Surgery versus no surgery in platinum-sensitive relapsed ovarian cancer: final overall survival analysis of the SOC-1 randomized phase 3 trial.

Surgery for platinum-sensitive, relapsed ovarian cancer (PSROC) is widely practiced but had contradictory survival outcomes in previous studies. In this multicenter, open-label, phase 3 trial, women with PSROC, and having had one previous therapy and no platinum-based chemotherapy (platinum-free interval) of 6 months or more, were randomly assigned to either the surgery group (182 patients) or the no-surgery group (control) (175 patients). Patients with resectable diseases were eligible according to the international model (iMODEL), combined with a positron emission tomography-computed tomography imaging. Overall survival (OS) and progression-free survival were coprimary endpoints in hierarchical testing, and a significantly longer progression-free survival with surgery was previously reported. Final analysis of OS was planned at data maturity of 59%. Between 19 July 2012 and 3 June 2019, 357 patients were enrolled. Median follow-up was 82.5 months. Median OS was 58.1 months with surgery and 52.1 months for control (hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.61-1.05, P = 0.11). The predefined threshold for statistical significance was not met, but prespecified sensitivity analysis was performed. Overall, 61 of 175 (35%) patients in control had crossed over to surgery following subsequent relapse, and adjusted HR for death in the surgery group compared with control was 0.76, 95% CI 0.58-0.99. In subgroup analysis of relapse sites by imaging, median survival was not estimable in the surgery group and was 69.5 months in control in patients with <20 sites (HR 0.69, 95% CI 0.46-1.03). Patients with a complete resection had the most favorable outcome, with a median OS of 73.0 months. Twenty-four of 182 (13.2%) patients remained relapse free and alive >60 months in the surgery group as compared with five of 175 (2.9%) patients in the control group. In patients with PSROC, surgery did not increase OS in the intention-to-treat population but resulted in a prolongation of survival following adjustment of crossover.ClinicalTrials.gov registration: NCT01611766 .

Phosphorylation of FOXK2 at Thr13 and Ser30 by PDK2 sustains glycolysis through a positive feedback manner in ovarian cancer.

Ovarian cancer is one of the most common gynecological malignant tumors with insidious onset, strong invasiveness, and poor prognosis. Metabolic alteration, particularly aerobic glycolysis, which is tightly regulated by transcription factors, is associated with the malignant behavior of OC. We screened FOXK2 in this study as a key transcription factor that regulates glycolysis in OC. FOXK2 is overly expressed in OC, and poor prognosis is predicted by overexpression. FOXK2 promotes OC cell proliferation both in vitro and in vivo and cell migration in vitro. Further studies showed that PDK2 directly binds to the forkhead-associated (FHA) domain of FOXK2 to phosphorylate FOXK2 at Thr13 and Ser30, thereby enhancing the transcriptional activity of FOXK2. FOXK2 transcriptionally regulates the expression of PDK2, thus forming positive feedback to sustain glycolysis in OC cells.

Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation.

Hyperthermic intraperitoneal chemotherapy's role in ovarian cancer remains controversial, hindered by limited understanding of hyperthermia-induced tumor cellular changes. This limits developing potent combinatory strategies anchored in hyperthermic intraperitoneal therapy (HIPET). Here, we perform a comprehensive multi-omics study on ovarian cancer cells under hyperthermia, unveiling a distinct molecular panorama, primarily characterized by rapid protein phosphorylation changes. Based on the phospho-signature, we pinpoint CDK1 kinase is hyperactivated during hyperthermia, influencing the global signaling landscape. We observe dynamic, reversible CDK1 activity, causing replication arrest and early mitotic entry post-hyperthermia. Subsequent drug screening shows WEE1 inhibition synergistically destroys cancer cells with hyperthermia. An in-house developed miniaturized device confirms hyperthermia and WEE1 inhibitor combination significantly reduces tumors in vivo. These findings offer additional insights into HIPET, detailing molecular mechanisms of hyperthermia and identifying precise drug combinations for targeted treatment. This research propels the concept of precise hyperthermic intraperitoneal therapy, highlighting its potential against ovarian cancer.

Prediction of recurrence-related factors for patients with early-stage cervical cancer following radical hysterectomy and adjuvant radiotherapy.

