High-grade Serous Histology Research Articles

Spectrum of Surgico-Pathological Factors and Lymph Node Metastasis among Epithelial Ovarian Cancers: Experience of a Single Tertiary Care Institution from India

Introduction Epithelial ovarian cancer (EOC) is one of the leading causes of mortality among women worldwide. The present study aimed to estimate the frequency of various histopathological types, clinical and surgico-pathological factors, and spectrum of lymph node (LN) metastasis in early and advanced EOC. Material and Methods Women with EOCs who underwent cytoreductive surgery (CRS) between January 2019 and May 2022 were included. The distribution of Clinico-demographic parameters, histological type, stage, and LN metastasis were analyzed. Results A total of 101 women with EOCs underwent CRS, out of which 5 (4.95%) with coexistent endometrial cancer were excluded (N = 96). Fifty women (52%) underwent primary CRS and 46 (48%) women underwent interval CRS. The mean age of the women was 48.42 ± 11.6 years. Initial serum cancer antigen 125 (CA 125) level was elevated (>35 U/mL) in 88 (91.67%) women and normal in 8 (8.33%) women. Complete cytoreduction was achieved in 75 (78.12%) cases. High-grade serous carcinoma was the most common histology (66/96, 68.75%), followed by mucinous carcinoma (15/96, 15.63%), endometrioid carcinoma (6/96, 6.25%), low-grade serous carcinoma (4/96, 4.17%), and carcinosarcoma (2/96, 2.08%). The majority of women, 69 (71.88%), were in stages III and IV at presentation. Most serous carcinomas were diagnosed at stage III (71.22%) or IV (13.64%). In contrast, the majority of endometrioid, mucinous, and clear cell carcinomas were diagnosed at stages I and II. Seventy-five women (78.13%) with EOC underwent pelvic and/or para-aortic lymphadenectomy, out of which 23 (30.67%) were histologically positive. Three out of 23 patients (13%) with early-stage disease showed positive LNs. Conclusion Serous carcinoma ovary is the most common histological subtype, presenting mostly in the advanced stage. A significant number of affected women were younger at presentation and diagnosis was made a decade earlier than the western population. A systematic pelvic and para-aortic lymphadenectomy in apparently early-stage (pelvic confined) ovarian cancer could detect additional LNs in 13% of women, especially in high-grade tumors and serous histology, suggesting the role of systematic lymphadenectomy for accurate staging in apparently early-stage ovarian cancer.

Factors associated with an inconclusive result from commercial homologous recombination deficiency testing in ovarian cancer.

Homologous recombination deficiency (HRD) testing is used to determine the appropriateness of poly ADP-ribose polymerase inhibitors for patients with epithelial ovarian cancer and no germline/somatic BRCA1/2 alterations. Myriad MyChoice CDx reports a genomic instability score (GIS) to quantify the level of HRD, with a positive score defined as ≥42. The authors sought to define factors associated with obtaining an inconclusive HRD test result. GIS was retrieved for patients at their institution with epithelial ovarian cancer without germline/somatic BRCA1/2 deleterious alterations who underwent HRD testing from April 2020-August 2023. Clinical data were abstracted from the medical record. Of 477 HRD test results identified, 57 (12%) were inconclusive. High-grade serous ovarian cancers had higher GIS than other histologic types (median 29 vs. 21, p<.001). Most HRD cases were of high-grade serous histology; no cases with clear cell or endometrioid histology were HRD-positive. On univariate analysis, interval versus primary cytoreductive surgery, other specimen sources versus surgical specimens, and chemotherapy exposure were risk factors for inconclusive HRD testing. On multivariable analysis, chemotherapy exposure, and tissue source were associated with an inconclusive test result, with surgical specimens more likely to yield a conclusive result than other sources (biopsy, cytology, other). Age, stage, self-reported race, and histology were not associated with an inconclusive result. Surgical tissue was more likely to yield a conclusive HRD test result versus other sources of epithelial ovarian cancer tissue acquisition. When feasible, laparoscopic biopsy before initiation of neoadjuvant chemotherapy may increase the likelihood of obtaining interpretable HRD test results.

Lymph node metastasis in grossly apparent early-stage epithelial ovarian cancer: A retrospective clinical study at a tertiary institute.

This study aimed to evaluate the incidence and predict the risk factors of lymph node (LN) metastasis among patients with grossly apparent early-stage epithelial ovarian cancer (EOC). We retrospectively reviewed the clinicopathologic data and follow-up information of 266 patients who underwent LN dissection for apparent early-stage EOC between January 2018 and September 2022 at the Obstetrics and Gynecology Hospital of Fudan University. Among 266 patients, 44 (16.5%) showed LN metastasis, of which 65.9% and 59.1% presented in the pelvic region and para-aortic region, respectively. Univariate analysis revealed higher LN positivity in patients with high-grade serous carcinoma (HGSC), preoperative imaging suggestive of LN metastasis, bilateral adnexal involvement, lymphovascular space invasion (LVSI), positive peritoneal cytology, and clinical stage IIA. LN metastases were identified in 7.9%, 10.2%, and 39.7% of clinical stage IA/B, IC, and IIA disease cases, respectively. Multivariate analysis confirmed significantly higher LN positivity rates in patients with HGSC, LVSI, and clinical stage IIA. In clinical stage IIA EOC, the 3-year progression-free survival (PFS) rates were 65.8% and 77.4% (P = 0.360) for LN-negative and LN-positive groups, respectively. In clinical stage I EOC, the 3-year PFS rates were 93.5% and 59.4% (P < 0.001) for LN-negative and LN-positive groups, respectively. High-grade serous histology, LVSI, and clinical stage IIA disease are predictive factors for LN involvement in early-stage EOC. In addition, LN metastasis appears to be associated with worse PFS in clinical stage I EOC compared with clinical stage IIA EOC.

