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Objective: Effective functional biomarkers that can be readily used in clinical practice to predict poly(ADP-ribose) polymerase inhibitor (PARPi) sensitivity are lacking. With the widespread adoption of PARPi maintenance therapy in ovarian cancer, particularly in patients with BRCA mutation or HR deficiencies, accurately identifying de novo or acquired resistance to PARPi has become critical in clinical practice. We investigated RAD51 immunohistochemistry (IHC) as a functional biomarker for predicting PARPi sensitivity in ovarian cancer. Methods: Ovarian cancer patients who had received PARPi and had archival tissue samples prior to PARPi exposure ("pre-PARPi") and/or after progression on PARPi ("post-PARPi") were selected. RAD51 IHC expression was semi-quantitatively evaluated using the H-score in geminin (a G2/S phase marker)- and γH2AX (a DNA damage marker)-positive tissues. A RAD51 H-score of 20 was used as the cutoff value. Results: In total, 72 samples from 56 patients were analyzed. The median RAD51 H-score was 20 (range: 0-90) overall, 10 (0-190) in pre-PARPi samples (n = 34), and 25 (1-170) in post-PARPi samples (n = 19). Among patients with BRCA mutations, RAD51-low patients had better progression-free survival (PFS) after PARPi treatment than RAD51-high patients (P = 0.029). No difference was found in PFS with respect to the genomic scar score (P = 0.930). Analysis of matched pre- and post-PARPi samples collected from 15 patients indicated an increase in the RAD51 H-score upon progression on PARPi, particularly among pre-PARPi low-RAD51-expressing patients. Conclusion: RAD51 is a potential functional IHC biomarker of de novo and acquired PARPi resistance in BRCA-mutated ovarian cancer and can be used to fine-tune ovarian cancer treatment.
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Platinum-based chemotherapy is the cornerstone treatment for female high-grade serous ovarian carcinoma (HGSOC), but choosing an appropriate treatment for patients hinges on their responsiveness to it. Currently, no available biomarkers can promptly predict responses to platinum-based treatment. Therefore, we developed the Pathologic Risk Classifier for HGSOC (PathoRiCH), a histopathologic image-based classifier. PathoRiCH was trained on an in-house cohort (n = 394) and validated on two independent external cohorts (n = 284 and n = 136). The PathoRiCH-predicted favorable and poor response groups show significantly different platinum-free intervals in all three cohorts. Combining PathoRiCH with molecular biomarkers provides an even more powerful tool for the risk stratification of patients. The decisions of PathoRiCH are explained through visualization and a transcriptomic analysis, which bolster the reliability of our model's decisions. PathoRiCH exhibits better predictive performance than current molecular biomarkers. PathoRiCH will provide a solid foundation for developing an innovative tool to transform the current diagnostic pipeline for HGSOC.
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Cistadenocarcinoma Seroso , Aprendizado Profundo , Neoplasias Ovarianas , Platina , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/genética , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/diagnóstico por imagem , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/genética , Platina/uso terapêutico , Pessoa de Meia-Idade , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Resultado do Tratamento , Gradação de Tumores , Estudos de Coortes , Adulto , Reprodutibilidade dos TestesRESUMO
Human epidermal growth factor receptor-2 (HER2)-targeting drugs are increasingly being incorporated into therapeutic paradigms for non-breast cancers, yet studies on HER2 expression in ovarian cancer (OC) are inadequate. Here, we studied the HER2 status and dynamic changes in OC by reviewing the records of patients who underwent HER2 testing at a single institution. Clinical parameters, including histology, BRCA status, and immunohistochemistry (IHC), were evaluated alongside HER2 expression, timing, and anatomical location. Among 200 patients, 28% and 6% exhibited expression scores of 2+ and 3+, respectively. HER2 3+ scores were observed in 23%, 11%, 9%, and 5% of mucinous, endometrioid, clear cell, and high-grade serous tumors, respectively, and were exclusively identified in BRCA-wildtype, mismatch repair-proficient, or PD-L1-low-expressing tumors. The TP53 mutation rate was low, whereas ARID1A, KRAS, and PIK3CA mutations were relatively more prevalent with HER2 scores of 2+ or 3+ than with 0 or 1+. Four of the five tumors with an HER2 3+ score exhibited ERBB2 amplification. Among 19 patients who underwent multiple time-lagged biopsies, 11 showed increased HER2 expression in subsequent biopsies. Patients with HER2-overexpressing OC exhibited distinct histological, IHC, and genomic profiles. HER2-targeting agents are potential options for BRCA-wildtype patients, particularly as later lines of treatment.
