Treatment Of Advanced Cervical Cancer Research Articles

Cost Effectiveness of Bevacizumab Plus Chemotherapy for the Treatment of Advanced and Metastatic Cervical Cancer in India-A Model-Based Economic Analysis.

PURPOSEPatients with advanced and metastatic cervical cancer have a poor prognosis with a 1-year survival rate of 10%-15%. Recently, an antiangiogenic humanized monoclonal antibody bevacizumab has shown to improve the survival of these patients. This study was designed to assess the cost effectiveness of incorporating bevacizumab with standard chemotherapy for the treatment of patients with advanced and metastatic cervical cancer in India.METHODSUsing a disaggregated societal perspective and lifetime horizon, a Markov model was developed for estimating the costs and health outcomes in a hypothetical cohort of 1,000 patients with advanced and metastatic cervical cancer treated with either standard chemotherapy alone or in combination with bevacizumab. Effectiveness data for each of the treatment regimen were assessed using estimates from Gynecologic Oncology Group 240 trial. Data on disease-specific mortality in metastatic cervical cancer, health system cost, and out-of-pocket expenditure were derived from Indian literature. Multivariable probabilistic sensitivity analysis was undertaken to account for parameter uncertainty.RESULTSOver the lifetime of one patient with advanced and metastatic cervical cancer, bevacizumab along with standard chemotherapy results in a gain of 0.275 (0.052-0.469) life-years (LY) and 0.129 (0.032-0.218) quality-adjusted life-years (QALY), at an additional cost of $3,816 US dollars (USD; 2,513-5,571) compared with standard chemotherapy alone. This resulted in an incremental cost of $19,080 USD (7,230-52,434) per LY gained and $34,744 USD (15,782-94,914) per QALY gained with the use of bevacizumab plus standard chemotherapy.CONCLUSIONAddition of bevacizumab to the standard chemotherapy is not cost effective for the treatment of advanced and metastatic cervical cancer in India at a threshold of 1-time per-capita gross domestic product.

Efficacy and Prognostic Factors for Response to PD-1 Inhibitors in Advanced Cervical Carcinoma: A Retrospective Study.

PurposeProgrammed cell death protein 1 (PD-1) inhibitors have shown a therapeutic effect in the treatment of advanced cervical cancer in clinical trials. However, the clinical characteristics associated with response remain undetermined. This study aimed to evaluate the efficacy and prognostic factors of PD-1 inhibitors in patients with advanced cervical cancer in clinical practice.Patients and MethodsThe study enrolled patients with recurrent or metastatic cervical cancer treated with PD-1 inhibitors at our center between March 2018 and November 2020. The primary outcomes were the objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints were overall survival (OS) and safety. In addition, independent prognostic factors were identified by multivariate regression analysis.ResultsA total of 102 patients were included, and the ORR and disease control rate (DCR) were 51.0% and 66.7%, respectively. Median PFS was 11.0 months (95% CI, 1.7–20.4), while median OS was not achieved. Multivariate analysis indicated that factors associated with a better prognosis (ORR and PFS) included squamous cell carcinoma, a time to recurrence >6 months, and PD-1 plus chemotherapy and anti-angiogenic drugs (p < 0.05). Lines of therapy were independent factors for ORR but not for PFS. We also observed a tendency for longer PFS in patients with lung metastases and lymph node metastases only. Treatment-related adverse events (AEs) were well tolerated and primarily included thrombocytopenia, hepatic dysfunction, anemia, and leukopenia.ConclusionPD-1 inhibitors demonstrated beneficial efficacy and safety in advanced cervical cancer, particularly for patients with squamous cell carcinoma, a time to recurrence >6 months, or PD-1 plus chemotherapy and anti-angiogenic drugs. Further studies are needed to confirm the long-term outcomes.

A phase Ib/II study (IMMCO-1) of atezolizumab plus tivozanib in castrate-resistant prostate cancer and certain other immunologically cold tumors.

