance therapy in PSROC.
{"title":"Adverse events in the placebo arm of SOLO2/ENGOT-Ov21 maintenance trial of olaparib in recurrent ovarian cancer","authors":"Katherine Elizabeth Francis , Sandy Simon , Val Gebski , Florence Joly , Jonathan A. Ledermann , Richard T. Penson , Amit M. Oza , Jacob Korach , Nuria Lainez , Sabrina Chiara Cecere , Giulia Tasca , Martina Gropp-Meier , Keiichi Fujiwara , Elizabeth S. Lowe , Michael Friedlander , Eric Pujade-Lauraine , Chee Khoon Lee","doi":"10.1016/j.ygyno.2024.11.004","DOIUrl":"10.1016/j.ygyno.2024.11.004","url":null,"abstract":"<div><h3>Background</h3><div>In women with platinum sensitive recurrent ovarian cancer (PSROC) undergoing maintenance treatment, adverse events (AEs) not attributable to the current treatment are not well understood. We used data from SOLO2/ENGOT-Ov21 to evaluate AEs reported in the placebo arm and to explore their longitudinal trajectories.</div></div><div><h3>Methods</h3><div>SOLO2/ENGOT-Ov21 (<span><span>NCT01874353</span><svg><path></path></svg></span>) randomly assigned 295 PSROC participants with a <em>BRCA1/2</em> mutation to maintenance olaparib tablets (<em>N</em> = 196) or matching placebo (<em>N</em> = 99). For those assigned to placebo, we analyzed the AE (CTCAE v4.0) data including type, grade, time of onset and resolution, and attribution by investigator.</div></div><div><h3>Results</h3><div>Amongst 99 participants who received placebo 788 AEs were reported (95 % reporting ≥1 AE). Twenty-two percent of participants reported at least one grade ≥ 3 AE. Grade ≥ 2 AEs that persisted for over 100 days affected 21 % of participants. Recurring grade ≥ 1 AEs were experienced by 44 % of participants. Study investigators attributed 25 % of all AEs to the placebo treatment, with neutropenia (88 %), nausea (52 %) and thrombocytopenia (50 %) most attributed. Three percent of participants had a dose reduction, 19 % had treatment delays, and 2 % had permanent treatment discontinuation, due to AEs attributed to placebo.</div></div><div><h3>Conclusion</h3><div>Virtually all PSROC participants in the SOLO2/ENGOT-Ov21 experienced one or more AE whilst on placebo. Furthermore, study investigators attributed one quarter of AEs to be related to placebo therapy and dose alterations and treatment changes were made based on these AE. Further work is needed to improve measurement and categorization of AEs in trials of maintenance therapy in PSROC.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"192 ","pages":"Pages 50-55"},"PeriodicalIF":4.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-12DOI: 10.1016/j.ygyno.2024.10.022
Matthew A. Powell , David Cibula , David M. O'Malley , Ingrid Boere , Mark S. Shahin , Antonella Savarese , Dana M. Chase , Lucy Gilbert , Destin Black , Jørn Herrstedt , Sudarshan Sharma , Stefan Kommoss , Michael A. Gold , Anna M. Thijs , Kari Ring , Magnus Frödin Bolling , Joseph Buscema , Sarah E. Gill , Paul Nowicki , Nicole Nevadunsky , Mansoor Raza Mirza
Objectives
Part 1 of the RUBY trial (NCT03981796) demonstrated improved survival in patients with primary advanced or recurrent endometrial cancer (EC) treated with dostarlimab plus carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel. Here, we examine additional efficacy and safety data from patients with mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) EC in the RUBY trial.
Methods
Patients were randomized 1:1 to dostarlimab 500 mg or placebo plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab or placebo every 6 weeks for up to 3 years. In the dMMR/MSI-H population of RUBY Part 1, analysis of progression-free survival by investigator assessment compared with blinded independent central review, sensitivity analyses of the source-verified population compared with the randomized population, and analysis of safety in this population were completed.
