Sunghoon Kim

Neoadjuvant Chemotherapy with Dual Immune Checkpoint Inhibitors for Advanced-Stage Ovarian Cancer: Final Analysis of TRU-D Phase II Nonrandomized Clinical Trial

Abstract Purpose: This open-label, investigator-initiated, phase II study was conducted to evaluate the safety, survival, and neoadjuvant outcomes of neoadjuvant chemotherapy (NAC) combined with dual immune checkpoint inhibitors in advanced-stage epithelial ovarian cancer (EOC). Patients and Methods: Between June 2019 and July 2021, 45 patients with unresectable stage III to IV EOC were enrolled. The patients received three cycles of NAC combined with durvalumab and tremelimumab. All patients underwent interval debulking surgery and received three cycles of durvalumab and adjuvant chemotherapy, followed by 12 cycles of durvalumab as maintenance therapy. The primary endpoint was the 12-month progression-free survival (PFS) rate; the secondary endpoints were the objective response rate after NAC, a chemotherapy response score, pathologic complete response, overall survival, and safety. The preplanned exploratory analyses assessed the lymphocyte infiltration, PD-L1 expression, and genomic profiles of pretreatment tumors. Results: The 12-month PFS rate was 65.9% [95% confidence interval (CI), 52.8–not estimated (NE)], whereas the 24- and 30-month PFS rates were 38.6% (95% CI, 26.7–NE) and 36.4% (95% CI, 24.7–NE), respectively. After NAC, the objective response rate was 86.7%, whereas 14 patients (31.1%) had a chemotherapy response score of three, and five (11.1%) achieved pathologic complete response. The 30-month overall survival rate was 87.7%. The most common grade ≥3 adverse event was neutropenia (26.7%). In an exploratory analysis, patients with pre-NAC tumors showing PD-L1 (combined positive score) ≥1, high Mutation Signature 3, and a high extracellular matrix signature demonstrated improved PFS outcomes. Conclusions: NAC combined with dual immune checkpoint inhibitors is feasible for advanced-stage EOC and shows promising activity with a durable clinical response.

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.

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.

Modifying surgical extents in patients with preoperatively presumed early-stage endometrial cancer based on ProMisE classification: a retrospective, single-center study

This study aimed to explore differences in disease extent based on the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) classification and to establish personalized staging surgery strategies in patients with preoperatively presumed uterus-confined endometrial cancer. In this retrospective, single-center study, we reviewed the medical records of patients with endometrial cancer. These patients were classified according to the ProMisE classification based on tissue samples obtained from dilation and curettage or staging surgeries, and the disease extent was analyzed based on pathologic reports. A total of 345 patients were clinically estimated to be in stage 1/2 before staging surgery, with immunohistochemistry (IHC) results available. This cohort included 332 patients (96.2%) with clinical stage 1 and 13 patients (3.8%) with stage 2 based on the 2009 FIGO staging system. Among these, 81 patients (23.5%) were assigned to an mismatch repair deficient group (MMRd), 33 (9.6%) to an abnormal p53 group, and 123 (71.1%) to a no specific molecular profile (NSMP) group. Overall, 13 patients had nodal metastasis, with a higher rate observed in the abnormal p53 group (1.2%, 12.1%, and 2.2% for the MMRd, abnormal p53, and NSMP groups, respectively, p=0.013). One patient (0.3%) had parametrial metastasis and four (1.1%) had peritoneal metastasis. Patients with abnormal p53 IHC results exhibited a higher likelihood of lymph node metastasis, even when initially presumed to be at an early stage. For the abnormal p53 group, proactive lymphadenectomy surgery appears beneficial for accurate staging and establishing a subsequent treatment plan.

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.

Is presumed clinical stage I endometrial cancer using PET-CT and MRI accurate in predicting surgical staging?

To evaluate upstaging, lymph node (LN) metastasis, and recurrence in patients with presumed stage I endometrial cancer using preoperative magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT). Retrospective review of 422 patients with presumed clinical stage I endometrial cancer diagnosed via MRI and PET-CT (July 2014-June 2023). Surgical staging included pelvic lymph nodes (PLNs) and para-aortic lymph nodes (PALNs), classifying patients as low/intermediate- or high-risk groups. Post-operative upstaging rate was 14.5% (8.8% low/intermediate-risk vs. 22.8% high-risk, p2 cm on MRI (OR=2.9; 95% CI=0.8-9.9) increased LN metastasis risk. Median 48.5-month follow-up showed an 8.1% overall recurrence rate (4.0% low/intermediate-risk vs. 14.0% high-risk, p<0.001), with 2.4% nodal recurrences (1.2% low/intermediate-risk vs. 4.1% high-risk). High-risk patients had significant upstaging, LN metastasis, and recurrence rates. Even in low/intermediate-risk groups, some patients exhibited LN metastasis and nodal recurrence, underscoring the importance of comprehensive surgical staging, including PALN evaluation, for precise diagnosis and treatment.