TPS208 Background: Castrate resistant prostate cancer (CRPC) is an immunologically cold tumor, with a 5% response rate reported to the PD-L1 inhibitor pembrolizumab. VEGF secreted by tumors may play a key role in hindering the anti-tumor immune response, leading to the development of an abnormal vasculature that may limit immune surveillance. VEGF also inhibits dendritic cell differentiation, limiting the presentation of tumor antigens. The inhibition of VEGF may therefore potentiate the effect of PD-1/L1 directed therapy by enabling immune surveillance and antigen presentation. VEGF-TKI and checkpoint inhibitor combinations are currently approved in the treatment of advanced kidney, cervical, and endometrial cancers. This signal-seeking study aims to determine whether the combination of the VEGF-TKI tivozanib and the PD-L1 inhibitor atezolizumab may be effective in CRPC and certain other immunologically cold tumors. Methods: The trial is a single center phase Ib/II basket study in multiple immunologically cold tumors. Co-primary endpoints are safety and the overall response rate as measured via RECIST v1.1. The tivozanib dose will be determined via a 3+3 dose de-escalation phase Ib portion. Patients treated in the phase Ib portion will be included as study subjects for phase the II portion. The study is designed to test for a 25%+ response rate as compared to a null hypothesis of &lt;7% (one-sided alpha = 0.05; 80% power). A Simon’s two-stage design will be utilized and if ≥2 responses among the first 16 evaluable patients, a further 10 evaluable patients will be accrued for a total of 26. Up to 33 subjects will be enrolled to account for a 20% dropout rate. The null hypothesis will be rejected if at least 5 responses are observed. The University of Florida's Data Integrity and Safety Committee will review significant adverse events. Tivozanib will be given at a dose of 1.34 mg/day for 21 days of each 28-day cycle (potential dose reduction is to 0.89 mg/day). Atezolizumab is given at a dose of 1,680 mg every 28 days. Treatment is until disease progression or intolerance. Key inclusion criteria include a diagnosis of certain advanced and unresectable or metastatic immunologically cold tumors (CRPC previously treated with an androgen inhibitor or cytotoxic chemotherapy in the advanced or metastatic setting, bile duct or gallbladder cancer, certain HR-negative HER2-positive breast cancers, ovarian cancer, pancreatic adenocarcinoma, soft tissue sarcoma, or vulvar cancer), at least one prior systemic therapy in this setting, ECOG 0-1 (phase Ib) or ECOG 0-2 (phase II), age ≥ 18, adequate hematologic and end-organ function, life expectancy of at least 12 weeks, and measurable disease by RECIST v1.1. Key exclusion criteria include known mismatch repair deficiency, microsatellite instability, or high tumor mutational burden. Active enrollment continues. Clinical trial information: NCT05000294.

Concurrent chemoradiotherapy and salvage chemotherapy for advanced cervical cancer with a pedunculated cervical leiomyoma: a case report

Although concurrent chemoradiotherapy (CCRT) is an effective treatment for advanced cervical cancer, its use in advanced cervical cancer with a pedunculated cervical leiomyoma remains challenging. The prognosis of recurrent cervical cancer is poor, with a low possibility of complete response (CR). In this present study, after completion of external beam radiotherapy (EBRT) and chemotherapy (weekly cisplatin), we performed the resection of a pedunculated cervical leiomyoma. No malignant cells were identified in the pathological specimen. After the myoma resection, no cervical tumor was observed on follow-up magnetic resonance imaging (MRI). High-dose-rate intracavitary brachytherapy (HDR-ICBT) was also performed. Local control of the cervical tumor was achieved after 30 months of treatment. After CCRT, rectal hemorrhage was observed but was effectively controlled via local intervention. Twenty-four months after CCRT, the patient was given salvage chemotherapy (paclitaxel plus carboplatin) due to lymph node metastasis observed at the outside range of EBRT. Thirty months after CCRT, computed tomography showed that the metastatic lymph nodes had disappeared, and the patient achieved CR. Thus, for advanced cervical cancer with a pedunculated cervical leiomyoma, CCRT could be completed following myoma resection. In addition, salvage chemotherapy for lymph node metastasis might result in CR. In this present case, a gastrointestinal adverse event was observed after radiotherapy and salvage chemotherapy with paclitaxel plus carboplatin achieved CR.

Modern approaches to the choice of treatment tactics in patients with cervical cancer

Currently, approaches to the choice of treatment tactics for cervical cancer have changed significantly. According to the recommendations of ESGO (2018), RUSSCO (2020), the use of a combination of surgical treatment and radiation therapy significantly increases the incidence of complications. Therefore, when planning the treatment of patients with IB1–IIA1, a combination of surgical treatment and radiation therapy should be avoided. The article presents an analysis of modern approaches to the treatment of initial, locally advanced and advanced cervical cancer. Modern approaches to organ-preserving treatment are considered, including the view from the point of view of expanding the indications for trachelectomy as part of combined treatment. The question of the expediency of using hyperthermia and indications for this type of treatment in combination with radiation therapy is considered. The author presents his own view of the problem as a whole and possible ways to solve this problem.

