Background

PARP inhibitors (PARPi) have revolutionized the therapeutic landscape of epithelial ovarian cancer (EOC) treatment, showing outstanding benefits in regards to progression-free survival, especially in patients carrying BRCA1/2 mutations or harboring defects in homologous recombination repair. Yet, it remains uncertain which PARPi to choose and how to select responders by using clinical and molecular characteristics, especially in forefront therapy when platinum sensitivity is unknown.

Methods

Through a systematic literature review and the exploration of publicly available CRISPR-Cas9 library screens and Genomics of Drug Sensitivity in Cancer data, we identified potential genes linked with PARPi response. Using a CRISPR-Cas9 mutagenesis assay, we functionally tested 33 genes for PARPi and carboplatin response in six ovarian cancer (OC) cells lines.

Results

ATM was the only tested gene which induced olaparib sensitivity in a cell line-independent manner. Acquired olaparib sensitivity was also observed upon Cas9-mediated loss of MUS81, NBN, RAD51/B/C, RNASEH2A, PALB2, XRCC1, and XRCC3 in at least 3 out of 6 cell lines. As the major survival benefit of PARPi treatment was reported in chemo-sensitive tumors, we next assessed the effect of top candidate genes on olaparib, niraparib, talazoparib, and carboplatin response. Interestingly, we observed identical effects in a gene- and drug compound-independent manner on acquired drug sensitivity, supporting the strong correlation of cancer cell response to PARPi and chemotherapy. In contrast, we identified CDK12 as an essential gene for cell proliferation/survival in ovarian cancer cells, independent of PARPi and chemotherapy treatment.

Conclusions

Our data suggest a general mechanism of response to PARPi and chemotherapy as demonstrated by various overlapping gene dependencies. The screen of the genetic status of the genes identified correlated with PARPi sensitivity may allow better stratification of patients with increased benefit to this treatment.

Legal entity responsible for the study

The authors.

Funding

Swiss National Science Foundation (CRSII5_171037), Griesbach-Hallenstein Foundation (Walter Edwin Griesbach Award and Olga Hallenstein Award), Department of Biomedicine, University Hospital Basel and University of Basel.

Disclosure

All authors have declared no conflicts of interest.

Background

North Caucasus hosts several large ethnic groups, which preserved their national identity through the course of history. These populations are likely to have a unique pattern of disease-predisposing alleles reflecting the genetic background of their ancestors.

Methods

This study involved 180 ovarian cancer (OC) patients from Chechnya (n = 68), Kabardino-Balkaria (n = 49), North Ossetia (n = 32), Ingushetia (n = 16) and Dagestan (n = 15). The entire coding sequences of BRCA1, BRCA2, ATM and PALB2 genes were analyzed by next-generation sequencing.

Results

OC patients belonging to various ethnic groups had high frequency of BRCA1/2 mutations ranging from 18% to 33%. There were founder pathogenic alleles detected in Chechens (BRCA1 c.3629_3630delAG; 9 out of 15 BRCA1/2 mutations) and North Ossetians (BRCA2 c.6341delC; 6 out 8 BRCA1/2 mutations). Interestingly, Chechen BRCA1 c.3629_3630delAG allele was not present among patients of Ingush ethnicity, despite these nations are believed to have common roots. BRCA2 Q3299X mutation was repeatedly observed across several ethnic groups. Patients from Kabardino-Balkaria had unusually high frequency of germ-line ATM truncating alleles (3/49, 6%); all 3 ATM mutations were represented by distinct ATM pathogenic variants. There were no instances of PALB2 germ-line mutations.

Conclusions

Genetic analysis of ovarian cancer patients is efficient in revealing ethnicity-specific BRCA1/2 mutations. Contribution of BRCA1/2 pathogenic alleles in OC morbidity is high across various ethnic groups. Founder BRCA1/2 alleles are characteristic for some but not all North Caucasus nations.

Legal entity responsible for the study

The authors.

Funding

This study has been supported by the Russian Science Foundation, grant 21-75-30015.

Disclosure

All authors have declared no conflicts of interest.

Background

Ovarian clear cell carcinoma (OCCC) is characterised by a high prevalence of ARID1A mutations and chemotherapy resistance. We previously found that loss of ARID1A causes ATR inhibitor (ATRi) sensitivity, which led to the phase II ATARI clinical trial (NCT04065269). We aim to identify novel genetic determinants of ATRi response in ARID1A-mutant OCCC.

Methods

A genome wide CRISPR knockout (CRISPRn) screen was performed in OCCC TOV21G cells. CRISPR prime gene-editing was used to introduce PPP2R1A p.R183 mutations. In vitro and in vivo ATRi sensitivity was assessed in PPP2R1A isogenic models. Cell cycle analysis was performed via flow cytometry. Phospho-proteomic profiling was performed using mass spectrometry.

Results

A CRISPRn screen in ARID1A mutant OCCC cells identified protein phosphatase 2 (PP2A) complex subunits as ATRi response genes. In OCCC, PPP2R1A missense mutations cause amino acid substitutions at residue p.R183. Characterisation of a cohort of OCCC primary tumours revealed a higher prevalence of structural subunit (PPP2R1A) mutations than previously reported (50%) which frequently co-occurred with ARID1A mutations. ARID1A-mutant OCCC cells with heterozygous PPP2R1A p.R183P or p.R183W mutations displayed enhanced ATRi sensitivity in vitro and in vivo. The most profound cell-cycle defect caused by PPP2R1A missense mutation was an ATRi-induced reduction in active S phase. ATRi exposure in PPP2R1A mutants increased 53BP1 bodies, a mark of residual DNA damage in mitosis. Phospho-proteomic profiling of PPP2R1A mutant OCCC cells revealed the selective increase in phosphorylation of Lysine Deficient Protein Kinase 1 (WNK1) following ATRi exposure, as well as increased phosphorylation of the WNK1 substrate Oxidative Stress Response Kinase 1 (OSR1). Depletion of WNK1 rescued ATRi sensitivity and S phase defects in PPP2R1A mutant cells suggesting a novel role for this kinase.

Conclusions

The ability of PPP2R1A missense mutations to enhance ATRi sensitivity in tumours cells with pre-existing ARID1A mutations suggests that the co-occurrence of these mutations may be better predictors of ATRi sensitivity than either mutation alone. Increased phosphorylation of WNK1 may drive ATRi sensitivity in PPP2R1A mutant cells.

Legal entity responsible for the study

The authors.

Funding

Cancer Research UK.

Disclosure

S. Banerjee: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Genmabs; Financial Interests, Personal, Advisory Board: GlaxoSmithKline; Financial Interests, Personal, Advisory Board: Immunogen; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Merck Sereno; Financial Interests, Personal, Advisory Board: Mersana; Financial Interests, Personal, Advisory Board: Oxcerna; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Advisory Board: Shattuk Labs; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Immunogen; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Mersana; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Roche. C. Lord: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: KGaG; Financial Interests, Institutional, Research Grant: Artios; Financial Interests, Personal, Advisory Board: Syncona; Financial Interests, Personal, Advisory Board: Sun Pharma; Financial Interests, Personal, Advisory Board: Gerson Lehrman; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Vertex; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Dark Blue Therapeutics; Financial Interests, Personal, Stocks/Shares: Tango; Financial Interests, Personal, Stocks/Shares: Ovibio; Financial Interests, Personal, Stocks/Shares: Enedra Tx; Financial Interests, Personal, Stocks/Shares: Hysplex; Financial Interests, Personal, Stocks/Shares: Tesselate. All other authors have declared no conflicts of interest.

Background

In arm 1 of the phase II randomised OCTOPUS trial (ISRCTN16426935), no significant differences in Progression-Free Survival (PFS) or Overall Survival were observed with the addition of vistusertib (V), a dual mTORC1/2 inhibitor, to weekly paclitaxel (wP) in platinum-resistant/refractory ovarian high-grade serous carcinoma. However, preliminary immunohistochemistry (IHC) data suggested that PTEN status may be predictive of benefit of addition of V to wP. Aim: We evaluated if PTEN expression (scored using quantitative digital IHC) or specific genomic features might be predictive of V benefit. We also compared genomic profiles in archival and study entry specimens.

Methods

PTEN expression in archival samples (N=68) was scored using QuPath Histo-score (H-score; range 0-300), and compared to pathologist scoring. In archival (N=43) and study entry (N=35) samples, DNA copy number (CN) and CN signature exposure were assessed using shallow whole genome sequencing; target sequencing was performed using a custom panel (Illumina AmpliSeq).

Results

Digital quantification of PTEN status was feasible with a high correlation between QuPath and pathologist scores (r=0.94, p<0.0001 for tumour; r=0.70, p=0.009 for non-tumour). H-score variability was lower in non-tumour than in tumour cells. Patients with low PTEN tumours (defined as tumour<non-tumour H-score) showed a longer PFS compared with those with PTEN proficient (tumour≥non-tumour H-score) in the V+wP arm [respectively 9.4 vs 4.1 months (mo) p=0.003] but not in the wP arm (4.8 vs 4.2 mo p=0.60). There was no difference in overall ploidy, rates of focal somatic CN alterations or CN signature exposure between diagnosis and relapse. However, high exposure to CN signature 4 (defined as ≥median signature 4 exposure across all samples) appeared associated with longer PFS (5.4 vs 3.3 mo p=0.125) in the V+wP arm but worse outcome in the wP arm (2.3 vs 4.6 mo p=0.018).

Conclusions

PTEN loss by IHC and high exposure to CN signature 4 both appear to be associated with longer PFS in patients treated with V+wP. Validation in further sample sets will be required.

Clinical trial identification

ISRCTN16426935 (EudraCT 2014-005221-12).

Legal entity responsible for the study

NHS Greater Glasgow and Clyde/University of Glasgow.

Funding

The study has been funded by AstraZeneca, CRUK, the Imperial/China Scholarship Councill, the NIHR Imperial Biomedical Research Centre, Ovarian Cancer Action, Imperial College London.

Disclosure

G. Giannone: Financial Interests, Personal, Other: Mylan; Financial Interests, Personal, Research Grant, ESMO Translational Fellowship: ESMO. A.R. Clamp: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Other, research funding: AstraZeneca. R.M. Glasspool: Financial Interests, Personal, Invited Speaker: AstraZeneca, GlaxoSmithKline, Clovis Oncology; Financial Interests, Personal, Advisory Board: AstraZeneca, GlaxoSmithKline, Clovis Oncology; Financial Interests, Institutional, Other, Research funding: Clovis Oncology, Boehringer Ingelheim; Financial Interests, Personal, Other, Funding to attend virtual conferences: GlaxoSmithKline; Financial Interests, Institutional, Other, Drug Donation Scheme: GlaxoSmithKline. S. Banerjee: Financial Interests, Institutional, Other, Educational Grants: AstraZeneca, GlaxoSmithKline; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Genmabs, Immunogen, MSD, Merck Sereno, Mersana, Oncxerna, Seagen, Shattuck Labs; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Clovis, Immunogen, MSD, Mersana, Pfizer, Roche. I. McNeish: Financial Interests, Personal, Invited Speaker: AstraZeneca, GlaxoSmithKline/Tesaro, Clovis Oncology, Roche, Epsila, Takeda, Scancell, Theolytics; Financial Interests, Personal, Advisory Board: AstraZeneca, GlaxoSmithKline/Tesaro, Clovis Oncology, Roche, Epsila, Takeda, Scancell, Theolytics; Financial Interests, Institutional, Other, Institutional grant income: AstraZeneca. All other authors have declared no conflicts of interest.

Background

HOX genes are a group of 39 genes known best for their role in embryonal development. Their function in oncogenesis is an exciting and rapidly developing field. They have been shown to be important in proliferation, epithelial-to-mesenchymal transition and Platinum resistance in other types of cancer, but this is the first study of their role in endometrioid ovarian cancer.

Methods

HOX gene expression was examined in endometrioid ovarian cancer cell lines and tissue using public databanks. This was then verified using Nanostring gene expression assays in a cohort of 56 FFPE samples from patients with EOC. Immunohistochemistry using HOX antibodies was also used to validate gene expression data. HXR9, a small molecule inhibitor of HOX, was used to test the sensitivity of EOC cell line TOV-112D to HOX inhibition using the MTS cell proliferation assay and Incucyte live cell analysis system. HXR9 was also tested for synergy with Platinum chemotherapy using a BLISS analysis and the ability to reverse platinum reistance using a colony formation assay.

Results

Widespread HOX gene dysregulation was observed in public databanks in both EOC cell lines and tumour tissue. This was mirrored in my cohort of 56 patients with EOC. In particular, HOX B5 was over-expressed and HOX D10 was under-expressed in both RNA expression assays and at a protein level. However, there was no correlation between HOX gene expression and clinico-pathological variable such as stage, grade, time to progression or overall survival. HXR9 was able to effectively kill TOV-112D cells with an IC50 40uM. HXR9 worked in synergy with Cisplatin to kill more cells with BLISS values > 10. HXR9 was able to overcome Platinum resistance in the colony formation assay.

Conclusions

HOX genes are dysregulated in endometrioid ovarian cancer and can be targeted for therapeutic purposes. HXR9 is able to kill EOC in a cell line model and work synergistically with Platinum chemotherapy, helping to overcome platinum resistance which is the number one clinical challenge facing patients with advanced ovarian cancer.

Legal entity responsible for the study

University of Surrey.

Funding

GRACE Charity.

Disclosure

All authors have declared no conflicts of interest.

Background

Cancer screening methods transformed cancer management in the last decades. Ideally, a screening tool should be simple, non-invasive, cost-effective, and reliable. These criteria are only partially met for gynecological cancers, for the available screening methods; thus, newer, non-invasive techniques are being investigated. This study assesses the potential of combining Attenuated Total Reflection Fourier-Transform Infrared Spectroscopy (ATR-FTIR) in urine samples with machine learning (ML) algorithms to differentiate tumor patients from healthy controls.