Results
In total, 118 patients with dMMR/MSI-H were enrolled in the RUBY trial (53, dostarlimab arm; 65, placebo arm). At the first interim analysis, a 72% reduction in the risk of progression or death (P < 0.0001) was seen with dostarlimab plus carboplatin-paclitaxel by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), which was consistent with blinded independent central review per RECIST v1.1. Likewise, sensitivity analyses of the source-verified dMMR/MSI-H population compared with the randomized dMMR/MSI-H population were consistent for progression-free survival and overall survival. Safety results seen in the dMMR/MSI-H population were similar to those previously reported for the overall population.
Conclusions
All primary and secondary efficacy assessments demonstrate the consistent benefit of dostarlimab plus carboplatin-paclitaxel. The improvements seen in survival and the manageable safety profile support the favorable benefit–risk profile for dostarlimab plus carboplatin-paclitaxel in patients with dMMR/MSI-H primary advanced or recurrent EC.
{"title":"Efficacy and safety of dostarlimab in combination with chemotherapy in patients with dMMR/MSI-H primary advanced or recurrent endometrial cancer in a phase 3, randomized, placebo-controlled trial (ENGOT-EN6-NSGO/GOG-3031/RUBY)","authors":"Matthew A. Powell , David Cibula , David M. O'Malley , Ingrid Boere , Mark S. Shahin , Antonella Savarese , Dana M. Chase , Lucy Gilbert , Destin Black , Jørn Herrstedt , Sudarshan Sharma , Stefan Kommoss , Michael A. Gold , Anna M. Thijs , Kari Ring , Magnus Frödin Bolling , Joseph Buscema , Sarah E. Gill , Paul Nowicki , Nicole Nevadunsky , Mansoor Raza Mirza","doi":"10.1016/j.ygyno.2024.10.022","DOIUrl":"10.1016/j.ygyno.2024.10.022","url":null,"abstract":"<div><h3>Objectives</h3><div>Part 1 of the RUBY trial (NCT03981796) demonstrated improved survival in patients with primary advanced or recurrent endometrial cancer (EC) treated with dostarlimab plus carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel. Here, we examine additional efficacy and safety data from patients with mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) EC in the RUBY trial.</div></div><div><h3>Methods</h3><div>Patients were randomized 1:1 to dostarlimab 500 mg or placebo plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab or placebo every 6 weeks for up to 3 years. In the dMMR/MSI-H population of RUBY Part 1, analysis of progression-free survival by investigator assessment compared with blinded independent central review, sensitivity analyses of the source-verified population compared with the randomized population, and analysis of safety in this population were completed.</div></div><div><h3>Results</h3><div>In total, 118 patients with dMMR/MSI-H were enrolled in the RUBY trial (53, dostarlimab arm; 65, placebo arm). At the first interim analysis, a 72% reduction in the risk of progression or death (<em>P</em> < 0.0001) was seen with dostarlimab plus carboplatin-paclitaxel by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), which was consistent with blinded independent central review per RECIST v1.1. Likewise, sensitivity analyses of the source-verified dMMR/MSI-H population compared with the randomized dMMR/MSI-H population were consistent for progression-free survival and overall survival. Safety results seen in the dMMR/MSI-H population were similar to those previously reported for the overall population.</div></div><div><h3>Conclusions</h3><div>All primary and secondary efficacy assessments demonstrate the consistent benefit of dostarlimab plus carboplatin-paclitaxel. The improvements seen in survival and the manageable safety profile support the favorable benefit–risk profile for dostarlimab plus carboplatin-paclitaxel in patients with dMMR/MSI-H primary advanced or recurrent EC.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"192 ","pages":"Pages 40-49"},"PeriodicalIF":4.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-08DOI: 10.1016/j.ygyno.2024.10.021
Robert L. Coleman , Solomon J. Lubinga , Qin Shen , Lydia Walder , Mark Burton , Cara Mathews
Objective
Dostarlimab in combination with carboplatin-paclitaxel (CP) improves progression-free survival in patients with primary advanced or recurrent endometrial cancer (pA/rEC), including in patients whose cancer is mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H). This study examined the cost-effectiveness of dostarlimab plus CP as a first-line treatment in the dMMR/MSI-H and overall populations.