Comparison of progression-free survival outcome of sentinel node biopsy without ultrastaging versus lymphadenectomy in endometrial cancer: a propensity-matched analysis

We aimed to investigate the oncologic outcomes of patients with endometrial cancer who underwent sentinel lymph node (SLN) biopsy without ultrastaging compared with that of those who underwent lymphadenectomy (LND). Patients with endometrial cancer who underwent staging with SLN biopsy or LND during 2006 - 2021 were analyzed using propensity score matching (PSM). SLN metastasis was examined using hematoxylin and eosin staining, without ultrastaging. Progression-free survival (PFS) was compared between the two groups before and after PSM using age, histology, and stage as covariates. Clinical variables such as recurrence patterns and lymphatic complications, were assessed. After excluding 213 patients who underwent validation LND with SLN biopsy, 902 were identified. The demographics of the remaining patients differed according to histology, myometrial invasion depth, and stage. Lymph node metastasis was less frequent in the SLN group than in the LND group (9.4% vs. 3.8%, p=0.004). The recurrence rates within 2 years were lower in the SLN group. The SLN group exhibited significantly superior 2-year and overall PFS than the LND group. Among patients with uterus-confined disease, overall PFS was favorable for SLN biopsy. After matching, differences in PFS were no longer observed, although the lymphocele and lymphedema rates were significantly lower in the SLN group. In patients with endometrial cancer, SLN biopsy without ultrastaging did not compromise survival outcomes and was associated with significantly reduced lymphatic complication rates compared with LND. Therefore, SLN biopsy can be recommended for patients with endometrial cancer without definitive preoperative evidence of distant metastasis.

Real world effectiveness and safety of pegylated liposomal doxorubicin in platinum-sensitive recurrent ovarian, fallopian, or primary peritoneal cancer: a Korean multicenter retrospective cohort study

To evaluate the effectiveness and safety of the combination of pegylated liposomal doxorubicin with carboplatin (CD) compared with those of carboplatin and paclitaxel (CP) for platinum-sensitive recurrent ovarian, fallopian, or primary peritoneal cancer in a real-world setting in Korea. We enrolled relevant patients from 9 institutions. All patients received CD or CP as the second- or third-line chemotherapy in routine clinical practice during 2013-2018. The primary endpoints were progression-free survival (PFS) and toxicity. The secondary endpoint included the objective response rate (ORR). Overall, 432 patients (224 and 208 in the CD and CP groups, respectively) were included. With a median follow-up of 18.9 months, the median PFS was not different between the groups (12.7 vs. 13.6 months; hazard ratio, 1.161; 95% confidence interval, 0.923-1.460; p=0.202). The ORR was 74.6% and 80.1% in the CD and CP group, respectively (p=0.556). Age and surgery at relapse were independent prognostic factors. More patients in the CD group significantly experienced a grade 3 to 4 hematologic toxicity and hand-foot syndrome (13.8% vs. 6.3%), whereas grade 2 or more alopecia (6.2% vs. 36.1%), peripheral neuropathy (4.4% vs. 11.4%), and allergic/hypersensitivity reaction (0.4% vs. 8.5%) developed more often in the CP group. The safety and effectiveness of chemotherapy with CD in a real-world setting were consistent with the results from a randomized controlled study. The different toxicity profiles between the 2 chemotherapy (CD and CP) regimens should be considered in the clinical practice. ClinicalTrials.gov Identifier: NCT03562533.

Application of precision medicine based on next-generation sequencing and immunohistochemistry in ovarian cancer: a real-world experience

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. 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. 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 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.

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.

A Single-Center, Retrospective Study of Bevacizumab-Containing Neoadjuvant Chemotherapy followed by Interval Debulking Surgery for Ovarian Cancer

We evaluated whether adding bevacizumab to current platinum-based chemotherapy could improve clinical outcomes without affecting safety. We retrospectively reviewed medical records of patients with pathologically confirmed ovarian cancer who received neoadjuvant chemotherapy (NAC) at Yonsei Cancer Hospital. We divided the patients into groups based on the use of bevacizumab for NAC (CP group: carboplatin+paclitaxel vs. BCP group: bevacizumab+carboplatin+paclitaxel) and compared patient characteristics, responses to NAC, and surgical and survival outcomes between the two groups. Overall, 88 patients in the CP group and 16 patients in the BCP group received NAC. The primary endpoint was survival outcomes. Complete resection rate after interval debulking surgery (IDS), cancer antigen 125 (CA-125) normalization after NAC, and chemotherapy response score were secondary endpoints. After NAC treatment, all patients underwent IDS. There were no significant differences in adverse events during NAC or postoperative complications between the two groups ( Bevacizumab-containing NAC might be safe and provide longer PFS than chemotherapy alone in patients with advanced ovarian cancer. However, further study is necessary to investigate the impact of bevacizumab-containing NAC on OS.

