Yong Jae Lee

Changes in the tumor immune microenvironment during disease progression in clear cell ovarian cancer

The tumor immune microenvironment in ovarian clear cell carcinoma has not been clearly defined. We analyzed the immunological changes from treatment-naive to recurrence to correlate them with clinical outcomes. We compared the changes in immune infiltration of advanced-stage ovarian clear cell carcinoma samples before treatment and at the time of recurrence via immunohistochemistry (Programmed Cell Death-ligand 1 (PD-L1), cluster of differentiation 8 (CD8+), forkhead box P3 (Foxp3+)), tumor-infiltrating lymphocytes (TIL), and next-generation sequencing (54 patients). We analyzed the association between platinum sensitivity status and tumor immune microenvironment. Immunohistochemistry revealed significantly increased PD-L1 (p=0.048) and CD8+T cells (p=0.022) expression levels after recurrence. No significant differences were observed in TIL density or Foxp3+T cells. There was no significant correlation between TIL, PD-L1, CD8+T cell, and Foxp3+T cell levels in treatment-naive tumors and survival outcomes. The most common genomic alterations were We characterized the tumor immune microenvironment in patients with advanced-stage ovarian clear cell carcinoma. PD-L1 and CD8+T cell expression significantly increased after recurrence. Whether this could be used to select patients for immunotherapy in the recurrence setting should be investigated.

Major clinical research advances in gynecologic cancer in 2023: a tumultuous year for endometrial cancer

In the 2023 series, we summarized the major clinical research advances in gynecologic oncology based on communications at the conference of Asian Society of Gynecologic Oncology Review Course. The review consisted of 1) Endometrial cancer: immune checkpoint inhibitor, antibody drug conjugates (ADCs), selective inhibitor of nuclear export, CDK4/6 inhibitors WEE1 inhibitor, poly (ADP-ribose) polymerase (PARP) inhibitors. 2) Cervical cancer: surgery in low-risk early-stage cervical cancer, therapy for locally advanced stage and advanced, metastatic, or recurrent setting; and 3) Ovarian cancer: immunotherapy, triplet therapies using immune checkpoint inhibitors along with antiangiogenic agents and PARP inhibitors, and ADCs. In 2023, the field of endometrial cancer treatment witnessed a landmark year, marked by several practice-changing outcomes with immune checkpoint inhibitors and the reliable efficacy of PARP inhibitors and ADCs.

The effectiveness of CA125 and HE4 as clinical prognostic markers in epithelial ovarian cancer patients with BRCA mutation

To investigate the efficacy of cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) in predicting survival outcomes based on breast cancer gene (BRCA) mutational status in epithelial ovarian cancer. Medical records of 448 patients diagnosed with epithelial ovarian cancer at a single tertiary institution in Korea were retrospectively analyzed. Area under the curve, sensitivity, specificity, and accuracy were assessed using the CA125 and HE4 values after surgery and 3 cycles of chemotherapy to predict 1-year survival based on the BRCA mutational status. Kaplan-Meier analysis was used to obtain progression-free and overall survival to evaluate CA125 and HE4 effectiveness in predicting survival outcomes. A total of 423 patients were analyzed, including 180 (42.6%) who underwent interval debulking surgery (IDS) and 243 (57.4%) who underwent primary debulking surgery (PDS). BRCA mutations were observed in 37 (15.2%) and 44 (22.4%) patients in the PDS and IDS groups, respectively. CA125 and HE4 normalization demonstrated the highest specificity in patients with or without BRCA mutations, with specificities of 97.1% and 99.1% in the PDS group and 78.6% and 86.2% in the IDS group, respectively. Normalizing HE4 alone may be an effective prognostic marker, with an area under the curve of 0.774 and specificity of 75.0%, in patients with BRCA mutations. Normalizing both biomarkers emerged as the most effective predictive marker for the 1-year recurrence rate, regardless of BRCA mutational status. A negative HE4 value can be a useful predictor for 1-year recurrence-free survival in patients with BRCA mutations.