Methods
A partitioned survival model with three mutually exclusive health states (progression-free disease, progressed disease, death) was developed using a US base case and a third-party payer perspective. Clinical data were from the RUBY trial and published sources. Costs were from US databases. The primary outcomes were life-years (LYs), quality-adjusted life-years (QALYs), incremental costs, and incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses were also performed.
Results
In the dMMR/MSI-H population, the model predicted gains of 6.9 LYs and 5.4 QALYs with dostarlimab plus CP compared with CP; costs were $307,696 higher with dostarlimab plus CP, resulting in an ICER of $57,151 per QALY gained. In the overall population, gains of 2.0 LYs and 1.5 QALYs were predicted with dostarlimab plus CP compared with CP; costs were $215,876 higher, resulting in an ICER of $143,783 per QALY gained. ICERs were most sensitive to the overall survival hazard ratio. At a willingness-to-pay threshold of $150,000, dostarlimab plus CP had cost-effectiveness probabilities of 100 % and 53.7 % in the dMMR/MSI-H and overall populations, respectively.
Conclusions
Dostarlimab plus CP is cost-effective as a treatment for the dMMR/MSI-H and overall populations of US patients with pA/rEC.
{"title":"Cost-effectiveness of dostarlimab plus carboplatin-paclitaxel for primary advanced or recurrent endometrial cancer from a US payer perspective","authors":"Robert L. Coleman , Solomon J. Lubinga , Qin Shen , Lydia Walder , Mark Burton , Cara Mathews","doi":"10.1016/j.ygyno.2024.10.021","DOIUrl":"10.1016/j.ygyno.2024.10.021","url":null,"abstract":"<div><h3>Objective</h3><div>Dostarlimab in combination with carboplatin-paclitaxel (CP) improves progression-free survival in patients with primary advanced or recurrent endometrial cancer (pA/rEC), including in patients whose cancer is mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H). This study examined the cost-effectiveness of dostarlimab plus CP as a first-line treatment in the dMMR/MSI-H and overall populations.</div></div><div><h3>Methods</h3><div>A partitioned survival model with three mutually exclusive health states (progression-free disease, progressed disease, death) was developed using a US base case and a third-party payer perspective. Clinical data were from the RUBY trial and published sources. Costs were from US databases. The primary outcomes were life-years (LYs), quality-adjusted life-years (QALYs), incremental costs, and incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses were also performed.</div></div><div><h3>Results</h3><div>In the dMMR/MSI-H population, the model predicted gains of 6.9 LYs and 5.4 QALYs with dostarlimab plus CP compared with CP; costs were $307,696 higher with dostarlimab plus CP, resulting in an ICER of $57,151 per QALY gained. In the overall population, gains of 2.0 LYs and 1.5 QALYs were predicted with dostarlimab plus CP compared with CP; costs were $215,876 higher, resulting in an ICER of $143,783 per QALY gained. ICERs were most sensitive to the overall survival hazard ratio. At a willingness-to-pay threshold of $150,000, dostarlimab plus CP had cost-effectiveness probabilities of 100 % and 53.7 % in the dMMR/MSI-H and overall populations, respectively.</div></div><div><h3>Conclusions</h3><div>Dostarlimab plus CP is cost-effective as a treatment for the dMMR/MSI-H and overall populations of US patients with pA/rEC.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"192 ","pages":"Pages 24-31"},"PeriodicalIF":4.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1016/j.ygyno.2024.10.020
Emiel A. De Jaeghere , Hannelore Hamerlinck , Sandra Tuyaerts , Lien Lippens , An M.T. Van Nuffel , Regina Baiden-Amissah , Peter Vuylsteke , Stéphanie Henry , Xuan Bich Trinh , Peter A. van Dam , Sandrine Aspeslagh , Alex De Caluwé , Eline Naert , Diether Lambrechts , An Hendrix , Olivier De Wever , Koen K. Van de Vijver , Frédéric Amant , Katrien Vandecasteele , Bruno Verhasselt , Hannelore G. Denys
Background
The phase II PRIMMO trial investigated a pembrolizumab-based regimen in patients with recurrent and/or metastatic cervical (CC) or endometrial (EC) carcinoma who had at least one prior line of systemic therapy. Here, exploratory studies of the gut microbiome (GM) are presented.
