Tube Cancer Research Articles

Predictors of long-term progression-free survival (PFS) in niraparib-treated patients (pts) from the PRIMA/ENGOT-OV26/GOG-3012 study.

5589 Background: Niraparib was approved as maintenance therapy for pts with advanced ovarian cancer (OC) after complete or partial response (CR/PR) to first-line (1L) platinum-based chemotherapy (CT) based on results from the PRIMA study. In this post hoc analysis, we identified factors associated with long-term PFS. Methods: PRIMA is a phase 3, randomized study of pts with newly diagnosed advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer at high risk for relapse with CR/PR after 1L platinum-based CT. Pts were randomized 2:1 to niraparib 200 or 300 mg or placebo QD, and stratified by best response to 1L CT (CR/PR), neoadjuvant CT (yes/no), and homologous recombination deficiency (HRD) status (deficient [HRd]/proficient or not determined [HRp/nd]). Investigator-assessed PFS was dichotomized in niraparib-treated pts with progressive disease (PD)/censoring <2 years vs PD/censoring ≥2 years after randomization (data cut, Nov 17, 2021). Logistic regression modeling using backward elimination (significance level=0.15) was used to identify baseline covariates associated with long-term PFS. Results: Of 487 niraparib-treated pts, 152 (31%) had PD/censoring ≥2 years after randomization. Odds ratios (OR) for PFS ≥2 years by baseline subgroup are shown (Table). The logistic regression model showed that BRCA mutation and HRD status, International Federation of Gynecology and Obstetrics (FIGO) stage, fallopian tube as the site of the primary tumor, and absence of baseline nontarget lesions were associated with longer PFS. Eastern Cooperative Oncology Group (ECOG) performance score, body mass index, age, time from CT to randomization, number of target lesions, best response after CT, number of CT cycles, type of debulking surgery, and residual disease were not associated with PFS ≥2 years. Safety has been reported previously ( Ann Oncol. 2022;33[suppl 7]:S789). Conclusions: Results suggest that long-term PFS in pts treated with niraparib may be associated with BRCA/HRd biomarker status, FIGO stage, primary tumor site, and number of baseline non-target lesions. These data are hypothesis generating. Clinical trial information: NCT02655016 . [Table: see text]

Correlation of cyclin E1 expression and clinical outcomes in a phase 1b dose-escalation study of azenosertib (ZN-c3), a WEE1 inhibitor, in combination with chemotherapy (CT) in patients (pts) with platinum-resistant or refractory (R/R) epithelial ovarian, peritoneal, or fallopian tube cancer (EOC).

5513 Background: Azenosertib (ZN-c3) is a novel, selective, and orally bioavailable WEE1 inhibitor demonstrating single-agent antitumor activity. Azenosertib may inhibit CT-induced DNA damage repair and provide benefit in pts with platinum R/R EOC. Cyclin E1 amplification/overexpression is present in ≥35% of metastatic ovarian cancer. High expression/amplification of Cyclin E1 is a poor prognostic marker and predictive of lack of response to platinum-based CT. Ovarian models overexpressing Cyclin E1 have exquisite sensitivity to azenosertib in vitro and in vivo; forced Cyclin E1 overexpression sensitizes cell lines with low endogenous Cyclin E1 to azenosertib. Methods: This open-label, multicenter study (NCT04516447) assessed azenosertib + paclitaxel (PAC), carboplatin (Carbo), gemcitabine (GEM), or pegylated liposomal doxorubicin (PLD) in pts with metastatic high-grade serous EOC after ≤2 lines of CT including platinum CT. Primary endpoint is safety and identification of RP2D of each combination. Secondary endpoints include clinical activity. Azenosertib was given continuously or intermittently QD in 21 or 28D cycles until PD or unacceptable toxicity. Results: 103 pts were enrolled; at data cut-off, 94 were efficacy evaluable. 26.6% had a partial response (PR) and median progression free survival (PFS) = 9.03 mo (95%CI: 5.52-11.01). Azenosertib + PAC demonstrated the highest ORR [9/18 (50%)], followed by Carbo [9/27 (33.3%)]; ORR for azenosertib + PLD or + GEM was 14.3% (5/35, 2/14 respectively). 80 pts had available Cyclin E1 expression data by IHC; higher Cyclin E1 (H-score >50) correlated with higher ORR and longer PFS (ORR = 31.3% vs 7.7%; PFS = 10.35 vs 3.25 mo, HR=0.3; Table). Frequent Grade ≥3 TEAEs (%) were neutropenia (44.4), thrombocytopenia (30.3), anemia (12.1), leukopenia (11.1), fatigue (10.1), diarrhea (6.1), nausea (5.1), and vomiting (5.1). Conclusions: Azenosertib + CT is well tolerated and has encouraging clinical activity, with durable responses in pts with platinum R/R EOC. Pts with Cyclin E1 overexpressing tumors, a subgroup with suboptimal benefits from CT, demonstrated significant improvements in ORR and PFS vs pts with tumors having low expression. These data support a planned trial of azenosertib + CT vs CT alone in Cyclin E1 overexpressing platinum R/R EOC. Clinical trial information: NCT04516447 . [Table: see text]