Fertility-Sparing Surgery for Stage I Epithelial Ovarian Cancer.

To describe population-level utilization of fertility-sparing surgery and outcome of reproductive-aged patients with early epithelial ovarian cancer who underwent fertility-sparing surgery in the United States. This retrospective study queried the National Cancer Institute's Surveillance, Epidemiology, and End Result Program. The study included 3,027 patients younger than age 50 years with stage I epithelial ovarian cancer receiving primary surgical therapy from 2007 to 2020. Fertility-sparing surgery was defined as preservation of one ovary and the uterus for unilateral lesion and preservation of the uterus for bilateral lesions. Temporal trend of fertility-sparing surgery was assessed with linear segmented regression with log-transformation. Overall survival associated with fertility-sparing surgery was assessed with Cox proportional hazard regression model. A total of 534 patients (17.6%) underwent fertility-sparing surgery. At the cohort level, the utilization of fertility-sparing surgery was 13.4% in 2007 and 21.8% in 2020 (P for trend=.009). Non-Hispanic White individuals (2.8-fold), those with high-grade serous histology (2.2-fold), and individuals with stage IC disease (2.3-fold) had a more than twofold increase in fertility-sparing surgery utilization during the study period (all P for trend<.05). After controlling for the measured clinicopathologic characteristics, patients who received fertility-sparing surgery had overall survival comparable with that of patients who had nonsparing surgery (5-year rates 93.6% vs 92.1%, adjusted hazard ratio 0.87, 95% CI, 0.57-1.35). This survival association was consistent in high-grade serous (5-year rates 92.9% vs 92.4%), low-grade serous (100% vs 92.2%), clear cell (97.5% vs 86.1%), mucinous (92.1% vs 86.6%), low-grade endometrioid (95.7% vs 97.7%), and mixed (93.3% vs 83.7%) histology (all P>.05). In high-grade endometrioid tumor, fertility-sparing surgery was associated with decreased overall survival (5-year rates 71.9% vs 93.8%, adjusted hazard ratio 2.90, 95% CI, 1.09-7.67). Among bilateral ovarian lesions, fertility-sparing surgery was not associated with overall survival (5-year rates 95.8% vs 92.5%, P=.364). Among 41,914 patients who had epithelial ovarian cancer with any age and stage, those younger than age 50 years with stage I disease increased from 8.6% to 10.9% during the study period (P for trend=.002). Nearly one in five reproductive-aged patients with stage I epithelial ovarian cancer underwent fertility-sparing surgery in recent years in the United States. More than 90% of reproductive-aged patients with stage I epithelial ovarian cancer who underwent fertility-sparing surgery were alive at the 5-year timepoint, except for those with high-grade endometrioid tumors.

Trends in specific procedures performed at the time of cytoreduction for ovarian cancer: Is interval debulking surgery truly less radical? A Memorial Sloan Kettering Cancer Center Team Ovary study

ObjectivesTo evaluate procedures performed during primary debulking surgery (PDS) and interval debulking surgery (IDS) for ovarian cancer. MethodsPatients surgically treated at our institution for newly diagnosed stage IIIC/IV epithelial ovarian cancer between 6/1/2015–12/31/2021 were identified using a prospectively collected database. Patients were triaged to PDS or neoadjuvant chemotherapy (NACT) followed by IDS using an institutional algorithm. Data on specific procedures performed, including consultants called, were collected from operative and pathology reports. Appropriate statistical analyses were applied. ResultsOverall, 467 patients underwent PDS and 434 underwent IDS; 76% (PDS) and 71% (IDS) of cases achieved complete gross resection. Comparing PDS vs IDS cohorts, median age was 63 years (range, 23–86) vs 67 years (range, 35–95), 79% vs 86% of patients had high-grade serous histology, and 38% vs 70% had stage IV disease. Most procedures (except ostomy, distal pancreatectomy) were more common during PDS (P < .05). Bowel surgery was performed during 65% of PDS and 33% of IDS, and upper abdominal surgery during 72% of PDS and 52% of IDS; both were more common during PDS (P < .001). Estimated blood loss (median, 500 mL [PDS] vs 300 mL [IDS]) and operative time (median, 362 min [PDS] vs 267 min [IDS]) were higher for PDS (P < .001). A consulting surgeon was utilized during 31% of PDS and 18% of IDS, with hepatopancreaticobiliary as the most commonly called service (61% and 65%, respectively). ConclusionsIn our study of patients with advanced-stage ovarian cancer, while most procedures were more often performed during PDS, NACT did not obviate the need for radical surgical resection. Thus, advanced surgical skills remain essential.