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Neoplasias Ovarianas , Receptor ErbB-2 , Feminino , Humanos , Mutação , Taxa de Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Receptor ErbB-2/metabolismoRESUMO
AIM: We investigated the efficacy and safety of durvalumab (D) with or without tremelimumab (T) in addition to single-agent chemotherapy (CT) in patients with platinum-resistant recurrent ovarian cancer (PROC) lacking homologous recombination repair (HRR) gene mutations. PATIENTS AND METHODS: KGOG 3045 was an open-label, investigator-initiated phase II umbrella trial. Patients with PROC without HRR gene mutations who had received ≥2 prior lines of therapy were enrolled. Patients with high PD-L1 expression (TPS ≥25%) were assigned to arm A (D + CT), whereas those with low PD-L1 expression were assigned to arm B (D + T75 + CT). After completing arm B recruitment, patients were sequentially assigned to arms C (D + T300 + CT) and D (D + CT). RESULTS: Overall, 58 patients were enrolled (5, 18, 17, and 18 patients in arms A, B, C, and D, respectively). The objective response rates were 20.0, 33.3, 29.4, and 22.2%, respectively. Grade 3-4 treatment-related adverse events were observed in 20.0, 66.7, 47.1, and 66.7 of patients, respectively, but were effectively managed. Multivariable analysis demonstrated that adding T to D + CT improved progression-free survival (adjusted HR, 0.435; 95% CI, 0.229-0.824; P = 0.011). Favorable response to chemoimmunotherapy was associated with MUC16 mutation (P = 0.0214), high EPCAM expression (P = 0.020), high matrix remodeling gene signature score (P = 0.017), and low FOXP3 expression (P = 0.047). Patients showing favorable responses to D + T + CT exhibited significantly higher EPCAM expression levels (P = 0.008) and matrix remodeling gene signature scores (P = 0.031) than those receiving D + CT. CONCLUSIONS: Dual immunotherapy with chemotherapy showed acceptable response rates and tolerable safety in HRR non-mutated PROC, warranting continued clinical investigation.
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Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais , Antígeno B7-H1 , Neoplasias Ovarianas , Humanos , Feminino , Molécula de Adesão da Célula Epitelial , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosAssuntos
Neoplasias Ovarianas , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Epitelial do Ovário , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Ftalazinas/efeitos adversosRESUMO
Cervical small cell neuroendocrine carcinoma (CSCNEC) is a rare, aggressive type of cervical cancer. The treatment for CSCNEC follows the chemotherapeutic regimens used for small cell lung cancer (SCLC), with which it shares similar clinical and histologic features. For the first time, we applied neuroendocrine (NE) and SCLC molecular subtyping immunohistochemical markers [achaete-scute homolog 1 (ASCL1), neurogenic differentiation factor 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1] in 45 patients with CSCNEC. For the combined NE score, 51.1% of NE-high and 48.9% of NE-low subtypes were identified. The NE-high subtype tended to show worse progression-free survival and overall survival (OS) than the NE-low subtype ( P =0.059 and P =0.07, respectively). Applying the SCLC molecular subtyping, 53.3% of cases were identified as NEUROD1-dominant, 17.8% as ASCL1-dominant, 13.3% as YAP-dominant, and 4.4% as POU2F3-dominant, while 11.1% of cases showed negative expression for all markers; the distribution was different from that of SCLC. The NEUROD1-dominant subtype exhibited the worst OS, while the POU2F3 subtype exhibited the best OS ( P =0.003), similar to SCLC. In addition, the ASCL1-dominant and NEUROD1-dominant subtypes showed high NE scores, while yes-associated protein 1-dominant and POU2F3-dominant subtypes showed low NE scores ( P =0.008). In multivariate analysis, the NEUROD1 expression was further identified as the independent prognostic factor for worse OS, together with the high FIGO stage. CSCNEC was revealed to be a heterogeneous disease with different biological phenotypes and to share some similarities and differences with SCLC. Regarding the ongoing development of tailored treatments based on biomarkers in SCLC, the application of biomarker-driven individualized therapy would improve clinical outcomes in patients with CSCNEC.