Methods

251 patients were recruited from the gynecological unit of the University Hospital Basel, 72 diagnosed with cancer (22 ovarian, 10 cervical, 25 endometrial, 24 breast, 1 vaginal) and 179 control with confirmed benign histology. After collection, samples were aliquoted and immediately frozen at -80C°. After thawing, 20 μl were deposited on ATR-FTIR crystal and directly measured. Each sample’s spectrum was created averaging 24 measurements, repeated 3 times, obtaining a total of 18072 spectra. Outliers were excluded using a Density-based spatial clustering algorithm. The data obtained were then processed using an “in-house” built algorithm to solve the binary classification of healthy VS cancerous patients.

Results

All data were preprocessed using standardization and constant removal to eliminate noise and went through a Least absolute shrinkage and selector operator (LASSO) feature selection process to select the most valuable parts of the spectra and reduce computational complexity. A set of classification algorithms was tested, including Support Vector Machines, Logistic Regression, Random Forest (RF), and Decision Trees. RF was the most performing reaching an accuracy of 90%. The final model was validated by using a 10-fold cross-validation technique.

Conclusions

This study presents promising results in using ATR-FTIR combined with ML Algorithms to detect urine samples from gynecological tumor patients VS healthy controls. Although we provide a significantly larger data volume than other published studies, further research in larger sample sizes is required to confirm the results and establish a possible screening method.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Cervical cancer is one of the leading cancers among women in India, and there is an increased need for screening as morbidity and mortality from the malignancy can be prevented. The prevention and control of cervical cancer requires a multidisciplinary effort to not only improve awareness but also to establish primary and secondary prevention strategies. As the population in remote villages do not have ease of access to major hospitals, the training of paramedical staff may be a viable option for screening women for cervical cancer.

Methods

19 rural villages with a combined population of 21,798 of whom 4121 were women above the age of 21 who never underwent screening for cervical cancer were selected. 10 villages with a population of 2113 females were willing to partake in the training of paramedical staff to screen for cervical cancer. The results of the number of positives and false positives were recorded over a 5-year span. The other 9 villages with a female population of 1968 that opted out of training paramedical staff were also followed during the same time period. Women who tested positive on VIA were treated with thermal ablation or referred to a higher medical center.

Results

Of the 2113 women screened for cervical cancer by paramedical staff, VIA came back positive in 19.64%. It was found that on biopsy 1.7% had high grade intraepithelial and 1.17% had low grade intraepithelial. 1.98% had cervical intraepitheial neoplasia stage 2 and above. In the 9 villages where training was not done the rates of screening were poor as only 20 women were screened.

Conclusions

There is an ever-growing need for cervical cancer screening in the rural areas of India, and the authors believe that screening through the usage of paramedical staff may be a good option as VIA and thermal ablation are easily done. Our results show that the overall diagnosis rates and the uptake of screening was more in villages with paramedical staff. We believe the implementation of paramedical staff who are trained in VIA and thermal ablation would ultimately lead to a reduction in the rates of cervical cancer and would better health for women in the rural areas.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Cervical cancer is one of the leading causes of death by neoplasia in the world. In Brazil, it is the 3rd cause of women's death by neoplasia. Since its implantation, 20 years ago, the federal program to prevent cervical cancer frequently had logistic and technical difficulties, especially in remote areas. Morbimortality studies are necessary to evaluate the evolution of the prevention program.

Methods

The present study evaluated cervical cancer hospitalizations in the state of Sergipe between 2008 and 2015. The data was extracted from a public database containing information about the unified public health system. The variables age, city of residence and type of hospitalization (clinical or surgical) were analyzed. Changes in hospitalization rates after the introduction of Papanicolaou test as a priority in primary care were considered through a temporal analysis using Joinpoint regression software. For this purpose, it was devised a linear logarithmic model that includes points and calculate the difference from a statistically significant value using a Monte-Carlo permutation test. The Average Annual Percent Change (AAPC), Annual Percent Change (APC) and temporal tendencies in hospitalization frequencies were calculated.

Results

873 hospitalizations were analyzed, the median age was 46 years. Surgical hospitalizations correspond to 67%.The temporal analysis showed a yearly decrease in hospitalizations of about 10%, both for the population living in the capital and in other cities of the state. When the hospitalizations in the whole state were divided by age subgroups, there was a statistically significant reduction in the subgroups 40 to 59 years and 60 years or more.

Conclusions

A consistent reduction in cervical cancer hospitalizations was observed in the state of Sergipe in the analyzed time period. This suggests an improvement after 20 years of the cervical cancer prevention program. Better access to diagnostic methods and appropriate treatment allow for more effective interventions, with fewer hospitalizations. There is, however, a long way to go, especially with regard to expanding health care for the population across the state, also aiming at reducing mortality rates.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Cervical cancer is the fourth most common cancers among women worldwide. Although the cure rates in early-stage disease are good, 30% to 40% of patients in advanced-stage disease ultimately develop locoregional or distal recurrence or both. The prognosis of recurrent cervical carcinoma is very poor, and treatment of such patients remains a challenge. Because of the limited success and significant toxicity with cytotoxic chemotherapy drugs in such subset of patients, interest has grown in EGFR targeted therapeutics. This prospective study defines the role of gefitinib in recurrent or metastatic cervical carcinoma.

Methods

The eligible criteria were patients with locoregional recurrence or distant metastasis, not suitable for curative surgery or re-irradiation or for active chemotherapy due to low performance score, patients who developed progression of disease during the salvage chemotherapy; and patients who developed severe toxicity during the course of chemotherapy and therefore could not continue it. Eligible patients were treated with gefitinib at a dose of 250 mg/d orally. It was continued until disease progression or till development of intolerable adverse effects.

Results

A total of 30 patients were enrolled. Median age was 55 years and median disease-free interval was 15 months. Median duration of gefitinib therapy was 6 months. 4 patients had complete response, 8 patient had partial response, 8 patients had stable disease, and 10 patients had progressive disease. None of the patient had severe drug related toxicity.

Conclusions

Gefitinib is tolerated and effective in recurrent or metastatic cervical carcinoma. Further studies are warranted to identify patients who are more likely to benefit from gefitinib.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Presently, the treatment of localized adenocarcinoma cervix patients is the same as squamous cell carcinoma. This study analyzes the long-term survival outcome and pattern of failure of adenocarcinoma patients treated at our institute.

Methods

All ladies diagnosed and treated with localized adenocarcinoma cervix at our institute between 2012 and 2018 were included. These patients were followed up till January 2022. The stages of all patients at the time of diagnosis were restaged according to FIGO 2018. The patient, treatment, and follow-up details were collected from the electronic filing system. Lost-to-follow-up patients were contacted through telephone. The statistical analysis was done using SPSS 23.0.

Results

Adenocarcinoma constituted 7.8% (66 out of 847 patients) of the entire cervical cancer patients detected during the study period – 44% of patients presented with either stage I or II. There were no patients with stage IVa. The median age was 53.5 years (66.7 % were 55 years or less). 69.7% of adenocarcinoma were HPV-associated. The treatment modalities undergone by these patients include radical concurrent chemoradiation and brachytherapy (36.4%), surgery alone (30.3%), surgery followed by adjuvant radiation in (15.2%), and surgery followed by concurrent chemoradiation in (18.2%). All the patients who underwent radiotherapy used the intensity-modulated radiotherapy technique for external beam radiotherapy and image-based adaptive brachytherapy. A few patients (16.7%) received neoadjuvant chemotherapy (NACT) before undergoing curative treatments. The median follow-up period was 54 months. The 10-year overall survival (OS) was 62.2% (84.2% in stage I, 56% in stage II, and 53.1% in stage III). The OS of those who received NACT was 72.7 percent versus 59.9% who did not receive it. Most of the patients who recurred had distant metastasis (64.3%), and the median disease-free interval of those who had distant metastasis was 7 months (2 - 30).

Conclusions

Further molecular studies should be done to better understand this distinctly different subset of cervical cancer patients to tailor the treatment modalities.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

To evaluate the impact of the Laparoscopic Approach to Cervical Cancer (LACC) trial on patterns of care and surgery-related morbidity in early-stage cervical cancer.

Methods

This is a retrospective, multi-institutional study evaluating 90-day surgery-related outcomes of patients undergoing treatment for early-stage cervical cancer before (period I: 01/01/2016-06/01/2018) and after (period II: 01/01/2019-06/01/2021) the publication of the results of the LACC trial.

Results

Charts of 1,295 patients were evaluated: 581 (44.9%) and 714 (55.1%) before and after the publication of the LACC trial, respectively. After the publication of the LACC trial the number of patients treated with minimally-invasive radical hysterectomy decreased from 64.9% to 30.4% (p<0.001). Overall, 90-day complications occurred in 110 (18.9%) and 119 (16.6%) patients in the period I and period II, respectively (p=0.795). Similarly, the number of severe (grade 3 or worse) complications did not differ between the two periods (38 (6.5%) vs. 37 (5.1%); p=0.297). Overall and severe 90-day complications were consistent between periods even evaluating stage IA (p=0.471), IB1 (p=0.929), and IB2 (p=0.074), separately.

Conclusions

The present investigation highlighted that in referral centers the shift from minimally invasive to open radical hysterectomy does not influence 90-day surgery-related morbidity.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Classification of lymph node metastases according to the size into macrometastases >2 mm (MAC), micrometastases 0.2 - 2 mm (MIC) and isolated tumor cells <0.2 mm (ITC) was adopted from breast cancer to other tumour types. In cervical cancer, MAC is well established as one of the main prognostic factors, indicating adjuvant treatment after primary surgery, while the impact of MIC and ITC has been subject of controversy. The aim of this study was to identify the cut-off for the minimal size of metastasis which is not associated with negative prognosis.

Methods

Data of 967 cervical cancer patients, T1a1 L1 - T2b stages, after primary surgical treatment with curative intent, including SLN biopsy followed by pathological ultrastaging, were obtained from the SCANN (Surveillance in Cervical CANcer) study. The size of SLN metastasis was considered a continuous variable, and multiple testing was performed for cut-offs ranging from 0.01 to 1.0 mm in 0.01 mm intervals. DFS in each subgroup was compared with the N0 cohort and each N1 group (> cut-off) using Log rank test.

Results

Positive SLN was found in 172 (18%) patients. Based on traditional classification, MAC, MIC, and ITC was the largest metastasis in 79 (8%), 54 (5%), and 39 (4%) cases. Patients with MAC and MIC had significantly shorter DFS than those with N0 disease (HR 2.20, p=0.003; HR 2.87, p < 0.001) with no difference between them (p=0.484). When subgroups were analysed using cut-off method, all patients with metastases ≥0.4 mm had significantly shorter DFS when compared to the N0 (HR = 2.311; p=0.04). The significance of metastases <0.4 mm could not be assessed due to the lack of power (<80%).

Conclusions

Lymph node metastases in patients with cervical cancer are associated with significantly negative impact on DFS irrespective of their size. No cut-off value for a minimal size of metastasis without negative prognostic impact can be found. Therefore, traditional classification to MAC/MIC/ITC should not be adopted in cervical cancer and the management should be uniform irrespective of the size of metastasis.

Legal entity responsible for the study

The authors.

Funding

Charles University, Prague (UNCE 204065 and PROGRES Q28/LF1).

Disclosure

All authors have declared no conflicts of interest.

Background

Brachytherapy is an important component in management of cervical cancer, enabling dose escalation with reasonable limitation of toxicity. However, in some patients, there is an inadvertent increase in OAR (Organs at Risk) doses. In our study, we analyse the dosimetric differences between the two commonly used ICBT (Intracavitary Brachytherapy) applicators in our hospital.

Methods

We performed a retrospective analysis of intracavitary brachytherapy (ICBT) plans using clinical records of 109 cervix cancer patients from Aug-2020 to Aug-2021. Patients who completed the ICBT course with the same applicators were chosen. 3 month follow up and symptom data was acquired from clinical records. The mean doses per patient were compared between FSD (Fletcher Suit Delclos) and Ring-Tandem applicator with ring cap.

Results

Ring and Tandem applicator was used in 67 patients while the Fletcher Suit Delclos applicator was used in 42 patients. The mean bladder D2cc (Highest irradiated 2cc area), rectum D2cc were 79.2% vs 79.2% and 50.4% vs 63.2%. (σ = 19.4) The mean (Posterior Inferior Border of Pubic Symphysis) PIBS +2 and PIBS dose was 146% vs 218.5% and 49% vs 83.6%. At the time of 3 months of follow up, incidence of Grade 2 dysuria was compared (0.5% v 19.5%, p<0.05) Analysing the anatomical parameters, the AP pelvic diameter correlated negatively with the average D2cc of OARs. The rectum volume correlated positively with D2cc rectum (ρ, correlation coefficient = 0.44). The rectum (ρ = 0.01) and bladder diameter (ρ = 0.15) at the level of the flange also correlated positively with OAR D2cc.

Conclusions

It can be inferred from the study that the ring and tandem has a comparably favorable dosimetric profile and it should be evaluated further, with a view to decrease OAR toxicities and improve symptom free quality of life. The dose at PIBS should also be looked into further as a marker of vaginal toxicity and urethral toxicity, and brachytherapy dose delivery should be optimised accordingly.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Cervical cancer is the 4th most common cancer in women in the world, and the 9th overall. External beam radiotherapy (EBRT) with concurrent cisplatin followed by brachytherapy forms the standard of care for advanced cervical carcinoma. High dose-rate (HDR) intracavitary brachytherapy (ICBT) for cervical cancer is now well established because of its numerous advantages. This study aimed to assess and compare the local control and toxicities between HDR ICBT with 7.5 Gy per fraction in three fractions (Control Arm) and 9 Gy per fraction in two fractions (Study Arm) after EBRT in treatment of carcinoma cervix.