Fertility-Sparing Surgery for Stage I Epithelial Ovarian Cancer: A Population-Based Assessment in the United States [ID 2693178

INTRODUCTION: The objective of this study was to assess population-level utilization and outcome of reproductive-aged patients with early epithelial ovarian cancer (EOC) who underwent fertility-sparing surgery (FSS) in the United States. METHODS: This population-based retrospective study queried the National Cancer Institute’s Surveillance, Epidemiology, and End Result Program. The study included 3,027 patients aged less than 50 years with stage I EOC receiving primary surgical therapy from 2007 to 2020. Fertility-sparing surgery was defined as preservation of one ovary and the uterus for unilateral lesion and preservation of the uterus for bilateral lesions. Temporal trend of FSS was assessed with linear segmented regression with log-transformation. Overall survival (OS) associated with FSS was assessed with Cox proportional hazard regression model. RESULTS: A total of 534 (17.6%) patients underwent FSS. At cohort level, the utilization of FSS was 13.4% in 2007 and 21.8% in 2020 (P-trend=.009). Non-Hispanic White individuals (2.8-fold), high-grade serous histology (2.2-fold), and stage IC disease (2.3-fold) had greater than 2-fold increase in FSS utilization during the study period (all, P-trend&lt;.05). After controlling for the measured clinico-pathological characteristics, patients who received FSS had OS comparable to those who had nonsparing surgery (5-year rates, 93.6% versus 92.1%; adjusted hazard ratio, 0.87; 95% CI, 0.57–1.35). This survival association was consistent in high-grade serous (5-year rates, 92.9% versus 92.4%), low-grade serous (100% versus 92.2%), clear cell (97.5% versus 86.1%), mucinous (92.1% versus 86.6%), low-grade endometrioid (95.7% versus 97.7%), and mixed histology (93.3% versus 83.7%) (all, P&gt;.05). In high-grade endometrioid tumor, FSS was associated with decreased OS (5-year rates, 71.9% versus 93.8%; adjusted-hazard ratio 2.90; 95% CI, 1.09–7.67). Among bilateral ovarian lesions, FSS was not associated with OS (5-year rates, 95.8% versus 92.5%; P=.364). CONCLUSION: Nearly one in five reproductive-aged patients with stage I EOC underwent FSS in recent years in the United States. The data suggest that FSS may not adversely affect OS, except for high-grade endometrioid tumors.

MIRRORS: a prospective cohort study assessing the feasibility of robotic interval debulking surgery for advanced-stage ovarian cancer

ObjectiveTo establish the feasibility and safety of robotic interval debulking surgery following the MIRRORS protocol (robot-assisted laparoscopic assessment prior to robotic or open surgery) in women with advanced-stage ovarian cancer....

Abstract 7047: Comparative analysis of transcriptomic and immunological profiles in treatment-naïve black and non-Hispanic White women with high-grade serous ovarian cancer

Abstract Background: Ovarian cancer is a highly lethal gynecological malignancy and high-grade serous histology (HGSOC) accounts for the majority of cases. Platinum-based chemotherapy is the primary treatment. Notably, Black women face the highest mortality-to-incidence ratio across all ethnic groups. This study investigated transcriptomic and immunological differences in tumors from Black compared to NHW women that might explain the poor clinical outcomes observed within this patient cohort. Methods: We collected primary tumor specimens from 36 Black and 31 treatment-naïve NHW patients. After RNA isolation, RNA sequencing (RNA-seq) identified differentially expressed transcripts and Enrichr performed pathway enrichment studies. To confirm the observed gene expression differences, we employed quantitative reverse transcription PCR (qRT-PCR), western blotting, and multiplex immunohistochemistry (mIHC). Additionally, we conducted cell proliferation, colony formation, and cell viability assays to functionally validate potential target genes of interest. Results: Our findings revealed 277 genes with significant differential expression between Black and NHW patients (FDR-adjusted p-value &amp;lt; 0.05). Among these, 103 coding genes were up-regulated, while 81 coding genes were down-regulated in tumors from Black compared to NHW patients. Gene Ontology analyses of these significantly differentially expressed genes highlighted enriched pathways related to DNA damage response, including the insulin receptor (INSR) gene, p53/apoptosis signaling components such as Forkhead box proteins A1 (FOXA1) and FOXB1, as well as genes involved in the cholesterol/lipid modulation pathway, including Low-density lipoprotein (LDL) receptor and Stearoyl-CoA Desaturase (SCD). Notably, silencing INSR and FOXA1 enhanced sensitivity to platinum-based drugs and inhibited cell growth and colony formation. Furthermore, we identified differences in the proportions of key immune cell types between the two patient groups, with tumors from Black patients exhibiting a significantly lower proportion of CD4+ Naïve T-cells and CD4+ regulatory T-cells (Tregs). Conclusions: Overall, our study reveals significant differential gene expression patterns between HGSOC tumors from Black and NHW patients, as well as differences in the proportions of immune cell types. These discoveries provide valuable insights into the biological mechanisms underlying the disparities in outcomes observed between black and NHW patients afflicted with HGSOC. It is critical to further investigate how these biological differences affect clinical outcomes and treatment response in Black women. Citation Format: Hao Huang, Russel Keathley, Ujin Kim Kim, Horacio Cardenas, Ping Xie, Jianjun Wei, Guangyuan Zhao, Emma L. Barber, Ernst Lengyel, Kenneth P. Nephew, Victoria Bae-Jump, Bin Zhang, Daniela Matei. Comparative analysis of transcriptomic and immunological profiles in treatment-naïve black and non-Hispanic White women with high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7047.