Serial Circulating Tumor DNA Analysis with a Tumor-Naïve Next-Generation Sequencing Panel Detects Minimal Residual Disease and Predicts Outcome in Ovarian Cancer

Abstract Circulating tumor DNA (ctDNA) may aid in personalizing ovarian cancer therapeutic options. Here, we aimed to assess the clinical utility of serial ctDNA testing using tumor-naïve, small-sized next-generation sequencing (NGS) panels. A total of 296 patients, including 201 with ovarian cancer and 95 with benign or borderline disease, were enrolled. Samples were collected at baseline (initial diagnosis or surgery) and every 3 months after that, resulting in a total of 811 blood samples. Patients received adjuvant therapy based on the current standard of care. Cell-free DNA was extracted and sequenced using an NGS panel of 9 genes: TP53, BRCA1, BRCA2, ARID1A, CCNE1, KRAS, MYC, PIK3CA, and PTEN. Pathogenic somatic mutations were identified in 69.2% (139/201) of patients with ovarian cancer at baseline but not in those with benign or borderline disease. Detection of ctDNA at baseline and/or at 6 months follow-up was predictive of progression-free survival (PFS). PFS was significantly poorer in patients with detectable pathogenic mutations at baseline that persisted at follow-up than in patients that converted from having detectable ctDNA at baseline to being undetectable at follow-up; survival did not differ between patients without pathogenic ctDNA mutations in baseline or follow-up samples and those that converted from ctDNA positive to negative. Disease recurrence was also detected earlier with ctDNA than with conventional radiologic assessment or CA125 monitoring. These findings demonstrate that serial ctDNA testing could effectively monitor patients and detect minimal residual disease, facilitating early detection of disease progression and tailoring of adjuvant therapies for ovarian cancer treatment. Significance: In ovarian cancer, serial circulating tumor DNA testing is a highly predictive marker of patient survival, with a significantly improved recurrence detection lead time compared with conventional monitoring tools.

Practice guidelines for management of uterine corpus cancer in Korea: a Korean Society of Gynecologic Oncology consensus statement

The Korean Society of Gynecologic Oncology (KSGO) had been making an effort to standardize and enhance the quality of domestic uterine corpus cancer treatment by developing updated clinical practice guidelines in 2021. The KSGO revised the guidelines based on a literature search using 4 key elements: Population, Intervention, Comparison, and Outcome framework. These elements include the evaluation of the efficacy and safety of immune checkpoint inhibitor treatment in recurrent/advanced endometrial cancer patients who have failed platinum-based chemotherapy, as well as the effect of combined treatment with trastuzumab in patients with HER2/neu-positive endometrial cancer. Additionally, the guideline assessed the efficacy and safety of omitting lymph node dissection in low-risk endometrial cancer patients, investigated the effect of sentinel lymph node mapping in early-stage endometrial cancer surgery, addressed the outcome of chemoradiation therapy as a postoperative treatment in patients with advanced (stage III-IVA) endometrial cancer, and explored the impact of initial treatment with immune checkpoint inhibitors on survival in patients with advanced or recurrent endometrial cancer patients.

Initial experience with the da Vinci SP robot-assisted surgical staging of endometrial cancer: a retrospective comparison with conventional laparotomy

To compare the perioperative outcomes of surgical staging performed using conventional laparotomy (LT) or the da Vinci SP robotic system (SP) in patients with endometrial cancer. We retrospectively analyzed 180 patients with stage I-III endometrial cancer who underwent surgical staging using LT (n = 126) or SP (n = 54) at the Yonsei Cancer Center between November 2018 and December 2022. Propensity score matching (PSM) was performed to mitigate potential confounding biases. Fifty-one pairs of patients were matched by PSM. SP required longer total operation time than LT (221 vs. 142 min in SP vs. LT, respectively, p < 0.001). However, estimated blood loss and postoperative hemoglobin change were lower in SP than in LT (30 vs. 100 mL, p < 0.001; 0.6 vs. 1.6 g/dL, p < 0.001 for SP vs. LT respectively). Furthermore, postoperative minor complications (13.7% in SP vs. 33.3% in LT, p = 0.02), perioperative transfusion rate (0% in SP vs. 11.8% in LT, p = 0.03), and postoperative hospital stay (2 days for SP vs. 8 days for LT, p < 0.001) were lower in SP than in LT. Although the patient-controlled analgesia administration rate was lower in SP (13.8% in SP vs. 100% in LT, p < 0.001), the median postoperative pain score at 6, 12, and 24 h after surgery was lower in SP than in LT (2 vs. 3, p = 0.002; 2 vs. 3, p = 0.005; 2 vs. 3, p = 0.001 for SP vs. LT, respectively). Although SP required longer total operation time, it demonstrated several advantages over LT in endometrial cancer staging.