Use of CLIA accredited multi-omic platforms to correlate clinical significance of WES/WTS testing with functional protein/phosphoprotein drug target activity.

e15150 Background: Targeted cancer therapies almost exclusively disrupt protein function and phosphorylation, but genomics-based biomarkers underpin the vast majority of oncology molecular profiling. The reverse phase protein array (RPPA) technology has been used in the clinical setting to identify potential drug targets and to monitor the effects of treatment on protein expression and phosphorylation. Here, we investigated the Theralink RPPA assay, a highly sensitive CAP/CLIA accredited protein/phosphoprotein profiling technology, across a pan-tumor cohort of 188 samples which had undergone whole exome sequencing and transcriptomics. Methods: Using the Theralink RPPA assay, 32 key protein and phosphoprotein cancer therapy targets were quantified from formalin-fixed, laser capture microdissected (LCM) tumor epithelium across a pan-tumor cohort of 188 cancer cases. All samples had concomitant CLIA-based whole exome and whole transcriptome analysis performed. Most of these tumors were head and neck cancer (34%), uterine cancer (23%), and ovarian/fallopian tube cancer (17%), with the remaining 26% made up of various cancer types, including skin, breast, lung, brain, and other cancers. Results: Of the pan-tumor cohort, 95% of cases had at least one actionable protein target identified, compared to 86% of cases with clinically relevant genomic alterations. Altered genes and Theralink RPPA assay protein targets were broadly classified into 10 biological pathways. The pathway most frequently identified as actionable via Theralink’s RPPA assay was HER-family protein signaling (85% of cases) with concurrent genomic alterations in HER-family genes found for 9% of cases. In contrast, mTOR signaling was found to be the most frequent clinically relevant genomically altered pathway (48% of cases). When using a clinical breast cancer reference for HER2 protein/phosphorylation levels that is guiding HER2-targeted therapy in the unamplified setting, actionable total and phospho-HER2 levels were found in 82% of the pan-tumor cases, overlapping with ERBB2 genomic alterations in 4% of cases. The gene found to be altered the most was TP53 (101 cases; 54%), which was not part of the targeted Theralink RPPA assay. Conclusions: Our data suggest that quantification of key cancer proteins and phosphoproteins using RPPA extend the identification of actionable drug targets beyond what was found with WES/WTS testing alone. Especially the quantification of total and phospho-HER2 identified a significant pan-tumor subpopulation that may benefit from HER2-targeted therapies, including trastuzumab deruxtecan (T-Dxd).

A real-world study of US patients with metastatic ovarian, fallopian tube, and peritoneal cancer (mOFPC) using integrated electronic health records (EHR) and claims datasets.

e17548 Background: Ovarian cancer is the most lethal gynecologic cancer. Detailed epidemiologic descriptions from a real-world database of a large population of ovarian and related cancer patients can provide insights into the characteristics, treatment patterns, and outcomes of these patients, and could serve as a useful benchmark while developing new therapies. Methods: This retrospective analysis uses the ConcertAI RWD360 dataset which is a real-world de-identified dataset of more than 6 million patients from across the United States derived from various EHR systems and integrated with a large administrative open claims dataset (>90% overlap). 60429 patients in this dataset had OFPC out which 12406 patients had metastatic cancer. We present here the key characteristics of this mOFPC cohort including histology, biomarkers and top treatment patterns. We also performed overall survival (OS), time to treatment discontinuation (TTD) and time to next treatment (TTNT) analyses starting from initiation of 1st line of therapy (LoT) for all patients who received systemic treatment after metastatic diagnosis (8308 patients). Results: The top 5 histologies and biomarkers tested in this mOFPC cohort are presented in Table. The median OS from start of 1st LoT for this cohort was 2.45 years. The median TTD and TTNT across all 1st line therapies were 2.5 months and 5.5 months respectively. Top 2 treatments given as 1st LoT after metastatic diagnosis are also presented in Table. Chemotherapy (cis/carboplatin + pacli/docetaxel) and chemotherapy + bevacizumab were the most common 1st LoTs and there was no difference in the OS of patients treated with these two LoTs. Conclusions: This study describes the characteristics of a large US real-world cohort of mOFPC patients. Here we have presented data on the overall cohort, but further analysis of outcomes stratified by treatment arms, biomarkers and histology can be performed to better inform best treatments for specific sub-cohorts. [Table: see text]

GLORIOSA: A randomized, open-label, phase 3 study of mirvetuximab soravtansine with bevacizumab vs. bevacizumab as maintenance in platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer.