Methods
The microbial composition of 77 longitudinal fecal samples obtained from 35 patients (CC, n = 15; EC, n = 20) was characterized using 16S rRNA gene sequencing. Analyses included assessment of alpha (Shannon index) and beta diversity (weighted UniFrac), unbiased hierarchical clustering, and linear discriminant analysis effect size. Correlative studies with demographics, disease characteristics, safety, efficacy, and immune monitoring data were performed.
Results
Significant enrichment in multiple bacterial taxa was associated with the occurrence or resistance to severe treatment-related adverse events (overall or gastrointestinal toxicity specifically). Consistent differences in GM taxonomic composition before pembrolizumab initiation were observed between patients with favorable efficacy (e.g., enriched with Blautia genus) and those with poor efficacy (e.g., enriched with Enterobacteriaceae family and its higher-level taxa up to the phylum level, as well as Clostridium genus and its Clostridiaceae family). Two naturally occurring GM clusters with distinct bacterial compositions were identified. These clusters showed a more than four-fold differential risk for death (hazard ratio, 4.4 [95 % confidence interval, 1.9 to 10.3], P < 0.001) and were associated with interesting (but non-significant) trends in peripheral immune monitoring data.
Conclusion
Although exploratory, this study offers initial insights into the intricate interplay between the GM and clinical outcomes in patients with CC and EC treated with a pembrolizumab-based regimen.
Trial registration: ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016–001569-97).
{"title":"Associations of the gut microbiome with outcomes in cervical and endometrial cancer patients treated with pembrolizumab: Insights from the phase II PRIMMO trial","authors":"Emiel A. De Jaeghere , Hannelore Hamerlinck , Sandra Tuyaerts , Lien Lippens , An M.T. Van Nuffel , Regina Baiden-Amissah , Peter Vuylsteke , Stéphanie Henry , Xuan Bich Trinh , Peter A. van Dam , Sandrine Aspeslagh , Alex De Caluwé , Eline Naert , Diether Lambrechts , An Hendrix , Olivier De Wever , Koen K. Van de Vijver , Frédéric Amant , Katrien Vandecasteele , Bruno Verhasselt , Hannelore G. Denys","doi":"10.1016/j.ygyno.2024.10.020","DOIUrl":"10.1016/j.ygyno.2024.10.020","url":null,"abstract":"<div><h3>Background</h3><div>The phase II PRIMMO trial investigated a pembrolizumab-based regimen in patients with recurrent and/or metastatic cervical (CC) or endometrial (EC) carcinoma who had at least one prior line of systemic therapy. Here, exploratory studies of the gut microbiome (GM) are presented.</div></div><div><h3>Methods</h3><div>The microbial composition of 77 longitudinal fecal samples obtained from 35 patients (CC, <em>n</em> = 15; EC, <em>n</em> = 20) was characterized using <em>16S rRNA</em> gene sequencing. Analyses included assessment of alpha (Shannon index) and beta diversity (weighted UniFrac), unbiased hierarchical clustering, and linear discriminant analysis effect size. Correlative studies with demographics, disease characteristics, safety, efficacy, and immune monitoring data were performed.