Anti-tumour effect of in situ vaccines combined with VEGFR inhibitors in the treatment of metastatic cervical cancer

Cervical cancer is the fourth most common malignant tumor in the world, for advanced cervical cancer, more than 30% of patients continue to have tumor and relapse or metastasis after the traditional treatment (concurrent chemoradiotherapy), and the response rate of immune checkpoint inhibitor (PD-1) is less 15%, so additional approaches are required. In situ vaccine is a very promising immunotherapy strategy. In the preclinical study, the combination of CPG and anti-Ox40 antibody can completely resolve injection site tumours and distant tumours and leads to the recovery of most mice with lymphoma. However, our early exploration process found that the effect of CpG + OX40 in the treatment of advanced cervical cancer is not ideal. Hence, we explored the anti-tumor effect of CpG + OX40 combined with anti-angiogenic therapy for the first time. The results showed that the combination significantly inhibited the proliferation of primary and secondary tumor volume and prolonged the survival time of mice, compared with the control group, CD3+, CD4 + and CD8 + T cells in the combined group showed an increasing trend. In addition, in terms of metabolism, the anti-vascular effect of anlotinib can significantly reduce the blood supply and metabolic level of tumor, the expression of Ki67 and CD31 in the control group was significantly higher than that in each administration group. In conclusion, our preclinical research results showed that the combination of in situ vaccine and anti-angiogenic therapy has a good anti-tumor effect, and may potentially offer an effective treatment option for patients with advanced cervical cancer.

Severity and Persistency of Late Gastrointestinal Morbidity in Locally Advanced Cervical Cancer: Lessons Learned From EMBRACE-I and Implications for the Future

The purpose was to evaluate patient- and treatment-related risk factors for physician-assessed and patient-reported gastrointestinal (GI) symptoms after radio(chemo)therapy and image guided adaptive brachytherapy in locally advanced cervical cancer. Of 1416 patients from the EMBRACE-I study, 1199 and 1002 were prospectively evaluated using physician-assessed (Common Terminology Criteria for Adverse Events [CTCAE]) and patient-reported (European Organization for Research and Treatment of Cancer [EORTC]) GI symptoms, respectively. CTCAE severe grade (grade [G] ≥3) events were pooled according to the location in the GI tract (anus/rectum, sigmoid, and colon/small bowel). CTCAE G ≥2 and EORTC "very much" and "quite a bit" plus "very much" scores (≥ "quite a bit") were analyzed for individual symptoms with Cox regression. Logistic regression was used for persistent G ≥1 and EORTC ≥ "quite a bit" symptoms, defined if present in at least half of follow-ups. The incidence of G ≥3 events was 2.8%, 1.8%, and 2.3% for G ≥3 anus/rectum, sigmoid, and colon/small bowel events, respectively. Among G ≥2 symptoms, diarrhea and flatulence were the most prevalent (8.5% and 9.9%, respectively). Among patient-related factors, baseline morbidity, increasing age, smoking status, and low body mass index were associated with GI symptoms tovarying degrees. Among treatment-related factors, rectum D2cm3 and the International Commission on Radiation Units and Measurements recto-vaginal reference point (ICRU RV-RP) correlated with G ≥3 anus/rectum events and moderate/persistent diarrhea, proctitis, bleeding, abdominal cramps, and difficulty in bowel control. Bowel D2cm3 correlated with G ≥3 sigmoid and colon/small bowel events and moderate/persistent diarrhea and flatulence. For external beam radiation therapy (EBRT), prescription dose correlated with G ≥3 anus/rectum, diarrhea, and difficulty in bowel control. Patients with large lymph-node boost (V57Gy) were at higher risk for G ≥3 sigmoid events, moderate/persistent diarrhea, proctitis, and cramps. The analysis showed that both EBRT and image guided adaptive brachytherapy contribute to GI symptoms after locally advanced cervical cancer treatment. Rectum D2cm3, ICRU RV-RP , and bowel D2cm3 are risk factors for GI morbidity. The risk for various symptoms was lower with an EBRT prescription of 45 Gy than 50 Gy and increased with larger V57Gy.

The Role of Immunotherapy in the Treatment of Advanced Cervical Cancer: Current Status and Future Perspectives.

Cervical cancer remains one of the most common cancers in women around the world however therapeutic options in the advanced and recurrent setting are limited. Immune checkpoint inhibitors (ICI) have been considered an attractive option given the viral etiology of cervical cancer although the majority of patients do not benefit from their use. This review summarises current knowledge and use of immune checkpoint blockade in cervical cancer as well as discussing the challenges faced in their clinical application, namely, the role of biomarker-driven ICI use, potential mechanisms of resistance, strategies to overcome such resistance and additional immunotherapy options beyond ICI.

Real-World Efficacy and Safety of Bevacizumab in the First-Line Treatment of Metastatic Cervical Cancer: A Cohort Study in the Total Population of Croatian Patients.