Methods

A total of 180 patients meeting the inclusion criteria were included in the study and randomly assigned to the 2 arms of 90 patients each. Arm A received HDR ICBT with a dose of 7.5 Gy per fraction, 1 fraction per week for 3 fractions and Arm B received HDR brachytherapy 9 Gy per fraction , 1 fraction per week for 2 fractions. Patients were evaluated monthly for assessment of local control and toxicities. Statistical evaluation was done with mean, percentage and frequency using Chi Square, and Student T test.

Results

A total of 180 patients were analysed with 90 patients in each arm. All patients had received EBRT with a dose of 50 Gy in 25 fractions. 91% of the patients received concurrent chemotherapy to a mean of 4 cycles. Complete response was seen in 80 patients (89%) in arm A and in 87 patients (96.7%) in arm B. 4 patients in arm A and 2 patients in arm B has local recurrence. Grade 2 and above proctitis was seen in 3.3 % of the patients in arm A and in 6.6 % of the patients arm B. 1 patient in arm A and 1 patient in arm B had grade 1 hematuria.

Conclusions

This study, with 9 Gy in 2 fractions showed a better local control of the tumour till 6 months when compared to 7.5 Gy in 3 fractions. Although there was no statistical significance, our study also suggested that the rate of rectal toxicities was slightly higher in the 9 Gy arm when compared with 7.5 Gy arm, which could be managed medically. The study also highlighted the need for completion of total treatment of EBRT and brachytherapy within 60 days to reduce recurrence rates.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Recent studies have indicated that N6-methyladenosine (m6A) methylation modification and regulators play a critical role in human cancers. However, the possible functions of m6A and its regulators on cervical cancer (CC) tumorigenesis are still unclear. This study explored the function and mechanism of METTL3 (methyltransferase-like 3) and its downstream target oncogenes in CC.

Methods

First, we investigated the expression of m6A regulator gene (METTL3) mRNA and proteins by qRT-PCR and western blot assays in cervical cancer cell lines. In addition, we performed a series of functional studies to investigate the oncogenic role of METTL3 and its downstream target oncogenes in CC cells. m6A-methylated RNA immunoprecipitation sequencing (MeRIP-seq) was used to screen the target genes of METTL3. m6A level of mRNA was measured by an m6A-RNA methylation quantification kit.

Results

The level of m6A RNA methylation was significantly increased in CC cells. METTL3 is a major catalytic enzyme involved in the abundant m6A RNA modification and plays an important role in carcinogenesis. We observed that METTL3 expression was frequently up-regulated in CC cell lines. Functional studies with METTL3 knockdown in CC cells dramatically inhibited cellular proliferation, migratory potential and colony formation abilities. Mechanistically, MeRIP-seq illustrated that Yin-Yang 1 (YY1) as a target of METTL3. Recent studies reported that YY1 is highly expressed in different types of cancer, whereby it is associated with cell proliferation, metastasis, survival, metabolic reprogramming, and poor patient survival. The TCGA data analysis revealed that YY1 mRNA and protein were highly expressed cervical cancer tissues. In addition, Pearson correlation analysis showed that highly expressed METTL3 was positively correlated with YY1 expression. Thus, the METTL3/m6A/YY1 axis promotes cervical carcinogenesis.

Conclusions

Taken together, our findings demonstrated the oncogenic role of METTL3 in cervical cancer by regulating YY1 expression in an m6A-dependent manner and provide a new insight into the pathogenesis of CC. Hence, METTL3/m6A/YY1 axis represents a potential target for CC therapy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

IL-8 gene polymorphisms are involved in the carcinogenesis of many malignant neoplasms, but their role in the development of cervical cancer (CC) has not been fully elucidated. The aim of the study was to evaluate the relationship between the presence of IL-8 gene polymorphism (845 T/C) and the development of severe cervical intraepithelial neoplasia (CIN) and cervical cancer.

Methods

The study included 21 patients with CIN III and stage Ia FIGO cervical cancer and 20 healthy women (control). The study was conducted in accordance with the requirements of the USU Ethics Commission (No. 9 dated September 15, 2016). We determined the level of IL-8 (CJSC Vector-Best-Volga, Russia) using ELISA in neutrophil lysate and serum. For the analysis of SNP IL-8 845 T/C (rs2227532), the samples were genotyped by PCR with restriction enzyme analysis using Vsp I endonuclease (SibEnzyme, Russia). The digested PCR products were separated by electrophoresis in 1.5% agarose gel. Statistical processing was carried out using Statistica 13 (StatSoft).

Results

We found that the -845C* allele was more common in the group with cervical lesions (76.2%) than in the control group (10%) (chi-square=18.223, p=0.001). The risk of developing CIN increased in the presence of the -845C* allele (OR=28.8, 95% CI 4.892-169.546, p=0.038). The level of IL-8 in neutrophils in CIN (p=0.015) was lower than that in the control. At the same time, the level of IL-8 in neutrophils and serum in CIN is not associated with the frequency of occurrence of the -845T* and -845C alleles.

Conclusions

The presence of IL-8 gene polymorphism (845 T/C) is associated with CIN.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Currently, there is a paucity of data evaluating post-treatment human papillomavirus (HPV) clearance in patients who receive definitive chemoradiotherapy (CRT) for the treatment of locally advanced cervical cancer and its correlation with oncological outcomes.

Methods

We included patients with histopathologically-confirmed locally advanced cervical cancer who were amenable to definitive CRT and brachytherapy. The subjects underwent a pretreatment liquid-based cytology to perform mRNA-based testing for HPV infection. We repeated the HPV testing 6 weeks after the patients completed their treatment. Response to treatment was evaluated with clinical examination, cervical cytology, and a contrasted pelvic MRI.

Results

Over a 6-month period, 23 patients were included in our study. The mean age at diagnosis was 65 years. Regarding clinical stage (CS), 13% of cases were classified as CS IIA1 non-bulky disease, whereas 87% were classified as CS IB2 to IVB disease. HPV infection was reported in 87% of cases, from which 34% presented more than one HPV genotype. The most prevalent HPV genotype was 16 (48%), followed by 72 (13%) and 18 (9%). Sixteen patients completed the treatment protocol and underwent evaluation for clinical response and post-treatment HPV testing. A complete response (CR) was documented in 81% of cases. Of the sixteen evaluable patients, 13 were initially positive for HPV infection; viral clearance was documented in 8 cases (62%). From all patients who achieved HPV clearance, we documented CR in 54% of cases, whereas only 31% of patients who did not achieve HPV clearance presented a CR. After analysis, we did not find a statistically significant correlation between HPV clearance and CR. HPV clearance was neither correlated with the CS at diagnosis.

Conclusions

Despite the high rate of post-treatment HPV clearance reported among our patients with locally advanced cervical cancer, we found no correlation with achieving a CR. The role of HPV clearance in this setting needs to be further evaluated to determine its value in clinical response and other oncological outcomes like disease-free interval or overall survival.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Advanced/recurrent cervical cancer has limited therapeutic options, with a median progression-free survival after the failure of systemic treatments ranging between 3.5 and 4.5 months. Here, we reported our preliminary experience in the use of BYL719 (alpelisib) in advanced/recurrent cervical cancer after failure of at least 2 lines of treatment.

Methods

This is a prospective trial testing the role of alpelisib in PIK3CA mutated patients. The Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (Italy) approved this prospective investigation (IRB number 20205720).

Results

From April 2020 to September 2020, 17 consecutive patients with recurrent cervical cancer had next-generation sequencing (NGS). Patients harboring PIK3CA mutation were included in the study. Overall, six patients were included in the study. All patients had been treated with at least 2 previous lines of systemic treatment: 3 patients received >2 prior lines of treatment in the recurrent or metastatic setting; 60% had received prior bevacizumab in combination with chemotherapy. All patients started alpelisib at the daily dosage of 300 mg. Investigator-assessed confirmed objective response rate (ORR) was 33%. The disease control rate (DCR) was 100%. According to RECIST 1.1, two patients had a partial response (PR), and four patients had stable disease (SD). No complete response was observed. The mean duration of response (DOR) was 11.5 (SD 3.75) months; five patients had PR lasting for >9 months. One patient stopped the treatment at 0.82 months due to the onset of a grade 2 adverse event (AE) (skin rash). Grade 3 treatment-related AEs included: lymphoedema (n=1, 20%) and rash (n=1, 20%). No treatment-related grade 4-5 AEs occurred.

Conclusions

Alpelisb seems associated with promising anti-tumor activity in cervical cancer patients harboring PIK3CA mutation. Further prospective trials are needed to assess the safety and effectiveness of alpelisib in PIK3CA-mutated pre-treated cervical cancer.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The prognosis of locally-advanced unresectable or metastatic (LA/M) cervical and uterine cancer remains poor, with HER2 alterations occurring in 0.5-21% of cervical cancers and 2-80% of uterine cancers, respectively. Tucatinib (TUC), a highly selective HER2 directed TKI, is approved in combination with trastuzumab (Tras) and capecitabine in multiple regions for HER2+ metastatic breast cancer and is being investigated in other HER2+ cancers, including LA/M cervical and uterine cancer. SGNTUC-019 (NCT04579380) is an open-label, international phase II basket study evaluating TUC and Tras in adult patients (pts) with LA/M HER2+ or HER2-mutated solid tumors.

Trial design

SGNTUC-019 will evaluate TUC and Tras in pts with previously treated, LA/M solid tumors that display HER2 overexpression/amplification or activating mutations, including HER2+ cervical and uterine cancer cohorts. Pts will receive TUC 300 mg PO BID and Tras 8 mg/kg IV on Cycle 1 Day 1 and 6 mg/kg q21 days from Cycle 2 Day 1. HER2+ cervical and uterine cancer cohorts will enroll 12 pts each with potential for expansion up to 30 pts. Pts with HER2-mutated cervical, uterine, and other gynecologic cancers may enroll in a pooled cohort of 30 pts with HER2-mutated solid tumor types. Eligible pts must have progressed on or after their last systemic therapy, with prior platinum-based chemotherapy ± bevacizumab required in pts with metastatic cervical cancer. Pts must have ECOG PS ≤1, adequate organ function, and have not received HER2-directed therapy; pts with uterine serous carcinoma may have received prior Tras. HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH, or by HER2 amplification/mutation in a prior or on-study NGS assay of ctDNA or prior tissue NGS assay. The primary endpoint is confirmed ORR per investigator. DCR, DOR, PFS, OS, safety, and PK are secondary endpoints. Disease assessments per RECIST 1.1 will occur q6 weeks for 24 weeks, then q12 weeks. QoL will be evaluated q2 cycles using EQ-5D-5L. Enrollment is now open in Europe, the US, and Asia Pacific.

Clinical trial identification

NCT04579380.

Legal entity responsible for the study

Seagen Inc., Bothell, WA, USA in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Ind., Kenilworth, NJ, USA.

Funding

Seagen Inc., Bothell, WA, USA in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Ind., Kenilworth, NJ, USA.