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Carcinoma Neuroendócrino , Carcinoma de Células Pequenas , Neoplasias Pulmonares , Proteínas do Tecido Nervoso , Carcinoma de Pequenas Células do Pulmão , Feminino , Humanos , Carcinoma de Pequenas Células do Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Sinalização YAP , Colo do Útero/patologia , Prognóstico , Carcinoma de Células Pequenas/genética , Fatores de Transcrição/genética , Biomarcadores Tumorais/genética , Carcinoma Neuroendócrino/patologia , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismoRESUMO
Data on genetic and immunophenotypical characteristics of uterine mesonephric-like adenocarcinoma (MLA) remain limited. Therefore, we aimed to investigate the clinicopathological, immunohistochemical, and molecular features of uterine MLA. We performed targeted sequencing, array comparative genomic hybridization, and immunostaining in 17, 13, and 17 uterine MLA cases, respectively. Nine patients developed lung metastases. Eleven patients experienced disease recurrences. The most frequently mutated gene was Kirsten rat sarcoma viral oncogene homolog (KRAS; 13/17). Both the primary and matched metastatic tumors harbored identical KRAS (3/4) and phosphatase and tensin homolog deleted on chromosome 10 (1/4) mutations, and did not harbor any additional mutations. A total of 2 of the 17 cases harbored tumor protein 53 (TP53) frameshift insertion and deletion, respectively. Chromosomal gains were detected in 1q (13/13), 10 (13/13), 20 (10/13), 2 (9/13), and 12 (6/13). Programmed cell death-ligand 1 overexpression or mismatch repair deficiency was not observed in any of the cases. Initial serosal extension and lung metastasis independently predicted recurrence-free survival with hazard ratios of 6.30 and 7.31, respectively. Our observations consolidated the clinicopathological and molecular characteristics of uterine MLA. Both clinicians and pathologists should consider these features to make an accurate diagnosis of uterine MLA and to ensure appropriate therapeutic management of this rare entity.
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Choosing an optimal concomitant drug for combination with poly-ADP ribose polymerase (PARP) inhibitor based on patient-specific biomarker status may help increase to improve treatment efficacy in patients with ovarian cancer. However, the efficacy and safety of different PARP inhibitor-based combinations in patients with homologous recombination repair (HRR) mutations have not been evaluated in ovarian cancer. In this sub-study of Korean Gynecologic Oncology Group (KGOG) 3045, we compared the efficacy and safety of two olaparib-based combinations and biomarkers of patients with platinum-resistant ovarian cancer with HRR gene mutations. Patients were randomized to receive either olaparib (200 mg twice a day) + cediranib (30 mg daily) (Arm 1, n = 16) or olaparib (300 mg) + durvalumab (1,500 mg once every 4 weeks) (Arm 2, n = 14). The objective response rates for Arm 1 and Arm 2 were 50.0% and 42.9%, respectively. Most patients (83.3%) had BRCA mutations, which were similarly distributed between arms. Grade 3 or 4 treatment-related adverse events were observed in 37.5% and 35.7% of the patients, respectively, but all were managed properly. A high vascular endothelial growth factor signature was associated with favorable outcomes in Arm 1, whereas immune markers (PD-L1 expression [CPS ≥10], CD8, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio) were associated with favorable outcomes in Arm 2. The activation of homologous recombination pathway upon disease progression was associated with poor response to subsequent therapy. Based on comprehensive biomarker profiling, including immunohistochemistry, whole-exome and RNA sequencing and whole blood-based analyses, we identified biomarkers that could help inform which of the two combination strategies is appropriate given a patient's biomarker status. Our findings have the potential to improve treatment outcome for patients with ovarian cancer in the PARP inhibitor era.