Background Although today it is almost preventable, cervical cancer still represents a significant cancer burden, especially in some developing parts of the world. Since the introduction of bevacizumab in the first-line treatment of metastatic disease, improvements of the outcomes were noted. However, results from randomized controlled trials are often hard to recreate in the real-world setting. Objective To assess the real-world efficacy and safety of bevacizumab as a first-line treatment of advanced cervical cancer. Methods We conducted a retrospective cohort study on the total population of Croatian patients diagnosed with metastatic cervical cancer from 2016 to 2019 who were treated with bevacizumab in combination with cisplatin and paclitaxel (TCB) in the first line. The comparison group was the consecutive sample of patients treated with chemotherapy alone. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate, incidence of adverse events, and the proportion of treatment discontinuation. Results We enrolled 67 patients treated with TCB and a control group of 62 patients treated with chemotherapy alone. The TCB cohort had significantly longer unadjusted OS with a median of 27.0 (95% CI 18.5; not calculable) months, compared to 15.5 (10.7; 30.1) months in the chemotherapy-alone cohort. Adjusted OS was not significantly different. PFS was significantly longer for the TCB cohort, with a median of 10.6 (95% CI 8.5; 15.4) months, than for the chemotherapy-alone cohort, with a median of 5.4 (95% CI 3.9; 9.1) months, even after adjustment for baseline covariates (HRadjusted = 0.60; 95% CI 0.39; 0.94; p=0.027; false discovery rate <5%). Conclusions In a real-world setting, TCB as a first-line treatment of metastatic cervical cancer was associated with longer PFS, better objective disease control rate, and acceptable toxicity profile in comparison to chemotherapy alone. These results may indicate its utility and potential applicability in other parts of the developing world.

Pembrolizumab treatment of advanced cervical cancer: updated results from the phase II KEYNOTE-158 study

<h3>Objectives:</h3> Pembrolizumab (pembro) showed durable antitumor activity and manageable safety in patients (pts) with advanced cervical cancer in an earlier interim analysis of KEYNOTE-158 (NCT02628067). Based on those results, the US FDA granted accelerated approval of pembro for pts with advanced, PD-L1-positive cervical cancer that progressed on or after chemotherapy. We present an updated analysis of pts included in the cervical cancer cohort of KEYNOTE-158 based on 17 months of additional follow-up. <h3>Methods:</h3> KEYNOTE-158 is a phase 2 basket study investigating the antitumor activity of pembro across several cancer types. Key eligibility criteria for the cervical cancer cohort included histologically or cytologically confirmed disease, progression on or intolerance to ≥1 line of standard therapy, an ECOG PS of 0 or 1, and provision of a tumor sample for biomarker analysis. Pts received pembro 200 mg once every 3 weeks for 2 years or until progression, intolerable toxicity, or physician or patient decision. Tumor imaging was performed every 9 weeks for the first 12 months, and every 12 weeks thereafter. PD-L1 positivity, defined as a combined positive score (CPS) ≥1, was evaluated retrospectively by immunohistochemistry. The primary endpoint was the objective response rate (ORR) assessed per RECIST v1.1 by independent central radiology review. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. <h3>Results:</h3> A total of 98 pts were treated. Median age was 46 (range, 24 to 75) years, 65.3% had ECOG PS 1, and 94.9% had stage M1 disease. A total of 83.7% of enrolled pts had PD-L1–positive tumors. As of the June 27, 2019 data cutoff, the median follow-up duration, defined as first dose of study medication to data cutoff, was 36.9 (range, 34.3 to 41.0) months. In the updated analysis, 2 partial responses (PR) converted to complete responses (CR) and 2 additional PR occurred for a total of 5 CR and 9 PR; ORR was 14.3% (95% CI, 8.0% to 22.8%). A total of16 pts had stable disease (SD), and the disease control rate (CR+PR+SD) was 30.6%. All 14 responses were in pts with PD-L1–positive tumors, resulting in an ORR of 17.1% (95% CI, 9.7% to 27.0%) in the PD-L1–positive cohort (N=82) and 0.0% (95% CI, 0.0% to 21.8%) in the PD-L1–negative cohort. A total of 7 of 14 responses were ongoing after ≥24 months of follow-up. Median DOR had not been reached (range, 3.7+ to 35.2+). Median (95% CI) PFS and OS were 2.1 (2.1 to 2.2) months and 9.3 (7.6 to 11.7) months, respectively. Treatment-related adverse events (AEs) occurred in 65.3% of pts, and the most common were hypothyroidism (11.2%), fatigue (11.2%), and decreased appetite (9.2%). 12.2% of pts had treatment-related grade 3-4 AEs; there were no grade 5 AEs. <h3>Conclusions:</h3> With 17 months of additional follow-up, pembro continues to show durable antitumor activity and manageable safety in pts with advanced cervical cancer, similar to the previous report.