Mainstreaming in parallel with ovarian cancer tumor testing to improve genetic testing uptake

ObjectivesAlthough genetic testing (GT) is universally recommended for patients with epithelial ovarian cancer (EOC), rates are low (34%). In 1/2019, we implemented mainstreaming—GT in parallel with tumor testing via MSK-IMPACT within oncology clinics. We sought to determine GT rates pre/post-mainstreaming and patient characteristics associated with GT. MethodsPatients with newly diagnosed EOC seen at our institution from 7/1/2015–3/31/2022 were included. Clinical data were abstracted including social determinants of health (SDOH) variables, race/ethnicity, marital status, insurance, language, comorbidities, employment, and Yost index, a measure of socioeconomic status. GT rates were calculated overall and pre−/post-mainstreaming (1/2019). Logistic regression models were fit to identify variables associated with GT. ResultsOf 1742 patients with EOC, 1591 (91%) underwent GT. Rates of GT increased from 87% to 95% after mainstreaming (p < 0.001). Among 151 patients not undergoing GT, major reasons were lack of provider recommendation (n = 76, 50%) and logistical issues (n = 38, 25%) with few declining (n = 14, 9%) or having medical complications preventing GT (n = 7, 4.6%). High-grade serous histology, advanced stage (III/IV), and having a spouse/partner were associated with increased GT uptake (p < 0.01). Among SDOH variables, there were no differences by insurance, Yost score, language, comorbidities, employment, or race/ethnicity. In multivariable models, likelihood of GT increased with mainstreaming, even after adjustment for histology, stage, and marital status (OR 3.77; 95% CI: 2.56–5.66). ConclusionsMainstreaming increased the likelihood of GT in patients with EOC. We found lower testing rates in patients without partners/spouses, non–high-grade serous histology, and early-stage disease, representing potential areas for future interventions.

Abstract A077: The utility of surgical minimal residual disease after frontline treatment for prognostic and investigational opportunities in advanced ovarian cancer

Abstract Cure rates for patients with advanced stage ovarian cancer have not changed significantly over the last four decades likely due to inability to eradicate residual cancer cells after frontline therapy. Identifying clinically undetectable minimal residual disease (MRD) after frontline therapy by second look laparoscopy (SLL) has potential to a) uncover mechanisms of chemoresistance and tumor dormancy, b) identify MRD-specific therapeutic targets, and c) allow for earlier intervention with investigational therapies. The objective of this study is to describe the initial safety and feasibility of SLL and illustrate clinical and pathological correlates. Methods: This IRB-approved observational, single-center study includes patients with epithelial high-grade ovarian cancer with complete CA-125 and radiologic response after frontline treatment (combination of surgery and platinum-taxane chemotherapy) who underwent SLL from 4/2017-6/2023. Patients were subsequently offered standard of care or investigational maintenance therapy options based on homologous recombination deficiency (HRD) and MRD status. Summary statistics described the study population, chi-square tests compared categorical variables, and progression free survival (PFS) based on MRD status was estimated using Kaplan-Meier method and compared using log rank test. Results: 70 patients underwent SLL with a median of 8.5 biopsies (range 3-16). The majority of patients had stage III-IV disease (90%), and high-grade serous histology (90%). Approximately half (51.4%) of patients underwent neoadjuvant chemotherapy (NACT) with interval tumor reductive surgery (TRS). MRD was present in 32 patients (45.7%), and the presence of MRD was associated with a worse PFS (HR 3.0, 95% CI 1.5-5.8; 12.5 vs. 24.8 months; p=0.001). MRD was more frequent among NACT recipients compared to those who underwent primary TRS (63% vs 26%, P=0.002), those with HRD negative tumors (58% vs 24%, P=0.025), and those with R1 versus R0 resections (71% vs 39%, P=0.024). Of patients with MRD, 22 patients (71%) received bevacizumab until progression as part of a clinical trial (NCT02884648), 3 (10%) received bevacizumab off trial, 5 (16%) received a PARP inhibitor (all HRD positive), and 1 received other therapy. There were two (2.9%) intraoperative complications (both enterotomies) requiring conversion to laparotomy. Conclusions: SLL is feasible, overall safe, and detected MRD in 46% of ovarian cancer patients who were in radiologic and CA-125 remission after frontline therapy. PFS was significantly shorter for patients with residual disease, despite those patients all receiving additional therapy. Knowledge of MRD status in this patient population enables interventional, observational, and translational opportunities, as well as personalized prognostic counseling. MRD rate may also have utility as an early surrogate for efficacy in trials evaluating novel frontline investigational therapies. Future studies will compare the performance of circulating tumor DNA (ctDNA) versus surgical MRD. Citation Format: Anne Knisely, Roni Nitecki, J. Alejandro Rauh-Hain, R. Tyler Hillman, Jolyn S. Taylor, Lois M. Ramondetta, Michaela O. Grinsfelder, Lauren P. Cobb, David M. Boruta, Gwyn Richardson, Pamela T. Soliman, Aaron Shafer, Shannon N. Westin, Nicole D. Fleming, Travis T. Sims, Anil K. Sood, Pedro T. Ramirez, Karen H. Lu, Amir A. Jazaeri. The utility of surgical minimal residual disease after frontline treatment for prognostic and investigational opportunities in advanced ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A077.

Abstract B080: AB-1015, an Integrated Circuit T (ICT) cell therapy containing an ALPG/MSLN logic gate and FAS/PTPN2 shRNA-miR, for the treatment of ovarian cancer

Abstract B080: AB-1015, an Integrated Circuit T (ICT) cell therapy containing an ALPG/MSLN logic gate and FAS/PTPN2 shRNA-miR, for the treatment of ovarian cancer

Survival outcomes of epithelial ovarian cancer treated at a tertiary-level hospital in India.