TPS5622 Background: Elevated folate receptor-alpha (FRα) expression is a characteristic of epithelial ovarian cancer (EOC), thereby providing a rational target for antibody drug conjugate (ADC) development in ovarian cancer. Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent that has received accelerated approval for patients with FRα positive platinum resistant ovarian cancer. MIRV in combination with BEV has demonstrated clinically meaningful activity, along with acceptable tolerability, in patients with FRα expressing ovarian cancer.1 Methods: GLORIOSA is a randomized, open-label, phase 3 study designed to evaluate the efficacy of in combination with bevacizumab compared with bevacizumab alone as maintenance for patients with FRα-positive recurrent platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancers who have not progressed after second line platinum-based chemotherapy plus bevacizumab (which may be given on protocol for patients with high FRα tumor expression). Confirmation of high FRα positivity by immunohistochemistry using the Ventana FOLR1 CDx Assay (high expression; ≥ 75% of viable tumor cells staining at 2+ intensity) and 1 prior line of therapy is required for inclusion. GLORIOSA is designed to randomize 418 patients, 1:1 receiving intravenous MIRV at a dose of 6 mg/kg adjusted ideal body weight plus bevacizumab 15mg/kg every 3 weeks or receiving bevacizumab 15mg/kg every 3 weeks until disease progression or unacceptable toxicity. Radiological assessments will be conducted every 9 weeks (± 2 weeks) for 72 weeks, and subsequently every 18 weeks (± 3 weeks) until progressive disease (PD), death, the start of new anticancer therapy, or withdrawal of consent from the study (whichever occurs first). The primary efficacy endpoint is progression-free survival by investigator and will also be assessed as a sensitivity analysis. The secondary endpoints include objective response rate, quality of life, overall survival, and safety and tolerability. GLORIOSA is a global study that opened for enrollment in December 2022. Reference: 1. Gilbert L, Oaknin A, Matulonis UA, et al. Safety and efficacy of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2023; 170: 241–247 Clinical trial information: NCT05445778 .

Use of germline testing in patients with prostate, pancreatic, or ovarian cancer in Washington (WA) state.

6572 Background: Germline genetic mutations are seen in approximately 10-15% of patients with prostate, pancreatic, and ovarian cancer. While universal germline testing is recommended for patients with these cancers to inform both familial risk and therapeutic approach, underutilization of germline testing has been reported. We investigated the rates of and factors associated with germline testing in a population-based sample of patients with prostate, pancreatic, and ovarian cancer in WA state. Methods: We linked Washington state cancer registry records from 2017-2019 with claims records for two large commercial insurers, Medicare, and Medicaid. Patients with prostate (metastatic, regional node-positive, or high-risk localized), pancreatic, and ovarian (including fallopian tube and peritoneum) cancer who were diagnosed in 2017-2019 were identified. Using claims from this database, we identified patients who received germline testing in the first two years of diagnosis. We excluded those who were not continuously enrolled in a health plan during the testing period of interest or died within 3 months of diagnosis. We used a multivariate logistic regression model to investigate factors associated with germline testing. Results: Among 2,077 patients, 429 (20.7%) received germline testing. Testing rates were 6.3% (53 of 842 patients) in prostate cancer, 15.4% (118 of 765 patients) in pancreas cancer, and to 54.9% (258 of 470 patients) in ovarian cancer; median time to testing for prostate, pancreas, and ovarian cancer was 162, 133, and 64 days respectively. Testing rates were higher in later years, in patients with more advanced stage cancers and lower in Asian patients and patients with more comorbid conditions. Conclusions: Despite guideline recommendations, germline testing rates are low among cancer patients in WA state, with the lowest rates in prostate cancer patients and in Asian and higher comorbidity populations. Underutilization of germline testing may not only adversely affect treatment, but also represents a missed opportunity for testing of high-risk families. Further studies should identify and address barriers to germline testing in high-risk populations. [Table: see text]

Phase 1 dose escalation study of SL-172154 (SIRPα-Fc-CD40L) in platinum-resistant ovarian cancer.

