Platinum-resistant Patients Research Articles

The Platelet to Lymphocyte and Neutrophil to Lymphocyte Ratios in Predicting Response to Platinum-based Chemotherapy for Epithelial Ovarian Cancer.

Objective: The patients with advanced-stage ovarian cancer have higher factors complicating surgery; thus, the best choice for them is surgery with chemotherapy with six cycles of adjuvant chemotherapy. Generally, chemotherapy can be evaluated in various ways, phsychal examination, radiology examination, and laboratory examination. This study aims is to examine if the measurement of the platelet/lymphocyte ratio (PLR) and neutrophil/lymphocyte ratio (NLR) can be used to predict a patient’s response to chemotherapy. Methods:Analytic observational study with a case-control design conducted in the Dr. Hasan Sadikin Hospital in Bandung from 2017 to 2018. This study used the medical record of ovarian cancer patients with post-surgery complete blood counts and histopathological reports. The sample size was determined based on the categorical test’s statistical calculation to obtain a total number of at minimal 90 samples. All the study subjects who had undergone complete chemotherapy were followed up for 6 months. Their response to chemotherapy was assessed with a clinical examination, ultrasonography, and a CA-125 blood test every 3 months. Results:In 2017–2018, 504 patients were diagnosed with ovarian cancer at the Dr. Hasan Sadikin Hospital in Bandung, Indonesia. After reassessment, 116 patients had stage I to III ovarian cancer and underwent cytoreduction followed by platinum chemotherapy. The age, cancer stage, and types of epithelial cells in the platinum-sensitive and platinum-resistant patients were characterized. There were significant differences between the two groups in age and cancer stage characteristics (p < 0.05). The increase in platelet/lymphocyte (p = 0.003) and neutrophil/lymphocyte ratios (p = 0.026) are associated with the increase in the response to platinum chemotherapy against epithelium-based cancers. Conclusion:A patient’s NLR and PLR are strongly associated with his response to chemotherapy.

Systematic Investigation of DNA Methylation Associated With Platinum Chemotherapy Resistance Across 13 Cancer Types.

Background: Platinum resistance poses a significant problem for oncology clinicians. As a result, the role of epigenetics and DNA methylation in platinum-based chemoresistance has gained increasing attention from researchers in recent years. A systematic investigation of aberrant methylation patterns related to platinum resistance across various cancer types is urgently needed. Methods: We analyzed the platinum chemotherapy response-related methylation patterns from different perspectives of 618 patients across 13 cancer types and integrated transcriptional and clinical data. Spearman’s test was used to evaluate the correlation between methylation and gene expression. Cox analysis, the Kaplan-Meier method, and log-rank tests were performed to identify potential risk biomarkers based on differentially methylated positions (DMPs) and compare survival based on DMP values. Support vector machines and receiver operating characteristic curves were used to identify the platinum-response predictive DMPs. Results: A total of 3,703 DMPs (p value < 0.001 and absolute delta beta >0.10) were identified, and the DMP numbers of each cancer type varied. A total of 39.83% of DMPs were hypermethylated and 60.17% were hypomethylated in platinum-resistant patients. Among them, 405 DMPs (Benjamini and Hochberg adjusted p value < 0.05) were found to be associated with prognosis in tumor patients treated with platinum-based regimens, and 664 DMPs displayed the potential to predict platinum chemotherapy response. In addition, we defined six DNA DMPs consisting of four gene members (mesothelin, protein kinase cAMP-dependent type II regulatory subunit beta, msh homeobox 1, and par-6 family cell polarity regulator alpha) that may have favorable prognostic and predictive values for platinum chemotherapy. Conclusion: The methylation-transcription axis exists and participates in the complex biological mechanism of platinum resistance in various cancers. Six DMPs and four associated genes may have the potential to serve as promising epigenetic biomarkers for platinum-based chemotherapy and guide clinical selection of optimal treatment.