Abstract 1749: DRAK1 suppresses inflammation-induced cervical cancer progression by targeting TRAF6 protein

Abstract Cervical cancer is a major cause of mortality in women worldwide and strongly associated with persistent infection with high-risk (HR) human papillomavirus (HPV), mainly HPV16 and HPV18. Most HPV viruses can be cleared by the immune system, and a preventive and effective vaccine against HPV infection decreases the development of cervical cancer. The adaptor protein TNF receptor-associated factor 6 (TRAF6) is a key mediator in inflammation. However, the molecular mechanisms controlling its activity and stability in cancer progression remain unclear. Here we show that death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK1) specifically decreases the stability of the TRAF6 protein via an autophagy-mediated degradation pathway by interfering with the homo-oligomerization of TRAF6, eventually suppressing tumor growth and metastasis in inflammation-associated advanced cervical cancer cells. DRAK1 bounds directly to the TRAF domain of TRAF6, preventing its autoubiquitination by interfering homo-oligomerization, eventually leading to autophagy-mediated degradation of TRAF6. Depletion of DRAK1 in cervical cancer cells resulted in markedly increased levels of TRAF6 protein, promoting activation of the IL1β signaling-associated pathway and pro-inflammatory cytokine production. DRAK1 knockdown accelerated cervical cancer tumorigenesis and metastasis whereas DRAK1 overexpression suppressed that phenomenon. DRAK1 was specifically underexpressed in metastatic cervical cancers and inversely correlated with TRAF6 expression in mouse xenograft model tumor tissues and human cervical tumor tissues. Collectively, our findings highlight DRAK1 as a novel potential biomarker and novel therapeutic target for treatment of TRAF6-associated advanced cervical cancers. [This work was supported by National R&amp;D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (HA17C0037).] Citation Format: Kyoungwha Pang, Jihee Lee, Jinah Park, Akira Ooshima, Kyung-Min Yang, Seong-Jin Kim. DRAK1 suppresses inflammation-induced cervical cancer progression by targeting TRAF6 protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1749.

Identifying Potential Neoantigens for Cervical Cancer Immunotherapy Using Comprehensive Genomic Variation Profiling of Cervical Intraepithelial Neoplasia and Cervical Cancer.

Cervical cancer (CC) is one of the most common gynecological malignant tumors. The 5-year survival rate remains poor for the advanced and metastatic cervical cancer for the lack of effective treatments. Immunotherapy plays an important role in clinical tumor therapy. Neoantigens derived from tumor-specific somatic mutations are prospective targets for immunotherapy. Hence, the identification of new targets is of great significance for the treatment of advanced and metastatic cervical cancer. In this study, we performed whole-exome sequencing in 70 samples, including 25 cervical intraepithelial neoplasia (CINs) with corresponding blood samples and 10 CCs along with paired adjacent tissues to identify genomic variations and to find the potential neoantigens for CC immunotherapy. Using systematic bioinformatics pipeline, we found that C>T transitions were in both CINs and CCs. In contrast, the number of somatic mutations in CCs was significantly higher than those in CINs (t-test, P = 6.60E-04). Meanwhile, mutational signatures analysis revealed that signature 6 was detected in CIN2, CIN3, and CC, but not in CIN1, while signature 2 was only observed in CCs. Furthermore, PIK3CA, ARHGAP5 and ADGRB1 were identified as potential driver genes in this report, of which ADGRB1 was firstly reported in CC. Based on the genomic variation profiling of CINs and CCs, we identified 2586 potential neoantigens in these patients, of which 45 neoantigens were found in three neoantigen-related databases (TSNAdb, IEDB, and CTDatabase). Our current findings lay a solid foundation for the study of the pathogenesis of CC and the development of neoantigen-targeted immunotherapeutic measures.

Efficacy of Huangqi Taohong Decoction Combined with TP Chemotherapy on Advanced Cervical Cancer and Its Influence on PD-L1/PD-1 Pathway, Tumor Markers and Th Cytokines