One needs to choose wisely between primary neoadjuvant chemotherapy and primary cytoreductive surgery in ovarian cancer. The aim was to determine the recurrence free survival and overall survival after surgery for epithelial ovarian cancer and also the risk factors for recurrence and death. Electronic medical records of 322 women operated for ovarian, fallopian or primary peritoneal cancer between 2011 and 2015table were reviewed. Descriptive statistics were used to describe patients and their clinical outcomes. Cox proportional hazard models were used for risk factor analysis. Adjusted hazard ratios were obtained for recurrence and death, adjusted for stage, primary treatment modality, residual disease and histology. Kaplan-Meier curves were drawn for probability of recurrence-free survival and overall survival. The log rank test was used to compare survival probabilities. The majority were stage III or stage IV (78%), serous histology (71%) and high grade (64%). Primary cytoreduction was done in 48% and interval cytoreduction in 52%. The median duration of follow up (survival) was 77 months (95% CI 72-82). There were 179 known recurrences (55.6 %). The estimated median time to recurrence was 22 (95% CI 14.5- 29.5) months. The independent risk factors for recurrence were neoadjuvant chemotherapy [HR 2.14, 95% CI 1.48-3.09], stage III/IV [HR 2.75; 95% CI 1.40-5.41], high grade serous histology [HR 1.69; 95% CI 1.12-2.54] and sub-optimal debulking [HR 3.15, 95% CI 2.19-4.55]. There were 78 known deaths (24.2 %) with a mean time to death of 24.3 (SD 16.1) months. The independent risk factors for death were sub-optimal debulking [HR 3.07; 95% CI 1.78-5.29] and stages III and IV cancer [HR 3.07; 95% CI 1.14-8.27]. Most ovarian cancers recur within 2 years. Risk factors for mortality are advanced stage and sub-optimal debulking. Maximal efforts at down staging and surgical resection will increase survival.

Characteristics, Treatment Patterns and Survival of International Federation of Gynecology and Obstetrics Stage IV Epithelial Ovarian Cancer—A Population-Based Study

Background: The aim of the present study was to describe an unselected population of patients with diagnosis of FIGO stage IV OC. Methods: Data from 1183 patients were available for analysis. Results: The majority of patients (962/1183, 81.3%) received cancer-directed treatment. The median follow-up time was 3.8 years, and the median overall survival duration was 1.9 years. Notably, patients &gt;80 years had a low overall survival rate (HR of age &gt;80 years vs. ≤50 years was 3.81, 95%-CI [2.76, 5.27], p &lt; 0.0001). The survival rate was best in patients with HGSOC (p &lt; 0.0001). The highest overall survival rate was observed in patients in the group with surgical intervention followed by systemic treatment, with an unadjusted HR of 0.72, 95%-CI [0.59, 0.86], p = 0.007 vs. systemic treatment only. After adjustment for age and histology, survival differences between treatment schemes were smaller (HR 0.81, 95%-CI [0.66, 1.00], p = 0.12). Conclusions: In this cohort of patients with FIGO stage IV OC, more than 80% of the patients received cancer-directed treatment. Age and high-grade serous histology were determinants for survival. The highest overall survival rate was observed in patients who underwent surgery followed by systemic treatment.

Germline Pathogenic Variants and Genetic Counseling by Ancestry in Patients With Epithelial Ovarian Cancer.

To evaluate rates of germline pathogenic/likely pathogenic variants (PVs) and genetic counseling by ancestry in patients with epithelial ovarian cancer (EOC). Patients with pathologically confirmed EOC who underwent clinical tumor-normal sequencing from January 1, 2015, to December 31, 2020, inclusive of germline analysis of ≥76 genes were included. Patients with newly identified PVs were referred for Clinical Genetics Service (CGS) counseling. Ancestry groups were defined using self-reported race/ethnicity and Ashkenazi Jewish (AJ) heritage. Genetic ancestry was inferred computationally using validated algorithms. Logistic regression models were built. Of 1,266 patients, self-reported ancestry (AJ, 17%; Asian, 10%; Black/African American, 5.4%; Hispanic, 6.2%; non-Hispanic White, 57%; other, 0.16%; unknown, 4.0%) correlated with genetic ancestry (AJ ancestry, 18%; admixed, 10%; African, 4%; East Asian [EAS], 6%; European, 56%; Native American, 0.2%; South Asian [SAS], 4%; unknown, 2%). Germline PVs were observed in 313 (25%) patients, including 195 (15%) with PVs in EOC-associated genes. Those with PVs were younger at diagnosis (59 v 62 years; P < .001) and more likely to have high-grade serous ovarian cancer (83% v 72%; P = .009). PV prevalence varied between ancestry groups (P < .001), with highest rates in the AJ (39.9%) and Asian (26.5%) groups and similar rates (>10%) across other ancestry groups. Use of genetic ancestry demonstrated similar findings and further characterized high rates of PV in EAS/SAS groups. Younger age, high-grade serous histology, and self-reported AJ or Asian ancestry were associated with PV in an EOC-associated gene. Rates of CGS counseling for newly identified PVs were high (80%) across ancestry groups. Rates of PV, particularly in EOC-associated genes, were high regardless of ancestry, with similar rates of counseling between groups, emphasizing the importance of universal genetic testing in all patients with EOC.