Efficacy of concurrent chemoradiotherapy for patients with limited-disease small-cell lung cancer: a retrospective, nationwide, population-based cohort study

BackgroundSmall-cell lung cancer (SCLC) is a highly proliferative, rapidly growing tumor with a poor prognosis, even in cases of limited disease (LD). Timely and accurate high-intensity therapy is necessary. For concurrent chemoradiotherapy (CCRT), etoposide/platinum (EP)-based regimens are recommended, although irinotecan/platinum (IP)-based regimens are also effective with radiotherapy. This large-scale, retrospective, nationwide cohort study aimed to analyze the efficacy of CCRT in patients with LD-SCLC.MethodsPopulation data registered between January 2008 and December 2018 was extracted from the Health Insurance Review and Assessment Service of Korea database. Survival outcomes of 4446 LD-SCLC patients who received CCRT were analyzed.ResultsPatients who received EP-CCRT (n = 4187) showed better time to first subsequent therapy (TFST: 11.2 months) and overall survival (OS: 22.2 months) than those who received IP-CCRT (n = 259; TFST: 9.6 months, P = 0.0477; OS: 16.4 months, P < 0.0001). When CCRT failed, dual-agent chemotherapy (n = 925; OS: 9.1 months) provided a better survival benefit than single-agent chemotherapy (n = 815; OS: 7.5 months). IP-based chemotherapy resulted in better OS (9.6 months) than EP-based chemotherapy (7.1 months, P = 0.017) in platinum-resistant relapsed patients; the opposite was observed for platinum-sensitive relapsed patients (OS: EP, 17.2 months; IP, 6.6 months; P < 0.0001). Poisson regression analysis demonstrated that age, EP-CCRT, and hypercholesterolemia retained significant associations with OS after adjustment for all variables.ConclusionIn the Korean population, the effects of EP-CCRT on OS and TFST are significantly more favorable than those of IP-CCRT.

Protein and Signaling Pathway Responses to rhIL-6 Intervention Before Lobaplatin Treatment in Osteosarcoma Cells.

Lobaplatin is a third-generation platinum-based antineoplastic agent and is widely used for osteosarcoma treatment before and after tumor removal. However, treatment failure often results from lobaplatin drug resistance. In our study, we found that SaOS-2 and SOSP-9607 osteosarcoma cells became less sensitive to lobaplatin after treatment with exogenous interleukin (IL)-6. Quantitative proteomic analysis was performed to elucidate the underlying mechanism in SaOS-2 osteosarcoma cells. Cells were divided into a control group (CG), a lobaplatin treatment group (LG), a recombinant human IL-6 (rhIL-6), and a lobaplatin treatment group (rhILG). We performed three biological replicates in each group to compare the differential protein expression between groups using a tandem mass tag (TMT) labeling technology based on liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 1,313 proteins with significant differential expression was identified and quantified. The general characteristics of the significantly enriched proteins were identified by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and protein–protein interaction (PPI) analysis was conducted using IntAct and STRING. In total, 31 proteins were further verified by parallel reaction monitoring (PRM), among which ras GTPase-activating protein-binding protein 1 (G3BP1), fragile X mental retardation syndrome-related protein 1 (hFXR1p), and far upstream element-binding protein 1 (FUBP1) were significantly differentially expressed. Immunohistochemistry results showed that these three proteins are highly expressed in specimens from platinum-resistant osteosarcoma patients, while the proteins are negatively or weakly expressed in specimens from platinum-sensitive osteosarcoma patients. The immunofluorescence staining results were in accord with the immunohistochemistry staining results. siRNA knockdown of FUBP1 showed a strikingly decreased IC50 value for lobaplatin in FUBP1-silenced cells, which verified the role of FUBP1 in the drug susceptibility of osteosarcoma and the potential therapeutic value for increasing the sensitivity to lobaplatin. This is the first proteomic study on a rhIL-6 intervention before lobaplatin treatment in osteosarcoma cells.

A Novel, Personalized Drug-Screening System for Platinum-Resistant Ovarian Cancer Patients: A Preliminary Clinical Report.