Objective. To observe the clinical efficacy of Huangqi Taohong Decoction combined with TP chemotherapy on advanced cervical cancer (CC) and its effect on programmed death molecule1/programmed death molecule-1 ligand pathway, tumor markers and Th cytokines. Methods . A total of 115 patients with advanced CC were randomly divided into two groups , 57 patients in the control group were treated with TP chemotherapy , 21 days as a course, and the treatment lasted for 4 courses. 58 cases in the treatment group were treated with Huangqi Taohong d ecoction on the basis of control group, and 4 weeks was as a course and the treatment was lasted for 3 courses. The curative effects of the two groups were compared. The changes of PD-1 on CD4+ T cells , PD-L1 on CD14+ monocytes were compared before and after treatment. The changes of tumor markers [carcinoembryonic antigen ( CEA) , sugar chain antigen ( CA199) , carbohydrate antigen ( CA125), squamous cell carcinoma antibody (SCC-A)] were compared, the levels of Th1 cytokines [γ-interferon ( INF-γ) , interleukin-2 ( IL-2) ] , th2 cytokine [interleukin-4 ( IL-4) , interleukin-6 ( IL-6) ], quality of life score and the incidence of adverse reactions were compared between the two groups before and after treatment. Results. The disease control rate (DCR) was 74.14% ( 43/58) in the treatment group and 63.16% (36 /57) in the control group, and there was no significant difference between the two groups( P > 0. 05). After treatment, PD-1on CD4+ T cells, PD-1 on CD8+ T cells and PD-L1on CD14+ monocytes in the treatment group were lower than those before treatment (P 0.05). After treatment, the levels of serum CEA, CA199, CA125 and SCC-A in the two groups were lower than those before treatment(P 0.05). The difference in the incidence of adverse reactions between the two groups was statistically significant (P<0.05). And the incidence of adverse reactions in the control group was higher. Conclusion. Huangqi Taohong Decoction combined with TP chemotherapy is effective in the treatment of advanced CC. It can block the expression of PD-1/PD-L1 pathway, reducing the expression levels of tumor markers, Th1 and Th2 cytokines, improving the quality of life and safety.

BRD4 inhibition sensitizes cervical cancer to radiotherapy by attenuating DNA repair.

Cisplatin-based chemoradiotherapy is the recommended treatment for local advanced cervical cancer, but radioresistance remains one of the most important and unresolved clinical problems. Investigations have revealed aberrant epigenetic modifications as one of the chief culprits for the development of radioresistance. Here, we attempt to identify a radiosensitizer from an epigenetic drug synergy screen and explore the underlying mechanism. We integrated epigenetic inhibitors and radiotherapy in cervical cancer cell lines to identify potential radiosensitizers. We further verified the sensitization effect of the drug and the function of its target gene both in vitro and in vivo. Finally, we validated the clinical significance of its target gene in clinical cervical cancer specimens. We identified JQ1, a BRD4 inhibitor, as a potent radiosensitizer. Functional assays demonstrated that repressing BRD4 activity led to significant radiosensitization and potentiation of DNA damage in cervical cancer cell lines. By using RNA-seq to determine JQ1-mediated changes in transcription, we identified RAD51AP1 as a major BRD4 target gene involved in radiosensitivity. A dual-luciferase reporter assay and ChIP-qPCR showed that BRD4 binds to the promoter region of RAD51AP1 and promotes its transcription, whereas this activity was attenuated by BRD4 inhibition. The in vivo experiments also suggested a synergy between BRD4 inhibition and radiotherapy. High BRD4 expression was found to be related to a worse prognosis and radiation resistance. BRD4 inhibition sensitizes cervical cancer to radiotherapy by inhibiting RAD51AP1 transcription. The combination of JQ1 with radiotherapy merits further evaluation as a therapeutic strategy for improving local control in cervical cancer.

Advanced cervical cancer in young women: imaging study of late and very late radiation-related side effects after successful treatment by combined radiotherapy