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Antineoplásicos , Neoplasias Ovarianas , Feminino , Humanos , Antineoplásicos/uso terapêutico , Biomarcadores , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/induzido quimicamente , Ftalazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Reparo de DNA por Recombinação , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
PROBLEM: Direct interactions between macrophages and lymphatic vessels have been shown previously. In pre-eclampsia (PE), macrophages are dominantly polarized into a proinflammatory M1 phenotype and lymphangiogenesis is defective in the decidua. Here, we investigated whether decidual lymphatic endothelial cells (dLECs) affect macrophage polarization in PE. METHOD OF STUDY: THP-1 macrophages were cocultured with dLECs or cultured in the conditioned medium (CM) of dLECs. Macrophage polarization was measured using flow cytometry. Granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in dLECs was measured using qRT-PCR and ELISA. The activation of nuclear translocation of nuclear factor-κ (NF-κB), an upstream signaling molecule of GM-CSF, was assessed by immunocytochemical localization of p65. Through GM-CSF knockdown and NF-κB inhibition in dLEC, we evaluated whether the GM-CSF/NF-κB pathway of PE dLEC affects decidual macrophage polarization. RESULTS: The ratio of inflammatory M1 macrophages with HLA-DR+ /CD80+ markers significantly increased following coculturing with PE dLECs or culturing in PE dLEC CM, indicating that the PE dLEC-derived soluble factor acts in a paracrine manner. GM-CSF expression was significantly upregulated in PE dLECs. Recombinant human GM-CSF induced macrophage polarization toward an M1-like phenotype, whereas its knockdown in PE dLECs suppressed it, suggesting PE dLECs induce M1 macrophage polarization by secreting GM-CSF. The NF-κB p65 significantly increased in PE dLECs compared to the control, and pretreatment with an NF-κB inhibitor significantly suppressed GM-CSF production from PE dLECs. CONCLUSIONS: In PE, dLECs expressing high levels of GM-CSF via the NF-κB-dependent pathway play a role in inducing decidual M1 macrophage polarization.
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NF-kappa B , Pré-Eclâmpsia , Gravidez , Feminino , Humanos , NF-kappa B/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Pré-Eclâmpsia/metabolismo , Células Endoteliais/metabolismo , Macrófagos/metabolismo , Fator Estimulador de Colônias de MacrófagosRESUMO
OBJECTIVE: To evaluate the landscape of gene alterations and immunohistochemistry (IHC) profiles of patients with ovarian cancer for targeted therapy and investigate the real-world experience of applying precision medicine. METHODS: Patients diagnosed with ovarian cancer between January 2015 and May 2021 at Severance Hospital and who underwent tumor next-generation sequencing (NGS) were reviewed. Data on germline mutation, IHC markers for mismatch repair deficiency (MMRd), programmed death ligand 1 (PD-L1) expression, and human epidermal growth factor receptor 2 (HER2) expression were acquired. The use of matched therapy and its clinical outcomes were evaluated. RESULTS: Of the 512 patients who underwent tumor NGS, 403 underwent panel-based germline testing. In patients who underwent both tests, tumor NGS identified 39 patients (9.7%) with BRCA mutations and 16 patients (4.0%) with other homologous recombination repair (HRR)-associated gene mutations, which were not found in germline testing. The most common single nucleotide variants were TP53 (82.2%), ARID1A (10.4%), PIK3CA (9.7%), and KRAS (8.4%). Copy number aberrations were found in 122 patients. MMRd was found in 3.2% of patients, high PD-L1 expression in 10.1%, and HER2 overexpression in 6.5%. Subsequently, 75 patients (14.6%) received a poly (ADP-ribose) polymerase inhibitor based on BRCA mutation and 11 patients (2.1%) based on other HRR-associated gene mutations. Six patients (1.2%) with MMRd underwent immunotherapy. Twenty-eight patients (5.5%) received other matched therapies targeting HER2, fibroblast growth factor receptor, folate receptor alpha, RAS, and PIK3CA. CONCLUSION: A comprehensive review of germline mutation, IHC, and tumor NGS helped identify candidates for precision therapy in patients with ovarian cancer, a proportion of whom received matched therapy.