</div></div><div><h3>Results</h3><div>Significant enrichment in multiple bacterial taxa was associated with the occurrence or resistance to severe treatment-related adverse events (overall or gastrointestinal toxicity specifically). Consistent differences in GM taxonomic composition before pembrolizumab initiation were observed between patients with favorable efficacy (e.g., enriched with <em>Blautia</em> genus) and those with poor efficacy (e.g., enriched with <em>Enterobacteriaceae</em> family and its higher-level taxa up to the phylum level, as well as <em>Clostridium</em> genus and its <em>Clostridiaceae</em> family). Two naturally occurring GM clusters with distinct bacterial compositions were identified. These clusters showed a more than four-fold differential risk for death (hazard ratio, 4.4 [95 % confidence interval, 1.9 to 10.3], <em>P</em> < 0.001) and were associated with interesting (but non-significant) trends in peripheral immune monitoring data.</div></div><div><h3>Conclusion</h3><div>Although exploratory, this study offers initial insights into the intricate interplay between the GM and clinical outcomes in patients with CC and EC treated with a pembrolizumab-based regimen.</div><div>Trial registration: <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> (identifier <span><span>NCT03192059</span><svg><path></path></svg></span>) and EudraCT Registry (number 2016–001569-97).</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"191 ","pages":"Pages 275-286"},"PeriodicalIF":4.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1016/j.ygyno.2024.10.028
Stephanie W. Vrede , Willem Jan Van Weelden , Johan Bulten , C. Blake Gilks , Steven Teerenstra , Jutta Huvila , Xavier Matias-Guiu , Antonio Gil-Moreno , Jasmin Asberger , Sanne Sweegers , Louis J.M. van der Putten , Heidi V.N. Küsters-Vandevelde , Casper Reijnen , Eva Colas , Jitka Hausnerová , Vit Weinberger , Marc P.L.M. Snijders , Petra Vinklerova , Antonella Ravaggi , Franco Odicino , Johanna M.A. Pijnenborg
Objective
The prognostic relevance of hormonal biomarkers in endometrial cancer (EC) has been well-established. A refined three-tiered risk model for estrogen receptor (ER)/progesterone receptor (PR) expression was shown to improve prognostication. This has not been evaluated in relation to the molecular subgroups. This study aimed to evaluate the ER/PR expression within the molecular subgroups in EC.
Methods
A retrospective multicenter cohort study was performed and data from the European Network for Individualized Treatment centers and Vancouver, Canada were used. ER/PR immunohistochemical expression was grouped as: ER/PR 0–10 %, 20–80 % or 90–100 %. Molecular subgroups were determined with full next-generation sequencing or combined with immunohistochemistry: POLEmut, mismatch repair deficient (MMRd), p53mut and no-specific molecular profile (NSMP).
Results
A total of 739 patients were included (median follow-up 5.0 years). Tumors were classified as POLEmut in 9.1 %(N = 67), MMRd in 27.6 %(N = 204), p53mut in 20.8 %(N = 154) and NSMP in 42.5 %(N = 314). Among all molecular subgroups, patients with ER/PR 90–100 % expression revealed the best disease-specific survival (DSS). Within p53mut, PR 90–100 % expression showed a 5-year DSS of 100.0 %. ER expression is prognostic more relevant in MMRd and NSMP tumors while PR expression in p53mut and NSMP tumors. Across all molecular subgroups, PR 0–10 %, p53mut, lympho-vascular space invasion and FIGO stage III-IV remained independently prognostic for reduced DSS Whereas PR 90–100 % and POLEmut remained independently prognostic for improved DSS.
Conclusion
We demonstrated that ER/PR expression remain prognostically relevant within the molecular subgroups, and that a three-tiered cutoff refines prognostication. These data support incorporating routine evaluation of ER/PR expression in clinical practice.