Genomic Profiling in Patients with Endometrial Cancer by Deep Sequencing of Vaginal Swabs and Plasma

Abstract Purpose: Endometrial cancer is a common gynecologic malignancy that lacks effective noninvasive screening tools as traditional approaches rely on invasive biopsies. In this large prospective study, we evaluated a novel approach combining vaginal swab DNA and plasma-based ctDNA for genomic profiling to provide a comprehensive framework for diagnosis, prognosis, and disease monitoring. Experimental Design: Adult patients with diverse stages of endometrial cancer, preneoplastic disease, and benign endometrial conditions were prospectively recruited over 2 years. Paired vaginal swab DNA and plasma-based ctDNA were collected preoperatively, and additional plasma samples were obtained at multiple time points postoperatively. Deep next-generation sequencing targeting 101 genes was performed, achieving an average depth exceeding 40,000×. Results: A total of 191 patients contributed 388 samples. Vaginal swab DNA demonstrated 77.7% sensitivity and 96.6% specificity. PTEN mutations were associated with favorable prognosis (HR: 0.27; 95% confidence interval, 0.092–0.77), and TP53 mutations were associated with poor prognosis (HR: 3.7; 95% confidence interval, 1.4–10). A novel classification system based on the mutational profile of PTEN/TP53 identified distinct prognostic groups. Plasma-based ctDNA was significantly associated with stage, lymphovascular invasion, and prognosis (P &amp;lt; 0.01 for all). Patients with preoperative positive plasma-based ctDNA results exhibited poorer outcomes (P &amp;lt; 0.01), whereas postoperative positive ctDNA results enabled early detection of recurrence. Conclusions: These two noninvasive methods play distinct, complementary roles in the management of endometrial cancer. Vaginal swab DNA and novel PTEN/TP53-based classification have distinct prognostic advantages over existing frameworks. Plasma-based ctDNA provides dynamic insights into recurrence risk and disease progression.

Clinical practice guidelines for uterine corpus cancer: an update to the Korean Society of Gynecologic Oncology guidelines

The Korean Society of Gynecologic Oncology has updated its clinical practice guidelines for endometrial cancer to incorporate advancements in recent high-quality randomized controlled trials. These guidelines address evolving treatment paradigms, and are tailored to the Korean medical context. Key updates include a strong recommendation for doxorubicin/trabectedin combination therapy in metastatic or recurrent unresectable leiomyosarcoma based on the significant survival benefits demonstrated in a randomized controlled trial. For advanced or recurrent endometrial cancer, immune checkpoint inhibitors combined with chemotherapy have received strong recommendations, owing to their proven efficacy and increased accessibility in Korea. Conditional recommendations were made for combination therapies involving durvalumab and olaparib, reflecting their potential benefits, but acknowledging regulatory and accessibility constraints. These guidelines aim to provide evidence-based, practical strategies to optimize care for patients with endometrial cancer while addressing unmet clinical needs and adapting global advancements to Korea's healthcare environment.

A phase II study of induction PD-1 blockade (nivolumab) in patients with surgically completely resectable mismatch repair deficient endometrial cancer (NIVEC)

Mismatch repair deficient (MMRd) tumors are known to be highly immunogenic and of great interest for immune checkpoint inhibitor. However, there is no data about the complete response (CR) rate of programmed cell death protein 1 (PD-1) blockade and surgery in subjects with MMRd surgically resectable endometrial cancer. In this regard, we suggest a window of opportunity study of induction PD-1 blockade (nivolumab) in patients with surgically resectable MMRd endometrial cancer. This is a multicenter, single-arm phase II trial. A total of 30 surgically resectable MMRd endometrial cancer patients will be enrolled. Inclusion criteria include clinical stage I-IIIC2, tumor specimen that demonstrates MMRd by immunohistochemistry or microsatellite instability. Exclusion criteria include multiple primary cancers, residual adverse effects of prior therapy or effects of surgery. Patients are treated with nivolumab 480 mg intravenously every 4 weeks up to 6 months followed by standard surgery and/or adjuvant treatment. The primary endpoint of the study is clinical CR rate or pathological CR rate after treatment of nivolumab. Secondary endpoints include objective response rate, progression-free survival, overall survival, and adverse events. Correlative studies include genomic characterization of tumors, assessment of immune infiltration of tumor microenvironment, and serial circulating cell-free DNA and immune biomarkers. ClinicalTrials.gov Identifier: NCT05795244.