5544 Background: SIRPα-Fc-CD40L is a hexameric, bi-functional fusion protein consisting of SIRPα linked to CD40L via an inert Fc linker. This molecule competitively inhibits CD47 to enhance tumor cell phagocytosis and activates CD40 to increase antigen processing and cross-presentation by antigen presenting cells (APCs) to CD8 T cells, thus bridging innate and adaptive immunity. Methods: This first-in-human, Phase 1 dose escalation study evaluated SL-172154 in patients (pts) with advanced platinum resistant ovarian, fallopian tube and primary peritoneal cancers (PROC). SL-172154 was administered intravenously across 5 dose levels (0.1, 0.3, 1.0, 3.0, 10mg/kg). Dose escalation followed a modified toxicity probability interval 2 design. Objectives included evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose, pharmacokinetic and pharmacodynamic (PD) parameters, and antitumor activity per RECIST 1.1. Results: As of 3 Jan 2023, 27 pts (median age 66 years [range 33-85]; median of 4 prior systemic therapies [range 2-9]) with ovarian (70%), fallopian tube (15%) or primary peritoneal (15%) cancer were dosed. Treatment-emergent AEs (>15%) regardless of grade (G) included infusion related reaction (IRR) (67%), fatigue (44%), nausea (33%), back pain (26%), constipation, diarrhea (both 22%), decreased appetite and pruritus (both 19%). There was one DLT of G3 ALT increased at 10mg/kg requiring dose interruption for resolution. A maximum tolerated dose was not reached. G3/4 treatment-related AEs (>1pt) were AST increased (G3) and lymphopenia (G4), each in 2 pts (7%); all were fully resolved with no dose modifications. There were no fatal AEs, no AEs that led to drug discontinuation and no events of cytokine release syndrome. The frequency of IRR events increased with increasing dose, and slowing the rate of infusion was utilized for mitigation. SL-172154 Cmax and AUC increased with dose with greater than proportional exposure noted at 3 and 10mg/kg potentially due to target saturation. These findings were supported by dose-dependent target engagement of CD47 and CD40 on CD4 T cells and B cells respectively, approaching 100% by 3 mg/kg. Rapid dose-dependent egress of CD40+ B cells was maximal at ≥3mg/kg. SL-172154 induced dose-dependent responses in IL-12, CXCL-8, CXCL-10, IL-10, CCL2, CCL20, and CCL22, which also approached a plateau at ≥3mg/kg. Analysis of peripheral and tumor immunophenotypes and anti-drug antibodies in response to SL-172154 is ongoing and will be presented. Best response was stable disease in 6/27 response evaluable (22%) pts. Conclusions: SL-172154 is well tolerated in heavily pretreated PROC pts. IRRs were readily manageable. Maximal CD47 and CD40 target engagement and CD40-dependent PD effects were observed with ≥3mg/kg SL-172154. 3mg/kg is a safe, tolerable, and pharmacologically active dose for evaluation in combination studies in pts with PROC. Clinical trial information: NCT04406623 .

Oregovomab and non-platinum chemotherapy in PARP inhibitor-resistant ovarian, fallopian tube, or primary peritoneal cancer patients not candidates for platinum retreatment: A multicenter, two-cohort, single-arm phase 2 trial (OPERA/KGOG 3065/APGOT-OV6).

TPS5621 Background: As PAPR inhibitors (PARPis) are becoming the standard of care option for epithelial ovarian cancer (EOC), PARPi-resistant patients are increasing. Moreover, non-platinum single agent chemotherapy in these patients has been found to elicit poor survival outcomes. Oregovomab, an investigational murine monoclonal antibody directed against CA-125, has shown promising efficacy in the previous phase II study of combinational front-line adjuvant chemotherapy. The aim of the present study is to investigate the efficacy of oregovomab + non-platinum-based chemotherapy in PARPi-resistant EOC patients not suitable for platinum-based therapy. Methods: OEPRA is a multi-centre, investigator-initiated, two-cohort, single-arm phase II trial recruiting PARPi-resistant EOC patients from five sites in South Korea. The trial includes patients with recurrent EOC who have experienced disease progression despite treatment with PARPis and who have either received bevacizumab or are not eligible for bevacizumab treatment. Mucinous histology type is excluded. Patients who have received one to three prior lines of chemotherapy are to be assigned to Cohort 1 (oregovamab 2 mg [C1,2,3,5,7 for five doses] + pegylated liposomal doxorubicin [PLD] 40 mg/m2 q4w, n = 28), while patients who have received more than three prior lines of chemotherapy are to be assigned to Cohort 2 (oregovamab 2 mg [C1,2,3,5,7 for five doses] + weekly paclitaxel 80 mg/m2 [D1,8,15 q4w], n = 28). A total of 56 patients will be recruited and treated with oregovomab + PLD / weekly paclitaxel until disease progression, unacceptable toxicity, or withdrawal of patient consent. The primary endpoint is objective response rate by RECIST 1.1. Accrual is expected to be completed in 2023, followed by presentation of results in 2024. The study is registered with Clinicaltrials.gov (NCT05407584). Clinical trial information: NCT05407584 .

Safety and feasibility of hyperthermic intraperitoneal chemotherapy during interval cytoreductive surgery in patients with advanced high‐grade serous ovarian, fallopian tube, peritoneal cancer in an Australian context

To assess the safety and feasibility of hyperthermic intraperitoneal chemotherapy (HIPEC) during cytoreduction surgery (CRS) in advanced high-grade serous ovarian, fallopian tube and peritoneal cancer within an Australian context. Data were collected from 25 consecutive patients undergoing CRS and HIPEC from December 2018 to July 2022 at the Peritoneal Malignancy Service at the Mater Hospital Brisbane, Australia. Data collected included demographics, clinical variables, surgical procedures and complications and intra-operative and post-operative indexes of morbidity. Twenty-five women who underwent CRS and HIPEC from December 2018 to July 2022 were included in analysis. Findings indicate that CRS with HIPEC is associated with low morbidity. While judicious patient selection is imperative, HIPEC during CRS was well tolerated by all patients and morbidity was comparable to results from the previously reported OVHIPEC-1 trial. HIPEC appears to be a safe and feasible addition to CRS for the treatment of advanced ovarian cancer in Australian practice.

Multidisciplinary Management of Ovarian, Fallopian Tube and Peritoneal Cancers with Emphasis on the Role of Cross-Sectional Imaging

Multidisciplinary Management of Ovarian, Fallopian Tube and Peritoneal Cancers with Emphasis on the Role of Cross-Sectional Imaging

Homologous Recombination Deficiency Score Determined by Genomic Instability in a Romanian Cohort.

The Homologous Recombination Deficiency (HRD) Score, determined by evaluating genomic instability through the assessment of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST), serves as a crucial biomarker for identifying patients who might benefit from targeted therapies, such as PARP inhibitors (PARPi). This study aimed to investigate the efficacy of HRD testing in high-grade serous ovarian carcinoma, tubal, and peritoneal cancer patients who are negative for somatic BRCA1 and BRCA2 mutations and to evaluate the impact of HRD status on Bevacizumab and PARPi therapy response. A cohort of 100 Romanian female patients, aged 42-77, was initially selected. Among them, 30 patients had unsuitable samples for HRD testing due to insufficient tumor content or DNA integrity. Using the OncoScan C.N.V. platform, HRD testing was successfully performed on the remaining 70 patients, with 20 testing negative and 50 testing positive for HRD. Among the HRD-positive patients, 35 were eligible for and benefited from PARPi maintenance therapy, resulting in a median progression-free survival (PFS) increase from 4 months to 8.2 months. Our findings support the importance of HRD testing in ovarian cancer patients, demonstrating the potential therapeutic advantage of PARPi therapy in HRD-positive patients without somatic BRCA1/2 mutations.

Apendektomi sonrası tesadüfen teşhis edilen tubal yüksek dereceli seröz karsinom olgu sunumu

Primary tubal carcinoma is a uncommon tumor of female ganitale system. The clinical approach of primary tubal cancers is similar to primary ovarian cancers. Fallopian tube carcinoma is hard to diagnosed preoperatively because of its uncertain symptoms. Providing optimal cytoreductive surgery is the most important treatment step in ovarian, tubal and peritoneal carcinomas.
 We report a case of serous tubal intraepithelial carcinoma and appendix metastasis. A 65 years old post-menopausal woman (gravida 4, para 3) submitted to an external hospital with lower abdominal pain and acute abdominal symptoms. Appendectomy was performed on the patient with preliminary diagnosis of appenditis. The pathology result was reported as high grade serous carcinoma infiltration. Staging surgery was performed with the diagnosis of carcinoma. Until the final pathology result, the diagnosis was considered as appendiceal metastasis of serous tubal cancer. Our clinical and surgical approach to the case, which was diagnosed incidentally with an appendectomy specimen and reported as high grade tubal serous carcinoma, is presented as a case study.

Itraconazole interferes in the pharmacokinetics of fuzuloparib in healthy volunteers.

Fuzuloparib is an orally administered poly [ADP-ribose] polymerase 1 (PARP1) inhibitor and has potential anti-tumor effect on ovarian cancer (such as fallopian tube cancer and primary peritoneal cancer) in China. As fuzuloparib is metabolized mainly by CYP3A4, we explored the effect of itraconazole, a strong CYP3A4 inhibitor, on a single oral dose of fuzuloparib in healthy male subjects. An open-label, single-arm, fixed sequence study was conducted. Twenty healthy adult males received one single dose of fuzuloparib (20mg) with one dose administered alone and the other dose coadministered with itraconazole. Subjects received 200mg QD itraconazole for 6days during the study. Serials of blood samples were collected pre-dose of each fuzuloparib capsule administration and 48h post-dose, and were used to analyze the PK parameters of fuzuloparib. Coadministration of repeated 200mg QD oral doses of itraconazole for 6days increased fuzuloparib exposure by 1.51-fold and 4.81-fold for peak plasma concentration and area under the plasma concentration-time curve (AUC), respectively. Oral administration of 20mg fuzuloparib alone or together with itraconazole was safe and tolerable in healthy male subjects. The CYP3A4 inhibitor itraconazole has a significant influence on the PK behavior of fuzuloparib, suggesting to avoid using strong CYP3A4 inhibitors simultaneously with fuzuloparib. If it is necessary to use a strong CYP3A4 inhibitor, fuzuloparib would be discontinued and be restored to the original dose and frequency of administration after 5-7 half lives of CYP3A4 inhibitor stopped. http://www.chinadrugtrials.org.cn/index.html , CTR20191271.

BRCA 1/BRCA 2 Pathogenic/Likely Pathogenic Variant Patients with Breast, Ovarian, and Other Cancers.

The demographic and clinical characteristics of patients who have BRCA 1/BRCA 2 pathogenic/likely pathogenic variants may differ from their relatives who had BRCA-related cancer. In this study, we aimed to demonstrate the clinical and demographic findings of patients who had BRCA-related cancer and to assess the differences comparing their relatives who had BRCA-related cancer with breast, genital tract, prostate, and pancreas cancers as well. The results of sequencing analysis of 200 cancer patients (190 women, 10 men) who have been directed to genetic counseling with an indication of BRCA1/BRCA2 testing from different regions across 9 medical oncology centers were retrospectively analyzed. A total of 200 consecutive cancer patients who harbored the BRCA1/BRCA2 pathogenic/likely pathogenic variant (130 (65%) patients harbored BRCA 1 pathogenic/likely pathogenic variant, and 70 harbored BRCA 2 pathogenic/likely pathogenic variant) were included. Of these, 64.0% had breast cancer (43.8% of them had the triple-negative disease, and about 2.3% had only the HER-2 mutant), 31.5% had genital cancers (92.1% of them had ovarian cancer, 3.2% had endometrium, and 1.6% had peritoneum cancer as the primary site and mostly serous adenocarcinoma was the most common histopathology and 14.3% of the patients had endometrioid adenocarcinoma), 3.5% had prostate (median time from metastasis to castration-resistant status was 28 months) and 1.0% had pancreas cancer. Newly diagnosed cancer (breast and ovary) patients who had BRCA 1/BRCA 2 pathogenic/ likely pathogenic variant were younger than their previous cancer diagnosed (breast, ovary, and pancreas) parents who harbored BRCA pathogenic/likely pathogenic variant. We suggest that the genetic screening of BRCA 1/ BRCA 2 pathogenic/likely pathogenic variant is needed as a routine screening for those with a personal or family history of breast, ovarian, tubal, or peritoneal cancer. In addition, once BRCA 1 or BRCA 2 germline pathogenic variant has been identified in a family, testing of at-risk next-generation relatives earlier can identify those family members who also have the familial pathogenic variant, and thus need increased surveillance.

Management of Advanced Ovarian, Fallopian Tube, and Primary Peritoneal Cancers

Treatment approaches for advanced ovarian cancer should consider several factors. Among the most important are platinum sensitivity, the status of BRCA and homologous recombination deficiency (HRD), and the changing indications for PARP inhibitors in recurrent disease and maintenance. PARP inhibitors have demonstrated clear benefit in patients with BRCA mutated tumors, especially in the first-line setting, and HRD testing can guide their use for patients without BRCA mutations. A new antibody–drug conjugate, mirvetuximab soravtansine, has been approved for use in a subset of patients with platinum-resistant disease. Newly diagnosed patients with advanced-stage ovarian, fallopian tube, or primary peritoneal cancers should always be evaluated by a gynecologic oncologist if possible.

Olaparib and advanced ovarian cancer: Summary of the past and looking into the future.

Ovarian cancer (OC) is women's eighth most common cancer, bearing the highest mortality rates of all female reproductive system malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have reshaped the treatment scenario of metastatic OC as a maintenance post platinum-based chemotherapy. Olaparib is the first PARPi developed for this disease. Results from Study 42, Study 19, SOLO2, OPINION, SOLO1, and PAOLA-1 clinical trials, led to the FDA and EMA approval of olaparib for the maintenance treatment of women with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer without platinum progression: in the platinum-sensitive recurrent OC; in the newly diagnosed setting in case Breast Cancer (BRCA) mutations and, in combination with bevacizumab, in case of BRCA mutation or deficiency of homologous recombination genes. In this review, we synthetized olaparib's pharmacokinetic and pharmacodynamic properties and its use in special populations. We summarized the efficacy and safety of the studies leading to the current approvals and discussed the future developments of this agent.

Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: a multi-national observational study

ObjectiveOlaparib plus bevacizumab maintenance therapy improves survival outcomes in women with newly diagnosed, advanced, high-grade ovarian cancer with a deficiency in homologous recombination. We report data from the first year...

Health services costs for ovarian cancer in Australia: Estimates from the 45 and Up Study.

There have been significant advancements in risk identification and treatment for ovarian cancer over the last decade. However, their impact on health services costs is unclear. This study estimated the direct health system costs (government perspective) for women diagnosed with ovarian cancer in Australia during 2006-2013, as a benchmark prior to opportunities for precision-medicine approaches to treatment, and for health care planning. Using cancer registry data, we identified 176 incident ovarian cancers (including fallopian tube and primary peritoneal cancer) in the Australian 45 and Up Study cohort. Each case was matched with four cancer-free controls on sex, age, geography, and smoking history. Costs were derived from linked health records on hospitalisations, subsidised prescription medicines and medical services to 2016. Excess costs for cancer cases were estimated for different phases of care relative to cancer diagnosis. Overall costs for prevalent ovarian cancers in Australia in 2013 were estimated based on 5-year prevalence statistics. At diagnosis, 10% of women had localised disease, 15% regional spread and 70% distant metastasis (5% unknown). The mean excess cost per ovarian cancer case was $40,556 in the initial treatment phase (≤12 months post-diagnosis), $9,514 per annum in the continuing care phase and $49,208 in the terminal phase (up to 12 months before death). Hospital admissions accounted for the greatest proportion of costs during all phases (66%, 52% and 68% respectively). Excess costs were higher for patients diagnosed with distant metastatic disease, particularly during the continuing care phase ($13,814 versus $4,884 for localised/regional disease). The estimated overall direct health services cost of ovarian cancer in 2013 was AUD$99million (4,700 women nationally). The excess health system costs of ovarian cancer are substantial. Continued investment in ovarian cancer research, particularly prevention, early detection and more effective personalised treatments is necessary to reduce the burden of disease.

Abstract CT046: A randomized, phase 2 study of pembrolizumab plus chemotherapy with or without anti—immunoglobulin-like transcript 4 monoclonal antibody MK-4830 as neoadjuvant treatment for high-grade serous ovarian cancer