Disclosure

D. O'Malley: Financial Interests, Personal and Institutional, Research Grant, Consultancy: AbbVie; Financial Interests, Personal and Institutional, Research Grant, Consultancy: Agenus; Financial Interests, Personal, Other, Consultancy: Ambry; Financial Interests, Personal, Other, Consultancy: Arquer; Financial Interests, Personal and Institutional, Research Grant, Consultancy: AstraZeneca; Financial Interests, Personal, Other, Consultancy: Celsion; Financial Interests, Personal and Institutional, Research Grant, Consultancy: Clovis; Financial Interests, Personal, Other, Consultancy: Corcept; Financial Interests, Personal and Institutional, Research Grant, Consultancy: Eisai; Financial Interests, Personal, Other, Consultancy: Elevar; Financial Interests, Personal and Institutional, Research Grant, Consultancy: Genentech/Roche; Financial Interests, Personal and Institutional, Research Grant, Consultancy: GOG Fnd; Financial Interests, Personal and Institutional, Research Grant, Consultancy: Immunogen; Financial Interests, Personal and Institutional, Research Grant: Inc. Research; Financial Interests, Personal and Institutional, Research Grant: InVentiv Health; Financial Interests, Personal and Institutional, Research Grant, Consultancy: Iovance; Financial Interests, Personal and Institutional, Research Grant, Consultancy: Janssen; Financial Interests, Personal and Institutional, Research Grant, Consultancy: Johnson & Johnson; Financial Interests, Personal, Other, Consultancy: Merck; Financial Interests, Personal and Institutional, Research Grant, Consultancy: Mersana; Financial Interests, Personal, Other, Consultancy: Myriad; Financial Interests, Personal, Other, Consultancy: Novartis Novocure; Financial Interests, Personal, Other, Consultancy: Regeneron; Financial Interests, Personal, Other, Consultancy: Roche; Financial Interests, Personal, Other, Consultancy: Rubis; Financial Interests, Personal, Other, Consultancy: SDPOnc; Financial Interests, Personal, Other, Consultancy: Seagen Inc.; Financial Interests, Personal, Research Grant, Consultancy: Amgen; Financial Interests, Personal, Other, Consultancy: Inxmed; Financial Interests, Personal and Institutional, Research Grant: Ajinomoto; Financial Interests, Personal and Institutional, Research Grant: Array; Financial Interests, Personal and Institutional, Research Grant: BMS; Financial Interests, Personal and Institutional, Research Grant: Cerulean; Financial Interests, Personal and Institutional, Research Grant: EMD Serono; Financial Interests, Personal and Institutional, Research Grant: Ergomed; Financial Interests, Personal and Institutional, Research Grant: GenMab; Financial Interests, Personal and Institutional, Research Grant: Ludwig Cancer Research; Financial Interests, Personal and Institutional, Research Grant: Merck; Financial Interests, Personal and Institutional, Research Grant: New Mexico CCA; Financial Interests, Personal and Institutional, Research Grant: Novocure; Financial Interests, Personal and Institutional, Research Grant: PRA Int'l; Financial Interests, Personal and Institutional, Research Grant: Regeneron; Financial Interests, Personal and Institutional, Research Grant: SDPOnc; Financial Interests, Personal and Institutional, Research Grant: Seagen Inc.; Financial Interests, Personal and Institutional, Research Grant: Serono; Financial Interests, Personal and Institutional, Research Grant: Stemcentrx; Financial Interests, Personal and Institutional, Research Grant: Tarveda; Financial Interests, Personal and Institutional, Research Grant: Tesaro/GSK; Financial Interests, Personal and Institutional, Research Grant: Tracon Pharma; Financial Interests, Personal and Institutional, Research Grant: VentiRx; Financial Interests, Personal and Institutional, Research Grant: Yale University; Financial Interests, Personal, Invited Speaker: Sorrento; Financial Interests, Personal, Other, Consultancy: Takeda; Financial Interests, Personal, Other, Consultancy: Tesaro/GSK; Financial Interests, Personal, Other, Consultancy: Toray. F.J. Jin: Financial Interests, Personal, Full or part-time Employment: Merck; Financial Interests, Personal, Ownership Interest: Merck; Financial Interests, Personal, Other, Travel Expenses: Merck. J.D. Ramos: Financial Interests, Personal, Full or part-time Employment: Seagen Inc.; Financial Interests, Personal, Ownership Interest: Seagen Inc. Q. Tan: Financial Interests, Personal, Full or part-time Employment: Seagen Inc.; Financial Interests, Personal, Ownership Interest: Seagen Inc.; Financial Interests, Personal, Other, Travel Expenses: Seagen Inc. B.J. Monk: Financial Interests, Personal, Other, Consultant: Agenus; Financial Interests, Personal, Other, Consultant: Akeso Bio; Financial Interests, Personal, Other, Consultant: Amgen; Financial Interests, Personal, Other, Consultant: Aravive; Financial Interests, Personal, Other, Speaker/Consultant: AstraZeneca; Financial Interests, Personal, Other, Consultant: Bayer; Financial Interests, Personal, Other, Speaker/Consultant: Clovis; Financial Interests, Personal, Other, Speaker/Consultant: Eisai; Financial Interests, Personal, Other, Consultant: Elevar; Financial Interests, Personal, Other, Consultant: EMD Merck; Financial Interests, Personal, Other, Consultant: Genmab/Seagen; Financial Interests, Personal, Other, Consultant: GOG Foundation; Financial Interests, Personal, Other, Consultant: Gradalis; Financial Interests, Personal, Other, Consultant: ImmunoGen; Financial Interests, Personal, Other, Consultant: Karyopharm; Financial Interests, Personal, Other, Consultant: Iovance; Financial Interests, Personal, Other, Consultant: Macrogenics; Financial Interests, Personal, Other, Speaker/Consultant: Merck; Financial Interests, Personal, Other, Consultant: Mersana; Financial Interests, Personal, Other, Honorarium: Novartis; Financial Interests, Personal, Other, Consultant: Novocure; Financial Interests, Personal, Other, Consultant: Myriad; Financial Interests, Personal, Other, Consultant: OncoC4; Financial Interests, Personal, Other, Consultant: Pieris; Financial Interests, Personal, Other, Consultant: Pfizer; Financial Interests, Personal, Other, Consultant: Puma; Financial Interests, Personal, Other, Consultant: Regeneron; Financial Interests, Personal, Other, Speaker/Consultant: Roche/Genentech; Financial Interests, Personal, Other, Consultant: Sorrento; Financial Interests, Personal, Other, Speaker/Consultant: Tesaro/GSK; Financial Interests, Personal, Other, Consultant & Investigator: US Oncology Research; Financial Interests, Personal, Other, Consultant: VBL.

Background

The new ESGO-ESTRO-ESP 2020 risk classification system (molecular classification unknown) has allocated fewer patients to the high-risk group compared to the previous risk stratification system in 2016. The study aims to clinically validate the new system in predicting the outcome compared to the previous one.

Methods

We retrospectively analyzed the data of 684 patients treated between 2009 and 2013 for carcinoma endometrium in a tertiary care oncology center. The three years overall survival (OS) and disease-free survival (DFS) estimates were generated independently using the Kaplan Meier method for the new and previous classification system. Akaike information criterion and concordance index was calculated between both staging systems to identify better predictive model.

Results

After re-classification, 43% of patients in the high-risk group based on the 2016 system are shifted to the high-intermediate group and 93% of patients migrated from the high-intermediate to intermediate-risk group (Table). The 3-year OS for low risk, intermediate risk, high intermediate risk, high risk, and advanced patients according to the 2016 risk stratification system was 98.3%,95.7%,98%,90.1%, and 64.2% respectively and was 98.3%, 96.6%,92.9%,88.9% and 61.3% respectively according to the 2020 system. The 3-year DFS was 97.9%,79.3%,88.9%,77.3% and 57.2% according to the 2016 system and 97.9%,83%,85.3%,72.2% and 53.8% respectively with the 2020 system. The survival rate decreased from low to advanced risk groups and the newer high-risk group has a lower survival rate than the previous one. The Akaike Information Criterion was lower (0.685 versus 0.702) and Concordance Index values were better (1566.661 versus1545.505) for ESGO 2020 system for DFS, indicating that the newer edition gives a better predictive model Table: 22P

ESGO 2016 and ESGO-2020 cross-tabulation

Conclusions

The new 2020 risk stratification appears better predictive of survival events.

Legal entity responsible for the study

Institutional Review Board, Regional Cancer Centre, Thiruvananthapuram.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Prognosis in advanced or recurrent endometrial cancer (aEC) is poor (5-year overall survival [OS] 15%-17%). Paclitaxel plus carboplatin (PC) is standard of care (SOC) first-line (1L) chemotherapy (CT), and no 2L SOC is established. We conducted a systematic literature review to assess the real-world effectiveness and safety of CTs in aEC.

Methods

MEDLINE, Embase, and the Cochrane Library and five relevant conference databases (2018-2020) were searched (January 2000-July 2020) for aEC studies that met prespecified inclusion/exclusion criteria. Uterine cancer was included to capture all relevant evidence. Key outcomes included OS, progression-free survival (PFS), and adverse events (AEs).

Results

84 publications met the criteria, and most assessed outcomes in (neo)adjuvant settings. Totals of five and six studies reported OS or PFS in 1L and ≥2L, respectively. Studies were from the US (n=6), Asia (n=2), Europe (n=2), and South America (n=1), and sample sizes ranged from 20 to 3197. CTs in 1L studies included PC (n=2), taxane-based CT (n=1), platinum-based CT (n=1), or any CT (n=1); ≥2L CTs included PC (n=3), doxorubicin (n=2), or any platinum-based CT (n=1) Median OS (mOS) was reported in four of five 1L studies: 11 to 28.5 months with CT not specified, 16.9 months with taxane-based CT, and 12.5 months with PC. A median PFS (mPFS) of 5.1 months was reported in one study. All six ≥2L studies reported mOS and mPFS. Of the four studies that investigated platinum-based therapies, two provided results split by treatment-free interval (TFI). One study reported mOS as 13 months for patients with treatment-free intervals (TFI) ≥ 6 months from prior systemic therapy and 5.5 months for those with TFI < 6 months. AEs (from 3 studies) were nausea (18.9%), palmar-plantar erythrodysesthesias (16.4%), and muscle weakness (12.3%) for doxorubicin, neurotoxicity (0%-10.6%) and hypersensitivity reaction (0%-2.4%) for PC, and neutropenia (16%) for carboplatin plus epirubicin.

Conclusions

The limited evidence found low OS and PFS for aEC following CT in both 1L and ≥2L settings, further emphasizing the high unmet need for new treatment options in this aggressive indication.

Legal entity responsible for the study

Eisai Inc.

Funding

Eisai Inc.

Disclosure

All authors have declared no conflicts of interest.

Background

The use of somatic tumor mutational profiling is growing. We envision that somatic alterations of the MMR genes can inform on the MMR-D phenotype in endometrial cancer.

Methods

We analyzed the whole-exome sequence data of 570 patients with endometrial cancer from two previously reported studies (Nature. 2013;497(7447):67–73 and Clin Cancer Res. 2018;24(23):5939–47). Another 148 patients not previously reported were included. We used the Benjamini-Hochberg procedure (q-value) for multiple hypothesis testing.

Results

A total of 706 pts were eligible for final analysis. Pts with somatic alterations in at least one of the MMR genes (MMR alt) were 16% (112/706) of pts. MMR alt group were diagnosed at an earlier median age than the non-MMR alt group (60 vs. 64 years, p = 0.005). No significant difference among pts of different races (p=0.24). The pts with MMR alt had a superior 5-year overall survival compared to the non-MMR alt pts (93.6% vs. 72.1%, Log-rank p=0.002). Pts with MMR alt were significantly enriched with mutations in cancer-related genes, such as PTEN and PIK3CA (q<0.0001). Meanwhile, TP53 mutations were enriched in the non-MMR alt group (q<0.0001). Pts with MMR alt had significantly higher MSI-high and POLE-hypermutated phenotype tumors compared to pts with non-MMR alt (52.04% vs. 23.72% and 43.88% vs. 1.47%, p< 0.001, respectively). Pts with MMR alt showed a higher MMR-D phenotype as detected by IHC compared to non-MMR alt pts (71.43% vs. 8%, p <0.001). In pts with available transcriptomic data from non-MMR alt (419 pts) and MMR alt (98 pts) subgroups, the expression of the mRNA transcripts of MSH6 was significantly higher in the non-MMR alt compared to the MMR alt group (Log ratio =0.24, q= 0.028), suggesting decreased expression in the MMR alt group. Moreover, PD-L1 expression was negatively correlated with PMS2 expression (Spearman’s R=-0.28, p<0.001).

Conclusions

Somatic MMR gene alterations delineated a subgroup of pts with endometrial cancer that had better survival, younger age, and highly mutated genomic profile. There is a significant association between somatic MMR alterations and standard MSI testing, suggesting the potential use of somatic tumor testing to identify MMR-D phenotype in tissue or liquid biopsies.

Legal entity responsible for the study

K. Shohdy.

Funding

European School of Oncology (ESO).

Disclosure

All authors have declared no conflicts of interest.

Background

The COVID-19 outbreak has correlated with the disruption of screening activities and diagnostic assessments. Endometrial cancer is one of the most common gynecological malignancies and it is often detected at an early stage because it frequently produces symptoms. Here, we aim to investigate the impact of the COVID-19 outbreak on patterns of presentation and treatment of endometrial cancer.

Methods

This is a retrospective study involving 54 centers in Italy. We evaluated patterns of presentation and treatment of endometrial cancer patients before (period 1: March 1, 2019, to February 29, 2020) and during (period 2: April 1, 2020, to March 31, 2021) the COVID-19 outbreak.

Results

Charts of 5,164 endometrial cancer patients were retrieved from 54 Italian centers over the whole study period. Overall, 2,718 and 2,446 women with endometrial cancer received treatment in periods 1 and 2, respectively. The prevalence of patients aged > 65 years was similar between the two study periods (1,400 (51.5%) in period 1 vs. 1,248 (51.0%); p=0.726). Similarly, the prevalence of elderly patients (i.e. aged >85 years) was comparable between groups (189 (6.9%) vs. 180 (7.4%); p=0.572). Considering data on the histological characterization, the prevalence of endometrioid FIGO grade 1, 2, and 3 was consistent over the study period (p=0.855). However, the prevalence of non-endometrioid endometrial cancer was lower in period 1 than in period 2 (15.6% vs. 17.9%; p=0.032). Surgery was the mainstay of treatment before and during the COVID-19 pandemic. Overall, 2,539 and 2,286 women received surgery in period 1 and 2, respectively (93.4% vs. 93.5%; p=0.948). Primary conservative attempts was performed in 72 (2.7%) and 56 (2.3%) patients in period 1 and 2, respectively (p=0.406). Overall, 1,280 (50.4%) and 1,021 (44.7%) patients had no adjuvant therapy in period 1 and 2, respectively (p<0.001). Adjuvant therapy use has increased during the COVID-19 pandemic (p<0.001).

Conclusions

Our data suggest that the COVID-19 pandemic had a significant impact on the characteristics and patterns of care of endometrial cancer patients. These findings highlight the need to implement healthcare services during the pandemic.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Uterine sarcomas (US) are rare tumors, representing less than 3% of gynecologic malignancies and between 3% and 7% of uterine malignancies. US are characterized by being aggressive with a high rate of local and metastatic recurrence. Their management is not well codified. The aim of our study was to investigate the epidemiological, clinical, therapeutic, and prognostic characteristics of US.

Methods

This was a monocentric, descriptive, retrospective study that included patients with US treated in Salah Azaiez Tunisian oncological institute between 2000 and 2020.

Results

The study included 103 patients. The average age was 50 years. Menometrorrhagia was the main circumstance of discovery (n=70). In 73.8% of cases, the diagnosis was postoperative. Histological confirmation was done on hysterectomy specimen in 82 patients. The most frequent histological type was leiomyosarcoma in 72.8% of cases. Stage I was the most represented (41.7%). Ninety-seven patients underwent surgery, 87 of them had a total hysterectomy associated with bilateral salpingo-oophorectomy and lymph node dissection. Adjuvant chemotherapy was indicated in 16.5% of cases. Adjuvant pelvic radiotherapy was performed in 35 patients. Thirty-one patients received first-line chemotherapy. The protocol used was the combination of doxorubicin and ifosfamide in 82.3% of cases. Two patients received palliative endocrine therapy after progression to first line. After a median follow-up of 56 months, the overall survival at 2 and 5 years, all stages combined, was 56% and 40%, respectively. For metastatic stages, the overall survival was 36% and 25% at 2 and 3 years, respectively. In multivariate analysis, no prognostic factors were identified. Progression-free survival at 3 and 5 years was 82% and 72%, respectively. In multivariate analysis, only the circumstance of discovery was a prognostic factor impacting progression-free survival (p=0.042).