Radical combined radiotherapy (RT) is a standard treatment for advanced cervical cancer. The aim of our study was to identify morphological late (≥6 months) and very late (≥5 years) radiation-related comorbidities on computed tomography (CT), positron emission tomography/computerized tomography (PET/CT) or magnetic resonance imaging (MRI) scans in young females who survived ≥5 years since RT and were considered as successfully treated. Secondly, we studied a rate of clinically silent radiation-related toxicities apparent on imaging scans that might influenced on future well-being of survived females. Thirdly, we analyzed reasons why patients underwent imaging scans. We included 41 subjects aged under 50 years (mean 41.8±7.2 years, median 41 years), who survived ≥5 years since RT, with at least one available imaging scan ≥3 years since RT. The mean time between RT and the last available scan was 12.3±7.9 years (median 9 years); the mean time of clinical follow-up was 15.4±7.1 years (median 14 years). Fourteen (34.1%) females underwent the first imaging scan in emergency situation and 27 (65.9%) patients due to variable chronic complaints. Grade III-V radiation-related comorbidities occurred in 19 (46.3%) females including one case of death due to radiation-induced osteosarcoma. In 14 of 19 patients, comorbidities were multiple. Four (9.8%) females suffered from life-threatening complications (grade IV): one from an uretero-arterial fistula with massive hematuria and 3 from bowel perforations. Eleven (26.8%) subjects suffered from bowel strictures with ileus development, they underwent mean 1.7±0.8 surgery (median 1.5). The mean time since RT to the first surgery for intestinal complications was 5.4±6.0 years (median 3 years), to the second 12.0±9.6 years (median 11.5 years) and to the third surgery 9.0±4.2 years (median 9 years). Late fistulas formations (vesico-recto-vaginal) were seen in 6 (14.6%) patients. Bone complications were diagnosed in 9 (22.0%) of treated females, one case of osteosarcoma included, 4 of 9 bone complications were clinically silent. In 5 (12.2%) subjects, toxicities grade III-IV first time manifested >5 years since RT, majority of them were multiple. The bowel perforation and fistulas formations were the earliest manifested grade III-IV toxicities, with median time 3 years since RT, the bone complications were the latest manifested with median time 16 years since RT. Our study is not able to bring information about the incidence of late and very late radiation related comorbidities, according to International Federation of Gynecology and Obstetrics (FIGO) recommendations patients are clinically followed only for 5 years and imaging cross-sectional scans are not recommended. However, our study shows that if females successfully treated for advanced cervical cancer report abdominal/pelvic clinical problems, it is highly probable their imaging scans will reveal late radiation related side-effects that may affect the rest of their life. It puts forward question whether females after radical RT should been regularly followed by cross-sectional imaging methods.

Identification of key genes and construction of regulatory network for the progression of cervical cancer

Across the globe, cervical cancer is the fourth main cause of cancer-associated deaths in women. The present study aimed to identify the differentially expressed genes (DEGs) and enriched pathways involved in cervical cancer. From the database, Gene Expression Omnibus (GEO) microarray data of 300 patients with cervical cancer (GSE44001) was used for analysis purposes. Statistical analysis was performed to identify DEGs between different stages of cervical cancer and progression, and a total of 36 common DEGs were screened. The Gene ontology analysis (GO) and protein-protein interaction (PPI) network were used to find relationship among the DEGs. The gene-miRNA interaction networks were constructed by NetworkAnalyst software. The study revealed that various DEGs are involved in the process of oncogeneis. Genes like TP63, IGF1, AIM2, ABCB7, ARHGAP6, RAP2B, HIST1H3C, THOC2, TRIM66, PKN3, CNBP & ATG3 may play a crucial role in cervical cancer. DEGs like THCO2, TAF5L, GPS1, PKN3 & VPSI3A are upregulated. The down regulated DEGs are KHL13, ST8IA4, RAP2B, FRMD8, EGL6, KLHDC10, TRIM66 & CNBP. Based on the investigation, miRNAs and associated DEGs were analyzed, which in turn helped us in a better understanding of the prognosis of cervical cancer. Comprehensively our results revealed the potential use of biomarkers in the diagnosis of cervical cancer and may uplift the development of advanced cervical cancer therapy and treatment of cancer.

ZNF582 methylation level may predict radiotherapy efficacy and radiotherapy inhibits cervical cancer cell proliferation by de-methylation of ZNF582

Objective: The treatment of advanced cervical cancer is mainly based on radiotherapy and chemoradiotherapy, but there are individual differences in efficacy. There is no effective biomarker predicting the efficacy of radiotherapy. Our previous study found that the methylation of ZNF582 in cervical exfoliated cells was associated with the prognosis of cervical cancer and may affect the sensitivity of chemoradiotherapy in cervical cancer cells. The aim of this study was to investigate the relationship between the methylation level of ZNF582 in cervical cytological specimens and the efficacy of radiotherapy in cervical cancer patients, and to study the molecular mechanism of ZNF582 affecting the efficacy of radiotherapy.

A 70-Gene Signature for Predicting Treatment Outcome in Advanced-Stage Cervical Cancer

Cervical cancer is the fourth most common cancer in women worldwide. The current approaches still have limitations in predicting the therapy outcome of each individual because of cancer heterogeneity. The goal of this study was to establish a gene expression signature that could help when choosing the right therapeutic method for the treatment of advanced-stage cervical cancer. The 666 patients were collected from four independent datasets. The 70-gene expression signature was established using univariate Cox proportional hazard regression analysis. The 70-gene signature was significantly different between low- and high-risk groups in the training dataset (p = 4.24e−6) and in the combined three validation datasets (p = 4.37e−3). Treatment of advanced-stage cancer patients in the high-risk group with molecular-targeted therapy combined with chemoradiotherapy yielded a better survival rate than with only chemoradiotherapy (p = 0.0746). However, treatment of the patients in the low-risk group with the combined therapy resulted in significantly lower survival (p = 0.00283). Functional classification of 70 genes revealed involvement of the angiogenesis pathway, specifically phosphatidylinositol 3-kinase signaling (p = 0.040), extracellular matrix organization (p = 0.0452), and cell adhesion (p = 0.011). The 70-gene signature could predict the prognosis and indicate an optimal therapeutic modality in molecular-targeted therapy or chemotherapy for advanced-stage cervical cancer.