OBJECTIVE: To analyze recurrent factors in patients with clinical early-stage cervical cancer (ESCC) following hysterectomy and adjuvant radiotherapy. METHODS: We collected data from patients with ESCC, staged according to the 2009 Federation International of Gynecology and Obstetrics (FIGO) staging criteria, who underwent hysterectomy followed by adjuvant radiotherapy between 2012 and 2019. These patients were subsequently restaged using the 2018 FIGO criteria. Univariable and multivariable analyses, along with nomogram analyses, were conducted to explore factors associated with recurrence-free survival (RFS). RESULTS: A total of 310 patients met the inclusion criteria, with a median follow-up time of 46 months. Among them, 126 patients with ESCC were restaged to stage III C1 or III C2 after surgery due to lymph node metastasis (LNM) based on the 2018 FIGO staging criteria. Of these, 60 (19.3%) experienced relapse. The 1-, 3-, and 5-year RFS rates were 93.9%, 82.7%, and 79.3%, respectively. Multivariate analysis revealed that the number of positive lymph nodes (LNs), tumor diameter (TD) > 4 cm, and parametrial invasion (PI) were associated with recurrence. The nomogram indicated their predictive value for 3-year and 5-year RFS. Notably, the 5-year recurrence rate (RR) increased by 30.2% in patients with LNM, particularly those with ≥ 3 positive LNs (45.5%). Patients with stage III C2 exhibited a significantly higher RR than those with IIIC1 (56.5% vs. 24.3%, p < 0.001). The 5-year RFS for patients with TD > 4 cm was 65.8%, significantly lower than for those with TD ≤ 4 cm (88.2%). Subgroup analysis revealed higher 5-year RRs in patients with stage III C2 than that in patients with III-C1 (56.5% vs. 24.3%, p < 0.001), demonstrating a significant difference in the RFS survival curve. CONCLUSION: RR in patients with clinical ESCC after hysterectomy followed by adjuvant radiotherapy is correlated with the number of positive LNs, TD > 4 cm, and PI. Emphasis should be placed on the common high-risk factor of LNM association with recurrence after radical hysterectomy in ESCC.

Therapeutic targeting of CPSF3-dependent transcriptional termination in ovarian cancer.

Transcriptional dysregulation is a recurring pathogenic hallmark and an emerging therapeutic vulnerability in ovarian cancer. Here, we demonstrated that ovarian cancer exhibited a unique dependency on the regulatory machinery of transcriptional termination, particularly, cleavage and polyadenylation specificity factor (CPSF) complex. Genetic abrogation of multiple CPSF subunits substantially hampered neoplastic cell viability, and we presented evidence that their indispensable roles converged on the endonuclease CPSF3. Mechanistically, CPSF perturbation resulted in lengthened 3'-untranslated regions, diminished intronic polyadenylation and widespread transcriptional readthrough, and consequently suppressed oncogenic pathways. Furthermore, we reported the development of specific CPSF3 inhibitors building upon the benzoxaborole scaffold, which exerted potent antitumor activity. Notably, CPSF3 blockade effectively exacerbated genomic instability by down-regulating DNA damage repair genes and thus acted in synergy with poly(adenosine 5'-diphosphate-ribose) polymerase inhibition. These findings establish CPSF3-dependent transcriptional termination as an exploitable driving mechanism of ovarian cancer and provide a promising class of boron-containing compounds for targeting transcription-addicted human malignancies.

ZFP57 promotes ovarian cancer progression by transcriptionally regulating BRCA1 and managing G1 checkpoint.

Ovarian cancer (OC) which is one of the frequently-occurring gynecologic malignant tumors, endangers the health of women. The zinc finger protein 57 (ZFP57) plays crucial functions during the progression of cancer and is reported as a prognostic and therapeutic candidate in a variety of cancer. However, the biological function as well as the underlying mechanism of ZFP57 during OC progression remains unknown. Here, ZFP57 expression was found prominently increased in OC tissues and correlated with the prognosis of OC patients. Knock down of ZFP57 in OC cells inhibited the cell proliferation and migration, and also arrested the cells at G1 phase as well as accelerated the apoptosis. Additionally, ZFP57 transcriptionally regulated BRCA1 expression in OC, indicating that ZFP57 may affect BRCA1 mediated G1 checkpoint to regulate the cell cycle of OC cells and further influence the progression of OC. Taken together, our present study discovered a novel function of ZFP57 in OC, suggesting that ZFP57 could be potentially treated as a prognostic biomarker and therapeutic target for OC patients.