Prognostic and predictive significance of CA-125 elimination rate constant K (KELIM) in ovarian cancer patients treated with neoadjuvant chemotherapy in a real-world setting.

e17594 Background: CA-125 ELIMination Rate Constant K (KELIM) is considered a marker of chemosensitivity in ovarian cancer patients and its prognostic and predictive significance in Neo-adjuvant Chemotherapy (NACT) treated patients has been established through prospective trials. Limited data exist regarding the feasibility of its application in the real-world setting. Under this perspective, we undertook a retrospective study of the predictive and prognostic significance of KELIM in ovarian cancer patients treated with NACT in our institution. Methods: Medical records of women with aEOC treated with NACT at Alexandra Hospital from 2010 to 2019 were retrospectively identified. Clinicopathological data, treatment and survival data were analysed. Modeled CA-125 KELIM score was calculated from the available online tool ( https://www.biomarker-kinetics.org/CA-125-neo ). Kaplan-Meier Survival curves were generated using SPSS; survival differences were estimated using the long-rank test. Results: 99 patients treated with 3-4 cycles of NACT with Paclitaxel and Carboplatin with available at least three CA125 measurements within 100 days from the beginning of chemotherapy were included. Median age was 66.6 years (25th-75th percentile was 59.8 and 74.5 years respectively) and median numbers of CA125 measurements were 3. KELIM score &lt; 1 (unfavorable) had 56 patients (56.6%) while score ≥1 had 43 patients (43.4%). All patients had high grade serous histology and 72 patients were treated with debulking surgery (72.8%). BRCA1/2 mutation status was known in 66 patients, among them 18 patients (27.3%) were positive for the presence of BRCA1/2 mutations. Favorable KELIM score was predictive of both increased PFS [mPFS 16.6 months (95% CI 12.6-20.5) in favorable group vs 11.9 months (95% CI 10.6-13.4) in unfavorable, p &lt; 0.001] and OS [mOS 44.7 months (95% CI 40.2-49.1) in favorable group vs 27.2 months (95% CI 18.5-35.9) in unfavorable, p = 0.013]. Predictive and prognostic significance of KELIM was retained in multivariate analysis when other prognostic parameters as age, ECOG-PS, quality of debulking surgery were taken into account. Bevacizumab administration post NACT increased statistical significantly both PFS and OS only in patients with unfavorable KELIM score. There was no statistical correlation between favorable KELIM score and presence of BRCA1/2 mutations, however our analysis is limited by the small number of patients. Conclusions: KELIM score can be easily applied in common clinical practice of ovarian cancer patients treated with NACT and provide valuable prognostic and predictive information. Despite in our analysis no correlation with presence of BRCA1/2 mutations was found further investigation is warranted, since PARP inhibitors constitute the established maintenance treatment in the frontline setting.

Circulating tumor DNA (ctDNA) as a marker of residual disease and recurrence in resected stage I-IV epithelial ovarian cancer (EOC).

5553 Background: The management of EOC remains challenging, with a high risk of relapse despite surgery, chemotherapy and maintenance therapy. Detection of ctDNA after surgery and adjuvant chemotherapy (CT) may identify patients (pts) at highest risk of recurrence suitable for treatment escalation. Our primary aim was to investigate the use of ctDNA as a marker of residual disease following both surgery and adjuvant CT that might predict later recurrence. Methods: In this multi-centre observational study, we collected blood samples post-op and 6-8 weeks post-CT completion from pts with debulked stage I-IV EOC planned for adjuvant CT. Pre-cycle 1 CT and pre-op blood was also collected from some pts who received neoadjuvant CT. We used a tumor-informed approach for ctDNA analysis with whole exome sequencing of tumor tissue followed by detection of up to 50 variants in the plasma with the SaferSeqS assay. The primary outcome was recurrence-free survival (RFS), calculated using the Cox proportional-hazards model. Results: 81 pts who had post-op ctDNA results were included. 84% had high grade serous histology and 23% had BRCA mutations. Median number of tumor-informed variants analyzed in the plasma was 44 (range 3-60). Overall, post-operative ctDNA was detected in 63 of 81 (78%) of pts, 18 of 26 (69%) in Stage I-II and 45 of 55 (82%) in Stage III-IV. Pts who were ctDNA negative post-surgery had longer RFS versus who were ctDNA positive (HR 3.28, 95% CI 1.39 to 7.72, p = 0.007). Estimated RFS at 2 years was 78% among pts who were ctDNA negative post-surgery and 44% among the ctDNA positive group. Pts with BRCA mutations were less likely to have positive post op ctDNA (OR 0.12, 95% CI 0.036 to 0.39, p &lt; 0.001). For post-CT ctDNA, estimated RFS at 2 years was 74% in the ctDNA negative pts versus 43% in the ctDNA positive group but this was not statistically significant (HR 1.64, 95% CI 0.84 to 3.18, p = 0.15). Pts with zero residual disease were more likely to be ctDNA negative post-surgery (OR 12.36, 95% CI 1.54 to 99.4, p = 0.018). Post-op ctDNA outperformed post-op CA-125 in predicting recurrence; pts with elevated CA-125 post-surgery had shorter RFS compared to those with normal CA-125 post-surgery (HR 1.99, 95% CI 1.15 to 3.42, p = 0.013). Of 18 pts who had neoadjuvant CT, pre-treatment ctDNA was detected in 17 (94%). Only two pts had clearance of ctDNA post neoadjuvant CT and both had zero residual disease at surgery. For the pts that maintained positive ctDNA results post-op, 7/15 (47%) pts had zero residual disease. Conclusions: ctDNA detection after ovarian cancer cytoreduction identifies pts at very high risk of recurrence. Pts with BRCA mutations were more likely to have negative ctDNA post-op. The role of ctDNA in guiding neoadjuvant and adjuvant therapy to improve outcomes, warrants further investigation. Clinical trial information: ACTRN12617001119381 .

Utility of surgically documented minimal residual disease as a therapeutic target and early surrogate of frontline treatment outcomes in ovarian cancer.