PurposeWith this study, we intended to construct a personalized drug-screening system for platinum-resistant ovarian cancer patients by consulting a patient’s medical history, data derived from gene mutation detection, and drug screening results derived from mini-PDX (patient-derived xenograft) models. We also aimed to evaluate the efficacy and safety of our system.Patients and MethodsWe selected 12 patients with platinum-resistant ovarian cancer who were treated at our hospital from January 2018 to December 2019 to design a single-arm clinical trial. The subsequent chemotherapeutic plans were selected according to a personalized drug-screening system that circulating tumor DNA (ctDNA) testing and the establishment of mini-PDX models. We then analyzed the patients for clinical benefits side-effects in response to chemotherapy in order to evaluate the clinical effects and safety of our new personalized drug-selection system.ResultsWe successfully established an individualized and sensitive drug-screening system for the 12 patients. Mini-PDX models verified that potentially effective drugs were identified for 11 of the patients. Treatment resulted in complete remission (one patient), partial remission (five patients), and stable disease (three patients). The remaining three patients experienced disease progression. The overall clinical-benefit rate was 75.0%. Following treatment, the levels of CA125 levels decreased significantly in seven of the 12 patients. Severe side effects, arising from chemotherapy, were only observed in one case.ConclusionConstructing a personalized drug-screening system for platinum-resistant ovarian cancer patients can be used to guide clinical drug selection and improve the clinical-benefit rate for patients.Trial Registration NumberChiCTR1800016766 (Chinese Clinical Trial Registry Center).

Bioinformatics analysis of drug-resistant ceRNA in epithelial ovarian cancer

Objective: To explore the possible biological function of long-chain non-coding RNA (lncRNA) on epithelial ovarian cancer (EOC) drug resistance and the value of new diagnostic markers through bioinformatics analysis, clinical testing and verification methods. Methods: (1) Mining the lncRNA related to EOC and constructing the competing endogenous RNA (ceRNA) regulatory network: comprehensively apply text mining, data prediction and network construction and other bioinformatics methods to establish a potential ceRNA regulatory network related to EOC drug resistance, namely lncRNA-microRNA (miRNA)-mRNA regulatory network. (2) Clinical verification: a total of 95 cancer tissue specimens were collected from EOC patients who underwent cytoreductive surgery at the Affiliated Tumor Hospital of Guangxi Medical University from June 2008 to October 2016, of which 54 were platinum-resistant patients (resistance group), 41 platinum-based drug-sensitive patients (sensitive group). Real-time fluorescent quantitative PCR was used to detect the expression of lncRNA in EOC tissues of the two groups, the effect of lncRNA expression on the prognosis of EOC patients, and the diagnostic efficacy of lncRNA expression on resistance to EOC were also analyzed. Results: (1) Text mining preliminarily screened out 25 differentially expressed lncRNA related to the occurrence and development of EOC, and further subcellular localization analysis found that 8 lncRNA exist in the cytoplasm. Through further data mining, collinear literature analysis and construction of ceRNA, the regulatory network predicts that the two lncRNA molecules, GAS5 and HOTAIR, could serve as key ceRNA molecules. (2) Through real-time fluoressent quantitative PCR verification, it was found that both GAS5 and HOTAIR were highly expressed in drug-resistant EOC tissues, which affects the progression-free survival (PFS) and overall survival (OS) time of patients with drug-resistant EOC independent risk factors (P<0.05). The receiver operating characteristic (ROC) area under the curve (AUC) of GAS5 alone was 0.678, the AUC of HOTAIR alone was 0.863, and the AUC of GAS5 combined with HOTAIR was 0.871, and there were statistically significant differences (all P<0.05). Conclusions: The high expression of GAS5 and HOTAIR is closely related to the drug resistance of EOC, which could be used as a potential predictor of response to chemotherapy. At the same time, the combined detection of GAS5 and HOTAIR has a certain diagnostic efficiency for patients with platinum-resistant EOC. This method of using the ceRNA regulatory network to predict key molecules will provide new ideas for the diagnosis and treatment of EOC.

Exploring the clinical value of tumor microenvironment in platinum-resistant ovarian cancer.