Minimally invasive injection of biomimetic Nano@Microgel for in situ ovarian cancer treatment through enhanced photodynamic reactions and photothermal combined therapy.

Photodynamic therapy (PDT) induces immunogenic cell death (ICD) by producing reactive oxygen species (ROS), making it an ideal method for cancer treatment. However, the extremely lower level of oxygen, short half-life of produced ROS, and limited photosensitizers accumulating in the tumor site via intravenous administration are the main reasons that limit the further application of PDT. To address these issues, we loaded the photosensitizer porphine (THPP) into biomimetic gold nanorod-mesoporous silica core-shell nanoparticles (Au-MSN NPs) to prepare Au@MSN/THPP@CM NPs. We then seeded the NPs together with catalase (CAT) into a gelatin methacryloyl (GelMA) microgel matrix to form Au@MSN-Ter/THPP@CM@GelMA/CAT microspheres consisting of biomimetic nano@microgel. The NPs and biomimetic nano@microgel exhibited enhanced photodynamic (PD) reaction and excellent photothermal conversion ability. Moreover, we further conjugated an endoplasmic reticulum (ER) targeting ligand Tosyl Ethylenediamine (Ter) on the surface of Au-MSN NPs. The results showed that both Au@MSN-Ter/THPP@CM NPs and the finally formed Au@MSN-Ter/THPP@CM@GelMA/CAT biomimetic nano@microgel induced precise and prolonged ER stress through photodynamic reactions, which stimulated the exposure of the proapoptotic calreticulin (CRT) on the cell membrane and increased the release of high mobility group box 1 (HMGB1) form the nucleus in SKOV3 cells under near-infrared (NIR) laser irradiation. Additionally, a single dose of the nano@microgel delivered through minimally invasive injection generated a significant anti-tumor effect in the SKOV3 cell line-derived orthotopic ovarian cancer mouse model through a PD and PT combination therapy. This study offers a new strategy for enhanced PDT and provides a PD/PT synergistic treatment method for ovarian cancer.

Comparison of contrast-enhanced ultrasound, IOTA simple rules and O-RADS for assessing the malignant risk of sonographically appearing solid ovarian masses.

PURPOSE: To explore the diagnostic accuracy of ovarian solid tumors by 2D ultrasound and contrast-enhanced ultrasound (CEUS). MATERIALS AND METHODS: We retrospectively evaluated the CEUS characteristics of prospectively enrolled 16 benign and 19 malignant ovarian solid tumors. We performed International Ovarian Tumor Analysis (IOTA) simple rules and Ovarian-Adnexal Reporting and Data System (O-RADS) for all lesions, and evaluated their characteristics on CEUS. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of IOTA simple rules, O-RADS and CEUS in the diagnosis of ovarian solid malignancies were calculated. RESULTS: The combination of time to wash-in earlier than or equal to the myometrium, time to PI earlier than or equal to the myometrium and the intensity at peak were higher than or equal to myometrium with sensibility of 0.947, specificity of 0.938, and PPV of 0.947, NPV of 0.938 which were higher than IOTA simple rules and O-RADS. According to the definition of ovarian solid tumor, the diagnostic accuracy of O-RADS 3 and CEUS were both 100%, CEUS improved the accuracy of O-RADS 4 from 47.4% to 87.5%, the accuracy of solid smooth CS 4 in O-RADS 5 and CEUS were both 100%, CEUS improved the accuracy of solid irregular in O-RADS 5 from 70% to 87.5%. CONCLUSION: For ovarian solid tumors that are difficult to distinguish between benign and malignant, the introduction of CEUS on the basis of 2D classification criteria can significantly improve the diagnostic accuracy.

Promises and challenges of adoptive T-cell therapies for solid tumours.

Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas-cancer genomics, cancer immunology and cell-therapy manufacturing-that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours.