5549 Background: Cure rates for patients with advanced stage ovarian cancer have not changed over the last four decades likely due to inability to eradicate residual cancer cells after frontline therapy. Identifying clinically undetectable minimal residual disease (MRD) after frontline therapy by second look laparoscopy (SLL) has potential to a) uncover mechanisms of chemoresistance, b) identify MRD-specific therapeutic targets, and c) allow for earlier intervention with investigational therapies. The objective of this study is to describe the initial safety and feasibility of SLL and illustrate clinical pathologic correlates. Methods: This IRB-approved observational, single-center study includes patients with epithelial high-grade ovarian cancer with complete CA-125 and radiologic response after frontline treatment who underwent SLL from 4/2017-12/2022. Patients were subsequently offered standard of care or investigational maintenance therapy options based on homologous recombination deficiency (HRD) and MRD status. Summary statistics described the study population, chi-square tests compared categorical variables, and progression free survival (PFS) based on MRD status was estimated using Kaplan-Meier method and compared using log rank test. Results: 64 patients underwent SLL with a median of 8 biopsies (range 1-16). The majority of patients had stage III-IV disease (89%), and high-grade serous histology (89%). Approximately half (52%) of patients underwent neoadjuvant chemotherapy (NACT) with interval tumor reductive surgery (TRS). MRD was present in 28 patients (44%), and the presence of MRD was associated with a worse PFS (HR 3.1, 95% CI 1.5-6.3; 9.2 vs 24.6 months; P=0.002). MRD was more frequent among NACT recipients compared to those who underwent primary TRS (61% vs 26%, P=0.005), those with HRD negative tumors (63% vs 22%, P=0.003), and those with R1 versus R0 resections (71% vs 35%, P=0.012). Of patients with MRD, 20 patients (71%) received bevacizumab until progression as part of a clinical trial (NCT02884648), 3 (11%) received bevacizumab off trial, 4 (14%) received a PARP inhibitor (all HRD positive) and 1 received other therapy. There was one (1.6%) intraoperative complication requiring conversion to laparotomy. Conclusions: SLL is feasible, overall safe, and detected MRD in 44% of ovarian cancer patients who were in radiologic and CA-125 remission after frontline therapy. MRD rates were higher in patients who received NACT and HRD negative patients, and PFS was significantly longer in patients without residual disease. MRD rate by SLL may have utility as an early surrogate for efficacy in trials evaluating novel frontline investigational therapies. Knowledge of MRD status in this patient population enables interventional, observational, and translational investigations, as well as personalized prognostic counseling.

A phase 1 study of the SYK inhibitor fostamatinib and weekly paclitaxel for recurrent platinum-resistant ovarian cancer.

5574 Background: Response to chemotherapy in patients (pts) with recurrent platinum-resistant ovarian cancer (PROC) is generally &lt; 15%. Spleen tyrosine kinase (SYK) is overexpressed in PROC and is a key mediator of paclitaxel resistance in ovarian cancer cells. Fostamatinib (Fos), an orally available inhibitor of SYK, is currently FDA approved for the treatment of idiopathic thrombocytopenic purpura. The active form of Fos (R406) was shown to synergistically enhance taxane-mediated cytotoxicity in preclinical ovarian cancer models. This phase 1 study aimed to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of Fos when combined with standard weekly paclitaxel (wPac) for pts with PROC. Methods: Pts with PROC, defined as progression ≤6 months of last platinum, were eligible. A modified toxicity probability interval (mTPI) dose escalation design was used to determine the MTD/RP2D and response was assessed using RECISTv1.1 criteria. All pts received paclitaxel (wPac) 80mg/m2 intravenously on Days 1, 8, and 15, of a 28-day cycle. Fos was administered orally twice a day (BID) on a continuous schedule. Three dose levels (DL) were planned: DL1 - 100mg, DL2 - 150mg, and DL3 - 200mg. MTD was determined based on cycle 1 dose-limiting toxicities (DLTs) and responses were assessed every 2 cycles. A dose expansion cohort to further assess adverse events (AEs) and tolerability was performed. Results: 27 eligible pts, median age 62 years (range 35-79 years) with high-grade serous (n = 18), clear cell (n = 4), carcinosarcoma (n = 3), or other (n = 2) histology were treated at 3 centers. Twelve pts were treated in the dose escalation cohort (DL1 = 6, DL2 = 3, DL3 = 3). Common AEs at least possibly attributed to Fos, wPac, or both included diarrhea (70%), fatigue (52%), anemia (44%), neutropenia (33%), nausea (33%), hypertension (30%), and dysgeusia (30%). Treatment-emergent grade 3-4 AEs were neutropenia (37%), anemia (26%), and thromboembolic event (22%). During DL1, updated toxicity management guidelines not consistent with the original protocol were released and 2 of the 3 pts treated prior to the amendment were not considered evaluable for DLT. Thus 3 more pts were enrolled to DL1 after the amendment. Of the 10 pts evaluable for DLT in dose escalation, no DLTs were reported on any of the 3 DLs (DL1 = 4, DL2 = 3, DL3 = 3). DL3 was selected for dose expansion. One of 15 pts in the dose expansion cohort had a DLT (neutropenia) and one patient had a grade 5 infection. Of 18 pts treated at DL3, 7 (39%) had partial or complete response (95% CI: 17.3, 64.3%). Overall, 27 patients received a median of 3 cycles (range 0-10). Analysis of pharmacokinetic and correlative molecular studies of target expression are ongoing. Conclusions: The RP2D of Fos will be 200 mg orally BID when combined with wPac. AE profile of the combination was as expected and the combination demonstrated promising efficacy in pts with recurrent PROC. Clinical trial information: NCT03246074 .

Toxicity profile and discordance between patients/physicians regarding niraparib maintenance in recurrent ovarian cancer (ROC) patients: Lessons from the NIQOLE real-life study—GINECO study.