Platinum resistance in epithelial ovarian cancer (OvCa) is rising at an alarming rate, with recurrence of chemo-resistant high grade serous OvCa (HGSC) in roughly 75 % of all patients. Additionally, HGSC has an abysmal five-year survival rate, standing at 39 % and 17 % for FIGO stages III and IV, respectively. Herein we review the crucial cellular interactions between HGSC cells and the cellular and non-cellular components of the unique peritoneal tumor microenvironment (TME). We highlight the role of the extracellular matrix (ECM), ascitic fluid as well as the mesothelial cells, tumor associated macrophages, neutrophils, adipocytes and fibroblasts in platinum-resistance. Moreover, we underscore the importance of other immune-cell players in conferring resistance, including natural killer cells, myeloid-derived suppressive cells (MDSCs) and T-regulatory cells. We show the clinical relevance of the key platinum-resistant markers and their correlation with the major pathways perturbed in OvCa. In parallel, we discuss the effect of immunotherapies in re-sensitizing platinum-resistant patients to platinum-based drugs. Through detailed analysis of platinum-resistance in HGSC, we hope to advance the development of more effective therapy options for this aggressive disease.

Role of BRCA Mutation and HE4 in Predicting Chemotherapy Response in Ovarian Cancer: A Retrospective Pilot Study.

Even though 80% of patients with High-Grade Serous Ovarian Cancer respond to standard first-line chemotherapy, a majority of them could relapse in the following five years due to a resistance to platinum. Human Epididymis protein 4 (HE4) is one of the most promising markers in predicting platinum therapy response. This pilot study aims to evaluate the potential role of HE4 value in predicting chemotherapy response in BRCA mutated patients and in BRCA wild-type (non-mutated) ones. We selected 69 patients, affected by High-Grade Serous Ovarian Cancer, and optimally debulked and submitted to standard chemotherapy protocols. HE4 was dosed during every chemotherapy course. Patients were classified as platinum-resistant and platinum-sensitive. According to BRCA mutation test, patients were further divided into BRCA wild-type (53 patients), and BRCA mutated (16 patients). 35 patients out of 69 (52%) were platinum-sensitive (recurrence > 12 months), while 33 patients (48%) were platinum-resistant (recurrence < 12 months). Thus, in the total population, HE4 performed as a marker of chemosensitivity with a sensibility of 79% and a specificity of 97%. In the BRCA WT group, 23 patients out of 53 (43%) were platinum-sensitive, while 30 patients out of 53 (57%) were platinum-resistant. In the BRCA WT group, HE4 performed as a predictive marker of chemosensitivity with a sensibility of 80% and a specificity of 100%. In the BRCA mutated group, 13 patients out of 16 (82%) were platinum-sensitive, while 3 patients (18%) were platinum-resistant. In the BRCA mutated group, HE4 performed as a predictive marker of chemosensitivity in all patients. The ability to detect platinum-resistant patients before tumor relapse probably could open new therapeutic scenarios.

DNA methylome profiling identifies novel methylated genes in epithelial ovarian cancer patients with platinum resistance.

Platinum-based chemotherapy is widely used for epithelial ovarian cancer (EOC). As high as 20-25% of EOC patients will not respond to the initial chemotherapy. Accumulated evidences have implied that DNA methylation may serve as a potential bio-marker for chemotherapy-resistant phenotypic screening; however, the pattern underlying primary platinum resistance remains unclear. Reduced representation bisulfite sequencing (RRBS) analysis was performed to identify differences in methylation status between primary platinum-resistant patients Progression free survival (PFS) (PFS < 6 months, n = 8) and extreme sensitive patients (PFS ≥ 24 months, n = 8). The Qubit 3.0 Fluorometer was used for the quantification of RRBS library. The RRBS library was sequenced on Illumina HiSeq2500 sequencer as 50 bp paired-end reads. After screening, 94 valid hyper-/hypo-methylated regions were identified to be located within 94 gene promoter and exon regions (adjusted q ≤ 0.5), which were primarily associated with cell-cell adhesion, B cell activation and lymphocyte activation according to GO analysis. The 19 differentially methylated regions (DMR) located in the promoter region including TRC-GCA11-1, LOC105370912, ANO7P1, DHX4,MSH2, CDCP2, CCNL1, ARHGAP42P2, PRDM13, LOC101928344, USP29, ZIC5,IL1RAPL1, EVX2, ABR, MGRN1, UBALD1, LINC00261, and ISL2 were identified according to the order of P-values from low to high, of which MSH2, LINC00261, MGRN1, ZIC5, EVX2, CCNL1, and DHX40 were presented to play a variety of roles in cancers process based on the previous studies. DNA methylome profiling based on RRBS assay is an effective method for screening aberrantly methylated genes in primary platinum-resistant patients, which may serve as a potential epigenetic bio-marker for the prediction of primary platinum resistance.