Secondary cytoreduction followed by chemotherapy versus chemotherapy alone in platinum-sensitive relapsed ovarian cancer (SOC-1): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: The benefits of secondary cytoreduction for platinum-sensitive relapsed ovarian cancer are still widely debated. We aimed to assess the efficacy of secondary cytoreduction plus chemotherapy versus chemotherapy alone in this patient population. METHODS: This multicentre, open-label, randomised, controlled, phase 3 trial (SOC-1), was done in four primarily academic centres in China (two in Shanghai, one in Hangzhou, and one in Guangzhou). Eligible patients were women aged 18 years and older with platinum-sensitive relapsed epithelial ovarian cancer with a platinum-free interval of at least 6 months after the end of first-line platinum-based chemotherapy and were predicted to have potentially resectable disease according to the international model (iMODEL) score and PET-CT imaging. iMODEL score was calculated using six variables: International Federation of Gynecology and Obstetrics stage, residual disease after primary surgery, platinum-free interval, Eastern Cooperative Oncology Group performance status, serum level of cancer antigen 125 at recurrence, and presence of ascites at recurrence. An iMODEL score of 4·7 or lower predicted a potentially complete resection. As per a protocol amendment, patients with an iMODEL score of more than 4·7 could only be included if the serum level of cancer antigen 125 was more than 105 U/mL, but the principal investigators assessed the disease to be resectable by PET-CT. Eligible participants were randomly assigned (1:1) via a permuted block design (block size of six) and stratified by study centre, iMODEL score, residual disease at primary surgery, and enrolment in the Shanghai Gynecologic Oncology Group SUNNY trial, to undergo secondary cytoreductive surgery followed by intravenous chemotherapy (six 3-weekly cycles of intravenous paclitaxel [175 mg/m2] or docetaxel [75 mg/m2] combined with intravenous carboplatin [area under the curve of 5 mg/mL per min]; surgery group) or intravenous chemotherapy alone (no surgery group). Primary endpoints were progression-free survival and overall survival, analysed in all participants randomly assigned to treatment, regardless of treatment received (intention-to-treat [ITT] population). Here, we report the final analysis of progression-free survival and the prespecified interim analysis of overall survival. Safety was assessed in all participants who received their assigned treatment and had available adverse event data. This study is registered with ClinicalTrials.gov, NCT01611766, and is ongoing but closed to accrual. FINDINGS: Between July 19, 2012, and June 3, 2019, 357 patients were recruited and randomly assigned to the surgery group (182) or the no surgery group (175; ITT population). Median follow-up was 36·0 months (IQR 18·1-58·3). In the no surgery group, 11 (6%) of 175 participants had secondary cytoreduction during second-line therapy while 48 (37%) of 130 participants who had disease progression crossed-over and had surgery at a subsequent recurrence. Median progression-free survival was 17·4 months (95% CI 15·0-19·8) in the surgery group and 11·9 months (10·0-13·8) in the no surgery group (hazard ratio [HR] 0·58; 95% CI 0·45-0·74; p<0·0001). At the interim overall survival analysis, median overall survival was 58·1 months (95% CI not estimable to not estimable) in the surgery group and 53·9 months (42·2-65·5) in the no surgery group (HR 0·82, 95% CI 0·57-1·19). In the safety population, nine (5%) of 172 patients in the surgery group had grade 3-4 surgical morbidity at 30 days, and no patients in either group had died at 60 days after receiving assigned treatment. The most common grade 3-4 adverse events during chemotherapy were neutropenia (29 [17%] of 166 patients in the surgery group vs 19 [12%] of 156 patients in the no surgery group), leucopenia (14 [8%] vs eight [5%]), and anaemia (ten [6%] vs nine [6%]). Four serious adverse events occurred, all in the surgery group. No treatment-related deaths occurred in either group. INTERPRETATION: Secondary cytoreduction followed by chemotherapy was associated with significantly longer progression-free survival than was chemotherapy alone in patients with platinum-sensitive relapsed ovarian cancer, and patients should be counselled about the option of secondary cytoreduction in specialised centres. Long-term survival outcomes will be assessed using mature data on overall survival. FUNDING: Zhongshan Development Program. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Amplified photocurrent signal for fabricating photoelectrochemical sulfadimethoxine aptasensor based on carbon nitride photosensitization with visible/near-infrared light responsive zinc phthalocyanine.