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.

Biomarker-guided targeted therapy in platinum-resistant ovarian cancer (AMBITION; KGOG 3045): a multicentre, open-label, five-arm, uncontrolled, umbrella trial

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. 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). 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. 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. ClinicalTrials.gov Identifier: NCT03699449.

Prognostic value of complete metabolic response on 18F-FDG-PET/CT after three cycles of neoadjuvant chemotherapy in advanced high-grade serous ovarian cancer

We investigated the prognostic value of complete metabolic response (CMR) on ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) after 3 cycles of neoadjuvant chemotherapy (NAC) in advanced high-grade serous ovarian cancer (HGSC). PET/CT at baseline and after 3 cycles of NAC were performed; peak standardized uptakes were measured. PET parameters were compared with NAC parameter: cancer antigen-125 (CA-125) normalization before interval debulking surgery (IDS) and chemotherapy response score (CRS) to predict platinum-sensitivity. Kaplan-Meier analysis was used to determine correlations between PET parameters and survival. Prognostic factors were obtained by multivariate Cox regression analysis. Between 2007 and 2020, 102 patients were recruited: 19 (18.6%) were designated as CMR group and 83 (81.4%) as non-CMR group. CMR after 3 cycles of NAC showed the highest accuracy in predicting platinum-sensitivity (area under the curve [AUC]=0.729; 95% confidence interval [CI]=0.552-0.823; p=0.017), compared with CA-125 normalization before IDS (AUC=0.626; 95% CI=0.542-0.758; p=0.010) and CRS (AUC=0.613; 95% CI=0.490-0.735; p=0.080). CMR demonstrated better prognosis than non-CMR in progression-free survival (PFS) (median PFS, 23.9 months vs. 16.4 months; p=0.021) and overall survival (OS) (median OS, not reached vs. 69.7 months; p=0.025). In multivariate analysis, CMR was associated with a lower risk of recurrence (adjusted hazard ratio [aHR]=0.50; 95% CI=0.27-0.92; p=0.027) and death (aHR=0.23; 95% CI=0.05-0.99; p=0.048). CMR after 3 cycles of NAC can be a prognostic factor for both recurrence and death in advanced HGSC.

MicroRNA216b mediated downregulation of HSP27/STAT3/AKT signaling is critically involved in lambertianic acid induced apoptosis in human cervical cancers

Since heat shock protein (HSP27) is a prognostic marker in cervical cancer, in the present study, the apoptotic mechanism of lambertianic acid (LA) was investigated in human cervical cancers in association with HSP27/STAT3/AKT signaling axis. LA exerted significant cytotoxicity, induced sub‐G1 population, and increased the cleavage of Poly (ADP‐ribose) polymerase (PARP) and cysteine aspartyl‐specific protease 3 (caspase3) in HeLa and Caski cancer cells. Consistently, LA downregulated anti‐apopotic genes such as B‐cell lymphoma 2 (Bcl‐2) and inhibitors of apoptosis proteins (c‐IAP) in HeLa and Caski cells. Furthermore, LA‐inhibited phosphorylation of HSP27, signal transducer, and activator of transcription 3 (STAT3) and Protein kinase B (AKT) through disturbing the binding of HSP27 with STAT3 or AKT in HeLa cells. Notably, LA upregulated the level of miR216b in HeLa and Caski cells. Consistently, miR216b mimic suppressed phosphorylation of HSP27 and reduced the expression of pro‐PARP, while miR216b inhibitor reversed the ability of LA to attenuate phosphorylation of AKT, HSP27, and STAT3 and to reduce the expression of pro‐PARP in HeLa cells. Overall, our findings suggest that miRNA216b mediated inhibition of HSP27/STAT3/ AKT signaling axis is critically involved in LA‐induced apoptosis in cervical cancers.

An uMbrella Study of BIomarker-driven Targeted Therapy In Patients With Platinum-resistant Recurrent OvariaN Cancer(AMBITION)

This study is a pilot study of biomarker-driven targeted therapy in patients with platinum-resistant recurrent ovarian cancer. More specifically, this is a randomized, multi-center, open label, phase II study for Homologous Recombination Deficiency(HRD)+ patients and a biomarker-driven multiple-arm phase II study for Homologous Recombination Deficiency(HRD)- patients. This study will consist of a number of study modules (substudies), each evaluating the antitumor activity of targeted agents in patients whose tumors express specific phenotype relevant to the molecules under investigation.

Real-World Effectiveness of PLD in Platinum- Sensitive Recurrent Ovarian Cancer

This retrospective multicenter study aimed to evaluate the effectiveness of pegylated liposomal doxorubicin (PLD) with carboplatin (CD) compared with carboplatin and paclitaxel (CP) in patients who had disease progression longer than 6 months after first-line platinum+taxane chemotherapy for ovarian cancer in real world clinical practice.

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.