Treatment Free Intervals after Subsequent Chemotherapy Lines in Recurrent Ovarian Cancer

Aim: Despite recent advances in the treatment of ovarian cancer, recurrence of the disease is still frequent. This study evaluated whether multiple lines of chemotherapy have impact on overall survival (OS), progression free survival (PFS) or on treatment free intervals (TFIs) after serial chemotherapy lines in recurrent settings. Methods: A total of 189 patients with ovarian cancer (including fallopian tube and primary peritoneal cancer), who were treated in Kuopio University Hospital in Finland during 2009-2014, were enrolled. The medical files of these patients were retrospectively reviewed. Results: Median OS and PFS were significantly higher at the time of the first relapse compared to subsequent relapses (p platinum sensitive, semi-sensitive and platinum resistant patients. The total amount of TFI times during the whole follow-up time was significantly reduced in those patients that received at least one form of aggressive care at the end of life (p = 0.004). Conclusions: Ovarian cancer patients received often multiple lines of chemotherapy. TFIs after subsequent chemotherapy lines decreased during the disease course. More efforts should be taken to avoid unnecessary and ineffective treatments especially in recurrent phase of the disease.

Lurbinectedin for the treatment of small cell lung cancer.

Small cell lung cancer (SCLC) is a rapidly progressive, aggressive metastatic and lethal subtype of lung cancer. Unfortunately, there has been little progress regarding the development of novel treatments for SCLC. However, lurbinectedin, a transcriptional inhibitor, has emerged as a potential novel treatment for cancer. It produces antitumor efficacy by inhibiting oncogenic transcription activity, inducing the accumulation of DNA double-strand breaks and modulating the tumor microenvironment (TME). Data from phase I/II trials indicates that lurbinectedin has significant antitumor efficacy and tolerable adverse effects in SCLC patients. Furthermore, lurbinectedin is efficacious in platinum-sensitive and platinum-resistant SCLC patients and in those with SCLC relapse after second-line treatment. In 2020, the U.S. Food and Drug Administration (FDA) approved lurbinectedin for the treatment of adult patients with metastatic SCLC or for patients that have received platinum-based chemotherapy. In this review, we discuss the molecular profile and the preclinical and clinical studies of lurbinectedin in the treatment of SCLC patients.

Feasibility of Bone Marrow Mesenchymal Stem Cell-Mediated Synthetic Radiosensitive Promoter-Combined Sodium Iodide Symporter for Radiogenetic Ovarian Cancer Therapy.

Ovarian cancer is the most lethal gynecological cancer, most patients relapse within 12-24 months, and eventually die, especially platinum-resistant patients. Gene therapy has been one of the most potential methods for tumor treatment. Bone marrow mesenchymal stem cells (BMSCs) have been used for systemic delivery of therapeutic genes to solid tumors. Sodium iodide symporter (NIS) is an intrinsic membrane glycoprotein and can concentrate 131I, which is important for radionuclide therapy and nuclear medicine imaging in recent years. However, the rapid iodine efflux has become a bottleneck for NIS-mediated radionuclide gene therapy. Our previous studies found that the early growth response-1 (Egr1) promoter containing CC(A/T)6GG (CArG) elements had an 131I radiation-positive feedback effect on the NIS gene. Other research showed the synthesized Egr1 promoter containing four CArG elements, E4, was nearly three times as sensitive as the Egr1 promoter. In our study, BMSC-E4-NIS was engineered to express NIS under the control of E4 promoter using lentivirial vectors. After BMSC-E4-NIS implantation, no tumors were seen in BALB/c nude mice and BMSC-E4-NIS did not promote the growth of SKOV3 tumor. BMSCs migrated toward ovarian cancer samples in chemotaxis assays and to ovarian tumors in mice. Using micro-single-photon emission computed tomography/computed tomography (SPECT/CT) imaging, we found that E4 promoter produced a notable increase in 125I uptake after 131I irradiation, the radionuclide uptake is almost three and six times more than Egr1 and cytomegalovirus (CMV) promoters. These studies confirmed the feasibility of using BMSCs as carriers for lentivirus-mediated E4-NIS gene therapy for ovarian cancer. Further research on BMSC-E4-NIS gene therapy for ovarian cancer in vivo will also be carried on, and if successful, this might provide a new adjuvant therapeutical option for platinum-resistant ovarian cancer patients and provide a new method for dynamic evaluation of curative effect.