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Antígeno B7-H1 , Neoplasias Ovarianas , Humanos , Feminino , Antígeno B7-H1/genética , Antígeno B7-H1/uso terapêutico , Medicina de Precisão , Imuno-Histoquímica , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/uso terapêutico , MutaçãoRESUMO
Purpose: This study aimed to investigate genomic and immunohistochemical (IHC) profiles and immunotherapy outcomes in patients with cervical cancer. Methods: Patients with recurrent cervical cancer who underwent tumor next-generation sequencing (NGS) with the TruSight Oncology 500 panel at Yonsei Cancer Center between June 2019 and February 2022, were identified. Patients who received treatment with checkpoint inhibitors during the same period were also identified. Clinical information, including histology, stage, human papillomavirus (HPV) genotype, IHCs profile, and therapy outcome, was reviewed. Results: We identified 115 patients treated for recurrent cervical cancer, including 74 patients who underwent tumor NGS. Most of these 74 patients were initially diagnosed with advanced stage (63.6%) and had squamous cell histology (52.7%), and high-risk HPV (76.9%). Based on IHC analysis, the programmed death-ligand 1 combined positive score (PD-L1 CPS) was higher in patients with squamous cell carcinoma (SCC) than in those with adeno or mucinous types (P=0.020). HER2 receptor expression of 2+ and 3+ were identified in 5 and 1 patients, respectively, and significantly varied based on histology (p=0.002). Among the 74 patients, single nucleotide variants (SNVs) and copy number variations (CNVs) were identified in 60 (81.1%) and 13 patients (17.6%), respectively. The most common SNVs were PIK3CA, TP53, STK11, FAT1, and FBXW7 mutations. Mutations in PIK3CA, with two hotspot mutations, were frequently observed in patients with SCC histology, whereas mutations in TP53 were frequently observed in patients with non-SCC histology. Additionally, variations in FAT1 were exclusively identified in patients with SCC histology. Mutations in homologous recombination repair-associated genes were identified in 18 patients (24.3%). The most frequent CNV alteration was CCNE1 amplification. Moreover, among the 36 patients who underwent NGS and received immunotherapy, the tumor mutational burden and microsatellite instability were significantly correlated with immunotherapy duration. During this timeframe, 73 patients received pembrolizumab monotherapy, among whom a small portion showed a durable response. Conclusion: Comprehensive genomic and IHC profiling may help identify potential candidates for targeted immunotherapy in patients with cervical cancer.
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BACKGROUND: Although several studies have documented the histological features of uterine mesonephric-like adenocarcinoma (MLA), its cytological features have been rarely reported. METHODS: We searched for histologically confirmed uterine MLA cases in the pathology archives of three institutions between 2010 and 2021. All available cytology slides were examined to identify the cytological features of uterine MLA. RESULTS: We included 16 patients with uterine MLA and reviewed the slides obtained from 21 cytology samples. Samples were obtained from the cervicovagina (9/21, 42.9%), peritoneal washing (8/21, 38.1%), pleural effusion (2/21, 9.5%), and transbronchial needle aspiration of mediastinal lymph node (2/21, 9.5%). Preparation methods included ThinPrep (11/21, 52.4%), SurePath (8/21, 38.1%), and conventional smear (2/21, 9.5%). Regardless of the sampling site and preparation method, cytology samples displayed tight three-dimensional cellular clusters showing monotonous, small-to-medium-sized, round, hyperchromatic nuclei, indistinct nucleoli, scant cytoplasm, and high nuclear-to-cytoplasmic ratio. Approximately half of the samples (10/21, 47.6%) showed hyaline-like globules. Mitotic figures (7/21, 33.3%) and apoptotic bodies (13/21, 61.9%) were also observed. No tumor diathesis or nuclear feathering was identified. CONCLUSIONS: Irrespective of sampling site and preparation method, the majority of uterine MLA cases showed the following cytological features: tight three-dimensional cellular clusters showing small-to-medium-sized, round, hyperchromatic nuclei with indistinct nucleoli and high nuclear-to-cytoplasm ratio. In case a cytology sample suspicious of a glandular lesion displays these cytological features, which are distinct from those of endocervical adenocarcinoma, uterine MLA should be included in the differential diagnosis.