Abstract Background: Combination therapy with the anti-PD-1 monoclonal antibody (mAb) pembrolizumab and chemotherapy in advanced solid tumors has shown efficacy in the (neo)adjuvant and first-line setting, including high-grade serous ovarian cancer (HGSOC). The immunoglobulin-like transcript 4 (ILT4) receptor expressed on myeloid cells is involved in immune tolerance and suppression within the tumor microenvironment, and its blockade may improve treatment outcomes with combination therapies. Pembrolizumab plus chemotherapy with or without MK-4830 (a novel humanized anti-ILT4 mAb) will be investigated as neoadjuvant therapy for HGSOC in a randomized, open-label, phase 2 study (NCT05446870). Specifically, this trial is designed to evaluate the utility of circulating tumor DNA (ctDNA) as a biomarker of response and minimal residual disease in patients with treatment-naive HGSOC. Methods: Key eligibility criteria include adult patients with treatment-naive International Federation of Gynecology and Obstetrics Stage IIIA-C/IV HGSOC, primary peritoneal cancer, or fallopian tube cancer who are candidates for neoadjuvant and adjuvant chemotherapy and interval debulking surgery (IDS), and have an ECOG performance status of 0 or 1. Approximately 160 patients will be randomly assigned (1:1) to receive 3 cycles each of neoadjuvant and adjuvant therapy with patients in arm 1 receiving chemotherapy (carboplatin AUC 5 or 6 plus paclitaxel 175 mg/m2 or docetaxel 75 mg/m2) + pembrolizumab 200 mg and patients in arm 2 receiving chemotherapy + pembrolizumab + MK-4830 800 mg. Bevacizumab (or biosimilar) may be added to either arm in the adjuvant setting. All treatments will be given on day 1 of each 3-week cycle. For patients who undergo IDS, the last dose of neoadjuvant therapy will be administered 3-6 weeks before IDS, and adjuvant therapy will commence <7 weeks after IDS. Adjuvant therapy will be administered for up to 3 cycles or until disease progression, unacceptable toxicity, or withdrawal. Upon completion of adjuvant therapy, patients may undertake maintenance therapy per investigator discretion and local guidelines. Tumor imaging will be performed at baseline, ≥21 days after neoadjuvant therapy or prior to IDS, after IDS or prior to the start of adjuvant therapy, and at the end of treatment. The primary objective is to evaluate the change from baseline in ctDNA, defined as the continuous mean mutant/tumor molecules/mL as measured in a blood sample, at cycle 3. Secondary objectives are to evaluate the association between change from baseline in ctDNA at cycle 3 and surgical outcomes (including pathologic complete response and chemotherapy response score), and safety and tolerability. Enrollment is ongoing. Citation Format: Jung-Yun Lee, Maria Bell, Mariusz Bidzinski, Lubomir Bodnar, Jack Junjie Chan, Marta Gill-Martin, Carolina Ibanez, Domenica Lorusso, Chien-Hsing Lu, Ora Rosengarten, Steven M. Townson, Julie Kobie, Yiwei Zhang, Scott Pruitt, Ronnie Shapira-Frommer. A randomized, phase 2 study of pembrolizumab plus chemotherapy with or without anti—immunoglobulin-like transcript 4 monoclonal antibody MK-4830 as neoadjuvant treatment for high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT046.

Real-world study of bevacizumab treatment in patients with ovarian cancer: a Chinese single-institution study of 155 patients

ObjectiveThe purpose of this study was to retrospectively assess the pattern, compliance, efficacy and safety of bevacizumab in Chinese ovarian cancer patients.MethodsWe reviewed the clinicopathological data of patients with histologically confirmed epithelial ovarian cancer, fallopian tube cancer and primary peritoneal adenocarcinoma, who were diagnosed and treated at the Department of Gynecologic Oncology of Peking University Cancer Hospital between May 2012 and January 2022.ResultsA total of 155 patients were eventually enrolled in this study, with 77 as first-line chemotherapy (FL) and 78 as recurrence therapy (RT) among which 37 patients were platinum sensitive and 41 were platinum resistant. Among the 77 patients in the FL group, 35 received bevacizumab during neoadjuvant chemotherapy (NACT) alone (NT), 23 received bevacizumab during both neoadjuvant and first-line chemotherapy (NT + FL) and 19 received bevacizumab during first-line chemotherapy alone (FLA). Among the 43 patients of NT and NT + FL groups undergoing interval debulking surgery (IDS), 38(88.4%) patients achieved optimally debulking and 24 (55.8%) patients had no residual disease after IDS. The patients in the FL group had a median progression free survival (PFS) of 15(95%CI: 9.951–20.049) months, and the 12-month PFS was 61.7%. In the RT group, the overall response rate (ORR) was 53.8%. According to multivariate analysis, the patients' platinum sensitivity had a significant impact on the PFS in the RT group. 13(8.4%) patients discontinued bevacizumab due to toxicity. Seven patients were in the FL group while 4 patients were in the RT group. The most common adverse event associated with bevacizumab therapy was hypertension.ConclusionBevacizumab is effective and well-tolerated in the real world setting of ovarian cancer treatment. Adding bevacizumab to NACT is feasible and tolerable. Receiving the regimen containing bevacizumab in the last preoperative chemotherapy did not result in increased intraoperative bleeding of IDS. Platinum sensitivity is the most important factor affecting the effectiveness of bevacizumab in recurrent patients.