Conclusions

US is a particular neoplasm. Prospective randomized studies are needed to better codify its management.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

No residual disease after debulking surgery is the most critical independent prognostic factor for advanced ovarian cancer (AOC). There is an unmet clinical need for selecting primary or interval debulking surgery in AOC patients using existing prediction models such as CA-125, CT, PET-CT, or laparoscopy.

Methods

In this multiphase cohort study, 348 pre-treatment plasma and postsurgical tissue consecutive samples, and 272 patients were collected from four clinical centers. Circulating sEVs miRNAs profile associated with residual disease was revealed by RNA sequencing in AOC patients. MiRNAs expression was measured via TaqMan quantitative real-time PCR. The prediction model was established via the least absolute shrinkage and selection operator (LASSO), and logistic regression analysis based on the discovery-validation set. Plasma and tissue sEVs were captured by the magnetic bead sorting system (MACS) using cell-type-specific proteins as markers (EpCAM, FAP, CD45, CD235a, CD31).

Results

After analyzing a comprehensive plasma sEVs miRNAs profile in AOC, we identified and optimized a risk prediction model consisting of plasma sEVs-derived 4-miRNA (miR-320a-3p, miR-378a-3p, miR-1307-3p, let-7d-3p) and CA-125 (AUC:0.903; sensitivity:0.897; specificity:0.910; PPV:0.926; NPV:0.871). The quantitative evaluation of Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) suggested that the additional predictive power of the combined model was significantly improved contrasted with CA-125 or 4-miRNA alone (model vs CA-125, NRI=0.471, P<0.001; IDI=0.538, P<0.001; model vs 4-miRNA panel, NRI=0.122, P=0.001; IDI=0.185, P=0.003). Tumor cells-derived sEVs captured on EpCAM+ magnetic beads were the major vehicles affecting circulating sEVs 4-miRNA expressions. Moreover, the model index scores were significant differences between AOC and other confusable diseases (e.g., advanced colorectal cancer).

Conclusions

A reliable and stable model of circulating tumor-derived sEVs 4-miRNA plus CA-125 was established for preoperatively anticipating the high-risk AOC patients of residual disease to optimize clinical therapy.

Legal entity responsible for the study

J. Tang.

Funding

This work was supported by Grants from the General Project of Natural Science Foundation of Hunan Province (No. 2020JJ4051); Promotion Project of Health Suitability Program in Health Department of Hunan Province (No. WZ2020-15); Science and Technology Innovation Program of Hunan Province (No. 2020SK51101); Hunan Cancer Hospital Climbing Fund (No. ZX2020004); Capacity Building Project of Central Subsidy Medical and Health Institutions (No. 20201127-1001); Key Specialty Construction Project in Hunan Province (No. 20210826-1004); General Project in Health Department of Hunan Province (No. 202205015388).

Disclosure

The author has declared no conflicts of interest.

Background

Ovarian cancer (OC) is the most common cause of gynecologic cancer mortality worldwide. Next generation sequencing (NGS) provides molecular biomarkers which can potentially predict oncological outcomes. We performed a retrospective study to examine progonostic biomarkes for ovarian cancer patients treated in our institution.

Methods

We retrospectively evaluated demographic and clinical information of OC patients referred for NGS molecular testing between 2011-2020 at the Tel-Aviv Medical Center. Cox models were used to analyze the clinical impact of molecular biomarkers including LOH and TMB by assessing overall survival (OS) and progression free survival (PFS).

Results

Of 1026 consecutive patients reviewed, 946 were included in the analysis: 108 (11.4%) were referred to NGS and 838 (88.6%) served as control. Patient baseline parameters were similar between the groups. High loss of heterozygosity (LOH) was associated with longer mOS (99.0 vs. 48.2 months, p=0.004). Sixty-six patients had information on TMB status: 75.8% (50/66) had low TMB status (<5) and 24.2% (16/66) had intermediate TMB status (5-15). None had a high TMB status. Analysis of TMB using the Breslow test showed that patients with TMB ≥4 had a statistically significant longer OS compared with patients with TMB<4 (92.8 months [95%CI, 47.1-138.6] vs. 52.77 months [95% CI, 26.4-79.2], p=0.026).

Conclusions

We identified LOH and TMB ≥4 as strong prognostic biomarkers among OC patients. Prospective studies evaluating larger cohorts are necessary to generate a more extensive evaluation of additional prognostic and predictive biomarkers.

Legal entity responsible for the study

The authors.

Funding

Roche Israel.

Disclosure

All authors have declared no conflicts of interest.

Background

Correlation between BRCA 1 / 2 pathogenetic mutations and response to Poly (ADP-Ribose) Polymerase inhibitors (PARPi) has been fully investigated and amply recognized in ovarian cancer (OC) patients. Moreover, data about clinical implication of variant of unknown significance (VUS) are lacking. The aim of this study was to evaluate differences in survival outcomes in BRCA 1 / 2 pathogenetic mutated, VUS and wild type (WT) relapsed OC patients treated with PARPi.

Methods

In this retrospective case control study OC patients, whose BRCA 1 / 2 genetic tests were available and receiving PARPi as maintenance at the time of first relapse between 2014 and 2021, were included. Patients were divided into three groups according to BRCA mutational status (BRCA 1 / 2 pathogenetic mutated, VUS and WT). Clinical characteristics at baseline and at the time of relapse before PARPi therapy were evaluated and progression free survival (PFS), defined as the time between date of last platinum and date of progression during PARPi or last follow-up, were assessed in each study group.

Results

Out of 67 patients identified, 24 (35.8%), 20 (29.9%) and 23 (34.3%) presented with BRCA 1 / 2 mutation, VUS and BRCA WT, respectively. In the overall population, most patients were diagnosed at an advanced stage, with 82.1% (n=55) at stage III and 8.9% (n=6) at stage IV. Median age at the time of first recurrence before PARPi was 58 years (Interquartile Range 55-61). Patients received Olaparib, Niraparib and Rucaparib as maintenance at the time of fist relapse after complete or partial response to platinum-based chemotherapy and no statistically significant differences were found in previous Platinum Free Interval (PFI) among the analyzed groups. Median PFS of BRCA 1 / 2 pathogenetic mutated patients was significantly longer than patients BRCA WT or VUS (Not Reached versus 4 months vs 7 months, respectively; p<0.001). Additionally, no significant difference was found between BRCA WT and BRCA VUS (p = 0.50).

Conclusions

Our study suggests that BRCA VUS carriers present survival outcomes comparable with BRCA 1 / 2 wild type patients and with shorter PFS than women harboring BRCA 1 / 2 pathogenetic mutations.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

C. Marchetti: Financial Interests, Personal, Other: GSK; Financial Interests, Personal, Other: Clovis Oncology; Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Other: PharmaMar. V. Salutari: Financial Interests, Personal, Other: GSK; Financial Interests, Personal, Other: PharmaMar; Financial Interests, Personal, Other: Roche; Financial Interests, Personal, Other: MSD; Financial Interests, Personal, Other: Eisai; Financial Interests, Personal, Other: Clovis; Financial Interests, Personal, Other: AstraZeneca. S. Pignata: Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Other: MSD; Financial Interests, Personal, Other: Roche; Financial Interests, Personal, Other: Pfizer; Financial Interests, Personal, Other: Clovis; Financial Interests, Personal, Other: GSK; Financial Interests, Personal, Other: PharmaMar; Financial Interests, Personal, Sponsor/Funding: MSD; Financial Interests, Personal, Sponsor/Funding: Roche; Financial Interests, Personal, Sponsor/Funding: AstraZeneca; Financial Interests, Personal, Sponsor/Funding: Pfizer. G. Scambia: Financial Interests, Personal, Research Grant: MSD; Financial Interests, Personal, Other: Clovis Oncology; Financial Interests, Personal, Other: Tesaro; Financial Interests, Personal, Other: Johnson & Johnson. D. Lorusso: Financial Interests, Institutional, Sponsor/Funding: Clovis; Financial Interests, Institutional, Sponsor/Funding: GSK; Financial Interests, Institutional, Sponsor/Funding: MSD; Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Other: Clovis; Financial Interests, Personal, Other: GSK; Financial Interests, Personal, Other: PharmaMar; Financial Interests, Personal, Other: MSD; Financial Interests, Personal, Other: Genmab; Other, Personal, Member of the Board of Directors: GCIG. All other authors have declared no conflicts of interest.

Background

The presence of germline or somatic BRCA1/2 mutation (gBRCA1/2 or sBRCA1/2) on epithelial ovarian cancer (EOC) patients (pts) improves progression-free survival (PFS) and overall survival (OS). BRCAm is the only validated molecular biomarker both prognostic and predictive of platinum and PARPi response. Identification of these pts is already mandatory to optimize treatment strategies and the need for genetic counselling. We aimed to describe our BRCAm EOC population to analyse tumor response and survival outcomes.

Methods

This was an observational, retrospective study with 194 pts diagnosed with advanced EOC (FIGO stage III-IV) in our institution from 01/2015 to 01/2021. The presence of BRCA1/2 mutation was determined using next generation sequencing (NGS).

Results

The most common histology was high-grade serous carcinoma in 86’6%. Median age was 59 years (25-87). BRCA status was WT/mut/unk: 71’1%/19’1%/9’8% (17/37 BRCA1, 20/37 BRCA2). On BRCAm population, 40’5% pts had a family history of EOC or breast cancer (BC) (2/35 pts had a previous BC, 100% BRCA1m). 37’8% had a primary debulking surgery (PDS) (8/13 R0) and 40’5% had an interval debulking surgery (IDS) (14/15 R0). Median OS in pts with PDS was 64 months (mo) (43 mo on WT population) vs 30 mo in pts who were not candidates for surgery (7/37 pts with FIGO stage IV; 13 mo on WT population) (p<0.04). Carboplatin/paclitaxel was the most frequently prescribed CT (70’3%, 10/26 pts neoadjuvant) as first line followed by PARPi in 8 pts (pts newly diagnosed). 15/37 pts progressed to first line (0/15 pts treated with PARPi) and 73% showed a platinum-sensitive disease (9/11 received maintenance PARPi, 3/9 of them relapsed after 12 mo of treatment). First-line PFS was 19 mo. The median follow up was 26 mo. 5/37 pts died due to clinical impairment or relapsed.

Conclusions

Early identification of BRCAm EOC pts is essential in order to optimize treatment sequence, and identify women who can receive PARPi therapy which is established as the standard of care for this population.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

P. Estévez García: Financial Interests, Personal, Invited Speaker: PharmaMar; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: GSK; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Clovis; Financial Interests, Personal, Advisory Board: PharmaMar; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Clovis. All other authors have declared no conflicts of interest.

Background

In patients with ovarian cancer effective testing for homologous recombination deficiency (HRD) is crucial to guide the use of PARP inhibitors, with or without bevacizumab. However, variations in uptake of testing and the quality and quantity of specimens are major barriers to the implementation of rapid universal molecular profiling. There are no national standards for diagnostic biopsies to ensure their suitability for molecular diagnostics. The aims of this study are to identify and mitigate the causes of demographic (including ethnicity) and clinical pathway variation for molecular testing in patients diagnosed with ovarian cancer.

Methods

DEMO is a multi-centre quality improvement study based on a Plan-Do-Study-Act approach. The three components include 1) the establishment of a patient advisory group to explore the variations in uptake and co-produce multimedia, multilingual patient information package to support informed decision making; 2) use of improvement methodology to analyse existing diagnostic pathways and 3) the development of a multidisciplinary consensus guideline to increase the reliability of current biopsy pathways for molecular diagnostics.

Results

A retrospective combined audit from Cambridge and Birmingham of 75 patients over 8 months in 2021 showed high failure rates for somatic molecular testing (tumoural BRCA or HRD testing). Failure rates of 25% (3/12) and 35% (11/31) failed when samples from image-guided biopsies and after chemotherapy were used, respectively. Low uptake of mainstreamed genetic testing in Cancer Centers with high ethnic diversity (∼15% of women diagnosed with ovarian cancer are in the ethnic minorities groups at Birmingham City Hospital) can be related to a gap in understanding the importance of tumour testing in the wider multidisciplinary team and to language and culture barriers.

Conclusions

Failure to address the systemic problems of the biopsy pathway will perpetuate substandard treatments and clinical trial opportunities for women receiving neoadjuvant chemotherapy. Provision of easily accessible video information to initiate patient dialogue and decision making could address the information gap to support informed decision making in women whose English is not their first language.

Legal entity responsible for the study

The authors.

Funding

Ovarian Cancer Action.

Disclosure

S. Sundar: Financial Interests, Personal, Invited Speaker for conference: AstraZeneca; Financial Interests, Personal, Invited Speaker for conference: MSD; Financial Interests, Personal, Invited Speaker at workshop: GSK; Non-Financial Interests, Personal, Leadership Role, President of the British Gynaecological Cancer Society: BGCS. J.D. Brenton: Financial Interests, Personal, Invited Speaker: GSK; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Tailor Bio; Financial Interests, Personal, Stocks/Shares: Tailor Bio; Financial Interests, Institutional, Invited Speaker: Clovis Oncology; Financial Interests, Institutional, Invited Speaker: Aprea AB; Non-Financial Interests, Personal, Member: Association of Cancer Physicians. All other authors have declared no conflicts of interest.