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Adenocarcinoma , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/patologia , Útero/patologia , Colo do Útero/patologia , Citodiagnóstico , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologiaRESUMO
Recent advances in computer-aided detection via deep learning (DL) now allow for prostate cancer to be detected automatically and recognized with extremely high accuracy, much like other medical diagnoses and prognoses. However, researchers are still limited by the Gleason scoring system. The histopathological analysis involved in assigning the appropriate score is a rigorous, time-consuming manual process that is constrained by the quality of the material and the pathologist's level of expertise. In this research, we implemented a DL model using transfer learning on a set of histopathological images to segment cancerous and noncancerous areas in whole-slide images (WSIs). In this approach, the proposed Ensemble U-net model was applied for the segmentation of stroma, cancerous, and benign areas. The WSI dataset of prostate cancer was collected from the Kaggle repository, which is publicly available online. A total of 1000 WSIs were used for region segmentation. From this, 8100 patch images were used for training, and 900 for testing. The proposed model demonstrated an average dice coefficient (DC), intersection over union (IoU), and Hausdorff distance of 0.891, 0.811, and 15.9, respectively, on the test set, with corresponding masks of patch images. The manipulation of the proposed segmentation model improves the ability of the pathologist to predict disease outcomes, thus enhancing treatment efficacy by isolating the cancerous regions in WSIs.
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OBJECTIVE: The RAD51 assay is a recently developed functional assay for homologous recombination deficiency (HRD) that reflects real-time HRD status. We aimed to identify the applicability and predictive value of RAD51 immunohistochemical expression in pre- and post-neoadjuvant chemotherapy (NAC) samples of ovarian high-grade serous carcinoma (HGSC). METHODS: We evaluated the immunohistochemical expression of RAD51/geminin/γH2AX in ovarian HGSC before and after NAC. RESULTS: In pre-NAC tumors (n=51), 74.5% (39/51) showed at least 25% of γH2AX-positive tumor cells, suggesting endogenous DNA damage. The RAD51-high group (41.0%, 16/39) showed significantly worse progression-free survival (PFS) compared to the RAD51-low group (51.3%, 20/39) (p=0.032). In post-NAC tumors (n=50), the RAD51-high group (36.0%, 18/50) showed worse PFS (p=0.013) and tended to present worse overall survival (p=0.067) compared to the RAD51-low group (64.0%, 32/50). RAD51-high cases were more likely to progress than RAD51-low cases at both 6 months and 12 months (p=0.046 and p=0.019, respectively). Of 34 patients with matched pre- and post-NAC RAD51 results, 44% (15/34) of pre-NAC RAD51 results were changed in the post-NAC tissue, and the RAD51 high-to-high group showed the worst PFS, while the low-to-low group showed the best PFS (p=0.031). CONCLUSION: High RAD51 expression was significantly associated with worse PFS in HGSC, and post-NAC RAD51 status showed higher association than pre-NAC RAD51 status. Moreover, RAD51 status can be evaluated in a significant proportion of treatment-naïve HGSC samples. As RAD51 status dynamically changes, sequential follow-up of RAD51 status might reflect the biological behavior of HGSCs.
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Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Feminino , Humanos , Neoplasias Ovarianas/patologia , Geminina , Intervalo Livre de Progressão , Rad51 RecombinaseRESUMO
Background/Aims: Programmed death-ligand 1 (PD-L1) expression in tumor cells is associated with a poor biliary tract cancer (BTC) prognosis; tumor-infiltrating immune cells in the tumor microenvironment are associated with a better prognosis. The effect of PD-L1 expression on immune cells on survival is unclear. We investigated the relationship between PD-L1 expression in immune cells and BTC prognosis. Methods: PD-L1 expression was evaluated using an anti-PD-L1 22C3 mouse monoclonal primary antibody, and its relationships with clinical characteristics and prognosis were analyzed using the Cox proportional hazard model to investigate the prognostic performance of PD-L1 in BTC. Results: Among 144 analyzed cases, patients with positive PD-L1 expression in tumor cells and negative PD-L1 expression in immune cells showed poorer overall survival rates than those exhibiting other expressions (tumor cells: hazard ratio [HR]=1.023, p<0.001; immune cells: HR=0.983, p=0.021). PD-L1 expression in tumor cells was an independent predictor of poor overall survival (HR=1.024, p<0.001). In contrast, PD-L1 expression in immune cells was a predictive marker of good prognosis (HR=0.983, p=0.018). Conclusions: PD-L1 expression in immune cells may be used as an independent factor to evaluate the prognosis of patients with BTC.
