Background

Human epidermal growth factor 2 (HER2) encoded by the ERBB2 gene. In serous endometrial carcinoma (SEC) , HER2 is amplified in 17-30% cases. ERBB2 alterations are also present across other gynecological histologies. A randomized phase II study showed that the addition of trastuzumab to 1^st line platinum chemotherapy increased PFS and OS in HER2 amplified SEC , yet there is currently no approval for those drugs in gynecological malignancies.

Methods

We retrospectively collected data from patients with gynecological cancers who were screened by next generation sequencing (NGS) on tumor and/or circulating tumor DNA (ctDNA) and discussed at Gustave Roussy’s molecular tumor board between March 2021 and June 2022. The objective of this study was to describe the outcomes of gynecological patients harboring HER2 amplifications or pathogenic mutations that were identified through Gustave Roussy’s molecular program

Results

Between March 2021 and June 2022, 19 patients had a HER2 amplification and/or mutation. 11 patients (58%) exhibited an amplification, 6 (32%) a mutation and 2 (10%) both. All patients had metastatic disease at the time of screening. Regarding tumor types: 10 patients (53%) had endometrial carcinoma, 5 (26%) had ovarian carcinoma and 4 (21%) had cervix carcinoma. Only 9 patients (47%) received a HER2 directed therapy. All patient had ERBB2 amplification.1 patient was treated within a trial and 8 were treated off label with a trastuzumab containing regimen. 2 patients (22%) had a complete response and 5 (55%) had a partial response. Median duration of response was 7,6 months and median progression free survival was 8.1 month [min : 2.6m; max:11.6m]. Overall survival was significantly longer in patients receiving HER2 targeted therapy compared to those harboring HER2 abnormalities who did not receive them (mOS: NR vs 15.06m, HR : 0.18, IC95% 0.037 - 0.89).

Conclusions

Gynecological cancer harboring HER2 amplification and/or mutation are rare but can benefit from HER2 targeted therapy. There is a need to to test patients for ERBB2 alteration and develop trials with HER2 targeted therapies including gynecological tumors in order to obtain approvals in routine care

Background

NaPi2b is a sodium-dependent phosphate transporter broadly expressed in high-grade serous ovarian cancer (HGSOC), with limited expression in normal tissues. Uptifitamab rilsodotin (UpRi) is a first-in-class NaPi2b-targeting antibody drug conjugate (ADC) with a novel scaffold-linker-payload that enables high drug-to-antibody ratio and controlled bystander effect. NaPi2b is a new target currently being studied in ovarian cancer; understanding its expression and prevalence across HGSOCs is key in developing a biomarker-driven therapy.

Methods

Multiple datasets were used to address the question of NaPi2b expression and prevalence. In all datasets, NaPi2b expression was assessed by IHC with NaPi2b positivity defined as a tumor proportion score ≥75. Sample sets included commercially procured HGSOC representing synchronous sampling of primary and metastatic lesions, matched metachronous samples (“archival” and “fresh”) from the Ph1b UpRi trial and HGSOC tissues sampled at multiple time points throughout the course of their disease.

Results

Our results suggest high prevalence of NaPi2b positive expression in HGSOC. In the UpRi Ph1b clinical trial, 64% (50/78; 95% CI 52.4 - 74.7) of patients were determined to be NaPi2b positive, as determined by the GLP (good laboratory practices) assay.

When NaPi2b expression was examined from synchronous sampling of primary and metastatic lesions (N=18 pairs), as well as matched metachronous samples (N=56 pairs), there was high concordance rate ranging from 72-76% regardless of whether expression was evaluated over time or between anatomic locations.

Conclusions

NaPi2b is a stable biomarker that is highly expressed in the majority of HGSOC patients. Expression remains stable over time - regardless of biopsy sites or treatment history. These data are consistent with data previously published from an investigational companion diagnostic assay study from 398 unique HGSOC tissue samples suggesting a prevalence of 59% (Patel et al., USCAP 2022). These findings support early NaPi2b testing and the continued development of NaPi2b-directed agents for HGSOC. Further analyses from ongoing trials and data sets will provide additional information on NaPi2b expression.

Background

MORAb-202 is an antibody–drug conjugate comprised of the humanized anti-folate receptor-alpha (FRα) monoclonal antibody, farletuzumab, conjugated to the cytotoxic microtubule inhibitor, eribulin. In a phase 1 study (NCT03386942), MORAb-202 showed antitumor activity across varying FRα-expression levels at doses of 0.9 mg/kg (cohort 1) and 1.2 mg/kg (cohort 2) in patients with platinum-resistant (PR) OV. The disease control rate was 66.7% in cohort 1 and 95.2% in cohort 2. To evaluate the antitumor activity of MORAb-202 against high-grade serous OV, we investigated its biological mechanism of action, focusing on its ability to induce ICD using in vitro and in vivo models.

Methods

In vitro induction of ICD was evaluated in human OV cell lines treated with either MORAb-202 or eribulin by measuring HMGB1, HSP70, HSP90, and calreticulin. Antitumor activity of MORAb-202 was examined in OV cell line derived xenografts (CDx), and platinum sensitive (Pt-S) and platinum refractory (Pt-R) OV patient-derived xenografts (PDx). Immunohistochemistry/immunofluorescence (IHC/IF) staining in an OV CDx model was used to assess target engagement (anti-eribulin) and in vivo ICD induction (anti-HMGB1, anti-HSP90).

Results

Both eribulin and MORAb-202 elicited in vitro ICD induction of HMGB1, calreticulin, HSP70, and HSP90. HMGB1 increased in a dose-dependent manner; a time-course study in multiple cell lines showed this release to occur 72 hrs post treatment. In OV CDx and PDx models, a single dose of MORAb-202 (5 mg/kg) showed notable tumor shrinkage which was superior to eribulin monotherapy at a dose of 3.2 mg/kg (32 times the molar equivalent of eribulin in a 5 mg/kg dose of MORAb-202). A higher dosage of MORAb-202 (12.5 mg/kg) was required for durable tumor shrinkage in the Pt-R OV PDx model. In an OV CDx model, target engagement of MORAb-202 was confirmed. Translocation of HMGB1 and enhanced HSP90 production as ICD biomarkers were observed in triplicate tumor samples treated with MORAb-202 and eribulin.

Conclusions

These preclinical data illustrate ICD as a notable mode of action of MORAb-202 and suggest potential for effective antitumor activity in the clinic.

Editorial acknowledgement

Editorial support was provided by Dolly Al Koborssy, PhD, of Oxford PharmaGenesis Inc., Newtown, PA, USA, and was funded by Eisai Inc., Nutley, NJ, USA.

Background

The prognosis for patients with platinum-resistant ovarian High Grade Serous Carcinoma (HGSC) remains poor. BriTROC-1 data indicate that genomic alterations alone cannot explain acquired platinum resistance. We investigate epigenetic changes that may drive platinum resistance in HGSC.

Methods

Using in an in vitro two-dimensional model, we recreated multiple cycles of chemotherapy. We utilised both established cell lines and primary cultures derived from HGSC ascites. Following cell characterisation (p53, PAX8 IHC), carboplatin sensitivity was assessed (sulforhodamine B assay). Cells were then pulsed with four cycles of carboplatin (50μM for 6 hours) with a week of recovery between each cycle. Methylation (Illumina 850k array), transcriptomic (RNAseq) and chromatin accessibility (ATACseq) assays were performed. Cells were also imaged using Stochastic Optical Reconstruction Microscopy.

Results

Firstly, we focused on RNAseq analysis to evaluate genes (and related biological processes) that are consistently enriched following carboplatin cycles and the unique genes that are conversely enriched at cycle level. We attempted to identify uniformly up-/down-regulated pathways across the different cultures. These data were compared with the same results obtained from the OvCar4, an established HGSC cell line and IVR01, an in-vivo resistant OvCar4 derivative. The ATACseq and methylation analyses are still ongoing, aiming to identify possible concordant changes in the chromatin accessibility and the methylation patterns that will allow us to clarify the changes observed in transcriptomic. The preliminary data obtained from the RNAseq analysis show that the highest number of enriched genes seems to occur after the first Carboplatin cycle, with a lower number of progressively enriched genes across all other ones. No constant biological processes were identified for the moment, across the different primary cell cultures. Further comparisons will be certainly needed.

Conclusions

Understanding the epigenetic landscape of HGSC using physiologically relevant models will allow us to identify possible therapeutic targets that could eventually prevent platinum resistance.

Background

Background: Mortality in patients with high-risk and recurrent endometrial cancer (EC) is high since treatment options are limited, and tumors are extremely chemoresistant. In this study, we unveil the possible impact of molecular ITH in treatment response in EC; and we incorporate the molecular ITH of the tumor in the definition of a personalized medicine for EC patients.

Methods

Methods: Patient-derived xenograft (PDX) models were generated from 32 different tumor areas of a total of 13 EC patients. PDX tumors and a patient counterpart were analyzed by whole exome sequencing (WES) to unveil single nucleotide variation (SNV) and copy number variation (CNV) alterations. A bioinformatic pipeline was conducted to find the best candidate’s drugs targeting the specific mutated genes of each tumor area. Viability assays were performed to assess the efficacy of the selected drugs in organoids derived from patient-derived xenograft (PDX) organoids and mice models representing ITH.

Results

Results: All EC models presented molecular ITH. A subset of the most relevant altered tumor drivers and pathogenic genes were used to select drugs targeting specific ITH genes or homogenously altered genes in the primary tumor. Targeted drugs and standard chemotherapy were tested in deep and superficial areas of two EC patients using their PDXOs. A relevant difference between the IC50 of both areas (50 µM vs 12 µM) was encountered when assessing the efficacy of the Geldanamycin, which is a HSP90 inhibitor, targeting the ITH alteration of the deep area of one patient.

Conclusions

Conclusions: We have established a workflow for the identification of specific drugs targeting the molecular ITH in EC. Our preliminary results indicate that ITH might have an important role in treatment response.

Background

Current molecular testing of HGOC uses panel testing of fixed tumour tissue. Matched tumour-germline WGS is now in the NHS National Genomic Test Directory for fresh frozen (FF) samples. WGS offers significant advantages over panel tests, particularly for accurate measures of mutational processes (homologous recombination deficiency [HRD], tumour mutational burden [TMB]). We report the experience of integrating WGS into routine NHS pathways for women with HGOC between April and November 2022.

Methods

WGS of somatic (×80) and germline (×30) was performed by the NHS Genomics Medicine Sequencing Centre using Illumina chemistries. Processing of the sequence data and variant triage was performed by Genomics England WGS analysis pipeline. All patients (pts) gave written informed consent for germline and tumour testing.

Results

WGS was performed in 19 pts (table). After an initial 3 month run-in period using banked FF samples, prospective testing was integrated into routine care from July 22. The median time from consent to clinical reporting was 48 days (IQR 44-68).

WGS results changed the diagnosis in 3 patients: 2 with image-guided biopsies were changed from HGOC to low grade subtype and 1 recurrent poorly differentiated gynaecological carcinoma had unusually high TMB and APOBEC signatures that was inconsistent with HGOC enabling compassionate use of pembrolizumab.

Estimating HRD from WGS using the CHORD algorithm showed strong concordance with Myriad MyChoice (9/11; 82%). One clinically platinum-refractory case was proficient by CHORD and had a genomic instability score [GIS] of 42. The second pt had a germline deleterious BRIP1 variant with GIS 36 and was deficient by CHORD. CCNE1 amplification was only present in platinum resistant cases.

Conclusions

Biopsy pathways for FF and WGS are feasible for diagnostic pathways in the NHS. WGS offers clinically relevant measures of mutational processes in HGOC with diagnostic and predictive value.

Background

NXP800 (CCT361814) is a Heat Shock Factor (HSF1) pathway inhibitor currently being studied in a Phase 1 clinical trial (NCT05226507). NXP800 demonstrated substantial antitumor activity in cancer cell lines of different histologies, including ovarian clear cell and endometrioid carcinoma (OCCC and EOC), gastric carcinoma, and haematological cancers. Loss of function of ARID1A was identified as a predictive marker for response to NXP800 in OCCC and EOC. Here we describe an in vivo study of NXP800 versus cisplatin as an active control in cisplatin-resistant and cisplatin-sensitive ARID1A-mutated OCCC xenografts, supporting the clinical development of NXP800 in this indication.

Methods

In vivo studies were performed by generating subcutaneous tumors in Nude (nu/nu) mice using TOV-21G and SKOV3 cell lines. Loss of ARID1A was confirmed in western blot.

Results

Treatment with NXP800 resulted in substantial tumor growth inhibition (TGI) in both models. In the TOV-21G model, baseline tumor volumes for the vehicle, cisplatin and NXP800 groups were 201.71, 205.66 and 202.20 mm³, respectively; on Day 28, average tumor volumes were 399.84, 236.68 and 121.47 mm³, respectively, representing increases in tumor volume of 98% for the vehicle control group and 15% for the cisplatin group, and a decrease in tumor volume of 41% for the NXP800 group. In the SKOV3 model, baseline tumor volumes for the vehicle, cisplatin and NXP800 groups were 136.2, 138.5 and 134.7 mm³, respectively; on Day 28, average tumor volumes were 312.94, 253.71 and 53.33 mm³, respectively, representing increases in tumor volume of 130% for the vehicle control group and 80% for the cisplatin group, and a decrease in tumor volume of 60% for the NXP800 group.

Conclusions

NXP800 exhibits notable therapeutic activity in xenografts of OCCC – a condition of high unmet medical need with limited treatment options – including sustained tumour growth inhibition and regression both in cisplatin resistant (SKOV3) and sensitive (TOV-21G) OCCC models. Planned Phase 1b expansion cohorts will include ovarian clear cell carcinoma and ovarian endometrioid carcinoma patients with ARID1A mutation.

Background

Detection of residual tumor after radio-chemotherapy(RCX) in patients with locally advanced cervical cancer creates problems in clinical management. The aim of study is to evaluate the survival effect and prognostic importance of the residual tumor limited to the uterus in patients with advanced cervical cancer who received primary RCX.

Methods

125 cases of inoperable cervix cancer applied to our clinic between June 2012 and December 2018. Patients undergo magnetic resonance imaging of the pelvis to evaluate residual tumor before brachytherapy treatment, and positron emulsion tomography (PET-CT) to evaluate treatment response at 6 months after radical treatment.

Results

The median age was 50 and 111 patients (88.8% were diagnosed with squamous cell carcinoma and 14(11.2% with adenocarcinoma. Median tumor size was 5 cm and 71 patients were stage IIB (56.8%, and lymphnodes(LN) were detected in PET-CT before treatment in 70 patients. Residual tumor was found in 47 patients (37.6% median follow-up after external RCX 45 months (7-91) , and in 10 patients at 6 months.Three-year overall survival (OS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) rates were 86.9%, 89.1%, and 76.4%, respectively. In the univariate analysis, it was seen that the presence of residual tumor detected at 6 months was an unfavorable prognostic factor on LRFS (p=0.01), OS (p=0.001), and DMFS (p=0.01.Pre-treatment evaluation, presence of pelvic LN in PET-CT (p=0.05) and detection of residual tumor after external pelvic radiotherapy (p=0.015) were unfavorable prognostic factors on LRFS and DMFS.Local control (LC) was better in patients < 60 years (p=0.001), and distant metastases were more common in tumors > 5 cm (p=0.02. LC was better in <60 years (p=0.001), and distant metastases were more common in > 5 cm (p=0.02. Presence of residual tumor on PET-CT 6 months after treatment was determined in multivariate analysis as an important prognostic factor on OS and LRFS.

Conclusions

Treatment is controversial in patients with residual tumor after RCX.. Survival is worse in patients with residual tumor at 6-month follow-ups after treatment. The need for adjuvant therapy should be considered in these patients.

Editorial acknowledgement

Bedriye Doğan¹, Özlem Yetmen Doğan¹, Makbule Doğan Eren¹, Evrim Amodor²

¹Istanbul Kartal Dr Lutfi Kırdar City Hospital, Radiation Oncology Department

²Istanbul Kartal Dr Lutfi Kırdar City Hospital, Nuclear Medicine Department

Background

Cervical cancer is the second most frequent cancer among women in Uzbekistan. Due to poor accessibility of radiation therapy, especially in remote regions, addition of bevacizumab to platinum containing chemotherapy leads to improvement in overall survival in advanced cervical cancer. We therefore studied addition of bevacizumab to chemotherapy in a group of cervical cancer patients

Methods

The prospective study enrolled 54 patients with cervical cancer FIGO IIB stage, who underwent neoadjuvant chemotherapy: paclitaxel 175mg/m2 + carboplatin AUC6 + bevacizumab 15 mg/kg every 21 days. The control arm included 55 patients with the same stage cervical cancer, who underwent platinum containing chemotherapy in the same dosage, but without bevacizumab. The response rates were determined by means of preoperative clinical examination, diagnostic imaging (RECIST), changes in tumour markers (SCC) and by histopathology

Results

Clinical response rate after addition of bevacizumab was found in 88,8% of patients, and 74,5 % of patients who were treated without bevacizumab (p = 0.025), Addition of bevacizumab to platinum containing therapy led to higher rate of clinical complete remission (44.9 vs. 15.5%; p = 0.072). Significant reduction of tumor size was observed in all patients 100% who were treated chemotherapy + bevacizumab, and in 75% cases in patients only chemotherapy, this fact led to higher operability rates in both. The rate of pathological complete response(pCR) was altered significantly 28.6% bevacizumab free therapy vs. 44.5% chemotherapy + bevacizumab (p ≤ 0.005)

Conclusions

Addition of bevacizumab led to avoiding radiation therapy, better clinical response, higher operability and PCR rates. Further validation of angiogenesis Inhibitors in neoadjuvant treatment of cervical cancer needs larger multicentric randomized clinical trials

Background

To identify a specific population who might benefit from cervical conization prior to radical hysterectomy (RH).

Methods

From six institutions in Korea, we identified patients with node-negative, margin-negative, parametria-negative, 2009 FIGO stage IB1 cervical cancer who received primary Type C RH between January 2006 and December 2021. Patients were divided into multiple groups by cervical tumor size, surgical approach, and histology. We conducted a series of independent 1:1 propensity score matching and compared survival outcomes between the conization and control groups.

Results

In total, 1254 patients were included in this analysis: conization (n=355) and control (n=899). After matching, the conization group showed significantly better DFS (P=0.001) and OS (P=0.019) than the control group. Among the matched patients with squamous cell carcinoma (SCC) and cervical tumor >2 cm, the conization group showed significantly better DFS than the control group when MIS RH was conducted (3-year DFS rate, 96.3% vs. 87.4%; P=0.007 and aHR, 0.271; 95% CI, 0.100–0.736; P=0.010), but not open RH. Among the matched patients with non-SCC and cervical tumor >2 cm, the conization group showed significantly better DFS than the control group when MIS RH was conducted (3-year DFS rate, 97.0% vs. 74.8%; P=0.021 and aHR, 0.198; 95% CI, 0.043–0.916; P=0.038), but not open RH. However, no difference in DFS was observed between the conization and control groups among the matched patients with cervical tumor ≤2 cm, regardless of the surgical approach. In patients who underwent open RH, DFS did not differ by uterine residual tumor size. In contrast, DFS was significantly worsened as the size of the uterine residual tumor increased from >0 and ≤1 cm to >3 and ≤4 cm in patients who underwent MIS RH (P

Conclusions

Patients with 2009 FIGO stage IB1 cervical cancer having a cervical tumor >2 cm who are scheduled to undergo primary MIS RH might benefit from cervical conization, as conization was associated with a lower recurrence rate. Although there was no survival benefit from cervical conization in patients with cervical tumor ≤2cm, cervical conization purporting to minimize the uterine residual tumor may be worth considering before MIS RH.

Background

Tisotumab vedotin (TV) is an antibody-drug conjugate used for the treatment of adult patients with recurrent or metastatic cervical cancer. TV comprised of a monoclonal antibody against tissue factor and monomethyl auristatin E (MMAE), a potent inhibitor of cell division.

Methods

This is a systematic review of data about the safety and antitumor activity of TV in cervical cancer patients

Results

The innovaTV-201 and innovaTV-204/GO30xx/ENGOT-cx6 trials showed that TV has clinically meaningful and durable anti-tumor activity in pre-treated patients with recurrent or metastatic cervical cancer. The innovaTV-204 trial showed that TV monotherapy resulted in an objective response rate of 24% (including 7% and 17% complete and partial responses, respectively). In September 2021, the US Food and Drugs Administration (FDA) granted accelerated approval to TV for the treatment of recurrent or metastatic cervical cancer patients with disease progression on or after chemotherapy. The ongoing randomized, open-label Phase 3 innovaTV-301/ENGOTcx12/GOG-30xx trial will assess the effect of TV alone vs. the investigator’s choice of chemotherapy in second- or third-line recurrent or metastatic cervical cancer. Meanwhile, the multicohort phase 1b/2 trial ENGOT Cx8/GOG 3024/innovaTV-205 is testing the combination with TV alone and in combination with (i) bevacizumab, (ii) carboplatin, (iii) pembrolizumab, and (iv) pembrolizumab plus carboplatin with or without bevacizumab. The preliminary data highlighted the feasibility of the combination due to a good toxicity profile and suggest good clinical activity. In the first line, TV in combination with carboplatin or pembrolizumab provides an ORR of 55% and 41%, respectively. The effect of adding TV to the current standard of care in first-line (pembrolizumab plus carboplatin with or without bevacizumab) is still under evaluation.

Conclusions

Several trials tested the role of TV monotherapy for pre-treated recurrent or metastatic cervical cancer. Although the phase III randomized controlled trial (ENGOT-cx12/GOG-3057/innovaTV-301) is still enrolling, the available evidence from phase II studies supports the adoption of TV in pre-treated recurrent or metastatic cervical cancer patients.

Background

About 90% of the estimated cervical cancer deaths occur in low and middle-income countries. In Brazil, cervical cytology (i.e Pap smear) is a widely used strategy for its early detection. Considering the crucial role of the primary care in women’s health in Brazil and the COVID-19 pandemic related health crisis, this cross-sectional study aimed to analyze the repercussions of the COVID-19 pandemic in cervical cancer screening in a teaching Basic Health Unit (BHU) from South of Brazil, in the city of Pelotas.

Methods

This study was approved by the institutional ethics committee (5.706.229). We analyzed records of Pap smears performed between February 2019 to February 2020 and March 2020 to April 2022, referred to as pre-pandemic and pandemic period. The statistical analysis was performed using the Statistical Package for the Social Sciences program.

Results

The sample mean age was 43.6 years and they were mostly residents of the area covered by the BHU (94.35%). During the pre-pandemic and pandemic period 339 and 653 exams were collected, respectively. A 42% reduction in tests performed in 2020 compared to 2019 was observed as well as an increase of 107% in 2021 compared to 2020. An increase was assessed in the rate of non-residents (of the area of responsibility of the BHU) performing Pap tests in the Unit during the pandemic period (p = 0.001). Most of the results were negative for intraepithelial lesion or malignancy (NILM). A significant difference in abnormal results in the pre-pandemic and pandemic period, respectively, was seen (p = 0.012) (table 1).

Table 1: Association between the pre-pandemic and COVID-19 pandemic period and Pap smears results.

*Variables with data missing

Conclusions

The crisis brought on by the COVID-19 pandemic may have exacerbated pre-existing health disparities in cervical cancer already present in Brazil in pre-pandemic periods. Recovery strategies in primary care are needed to prioritize high-risk patients and lessen the burden of cervical cancer in the future.

Background

Cervical cancer ranks the fourth most frequently diagnosed cancer and the fourth leading cause of cancer-related deaths among women globally. In LMIC, most women with cervical cancer are diagnosed at an advanced stage because they have limited access to proper diagnosis. Treatment options are limited due to limited access to radiation therapy. Thus, survival outcomes are poor. There is no data on this issue in Cameroon so we undertook to determine the survival outcomes for women who present with cervical cancer to the CBCHS.

Methods

Data was extracted Women’s Health Program (WHP) database. Outcomes were categorized as alive with disease, alive without disease, or dead. Kaplan-Meier (KM) curves for survival were plotted stratified by age, HIV status, and histologic subtype. Cox regression model for survival analysis was used to determine the impact of some variables on the mean time of patient survival after diagnosis.

Results

Between 2013 and 2018, 752 women were diagnosed with cervical cancer. The average age at cervical cancer diagnosis was 53.33 (+/-13.82) with a mean survival time of 2.34 years (+/-2.00). Within five years of diagnosis, the overall survival for women diagnosed with cervical cancer was 27.1%. 285 (37.5%) of cases diagnosed did not go in for treatment. 387 (51.5%) went in for treatment, including 205 who did not complete their treatment. Age at diagnosis (HR 1.007 (95% Cl ( 1.000-1.013), p=0.035), a positive HIV status (HR 1.032 (95%Cl (0.930-1.145)) p = 0.558), and histologic subtype of adenocarcinoma (HR 1.026 (95% Cl (0.705-1.493), p=0.894) were associated with lower survival (although these associations were not statistically significant).

Conclusions

A diagnosis of cervical cancer is a serious threat to the health of women, especially in LMIC like Cameroon. Survival from the disease is extremely poor in this country, consistent with data from other LMICs. Most cases present late with symptoms, and the majority cannot afford treatment reflected by the very few who attend recommended forms of treatment or are unable to complete it. Education, and creating awareness around primary and secondary prevention and universal health care funding are necessary steps to strengthen cervical cancer control in Cameroon

Background

There are few clinical studies on Recombinant human endostatin (Endostar) which is a broad-spectrum antiangiogenic agent in the treatment of cervical cancer, and its efficacy in the treatment of cervical cancer has not been confirmed. This study aims to analyze the efficacy, safety and prognostic factors of Endostar combined with chemoradiotherapy in the treatment of local advanced cervical cancer (LACC).

Methods

The clinical data of 41 patients with locally advanced cervical cancer admitted to the Department of Radiotherapy of Changzhou Second People's Hospital Affiliated to Nanjing Medical University and the First Affiliated People's Hospital of Soochow University from 2017 to 2020 were retrospectively analyzed. The patients with LACC who received Endostar combined with and chemoradiotherapy were set as the A group. The B group (patients with LACC who received chemoradiotherapy) was set up by the method of 1:1 case-control matching in SPSS software.

Results

The complete response (CR) rate was 48.8% and 26.8% in A group and B group, respectively (χ²=4.20, p<0.05). However, the objective response rate (ORR) and disease control rate (DCR) have no significant difference found in the two groups (82.9% vs.70.7%, 92.7% vs. 80.5%, p>0.05). The 2-year OS rate in the two groups was 73.2% vs. 48.8%, with no significant difference (p=0.154). The 2-year PFS rates were not significantly different between A group and B group 68.3% vs. 46.3%, p=0.323). In terms of safety, acute adverse events such as gastrointestinal reaction, radiation enteritis and radiation cystitis had no significant difference between the two groups（p＞0.05）. Multivariable analysis identified ECOG 0-1 and tumor size < 4cm had a significantly improved OS of cervical cancer (p＜0.05), and staged IIB disease (FIGO 2009), ECOG 0-1 and tumor size < 4cm had a significantly improved PFS (p＜0.05).

Conclusions

Endostar combined with chemoradiotherapy exihibited a higher CR rate and does not increase the incidence of adverse events compared to chemoradiotherapy alone in the treatment of LACC. Additionally, there was a trend favoring the A group in OS and PFS. Disease stage, ECOG score and tumor size were independent predictive factors.

Background

Cervical cancer is a serious health problem, with nearly 500,000 women developing the disease each year worldwide. Most early-stage tumors women are curable. After careful clinical evaluation and staging, the primary treatment of early-stage cervical cancer is either surgery or radiotherapy or combined and there is a lack of preoperative radiotherapy trials alone so we aim to assess its impact on survival in early stage versus postoperative radio and surgery.

Objective

to evaluate the survival rate of pre versus postoperative radiotherapy compared to radical hysterectomy without systemic treatment in early stage (I, IIA2) cervical cancer patients.

Methods

We conducted a study using population-based data. Data was extracted from the Surveillance, Epidemiology, and End Results Program (SEER) database. Diagnosed women with early stage cervical cancer (I,IIA2) from 2010 to 2015 and received treatment into three groups preoperative, surgery only and postoperative radiotherapy. We calculated the survival rate.

Results

Out of 4399 female patients, 3988 were treated with radical hysterectomy without systemic therapy while 493 had postoperative radiation and 7 had preoperative radiation. The 5 year overall survival for postoperative radiation is better than preoperative radiation (85.8%,71.4% respectively) while radical hysterectomy without systemic treatment has 5 year survival of 93.2%,P> 0.00) .pre-operative radiation shows the worst survival outcome in the age groups 20-45 years and 46-70 years(80%,50%).

Conclusions

The results obtained in this study demonstrated that radical hysterectomy has survival benefit of 8 % than postoperative radiotherapy. Preoperative radiotherapy alone needs more studies to evaluate its impact on survival rate and patients have to be evaluated individually.

Background

cervical cancer is very common among females. Surgery, Chemotherapy and radiotherapy are different treatment options for cervical cancer. In 2018, the FIGO staging system has implemented lymph node status in the staging criteria but didn’t consider the number of positive lymph nodes. The current guidelines recommends primary chemoradiotherapy to treat the advanced stages but combined treatment regimens for node positive cervical cancer remains controversial, so this study aims to evaluate the survival outcome of different treatment modalities with further stratification by the positive lymph node number.

Methods

we used Surveillance, Epidemiology, and End Results (SEER) database to extract the data of 3146 patients with node positive cervical cancer diagnosed from 2000 to 2018, they were treated with different approaches: adjuvant chemoradiotherapy, adjuvant radiotherapy, surgery without systemic treatment, adjuvant chemotherapy and primary chemoradiotherapy.We divided patients into four groups according to the number of involved lymph nodes: one node, two to three nodes, four to 10 nodes, more than 10 nodes . We used SPSS for data analysis.

Results

The overall 5-year survival outcome was higher for adjuvant chemoradiotherapy compared to adjuvant radiotherapy, surgery, primary chemoradiotherapy and adjuvant chemotherapy (68.7%, 63.4%, 59.1%, 47.5%, 40.7% ; P-value >0.00). Out of Adjuvant chemoradiotherapy showed better 5-year overall survival outcome in patients with one lymph node involvement 73.1% and in patients with 2-3 positive lymph nodes 63.9%.

Conclusions

These results highlighted adjuvant chemo-radiotherapy as the treatment of choice for node cervical cancer stage IIIc, surgery and adjuvant chemoradiotherapy has have qiuet similar survival outcome .We also recommend the number of positive lymph nodes to be implemented in the upcoming FIGO system as a predictor for survival outcome and a factor for the treatment plan. Further evaluation is necessary to weigh the benefit versus side effects of the best regimen for each patient

Background

The quality of life (QoL) of patients with cervical cancer is of paramount concern in addition to their survival outcomes. The rationale of this study was to assess the QoL of the patients of locally advanced cervical cancer treated with chemoradiation and to estimate its difference when treated with two different brachytherapy (BT) techniques: Intracavitary (ICRT) or Interstitial brachytherapy (ISBT).

Methods

Forty-five, previously untreated, carcinoma cervix patients of FIGO stage IIB to IVA who were registered at the Institute of medical sciences, Banaras Hindu University, from December 2019 to March 2021 were included in the study. The patients were randomized into two BT arms, ICRT & ISBT, using simple randomization. The QoL was studied using structured European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaires C30 (QLQ-C30), and Cervical Cancer Module (Cx24). The baseline observations were recorded on the day of registration and then after three months of completion of treatment. These patients were treated with 6 MV photon with VMAT to a dose of 45Gy-55Gy in 25 fractions followed by ICRT (7Gy/#,3 #, 1#/week) or ISBT (6 Gy/#,4#, 6 hours apart over 2 consecutive days). BT planning was done on Oncentra treatment planning system.

Results

At 3 months of treatment completion, mean scores of global health status were 84.93 and 77.8 in the ICR and ISBT arm (p=0.019). The mean scores for physical functioning, emotional functioning, and social functioning were 92.81 and 94.3 (p=0.039), 96.75 and 87.16 (p= 0.000), 56.76 and 53.34 (p=0.002) for ICR and ISBT arms respectively. The difference in mean scores of fatigue, menopausal symptoms, the sexual worry was significant. The increment in peripheral neuropathy scores was more in the ISBT arm as compared to the ICRT arm (p=0.05) post-treatment completion. There was also a significant increase in sexual activity and an improvement in sexual enjoyment scores for the patients treated with ISBT(p=0.02).

Conclusions

QoL was improved in both treatment arms. However, the improvement was significantly more in the patients treated with intracavitary brachytherapy as compared to those treated with interstitial brachytherapy.

Background

Improving the results of treatment of patients with stage IIB cervical cancer by introducing the most effective, less toxic chemoradiotherapy at one of the phases of complex or combined treatment.

Methods

This study based on a prospective analysis of 215 women diagnosed with stage IIB cervical cancer. The median age was 47 years (28-64). The patients were divided into two groups: the NACT+S group, 105 patients who recive 2-3 cycles of neoadjuvant chemotherapy (paclitaxel+carboplatin) followed by surgical treatment. Radiotherapy (1,8 Gy, 45 Gy ± SIB on the metastatically involved lymph nodes 2,2 Gy, 55 Gy) was performed 1-2 months after surgical treatment. Patients also received cycles of cisplatin (40 mg/m2), administered once every week. The second group (CRT group) included 110 patients who underwent radiotherapy (regime was same with NACT+S = 1,8 Gy, 45 Gy ± SIB 2,2 Gy, 55 Gy). Brachytherapy was performed for all patients (6 Gy x 5 fr, to point A 30 Gy).

Results

The median follow-up was 23 months (8-38). In the NACT+S group, thrombocytopenia and neutropenia of the 3 - 4 degree were more common than in the CRT group (6.6% and 7.6% vs. 0.9% and 0.9%, respectively; p = 0.026; p = 0.015). However, there was no significant difference between the two groups studied in relation to the 3 - 4 degree of radiation toxicity of the GI and genitourinary system. 26 cases of disease progression (24.8%) occurred in the NACT+S group, and 15 events (13.6%) occurred in the CRT group; the corresponding 3-year DFS rates were 75.2% and 86.4%, respectively (HR 1.83; 95% CI 1.99-3.40; p = 0.05). Nineteen patients (18.1%) died in the NACT+S group, and 18 patients (15.5%) died in the CRT group, with corresponding 3-year indicators of OS was 81.9% and 84.5%, respectively (HR 1.11; 95% CI from 0.58 to 2.14; p = 0.736).

Conclusions

Cisplatin-based chemoradiation resulted in superior DFS compared with neoadjuvant chemotherapy followed by radical surgery in locally advanced cervical cancer. In the NACT+S group, thrombocytopenia and neutropenia grade 3 or 4 at a higher rate than in the concomitant CRT group. Despite this, there was no significant difference between the two study groups with 3-year indicators of OS and respect to grade 3 or 4 GI and bladder toxicities.

Background

The study was conducted with the aim to compare four radiotherapy schedules in terms of overall survival (OS), disease-free survival (DFS), acute & late toxicities in locally advanced cervical cancer.

Methods

A total of 73 patients (ECOG 0-1) with histologically proven cervical cancer, FIGO stage IIB-IVA were included in the study (December 2020 to July 2022). All the patients were treated with 6 MV Linear Accelerator with Volumetric modulated arc therapy (VMAT) to the whole pelvis. This was followed by High dose rate brachytherapy (HDR-BT) with intracavitary(ICRT) or interstitial(ISBT) application. Patients were randomized into four treatment arms:

Arm A- EBRT: 45 Gy/ 25 fractions/ 5 weeks; ISBT: 6 Gy / fraction, 4 fractions, twice daily.

Arm B- EBRT: 50 Gy/ 25 fractions/ 5 weeks; ISBT: 6 Gy / fraction, 4 fractions, twice daily.

Arm C- EBRT: 45 Gy/ 25 fractions/ 5 weeks; ICRT: 7 Gy / fraction, 4 fractions, weekly.

Arm D- EBRT: 45 Gy/ 25 fractions/ 5 weeks; ICRT: 7 Gy / fraction, 3 fractions, weekly.

Positive lymph nodes were treated with simultaneous integrated boost (SIB) of 55 Gy in 25 fractions and concurrent cisplatin at 40mg/m² in all four arms. The patients were contoured and planned on CT based planning system. Response assessment was done with functional MRI after completion of EBRT & after 3 months of treatment completion.

Results

The median follow-up of the study was 19.4 months. The mean OS in arms A, B, C & D was 32.3, 15.7, 15.3 & 34.5 months respectively (p= 0.954). The mean DFS in arms A, B, C & D was 31.9, 11.9, 11.0, and 28.8 months respectively (p= 0.562). Grade 3/4 acute hematological toxicity was seen in arm A (18.2%), C (5.6%) & D (17.3%). Grade 3/4 GI toxicity was present in arms C (5.6%) & D (13%). Radiation proctitis was significantly more in the arm A & B (p=0.007).

Conclusions

All the treatment arms were similar in survival outcomes and acute toxicities. However, radiation proctitis was significantly more in patients receiving ISBT.

Background

Cervical cancer remains the second cause of cancer death in women worldwide. Despite of good histological and clinical features, some patients relapse after the treatment of early stage cervical cancer. Recent studies identified correlation between some genetic alterations and poor prognosis in advanced-staged cervical cancer. Yet, the literature remains scarce about molecular alterations and outcome correlation in early stage cervical cancer.

Our translational study investigate recurrent molecular alterations predictive of outcome in early stage cervical cancer.

Trial Design

We included the first 100 patients randomized in the Senticol III trial. This large multicentric, prospective, randomized, and international “validation study” tries to validate sentinel node biopsy as nodal staging of early cervical cancers (stage Ia – IIa1).

Cervical tumor slides with contributive FFPE sample are analyzed and stratified based on well-established histological criteria (SEDLIS criteria). The immune microenvironment characteristics including TIL’s infiltration and PDL1 expression. PDL1 expression is assessed by IHC using the 22C3 antibody and quantified using CPS score. We made HPV detection and typing by PCR of the tumor samples. We performed DNA and RNA extractions from the FFPE tumor specimens. Using the dedicated gene panel developed by our team, we analyzed 571 genes commonly altered in cancer. We performed high throughput RNA sequencing to establish the gene expression profile of each tumor and its associated stroma.

The genomic and transcriptomic analysis assessed the tumor mutational load, the most frequently altered genes and their expression. The biostatistical analyses will correlate molecular alterations, histopathological and clinical classical features, with patient outcome. The different parameters will be first analyzed independently (univariate analysis) and then in a multiparametric manner (logistic regression).

Clinical trial identification

ClinicalTrials.gov identifier (NCT number) : NCT03386734

Editorial acknowledgement

This paper and the research behind it would not have been possible without the financial support of the CHU de Besancon and the Institut Curie Paris. We acknowledge ARCAGY-Gineco Group, the Senticol Group, the European Network of Gynaecological Oncological Trial Groups (ENGOT), Gynecologic Cancer Intergroup (GCIG) and the Cervical Cancer Research Network (CCRN) for their precious contribution.

Background

Chronic inflammation is one of the possible biological mechanisms underlying endometrial carcinogenesis. The aim of this study was to investigate whether pre-treatment biomarkers of systemic inflammation were associated with clinical outcomes in endometrial cancer (EC).

Methods

A total of 114 EC patients were analyzed in this multicenter retrospective study. All patients included in the study underwent chemotherapy. Blood count values were collected before the start of treatment. The correlation between platelet count, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and systemic immune inflammation index (SII - calculated as (platelet count × neutrophil count)/lymphocyte count), and progression-free survival (PFS) and overall survival (OS) were analyzed using the Cox regression model.

Results

Endometrioid histology (70.2%), high grade (64.3%) and good (0) ECOG performance status (PS) (77%) were present in the majority of patients. Approximately half of the patients (51.8%) received adjuvant radiotherapy, 20.2% were metastatic and 26.8% were obese. Patients with high NLR (≥3), PLR (≥169), SII (≥730) and platelet count (>400 thousands) had significantly shorter PFS and OS. In multivariate analysis adjusted for age, histology, grade, stage, adjuvant radiotherapy, body mass index and PS, NLR, PLR, SII and platelet count were predictive for PFS. All inflammatory indexes except SII were also significantly associated with OS (table).

Conclusions

NLR, PLR and platelet count were independent predictors of PFS and OS in patients with EC treated with chemotherapy. High SII was associated with worse PFS but not OS.

Background

The purpose of this study was to evaluate the efficacy of docetaxel/cisplatin chemotherapy followed by pelvic radiation therapy after staging surgery in high-risk endometrial cancer patients.

Methods

This was a prospective, phase 2, multicenter clinical trial (Clinical trial identifier : NCT01461746). Eligible patients included surgically staged stage I-II endometrial cancer with high-risk factors and stage III–IV endometrial cancer. Three cycles of chemotherapy consisting of docetaxel (70 mg/m²) and cisplatin (60mg/m²) was started within 5 weeks after staging surgery. Pelvic radiation therapy (45-50.4Gy) was started within 4 weeks after chemotherapy. The primary endpoint was progression-free survival(PFS).

Results

A total of 67 patients were enrolled but 9 were excluded. Median age was 54 years (range, 31-73 years). Forty patients (69%) had endometrioid adenocarcinoma. Stage was IIIC in 9 (15%), IVA in 15 (26%), and IVB in 11 patients (19%). Staging surgery was performed by open surgery in 27 patients (46%), laparoscopic surgery in 23 patients (40%), and robotic surgery in 8 patients (14%). Grade 3 and 4 hematologic toxicity was reported in 26 and 43 patients, grade 3 non-hematologic toxicity was reported in 13 patients. After a median follow-up of 58 months (range, 2-101 months), 11 patients had recurrence and 2 of them died of disease. PFS (± SE) was 90% (± 4%), 84.3% (± 4.8 %), 79.9% (± 5.5 %) at 1, 3, and 5 year, respectively. Overall survival (± SE) was 98.3% (± 1.7%), 96.2%, (± 2.6%), 96.2 (± 2.6%) at 1, 3, and 5 year, respectively.

Conclusions

Endometrial cancer with high risk factors could benefit from adjuvant chemotherapy using docetaxel/cisplatin followed by radiation therapy with manageable toxicities. Further studies are needed with the incorporation of biological agents to estimate the real benefit of these treatment strategy.

Clinical trial identification

NCT01461746

Background

The Cancer Genome Atlas (TCGA) Project defined four prognostic subgroups of Endometrial Cancer (EC): POLE (favorable prognosis), MSI and Copy Number Low (CNL) the intermediate prognosis; and Copy Number High (CNH) unfavorable prognosis.

The aim of the study is to perform a characterization at immune level of the prognostic EC-TCGA groups to identify those cases that could be benefited of immunotherapy.

Methods

A total of 48 FFPE EC were retrospectively selected (Ref): POLE (n=6); MSI (n=9); CNL (n=16) and CNH (n=17). Transcriptomic profiling was performed with HTG EdgeSeq Precision Immuno-Oncology Panel (PIO), which interrogates 1392 genes involved in tumor/immune interaction. The estimation of the relative abundance of immune and stromal cellular content and cell types was assigned to the 23 HTG EdgeSeq Reveal software immunophenotyping signatures. DESeq2 R package was used for differential expression analysis. Statistical analysis and data visualization was performed in R version 4.1.2. Clinicopathological information is collected in Table 1.

Results

Unsupervised analysis showed 2 clusters with different prognosis in terms of OS (p=0.0033) and DFS (p=0.00055) (Table 1). Cluster 1 was constituted by 8 MSI, 6 POLE, 14 CNL and 7 CNH while cluster 2 was mainly formed by CNH (10), followed by 1 MSI and 2 CNL. Differential expression analysis resulted in 897 genes between clusters, 400 overexpressed and 497 under expressed in Cluster 1. The 6 most significant genes were TGFB1, BEX1, CDK4, TUBB, RFC4 and TRIP13. In addition, cluster 1 was related with higher PD-1 (p=4.4·10^-4), PD-L1(p=9.9·10^-6) and CTL4 (p=4·10^-4) expression and immune related scores (immune; p=0.00019 and stroma; p=0.00014)

Conclusions

Cluster stratification suggests implication of immune-related features in classification of EC-patients beyond TCGA subgroups. These findings could be useful in the clinical management of the disease, constituting an open window in the selection of EC patients for immunotherapy

Background

There is limited evidence of RW outcomes for pts with A/R EC. This descriptive, noninterventional, retrospective study reports RW pt characteristics and survival outcomes in a cohort of pts with A/R EC in England who received first-line (1L) therapy and could have been eligible for a clinical trial of an immune checkpoint inhibitor (ICI) in EC.

Methods

This study used routine population-level data, available through the National Disease Registration Service in England. Pts diagnosed with A/R EC (recurrences identified via a defined algorithm) between 1 Jan 2013 and 31 Dec 2019 were included (follow-up until 23 Aug 2021). Patients in the ICI cohort had received any 1L therapy for A/R EC and met the key eligibility criteria of the RUBY trial (A Study to Evaluate Dostarlimab Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Participants With Recurrent or Primary Advanced Endometrial Cancer; NCT03981796). Demographics, baseline characteristics, and therapy received were reported. Overall survival (OS), time to next treatment (TTNT; a proxy for progression-free survival), and time to treatment discontinuation (TTD) from 1L chemotherapy initiation (index date) were assessed using Kaplan-Meier methodology.

Results

Of 9629 identified pts with A/R EC who received any 1L therapy, 24.7% (N=2376) were in the ICI cohort (demographics in table). Median TTNT, median TTD, and median OS in months from 1L chemotherapy initiation were 16.9 (95% confidence interval [CI]: 15.8–18.5), 3.4 (95% CI: 3.4–3.4), and 27.2 (95% CI: 24.7–30.2), respectively.

Conclusions

This RW study in England demonstrates that 1L survival outcomes are poor for pts with A/R EC who received 1L therapy, highlighting the critical unmet need for more effective therapies to delay EC relapse and prolong pt survival.

Clinical trial identification

OneCDP218291

Editorial acknowledgement

Editorial support provided by Hayley Butler, PhD, of Fishawack Health, funded by GSK.

Background

While endometrial cancers are associated with favourable outcomes due to early symptomatic evaluation, patients with high-risk features are at a higher risk of recurrence. Although results of PORTEC-3 trial established the role of concurrent chemoradiation followed by adjuvant chemotherapy for high-risk endometrial cancer patients, its concordance data in South Asian populations is lacking. Present study aims to assess toxicity profiles and outcomes in this cohort of patients.

Methods

Patients planned for endometrial cancer treatment as per PORTEC-3 trial regimen from October 2016 to August 2022 at our institute were ambispectively analysed for toxicity with RTOG grading and treatment outcomes.

Results

58 patients were included (Median age 61 years) with FIGO stages I (26, 44.8%), II (5, 8.6%) and III (27, 46.6%). Patients were surgically staged using robotic (33, 56.9%), laparoscopic (9, 15.5%) and open (16, 27.6%) methods. 40 patients (69%) had Type II histology, p53 and Napsin A positivity was seen in 38 and 3 patients respectively. IMRT was used in 44 patients (79.3%). Acute Toxicity analysis showed that most common complaint during CTRT was diarrhoea (38 patients, 65.5%) of which only 10 were Grade 2. Grade 2 hematological and GU toxicities were noted in 2 and 0 patients respectively. Regarding adjuvant chemotherapy; 2 patients withdrew consent, 14 had peripheral neuropathies (3 discontinued treatment) and 15 had Grade 2 hematological toxicities. No patient stopped treatment during CTRT, 4 discontinued adjuvant chemotherapy due to toxicities and further 6 required dose reduction. At median followup of 24 months, 15 patients recurred (Isolated paraaortic recurrences in 2, distant metastases in 13). Medication requiring neuropathies persisted in 11 patients, 1 needed surgery for bowel obstruction due to incisional hernia, and no late GU toxicities were seen.

Conclusions

There is good tolerance and compliance to adjuvant treatment with chemoradiation and chemotherapy in this South Asian cohort of patients, with no toxicity related treatment breaks during CTRT. Relapse was majorly seen at distant sites. These findings are in line with outcomes of PORTEC 3 trial.

Background

To investigate the clinicopathologic characteristics and the impact of mismatch repair-deficient/microsatellite instability-high (MMRd/MSI-H) on oncologic outcomes of patients with endometrial cancer.

Methods

In this single-center, retrospective study, patients with endometrial cancer who underwent immunohistochemistry staining for MMR proteins (MLH1/MSH2/MSH6/PMS2) and/or next-generation sequencing for MSI status and genomic alterations between January 2011 and June 2021 were included. Data collected included patient demographics, clinicopathologic characteristics, treatment, and clinical outcomes.

Results

Of the total 234 eligible patients, 182 patients (77.8%) had MMRp/non-MSI-H tumors and 52 patients (22.2%) had MMRd/MSI-H tumors. Between two groups, clinicopathologic characteristics including histologic type, grade, myometrial invasion, LVSI, LN metastasis were not statistically different. A total of 74 out of 234 patients were tested for PD-L1, and PD-L1 expression was observed in 52.6% in the MMRp/non-MSI-H group and 88.2% in the MMRd/MSI-H group (p=0.028). There was no statistically significant difference in recurrence rates and survival outcomes in relation to MMRd/MSI-H status (p=0.244 and 0.240, respectively). Among MMRd/MSI-H patients, six patients were treated with immune checkpoint inhibitors and objective response rate was 50.0%, comprised of 3 partial responses. A grade 3 or higher adverse event occurred in one patient, thrombocytopenia.

Conclusions

In patients with endometrial cancer, MMRd/MSI-H is not associated with oncologic outcomes. In clinical practice, immunotherapy was safe and efficacious in MMRd/MSI-H recurrent endometrial cancer.

Background

Management of intermediate-high risk early stage endometrial cancer (EC) can be challenging since a proportion of these patients (pts) relapse and the role of adjuvant chemotherapy (CT) is unclear. We aimed to evaluate the role of adjuvant CT for this population.

Methods

This retrospective study evaluated pts with intermediate-high risk early stage EC treated in a single center from 2009 to 2021. Endpoints were overall survival (OS) and disease free survival (DFS) according to the adjuvant systemic treatment used after surgery. The Kaplan-Meier method was used for survival analyses. Hazard ratio (HR) and 95% confidence interval (95% CI) were calculated using Cox regression.

Results

175 pts were evaluated and median age was 63 years (IQR 34-88). About the risk category, 33% had stage I disease with lymphovascular invasion (LVI); 22% had stage IB with grade 3 disease and 43% had stage II disease. Regarding surgery, 144 pts (82%) were submitted to pelvic and 107 (61%) to paraortic lymphadenectomy. 41 pts (29%) received CT (96% carboplatin and paclitaxel), 37 (21%) received adjuvant external beam radiotherapy (EBRT), 37 (21%) received adjuvant brachytherapy (BCT), and 77 (44%) received both EBRT and BCT.

With a median follow-up of 64 months, 33 pts had a disease recurrence; 10% had a locoregional recurrence, 7% a distant recurrence, and 2% had both locoregional and distant recurrence. No difference was observed in DFS or OS according to the use of adjuvant CT. 5-year DFS rates were 74.7% (95% CI 64.7 - 82.2%) in those who received CT and 77% (95% CI 62.3- 86.6%) in pts who did not received CT (p= 0.392). 5-year OS were 87.1% (95% CI 78.2 - 92.5%) in and 93.3% (95% CI 80.6 - 97.8%), respectively (p= 0.259). BCT (HR 0.36, 95% CI 0.18 - 0.68, P=0.002) and pelvic lymphadenectomy (HR 0.42, 95% CI 0.21 - 0.83, P=0.014) were identified as factors associated with a superior DFS, while FIGO stage II (HR 2.17, 95% CI 1.12 - 4.22, P=0.021) was associated with inferior DFS. Pts that received BCT had less locoregional recurrence than those who did not receive it (4,4% vs 10,3%).

Conclusions

Pts with intermediated-high risk early stage EC does not seem to benefit from adjuvant CT. In this cohort, BCT and pelvic lymphadenectomy were associated with a better DFS.

Background

According to the molecular classification based on TCGA data, endometrial cancer can be
separated into 4 groups harboring prognostic and therapeutic implications: 1) Ultramutated
(with mutations in POLE gene) 2) Hypermutated, 3) Copy
Number Low and 4) Copy Number High.
To bring this classification into clinical practice, some authors have proposed a simplified
scheme using three immunohistochemical markers (p53, MSH6, and PMS2) and a molecular
test for detecting mutations on POLE.
The lack of a cost-effective Gold Standard has prompted the development of new techniques
such as MODAPLEX (BIOTYPE). In this study, we intend to explore the diagnostic performance
of this technology in order to study POLE “Hotspot” mutations in endometrial carcinoma samples

Methods

The number of recruited cases has been 258 ECs. From each case a tumor paraffin block has been selected. Sections of 10 µm thickness, have been obtained, subsequently performing DNA isolation and quantification.

Cses with a DNA concentration under 10 ng/µl have been excluded, the rest have been tested by MODAPLEX. Every positive result has been reconfirmed by Sanger sequencing.

The pilot phase is composed of 105 EC, diagnosed between 2016 and 2020 and with available molecular classification.

The second phase includes a retrospective cohort of 30 EC diagnosed between 2000 and 2015, with the aim of checking diagnostic performance of the test when applied to samples with a lesser DNA quality. Finally, we have recruited a prospective cohort, made up of EC diagnosed from the end of 2020 to the present and in which the molecular classification has not been yet performed.

Results

A total of 258 samples have been finally submitted to the test. Regarding the first two phases, 30 positive and 103 negative cases have been detected with just a false negative. In this subset, the test have revealed sensitivity and specificity values of 97% and 100%, and positive/negative predictive values of 100% and 99%.
Out of 123 prospective cases, the test have detected 16 positive samples. All of them subsequently confirmed by Sanger sequencing.

Conclusions

MODAPLEX is a promising technology that allows the determination of the main “Hotspot” mutations in POLE gene in a fast, practical and efficient way.

Background

Metastasis is a poor prognostic factor for endometrial cancer. Disparities between African-Americans and Caucasians in metastasis patterns require further investigation. Thus, this study aims to compare the patterns of metastasis between African-Americans (AA) and Caucasians (C) among different histological subtypes of endometrial cancer.

Methods

Data was extracted from Surveillance, Epidemiology, and End Results Program (SEER) database from 2010-2019. We extracted data of patients with endometroid, cyst, mixed cell adenocarcinoma and adenocarcinoma not otherwise specified who presented with metastasis to bone, brain, liver, or lung at the time of diagnosis. We calculated the relative risk (RR) and confidence interval (CI) using SPSS software, version 25.0 (IBM).

Results

Compared to Caucasians, African-Americans had higher risk of lung and liver metastasis in all subtypes except cyst adenocarcinoma. Additionally, African-Americans with endometroid adenocarcinoma had higher risk of bone metastasis (RR=2.01, 95% CI 1.44-2.81, P>0.001). Lungs were the most prevalent site of metastasis in African-Americans and Caucasians across all subtypes. Adenocarcinoma not otherwise specified was the most common subtype associated with metastasis at the time of diagnosis.

Conclusions

Across multiple subtypes of endometrial cancer, African-Americans are at increased risk of metastasis compared to Caucasians. Further studies of genetic and biological factors are warranted.

Background

Ubamatamab (REGN4018) is a mucin 16 x cluster of differentiation 3 (MUC16xCD3) bispecific antibody that promotes T cell–mediated cytotoxicity by binding MUC16-expressing ovarian cancer (OC) cells and CD3+ T cells. We present safety, efficacy and pharmacokinetic (PK) modelling from a first-in-human study of ubamatamab (NCT03564340).

Methods

Patients (pts) with recurrent platinum-experienced OC received ubamatamab 0.3–800 mg intravenously weekly (QW) after initial step-up dosing. Primary endpoints were safety and PK. Secondary and exploratory endpoints included objective response rate per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, disease control rate (a response or stable disease) and cancer antigen 125 (CA-125) response per Gynecological Cancer InterGroup criteria.

Results

78 pts received ubamatamab 0.3–800 mg without reaching maximal tolerated dose. Median number of prior therapies was 4.5 (range 1–17). Median ubamatamab exposure was 12 (range 1–117) weeks. Commonest treatment-emergent adverse events (TEAEs) were cytokine release syndrome (73.1%, all Grade 1/2) and pain (87.2%), primarily occurring in Weeks 1–2 of step-up dosing. Commonest Grade ≥3 TEAEs were anemia (24.4%) and abdominal pain (20.5%). Objective responses were observed between 20–800 mg. In 42 pts receiving ≥1 full dose of ≥20 mg, ORR was 14.3% (95% CI, 5.4–28.5), disease control rate was 57.1% (41–72.3), and median duration of response was 12.2 months. 23.8% of pts (12.1–39.5%) had a CA-125 response. Serum ubamatamab concentrations increased dose proportionally. No apparent dose-response relationship was observed from 20–800 mg for safety or efficacy. PK modelling supported the selection of 250 and 800 mg every-3-weeks (Q3W) regimens for Phase 2, as both regimens had a maximum concentration (C_max) below the C_max of 800 mg QW, and trough concentration (C_min) above that of the minimal effective dose (20 mg QW).

Conclusions

Ubamatamab resulted in an acceptable safety profile and durable responses in a heavily pretreated OC population across a wide dose range. A randomised Phase 2 expansion trial with initial step-up dosing followed by Q3W dosing has been initiated.

Clinical trial identification

ClinicalTrials.gov: NCT03564340

Editorial acknowledgement

Editorial support was provided by Rachel McGrandle of Prime Medica, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc.

Background

Currently little is known about correlations between the type and the location of the BReast CAncer genes (BRCA) 1/2 mutations and response to Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer (OC). Clinical data from PAOLA1 study suggest that patients with mutations in DNA binding domain (DNA-BD) of BRCA1 are more sensitive to the combination olaparib/bevacizumab and those in the DNA-BD of BRCA2 confer excellent outcomes. We investigated if the type and the location of the BRCA 1/2 mutations are related with PARPi sensitivity.

Methods

This multicenter and retrospective study evaluated the efficacy of PARPi according to the mutation type and location in the functional domain (FD) of BRCA1 (RING, DNA-BD or BRCA1 C terminus [BRCT]) and BRCA2 (PALB2, RAD51-BD; DNA-BD). BRCA1/2 germline mutated OC patients receiving PARPi as maintenance, after a response to platinum-based first line chemotherapy were enrolled. Baseline characteristics and survival data were collected from 3 academic centers.

Results

Of 202 patients treated between December 2008 and October 2021, 122 (60.4%) received PARPi in the first-line setting and 80 (39.6%) at recurrence. Among the first group, 73 (60%) and 49 (40%) harbored BRCA1 and BRCA2 mutations, respectively. BRCA1 mutations in FDs of RING, DNA-BD and BRCT were found in 3 (2.5%), 8 (6.6%) and 21 (17.2%) patients, respectively. BRCA2 mutation were detected in FDs of RAD51-BD and DNA-BD in 25 (20.5%) and 5 (4.1%) patients, respectively. Median follow-up was of 20 (4-100) months. In patients with DNA-BD mutation of BRCA1/2, 2-yr Progression Free Survival PFS was 100%, compared with 80% in mutation in the other domains (log rank p= 0.079). With regard to the mutation type, patients harboring a missense BRCA1 mutation had a longer PFS (2-yr PFS 100%), compared with 50% of those with a splicing mutation (log rank p= 0.021) and 75% of those with a nonsense mutation (log rank p= 0.049). Mutation types in BRCA2 were not analyzed due to the small numbers.

Conclusions

The results confirmed that mutations in the DNA-BD region in the BRCA 1/2 genes confer longer PFS respect to other location of mutation. Besides, missense mutation has the best prognosis, compared with splicing and nonsense mutation.

Background

Real-world (rw) data on the outcomes of pts with EOC receiving 1Lm niraparib are limited. The CHAR1ZMA study characterizes TTNT for pts with EOC prescribed 1Lm niraparib monotherapy in the US using a rw database.

Methods

Pts diagnosed with EOC on or after 01Jan2011, who were ≥18 years old at initial diagnosis, treated with 1L platinum-based chemotherapy, and received 1Lm niraparib monotherapy between 01Jan2017–03Mar2022 were included from the nationwide electronic health record-derived de-identified Flatiron Health database and followed until last clinical activity or end of the data period. Index date was defined as the end of 1L platinum-based chemotherapy. TTNT (proxy for rwPFS) was defined as time from index date to start of 2L treatment/death and was estimated using the Kaplan-Meier method. Results were stratified by age, BRCA status, homologous recombination (HR) deficiency status, and residual disease (RD) status following cytoreductive surgery.

Results

Of 414 eligible EOC pts, 83.3% were diagnosed with stage III/IV disease and 42.5% had no visible RD following cytoreductive surgery. Median age at index was 67 years, 80.7% had an ECOG performance of 0–1, and 83.6% were BRCA wild-type. Median follow-up time was 13.8 months. Overall, observed median TTNT was 13.3 months (95% CI 12.0, 15.8). Observed TTNT varied by demographic and clinical characteristics (Table). Longest median TTNT was observed in pts with a BRCA mutation (BRCAm), followed by HR deficiency (HRd), <75 years of age, and those with no visible RD following cytoreductive surgery.

RW TTNT in EOC pts receiving 1Lm niraparib by subgroups

^aIncludes somatic and germline mutations

^bUnknown categories excluded in the KM analyses

CI, confidence interval; HRp, HR proficient

Conclusions

This rw study of 1Lm niraparib monotherapy in pts with EOC demonstrates the importance of considering pt characteristics and reinforces the PFS benefit first observed in the PRIMA trial.

Editorial acknowledgement

Editorial support by Claire Kelly, Fishawack Health, funded by GSK.

Background

NOVA was a randomized Phase 3 trial assessing the efficacy of niraparib maintenance for patients (pts) with platinum-sensitive recurrent ovarian cancer (OC); overall survival (OS) was the secondary endpoint. The aim of this real-world (RW) study was to compare OS in BRCA wild-type (BRCAwt) pts with recurrent OC receiving second-line maintenance (2Lm) niraparib monotherapy or active surveillance (AS) to complement NOVA trial results.

Methods

This study used the US nationwide Flatiron Health de-identified electronic health record-derived database. Pts diagnosed with epithelial OC from 1 Jan 2011–31 May 2021 and completed 2L therapy from 1 Jan 2017–2 Mar 2022 were eligible for inclusion. Pts were assigned to niraparib 2Lm or AS cohorts according to their treatment scenario after end of 2L therapy (≤120 days). Follow-up was measured from index date (end of 2L non-maintenance therapy) until end of study (31 May 2022), last activity or death, whichever came first. A target trial emulation cloned inverse probability of censoring weighting (IPCW) methodology was selected a priori to minimize bias. IPCW median OS and hazard ratios (HR) for 2Lm vs AS were estimated with Kaplan-Meier curves and Cox regression models.

Results

Overall, 199 and 707 BRCAwt pts received niraparib 2Lm or were under AS, respectively. Most pt characteristics were similar across cohorts (Table). Median follow-up was 15.6 and 9.3 months, and median OS was 24.1 (95% confidence interval [CI]: 20.9, 29.5) and 18.4 (95% CI: 15.1, 22.8) months for niraparib 2Lm and AS cohorts, respectively (HR: 0.77 [95% CI: 0.66, 0.89]).

Table. Patient characteristics and follow-up before adjustment

HRp, HR proficient; NR, not reported

Conclusions

This RW study provides supportive evidence of niraparib's OS benefit in BRCAwt pts in the 2Lm setting. Homologous recombination deficiency (HRD) testing in the RW is limited and prevented examination of BRCAwt + HR deficient (HRd) subgroup.

Editorial acknowledgement

Editorial support provided by Claire Kelly, Fishawack Health, funded by GSK.

Background

PLD-Trabectedin is currently an option for patients diagnosed with relapsed ovarian cancer (ROC) with a platinum free interval (PFI) of at least 6 months; also, the advent of PARP-i maintenance therapy has revolutionalized the landscape, creating an ever-growing population who progress afterwards and has yet to be addressed when it comes to efficacy and tolerability of CT schemes

Methods

This study is a multicenter, retrospective analysis aimed at comparing patients receiving PLD-Trabectedin after being treated with PARP-i (cases) with PARP-i naïve patients (controls).

Descriptive and survival analyses were performed. Probability of Progression Free Survival (PFS) was estimated using the Kaplan–Meier method and compared with the log‐rank test.

Results

Ninety patients were included in our analyses, 31 controls and 59 cases. The populations were compared for categorial variables (Age, Stage at diagnosis, type of surgery at diagnosis, histology) and no statistical difference was found.

Median PFS was 11 months (95% IC 10-12) in the control group vs 6 months (95% IC 6-9) in the case group (p value 0.0017), persisting when adjusted for BRCA mutation.

Clinical benefit Rate (CBR) was evaluated, with a HR for progression of 2.23 (95% IC 1.19-4.20, p value 0.012) for the case group.

We compared hematological toxicity, gastro-intestinal (GI) toxicity, hand-foot syndrome (HFS), fatigue and liver toxicity; no significant disparity was noted except for HFS with a p value of 0.006. The distribution of G3 and G4 toxicities was equally represented.

Conclusions

The MITO39 study showed a statistically significant difference in PFS between patients previously treated with PARP-i and PARP-i naïve patients for PLD-Trabectedin, therefore suggesting that a previous exposure to PARP-i might inhibit the efficacy of the regimen.

Regarding tolerability, the comparison did not yield a remarkable disparity.

To our knowledge, these is the first data regarding this topic; PARP-is have now been a standard of care for years, resulting in the need to further explore whether the exposure to this target therapy has any impact in later lines.

Background

Paclitaxel and carboplatin remains a backbone treatment of ovarian cancer (OC) inducing peripheral neuropathy in a significant proportion of patients. Meanwhile, long term survival of OC has dramatically increased with the recent therapeutic progress. Predictive factors for long-term CIPN are needed considering the impact on quality of life (Qol) of patients. We investigated the link between the incidence of CIPN and selected genetic polymorphisms in a cohort of ovarian cancer survivors.

Methods

Vivrovaire is a French multi-center long-standing cohort of ovarian cancer patients free of disease 3 years after the end of the primary treatment. Long-term analysis of Qol in linked with neuropathy was performed including peripheral neuropathy assessed by the FACT/GOG-Ntx4 self-questionnaire. CIPN scores were correlated with SNPs in the selected CYP2C8, CYP3A4, ERCC1 and XPC genes.

Results

130 patients were included with a median time from the end of chemotherapy of 63 months [35-180]. Median CIPN score was 37 [18-44] with 35 patients (27 %) having a severe score (< 33). SNPs (homozygotous/heterozygotous) were identified as follows: CYP2C8 [n=32 (24.6%)/ n=99 (76%)]; CYP3A4 [n=0 (0%)/ n=8 (6.1%)], ERCC1 [n=21 (16.1%)/ n=57 (43.8%)] and XPC [n=45 (34.6%)/ n=66 (50.8%)]. In univariate analysis, homozygous SNP (ho SNP) in any of the selected genes was associated with CIPN score as a continuous variable (p=0.045) but not with severe score (< 33) (OR: 1.66; 95% CI [0.74-3.88], p=0.22). Patients with CYP2C8_rs1934951 SNP tend to have CIPN score <33, (OR: 2.22; 95% CI [0.98-5.02], p=0.057). In multivariate analyses including age, interval from the end of chemotherapy, type and number of chemotherapy courses, identification of homozygotous or heterozygotous CYP2C8_rs1934951 SNP was associated with a severe CIPN score (OR: 2.41; 95% CI [1.02-5.70], p=0.043).

Conclusions

Our study shows that residual CIPN is a frequent concern for ovarian cancer survivors. CYP2C8_rs1934951 SNP may be associated with severe residual CIPN in long-term survivors of ovarian cancer.

Background

Platinum sensitivity may be a dynamic status in HGEOC pts. Currently, higher proportion of platinum-resistant (PR) pts exceeds the predicted median OS of 12 months (m) with an ECOG PS 0-1, and PtRc may be still an option. We aimed at evaluating the efficacy of retreating with platinum to HGEOC pts considered PR based solely on platinum-free interval (PFI) <6 m and exploring clinical and molecular predictive markers.

Methods

This is an ambispective observational, single-institution study that assessed PtRc efficacy in pts for whom last PFI was < 6 m and received non-platinum agents afterward for >1 year. Key clinical characteristics and BRCA mutation (BRCA-mut) data were analyzed from medical charts between 2010 and 2022. Objective response rate (ORR) and median progression-free survival (mPFS) were evaluated in the whole population, and according to BRCA status and prior number of lines.

Results

At time of data cut-off, 58 pts were included in the analysis. Median age was 57 years (IQR 48-63), 96.4% had ECOG <1, 93% had high-grade serous histology and 11 pts (18.9%) harbored tBRCA-mut. Median number of lines prior to PtRc were 6 (IQR 5-7), and median PFI prior to PtRc was 24.8m (IQR 19.7-33.5). Platinum doublets used in PtRc contained: paclitaxel (41.4%), PLD (39.7%), gemcitabine (15.5%); or carboplatin alone (3.4%). In the whole cohort, ORR was 56.9% (95%CI 43.2-69.8) and mPFS was 6.9m (95%CI 5.8-8.3). Improved PFS and ORR were observed in tBRCA-mut compared to BRCA wild type (wt) pts: ORR 81.8% (95%CI 48.2-97.7) vs 51.1% (95%CI 36.0-65.9, p=0.08), mPFS 9.0 vs 6.7m (HR 0.39, 95%CI 0.18-0.85; p=0.02), respectively. According to number lines prior to PtRc (</=4 vs >4), ORR was 76% (95%CI 54.9-90.6) vs 42.4% (95%CI 25.5-60.8; p=0.01), and mPFS 7.7m vs 6.7m (HR 0.57, 95%CI 0.32-1.0; p=0.05).

Conclusions

PtRc seemed to be an efficacious therapeutic approach for pts previously classified as PR who had received non-platinum therapies for >1 year, especially for those harboring tBRCA-mut or having received </=4 prior lines. These data seem to support the dynamic concept of platinum-sensitivity. Further research is warranted to better select pts for whom PtRc would be an option.

Background

Retrospective analyses show a lower-than-expected response to subsequent chemotherapy in recurrent platinum sensitive BRCA mutated OC patients who received a maintenance poly-adenosine ribose phosphatase inhibitor (PARPi). Does PARPi use affect real world outcomes for OC patients including BRCA wild-type?

Methods

We undertook a retrospective single-institution analysis of medical records for patients who received subsequent chemotherapy following a PARPi between January 2018-December 2021. Objective Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS) were calculated. Statistical tests used were Kaplan-Meier (OS and PFS) and Fisher’s Exact Test (DCR and ORR).

Results

We included 46 patients; mainly advanced stage III (n = 29, 63%) and IV (n = 16, 35%). Most were germline BRCA wild-type (n = 42, 91%) with 4 (9%) germline BRCA mutant. PARPi’s included olaparib (n = 2, 4%), niraparib (n = 37, 80%) and rucaparib (n = 7, 15%), with median duration of use of 150 days (range 9-630). Longer duration on PARPi showed a trend to progression at next treatment (non-significant). Subsequent post-PARPi chemotherapy was mainly platinum-based (n=39, 85%).

ORR to first post-PARPi treatment was 23% for a platinum-based (non-evaluable radiological response excluded 4 patients) and 0% for non-platinum chemotherapy (p = 0.31). DCR was 31% to platinum-based and 14% to non-platinum chemotherapy (p = 0.65). Median PFS was 5.0 months for platinum-based and 1.3 months for non-platinum chemotherapy (HR 0.65, p = 0.31). Median OS was 17 months for platinum-based and 10.7 months for non-platinum chemotherapy (HR 0.15, p < 0.008).

Stratification by previous platinum-free interval (PFI) of 6-12 months (n = 13), 12-24 months (n = 11) and >24 months (n = 12) showed no significant difference in ORR (p = 0.89), DCR (p = 0.90), PFS (p = 0.29) or OS (p = 0.79) following first post-PARPi treatment. Limitations include single institution experience and retrospective non-trial based follow up.

Conclusions

Maintenance PARPi use resulted in similar PFS, ORR and DCR to subsequent treatment when compared to historic studies in the BRCA wild-type population and was not affected by PFI.

Background

Inflammation is a hallmark of cancer. In our recent Umbrella systematic review of systematic reviews, we demonstrated that inflammatory biomarkers based on peripheral blood count impact both progression-free survival and overall survival (OS) in ovarian cancer. Pan-Immune-Inflammation Value (PIIV) is a new prognostic factor that was studied in breast cancer and other malignancies, but never in ovarian cancer. In this study, we provide the first results of the prognostic value of PIIV in a Moroccan cohort of ovarian cancer patients based on a biomarker-analysis of OVANORDEST-1 study.

Methods

An exploratory biomarker set from our OVANORDEST-1 database was included in the final analysis with OS as a primary endpoint. PIIV was calculated as previously described: (neutrophil count × platelet count × monocyte count)/lymphocyte count. Receiver operating characteristic (ROC) was used to evaluate the optimal cut-off of PIIV. Cox proportional hazard model was used for multivariable analysis and Kaplan-Meier method to estimate OS.

Results

A total number of 158 patients treated for epithelial ovarian cancer with a median age of 55 years were included in the survival analysis. A ROC-based cut off of 991.7 of PIIV was used for patients’ stratification. Survival analysis using Log rank test showed a significant association of PIIV with OS (p<0.0001). Women with high PIIV had the worst outcomes as compared to those with low PIIV (median OS: 16 months versus 35.4 months, respectively). On Cox proportional hazard model, PIIV was an independent predictor of OS (HR=2.38, CI:1.47-3.85; p<0.0001).

Conclusions

High PIIV is associated with an increased risk of death in women with epithelial ovarian cancer. A validation set of this study is ongoing and a prospective enrollment to develop a nomogram based on PIIV is being planned.

Background

Despite considerable efforts, little advances have been made in the treatment of platinum resistant ovarian cancer (PROC) in the last decade. The reasons for these dismal results remain controversial. Understanding phase (Ph) 3 randomized controlled trials (RCT) design and outcomes in PROC patients might provide indications for the development of future research.

Methods

We performed a systematic review searching in PubMed, Embase and CENTRAL for Ph3 RCT enrolling PROC patients, published between 2010 and 2022. For the meta-analysis, effect sizes (ES) for progression free survival (PFS) and overall survival (OS) were calculated using random-effect models with restricted maximum likelihood estimate.

Results

After screening and eligibility assessment, 15 records reporting the results of 13 RCT were included, for a total of 4606 patients. Experimental arm employed targeted agents in 6 trials, chemotherapy (Cht) in 4, immunotherapy in 2 and antibody-drug conjugate in 1. Control treatment was Cht in all studies. Only 3 trials included a biomarker-selected population. PFS and/or OS were the (co-)primary endpoints in all studies but one. Median PFS ranged from 1.9 to 6.7 months (m) in the experimental arms and from 1.2 to 5.7 m in the control arms; median OS ranged from 8.8 to 16.6 m in experimental arms and from 8.4 to 22.2 m in the control arms. All but two trials (TRINOVA1 and AURELIA) failed to show any PFS benefit in PROC patients and none had positive OS results. Overall ES for PFS was -0.03 (95% CI -0.23, 0.16), with high heterogeneity (I² 83.3%) while ES for OS was -0.02 (95% CI -0.10, 0.05) with negligible heterogeneity (I² <0.0001). Of the included Ph3 RCT, 6 were preceded by a single arm and 3 by a randomized Ph2 study.

Conclusions

The two RCT testing the anti-angiogenic agents bevacizumab and trebananib combined with Cht were the only reporting a PFS benefit in PROC. The lack of robust predictive biomarkers, of adequate preclinical and early clinical results and of a proper methodology might partly explain these disappointing outcomes. A better understanding of PROC biology and its implementation in study design are crucial to improve drug development in this population.

Background

Poly ADP-ribose polymerase inhibitors (PARPi) have revolutionized the treatment of high grade serous ovarian carcinoma (HGSOC), especially those harbouring BRCA1/2 mutations. Emerging preclinical evidence suggest a potential relationship between BRCA specific-domain defects and sensitivity to PARPi. In particular, ring-less BRCA1 protein, characterized by a residual activity in RAD51 foci formation, has been associated with a reduced response to PARPi. On the contrary, mutations (mut) in the BRCA2 DNA binding domain (BD), that is essential for RAD51-induced architectural rearrangement of BRCA2, have been associated with an increased sensitivity to PARPi. Real world data regarding PARPi efficacy according to specific BRCA domain mut are missing.

Methods

The clinical data for pts with advanced HGSOC and BRCA1/2mut who received first-line platinum-based chemotherapy followed by PARPi from 2018-2021 at the University of Naples Federico II were retrospectively collected. BRCA1/2mut were classified according to location in BRCA1 protein (DNA-BD, BRCT, RING finger domain, others) and in BRCA2 protein (DNA-BD, RAD51-BD, others). The log-rank test was used to assess the difference in progression-free survival (PFS) distribution between the groups.

Results

Among 41 pts, 25 harboured a BRCA1mut (61%) and 16 a BRCA2mut (39%). BRCA1 mut in the RING domain, DNA-BD and BRCT were detected in 3 (12%), 8 (32%), 7 (28%) pts, respectively; other mut in 7 pts (28%). BRCA2 mut in RAD51-BD and DNA-BD were detected in 8 (50%) and 6 (38%) pts, respectively; other mut in 2 pts (13%). No statistical differences in terms of PFS were observed according to the BRCA1mut (P = 0.87) or BRCA2mut (P = 0.18) domains. Interestingly, a numerically longer median PFS was observed in pts with BRCA2 BD mut compared to the other BRCA2 defects, (log-rank test for trend P = 0.05).

Conclusions

Pts diagnosed with advanced HGSOC derived similar PFS benefit from PARPi regardless the locations of BRCAmut. Although limited by a small cohort size our analysis suggests that DNA-BD BRCA2mut may predict increased sensitivity to PARPi.

Background

PARP (poly ADP–ribose polymerase) inhibitors are approved as maintenance therapy in platinum sensitive ovarian cancer (OC), in first line and in the recurrent setting, regardless BRCA mutational status. Real-world data after the introduction of these agents are needed to evaluate whether the benefit observed in phase III trials can be translated into clinical practice. The aim of our study was to provide real-life data on efficacy and safety of niraparib administered as maintenance in platinum sensitive relapsed OC patients (PSROC).

Methods

This retrospective/prospective multicenter study included relapsed OC patients treated in 17 MITO centers and receiving niraparib as maintenance, according to the label, at the time of first or subsequent platinum sensitive recurrence. Clinical data at the time of diagnosis and at the time of recurrence before Niraparib treatment were collected from the patients´ medical records at each institution, centralized into an electronic CRF at the coordinating center (Fondazione Policlinico Gemelli) and analyzed.

The efficacy and safety analysis, as primary objectives, was performed.

Median progression free survival (PFS) and overall survival (OS) were calculated as the time from start of niraparib treatment to subsequent radiologically confirmed relapse and death or last contact, respectively.

Results

The study included 304 patients with median age of 58 years (range 51-66).

260 (85%) enrolled patients were BRCA wild-type and 36 (11.9%) were BRCA mutated. At the time of diagnosis, most of patients (65.8%) underwent complete debulking surgery and were diagnosed with III-IV FIGO stage (78.8%). At the time of recurrence before niraparib maintenance 179 patients (58.9%) had received 2 previous lines of platinum-based chemotherapy and carboplatin in combination with PDL was the most frequent administered regimen (31.3%). Complete and partial radiological response to platinum-based CT was recorded in 44.4% and 27.0% of patients, respectively.

Median PFS was 9.1 months (95% CI: 7.6-10.7) and median OS was 41.7 months (95% CI: 32.4-51.1).

Conclusions

In a real-life setting, niraparib maintenance in patients with PSROC showed efficacy comparable with the published phase III data.

Clinical trial identification

NCT04617470

Background

Primary debulking surgery (PDS) or interval debulking surgery (IDS) and a platinum-based chemotherapy are the current standard approach for the treatment of advanced ovarian cancer (OC). Time to initiation of chemotherapy (TTC) could influence patient outcome.

Methods

In a multicenter retrospective cohort study of advanced (FIGO stage III or IV) OC, patients underwent a germline multi-gene panel evaluation between 2014-2018 TTC, calculated as the time from PDS or IDS to the start of chemotherapy, was assessed in relation to progression-free or overall survival (PFS, OS). Age, residual tumor (R: R0, R+), ascites (no, yes), bevacizumab use (no, yes), and mutational status (BRCAmut, other mut, wild-type - WT) were collected. Time-to-event endpoints were analyzed using the Cox model and results reported as hazard ratios (HRs) and 95% confidence intervals (CIs). All analyses were performed for PDS and IDS, separately.

Results

Among the 137 eligible patients, the median TTC was 45 days (1st–3rd quartile: 38; 58 days) and 21.9% of patients with a TTC≥60 days. BRCAmut patients were 18.3%, 10.2% with germline mutation in other DNA repair genes and 71.5% were WT. Median follow-up time was 67.9 months (95% CI: 56.6–87.8). TTC was significantly associated with R only in PDS patients (n=83): 16.9% with TTC<60 and 64.3% with TTC≥60 days, p<0.001. At univariate analysis, TTC≥60 days was associated with a shorter PFS in PDS patients (HR 2.02, 95% CI: 1.04-3.93, p=0.038), although this association lost statistical significance when adjusted for R (HR 1.52, 95% CI: 0.75-3.06, p=0.244 for TTC and HR 2.73, 95% CI: 1.50-4.96, p= 0.001 for R). In a stratified analysis by R, there appeared to be some evidence of an association between TTC and PFS among R+ patients, n=20, (HR 2.53, 95% CI: 0.86-7.47, p=0.093). Regarding OS, at univariate analysis TTC≥60 was associated with an adverse outcome even if not statistical significant (HR 2.03, 95% CI: 0.75-5.51, p=0.161). Among IDS patients we found no evidence of association between TTC and clinical outcomes.

Conclusions

A shorter TTC may affect patient prognosis in PDS patients, especially in case of R+, but larger casuistry is needed to confirm our hypothesis.

Background

Fallopian tube cancer is a rare tumor which accounts for only 1% of all gynaecological cancers. It is closely related and generally treated with a similar approach to ovarian cancer. We used the publicly available databases to provide a description of epidemiological patterns, clinical outcomes, and mutational landscape of fallopian tube cancer and compare it with that of ovarian cancer.

Methods

We extracted clinical and epidemiological data of fallopian tube and ovarian cancers from the SEER database [13 reg; Nov 2020 Submission]. The average annual percentage change (AAPC) of incidence rates was calculated using The NIH’s Joinpoint Regression Program. Sequencing data were obtained through The American Association of Cancer Research (AACR) project GENIE database.

Results

We included 4,240 cases of fallopian tube cancer and 74,837 cases of ovarian cancer diagnosed between 1992 and 2018. The overall incidence of fallopian tube cancer was 0.39 [95% CI, 0.38-0.40], whereas the overall incidence of ovarian cancer was 6.97 [95% CI, 6.92-7.02]. Between 1992 and 2018, there was a significant increase in the incidence of fallopian tube cancer (AAPC = 6.1% 95% CI, [4.6, 7.9], p<0.001) and a decrease in the incidence of Ovarian cancer (AAPC = -1.7% 95% CI, [-2, -1.4], p<0.001). The median overall survival of fallopian tube cancer was significantly higher than ovarian cancer (80 months vs 43 months, P<0.001). A presentation with stage IV disease was significantly less frequent in fallopian tube cancer compared to ovarian cancer (50% vs 70%, P<0.001). In 166 patients with fallopian tube cancer and 5,303 patients with ovarian cancer in GENIE, the most frequently mutated genes were TP53, SPTA1, LRP1B, FAT3, and NF1; and TP53, CSMD3, DNAH9, ARID1A, and PDE4DIP; for fallopian tube cancer and ovarian cancer respectively.

Conclusions

Fallopian tube cancer is a distinct disease entity different in genetic, epidemiological, and clinical characteristics from ovarian cancer. Cases with fallopian tube cancer are less likely to present with distant metastasis and have longer overall survival compared to cases with ovarian cancer. The most frequently mutated genes of both cancers are different.

Background

Circa 25% of all OC are heritable, mainly associated with BRCA1/2 genes. Due to BRCA1/2impact on carcinogenesis, prevention and treatment, all cases of OC (excluding mucinous) are candidates for genetic testing, even without family history. We analyzed genetic testing after OC diagnosis since 2014.

Methods

Identification of OC patients tested under the Breast/Ovarian/Prostate program (2014-2022) and analysis of referrals after primary diagnosis and access to testing. The subgroup of OC patients observed between November 2021 and October 2022, which included candidates for olaparib maintenance after primary treatment, is described.

Results

488 OC patients consented on germinal testing. Most of cases were HGSOC (n=347, 71%). Detection rate was 18.0%. Variant distribution: BRCA1-27; BRCA2- 34 BRCA2 (8 c.156_157insAlu, a founder variant); RAD51C-10; RAD51D-10; CHEK2-3; ATM-2, MUTYHand BARD1 (one each). After November 2021, from 61 OC women, 45 stage were III/IV and 34 had high grade disease (HGD), 27 of them under primary treatment. Five of 27 (18,5%) tested positive for BRCA1(2), BRCA2(2), ATM (1) and 1 patient had a somatic BRCA1variant. All these are under olaparib primary maintenance.

After OC diagnosis, median delay of testing referral was 3.6 years (5days-30years) between 2014-2022, 5yrs (5days-23years) between 2014-2016, 4years (22days-9.6years) between 2017-2019, and 2.7yrs (16days-30years) between 2020-2022. This delay decreased in 2022, significantly for HGOC patientss under primary treatment (177 d) (p<0.05). For this subgroup most women were tested at diagnosis, after surgery or during primary CT, but 6 (22%) patients were only identified after primary treatment was completed.

Medium delay for test reporting (2014-2022) was 176 days (12-524days). While a trend for reduction was observed after 2017, this was not significant (p=0.6). For the past year, median delay was 92 days and for the high grade subgroup under primary treatment 71 (22-141) days.

Conclusions

Referral delays after OC diagnosis reflect broadening of testing criteria after 2014. Patients should be tested early after diagnosis, to avoid cases without information regarding the possibility of maintenance after primary treatment. Other findings reinforce the role of BRCA2 in OC in Portugal.

Background

Ovarian cancer (OC) is an aggressive tumour that is usually diagnosed in an advanced stage. The presence of somatic and/or germinal mutations in the genes BRCA1 and BRCA2 is known to be predictive of response to platinum agents and inhibitors of PARP (iPARP). Nevertheless, in recent years it has been shown that the efficacy can vary according to the specific mutation. In our community there is a high prevalence of patients (pts) carrying the BRCA1 c.211 A>G germline pathogenic variant, which is a founder mutation originated in the northwest of Spain. The aim of our study was to evaluate if these pts presented different outcomes when treated with first line platinum agents and iPARP.

Methods

We performed a single-centre retrospective analysis of pts carrying somatic and/or germline pathogenic variants of BRCA1 and BRCA2 treated with platinum agents and iPARP between January 2014 and June 2022. Variants were detected with validated methods in tissue and/or blood samples. Data was extracted from electronic health records and analysed with SPSS software.

Results

We found 36 pts with the aforementioned characteristics. Median age upon diagnosis was 56.2 (range 41 – 82) years. The initial FIGO stage was IIIC in 55.6% and IV in 33.3% of the cases. The majority of pts had an ECOG PS of 1 (58.3%) or 0 (33.3%). 26 pts (72.2%) had a BRCA1 variant, and of those 13 pts carried the BRCA1 c.211 A>G variant. These pts presented a worse objective response rate (ORR) to first line platinum-based chemotherapy when compared to all the pts (61.5% vs 87.0%, p = 0.04) and to BRCA1 mutated pts (61.5% vs 84.6%, p = 0.18). They also had a lower ORR to iPARP (15.4% vs 21.7%, p = 0.21). Median progression free survival (PFS) to first line treatment was lower among BRCA1 c.211 A>G variant carriers than the rest of the pts (28 vs 33 months, p= 0.41), as it was overall survival (OS) (72 vs 91 m, p = 0.29).

Conclusions

We found that pts with BRCA1 c.211 A>G germline pathogenic variant presented numerically worse outcomes when treated with DNA damaging agents, with a significantly lower ORR to platinum agents. Further research should be carried out to confirm if this mutation conveys less sensitivity to these therapies.

Background

Amongst gynaecological cancers, ovarian cancers are associated with unfavourable prognosis and high mortality owing to presentation at advanced stages. Present study aims to compare two diagnostic algorithms, International Ovarian Tumor Analysis (IOTA) Simple Ultrasound Rules versus Risk of Malignancy Index (RMI 2) for detection of ovarian malignancies.

Methods

50 consenting patients with ovarian mass (reproductive and menopausal age groups) evaluated at our institute over a period of nine months were prospectively enrolled. Patients were subjected to detailed examination, ultrasonographic assessment by gynaecologists and lab investigations including CA 125 was done. Data was collected using a standardised pretested proforma. Patient management as per departmental protocol was continued.

Results

IOTA Simple Ultrasound Rules consistently performed better than RMI 2 in detection of ovarian malignancies, with better sensitivity (96.96% vs 75.6%), specificity (71.4% vs 64.7%), positive predictive value (88.8% vs 80.6%) and negative predictive value (90.9% vs 57.8%) respectively.

Conclusions

Results of present study indicates that IOTA Simple USG Rules has better Sensitivity, Specificity, Positive Predictive Value and Negative Predictive Value than Risk of Malignancy Index, and a larger study may be warranted to obtain results which can be extrapolated to the general population.

Background

Epithelial ovarian cancer requires the development of treatments according to histology, and immune checkpoint inhibitors may be a new therapeutic strategy in ovarian clear cell carcinoma (OCCC). Lymphocyte activation gene 3 (LAG-3), an immune checkpoint, is a poor prognostic factor and a new therapeutic target for several malignancies.

Methods

In this study, we demonstrated a correlation between LAG-3 expression and the clinicopathological features of OCCC. We evaluated LAG-3 expression in tumor-infiltrating lymphocytes (TILs) by immunohistochemistry using tissue microarrays containing surgically resected specimens from 171 patients with OCCC.

Results

The LAG-3-positive cases were 48 (28.1%); the LAG-3-negative cases were 123 (71.9%). The expression of LAG-3 significantly increased in patients with advanced stages (P = 0.036) and recurrence (P = 0.012). However, LAG-3 expression did not correlate with age (P = 0.613), residual tumor (P = 0.156), or death (P = 0.086). Using the Kaplan−Meier method, LAG-3 expression was observed to be correlated with poorer overall survival (P = 0.020) and progression-free survival (P = 0.019) than no expression. Multivariate analysis regarded LAG-3 expression (hazard ratio= 1.86; 95% confidence interval, 1.00−3.44, P = 0.049) and residual tumor (hazard ratio = 9.71; 95% confidence interval, 5.13−18.52, P < 0.001) as independent prognostic factors.

Conclusions

This study demonstrated that LAG-3 expression in patients with OCCC may be a useful biomarker for predicting prognosis and a new therapeutic target.

Background

CD47 is a potent ‘don’t eat me’ signal that promotes tumor immune evasion by inhibiting phagocytosis by macrophages. In OC, CD47 is reported to be overexpressed and its expression correlates with poor prognosis and shorter survival. However, how CD47 expression relates to other key features in the immune tumor microenvironment (iTME) or changes under treatment remains unknown. Here, we evaluated CD47 expression on a cohort of OC tumors from 188 patients at diagnosis and after NACT in a clinical trial, CHIVA, and its correlation with other iTME features.

Methods

105 patients in CHIVA were evaluable for CD47 expression by IHC in paired samples pre- and post-NACT. CD47 expression was scored by H-score: staining intensity (0, +1, +2, +3) x % cells positive (0-300). CD8+ T cells scored as number of positive cells, T cell co-regulators (PDL1, TIM3, LAG3) scored as % positive cells. The association of CD47 H‐score with other immune features was evaluated (Pearson test).

Results

Among 105 patients, 75% had serous OC (HGOC). CD47 median expression at baseline was high at 200 (SD=56) with 0% completely negative. CD47 expression at baseline was positively correlated with other immune tolerance mediators such as the M2 marker CD163 (p=0.003) or T cell exhaustion markers such as PD-L1 (p=0.005) and TIM-3 (p=0.006). However, correlation between CD47 and CD163 was lost after NACT (p=0.6). Interestingly, the expression of CD47 appears to be positively correlated with the presence of CD8+ T cells, but only after NACT (p=0.04). Evaluation of CD47 expression in paired samples before and after chemotherapy demonstrated a significant decrease (paired Wilcoxon ranked test, p<0.001) suggesting immunomodulatory effects of chemotherapy on the iTME of OC.

Conclusions

We show that NACT increases CD8+ T cell infiltration and decreased CD47 expression in support of favorable immunomodulatory effects on the iTME in HGOC. In addition, our data suggest that immune escape in HGOC could be the result of concerted overexpression of multiple immune suppressor molecules. Inhibiting both CD47 and other features from the iTME could represent an attractive strategy to enhance anti-tumor immunity in HGOC.

Clinical trial identification

NCT01583322

Background

The survival of patients with ovarian cancer (OC) is correlated with the presence of infiltrating CD8+ T lymphocytes in the tumor microenvironment, but the underlying regulatory mechanisms and therapeutic significance of CD8+ T cells are still not clearly known.

Methods

We retrieved 13 immune cell line-associated datasets, RNA-sequencing data and clinical information were downloaded from the Gene Expression Omnibus, The Cancer Genome Atlas, and the International Cancer Genome Consortium in an effort to find biomarkers to improve the treatment of OC. CD8+ T-cell-associated genes were identified with weighted correlation network analysis. Survival and nomogram analyses were performed. Model effects were also validated using the immunotherapy dataset IMvigor210. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) staining were used to evaluate the expression of the signature genes in OC.

Results

We identified 520 CD8+ T-cell-associated genes that were significantly enriched in immune function-related pathways, as well as 3 OC molecular subtypes (immune cluster 1 [IC1], IC2, IC3). The IC1 and IC2 subtypes have a worse prognosis than IC3. IC3 has higher IFNγ scores, immune T-cell lytic activity, immune cell infiltration, and high expression of immune checkpoint-related genes, which indicates that the IC3 subtype was more sensitive to immune checkpoint inhibitors. A 10-gene signature comprising SEMA4F, CX3CR1, STX7, PASK, AKIRIN2, HEMGN, GBP5, NSG1, CXorf65, and TXK was constructed. Multivariate Cox regression analysis showed that the gene signature-based risk model was significantly associated with OS (p<1e-5). A nomogram incorporating signature and age was constructed, and calibration plots and DCA confirmed its stable prognostic power. The accuracy of gene signatures in OC patient tissue samples was confirmed by IHC and qRT-PCR results, which were consistent with the bioinformatics analysis. The risk model's potency as a predictor was demonstrated using the Imvigor210 immunotherapy dataset.

Conclusions

We established a novel CD8+ T-cell-associated gene signature that can help assess prognostic risk and immunotherapy response in patients with OC.

Background

Cytological examination of intraoperative flushes makes it possible to clarify the prevalence of the process and determine the tactics of surgery for ovarian cancer (OC). But the existing subjective factors of evaluating the QI of the drug lead to the need for an integrated approach to evaluation, including the use of immunocytochemical examination (ICC). At the same time, the ICC method requires detailed compliance with the protocol and reaction time, which makes it difficult to use it in the study of intraoperative flushes. Using a fluorescent antibody label, it is possible to significantly speed up the reaction time and use the ICC method during surgical interventions.

The aim of the work is to evaluate the effectiveness of using a "liquid" biochip with a fluorescent label for ICS of intraoperative flushes in comparison with the traditional ICC method.

Methods

40 samples of intraoperative flushes obtained from patients with suspected OC performed during surgical intervention of the State Medical Institution NO City Hospital No. 35, Nizhny Novgorod in 2021-2022 were analyzed. All fluid samples were examined cytologically. Using the SER1 test system (RUSCELL LLC, Russia), an ICC study was conducted, the results of which were visualized using a Zeiss Primo Star microscope (Carl Zeiss, Germany), as well as additionally each sample of the resulting liquid was examined using a "liquid" biochip with a fluorescent EpCAM protein imaging label.

Results

According to the results of cytological examination, the following data were obtained: non–diagnostic material (ND) – 11.4%, absence of malignant cells (NFM) – 44.3%, presence of cells with atypia of unclear significance (AUS) - 10%, suspicion of the presence of a malignant process (SFM) – 20%, malignant nature of cells (MAL) – 14.3%. An additional ICC study of EpSAM protein expression using the SER 1 test system led to changes in diagnostic results within the following categories: NFM - 58.6%, AUS – 0%, SFM – 2.8%, MAL – 27.2%.

Conclusions

The combined use of CE and ICC studies of intraoperative flushes makes it possible to increase the detection of malignant tumor cells by 1.4 times. The use of a fluorescent label reduces the waiting time for the result by 3.1 times compared to the traditional ICC method

Background

Peritoneal carcinomatosis (PC) is frequently observed in newly diagnosed ovarian cancer and is associated with a poor prognosis. An accurate diagnosis of PC and indication of all lesions on pre-treatment imaging studies is very necessary. Thus, we aimed to develop deep learning-based auto-segmentation algorithms to diagnose and indicate PC lesions in ovarian cancer using computed tomography (CT) scan images.

Methods

We retrospectively collected pre-treatment CT scan images from patients with epithelial ovarian cancer who received primary treatment, consisting of cytoreductive surgery and postoperative adjuvant chemotherapy, between 2010 and 1019 at a tertiary institutional hospital. Patients were randomly assigned to training and test sets with 9:1 ratio. The tumors and PC lesions in the abdominal-pelvic cavity of the training set were manually drawn by two radiologists, who were experts in gynecologic malignancies, in the delayed phase. 3D nnU-Net was selected as the deep-learning architecture. Using the validation set, one radiologist manually drew lesions of interest twice, and the developed deep learning-based auto-segmentation algorithm was performed.

Results

The training and validation sets included 180 and 20 patients, respectively. The median age of patients in the validation set was 58.6 years; 86.1% and 85.0% of them had ascites and FIGO stage IIIC-IVB diseases, respectively, and 56.1% achieved complete cytoreduction. The model was validated using a validation set. Its predictive performance yielded a Dice similarity coefficient, sensitivity, and precision of 93.2%, 92.4%, and 94.1%, respectively.

Conclusions

We successfully developed deep learning-based auto-segmentation algorithms to identify and indicate PC lesions in ovarian cancer. This model can aid radiologists’ reading and facilitate image-guided surgery for advanced-stage ovarian cancer in clinical practice.

Background

In work up of adnexal masses, values of CA 19-9 have been used in conjunction with CA 125 to improve preoperative diagnostic accuracy and as a predictor of recurrence, especially in Mucinous Adenocarcinomas. Although raised levels of serum CA 19-9 are seen in Epithelial Ovarian Cancers (EOC), including HGSOC, but the clinical significance of such findings is unknown. The present study was conducted to evaluate the prognostic implication of raised CA19-9 levels in EOC patients.

Methods

A hospital based, retrospective study undertaken at tertiary Cancer Institute in North East India. The primary objective was to determine the prognosis of raised CA19-9 levels on survival in EOC patients in terms of DFS and OS. The secondary objectives were to estimate the prevalence of raised CA19-9 levels in patients with adnexal masses, and correlate with final histopathology.

The study included patients presenting to Gynaecological Oncology OPD with adnexal masses between September 2019 to December 2021. The relevant data was accrued from the electronic medical records. This study was done according to REMARK guidelines.

Results

827 patient records were analysed, of which 136 patients had raised CA 19-9 levels (16.4%). 73.5% (n=100) cases had malignant histology, 54.4% patients (n=74) cases were EOC, comprising of HGSOC histology in 36.7% (n=50), followed by Mucinous (13.2%, n=18).

26.4% Patients with raised CA 19-9 had platinum refractory disease vs 14.7% with normal CA 19-9 levels. Pearson's r value for association with CA 125 was -.133 (p=0.1). The mean values of CA 19-9 levels in HGSOCs was 215.286 U/mL versus 472.888 U/mL (p=0.01) in patients with Mucinous Adenocarcinoma.

Conclusions

Raised levels of CA 19-9 were associated with higher platinum refractoriness and poorer Overall Survival (p=0.008). These novel findings need to be validated in a prospective trial. Our study reinforces the utility of CA 19-9 as a mandatory marker in both diagnosis, as well as prognostication of EOC patients.

Background

Brenner tumors represent 1% of all ovarian tumors. They are classified histologically as three types: benign, proliferative and malignant. Malignant Brenner tumors are less than 5% of all diagnosed Brenner tumors and have poor prognosis. Treatment approach for malignant Brenner tumors is not well established but surgical resection is widely accepted and indications for adjuvant chemotherapy is controversial. Current evidence on treatment is limited to few case studies and case series due to its scarcity. So the aim of this study is to add to the available limited data of malignant Brenner tumor of the ovary and evaluate the impact of adjuvant chemotherapy, age, race, laterality and stage on survival outcome.

Methods

We used Survellence,Epidemiology and End Results(SEER) program software to extract the data of 139 female patients with malignant Brenner tumor of the ovary diagnosed from 2000-2019. We divided them into two subgroups according to the treatment modality: adjuvant chemotherapy gouup and surgery with no systemic therapy group. We used SPSS for data analysis. Kaplan-Miere curve, Log-rank test for survival analysis.

Results

Age standardized 5-year survival for malignant Brenner ovarian tumor is 55.9% while the overall 5-year survival is 63.2% . The median age is 61. Out of 139 cases, 55.4% were treated surgically with no systemic treatment and 44.6% received adjuvant chemotherapy with overall 5-year survival outcome for both treatment regimens(68%,61% respectively; P=0.5). Performing Cox-regression analysis for the predictors: age, race, laterality and stage, tumor stage is the only predictor with statistical significance on survival (P >0.00)

Conclusions

Adjuvant chemotherapy and surgical resection with no systemic therapy has quiet similar survival outcome. This result highlight surgical management with no systemic therapy to be the first line therapy to avoid unnecessary chemotherapy complications. Further evaluation for each patient is needed and we encourage more studies to evaluate radiotherapy impact on this rare type.

Background

Ovarian clear cell carcinoma (OCCC) is a rare subtype of epithelial ovarian carcinoma with poor prognosis in advanced stages and recurrent disease. Recent literature on outcomes in clinical practice for OCCC including advanced stage (stage III and IV) is limited.

Methods

A retrospective review of patients with OCCC treated at The Royal Marsden between March 2003 and July 2022 was conducted. Demographic and clinicopathologic factors were abstracted and evaluated using Kaplan-Meier analyses.

Results

184 evaluable patients were identified (median follow up time 37.5 months). Median age was 53.7 (range 30.6-79.6). The FIGO stage distribution at diagnosis was: I 81/184 (44%); II 37/184 (20%); III 58/184 (32%) and IV 8/184 (4%). 169/184 (92%) received adjuvant chemotherapy, whereas 5/184 patients (3%) had adjuvant radiotherapy. 56 patients (30%) were treated within clinical trials. 117/184 (64%) developed disease relapse (61/117 (52%) and 56/117 (48%) had early and advanced disease at diagnosis, respectively). The median time from first recurrence to death was 14.7 (range 0-123.1) months. For patients with stage III/IV disease at diagnosis, median progression free survival from last platinum treatment was 23.1 (95% CI 13.8-32.3) and 18.3 months (95% CI 8.3-24.4) for stage III and IV, respectively. Median overall survival was 131.3 (95% CI 54.1-208.5), 79.5 (95% CI 31.1-127.9), 24.2 (95% CI 5.4-43) and 22.4 (95% CI 11.9-32.8) months for stage I, II, III and IV respectively. Time to progression among patients with recurrent disease treated with radiotherapy (n=19, 10%), Bevacizumab (n=12, 7%) and immunotherapy (n=14, 8%) was 10.2, 6.6 and 6.9 months, respectively.

Conclusions

We report a large, single centre retrospective series of OCCC outcomes in clinical practice in an era of novel therapies and clinical trials. Survival remains poor for advanced/recurrent OCCC and improved treatment strategies are urgently needed.

Background

Patients with high-grade serous ovarian carcinoma (HGSOC) gradually acquire resistance to standard chemotherapy after recurrence. In our previous study of HGSOC, histone deacetylase (HDAC)6 upregulation led to poor prognosis, and programmed cell death ligand-1(PD-L1) expressions positively correlated with HDAC6 expression. We analyzed the expression of HDAC6 and PD-L1 pre- and post-chemotherapy to investigate their association with chemotherapy resistance.

Methods

PD-L1 and HDAC6 expressions were immunohistochemically analyzed using clinical samples obtained before and after standard chemotherapy (combination of platinum and taxane agents) from 54 patients with HGSOC. The clinicopathological characteristics, including surgical status, RECIST status, and chemotherapy response score, were reviewed.

Results

High expression (≥ 5%) of PD-L1 was detected in 5 and 8 cases pre- and post-chemotherapy, respectively. The mean PD-L1 positive rate post-chemotherapy was 3.88%, which was significantly higher than 0.68% pre- chemotherapy (p=0.045). The high expression frequency of HDAC6 significantly increased from 4 patients pre-chemotherapy to 13 patients post-chemotherapy (p=0.019). High PD-L1 expression post-chemotherapy was significantly correlated with chemotherapy response score 3, signifying chemosensitivity. High post-chemotherapy PD-L1 expression led to poor progression-free (p=0.037) and overall survival (p=0.049), in the group with complete surgical resection.

Conclusions

In HGSOC, residual tumors post-chemotherapy had enhanced expression of HDAC6 and PD-L1, which are associated with tumor immunity, cell proliferation, and hypoxic responses. PD-L1 was also correlated with patient prognosis. These results suggest that HDAC6 and PD-L1 may serve as therapeutic targets and prognostic factors for residual tumors after standard chemotherapy in HGSOC.

Background

Malignant ovarian germ cell tumors [MOGCT]are rare cancers occurring in young girls in the childbearing age groups. Even in advanced stages long term survival rates can be achieved with conservative fertility sparing surgery and chemotherapy.

Methods

This is a retrospective study of patients diagnosed with MOGCT between 2013- 2017. Data of 172 eligible patients were retrieved from electronic medical records. Clinico-pathologic features, treatment details were recorded and survival analysis was performed. Reproductive outcomes in terms of percentage of patients having successful pregnancy outcome after treatment were also analyzed.

Results

The median age was 23 years (range 10-68). Sixty three (36.6%) had dysgerminoma, 35 (20.3%) had immature teratoma, 30 (17.4%) had mixed germ cell tumors, 36 (20.9%) had yolk sac tumors, and 8 (4.7%) had mature teratoma with somatic malignancy. FIGO stage distribution was as follows: stage I, 104(60.4%); stage II, 4 (2.3%); stage III, 49 (28.6%); and stage IV, 15 (8.7%).Fertility-sparing surgery was performed in 136 (79%) patients. Chemotherapy (adjuvant ors neoadjuvant) was received by 122 patients. 13 patients received EP, 106 patients received BEP and 3 patients (somatic transformation in teratoma) received Paclitaxel and carboplatin. In patients with advanced disease (stage III, IV) neoadjuvant chemotherapy (NACT) was received by 52 patients. In 136 (79%) patients fertility sparing surgery was performed, 41 of whom had received NACT. Febrile neutropenia was seen in 34 (27.8%) patients. Any grade bleomycin induced lung toxicity was seen in 22 (12.7%) patients resulting in omission of same in subsequent cycles. At a median follow-up of 56 months, the median progression-free survival (PFS) was 47 months and median overall survival (OS) was 55 months.117 patients resumed menstruation after completion of chemotherapy. 18 patients successfully conceived after treatment completion out of which 3 conceived using in vitro fertilization method.

Conclusions

Patients presenting with advanced MOGCT can be offered fertility sparing surgery after neoadjuvant chemotherapy with no detriment in oncological outcome.

Background

Mexican women with ovarian cancer have a high prevalence of germline BRCA mutations. The most frequent alteration is the deletion of exons 9 to 12 of BRCA1 (BRCA1-Del Exon 9-12), which has been associated with a founder effect in this population. The Mexican founder mutation is a long genomic rearrangement that could affect not only clinical features but also the prognosis of patients carrying this alteration.

Methods

This retrospective study evaluated the clinical characteristics and prognosis of Mexican patients with BRCA1/2 germline mutations after receiving first line treatment with platinum-based chemotherapy between 2015 and 2022. The aim of the study was to compare the progression-free survival (PFS) of patients with the Mexican founder mutation and patients with other BRCA1/2 mutations. Patients treated with front-line iPARP maintenance treatment were excluded.

Results

Of 531 patients who were tested for a BRCA1/2 mutation, 181 were positive (34.1%). Thirty-seven patients (20.4%) were Mexican founder mutation carriers and 144 (79.6%) had other BRCA1/2 mutations. One hundred fifty-seven patients were included in the final survival analysis. The median follow-up time was 57 months. Patients with the founder mutation had a median PFS of 28.7 months, while patients with other BRCA1/2 mutations had a median PFS of 15.3 months (HR, 0.72; CI 95% 0.46 – 0.95; P= 0.05). (Table 1) Median overall survival was not reached for patients with the founder mutation and 131 months for patients with other BRCA1/2 mutations (HR 0.25; CI 95% 0.0.88 – 0.72; P=0.01).

Conclusions

Patients with the Mexican founder BRCA1 mutation treated with first line platinum-based chemotherapy have better survival compared with patients with other BRCA1/2 mutations.

Background

Treatment with PARP inhibitors in the maintenance of ovarian cancer has been a revolution in the natural history of the disease, especially in those cases carrying BRCA mutations. Within this population, it has been described that alterations in the RING region of BRCA-1 confer resistance to PARP inhibitors by forming a hypomorphic protein that can activate RAD51. There is little data on whether different functional domains in the BRCA 1 and 2 genes can modulate the response to PARP inhibitors and there is no validation of these in real-life data.

Methods

Among the 195 collected cases of high-grade ovarian cancer, 38 patients were identified as BRCA gene mutation carriers, either germinal or somatic.

To determine the functional domain of each of the mutations, Clinvar search engine was used.

Statistical analysis was performed using nonparametric tests due to the small sample size.

Results

27 patients were treated with iPARP maintenance and are included in the study.

The median age at diagnosis was 55 years.

33% were treated as first line maintenance, 42% after first relapse and 25% in subsequent lines. 15% received Niraparib, 78% received Olaparib and 7% received the combination of Olaparib and Bevacizumab as maintenance treatment.

Among the BRCA 1 mutation carriers (55.5% of the total), 13% had mutations in the DBD domain, 13% in BRCT and 6% in RING. The rest were located outside the functional domains of the protein.
Among patients with BRCA-2 mutation, 16% had mutations in the DBD domain and 58% in RAD51.

With a median follow-up of 23 months (range 2-79), thirty-three percent of patients have experienced disease progression after iPARP treatment. It is noteworthy that among cases carrying mutations in the RING domain, the progression-free interval with iPARP was only 2 months.

Even so, no statistically significant differences were detected between genotype and progression-free interval.

Conclusions

Despite the small number of cases and the paucity of progression events, no differential pattern between genotype and duration of response with iPARP treatment is apparent. In the few cases with mutations in the RING domain, the benefit with iPARP is very limited, although these data require validation in series with larger numbers of patients.

Background

Various prognostic factors are reported worldwide for granulosa cell tumor ovary.

Methods

Data of all biopsy proven granulosa cell tumor patients with age >18years were retrospectively collected from the Institute Registry between Jan 2011 and May 2022. The chemotherapy was given if capsule breached, size >10cm,>10/10HPF in tumor or > FIGO stage IA/IB. Variables like age, stage, size of tumor(T), mitotic rate, metastatic sites, treatment modality, chemotherapy regimen and response to therapy were collected.

Objectives To find-out overall survival (OS) and event-free survival (EFS) and identify prognostic factors influencing them. Prognostic factors were analysed by univariate and multivariate cox regression. Survival curves were plotted via Kaplan Meier.

Results

There were 57 patients. Fifty-five were diagnosed and treated in this Institute while two of them presented at recurrence. Median age group was 47years (yrs). Median follow up was 48 months. Median OS and EFS were not reached (NR) at the time of analysis. Out of 55 one died due to disease progression and 10 relapsed (18.2%). Peritoneum was the most common recurrence site. Patients who presented with recurrence survived >5years after secondary cytoreductive surgery (CRS) and chemotherapy.

The 5yr OS rate was 100% for stages I-III, T size >10cm, age ≥40 yrs, ≤ 10/10 HPF and complete CRS. Similarly, 5yr EFS rates were >65% except for stage IV (0%) and fertility sparing surgery (FSS) (63.2%). Univariate analysis showed significant OS benefit for stage I-III vs IV (p=0.022) and EFS benefit for CRS vs FS (p = 0.047). Multivariate analyses found significant EFS benefits for stage I-III vs stage IV (p= 0.033), CRS (p= 0.005), and mitotic rate >10/10HPF (p=0.042). However, no factors showed statistically significant OS outcome.

Conclusions

The present study showed significant EFS benefits for stage I-III, mitotic rate >10/10HPF and CRS modality. But nonsignificant favourable OS outcomes were seen with T size >10cm, age ≥40 yrs compared to literature review. Need prospective evidence on combined modality in overcoming prognostic factors.

Background

Treatment of recurrent malignant ovarian germ cell tumors(MOGCT) are complex and challenging.There is limited data on outomes of these patientsafter salvage therapy in real world setting.

Methods

This is a retrospective study of all patients diagnosed with recurrent MOGCT at our center between 2013-2017. Out of 43 patients 12 patients were excluded as they have not followed up after first visit..Clinico- pathological and treatment details of 31 patients were extracted from electronic medical records and were included in the analysis

Results

Table-1

Baseline charechterstics initial stage,adequacy of treatment, Sites of recurrence and treatment were in tabular form

Salvage chemotherapy was given in all patients.Ten (33%)patients who were inadequately treated upfront at outside recieved BEP/ EP as salvage regimen in our centre .Other regimens used were VeIP 8 (25%), TIP 6 (19%) and VIP 4 (13%) Others 3(10%). After salvage chemotherapy 19 (61%) patients underwent second surgery, R0 resection was achieved in 13(42%) patients

After Median follow up of 66 months, 21 patients were alive (18 -with no disease, and 3 were alive with stable teratoma component) after salvage therapy, and 10 patients were dead.

Out of 13 patients with yolk sac histology( Pure yolk sac -6; Mixed GCT-7)only 6 could be salvaged.Those who could not be salvaged had effusions or extensive liver disease .Two patients out of 8 reccurent dysgerminoma had bulky multi station lymph nodal relapse could not be salvaged. The median PFS was after relapse was 26 months and median OS was 33 months post relapse.

Conclusions

Adequate treatment at initial diagnosis is of paramount importance along with active surveillance to minimize default rates especially in low middle-Income countries. 67% of our recurrent cases were effectively salvaged. If managed at experienced centres with multidisciplinary approach using salvage chemotherapy and surgery, majority of recurrences can result in long term cure.

Background

Ovarian cancer (OvCa) is the most lethal gynecological malignancy with an annual incidence of >300,000 and a mortality of 200,000 worldwide (Sung et al 2020). Survival rates have only shown marginal improvement over the past decades with a 5-year survival of ~30-35% in advanced cases (Howlader et al 2020).

The initial treatment of ovarian cancer involves surgery and platinum-based chemotherapy. The majority of patients respond well to initial therapy but the risk of recurrence is high and most patients will develop platinum-resistant disease with clinical response rates of ~10-20% to any additional therapies (Davis et al 2014, van Zyl et al 2018, Hamanishi et al 2015, Garcia et al 2013). The limited effective and well-tolerated options beyond platinum-based therapies justify the need for new treatments to improve both outcome and quality of life of patients.

Maveropepimut-S (MVP-S) uses the DPX platform, a non-aqueous, lipid-based delivery system, to educate a specific and persistent immune response to 5 HLA-restricted peptides of survivin, a cancer-associated protein commonly upregulated in advanced OvCa. In a prior study in patients with advanced, metastatic recurrent ovarian cancer, MVP-S with low-dose cyclophosphamide (CPA) led to clinical responses, durable benefit, and persistent, survivin-specific T cells. Treatment was well-tolerated. Further exploration of the regimen in platinum resistant ovarian cancer is warranted to confirm and extend these initial results.

Trial Design

The AVALON study (NCT05243524) is a phase 2b, single-arm trial assessing the efficacy and safety of subcutaneous MVP-S in combination with low-dose oral CPA. Eligible patients have recurrent platinum resistant OvCa, ≤4 lines of prior OvCa therapy, and no single lesion >4 cm. The primary endpoint is objective response rate (ORR) per RECIST 1.1 and secondary endpoints include ORR per iRECIST, disease control rate, duration of response, and survival rates. Exploratory objectives include characterization of MVP-S induced immune responses in peripheral blood and the tumor microenvironment of paired tissue samples. The study will enroll 73 subjects in North America and Europe.

Clinical trial identification

NCT05243524

Background

Ovarian cancer (OC) is the fifth cause of cancer death in women and the deadliest of gynecologic cancers.First-line treatment of newly diagnosed OC includes a combination of surgery and chemotherapy.However, 85% of patients experience recurrence.Prolonging the benefit of first-line platinum with a maintenance therapy is currently the best chance for these patients.PARP inhibitors are essential to improve outcome:Olaparib, Niraparib, and olaparib/bevacizumab are approved with different indications.Niraparib is an highly selective PARP-1 and -2 inhibitor and recent trials showed its activity both in recurrence (NOVA trial) and first diagnosis (PRIMA trial).In the last study, evaluating patients with newly diagnosed advanced OC with residual cancer at primary surgery who had a response to platinum-based chemotherapy, niraparib met the primary endpoint of prolonging progression-free survival (PFS) versus placebo regardless of BRCA mutation or HRD tumor status.A Niraparib Expanded Access Programme (EAP) started in Italy in March 2020 as first-line maintenance treatment option for patients with newly diagnosed advanced OC,before the commercial approval.Until July 2021, 600 patients have been enrolled.This EAP represents an opportunity to evaluate drug efficacy and safety in the real live world.MITO 40 aims to collect retrospectively the data from the patients of the EAP programme that for several characteristics (any residual diseasafter primary surgery, and histotypes) differs from the population enrolled in PRIMA.

Trial Design

This is a no profit observational retrospective real life multicenter study, the promoter is the NCI Fondazione G. Pascale. The involved centers are part of the MITO group (Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies).The primary objective is to observe efficacy of niraparib as maintenance treatment in a real life setting for newly diagnosed ovarian cancer patients within the EAP. The secondary objective is to assess safety and long term clinical outcomes in the same population. Patients retrospectively included in EAP will be followed up prospectively up to 3 years from inclusion in EAP independently of whether they are continuing treatment with niraparib or not.

Background

Background: The incidence of chemotherapy-induced hypersensitivity reactions has increased gradually. This study aimed to describe clinical manifestations of hypersensitivity reactions to chemotherapy and the outcomes of management using desensitization protocol in patients with gynecologic cancers.

Methods

Methods: We conducted a retrospective study of patients with hypersensitivity reactions to chemotherapy drugs in gynecologic cancer between January 01, 2019 and July 31, 2021. (IRB number: 2021-1607)/ The severity of hypersensitivity reaction to chemotherapy was graded according to Brown’s classification and desensitization protocol by Castells, et al was performed.

Results

Results: Among the 3147 patients, ninety-one patients experienced hypersensitivity reaction to chemotherapy. The mean age of the patients was 56.05 years and the proportion of underlying malignancy was ovarian cancer (81.3%), followed by cervical cancer (9.9%), and endometrial cancer (8.8%). The desensitized drugs were carboplatin, cisplatin, paclitaxel, docetaxel, bevacizumab, bleomycin, and ifosfamide. The most common allergic reactions was a cutaneous symptom (65.9%), followed by cardiovascular (60.4%), respiratory (41.8%), gastrointestinal (41.8%), neuromuscular (15.4%), and other system (12.1%). Seventy-five patients (82.5%) have experienced moderate to severe hypersensitivity reactions and 80 patients (87.9%) have successfully completed their planned cycles by 12 or 16-step protocol, whereas 11 patients (12.1%) have decided to stop consecutive chemotherapy due to failure of desensitization. There was no significant difference of clinical characteristics and outcome except death between two groups. These results demonstrate that desensitization protocol was safe and effective in highly sensitized patients.

Conclusions

Conclusions: In our study, we present the clinical characteristics of chemotherapy-induced hypersensitivity reactions and show that desensitization protocol was a best alternative strategy to maintain optimal chemotherapy in gynecologic cancer patients.

Background

Current guidelines suggest endometrial biopsy in women ³40 years old with abnormal uterine bleeding (AUB) as they are at greater risk of endometrial hyperplasia (EH) or cancer (EC). In women under 40 years old, there are no clear recommendations regarding endometrial biopsy. This should be carefully considered in younger women due to the associated risks that may affect fertility. We aim to study the profile of younger women with EH/EC in our population, to optimise endometrial biopsy in these high-risk patients.

Methods

This is an observational retrospective study that included women under 40 years old with AUB (according to the International Federation of Gynaecology and Obstetrics definition) who had endometrial biopsy in KK Women’s and Children’s Hospital Singapore in 2020. Institutional review board approval was not required for this study. Women with persistent intermenstrual bleeding > 3months or postcoital bleeding were also included. Women who had endometrial sampling on a known background of EH were excluded. Data on patient characteristics, ultrasound findings, histology and treatment were collected. Odds ratio (OR) for EH/EC as a measure of relative risk were computed.

Results

In 2020, 128 women under 40 years old underwent endometrial biopsy for AUB. The median age was 34 years old. 40.6% were nulliparous, 21.1% had polycystic ovarian syndrome, 5.5% had diabetes mellitus, and 49.2% had a BMI > 30. The median endometrial thickness was 10mm and 18.3% had cystic spaces reported on ultrasound. Majority of histology were benign (79.0%). 13.3% had EH without atypia, 2.3% had EH with atypia, and 1.6% had EC. 75% of women with EH were treated with oral progestogen and 10% had Mirena inserted. Nulliparity (OR 6.53, 95% confidence interval (CI) 1.96-21.78) and cystic spaces (OR 7.20, 95% CI 1.87-27.64) were associated with an increased likelihood of EH/EC in these women.

Conclusions

The risk of EH/EC in women <40 years old is low. Endometrial biopsy should be carefully considered in younger women with AUB, and reserved for those with risk factors.

Background

It has been almost three years since the COVID-19 outbreak, yet evidence of its impact on the cancer care landscape remains scant. The present single-center study examines patterns in gynecological cancer diagnoses before and during the pandemic.

Methods

All female patients diagnosed in our academic hospital with gynecological cancer, between January 2017 and December 2020, were retrospectively identified. Pre-defined subgroup analyses were performed in patients who had been newly diagnosed during 2020 and in the pre-pandemic 3-year period. The study was approved by the Institutional Ethical Committee and was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization for Good Clinical Practice.

Results

In total, 1,193 women were included in this case-control study; 1,001 (83.91%) were identified in the pre-pandemic period as a control, while 192 (16.09%) cases were allocated in the pandemic group. The two cohorts were similar regarding demographic and clinical characteristics. For the pre-pandemic period, the mean yearly number of patients with newly identified cancer was highest for endometrial (149; 44.61%), followed by ovarian (92; 27.5%) carcinomas. During the first year of the pandemic, the number of new diagnoses significantly decreased by 42.5% (from 334 to 192) for all types of malignancies combined (one sample t-test p-value= 0.014). Declines ranged from 36.96% to 49% for ovarian and endometrial cancer, respectively.

Conclusions

This is the first study to appraise a timely snapshot of the effect of COVID-19 on newly diagnosed gynecological tumors in a European Society of Gynaecological Oncology (ESGO)-certified center in Greece, demonstrating an alarmingly sharp decline in the number of new cases during the pandemic. It is of utmost importance the gynecologic oncologists to ensure the continuum of care for their patients.

Demographic data for patients with newly diagnosed gynecological cancer, by time period

Pearson chi2 (12) = 13.1806; Pr= 0.356

Background

Accurate and timely evaluation of AEs on ClinT is critical to assure patient (pt) safety. In PM ClinT toxicity is captured in real time with AEs assessed by a ClinT nurse, standardized with CTCAE and electronically sourced, and approved by a physician.

Methods

AEs recorded in the PM ClinT AE database between 01/2016 and 12/2018 were evaluated. Gyne ClinT assessing systemic therapy were included. Inferential statistics on risk factors of grade ≥ 3 (G3+) AE reporting and GEE logistic models with Odds Ratios (OR) were performed. Multivariate (m/v) analysis was adjusted to age, ClinT phase, sponsor, therapy combination and type.

Results

We identified 516 ClinT with 3,467 pts on therapy. Among them, 42 ClinT were launched in the gyne site (52% ovarian, 10% uterine, 10% cervix, 28% multiple). 317 unique pts were accrued in gyne ClinT (38 pt in >1ClinT [range 1–4 ClinT]), yielding 362 pts on therapy (Table). 17,187 AEs were reported, 10.6% were grade ≥3 (G3+), 0.9% G4+ and 0.02% G5 . The most common G3+ AEs were hematological (49%), gastro-intestinal (13%). On m/v analysis, no odds differences of G3+ AEs were detected according to study phase. Pts enrolled in immunotherapy ClinT had lower odds of G3+ AE than pts on targeted or other therapy (OR 0.55; 0.32-0.96). There was greater odds of G3+ AEs in ClinT assessing combination vs single therapeutics (OR 2.27; 1.40-3.69), and in investigator initiated ClinT vs not (OR 2.29; 1.24-4.23). Pts aged <50 (OR 2.13; 1.01-4.48) and >65 (OR 1.72; 1.03-2.83) had greater odds of G3+ AEs than pts aged 50 to 65 years. Overall, when compared to other disease sites, the odds of having a G3+ AE reported in gyne ClinT was no different, but the odds of G4+ AEs (OR 0.54; 0.38-0.74) and G5 AEs (OR 0.08; 0.01-0.26) was lower.

Conclusions

In gyne ClinT the odds of having a G3+ AE reported were more frequent on combination therapy studies and investigator initiated trials. Lower odds of having G3+ AEs were detected in immunotherapy trials and pts aged 50-65.

Background

On March 2020, the federal government of Kosovo declared a nationwide lockdown due to the COVID-19 pandemic until May 2020. Since the lockdown, examinations and routine checkups have been restricted .This resulted in a severe decline in patient referrals to the hospitals.We want To assess the impact of the COVID-19 pandemic on the rate of newly diagnosed gynecological cancers.

Methods

The data are taken from our patient database. Data from 752 patients from the only cancer centre in Kosovo with newly diagnosed gynaecological cancer between 2019, 2020 and 2021 were collected. Incidence, age group, stages of diagnosis and geographical distribution were compared between the time before and after the COVID-19 outbreak.

Results

Our results showed a slight decline in newly diagnosed cancers in 2020 as compared with 2019 and 2021: -17 % in 2020 versus an increase of 18% in 2019. We expected to have a major increase in 2021 but data shows that it was a slight increase of 17%. As we not expected after the COVID-19 pandemic we have a strong decline of metastatic new cases of 39% in 2021 compared to 2020 and a 60% decline in 2020 compared to 2019. The results show a slight increase of 13 % in the early stages from 2020 to 2021 and the same rates come up from 2019 to 2020.

In all three years in a row the dominant type of cancer according to localization is corpus uteri then cervix uteri and ovarian cancer with respectively 39%, 26%, and 33% in 2019, 36%, 33%, and 29% in 2020 and the last, 40%, 26% and 32% in 2021.The groupages have a slight shift from 45-49 years old the peak of new cases in 2021.

Conclusions

The lockdown led to a slight decrease in the number of newly diagnosed cases. The decreased accessibility of the medical services has not led to significant higher number of metastatic new diagnosed cases, on contrary lower metastatic cases and higher number of early cases and slight increase on advanced cases were presented in 2021. The impact on incidence were not significantly higher in 2021 despite the lockdown. Therefore, new strategies to manage early cancer detection are needed to optimize cancer care in a time of pandemic in the future. Effective, appropriate and affordable cancer prevention and control strategies are urgently needed in Kosovo for gynaecological cancer especially cervical cancer.

Background

This analyzes the innovativeness, clinical evidence, and efficacy of new drug indications with US Food and Drug Administration (FDA) approval for breast, ovarian, endometrial, and cervical cancer.

Methods

We identified 26 drugs with FDA approval in 55 gynecological cancer indications from 2000 to 2021. For each indication, we collected drug, indication, and clinical trial characteristics from FDA labels. Hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS), and relative risk (RR) for tumor response were meta-analyzed. Monthly treatment costs were calculated for US patients covered under Medicare & Medicaid.

Results

Of 55 indications, 36 received approval for breast, 12 for ovarian, 3 for endometrial, and 4 for ovarian cancer. Drugs acted via a targeted (84%), immune-regulating (13%), and cytotoxic (4%) mechanism of action. Approval was granted to 34 (62%) small-molecules, 16 (29%) antibodies, and 5 (9.1%) antibody-drug conjugates. Indications were predominantly first-or second-line (82%) combination therapies (62%) with a biomarker (84%). Indications frequently received the orphan (24%), fast track (20%), accelerated approval (27%), priority review (82%), and breakthrough therapy (40%) designation. Approval was mostly supported by double-blind (51%) phase 3 (75%) randomized-controlled (82%) trials enrolling a median of 521 patients (IQR: 302-724) for 3.8 years (IQR: 2.5-5.2). On average, new drugs HRs were 0.79 for OS (95%CI: 0.75-0.82) and 0.55 for PFS (95%CI: 0.50-0.60), whereas tumor response was 1.48 (95%CI: 1.37-1.60). Novel drugs increased patient survival by a median of 3.20 months for OS (IQR, 2.0-4.90 months) and 4.75 months for PFS (IQR, 2.40-7.10 months). Greater OS benefits were observed for drugs with a biomarker (HR: 0.76 vs. 0.84, p=.034). In 2022, Gynecological cancer drugs cost an average of $13,053.30 per month.

Conclusions

Over the past 22 years, the approval of innovative and effective drugs transformed the landscape of gynecological cancer treatments. Especially biomarker-guided targeted therapies resulted in substantial improvements in OS and PFS. However, rising drug prices pose a challenge to healthcare systems and patient access.