Comparison of oncological outcomes between sentinel lymph node biopsy and complete lymphadenectomy for endometrial cancer

AbstractAimSentinel lymph node (SLN) mapping allows node‐negative patients to be spared from the surgical comorbidities associated with total lymphadenectomy. This study aimed to evaluate the oncological outcomes of SLN biopsy versus complete lymph node dissection in patients with early‐stage endometrial carcinoma.MethodsRetrospective analyses were performed in patients with pathologically confirmed endometrioid endometrial carcinoma, who underwent minimally invasive surgical staging with SLN biopsy or complete lymph node dissection at Yonsei Cancer Center between 2015 and 2019.ResultsA total of 301 patients were included in this study. Eighty‐two patients underwent SLN biopsy, while 219 underwent complete lymph node dissection. There were no significant differences in patient characteristics between the two groups. In terms of operative characteristics, the SLN biopsy‐only group had a significantly shorter surgical duration (p &lt; 0.001) than the lymphadenectomy group. The mean follow‐up period was 41.4 months. There were no differences in progression‐free survival (PFS) and overall survival (OS) between the two groups (SLN biopsy vs. complete lymph node dissection; p = 0.798 and 0.301, respectively). Multivariate analysis revealed that SLN biopsy was not an independent prognostic factor for PFS or OS.ConclusionOur results showed that SLN biopsy provided oncological outcomes similar to those of lymphadenectomy.

Investigation of PARP Inhibitor Resistance Based on Serially Collected Circulating Tumor DNA in Patients With BRCA -Mutated Ovarian Cancer

Abstract Purpose: Patient-specific molecular alterations leading to PARP inhibitor (PARPi) resistance are relatively unexplored. In this study, we analyzed serially collected circulating tumor DNA (ctDNA) from patients with BRCA1/2 mutations who received PARPis to investigate the resistance mechanisms and their significance in postprogression treatment response and survival. Experimental Design: Patients were prospectively enrolled between January 2018 and December 2021 (NCT05458973). Whole-blood samples were obtained before PARPi administration and serially every 3 months until progression. ctDNA was extracted from the samples and sequenced with a 531-gene panel; gene sets for each resistance mechanism were curated. Results: Fifty-four patients were included in this analysis. Mutation profiles of genes in pre-PARPi samples indicating a high tumor mutational burden and alterations in genes associated with replication fork stabilization and drug efflux were associated with poor progression-free survival on PARPis. BRCA hypomorphism and reversion were found in 1 and 3 patients, respectively. Among 29 patients with matched samples, mutational heterogeneity increased postprogression on PARPis, showing at least one postspecific mutation in 89.7% of the patients. These mutations indicate non-exclusive acquired resistance mechanisms—homologous recombination repair restoration (28%), replication fork stability (34%), upregulated survival pathway (41%), target loss (10%), and drug efflux (3%). We observed poor progression-free survival with subsequent chemotherapy in patients with homologous recombination repair restoration (P = 0.003) and those with the simultaneous involvement of two or more resistance mechanisms (P = 0.040). Conclusions: Analysis of serial ctDNAs highlighted multiple acquired resistance mechanisms, providing valuable insights for improving postprogression treatment and survival.

Role of diagnostic laparoscopy in deciding primary treatment in advanced-stage ovarian cancer

We evaluated the usefulness of preoperative diagnostic laparoscopy for treatment planning in patients with advanced-stage ovarian cancer. We retrospectively analyzed 614 patients diagnosed with advanced-stage ovarian cancer between January 2010 and May 2018. Primary debulking surgery (PDS) or neoadjuvant chemotherapy (NAC) followed by interval debulking surgery were selected based on preoperative laparoscopic (Group 1, n=192) and computed tomography findings (Group 2, n=422). The primary outcomes in the PDS and NAC groups were suboptimal cytoreduction (residual disease >1 cm) rate and non-high-grade serous carcinoma (non-HGSC) rate, respectively. The patients who underwent PDS in group 1 and group 2 were 49 (25.5%) and 279 (66.1%), respectively. The suboptimal cytoreduction rate after PDS was lower in Group 1 than in Group 2 (2.0% vs 11.1%, p=0.023). Moreover, Group 1 showed a tendency toward a lower proportion of non-HGSC patients who underwent NAC than that in Group 2 (9.1% vs. 15.4%, p=0.069). Further, Group 1 showed lower rates of postoperative morbidity than Group 2 (5.2% vs. 10.4%, p=0.033). However, Kaplan-Meier analysis showed no significant differences in survival outcomes between the 2 groups. Diagnostic laparoscopy reduced the suboptimal cytoreduction rate in the PDS group and the implementation rate of NAC in non-HGSC patients. Moreover, it reduced postoperative morbidity without affecting survival in both groups. Thus, diagnostic laparoscopy is a valuable diagnostic tool for determining the primary treatment.