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Antígeno B7-H1 , Neoplasias do Sistema Biliar , Animais , Camundongos , Humanos , Prognóstico , Microambiente TumoralRESUMO
BACKGROUND/AIM: This study aimed to investigate the clinicopathological, prognostic and molecular characteristics of uterine mesonephric-like carcinosarcoma (MLCS). PATIENTS AND METHODS: We collected clinical, pathological, and genetic information from 12 MLCS patients, and analyzed their differences from mesonephric-like adenocarcinoma (MLA) and conventional endometrial carcinosarcoma (CECS). RESULTS: The epithelial component was exclusively MLA in all MLCS cases. Metastatic and recurrent tumors consisted predominantly or exclusively of MLA in the majority of MLCS cases. Patients with MLCS and MLA presented with more advanced-stage disease than those with CECS. They also exhibited post-treatment recurrence and lung metastases more frequently than CECS. Disease-free survival rates of MLCS and MLA were shorter than those of CECS. Tumor protein 53 gene mutations were detected in four MLCS cases. CONCLUSION: The predominance or exclusive presence of MLA in metastatic and recurrent tumors highlights the possibility that MLA may determine the clinical outcomes of patients with MLCS. Further studies are required to provide direct molecular evidence of the monoclonal origin of uterine MLCS.
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Adenocarcinoma , Carcinossarcoma , Neoplasias do Endométrio , Feminino , Humanos , Prognóstico , Carcinossarcoma/genética , Carcinossarcoma/patologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Adenocarcinoma/patologiaRESUMO
BACKGROUND: Sentinel lymph node (SLN) mapping has been suggested as an alternative surgical technique to full lymphadenectomy for early-stage endometrial cancer. However, the survival outcomes of SLN mapping compared with lymphadenectomy have not been established via a prospective study. METHODS: A multi-center, single-blind, randomized controlled trial has been designed to determine the prognostic value of SLN mapping alone compared with conventional lymphadenectomy for patients with clinical stage I-II endometrial cancer. Eligible participants will be randomly assigned in a 1:1 ratio between the group to undergo SLN mapping using indocyanine green and the conventional lymph node dissection group. A high-risk group will undergo a 2-step SLN mapping procedure. The primary endpoint is the 3-year disease-free survival (DFS). The secondary endpoints are 3-year overall survival (OS), 5-year DFS, 5-year OS after surgery, pattern of recurrence, immediate surgical outcomes, success rate of SLN mapping, postoperative lymph-related complications, postoperative quality of life, and postoperative cost effectiveness. The role of pathologic ultrastaging of SLNs will also be assessed. TRIAL REGISTRATION: ClinicalTrials.gov Identifier (NCT number): NCT04845828.
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Neoplasias do Endométrio , Linfonodo Sentinela , Humanos , Feminino , Verde de Indocianina , Linfonodo Sentinela/cirurgia , Linfonodo Sentinela/patologia , Biópsia de Linfonodo Sentinela/métodos , Estudos Prospectivos , Qualidade de Vida , Método Simples-Cego , Neoplasias do Endométrio/cirurgia , Neoplasias do Endométrio/patologia , Excisão de Linfonodo/métodos , Corantes , Linfonodos/patologia , República da Coreia , Estadiamento de NeoplasiasRESUMO
Purpose: Cervical smear samples are easily obtainable and may effectively reflect the tumor microenvironment in gynecological cancers. Therefore, we investigated the feasibility of genomic profiling based on tumor DNA analysis from cervical smear samples from endometrial cancer patients. Materials and methods: Preoperative cervical smear samples were obtained via vaginal sampling in 50 patients, including 39 with endometrial cancer and 11 with benign uterine disease. Matched blood samples were obtained simultaneously. Genomic DNA (gDNA) from cervical smear and/or cell-free DNA from whole blood were extracted and sequenced using the Pan100 panel covering 100 endometrial cancer-related genes. Results: Cervical swab-based gDNA analysis detected cancer with 67% sensitivity and 100% specificity, showing a superior performance compared to that of the matched blood or Pap smear tests. Cervical swab-based gDNA effectively identified patients with loss of MSH2 or MSH6 and aberrant p53 expression based on immunohistochemistry. Genomic landscape analysis of cervical swab-based gDNA identified PTEN, PIK3CA, TP53, and ARID1A as the most frequently altered genes. Furthermore, 26 endometrial cancer patients could be classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer. Conclusion: Cervical swab-based gDNA test showed an improved detection potential and allowed the classification of patients, which has both predictive and prognostic implications.