Non-brachytherapy approach for locally advanced cervical cancer treatment.

e18023 Background: Concomitant chemoradiation therapy (CRT) that includes both external beam radiotherapy (EBRT) and brachytherapy (BT) is the current standard of care in treatment of locally advanced cervical cancer (LACC). Adaptive EBRT using volumetric modulated arc technology without BT allows dose escalation and decreases toxicities. Non-brachytherapy treatment is an evolving alternative approach provides geographical radiation accuracy but the oncological outcomes still to be evaluated. Methods: Patients with LACC (stages 1B3–IVA) who underwent non-brachytherapy CRT using adaptive EBRT with simultaneous integrated boost at our institution were evaluated prospectively from May 2015 to December 2019. All patients were initially assessed by a gynecologic oncologist, pelvic MRI and 18FDG-PET/CT scan were conducted. Follow-up pelvic examinations with cytology every 3 months and PET/CT at 3 and 12 months after completion of treatment were performed. Oncological outcomes and toxicities were assessed. Results: Twenty-one patients were analyzed: median age was 54 years (30–76 years); 19 patients had squamous cell histology and 2 had adenocarcinoma. Median follow-up was 32 months (8–56). The average dose administered to the gross tumor volume was 90.2 Gy (79.5–96.6), 79.8 Gy to all PET/MRI positive lymph nodes (63.0–89.7). No patents received BT; all but 3 received chemotherapy. Three-year local control was 100% (PFS = 90.4% and OS = 100%). There were 2 recurrences: a solitary skull lesion 18 months following CRT in a patient with mesonephric adenocarcinoma and a metastasis to a transposed ovary 15 months after CRT. No grade 3–4 toxicities were seen. Only 1 patient (4.7%) had late rectal grade II toxicity. Conclusions: Non-brachytherapy adaptive CRT for LACC is feasible. It allows for a significant dose escalation, thus providing better local control and likely increases PFS and OS at no cost of serious toxicity. Randomized studies comparing this approach to the current standard of care are needed.

Leonurine Promotes Cisplatin Sensitivity in Human Cervical Cancer Cells Through Increasing Apoptosis and Inhibiting Drug-Resistant Proteins.

BackgroundCisplatin-based neoadjuvant chemotherapy and concurrent radiotherapy and chemotherapy are the main treatment for advanced cervical cancer. However, the development of multidrug resistance (MDR) leads to chemotherapy failure, tumor recurrence and poor survival. In this research, we investigated the effect and corresponding mechanism of leonurine on cisplatin sensitivity of cervical cancer cells.MethodsAnti-cervical cancer efficacy of leonurine and leonurine combined with cisplatin was examined in C33A and Ms751 cells. The cell counting kit-8 assay and bromodeoxyuridine assay were applied for measuring cell proliferation. CompuSyn software was used to calculate the combination index and assess the synergistic effect of leonurine and cisplatin on cell proliferation. The cell cycle distribution and cell apoptosis were analyzed by flow cytometry. The expression of cleaved caspase-3, poly ADP-ribose polymerase (PARP), B-cell lymphoma-2 associated X (BAX), B-cell lymphoma-2 (BCL-2), P glycoprotein (P-Gp) protein and multiple drug resistance protein 1 (MRP1) was analyzed by Western blotting.ResultsLeonurine had time- and dose-dependent anti-proliferative effects on C33A and MS751 cells. Leonurine and cisplatin combination was more efficacious in inhibiting the growth of cervical cancer cells than either of the two drugs. The combined application has shown that the cervical cancer cells were arrested at G1 phase after treatments. Moreover, flow cytometry analysis indicated that the combined treatment could cause more cell apoptosis than the single drug treatment. Consistently, combined treatment elevated BAX/BCL-2 ratio, and the expression of BAX, PARP and cleaved caspase-3 proteins. Mechanistic investigations uncovered that the tumor-inhibiting effects of the co-treatment were mediated by repressing MDR, including MRP1 and P-Gp protein, thereby enhancing the efficiency of cisplatin.ConclusionLeonurine and cisplatin have synergistic antitumorigenic effects on cervical cancer. Combination with leonurine may serve as a novel strategy for enhancing cisplatin sensitivity via the inhibition of the expression of MRP1 and P-Gp.