NOTCH signalling in ovarian cancer angiogenesis.

The Notch signalling pathway is involved in the new vessel formation process by regulating tip and stalk cells, which are key cells in the sprout formation. This process is essential in both normal ovary and cancer angiogenesis and is regulated by Notch-VEGF crosstalk. Furthermore, Notch has been linked in ovary with stem cell maintenance and epithelial mesenchymal transition processes. Dysregulation of the Notch pathway is frequent in ovarian cancer (OC) and it has been associated with impaired survival and advanced stages or lymph node involvement. Notch also plays a role in chemoresistance to platinum. In this context, this pathway has emerged as an attractive target for precision medicine in OC. Two main targets of this pathway concentrate the clinical development of compounds blocking Notch: gamma secretase and Delta-like ligand 4. Most of the clinical trials including OC patients have been developed in phase I or phase Ib. Despite being in an early phase, both of these compounds, navicixizumab or demcizumab, two monoclonal antibodies targeting Dll4, showed promising efficacy data in platinum-resistant OC patients in recent studies. This review will focus on the mechanisms of the Notch pathway with special interest in angiogenesis regulation and the implication of Notch as a potential therapeutic target in OC.

Oncoguía de cáncer de ovario 2020

The epithelial ovarian cancer is the second gynecological cancer cause of death worldwide and has a high lethality. In Mexico, it is diagnosed primarily in advanced stages. The main risk factor is genetic, specifically the BRCA1/2 mutations. Specialists from Instituto Nacional de Cancerología developed Oncoguía de cáncer de ovario 2020 in a consensus they conducted, based on their expertise and the analysis of the current evidence. They contain risk factors, screening, diagnostic elements (clinical and histologic), classification, and the treatment, which may be surgical, cytoreduction in patients with recurrent disease, chemotherapy (adjuvant, intraperitoneal, neoadjuvant), antiangiogenic agents, and the use of PARP inhibitors. These guidelines also describe the recurrent disease management of platinum-sensitive and platinum-resistant patients, as well as the use of immunotherapy.

Pathogenic Heteroplasmic Somatic Mitochondrial DNA Mutation Confers Platinum-Resistance and Recurrence of High-Grade Serous Ovarian Cancer.

PurposePlatinum resistance is a primary barrier to improving the survival rate of ovarian cancer. The relationship between mtDNA somatic mutations and response to platinum-based chemotherapy in ovarian cancer has not been well clarified.Patients and MethodsHere, we employed the next-generation sequencing (NGS) platform to identify mtDNA mutations of the unrelated high-grade serous ovarian cancer (HGSOC) patients.ResultsWe identified 569 germline variants and 28 mtDNA somatic mutations, and found the platinum-sensitive relapsed HGSOC patients had more synonymous mutations while the platinum-resistant relapsed HGSOC patients had more missense mutations in the mtDNA somatic mutations. Meanwhile, we found that the HGSOC patients who harbored heteroplasmic pathogenic mtDNA somatic mutations had significantly higher prevalence of both platinum-resistance and relapse than those without (80.0% versus 16.7%, p=0.035). Additionally, we observed that the tumor tissues had significantly higher lactate-to-pyruvate (L/P) ratio than the paired nontumor tissues (p<0.001), and L/P ratio of tumors with any heteroplasmic pathogenic mtDNA mutations was significantly higher than that of the tumors free of pathogenic mtDNA mutations (p=0.025).ConclusionOur findings indicate that these heteroplasmic pathogenic mtDNA somatic mutations may cause decreased respiratory chain activity and lead to the metabolism remodeling that seem to be beneficial for progression of both platinum-based chemotherapy resistance and relapse.