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The dynamic changes in the tumor immune microenvironment (TIME) triggered by neoadjuvant chemotherapy (NAC) have not been clearly defined in advanced-stage ovarian cancer. We analyzed the immunologic changes induced by NAC to correlate them with clinical outcomes. We compared the changes in the immune infiltration of high-grade serous carcinoma biopsies before and after NAC via immunohistochemistry (147 paired samples) and whole transcriptome sequencing (35 paired samples). Immunohistochemistry showed significantly increased PD-L1 levels and TIL levels after NAC. Whole transcriptome sequencing revealed that the stromal score, immune score, and cytolytic activity score significantly increased after NAC. An increased tumor-infiltrating lymphocyte (TIL) level in response to NAC was associated with shorter progression-free survival compared with decreased TIL level after NAC. In tumors with increased TIL levels after NAC, the relative fraction of CD8 T cells and regulatory T cells significantly increased with immunohistochemistry. Post-NAC tumors were enriched in gene sets associated with immune signaling pathways, such as regulatory T cell and JAK/STAT signaling pathways. NAC induced dynamic changes in the TIME that increased TIL levels, but their high abundance did not impart any survival benefit. Our data may provide therapeutic strategies to improve the survival benefit from immunotherapies in ovarian cancer.
RESUMO
OBJECTIVE: Management of heavily pre-treated platinum-resistant ovarian cancer remains a therapeutic challenge. Outcomes are poor with non-platinum, single-agent chemotherapy (CT); however, molecularly targeted anticancer therapies provide new options. METHODS: This open-label, investigator-initiated, phase 2 umbrella trial (NCT03699449) enrolled patients with platinum-resistant ovarian cancer (at least 2 prior lines of CT and Eastern Cooperative Oncology Group 0/1) to receive combination therapy based on homologous recombination deficiency (HRD) and programmed death ligand 1 (PD-L1) status determined by archival tumour sample assessment. HRD-positive patients were randomised to either olaparib 200mg bid tablet + cediranib 30mg qd (arm 1) or olaparib 300mg bid tablet + durvalumab 1,500mg q4w (arm 2). HRD-negative patients were allocated to either durvalumab 1,500 mg q4w + pegylated liposomal doxorubicin (PLD) or topotecan or weekly paclitaxel (6 cycles; arm 3, those with PD-L1 expression) or durvalumab 1,500 mg q4w + tremelimumab 75mg q4w (4 doses) + PLD or topotecan or weekly paclitaxel (4 cycles; arm 4, those without PD-L1 expression). Arm 5 (durvalumab 1,500 mg q4w + tremelimumab 300mg [1 dose] + weekly paclitaxel [60 mg/m² D1,8,15 q4w for 4 cycles] was initiated after arm 4 completed. The primary endpoint was objective response rate (ORR; Response Evaluation Criteria in Solid Tumours 1.1). RESULTS: Between Dec 2018 and Oct 2020, 70 patients (median 57 years; median 3 prior treatment lines [range 2-10]) were treated (n=16, 14, 5, 18, and 17, respectively). Overall ORR was 37.1% (26/70, 95% confidence interval=25.9, 49.5); 2 achieved complete response. ORR was 50%, 42.9%, 20%, 33.3%, and 29.4%, respectively. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 37.5%, 35.7%, 20%, 66.7%, and 35.3% of patients, respectively. No TRAEs leading to treatment discontinuation and no grade 5 TRAEs were observed. CONCLUSION: This study, the first biomarker-driven umbrella trial in platinum-resistant recurrent ovarian cancer, suggests clinical utility with biomarker-driven targeted therapy. All treatment combinations were manageable, and without unexpected toxicities. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03699449.