{"title":"Hormonal biomarkers remain prognostically relevant within the molecular subgroups in endometrial cancer","authors":"Stephanie W. Vrede , Willem Jan Van Weelden , Johan Bulten , C. Blake Gilks , Steven Teerenstra , Jutta Huvila , Xavier Matias-Guiu , Antonio Gil-Moreno , Jasmin Asberger , Sanne Sweegers , Louis J.M. van der Putten , Heidi V.N. Küsters-Vandevelde , Casper Reijnen , Eva Colas , Jitka Hausnerová , Vit Weinberger , Marc P.L.M. Snijders , Petra Vinklerova , Antonella Ravaggi , Franco Odicino , Johanna M.A. Pijnenborg","doi":"10.1016/j.ygyno.2024.10.028","DOIUrl":"10.1016/j.ygyno.2024.10.028","url":null,"abstract":"<div><h3>Objective</h3><div>The prognostic relevance of hormonal biomarkers in endometrial cancer (EC) has been well-established. A refined three-tiered risk model for estrogen receptor (ER)/progesterone receptor (PR) expression was shown to improve prognostication. This has not been evaluated in relation to the molecular subgroups. This study aimed to evaluate the ER/PR expression within the molecular subgroups in EC.</div></div><div><h3>Methods</h3><div>A retrospective multicenter cohort study was performed and data from the European Network for Individualized Treatment centers and Vancouver, Canada were used. ER/PR immunohistochemical expression was grouped as: ER/PR 0–10 %, 20–80 % or 90–100 %. Molecular subgroups were determined with full next-generation sequencing or combined with immunohistochemistry: <em>POLE</em>mut, mismatch repair deficient (MMRd), p53mut and no-specific molecular profile (NSMP).</div></div><div><h3>Results</h3><div>A total of 739 patients were included (median follow-up 5.0 years). Tumors were classified as <em>POLE</em>mut in 9.1 %(<em>N</em> = 67), MMRd in 27.6 %(<em>N</em> = 204), p53mut in 20.8 %(<em>N</em> = 154) and NSMP in 42.5 %(<em>N</em> = 314). Among all molecular subgroups, patients with ER/PR 90–100 % expression revealed the best disease-specific survival (DSS). Within p53mut, PR 90–100 % expression showed a 5-year DSS of 100.0 %. ER expression is prognostic more relevant in MMRd and NSMP tumors while PR expression in p53mut and NSMP tumors. Across all molecular subgroups, PR 0–10 %, p53mut, lympho-vascular space invasion and FIGO stage III-IV remained independently prognostic for reduced DSS Whereas PR 90–100 % and <em>POLE</em>mut remained independently prognostic for improved DSS.</div></div><div><h3>Conclusion</h3><div>We demonstrated that ER/PR expression remain prognostically relevant within the molecular subgroups, and that a three-tiered cutoff refines prognostication. These data support incorporating routine evaluation of ER/PR expression in clinical practice.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"192 ","pages":"Pages 15-23"},"PeriodicalIF":4.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-06DOI: 10.1016/j.ygyno.2024.10.029
Sara Moufarrij , Yulia Lakhman , Carol Aghajanian , Nadeem R. Abu-Rustum , Lora H. Ellenson , Britta Weigelt , Amir Momeni-Boroujeni
Objective
To characterize the genomic landscape of FIGO 2009 stage IA, non-myometrial invasive endometrioid endometrial cancers (ECs) of no specific molecular profile (NSMP) and define the earliest driver genetic alterations and subsequent tumor evolution.
Methods
Early-stage (FIGO 2009 stage IA), non-myoinvasive endometrioid NSMP ECs subjected to clinical tumor-normal targeted sequencing between 2014 and 2022 were identified. ECs were dichotomized into low- and high-volume disease based on gross and histologic measurement using a cutoff of 1.8 cm3. Cancer cell fractions (CCF) of somatic mutations were determined.