Developing effective analytical method for sulfadimethoxine (SDM) detection is highly desirable and vitally crucial for protecting environment safety and human health. Herein, a highly selective and sensitive photoelectrochemical (PEC) aptasensor for accurate detection of SDM was proposed, which employed zinc phthalocyanine/graphitic carbon nitride (ZnPc/CN) nanocomposite as photosensitive material. The ZnPc/CN nanocomposite was constructed by modification of CN nanosheet with visible/near-infrared light responsive photosensitizer ZnPc. The introduction of ZnPc into CN exhibited amplified PEC response, which was 5.7 and 18.3 times than pure ZnPc and CN, attributed to the enhanced light harvesting ability and improved photoelectric conversion efficiency of such nanocomposite. By using ZnPc/CN and sulfadimethoxine (SDM) aptamer as PEC response material and specific probe, a PEC aptasensor was established for SDM detection. The aptamer was connected to the surface of chitosan/ZnPc/CN/ITO through the formation of phosphoramidate bonds between the amino group of the chitosan and phosphate group of the aptamer at 5' end. The fabricated aptasensor displayed good detection linearity of 0.1 ~ 300 nM and low detection limit of 0.03 nM (S/N = 3) under optimized conditions, and the potential applicability of the PEC aptasensor was confirmed by detecting SDM in milk powder samples.

Functional genetic variants of CTNNBIP1 predict platinum treatment response of Chinese epithelial ovarian cancer patients.

Chemotherapy resistance remains a blockade for successful treatment and longer overall survival of patients with epithelial ovarian cancer (EOC). CTNNBIP1 is an inhibitor of ß-catenin that is a chemotherapeutic target for EOC treatment. In the present study, we investigated associations between single nucleotide polymorphisms (SNPs) of CTNNBIP1 and platinum treatment response of Han Chinese EOC patients and subsequently performed functional prediction and validation of the resultant SNPs. We found that CTNNBIP1 rs935072 AT/TT variant genotypes were associated with platinum treatment response in the multivariate logistic regression analysis of EOC patients. Specifically, the CTNNBIP1 rs935072 AT/TT genotypes were associated with a decreased risk of developing chemoresistance ([adjusted odds ratio (OR)] = 0.89, 95% confidence interval (CI) = 0.82-0.97 and P=0.010), compared with the AA genotype. Further experiments showed that the underlying mechanism for the CTNNBIP1 rs935072 A>T change in chemotherapy treatment response resulted from a lower binding affinity of miR-27a-3p, thereby leading to up-regulation of the CTNNBIP1 expression. We further found that overexpression of CTNNBIP1 sensitized ovarian cancer cells to platinum treatment. Thus, the present study provides evidence that functional variants of CTNNBIP1 may regulate the expression of CTNNBIP1, a possible mechanism affecting platinum treatment response of EOC patients.

Study of upfront surgery versus neoadjuvant chemotherapy followed by interval debulking surgery for patients with stage IIIC and IV ovarian cancer, SGOG SUNNY (SOC-2) trial concept.

BACKGROUND: Two randomized phase III trials (EORTC55971 and CHORUS) showed similar progression-free and overall survival in primary or interval debulking surgery in ovarian cancer, however both studies had limitations with lower rate of complete resection and lack of surgical qualifications for participating centers. There is no consensus on whether neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) could be a preferred approach in the management of advanced epithelial ovarian cancer (EOC) in the clinical practice. METHODS: The Asian SUNNY study is an open-label, multicenter, randomized controlled, phase III trial to compare the effect of primary debulking surgery (PDS) to NACT-IDS in stages IIIC and IV EOC, fallopian tube cancer (FTC) or primary peritoneal carcinoma (PPC). The hypothesis is that PDS enhances the survivorship when compared with NACT-IDS in advanced ovarian cancer. The primary objective is to clarify the role of PDS and NACT-IDS in the treatment of advanced ovarian cancer. Surgical quality assures include at least 50% of no gross residual (NGR) in PDS group in all centers and participating centers should be national cancer centers or designed ovarian cancer section or those with the experience participating surgical trials of ovarian cancer. Any participating center should be monitored evaluating the proportions of NGR by a training set. The aim of the surgery in both arms is maximal cytoreduction. Tumor burden of the disease is evaluated by diagnostic laparoscopy or positron emission tomography/computed tomography scan. Patients assigned to PDS group will undergo upfront maximal cytoreductive surgery within 3 weeks after biopsy, followed by 6 cycles of standard adjuvant chemotherapy. Patients assigned to NACT group will undergo 3 cycles of NACT-IDS, and subsequently 3 cycles of adjuvant chemotherapy. The maximal time interval between IDS and the initiation of adjuvant chemotherapy is 8 weeks. Major inclusion criteria are pathologic confirmed stage IIIC and IV EOC, FTC or PPC; ECOG performance status of 0 to 2; ASA score of 1 to 2. Major exclusion criteria are non-epithelial tumors as well as borderline tumors; low-grade carcinoma; mucinous ovarian cancer. The sample size is 456 subjects. Primary endpoint is overall survival. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02859038.