Background

The most common first symptom of ovarian cancer (OC) is the accumulation of serous fluid in the abdominal cavity. Morphological verification is necessary to resolve the issue of the nature of the process and the purpose of treatment. Cytological examination (CE) of ascitic fluid is a subjective method based on the knowledge and experience of a morphologist. The use of a comprehensive assessment of the CE with subsequent immunocytochemical (ICH) revision is a trend of modern diagnostics, and the use of test systems for the diagnosis of ICH, focused on one patient, will increase the availability of this type of study in the primary polyclinic. The aim of the work is to evaluate the diagnostic informativeness of using the SER 1 test system in the biochip format to determine the expression of EpCAM protein in ascitic fluid cells in the detection of OC.

Methods

70 samples of ascitic fluid obtained from patients with suspected OC who sought planned or emergency medical care at the surgical hospital of Nizhny Novgorod City Hospital No. 35 in 2021 were analyzed. All samples of ascitic fluid were examined cytologically. Using the SER1 test system (RUSSELL LLC, Russia), an ICH study was conducted, the results of which were visualized using a Zeiss Primo Star microscope (Carl Zeiss, Germany). The findings were classified in accordance with the International Cytological Classification of Effusion Fluids (TIS RSFC).

Results

During CE, 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 cancer (SFM) - 20%, malignant nature of cells (MAL) - 14.3%. An additional ICC study of EpCAM protein expression on SER 1 test systems changed the results within the categories: NFM - 58.6%, AUS - 0%, SFM - 2.8%, MAL - 27.2%.

Conclusions

A comprehensive assessment of the CE of effusion fluids, supplemented by ICH staining, increases the detectability of malignant tumor cells by 1.9 times, reducing the number of conclusions in the AUS,SFM categories. The use of the SER1 test system introduces ICH research into the practice of primary hospitals that do not belong to the oncology profile and contributes to the earlier diagnosis of OC.

Legal entity responsible for the study

The authors.

Funding

Russell Llc, Russian Federation.

Disclosure

All authors have declared no conflicts of interest.

Background

Ovarian malignancies are the 7th diagnosed malignancy and the 8th cause of death in females worldwide. Ovarian cancer includes a great heterogeneous group of neoplasms that differs in histological type, pathological stage, risk factors, prognosis, and treatment. Racial disparities in incidence, treatment, and mortality in cancers exist globally. With Surveillance, Epidemiology, and End Results (SEER) program in place, detection of these disparities would be feasible. herein racial disparities in ovarian cancer are analyzed.

Methods

Using SEER*Stat 8.3.9 program and then Case listing session and extracting data from Incidence - SEER Research Data, 13 Registries, Nov 2020 Sub (1992-2018). Patients with malignant behavior and known age diagnosed between 1992 to 2018 and site recode ICD-O-3 WHO 2008(ovary) were included; patients with incomplete data were excluded. Descriptive analysis and Kaplan Miere survival are done using IBM SPSS Statistics 25.

Results

46854 patients were included in the analysis, Non-Hispanic (NH) white race was 69.9% of them followed by the Hispanic group represents 11.8%. There was a great association between races and histology; eta was 0.06, Most predominant histological type was non-invasive low-grade serous carcinoma by 22.9%,20.7%,18.9% in NH white, Hispanic, NH black respectively. 2nd most predominant was Serous tubal intraepithelial carcinoma in NH American Indian/Alaska Native and NH Asian or Pacific Islander by 24.0% and 18.8% respectively. Kaplan Meier analysis revealed the best median survival time of 78 months (95%CI 70.89:85.12, SE 3.63) in NH Asian or Pacific Islander group, followed by Hispanic (All Races) with 56 months (95%CI 52.09:59.91, SE 1.99). The worst survival time was noticed in Non-Hispanic Black with a median survival time of 27 months (95%CI 24.95:29.05 SE 1.04). Log Rank p-value =0.001. Regarding Racial association with staging; eta was 0.04 and distant stage was predominant in all races 68.0%,68.7%,57.7%,67.1%,62.6% for NH White, NH Black, NH Asian or Pacific Islander, NH American Indian/Alaska Native, Hispanic (All Races) respectively.

Conclusions

Our analysis goes along with present literature regarding racial disparities.

Legal entity responsible for the study

The author.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

Background

Currently, researchers have found that neoadjuvant chemotherapy (NACT) which could enhance the stemness of ovarian cancer cells and induce platinum resistance gene mutations is an independent risk factor for platinum resistance. However, there is little data concerning the potential factors contributing to platinum resistance in patients receiving NACT. Herein, we conducted this real-world retrospective study to explore the factors associated with platinum resistance in NACT population.

Methods

Patients with histologically confirmed advanced ovarian cancer (IIIC-IV) who had received NACT at seven hospitals in China were enrolled from May 2004 to June 2020. Univariate and multivariate logistic regressions were performed with odds ratios (ORs) and 2-tailed 95% confidence intervals (CIs) to analyze the impacts of age, type, grade, stage, CA125 level, number of NACT cycles, and postoperative residual disease (R0, no macroscopic residual disease; R1, the maximum diameter of postoperative residual disease ≤ 1cm; R2, the maximum diameter of postoperative residual disease > 1cm) on platinum resistance. Statistical significance was considered at P < 0.05.

Results

A total of 630 patients with stage IIIC-IV ovarian cancer who received NACT were included in the analysis. 316 (50.2%) patients received no more than two cycles of neoadjuvant chemotherapy. Patients with 1 or 2 NACT cycles had a lower rate of platinum resistance recurrence than patients with more than 2 NACT cycles (26.3% vs 35.4%, P = 0.017). In the univariate analyses, Stage IV and more than 2 NACT cycles were risk factors for platinum resistance (OR = 1.44, P = 0.039; OR = 1.54, P = 0.014). Besides, R1 and R2 were also risk factors for platinum resistance (OR = 1.61, P = 0.017; OR = 2.19, P = 0.001). In the multivariate logistic regression analyses, more than 2 NACT cycles was an independent risk factor for platinum resistance (OR = 1.79, P = 0.005). R1 and R2 were also independent risk factors for platinum resistance (OR = 2.00, P = 0.004; OR = 3.17, P < 0.001).

Conclusions

More than 2 cycles of NACT and residual disease were independent risk factors for platinum resistance in advanced ovarian cancer patients receiving neoadjuvant chemotherapy.

Legal entity responsible for the study

Tongji Hospital.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Ovarian cancer is the eighth most common malignancy in females and the third most common gynaecological malignancy in the world. It is the leading cause of gynaecological cancer death in the world. Obesity, which is increasing worldwide, is still a controversial risk factor for ovarian cancer and till now there is no consensus on the obesity role on ovarian cancer. Therefore, we investigated the association between obesity and ovarian cancer using a large inpatient database.

Methods

We used the National Inpatient Sample (NIS) database to review female admissions between 2002 and 2015. Patients were grouped based on the presence or absence of obesity using the appropriate ICD-9 codes. We used a multivariate logistic regression to assess the association between obesity and ovarian cancer.

Results

We reviewed 50,469,770 admissions of which 4,365,971 (8.7%) were obese. Both groups had a similar median age (54 years) but obese patients were more likely to be black (20% vs. 14%, P<.001), have polycystic ovarian syndrome (PCOS) (0.5% vs 0.1%, P<.001), endometriosis (0.9% vs. 0.7%, P<.001) and be smokers (12% vs 9%, P<.001). Family history of ovarian cancer was similar in both groups. After adjusting for age, BRCA1/BRCA2 mutations, family history, lynch syndrome, smoking, IUD, endometriosis, PCOS, infertility, oral contraceptive pills, and hormone replacement therapy, obese patients were significantly less likely to have ovarian cancer (OR=0.821, 95%CI[0.808-0.835], P< .001) compared with patients without obesity. To further assess the association between obesity and ovarian cancer in pre-menopause vs post-menopause, we did a subgroup analysis based on age, the same trend was observed in both patients younger and older than 50 years.

Conclusions

In our large database study, we found that obesity was associated with lower rate of ovarian cancer and that association was seen in both young and older patients. However, the timeliness of obesity in relation to ovarian cancer cannot be determined through the NIS database and thus further prospective epidemiological studies are warranted.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The COVID-19 pandemic has represented a major cause of morbidity/mortality worldwide, overstressing health systems. Patients with ovarian cancer (OC) have been affected by a delay in diagnosis, surgery, and chemotherapy treatment (Jacome LS et al. Cancer Manag Res. 2021).

Methods

Here we have obtained a comprehensive overview of the impact of COVID-19 in patients with OC on a global scale using a federated data research network (TriNetX) that provided access to Electronic Medical Records (EMR) from Health Care Organizations (HCOs) all over the world. Descriptive statistics were used, and survival analyses were conducted using the Kaplan-Meier method.

Results

Through propensity score matched analyses of 74 global HCOs from 14 countries[AM1] we found that the number of new diagnoses of OC was reduced between the period from March 2020 to March 2021 (n=10.453) compared to 1-year prior to the COVID-19 pandemic (n=11.449), RR 0.91 [95%CI 0.88–0.9], p< 0.0001. SARS-CoV-2 infection in patients with OC treated with chemotherapy (n=710) was associated with worse overall survival than in patients without chemotherapy (n=1.770), HR 0.33 [95%CI 0.23-0.48], p< 0.0001.The risk of inpatient hospitalisation due to COVID-19 infection was higher in patients receiving chemotherapy vs no chemotherapy, RR 0.50 [95%CI 0.43-0.59], p < 0.0001. Overall, there was a very low rate of invasive mechanical ventilation utilization, with no differences in its use detected between those patients undergoing chemotherapy (n=24) and those who did not (n=18), RR 0.75 [95%CI 0.41-1.37), p=0.347.

Conclusions

This study highlights the necessity of extending preventive measures worldwide to protect vulnerable OC patients from SARSCoV-2 infection and promote intensive vaccination strategies.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Screening methods for ovarian cancer are urgently needed. Previously, we showed that women who develop ovarian cancer show an increase in serum calcium and a decrease in serum albumin (Schwartz et al, 2020, Gynecol Oncol 2020:159:264-269). These changes could be useful in screening. We asked, prior to their diagnosis, are women with ovarian cancer more likely to show a positive slope in their in albumin-adjusted serum calcium (a-asc)?

Methods

This is a population-based case-control study based in Sioux Falls, SD. Cases were women with epithelial ovarian cancer. Controls are women without a diagnosis of cancer. Patients with a history of cancer and/or parathyroid disease were excluded. Data are from patients’ Comprehensive Metabolic Panels (CMPs). We calculated albumin-adjusted serum calcium (a-asc) and estimated regression equations of each woman’s a-asc from pre-diagnosis to diagnosis. Data were analyzed by multiple regression, ANCOVA and logistic regression.

Results

We studied 124 cases and 98 controls. Cases were significantly older than controls (64.7 12.9 SD, vs. 41.0 16.8 years). For controls, the first and last a-asc was 9.23 mg/dL, for a slope of 0. For cases, the first and last values of a-asc were 9.28 and 9.37 mg/dL, for a slope of 0.04 mg/dl per year (P<0.001). The probability of cancer for a 0.04 mg/dL/year increase in a-asc increased with age until age 70 and showed a significant dose-response. The Odd Ratio (OR) of ovarian cancer for a 65 yr old woman with a 0.06 mg/dL increase/year was ∼3.0; the OR for a 1 mg/dl increase/year was ∼10. This effect was also seen for early stage tumors and persisted after age-adjustment.

Conclusions

In health, serum calcium levels are tightly regulated and the “expected” slope of a-asc is zero. A significant positive slope of a-asc in women with ovarian cancer, if confirmed by future studies, suggests that an increase in the slope a-asc could help identify women with undiagnosed ovarian cancer. Increases in a-asc were often small and could be easily overlooked. However, a computer algorithm could calculate the slope from patients’ annual records. Women with rising a-asc could be candidates for increased medical surveillance (e.g., transvaginal ultrasonography).

Legal entity responsible for the study

The authors.

Funding

This research was funded by grants from the University of North Dakota School of Medicine & Health Sciences, the Great Plains IDeA-CTR and the Coverys Community HealthCare Foundation (to GGS).

Disclosure

All authors have declared no conflicts of interest.

Background

Ovarian carcinomas (OCs) are highly sensitive to platinum-based therapy, however most of OCs eventually relapse. This study aimed to compare genomic profiles in primary vs. recurrent OCs.

Methods

Primary, recurrent and normal tissue triplets obtained from 15 patients were subjected to exome sequencing. The comparison included 1) spectrum of driver mutations [Tamborero et al., 2018; PMID: 29592813]; 2) tumor mutation burden (TMB); 3) HRD score [Telli et al., 2016; PMID: 26957554]; 4) mutational signatures [Degasperi et al., 2020; PMID: 32118208].

Results

All driver mutation present in primary tumors remained in the genome through the treatment course. One or several new driver somatic mutations emerged in 6/15 (40%) recurrent lesions. These alterations involved RB1 and ELAC2 (n = 1), TNC (n = 1), TRIO and IKBKB (n = 1), PAX5 and CDH10 (n = 1), SOX9 (n = 1), ABCB4 and EEF1A1 (n = 1) genes. Recurrent tumors demonstrated small but statistically significant increase of TMB as compared to primary lesions (4.7 vs. 3.9 per megabase, p = 0.01). HRD demonstrated high degree of similarity within primary/recurrent tumor pairs. PLATINUM mutation signature was characteristic for platinum-sensitive relapses, but not for platinum-resistant recurrences or chemonaive tumors (p = 0.02).

Conclusions

HRD score remains stable through the treatment history. PLATINUM mutation signature reflects not only the mere fact of prior exposure to platinum-based therapy, but also the efficacy of this therapeutic regimen.

Legal entity responsible for the study

The authors.

Funding

Russian Science Foundation, grant 21-75-30015.

Disclosure

All authors have declared no conflicts of interest.