Results
A total of 171 noninvasive, FIGO 2009 stage I endometrioid ECs of NSMP subtype were identified, of which the majority (n = 139; 81 %) were FIGO grade 1. The median calculated volume of disease was 1.8 cm3 at diagnosis. The ECs had on average 6 pathogenic mutations, affecting known EC cancer-related genes, including PTEN (80 %), ARID1A (52 %), PIK3CA (52 %), CTNNB1 (39 %), PIK3R1 (37 %), and KRAS (29 %). Genomic alterations did not correlate with tumor volume. PTEN mutations had the highest CCFs. Unsupervised hierarchical clustering based on CCF revealed 4 main groups characterized by: 1. clonal alterations in PTEN accompanied by PIK3CA, PIK3R1, or ARID1A alterations, 2. mutations in PIK3CA co-occurring with ARID1A alterations, 3. KRAS mutations, particularly associated with 1q high-level gain, or 4. AKT1 mutations, which uniquely occurred without concurrent PTEN, PIK3CA, or PIK3R1 alterations.
Conclusion
Stage IA non-myoinvasive NSMP ECs show genomic heterogeneity suggestive of multiple evolutionary pathways. Further studies are warranted to define whether this is a sign of early genomic drift.
{"title":"Evolutionary pathways in early-stage, non-myoinvasive endometrioid endometrial cancers of no specific molecular profile","authors":"Sara Moufarrij , Yulia Lakhman , Carol Aghajanian , Nadeem R. Abu-Rustum , Lora H. Ellenson , Britta Weigelt , Amir Momeni-Boroujeni","doi":"10.1016/j.ygyno.2024.10.029","DOIUrl":"10.1016/j.ygyno.2024.10.029","url":null,"abstract":"<div><h3>Objective</h3><div>To characterize the genomic landscape of FIGO 2009 stage IA, non-myometrial invasive endometrioid endometrial cancers (ECs) of no specific molecular profile (NSMP) and define the earliest driver genetic alterations and subsequent tumor evolution.</div></div><div><h3>Methods</h3><div>Early-stage (FIGO 2009 stage IA), non-myoinvasive endometrioid NSMP ECs subjected to clinical tumor-normal targeted sequencing between 2014 and 2022 were identified. ECs were dichotomized into low- and high-volume disease based on gross and histologic measurement using a cutoff of 1.8 cm<sup>3</sup>. Cancer cell fractions (CCF) of somatic mutations were determined.</div></div><div><h3>Results</h3><div>A total of 171 noninvasive, FIGO 2009 stage I endometrioid ECs of NSMP subtype were identified, of which the majority (<em>n</em> = 139; 81 %) were FIGO grade 1. The median calculated volume of disease was 1.8 cm<sup>3</sup> at diagnosis. The ECs had on average 6 pathogenic mutations, affecting known EC cancer-related genes, including <em>PTEN</em> (80 %), <em>ARID1A</em> (52 %), <em>PIK3CA</em> (52 %), <em>CTNNB1</em> (39 %), <em>PIK3R1</em> (37 %), and <em>KRAS</em> (29 %). Genomic alterations did not correlate with tumor volume. <em>PTEN</em> mutations had the highest CCFs. Unsupervised hierarchical clustering based on CCF revealed 4 main groups characterized by: 1. clonal alterations in <em>PTEN</em> accompanied by <em>PIK3CA, PIK3R1,</em> or <em>ARID1A</em> alterations, 2. mutations in <em>PIK3CA</em> co-occurring with <em>ARID1A</em> alterations, 3. <em>KRAS</em> mutations, particularly associated with 1q high-level gain, or 4. <em>AKT1</em> mutations, which uniquely occurred without concurrent <em>PTEN</em>, <em>PIK3CA</em>, or <em>PIK3R1</em> alterations.</div></div><div><h3>Conclusion</h3><div>Stage IA non-myoinvasive NSMP ECs show genomic heterogeneity suggestive of multiple evolutionary pathways. Further studies are warranted to define whether this is a sign of early genomic drift.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"192 ","pages":"Pages 8-14"},"PeriodicalIF":4.5,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142593098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号