5521 Background: Niraparib (NI) maintenance is a standard of care in platinum-sensitive ROC. Based on pivotal randomized trials, toxicity profile appears manageable through adapted drug dosing. However, data on tolerance and feasibility for unselected patients (pts) are missing, especially regarding pts’ reported adverse events (AE). Methods: NIQOLE study is a real-life longitudinal multicenter, phase IV study in ROC pts treated with NI maintenance. NI starting dose was adapted to pts’ weight and platelet count. The primary endpoint was to describe physicians’ reported AE (NCI-CTC-AE, grading from 0 to 5) leading to treatment modifications (TM), defined by dose reduction or treatment interruption/discontinuation from baseline to month 3 and delay of first TM. Secondary endpoints included duration of treatment and pts’ reported AE. Progression rates were exploratory endpoints. Owing to a digital device, pts provided remoted weekly AE (NCI PRO-CTC-AE, grading from 0 to 3) which were accessible to investigators. Concordance between the main symptomatic AEs reported by pts and those reported by physicians was analyzed. Results: 139 pts were treated: median age 70 [44-88], high-grade serous histology 91%, BRCA mutation 5%, first relapse 72%, prior bevacizumab 71%. The median delay from platinum-based regimen and NI was 49 days [15-109]. NI starting dose was 200 mg in 80% of pts and the median treatment duration was 5.6 months [0.2-21]. Progression rates at 3 and 6 months were 19 and 45%, respectively. At 3 months, 60% (n=84%) of pts had at least one TM, of whom 47% (n=66) were treatment-related AEs: dose reduction in 17/66 (26%), interruption in 53/66 (80%) and discontinuation in 11/66 (17%). The first AE inducing TM occurred at 22 days (median) [2 -91]. Thrombocytopenia was the main AE leading to TM (70% of cases). 24% of AEs were grade 3-4. Remoted PRO-CTC-AEs were acknowledged by physicians in 59% of cases of whom 31% led to adaptation of pts’ care. During the 3 months, 98% of pts reported symptomatic AEs (including nausea, constipation, fatigue, dry mouth and insomnia), of which 66% were grade 3. There was a very poor correlation (&lt;0.20) between symptomatic AEs reported by the pts vs by the physicians (table). Conclusions: In real life, despite initial individual dosing, NI maintenance requires frequent TM during the first 3 months of treatment. There is a strong discrepancy between symptomatic AEs regularly captured by pts and those reported by physicians during clinics. Next generation of clinical trials should integrate pts' perspective to better assess toxicity and manage treatment course. Clinical trial information: NCT03752216 . [Table: see text]

Germline variants in non-BRCA1/2 homologous recombination-related genes and ovarian cancer: Analysis of tumor phenotype and survival.

5565 Background: BRCA1/2-associated ovarian cancer (OC) exhibits homologous recombination (HR)-deficiency (HRD) and a better prognosis than BRCA1/2-wildtype (WT) OC. However, it is unclear if patients with germline pathogenic variants (gPV) in other HR-related genes have a similar tumor phenotype. We sought to define OC molecular features from patients with gPV in other HR genes and analyze survival compared to patients with BRCA1/2 and WT OC. Methods: We identified patients with OC treated at our institution who underwent tumor-normal sequencing using MSK-IMPACT targeting 341-505 cancer-related genes with germline analysis of ≥76 genes from 7/2015-12/2020. Biallelic inactivation was inferred via assessments of loss of heterozygosity (LOH) at gPV in non- BRCA1/2 HR-related genes ( ATM, BARD1, BRIP1, FANCA, FANCC, NBN, PALB2, RAD50, RAD51B, RAD51C, and RAD51D). Clinical characteristics were compared to patients with BRCA1/2-associated and WT OC using non-parametric tests. Progression-free (PFS) and overall-survival (OS) were calculated from date of pathologic diagnosis using the Kaplan-Meier method. Left truncation at date of MSK-IMPACT consent was applied. Whole-exome sequencing (WES) was performed in a subset of OCs. Results: Of 882 patients with OC, 56 (6.3%) had gPV in non- BRCA1/2 HR-related genes compared to 95 (10.8%) patients with BRCA1-associated OC (58 germline, 37 somatic) and 59 (6.7%) patients with BRCA2-associated OC (40 germline, 19 somatic). Patients with a deleterious genetic alteration were diagnosed with OC at younger age and more likely to have high-grade serous histology compared to the WT group (p &lt; 0.01). High rates of biallelic alterations were observed amongst gPV in BRIP1 (11/13), PALB2 (3/4), RAD51B (3/4), RAD51C (3/4), and RAD51D (8/10), and WES was performed in a subset (n = 27) of tumors from these patients with adequate tumor purity (&gt;30%). We observed a higher tumor mutational burden (TMB), median 2.5 (1.1-6.0) vs. 1.2 (0.6-2.6) mut/Mb, and enrichment of HRD mutational signatures in tumors associated with PALB2 and RAD51B/C/D compared with BRIP1 (p &lt; 0.01), although markers of telomeric-allelic imbalance (TAI), large-scale state transitions (LST) and fraction of genome altered (FGA) were similar. PFS and OS varied by gene group with best survival in BRCA1/2-associated OC, even after adjustment for clinical covariates in multivariable models (p &lt; 0.01). Although we observed heterogeneity in PFS and OS for those with gPV in other HR-related genes by biallelic status and HRD phenotype, none had significantly better survival than those with WT OC. Conclusions: OCs associated with gPV in non- BRCA1/2 HR-related genes represent a heterogenous group. OCs in those with gPV in PALB2 and RAD51B/C/D preferentially harbored biallelic alterations and displayed an HRD phenotype.