Background

Today, in the era of precision medicine, the determination of genomic instability or other potentially targetable mutations, along with BRCA 1 and BRCA 2, is a crucial component of the diagnosis and treatment management of locally advanced or metastatic ovarian cancer. Advanced technologies such as next-generation sequencing (NGS) have enabled comprehensive genomic profiling (CGP) analysis to become more feasible for routine use in daily clinical work. Here, we present the results from the first two years of the CGP analysis of patients with locally advanced or metastatic ovarian cancer on a national level, aiming to establish its position in the daily clinical practice of treating ovarian cancer.

Methods

We performed a multicentre, retrospective, cross-sectional analysis of the total population of Croatian patients who were either newly diagnosed with locally advanced or metastatic ovarian cancer, whose initial disease had progressed from January 1, 2020, to December 1, 2021, and whose tumours underwent CGP analysis. The primary endpoint was to present and compare the proportion of patients carrying a BRCA 1 or BRCA 2 mutation with the proportion of patients with a homologous recombination deficiency (HRD) or loss of heterozygosity (LOH), for which targeted therapy with PARP inhibitors is chosen.

Results

All 86 patients (100%) analysed with CGP had at least one genomic alteration (GA). The median LOH was 14.6 (Interquartile range; IQR 6.8-21.7), with 35 (41%) patients having a LOH ≥16. We found a BRCA-positive status in 22 (26%) patients. Conventional testing using single-target assays, which detects only BRCA mutations, would have opted for targeted therapy with PARP inhibitors in 22 (26%) patients among our group of tested patients. Meanwhile, CGP revealed the need for targeted therapy with PARP inhibitors in 35 patients (41%).

Conclusions

The results have identified clinically significant higher number of women who would achieve a possible benefit from targeted therapy. Hence, we believe that CGP should be integrated into the diagnostic workup of patients with locally advanced and metastatic ovarian cancer as a backbone diagnostic tool.

Legal entity responsible for the study

The authors.

Funding

Hoffmann-La Roche.

Disclosure

D. Čerina, V. Matkovic, K. Katić, I. Belac Lovasic, R. Separovic, I. Canjko, E. Vrdoljak: Financial Interests, Personal, Invited Speaker: Hoffmann-La Roche. All other authors have declared no conflicts of interest.

Background

IPARPs are the latest advance in ovarian cancer treatment and have been shown and have been shown in clinical trials to be an effective and safe treatment. The increase in life expectancy implies an increase in the age of the patients treated, so the development of effective drugs with few adverse effects is becoming more important every day. The objective of the study was to establish the clinical and toxicity differences of iPARP treatment between patients older and younger than 65 years.

Methods

A retrospective, single-center study was conducted. All patients diagnosed of high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer treated with iPARPs between 2017 and 2021 in Puerta de Hierro Hospital were included. Epidemiological and clinical data were registered.

Results

The table describes the characteristics of both populations. 60 patients were analyzed and 31.7% were >65 years. 25% received maintenance iPARP after a first platinum-based line. No differences in toxicity were observed between both groups. Within cardiological toxicity, tachycardias were significantly more frequent in the >65 years subgroup (7.3 vs 47.4% p= 0.0001). There was no difference in the suspension of treatment between both groups (9.8% vs 15.8% p= 0.231). No patient died as a result of an adverse event to the treatment Table: 42P

Conclusions

Patients >65 years treated with iPARPs did not experience higher rates of adverse events or treatment interruptions/discontinuations. iPARPs should be a valid treatment option for ovarian cancer in this increasingly frequent subgroup of patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Malignant bowel obstruction (MBO) is common in advanced ovarian cancer (AOC). Treatment options are limited as majority of cases present with widespread, multilevel peritoneal dissemination and platinum-resistant disease. The benefit of Parenteral Nutrition (PN) in MBO is debated, given the limited overall survival (OS) of this patient group. Aim: to identify which clinical features correlate with improved survival in AOC and MBO, to support clinical decision-making.

Methods

Retrospective review of patients admitted with MBO between April 2019 and October 2021 to a single tertiary cancer centre. Those with AOC established on PN with the aim to discharge home on PN were included. Univariate analysis for survival after commencing PN was performed using log-rank test.

Results

103 patients with MBO were identified with 33 patients excluded (PN not initiated, 15; PN withdrawn: covid service constraint, 5, acute medical event, 13). 70 patients were successfully established on PN and 49 discharged on PN; 16 patients clinically deteriorated; 5 returned to enteral diet. Median OS of patients that did not receive PN was 19 days, PN stopped due to general deterioration 39 days and 100 days (range 18-807) for those established on PN (p<0.0001). Clinical features associated with improved OS: no prior systemic therapy (p=0.0067), platinum sensitivity (p=0.043), ECOG performance status (PS) 1 vs 2-3 (p=0.004), falling modified Glasgow Prognostic Score (mGPS) during admission (p=0.0027). In the treatment naïve group, chemotherapy resolved MBO in 6/9 cases. In the pre-treated group, 60% of patients received subsequent chemotherapy (median duration 8 weeks), with early cessation due to toxicity and no clinical benefit. Only 1 patient achieved resolution of MBO on chemotherapy.

Conclusions

PN may improve survival of patients with AOC in MBO. ECOG PS, platinum sensitivity and mGPS trend may be useful to select patients for PN. In those presenting with MBO at AOC diagnosis, PN can enable safe delivery of chemotherapy, which usually will resolve MBO. In pre-treated patients, PN is a life-long commitment and chemotherapy is largely ineffective in resolving MBO. Further research should focus on quality of life in patients receiving PN.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

There is an urgent need for new treatments for platinum-resistant recurrent ovarian cancer (PROC). Addition of bevacizumab (bev) to non-platinum-based chemotherapy (chemo) significantly improved PFS in patients (pts) with PROC but did not show a clear OS benefit. Thus far, the combination of paclitaxel + bev has shown the most promise in PROC, although the proportion of pts eligible for bev is limited by treatment-related toxicities. Combination of the anti-PD-1 antibody pembrolizumab (pembro) with weekly paclitaxel showed antitumor activity and manageable toxicity in pts with PROC in a single-arm, phase II study. ENGOT-ov65/KEYNOTE-B96 (NCT05116189) compares the efficacy and safety of pembro + standard of care chemo (weekly paclitaxel) ± bev vs placebo (pbo) + weekly paclitaxel ± bev in pts with PROC.

Trial design

In this randomized, pbo-controlled, double-blind, phase III study, eligible pts are aged ≥18 y with histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with 1-2 prior lines of systemic therapy, including ≥1 prior platinum-based therapy with ≥4 cycles in first line. Pts must have platinum-resistant disease (radiographic evidence of PD ≤6 mo after last platinum-based therapy dose), be eligible for paclitaxel (± bev per investigator discretion), have ECOG PS ≤1, radiographically evaluable disease per RECIST v1.1, and have a tumor sample for central evaluation of PD-L1 status. ∼616 pts will be randomized 1:1 to pembro 400 mg IV or pbo Q6W for up to 18 cycles (∼2 y) + paclitaxel 80 mg/m² on days 1, 8, and 15 of each Q3W cycle (± bev 10 mg/kg Q2W per investigator discretion) until PD or unacceptable toxicity. Randomization is stratified by planned bev use (yes vs no), region (US vs Europe vs rest of world), and PD-L1 status (combined positive score [CPS] <1 vs CPS 1-<10 vs CPS ≥10). Primary endpoint is PFS per RECIST v1.1 by investigator review in pts with tumor PD-L1 CPS ≥1 and in all pts. Secondary endpoints are OS in pts with tumor PD-L1 CPS ≥1 and in all pts, PFS per RECIST v1.1 by blinded independent central review in pts with tumor PD-L1 CPS ≥1 and in all pts, safety, and pt-reported outcomes. Enrollment is ongoing.

Clinical trial identification

NCT05116189.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

N. Colombo: Financial Interests, Personal, Full or part-time Employment, Employment of Immediate Family Member: Sarepta Therapeutics; Financial Interests, Personal, Advisory Role: Roche/Genentech, AstraZeneca, Clovis Oncology, Pfizer, MSD Oncology, Tesaro, GlaxoSmithKline, Immunogen, Mersana, Eisai, Advaxis, Nuvation Bio, Advaxis; Financial Interests, Personal, Other, Honoraria: Roche/Genentech, AstraZeneca, Tesaro, GlaxoSmithKline, MSD Oncology, Clovis Oncology, Pfizer, Amgen, Immunogen, Novartis, Pfizer, Mersana, Eisai, Advaxis, Nuvation Bio. R.L. Coleman: Financial Interests, Personal, Full or part-time Employment: US Oncology; Financial Interests, Personal, Advisory Role: Clovis Oncology, Genentech/Roche, AstraZeneca/MedImmune, Genmab, Tesaro, OncoMed, Sotio, Oncolytics, AbbVie/Stemcentrx, Immunogen, AbbVie, Agenus, Novocure, Merck, OncXerna Therapeutics, Alkermes, Gradalis, Regeneron; Financial Interests, Personal, Leadership Role: Onxeo; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Merck, AstraZeneca/MedImmune, Array BioPharma, Clovis Oncology, Roche/Genentech, Research to Practice, GOG Foundation, Sotio, Vaniam Group; Financial Interests, Personal, Stocks/Shares: McKesson; Financial Interests, Personal, Ownership Interest: McKesson; Financial Interests, Personal, Research Grant: AstraZeneca/MedImmune, Esperance Pharmaceuticals, Array Biopharma, Clovis Oncology, Johnson & Johnson, Merck, Roche/Genentech, Abbott/AbbVie; Financial Interests, Institutional, Research Grant: Immunogen, Mirati Therapeutics, Amgen, Pfizer, Lilly, Regeneron. F. Kose: Financial Interests, Personal, Advisory Role: Roche, AstraZeneca, MSD/Merck, GlaxoSmithKline, Novartis, Pfizer, Takeda, Deva, Nobel, Astellas, Janssen; Financial Interests, Institutional, Other, Honoraria: Roche, AstraZeneca, MSD/Merck, GlaxoSmithKline, Novartis, Pfizer, Takeda, Deva, Nobel, Astellas, Janssen; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Roche, AstraZeneca, MSD/Merck, GlaxoSmithKline, Novartis, Pfizer, Takeda, Deva, Nobel, Astellas, Janssen. R. Wenham: Financial Interests, Personal, Advisory Role: Mersana, Merck, Tesaro, Clovis Oncology, Genentech, Regeneron, AbbVie, AstraZeneca, GlaxoSmithKline, Seattle Genetics/Astellas, Legend Biotech; Financial Interests, Personal, Speaker’s Bureau: Tesaro, Clovis Oncology, Genentech; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: TapImmune Inc; Financial Interests, Personal, Stocks/Shares: Ovation Diagnostics; Financial Interests, Personal, Ownership Interest: Ovation Diagnostics; Financial Interests, Personal, Other, Honoraria: Tesaro, Seattle Genetics; Financial Interests, Institutional, Research Grant: Merck, Prescient Therapeutics, Anixa Biosciences. Other Relationship: AstraZeneca, GlaxoSmithKline/Tesaro; Other, Personal, Other: AstraZeneca, GlaxoSmithKline/Tesaro. A. Sebastianelli: Financial Interests, Personal, Advisory Role: AstraZeneca, Merck, GlaxoSmithKline; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Merck, GlaxoSmithKline. K. Hasegawa: Financial Interests, Personal, Advisory Role: MSD K.K., Kaken Pharmaceutical, Eisai, Takeda; Financial Interests, Personal, Other, Honoraria: MSD K.K., Daiichi Sankyo, Chugai Pharma, AstraZeneca, Eisai, Kyowa Kirin, Takeda, Genmab; Financial Interests, Personal, Research Grant: Ono Pharmaceutical, Daiichi Sankyo, Merck, Takeda, Eisai. E. Zsiros: Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Other, Honoraria: Survivornet, AstraZeneca, TeneoBio; Financial Interests, Personal, Research Grant: Merck. T. De La Motte Rouge: Financial Interests, Personal, Other, Honoraria: AstraZeneca, MSD/Merck, Clovis Oncology, Tesaro, GlaxoSmithKline, Pfizer, Gilead Sciences, Eisai, French National Cancer Institute (INCa); Financial Interests, Personal, Advisory Role: AstraZeneca, MSD/Merck, Clovis Oncology, Tesaro, GlaxoSmithKline, Pfizer, Gilead Sciences, Eisai, French National Cancer Institute (INCa); Financial Interests, Institutional, Research Grant: Pfizer, Novartis, Seagen; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca, MSD/Merck, Clovis Oncology, Tesaro, GlaxoSmithKline, Pfizer, Gilead Sciences, French National Cancer Institute (INCa). M. Bidzinski: Financial Interests, Personal, Other, Honoraria: AstraZeneca, MSD/Merck, GlaxoSmithKline, Johnson & Johnson, Olympus. I. McNeish: Financial Interests, Personal, Advisory Role: Clovis Oncology, AstraZeneca, Carrick Therapeutics, Roche, BeiGene, Scancell Ltd., GlaxoSmithKline, Epsila; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca; Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca. J. Sehouli: Financial Interests, Personal, Advisory Role: AstraZeneca, Clovis Oncology, PharmaMar, Merck, Pfizer, Tesaro, MSD Oncology, Lilly, Novocure, Johnson & Johnson, Roche, Ingress Health, Riemser, Sobi, GlaxoSmithKline, Novartis; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca, Clovis Oncology, PharmaMar, Roche Pharma AG, Tesaro, MSD Oncology, Olympus; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Eisai, Clovis Oncology, Olympus Medical Systems, Johnson & Johnson, PharmaMar, Pfizer, Teva, Tesaro, MSD Oncology, GlaxoSmithKline, Bayer; Financial Interests, Institutional, Research Grant: AstraZeneca, Clovis Oncology, Merck, Bayer, PharmaMar, Pfizer, Tesaro, MSD Oncology, Roche. J. Korach: Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. P.R. Debruyne: Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Janssen; Financial Interests, Personal, Stocks/Shares: Alkermes, Biocartis Group NV; Financial Interests, Personal, Ownership Interest: Alkermes, Biocartis Group NV; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb, Merck/Pfizer, MSD, Roche, Bayer. J. Kim: Financial Interests, Personal, Advisory Board: Takeda Korea, GSK Korea, Boryung, Vifor Pharma, MSD Korea; Financial Interests, Personal, Invited Speaker: CMIC, AstraZeneca, Janssen; Financial Interests, Personal, Expert Testimony: LG Pharma. A.C. De Melo: Financial Interests, Personal, Speaker’s Bureau: BMS Brazil, MSD Oncology; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: MSD Oncology; Financial Interests, Personal, Other, Honoraria: MSD Oncology, Novartis, BMS Brazil; Financial Interests, Institutional, Research Grant: Roche, MSD Oncology, BMS Brazil, Novartis, Clovis Oncology, AstraZeneca. X. Peng: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. A.M. Bogusz: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Kenilworth, NJ, USA; Financial Interests, Personal, Ownership Interest: Merck & Co., Inc., Kenilworth, NJ, USA. K. Yamada: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Kenilworth, NJ, USA; Financial Interests, Personal, Ownership Interest: Merck & Co., Inc., Kenilworth, NJ, USA. B.J. Monk: Financial Interests, Personal, Advisory Role: Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Clovis Oncology, Eisai, Genmab/Seattle Genetics, GOG Foundation, ImmunoGen, Iovance Biotherapeutics, Merck, Mersana, Myriad Pharmaceuticals, Pfizer, Puma Biotechnology, Regeneron, Roche/Genentech, Tesa; Financial Interests, Personal, Leadership Role: US Oncology; Financial Interests, Personal, Speaker’s Bureau: Roche/Genentech, AstraZeneca, Clovis Oncology, Eisai, Tesaro/GlaxoSmithKline, Merck; Financial Interests, Personal, Other, Honoraria: Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Clovis Oncology, Eisai, Genmab/Seattle Genetics, ImmunoGen, Iovance Biotherapeutics, Merck, Mersana, Pfizer, Puma Biotechnology, Regeneron, Roche/Genentech, Tesaro/GlaxoSmithKline, Vascular Biogenics; Financial Interests, Institutional, Research Grant: Novartis, Amgen, Genentech, Lilly, Janssen, Array BioPharma, Tesaro, Morphotek, Pfizer, Advaxis, AstraZeneca, Immunogen, Regeneron, Nucana. All other authors have declared no conflicts of interest.