Potentially functional variants in nucleotide excision repair pathway genes predict platinum treatment response of Chinese ovarian cancer patients.

Acquired platinum resistance impedes successful treatment of epithelial ovarian cancer (EOC), and this resistance may be associated with inherited DNA damage-repair response. In the present study, we performed a two-phase analysis to assess associations between 8191 single-nucleotide polymorphisms within 127 genes of nucleotide excision repair pathway from a genome-wide association study dataset and platinum treatment response in 803 Han Chinese EOC patients. As a result, we identified that platinum-based chemotherapeutic response was associated with two potentially functional variants MNAT1 rs2284704 T>C [TC + CC versus TT, adjusted odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.83-0.95 and P = 0.0005] and HUS1B rs61748571 A>G (AG + GG versus AA, OR = 1.10, 95% CI = 1.03-1.18 and P = 0.005). Compared with the prediction model for clinical factors only, models incorporating HUS1B rs61748571 [area under the curve (AUC) 0.652 versus 0.672, P = 0.026] and the number of unfavorable genotypes (AUC 0.652 versus 0.668, P = 0.040) demonstrated a significant increase in the AUC. Further expression quantitative trait loci analysis suggested that MNAT1 rs2284704 T>C significantly influenced mRNA expression levels of MNAT1 (P = 0.003). These results indicated that MNAT1 rs2284704 T>C and HUS1B rs61748571 A>G may serve as potential biomarkers for predicting platinum treatment response of Chinese EOC patients, once validated by further functional studies.

A phase II trial of cytoreductive surgery combined with niraparib maintenance in platinum-sensitive, secondary recurrent ovarian cancer: SGOG SOC-3 study.

BACKGROUND: In China, secondary cytoreductive surgery (SCR) has been widely used in ovarian cancer (OC) over the past two decades. Although Gynecologic Oncology Group-0213 trial did not show its overall survival benefit in first relapsed patients, the questions on patient selection and effect of subsequent targeting therapy are still open. The preliminary data from our pre-SOC1 phase II study showed that selected patients with second relapse who never received SCR at recurrence may still benefit from surgery. Moreover, poly(ADP-ribose) polymerase inhibitors (PARPi) maintenance now has been a standard care for platinum sensitive relapsed OC. To our knowledge, no published or ongoing trial is trying to answer the question if patient can benefit from a potentially complete resection combined with PARPi maintenance in OC patients with secondary recurrence. METHODS: SOC-3 is a multi-center, open, randomized, controlled, phase II trial of SCR followed by chemotherapy and niraparib maintenance vs chemotherapy and niraparib maintenance in patients with platinum-sensitive second relapsed OC who never received SCR at recurrence. To guarantee surgical quality, if the sites had no experience of participating in any OC-related surgical trials, the number of recurrent lesions evaluated by central-reviewed positron emission tomography-computed tomography image shouldn't be more than 3. Eligible patients are randomly assigned in a 1:1 ratio to receive either SCR followed by 6 cycles of platinum-based chemotherapy and niraparib maintenance or 6 cycles of platinum-based chemotherapy and niraparib maintenance alone. Patients who undergo at least 4 cycles of chemotherapy and must be, in the opinion of the investigator, without disease progression, will be assigned niraparib maintenance. Major inclusion criteria are secondary relapsed OC with a platinum-free interval of no less than 6 months and a possibly complete resection. Major exclusion criteria are borderline tumors and non-epithelial ovarian malignancies, received debulking surgery at recurrence and impossible to complete resection. The sample size is 96 patients. Primary endpoint is 12-month non-progression rate. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03983226.

The Repertoire of Serous Ovarian Cancer Non-genetic Heterogeneity Revealed by Single-Cell Sequencing of Normal Fallopian Tube Epithelial Cells.

The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH in serous ovarian cancer (SOC) can be accurately measured when informed by the molecular signatures of the normal fallopian tube epithelium (FTE) cells, the cells of origin of SOC. Surveying the transcriptomes of ∼6,000 FTE cells, predominantly from non-ovarian cancer patients, identified 6 FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH. Importantly, NGH-based stratification of ∼1,700 tumors robustly correlated with survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC.