Pub Date : 2025-02-18DOI: 10.1016/j.ygyno.2025.02.010
Ayesha B. Alvero , Sharon Wu , Alex Farrell , Seongho Kim , John J. Wallbillich , Ira Winer , Robert Morris , David Spetzler , Matthew L. Anderson , Alberto Puccini , Nathaniel L. Jones , Thomas J. Herzog , Premal H. Thaker , Gil Mor , Radhika P. Gogoi
Objective
The purpose of this study was to evaluate the transcriptomic profile of BRCA1 mutant (BRCA1mut) and BRCA2 mutant (BRCA2mut) HGSOC compared to homologous recombination wild-type (HRwt) tumors utilizing the CARIS database.
Methods
Next-generation and Whole Transcriptome Sequencing (WTS; Caris Life Sciences, Phoenix, AZ) was performed on a total of 2745 HGSOC tumor samples. BRCA mutations were defined as variants resulting in loss-of-function of the protein and HRwt was defined as samples wildtype for aberrations in both BRCA1 and BRCA2, as well as for 28 other HR genes. HRwt group was further classified into HRwt/LOH-low (<16 %) and HRwt/LOH-high (≥16 %). Genomic analysis consists of mutation analysis and measurements of TMB and MSI. Transcriptomic analysis included identification of Differentially expressed genes (DEGs), GSEA and immune deconvolution.
Results
We identified 519 (19 %) BRCA1-mut, 302 (11 %) BRCA2-mut, and 739 (27 %) HRwt/LOH high and 1181 (43 %) HRwt/LOH low HGSOC. TP53 was the most commonly mutated gene in all groups. Mutations in PIK3CA were most common in HRwt/LOH-low compared to BRCA1-mut and BRCA2-mut HGSOC. TMB-H was highest in BRCA2-mut compared to BRCA1-mut, HRwt/LOH high and HRwt/LOH low tumors. In contrast, higher NKT cell infiltration, higher T cell inflamed and IFNγ scores, and higher PDL1 expression were observed in BRCA1-mut tumors.
Conclusion
Our findings emphasize the differential immune profiles based on BRCA1 and BRCA2 mutations and suggest potential therapeutic targets, including treatment strategies that incorporate immunotherapy and target specific genomic alterations.
{"title":"Exploring the differences between BRCA mutated and HRwild-type high grade serous ovarian cancer: A multiomic analysis","authors":"Ayesha B. Alvero , Sharon Wu , Alex Farrell , Seongho Kim , John J. Wallbillich , Ira Winer , Robert Morris , David Spetzler , Matthew L. Anderson , Alberto Puccini , Nathaniel L. Jones , Thomas J. Herzog , Premal H. Thaker , Gil Mor , Radhika P. Gogoi","doi":"10.1016/j.ygyno.2025.02.010","DOIUrl":"10.1016/j.ygyno.2025.02.010","url":null,"abstract":"<div><h3>Objective</h3><div>The purpose of this study was to evaluate the transcriptomic profile of BRCA1 mutant (BRCA1mut) and BRCA2 mutant (BRCA2mut) HGSOC compared to homologous recombination wild-type (HRwt) tumors utilizing the CARIS database.</div></div><div><h3>Methods</h3><div>Next-generation and Whole Transcriptome Sequencing (WTS; Caris Life Sciences, Phoenix, AZ) was performed on a total of 2745 HGSOC tumor samples. BRCA mutations were defined as variants resulting in loss-of-function of the protein and HRwt was defined as samples wildtype for aberrations in both BRCA1 and BRCA2, as well as for 28 other HR genes. HRwt group was further classified into HRwt/LOH-low (<16 %) and HRwt/LOH-high (≥16 %). Genomic analysis consists of mutation analysis and measurements of TMB and MSI. Transcriptomic analysis included identification of Differentially expressed genes (DEGs), GSEA and immune deconvolution.</div></div><div><h3>Results</h3><div>We identified 519 (19 %) BRCA1-mut, 302 (11 %) BRCA2-mut, and 739 (27 %) HRwt/LOH high and 1181 (43 %) HRwt/LOH low HGSOC. <em>TP53</em> was the most commonly mutated gene in all groups. Mutations in <em>PIK3CA</em> were most common in HRwt/LOH-low compared to BRCA1-mut and BRCA2-mut HGSOC. TMB-H was highest in BRCA2-mut compared to BRCA1-mut, HRwt/LOH high and HRwt/LOH low tumors. In contrast, higher NKT cell infiltration, higher T cell inflamed and IFNγ scores, and higher PDL1 expression were observed in BRCA1-mut tumors.</div></div><div><h3>Conclusion</h3><div>Our findings emphasize the differential immune profiles based on BRCA1 and BRCA2 mutations and suggest potential therapeutic targets, including treatment strategies that incorporate immunotherapy and target specific genomic alterations.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"194 ","pages":"Pages 71-79"},"PeriodicalIF":4.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437362","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 : 2025-02-18DOI: 10.1016/j.ygyno.2025.02.011
Hengzi Sun , Xiao Huo , Xiaoning Bi , Dongyan Cao , Jiaxin Yang , Keng Shen , Peng Peng
Purpose
This study investigates the role of exosomes in ovarian cancer heterogeneity, which contributes to metastasis. By examining the variability of exosomes from different ovarian cancer cells, which aims to elucidate the molecular mechanisms driving this heterogeneity.
Experimental design
Ovarian cancer cell lines were subjected to clonal culture and single-cell sorting. Monoclonal cell lines with different migration and invasion capabilities were identified using Transwell assays. The effect of exosomes on these abilities was assessed through Transwell, scratch tests, and in vivo experiments. High-throughput sequencing was used to compare miRNAs in exosomes with mRNAs in cells. Techniques like electron microscopy, immunofluorescence, adenoviral transduction, western blot, RNA-binding protein immunoprecipitation, and fluorescence in situ hybridization were employed to explore how exosomes affect cell migration and invasion.
Results
Two subpopulations, SK-H/A-H (highly invasive) and SK-L/A-L (less invasive), were isolated. Exosomes from SK-H and A-H cells enhanced the migration and invasion of SK-L and A-L cells. Hsa-miR-328-3p was significantly upregulated in exosomes from SK-H and A-H cells, promoting invasive traits in SK-L and A-L cells, reducing Raf1 and mTOR expression, and increasing ULK1 and LC3B levels to promote autophagy. Overexpression of pri-miR-328-3p in SK-L and A-L cells resulted in similar effects.
Conclusions
Ovarian cancer cells with different invasive capabilities secrete distinct exosomes. Exosomes from highly invasive cells enhance these traits in less aggressive cells via hsa-miR-328-3p, which targets Raf1, disrupts the mTOR pathway, and promotes autophagy. This study highlights exosomes as carriers of hsa-miR-328-3p, mediating intercellular communication and autophagy to influence ovarian cancer cell heterogeneity.
{"title":"Exosome transmit the ability of migration and invasion in heterogeneous ovarian cancer cells by regulating autophagy via targeting hsa-miR-328","authors":"Hengzi Sun , Xiao Huo , Xiaoning Bi , Dongyan Cao , Jiaxin Yang , Keng Shen , Peng Peng","doi":"10.1016/j.ygyno.2025.02.011","DOIUrl":"10.1016/j.ygyno.2025.02.011","url":null,"abstract":"<div><h3>Purpose</h3><div>This study investigates the role of exosomes in ovarian cancer heterogeneity, which contributes to metastasis. By examining the variability of exosomes from different ovarian cancer cells, which aims to elucidate the molecular mechanisms driving this heterogeneity.</div></div><div><h3>Experimental design</h3><div>Ovarian cancer cell lines were subjected to clonal culture and single-cell sorting. Monoclonal cell lines with different migration and invasion capabilities were identified using Transwell assays. The effect of exosomes on these abilities was assessed through Transwell, scratch tests, and in vivo experiments. High-throughput sequencing was used to compare miRNAs in exosomes with mRNAs in cells. Techniques like electron microscopy, immunofluorescence, adenoviral transduction, western blot, RNA-binding protein immunoprecipitation, and fluorescence in situ hybridization were employed to explore how exosomes affect cell migration and invasion.</div></div><div><h3>Results</h3><div>Two subpopulations, SK-H/A-H (highly invasive) and SK-L/A-L (less invasive), were isolated. Exosomes from SK-H and A-H cells enhanced the migration and invasion of SK-L and A-L cells. Hsa-miR-328-3p was significantly upregulated in exosomes from SK-H and A-H cells, promoting invasive traits in SK-L and A-L cells, reducing Raf1 and mTOR expression, and increasing ULK1 and LC3B levels to promote autophagy. Overexpression of pri-miR-328-3p in SK-L and A-L cells resulted in similar effects.</div></div><div><h3>Conclusions</h3><div>Ovarian cancer cells with different invasive capabilities secrete distinct exosomes. Exosomes from highly invasive cells enhance these traits in less aggressive cells via hsa-miR-328-3p, which targets Raf1, disrupts the mTOR pathway, and promotes autophagy. This study highlights exosomes as carriers of hsa-miR-328-3p, mediating intercellular communication and autophagy to influence ovarian cancer cell heterogeneity.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"194 ","pages":"Pages 60-70"},"PeriodicalIF":4.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143428740","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 : 2025-02-18DOI: 10.1016/j.ygyno.2025.02.007
Paulina Haight , Caroline Bilbe , Courtney Riedinger , Floor Backes , Kristin Bixel , Laura Chambers , David Cohn , Larry Copeland , Christa Nagel , David O'Malley , Adrian A. Suarez , Ashwini Esnakula , Casey M. Cosgrove
Background
Sentinel lymph node (SLN) mapping has become standard-of-care in endometrial cancer surgical staging. While removal of “enlarged” lymph nodes is recommended regardless of SLN mapping, there is no data to support definitive size criteria for intra-operative assessment. We sought to assess the size of negative and positive SLN in surgically-staged endometrial cancer patients.
Methods
Surgically-staged endometrial cancer patients undergoing SLN assessment of at least one hemipelvis at a single comprehensive cancer center were retrospectively reviewed from 2017 to 2020. SLN were categorized as negative (benign) or positive (metastatic). SLN size was defined as the largest diameter (cm) of the SLN as measured in the gross description of the surgical pathology report. Size of negative and positive SLN was compared using descriptive statistics.
Results
Of 597 patients, 575 had an evaluable negative SLN, and median size was 2.0 cm [0.4–4.5 cm]. 39 patients had an evaluable positive SLN, and median size was 2.1 cm [0.5–4.9 cm]. Lymph node size ≥2 cm was 67 % sensitive and 49 % specific for detecting metastatic disease. Age < 50 and BMI ≥30 were associated with larger lymph node size (p = 0.04 and p = 0.028, respectively). For evaluable positive SLN, mismatch repair (MMR) IHC (n = 39), and p53 IHC (n = 18) did not impact size (p = 0.71 and p = 0.83, respectively).
Conclusions
Negative and positive SLN are similar in size, thus SLN size is a poor predictor of metastasis in patients undergoing surgical staging of endometrial cancer. Intra-operative assessment of size should not serve as sole indication for targeted lymph node removal.
{"title":"Defining “enlarged” sentinel lymph nodes in the setting of endometrial cancer: What is the size cut-off?","authors":"Paulina Haight , Caroline Bilbe , Courtney Riedinger , Floor Backes , Kristin Bixel , Laura Chambers , David Cohn , Larry Copeland , Christa Nagel , David O'Malley , Adrian A. Suarez , Ashwini Esnakula , Casey M. Cosgrove","doi":"10.1016/j.ygyno.2025.02.007","DOIUrl":"10.1016/j.ygyno.2025.02.007","url":null,"abstract":"<div><h3>Background</h3><div>Sentinel lymph node (SLN) mapping has become standard-of-care in endometrial cancer surgical staging. While removal of “enlarged” lymph nodes is recommended regardless of SLN mapping, there is no data to support definitive size criteria for intra-operative assessment. We sought to assess the size of negative and positive SLN in surgically-staged endometrial cancer patients.</div></div><div><h3>Methods</h3><div>Surgically-staged endometrial cancer patients undergoing SLN assessment of at least one hemipelvis at a single comprehensive cancer center were retrospectively reviewed from 2017 to 2020. SLN were categorized as negative (benign) or positive (metastatic). SLN size was defined as the largest diameter (cm) of the SLN as measured in the gross description of the surgical pathology report. Size of negative and positive SLN was compared using descriptive statistics.</div></div><div><h3>Results</h3><div>Of 597 patients, 575 had an evaluable negative SLN, and median size was 2.0 cm [0.4–4.5 cm]. 39 patients had an evaluable positive SLN, and median size was 2.1 cm [0.5–4.9 cm]. Lymph node size ≥2 cm was 67 % sensitive and 49 % specific for detecting metastatic disease. Age < 50 and BMI ≥30 were associated with larger lymph node size (<em>p</em> = 0.04 and <em>p</em> = 0.028, respectively). For evaluable positive SLN, mismatch repair (MMR) IHC (<em>n</em> = 39), and p53 IHC (<em>n</em> = 18) did not impact size (<em>p</em> = 0.71 and <em>p</em> = 0.83, respectively).</div></div><div><h3>Conclusions</h3><div>Negative and positive SLN are similar in size, thus SLN size is a poor predictor of metastasis in patients undergoing surgical staging of endometrial cancer. Intra-operative assessment of size should not serve as sole indication for targeted lymph node removal.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"194 ","pages":"Pages 80-85"},"PeriodicalIF":4.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437363","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 : 2025-02-17DOI: 10.1016/j.ygyno.2025.02.012
Koji Matsuo , Joel Agarwal , Ling Chen , Katelyn B. Furey , Bonnie B. Song , Christian Pino , Shinya Matsuzaki , Yukio Suzuki , Maximilian Klar , Lynda D. Roman , Jason D. Wright
Objective
To examine the association between regional lymph node status based on metastatic size and anatomical location and survival per histology in endometrial cancer.
Methods
This retrospective study queried the Commission-on-Cancer's National Cancer Database. Study population included 87,904 patients with stage I-III endometrial cancer from 2018 to 2021. Multivariable Cox proportional hazard regression models were created to assess overall survival per histology (non-endometrioid / high-grade endometrioid or low-grade endometrioid).
Results
In both histology groups, comparing to pelvic micro-metastasis, macro-metastasis regardless of anatomical location (pelvic / para-aortic) was associated with decreased overall survival (non-endometrioid / high-grade endometrioid histology, adjusted-hazard ratio [aHR] 1.31, 95% confidence interval [CI] 1.08–1.59/aHR 1.39, 95%CI 1.13–1.72; and low-grade endometrioid histology, aHR 1.68, 95%CI 1.19–2.36 / aHR 1.78, 95%CI 1.10–2.88) while para-aortic micro-metastases had overall survival similar to pelvic micro-metastasis. Survival effects of macro-metastasis were larger in low-grade endometrioid compared to non-endometrioid / high-grade endometrioid histology (aHR range, 1.68–1.78 vs 1.31–1.39). For non-endometrioid / high-grade endometrioid histology, isolated tumor cells were associated with better overall survival compared to pelvic micro-metastasis (aHR 0.62, 95%CI 0.45–0.85); isolated tumor cells and negative nodal metastasis had similar overall survival (aHR 1.05, 95%CI 0.80–1.38). Contrary, in low-grade endometrioid histology, isolated tumor cells were associated with decreased overall survival compared to negative-node (aHR 1.55, 95%CI 1.18–2.04); isolated tumor cells had overall survival similar to pelvic micro-metastasis (aHR 0.83, 95%CI 0.56–1.24).
Conclusion
The results of this cohort study suggest that tumor metastatic size may be more prognostic than anatomical location in endometrial cancer. Histology-specific interaction of isolated tumor cells warrants further investigation, especially in low-grade endometrioid histology.
{"title":"Histology-specific prognostic significance of isolated tumor cells, micrometastases, and macrometastases in endometrial cancer","authors":"Koji Matsuo , Joel Agarwal , Ling Chen , Katelyn B. Furey , Bonnie B. Song , Christian Pino , Shinya Matsuzaki , Yukio Suzuki , Maximilian Klar , Lynda D. Roman , Jason D. Wright","doi":"10.1016/j.ygyno.2025.02.012","DOIUrl":"10.1016/j.ygyno.2025.02.012","url":null,"abstract":"<div><h3>Objective</h3><div>To examine the association between regional lymph node status based on metastatic size and anatomical location and survival per histology in endometrial cancer.</div></div><div><h3>Methods</h3><div>This retrospective study queried the Commission-on-Cancer's National Cancer Database. Study population included 87,904 patients with stage I-III endometrial cancer from 2018 to 2021. Multivariable Cox proportional hazard regression models were created to assess overall survival per histology (non-endometrioid / high-grade endometrioid or low-grade endometrioid).</div></div><div><h3>Results</h3><div>In both histology groups, comparing to pelvic micro-metastasis, macro-metastasis regardless of anatomical location (pelvic / para-aortic) was associated with decreased overall survival (non-endometrioid / high-grade endometrioid histology, adjusted-hazard ratio [aHR] 1.31, 95% confidence interval [CI] 1.08–1.59/aHR 1.39, 95%CI 1.13–1.72; and low-grade endometrioid histology, aHR 1.68, 95%CI 1.19–2.36 / aHR 1.78, 95%CI 1.10–2.88) while para-aortic micro-metastases had overall survival similar to pelvic micro-metastasis. Survival effects of macro-metastasis were larger in low-grade endometrioid compared to non-endometrioid / high-grade endometrioid histology (aHR range, 1.68–1.78 vs 1.31–1.39). For non-endometrioid / high-grade endometrioid histology, isolated tumor cells were associated with better overall survival compared to pelvic micro-metastasis (aHR 0.62, 95%CI 0.45–0.85); isolated tumor cells and negative nodal metastasis had similar overall survival (aHR 1.05, 95%CI 0.80–1.38). Contrary, in low-grade endometrioid histology, isolated tumor cells were associated with decreased overall survival compared to negative-node (aHR 1.55, 95%CI 1.18–2.04); isolated tumor cells had overall survival similar to pelvic micro-metastasis (aHR 0.83, 95%CI 0.56–1.24).</div></div><div><h3>Conclusion</h3><div>The results of this cohort study suggest that tumor metastatic size may be more prognostic than anatomical location in endometrial cancer. Histology-specific interaction of isolated tumor cells warrants further investigation, especially in low-grade endometrioid histology.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"194 ","pages":"Pages 51-59"},"PeriodicalIF":4.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418957","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 : 2025-02-13DOI: 10.1016/j.ygyno.2025.01.015
Stéphanie Gaillard , Neha Verma , Maureen Berg , Jeanne Harrison , Peng Huang , James M. Leatherman , Michele Doucet , Rupashree Sen , Aditya Suru , Hongyan Cai , Jennifer Durham , Danijela Jelovac , Ashley Cimino-Mathews , Christopher Cherry , Sudipto Ganguly , Leisha A. Emens
Objective
PARP inhibitors may work synergistically to improve the efficacy of immunotherapy in patients with epithelial ovarian cancer (EOC). We performed a parallel-arm study of tremelimumab, alone or with olaparib, in patients with recurrent EOC.
Methods
Eligibility criteria included measurable disease and progression <12 months from last platinum. Participants were randomized to Arm A (tremelimumab monotherapy, 10 mg/kg/dose intravenously [IV]) or Arm B (dose level 1 [DL1] olaparib orally 150 mg twice daily with tremelimumab IV 3 mg/kg/dose and DL2 olaparib orally 150 mg twice daily with tremelimumab IV 10 mg/kg/dose). Primary objectives were safety, change in peripheral ICOS+ T cells, and identification of optimal dose combination.
Results
Among 24 total patients (12 on Arm A, 6 on Arm B-DL1, 6 on Arm B-DL2), the most common grade 3 toxicities were rash (13 %), immune-mediated hepatitis (8 %), and colitis (8 %). No grade ≥ 4 toxicities were identified. No dose-limiting toxicities were identified. One patient (Arm B-DL2) experienced a partial response; no complete responses were observed. Ten patients (7 on Arm A, 2 on Arm B-DL2, and 1 on Arm B-DL1) had a best response of stable disease. There was a significant increase in CD4+ICOS+ and CD8+ICOS+ T cells at both C1D15 and C1D22 in groups treated with tremelimumab IV 10 mg/kg/dose, but not in those treated with tremelimumab 3 mg/kg/dose.
Conclusions
Tremelimumab IV 10 mg/kg/dose with olaparib 150 mg orally twice daily was safe and feasible. Tremelimumab 10 mg/kg/dose (as opposed to 3 mg/kg/dose) was required for immune activation, although this did not translate into clinical responses.
{"title":"A clinical study of tremelimumab, alone or in combination with olaparib, for recurrent epithelial ovarian cancer","authors":"Stéphanie Gaillard , Neha Verma , Maureen Berg , Jeanne Harrison , Peng Huang , James M. Leatherman , Michele Doucet , Rupashree Sen , Aditya Suru , Hongyan Cai , Jennifer Durham , Danijela Jelovac , Ashley Cimino-Mathews , Christopher Cherry , Sudipto Ganguly , Leisha A. Emens","doi":"10.1016/j.ygyno.2025.01.015","DOIUrl":"10.1016/j.ygyno.2025.01.015","url":null,"abstract":"<div><h3>Objective</h3><div>PARP inhibitors may work synergistically to improve the efficacy of immunotherapy in patients with epithelial ovarian cancer (EOC). We performed a parallel-arm study of tremelimumab, alone or with olaparib, in patients with recurrent EOC.</div></div><div><h3>Methods</h3><div>Eligibility criteria included measurable disease and progression <12 months from last platinum. Participants were randomized to Arm A (tremelimumab monotherapy, 10 mg/kg/dose intravenously [IV]) or Arm B (dose level 1 [DL1] olaparib orally 150 mg twice daily with tremelimumab IV 3 mg/kg/dose and DL2 olaparib orally 150 mg twice daily with tremelimumab IV 10 mg/kg/dose). Primary objectives were safety, change in peripheral ICOS<sup>+</sup> T cells, and identification of optimal dose combination.</div></div><div><h3>Results</h3><div>Among 24 total patients (12 on Arm A, 6 on Arm B-DL1, 6 on Arm B-DL2), the most common grade 3 toxicities were rash (13 %), immune-mediated hepatitis (8 %), and colitis (8 %). No grade ≥ 4 toxicities were identified. No dose-limiting toxicities were identified. One patient (Arm B-DL2) experienced a partial response; no complete responses were observed. Ten patients (7 on Arm A, 2 on Arm B-DL2, and 1 on Arm B-DL1) had a best response of stable disease. There was a significant increase in CD4<sup>+</sup>ICOS<sup>+</sup> and CD8<sup>+</sup>ICOS<sup>+</sup> T cells at both C1D15 and C1D22 in groups treated with tremelimumab IV 10 mg/kg/dose, but not in those treated with tremelimumab 3 mg/kg/dose.</div></div><div><h3>Conclusions</h3><div>Tremelimumab IV 10 mg/kg/dose with olaparib 150 mg orally twice daily was safe and feasible. Tremelimumab 10 mg/kg/dose (as opposed to 3 mg/kg/dose) was required for immune activation, although this did not translate into clinical responses.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"194 ","pages":"Pages 41-47"},"PeriodicalIF":4.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394589","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 : 2025-02-13DOI: 10.1016/j.ygyno.2025.02.003
Elizabeth A. Tubridy , Aaliyah Campbell , Lakeisha Mulugeta-Gordon , Leslie Andriani , Emily G. Gleason , Anna Jo Bodurtha Smith , Emily M. Ko
{"title":"Impact of telehealth legislation on gynecologic oncology services: Policy updates","authors":"Elizabeth A. Tubridy , Aaliyah Campbell , Lakeisha Mulugeta-Gordon , Leslie Andriani , Emily G. Gleason , Anna Jo Bodurtha Smith , Emily M. Ko","doi":"10.1016/j.ygyno.2025.02.003","DOIUrl":"10.1016/j.ygyno.2025.02.003","url":null,"abstract":"","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"194 ","pages":"Pages 48-50"},"PeriodicalIF":4.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394587","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 : 2025-02-12DOI: 10.1016/j.ygyno.2025.02.005
Alfonso Cortés-Salgado , Esther Moreno-Moreno , Irene Carretero-Barrio , Tamara Caniego-Casas , Eva Cristóbal , Laura Del Campo-Albendea , Eva Guerra , Víctor Alía , Patricia Pérez de Aguado , Virginia Corraliza , José Palacios , Belén Pérez-Mies
Background
HER2 antibody-drug conjugates like Trastuzumab deruxtecan (TDxd) have shown efficacy in HER2-low cancers, however the prevalence and clinical impact of HER2-low in endometrial cancer (EC) remains unclear. This study investigates HER2 expression in EC, focusing on HER2-low frequency, its distribution across histologic and molecular subtypes, intratumoral heterogeneity, and prognostic significance.
Methods
This retrospective analysis included EC patients categorized histologically and molecularly, using ASCO/CAP HER2 scoring guidelines for endometrial, gastric, and breast cancers. The main aim was to determine HER2-low frequency by molecular subtype, with secondary goals of assessing HER2 heterogeneity, changes between primary and recurrent tumors, guidelines concordance and the impact of HER2 status on recurrence-free (RFS) and overall survival (OS).
Results
193 EC patients were included, 111 low grade endometrioid EC and 82 high grade EC with various histotypes. Based on endometrial criteria, 69.9 % were HER2-negative, 25.8 % HER2-low, and 4.3 % HER2-positive, with HER2-low being most common in POLEmut (66.7 %) and p53abn (45.1 %) subtypes. Low heterogeneity in HER2 expression was observed between different tumors areas and between primary tumors and their recurrences. The endometrial and gastric criteria had high concordance (88.7 %), with endometrial guidelines detecting more HER2-low cases. Neither HER2-low nor HER2-positivity versus HER2-negativity had an impact on RFS or OS, with the stage at diagnosis being the only factor associated with survival, while age was associated only with OS.
Conclusions
This study highlights the distribution of HER2-low across EC molecular subtypes, with endometrial criteria proving more sensitive for identifying HER2-low cases, though HER2 status had no prognostic value in this cohort.
{"title":"HER2 expression in a molecularly defined cohort of endometrial cancer patients: The SPECTRUM study","authors":"Alfonso Cortés-Salgado , Esther Moreno-Moreno , Irene Carretero-Barrio , Tamara Caniego-Casas , Eva Cristóbal , Laura Del Campo-Albendea , Eva Guerra , Víctor Alía , Patricia Pérez de Aguado , Virginia Corraliza , José Palacios , Belén Pérez-Mies","doi":"10.1016/j.ygyno.2025.02.005","DOIUrl":"10.1016/j.ygyno.2025.02.005","url":null,"abstract":"<div><h3>Background</h3><div>HER2 antibody-drug conjugates like Trastuzumab deruxtecan (TDxd) have shown efficacy in HER2-low cancers, however the prevalence and clinical impact of HER2-low in endometrial cancer (EC) remains unclear. This study investigates HER2 expression in EC, focusing on HER2-low frequency, its distribution across histologic and molecular subtypes, intratumoral heterogeneity, and prognostic significance.</div></div><div><h3>Methods</h3><div>This retrospective analysis included EC patients categorized histologically and molecularly, using ASCO/CAP HER2 scoring guidelines for endometrial, gastric, and breast cancers. The main aim was to determine HER2-low frequency by molecular subtype, with secondary goals of assessing HER2 heterogeneity, changes between primary and recurrent tumors, guidelines concordance and the impact of HER2 status on recurrence-free (RFS) and overall survival (OS).</div></div><div><h3>Results</h3><div>193 EC patients were included, 111 low grade endometrioid EC and 82 high grade EC with various histotypes. Based on endometrial criteria, 69.9 % were HER2-negative, 25.8 % HER2-low, and 4.3 % HER2-positive, with HER2-low being most common in POLEmut (66.7 %) and p53abn (45.1 %) subtypes. Low heterogeneity in HER2 expression was observed between different tumors areas and between primary tumors and their recurrences. The endometrial and gastric criteria had high concordance (88.7 %), with endometrial guidelines detecting more HER2-low cases. Neither HER2-low nor HER2-positivity versus HER2-negativity had an impact on RFS or OS, with the stage at diagnosis being the only factor associated with survival, while age was associated only with OS.</div></div><div><h3>Conclusions</h3><div>This study highlights the distribution of HER2-low across EC molecular subtypes, with endometrial criteria proving more sensitive for identifying HER2-low cases, though HER2 status had no prognostic value in this cohort.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"194 ","pages":"Pages 33-40"},"PeriodicalIF":4.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394588","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 : 2025-02-08DOI: 10.1016/j.ygyno.2025.01.014
Carmine Valenza , Marta Mongillo , Maria Vittoria Visconti , Jalissa Katrini , Dario Trapani , Laura Boldrini , Lorenzo Guidi , Alessia Farfalla , Daniela Malengo , Giuseppe Caruso , Silvia Derio , Mariateresa Lapresa , Gabriella Parma , Elena Biagioli , Emanuela Omodeo Salé , Giuseppe Curigliano , Nicoletta Colombo
Background
According to the 2018 ESMO-ESGO consensus conference recommendations on ovarian cancer, platinum rechallenge could be considered in patients with platinum-resistant disease following a treatment with a non‑platinum regimen, if they had not progressed during prior platinum therapy. However, few data are available in this specific setting, especially after the incorporation of novel agents in the current treatment algorithm for ovarian cancer.
Methods
We conducted a single-center, retrospective, cohort study to evaluate the activity of platinum rechallenge in patients with high-grade ovarian cancer, progressing on at least one non‑platinum regimen for platinum-resistant disease, from January 2010 to June 2024, at the European Institute of Oncology (Italy). A sample size of 30 patients allowed to estimate a 6-month progression-free survival (PFS) rate of 30 %, with a 95 % confidence interval (CI) ranging from 14 % to 47 %.
Results
30 patients were included: 23 (77 %) received rechallenge with carboplatin and 7 (23 %) with cisplatin. The median number of previous treatment lines was 3 (interquartile range: 3–4). The objective response rate was 27 % (95 % CI: 12–46 %) and the disease control rate was 80 % (95 % CI: 61–92). After a median follow-up of 14.1 months (range: 3.3–52.7), the median PFS was 5.4 months (95 % CI: 2.5–8.2) and the 6-month PFS rate was 47 % (95 % CI: 28–63 %).
Conclusions
Platinum rechallenge can be a viable treatment option for selected patients with platinum-resistant ovarian cancer who have previously received a non‑platinum regimen. This study suggests that we could dynamically reassess whether platinum is the best option during the patient's treatment history.
{"title":"Rechallenge with platinum-based chemotherapy in patients with platinum-resistant ovarian carcinoma: A cohort study","authors":"Carmine Valenza , Marta Mongillo , Maria Vittoria Visconti , Jalissa Katrini , Dario Trapani , Laura Boldrini , Lorenzo Guidi , Alessia Farfalla , Daniela Malengo , Giuseppe Caruso , Silvia Derio , Mariateresa Lapresa , Gabriella Parma , Elena Biagioli , Emanuela Omodeo Salé , Giuseppe Curigliano , Nicoletta Colombo","doi":"10.1016/j.ygyno.2025.01.014","DOIUrl":"10.1016/j.ygyno.2025.01.014","url":null,"abstract":"<div><h3>Background</h3><div>According to the 2018 ESMO-ESGO consensus conference recommendations on ovarian cancer, platinum rechallenge could be considered in patients with platinum-resistant disease following a treatment with a non‑platinum regimen, if they had not progressed during prior platinum therapy. However, few data are available in this specific setting, especially after the incorporation of novel agents in the current treatment algorithm for ovarian cancer.</div></div><div><h3>Methods</h3><div>We conducted a single-center, retrospective, cohort study to evaluate the activity of platinum rechallenge in patients with high-grade ovarian cancer, progressing on at least one non‑platinum regimen for platinum-resistant disease, from January 2010 to June 2024, at the European Institute of Oncology (Italy). A sample size of 30 patients allowed to estimate a 6-month progression-free survival (PFS) rate of 30 %, with a 95 % confidence interval (CI) ranging from 14 % to 47 %.</div></div><div><h3>Results</h3><div>30 patients were included: 23 (77 %) received rechallenge with carboplatin and 7 (23 %) with cisplatin. The median number of previous treatment lines was 3 (interquartile range: 3–4). The objective response rate was 27 % (95 % CI: 12–46 %) and the disease control rate was 80 % (95 % CI: 61–92). After a median follow-up of 14.1 months (range: 3.3–52.7), the median PFS was 5.4 months (95 % CI: 2.5–8.2) and the 6-month PFS rate was 47 % (95 % CI: 28–63 %).</div></div><div><h3>Conclusions</h3><div>Platinum rechallenge can be a viable treatment option for selected patients with platinum-resistant ovarian cancer who have previously received a non‑platinum regimen. This study suggests that we could dynamically reassess whether platinum is the best option during the patient's treatment history.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"194 ","pages":"Pages 11-17"},"PeriodicalIF":4.5,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350424","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 : 2025-02-08DOI: 10.1016/j.ygyno.2025.01.013
Junhwan Kim , So-Yeon Park , Ju-Hyun Kim , Shin-Wha Lee , Jeong-Yeol Park , Jong-Hyeok Kim , Yong-Man Kim , Dae-Yeon Kim
Objective
To evaluate the real-world efficacy and toxicity of olaparib maintenance therapy in Korean patients with BRCA-mutated ovarian cancer (OC), with an exploratory analysis of BRCA mutations.
Methods
We conducted a retrospective analysis of Korean BRCA-mutated OC patients treated with olaparib maintenance therapy as first-line (1Lm) or second−/subsequent-line (2Lm +) at Asan Medical Center, South Korea, from August 2015 to April 2023. Survival outcomes, including progression-free survival (PFS) and overall survival (OS), as well as toxicity, were analyzed with patient characteristics and BRCA mutations.
Results
In 1Lm (n = 70), the 2-year PFS was 75.5 % and the 3-year OS was 98.5 %. In 2Lm + (n = 83), the 2-year PFS was 54.8 % and the 3-year OS was 87.3 %. The pathogenic p.Leu1780Pro BRCA1 mutation was a poor prognostic factor for PFS in 1Lm (hazard ratio [HR], 5.66). In 2Lm +, platinum-free interval ≥ 12 months was associated with better PFS (adjusted HR [aHR], 0.48) and OS (aHR, 0.31), whereas CA-125 ≥ 10 IU/mL at olaparib initiation was a poor prognostic factor (aHR, 2.12). A longer time interval between the last chemotherapy and maintenance therapy in 1Lm correlated with reduced hematologic toxicity ≥ grade 3 (odd ratio, 0.75) during maintenance therapy. Drug discontinuation due to toxicity occurred in 1.4 % of 1Lm and 6.0 % of 2Lm + .
Conclusions
Olaparib maintenance therapy was effective and tolerable in Korean BRCA-mutated OC patients, though the poor prognosis of the p.Leu1780Pro BRCA1 mutation in 1Lm warrants further investigation.
{"title":"Real-world efficacy and toxicity of olaparib maintenance therapy in Korean ovarian cancer patients with an exploratory analysis of BRCA mutations","authors":"Junhwan Kim , So-Yeon Park , Ju-Hyun Kim , Shin-Wha Lee , Jeong-Yeol Park , Jong-Hyeok Kim , Yong-Man Kim , Dae-Yeon Kim","doi":"10.1016/j.ygyno.2025.01.013","DOIUrl":"10.1016/j.ygyno.2025.01.013","url":null,"abstract":"<div><h3>Objective</h3><div>To evaluate the real-world efficacy and toxicity of olaparib maintenance therapy in Korean patients with <em>BRCA</em>-mutated ovarian cancer (OC), with an exploratory analysis of <em>BRCA</em> mutations.</div></div><div><h3>Methods</h3><div>We conducted a retrospective analysis of Korean <em>BRCA</em>-mutated OC patients treated with olaparib maintenance therapy as first-line (1Lm) or second−/subsequent-line (2Lm +) at Asan Medical Center, South Korea, from August 2015 to April 2023. Survival outcomes, including progression-free survival (PFS) and overall survival (OS), as well as toxicity, were analyzed with patient characteristics and <em>BRCA</em> mutations.</div></div><div><h3>Results</h3><div>In 1Lm (<em>n</em> = 70), the 2-year PFS was 75.5 % and the 3-year OS was 98.5 %. In 2Lm + (<em>n</em> = 83), the 2-year PFS was 54.8 % and the 3-year OS was 87.3 %. The pathogenic p.Leu1780Pro <em>BRCA1</em> mutation was a poor prognostic factor for PFS in 1Lm (hazard ratio [HR], 5.66). In 2Lm +, platinum-free interval ≥ 12 months was associated with better PFS (adjusted HR [aHR], 0.48) and OS (aHR, 0.31), whereas CA-125 ≥ 10 IU/mL at olaparib initiation was a poor prognostic factor (aHR, 2.12). A longer time interval between the last chemotherapy and maintenance therapy in 1Lm correlated with reduced hematologic toxicity ≥ grade 3 (odd ratio, 0.75) during maintenance therapy. Drug discontinuation due to toxicity occurred in 1.4 % of 1Lm and 6.0 % of 2Lm + .</div></div><div><h3>Conclusions</h3><div>Olaparib maintenance therapy was effective and tolerable in Korean <em>BRCA</em>-mutated OC patients, though the poor prognosis of the p.Leu1780Pro <em>BRCA1</em> mutation in 1Lm warrants further investigation.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"194 ","pages":"Pages 25-32"},"PeriodicalIF":4.5,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350423","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 : 2025-02-08DOI: 10.1016/j.ygyno.2025.02.001
Iris L. Romero , Ernst Lengyel , Andrea E. Wahner Hendrickson , Gustavo C. Rodriguez , Charles A. Leath III , Rodney P. Rocconi , Michael J. Goodheart , Summer Dewdney , Theodore Karrison , Gini F. Fleming , S. Diane Yamada
Objective
The primary aim of this study was to determine if metformin, an oral biguanide administered with first-line chemotherapy and continued as maintenance therapy, improves progression-free survival (PFS) for patients with advanced-stage ovarian cancer.
Methods
Patients with pathologically confirmed advanced-stage ovarian cancer undergoing primary debulking or neoadjuvant platinum-based chemotherapy followed by surgery were eligible to participate. Patients were randomized 1:1 to receive platinum/taxane-based chemotherapy with metformin 850 mg orally twice per day or placebo, followed by maintenance therapy (metformin or placebo) for two years from the date of randomization.
Results
108 evaluable patients were enrolled; 54 were randomly assigned to metformin, and 54 to placebo. Sixty-six percent (n = 71) received neoadjuvant therapy, 31 % (n = 33) primary debulking surgery, and 88 % (n = 93) had tumors of high-grade serous histology. The primary endpoint, PFS, was not significantly different between the treatment groups (1-sided p-value = 0.31; adjusted hazard ratio [HR] = 0.87, 95 % confidence interval [CI]: 0.56–1.36). Median PFS was 15.4 months (95 % CI: 11.2–23,5) for metformin and 14.3 months (95 % CI: 11.6–18.0) for placebo. Overall survival (OS) was not significantly different (2-sided p-value = 0.21; adjusted HR = 1.49, 95 % CI: 0.86–2.59), with a median of 40.7 months (95 % CI: 28.0–48.2) for metformin versus 43.8 months (95 % CI: 35.3–57.2) for placebo. The addition of metformin was well tolerated, and there were no differences in toxicity between the two groups.
Conclusion
Although it was well-tolerated, adding metformin to first-line platinum/taxane-based therapy does not improve PFS or OS for patients with newly diagnosed advanced stage ovarian cancer.
{"title":"Metformin for patients with advanced stage ovarian cancer: A randomized phase II placebo-controlled trial","authors":"Iris L. Romero , Ernst Lengyel , Andrea E. Wahner Hendrickson , Gustavo C. Rodriguez , Charles A. Leath III , Rodney P. Rocconi , Michael J. Goodheart , Summer Dewdney , Theodore Karrison , Gini F. Fleming , S. Diane Yamada","doi":"10.1016/j.ygyno.2025.02.001","DOIUrl":"10.1016/j.ygyno.2025.02.001","url":null,"abstract":"<div><h3>Objective</h3><div>The primary aim of this study was to determine if metformin, an oral biguanide administered with first-line chemotherapy and continued as maintenance therapy, improves progression-free survival (PFS) for patients with advanced-stage ovarian cancer.</div></div><div><h3>Methods</h3><div>Patients with pathologically confirmed advanced-stage ovarian cancer undergoing primary debulking or neoadjuvant platinum-based chemotherapy followed by surgery were eligible to participate. Patients were randomized 1:1 to receive platinum/taxane-based chemotherapy with metformin 850 mg orally twice per day or placebo, followed by maintenance therapy (metformin or placebo) for two years from the date of randomization.</div></div><div><h3>Results</h3><div>108 evaluable patients were enrolled; 54 were randomly assigned to metformin, and 54 to placebo. Sixty-six percent (<em>n</em> = 71) received neoadjuvant therapy, 31 % (<em>n</em> = 33) primary debulking surgery, and 88 % (<em>n</em> = 93) had tumors of high-grade serous histology. The primary endpoint, PFS, was not significantly different between the treatment groups (1-sided <em>p</em>-value = 0.31; adjusted hazard ratio [HR] = 0.87, 95 % confidence interval [CI]: 0.56–1.36). Median PFS was 15.4 months (95 % CI: 11.2–23,5) for metformin and 14.3 months (95 % CI: 11.6–18.0) for placebo. Overall survival (OS) was not significantly different (2-sided p-value = 0.21; adjusted HR = 1.49, 95 % CI: 0.86–2.59), with a median of 40.7 months (95 % CI: 28.0–48.2) for metformin versus 43.8 months (95 % CI: 35.3–57.2) for placebo. The addition of metformin was well tolerated, and there were no differences in toxicity between the two groups.</div></div><div><h3>Conclusion</h3><div>Although it was well-tolerated, adding metformin to first-line platinum/taxane-based therapy does not improve PFS or OS for patients with newly diagnosed advanced stage ovarian cancer.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"194 ","pages":"Pages 18-24"},"PeriodicalIF":4.5,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143348769","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}
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