Impact of subcutaneous negative pressure drains on surgical wound healing in ovarian cancer

Subcutaneous negative pressure wound drains have been used to reduce wound complication rates in various surgical procedures. However, research on the benefits of subcutaneous drains on wound healing after ovarian cancer surgery is limited. The aim of this study was to assess the effects of subcutaneous negative pressure drains on wound healing after abdominal surgery for ovarian cancer. Patients who underwent surgery with a midline incision for ovarian cancer between February 2015 and May 2019 were retrospectively examined. Patients were divided into two groups according to the presence (group 1; n=99) or absence (group 2; n=213) of subcutaneous wound drains. The primary endpoint was the incidence of wound complications within 8 weeks after abdominal surgery. The secondary endpoints were time interval from surgery to adjuvant chemotherapy and survival. Patients in group 1 were older (mean 58.5 vs 55.4 years; p=0.02), and had higher rates of previous abdominal surgery (66.7% vs 47.9%; p=0.002), bowel surgery (47.5% vs 34.3%; p=0.026), and had a high surgical complexity score (53.5% vs 33.8%; p<0.001) compared with patients in group 2. Median body mass index was not different between the two groups: group 1, 22.9 kg/m The prophylactic use of subcutaneous negative pressure drains after abdominal surgery for ovarian cancer significantly reduced the incidence of wound complications in this study.

Comparison between weekly versus 3-weekly paclitaxel in combination with carboplatin as neoadjuvant chemotherapy in advanced ovarian cancer

To compare the efficacy and toxicity of dose-dense weekly paclitaxel and 3-weekly carboplatin (ddPC) as neoadjuvant chemotherapy (NAC) with the standard 3-weekly regimen. A retrospective study of patients diagnosed with stage IIIc and IV ovarian cancer who received at least one cycle of NAC followed by interval debulking surgery between August 2015 and January 2018 was conducted. Patient characteristics, clinical and pathological response to NAC, surgical and survival outcome, and adverse event were compared. A total of 23 patients in the ddPC group and 50 patients in the standard group received a median of 3 cycles of NAC. Rate of grade ≥3 neutropenia was significantly higher in the ddPC group than the standard (82.6% vs. 22.0%, p<0.001). Patients in the ddPC group underwent dose-reduction more frequently (34.8% vs. 4.00%, p=0.001). Normalization of cancer antigen-125 post-NAC occurred more frequently in the ddPC group (73.9% vs. 46.0%, p=0.030). No residual disease rate (43.5% vs. 60.0%, p=0.188) and chemotherapy response score of 3 (34.8% vs. 26.0%, p=0.441) were not statistically different between two groups. There was no statistical difference in progression free survival (PFS) at 2 years (36.3% vs. 28.4%, p=0.454). Cox proportional hazard model showed that ddPC was not a significant determinant of PFS (p=0.816). There was no difference between both regimens in terms of NAC response and survival outcomes. However, ddPC group showed higher hematologic toxicity requiring dose reduction.

A single-arm phase II study of olaparib maintenance with pembrolizumab and bevacizumab in BRCA non-mutated patients with platinum-sensitive recurrent ovarian cancer (OPEB-01)

The optimal treatment of ClinicalTrials.gov Identifier: NCT04361370, Clinical Research Information Service Identifier: KCT0005144.

Study of Induction PD-1 Blockade (Nivolumab) in Patients With Surgically Complete Resectable Mismatch Repair Deficient Endometrial Cancer (NIVEC)

phase 2 clinical trial to confirm the pathological complete response rate of PD-1 blocker use in patients with Mismatch Repair Deficiency(MMRd) endometrial cancer that can be completely resected surgically.

Olaparib Maintenance With Pembrolizumab & Bevacizumab in BRCA Non-mutated Patients With Platinum-sensitive Recurrent Ovarian Cancer

This study is phase II, open label, clinical trial to determine the efficacy of Olaparib maintenance with Bevacizumab and Pembrolizumab by assessment progression-free survival(6 months PFS rate) in BRCA non-mutated patients with platinum-sensitive recurrent ovarian cancer.

Circulating Tumor DNA and BRCA Reversion Mutation in Advanced or Recurrent Ovarian Cancer Patients With Germline Mutation.

Increasing number of ovarian cancer patients are receiving PARP inhibitor as maintenance or salvage therapy. Predictive factors to PARP inhibitor other than BRCA mutation or HRD status as well as specific resistance mechanism are unknown. Thus, the objective of this study was to prospectively collect serial blood samples in ovarian cancer patients with germline BRCA mutation who receive PARP inhibitor. We investigated circulating tumor DNA (ctDNA) before patients are started on PARP inhibitor and every 3 months thereafter until progression on PARP inhibitor. Through assessment of the changes in ctDNA mutational landscape, we aimed to investigate resistance mechanism to PARP inhibitor including BRCA reversion mutation.