Background

Poly (ADP-ribose) polymerase (PARP) inhibitors alone and in combination with Bevacizumab have shown significant clinical benefit as maintenance therapy in women with newly diagnosed ovarian cancer (OC) regardless BRCA mutational status and in homologous-recombination deficiency (HRD)-positive patients, respectively. However, despite the remarkable improvements in the therapeutic algorithm of ovarian cancer disease over the years, several open questions remain: a) what is the best treatment in HRD-positive patients? b) what is the added value of bevacizumab in HRD positive tumors with respect to PARPi alone? c) what is the preferred treatment in HRD-negative tumors: PARPi or bevacizumab? MITO 25.1 aims to evaluate the best first line treatment regimen in the different molecular subgroups, HRD-positive and HRD-negative OC, evaluated with Foundation Medicine LOH test.

Trial design

MITO 25.1 is a multicenter, randomized open-label, phase II study in which patients with high-grade serous or endometrioid advanced OC will be randomized in a 1:1 ratio according to a molecular driven treatment to receive: HRD-negative patients · ARM A: Carboplatin AUC 5 + Paclitaxel 175 mg/m2 q 21 + Bev 15 mg/kg for 5 cycles (starting from cycle 2) followed by Bev 15 mg/kg q 21 for 16 cycles · ARM B: Carboplatin AUC 5 + Paclitaxel 175 mg/m2 q 21 for 6 cycles followed by Rucaparib 600 mg BID q 28 for 24 cycles as maintenance HRD-positive patients · ARM B: Carboplatin AUC 5 + Paclitaxel 175 mg/m2 q 21 for 6 cycles followed by Rucaparib 600 mg BID q 28 for 24 cycles as maintenance · ARM C: Carboplatin AUC 5+ Paclitaxel 175 mg/m2 q 21 + Bev 15 mg/kg for 5 cycles (starting from cycle 2) followed by Bev 15 mg/kg q 21 days for 16 cycles + Rucaparib 500 mg part BID q 28 for 24 cycles as maintenance The primary endpoint will be PFS. The secondary endpoints will be overall survival (OS), PFS2, adverse events according to CTCAE 5.0 and patient-reported outcome. Patients recruiting started in March 2021. To date, 136 of the 290 patients planned have been enrolled.

Clinical trial identification

NCT03462212.

Legal entity responsible for the study

D. Lorusso.

Funding

Clovis Oncology.

Disclosure

G. Scambia: Financial Interests, Personal, Other: MSD; Financial Interests, Personal, Invited Speaker: Clovis Oncology. V. Salutari: Financial Interests, Personal, Other: GSK; Financial Interests, Personal, Other: PharmaMar; Financial Interests, Personal, Other: Clovis-Oncology; Financial Interests, Personal, Other: MSD; Financial Interests, Personal, Other: AstraZeneca. S. Pignata: Financial Interests, Personal, Other: MSD; Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Other: Clovis-Oncology; Financial Interests, Personal, Other: Roche; Financial Interests, Personal, Other: Pfizer. D. Lorusso: Financial Interests, Personal, Other: GSK; Financial Interests, Personal, Other: MSD; Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Other: MSD; Financial Interests, Personal, Other: Genmab; Other, Institutional, Member of the Board of Directors: GCIG. All other authors have declared no conflicts of interest.

Background

While traditional pelvic exenterations (PE) represent a potentially curative treatment for recurrent tumours localized centrally in the pelvis, new surgical techniques have been developed recently to enable a complete resection even in tumours invading into the pelvic side wall. Extended pelvic exenterations (EPE) include resection of internal, external, or common iliac vessels, pelvic side-wall muscles, large pelvic nerves, or pelvic bones. EPE are currently performed only in a few institutions and data on treatment morbidity are not available. The aim of the study was to compare health-related quality of life (QoL) and oncological outcome after PE and EPE.

Methods

Data from 72 patients with cervical (36), vulvar (19), endometrial (14) and low-grade ovarian (5) cancer who underwent PE (42) or EPE (32) for persistent (20%) or recurrent (80%) disease between 2014 to 2019 at a single tertiary centre were analysed. Quality of life was evaluated in surviving patients using EORTC QLQ-C30, EORTC CX-24, and QOLPEX questionnaire developed specifically for patients after extensive pelvic procedures.

Results

Median overall and disease-specific survival reached in the whole cohort 45 and 49 months, without significant differences between PE and EPE groups (P >0.999). We did not observe any difference in post-surgical complication types or frequency between the groups. Thirty-one survivors participated in the QoL assessment (20 PE, 11 EPE) and no significant differences were found in global health status (P=0.951) or in any of the functional scales. The groups were not differing in therapy satisfaction (P=0.502), and both expressed similar willingness to potentially undergo treatment again (P=0.317) (Table). Table: 47P

EORTC QLQ 30, EORTC QLQ-CX24 – Main results

Conclusions

EPE are associated with similar post-treatment QoL and survival as traditional PE. These procedures represent potentially curative treatment option for patients with persistent or recurrent pelvic cancer invading into pelvic wall structures without further compromising QoL.

Legal entity responsible for the study

The authors.

Funding

Charles University in Prague (UNCE 204065 and PROGRES Q28/LF1).

Disclosure

All authors have declared no conflicts of interest.

Background

Malignant Mixed Mullerian Tumour (MMMT) also known as carcinosarcoma is a rare and aggressive malignancy involving the uterine corpus. Despite aggressive treatment, they have a poor outcome. We performed this study to analyze the clinical profile, prognostic features, and treatment outcome of patients with MMMT of uterine corpus treated in our center.

Methods

The study sample was drawn from a database of patients treated at the Department of Medical Oncology, Madras Medical College between January 2015 and December 2019. A total of 29 non-metastatic patients were included in the study. Information regarding the patient, tumour characteristics, details of the surgery, adjuvant therapy, and the follow-up details were collected retrospectively. Disease-free survival and overall survival were plotted using the Kaplan-Meier method and the log-rank test was used to identify any significant prognostic factor. Statistical analyses were performed using SPSS software version 21.

Results

The median age of the population was 60 years (IQR- 52- 65). The homologous type was the most common pathology seen in 21 patients. The median size of the tumor was 7 cm. (IQR- 6 – 10). The median DFS was 12 months (95% C.I 7.7 – 16.2). Paclitaxel and carboplatin-based adjuvant chemotherapy were used in 60 % of the patients. During the follow-up, 17 patients developed recurrence and almost 90% were distant recurrences. The median DFS was 12 months (95% C.I 7.7 – 16.2). The median Overall Survival was 26 months (95% C.I 10.6 – 41.3). The 3-year overall survival rate was 42 %. Patients with age >60 years had a median overall survival of 11 months vs 37 months for patients <60 years (p=0.026). The median overall survival of patients with tumour size >10 cm was 12.5 months and 35 months for tumour size <10 cm (p=0.03). Patients receiving RT had an improved survival (39 months) than those who did not receive RT (12.5 months) P=0.046. The median overall survival for patients after the recurrence was 12 months. As most patients were elderly and had a poor performance status during the relapse, only a few patients were fit for subsequent lines of chemotherapy.

Conclusions

MMMT is an aggressive tumor with poor survival rates. Age of the patient, tumor size, and radiation therapy were found to be prognostic factors.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Gestational trophoblastic neoplasia (GTN) is a rare tumor with an excellent prognosis. Despite the International Federation of Gynecology and Obstetrics (FIGO) risk score, other factors that may influence survival remain unknown. We evaluated the association of nutritional predictors as body mass index (BMI), prognostic nutritional index (PNI), anemia and neutrophil/lymphocyte index (NLI) with complete response (CR) to chemotherapy and overall survival (OS).

Methods

This is a retrospective analysis of women with newly diagnosed GTN between 2005 and 2019 at Instituto Nacional de Enfermedades Neoplasicas (INEN), Lima- Peru who received chemotherapy. Clinical and baseline nutritional factors were obtained from patient files. To evaluate association with CR, we performed a Student t test and ROC curves to determine the cutoff value of variables that significantly predicted CR. Cox proportional hazards regression models were used to identify independent variables with significant influence on the OS.

Results

166 patients with GTN were included, median age was 30 years (range 18-54 y) and median FIGO risk score was 10 points (range 2-21). Accordingly, 16% and 84% of patients belong to low-risk and high-risk groups, respectively. 17 patients were lost to follow up and CR was reported in 73% of patients after first-line chemotherapy. 3y-OS was 80%, after excluding early deaths, the survival rate was 83%. About nutritional predictors, the median for BMI was 23.28, for PNI was 36.01, for hemoglobin was 10.0 and for NLI was 2.69. There was a positive association between CR with PNI and NLI (p = 0.001), no association with BMI (p = 0.389) and hemoglobin (p = 0.23) were founded. Analysis of the ROC curve for PNI demonstrated an optimal cut off value of 32.5 (p < 0.05, sensitivity 66.7, and specificity 60.6) and for NLI was 3.74 (p < 0.05, sensitivity 31.5, and specificity 51.3); the area under the ROC curve was 0.709 and 0.312 for PNI and NLI, respectively. In addition, we found a significant association with PNI (HR 0.008- CI 0.865-0.978) and NLI (HR 0.029- CI 0.807-0.989) with OS.

Conclusions

Nutritional factors such as high PNI and low NLI showed an association with OS and CR after chemotherapy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Venous thromboembolism (VTE) is a major cause of death and morbidity in patients with cancer. Low molecular weight heparin (LMWH) has been the backbone of the treatment of cancer associated thrombosis (CAT). Direct-acting oral anticoagulants (DOAC) have shown efficacy and safety not inferior to LMWH and most recent guidelines included DOACs as an option for the CAT treatment.

Methods

The aim of the survey was to better understand the prescription trends of DOACs in patients with cancers in Italy, especially gynaecological cancers (GCs). The survey was made of 21 questions and the last 4 questions were addressed to doctors involved in Gynecological Oncology. An invitation to complete the survey was sent by e-mail to 691 MITO (Multicentre Italian Trials in Ovarian cancer and gynaecologic malignancies) and 2093 AIOM (Associazione Italiana di Oncologia Medica) members on 13 October 2021 and 14 October 2021, respectively. Respondents completed the survey by 15 November 2021.

Results

Overall, 113 medical doctors (MDs) completed the questionnaire and 69 of them were involved in Gynecological Oncology. Most of the respondents (46, 41%) were aged 30-40 years old, worked in a Public Hospital (59, 52.2%), were Medical Oncologists (86, 76.1%) and, at the time of the survey, were not allowed by Italian Regulations to prescribe a DOAC (108, 96%). LMWH was widely the preferred choice for the treatment of CAT (104, 92%). However, 89 (78.8%) of the respondents stated that they had prescribed or asked another specialist to prescribe a DOAC for CAT. The major concern about DOACs was the difficulty to verify the therapeutic effect/absence of antidotes in case of severe bleeding (37.9%). In patient with GCs, DOACs were used with Niraparib, Olaparib and Rucaparib in less than 10 patients by 23%, 20% and 9% of the respondents, respectively. They seemed to be more confident in the use of immune checkpoint inhibitors (ICIs) with a DOAC, indeed 10.2% (7/69) have employed them in more than 10 patients.

Conclusions

DOACs are still poorly prescribed in patients with cancer, especially for GCs.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.