Inflammatory indexes as predictive factors for platinum sensitivity and as prognostic factors in recurrent epithelial ovarian cancer patients: a MITO24 retrospective study

Neutrophil-to-lymphocyte ratio (NLR) and systemic inflammatory index (SII) are prognostic factors in epithelial ovarian cancer (EOC). Their predictive value for platinum-sensitivity and their role in recurrent EOC are unknown. A total of 375 EOC patients were retrospectively analyzed. The correlation between baseline NLR and SII, and platinum-free interval (PFI) according to first line bevacizumab treatment were analyzed using logistic regression analyses adjusted for baseline patient characteristics. Subsequently NLR and SII calculated before second line treatment initiation were evaluated to identify a potential correlation with progression-free survival (PFS) and overall survival (OS) in platinum-sensitive and in platinum-resistant population. In multivariate analysis, NLR ≥ 3 is an independent predictive factor for PFI at 6 months in the chemotherapy group (OR = 2.77, 95% CI 1.38–5.56, p = 0.004), not in bevacizumab treated patients. After having adjusted for ECOG performance status, histology, ascites, bevacizumab treatment at second line and BRCA status, NLR ≥ 3 and SII ≥ 730 are significantly associated with worse OS in platinum-sensitive (HR = 2.69, 95% CI 1.60–4.53, p = 0.002; HR = 2.11, 95% CI 1.29–3.43, p = 0.003, respectively), not in platinum-resistant EOC patients. Low NLR is an independent predictive factor for platinum-sensitivity in patients treated without bevacizumab. NLR and SII are prognostic factors in recurrent platinum-sensitive EOC patients.

Systematic Investigation of DNA Methylation Associated with Platinum Chemotherapy Resistance Across 13 TCGA Cancer Types

Background: Platinum resistance has always been an annoying problem for oncology clinicians. The role of epigenetics and DNA methylation in platinum-based chemoresistance is getting increasingly attention of researchers. A systematic investigation on aberrant methylation patterns related to platinum-response across various cancer types is in urgent need. Methods: We analyzed the platinum-response related methylation patterns from different perspectives across 13 TCGA cancer types and integrated transcriptional and clinical data. Spearman test were used to evaluate the correlation between methylation and expression of genes. Cox analysis, Kaplan-Meier (KM) methods, and log-rang test were performed to identify potential risk differentially methylation positions (DMP) and compare survival by values of DMP. Support vector machines (SVM) and receiver operating characteristic curve (ROC) were used to identify platinum-response predictive DMP. Results: A total of 3703 differentially DMP were identified related to platinum-response varies with cancer types. 39·83% of DMP are hypermethylated and 60·17% are hypomethylated in platinum-resistant patients. Among them, 823 DMP were found to be associated with prognosis in tumor patients treated with platinum-based regimens and 733 DMP have potential to predict platinum chemotherapy response. Besides, we defined seven DNA DMP consisting of five gene members (C11orf70, MSLN, PRKAR2B, MSX1, and PARD6A) might have favorable prognostic and predictive values of platinum chemotherapy. Conclusion: Methylation-transcription axis exists and participates in the complex biological mechanism of platinum resistance in various cancers. Seven DMP and associated five genes have the potential to be promising clinical biomarkers for platinum-based chemotherapy. Funding Statement: This study was supported by grants from the National Natural Science Foundation of China (No. 81972773) and the Hunan Province Natural Sciences Foundation of China (No.2019JJ40395, 2019JJ40161), Scientific Research Project of Hunan Provincial Health Commission (No. 20200216), and the Undergraduate Training Program for Innovation and Entrepreneurship (No.201910533180). Declaration of Interests: The authors have declared that no competing interest exists.

A phase Ib study of navicixizumab and weekly paclitaxel in heavily pretreated platinum resistant ovarian, primary peritoneal or fallopian tube cancer

Objective: Anti-VEGF and anti-DLL4 have both demonstrated single-agent activity in ovarian cancer. Navicixizumab is an anti-DLL4/VEGF IgG2 bispecific monoclonal antibody that had a response rate of 25% (3/12) in heavily pretreated ovarian cancer patients in an earlier single-agent phase 1a trial. This is an ongoing phase 1b study designed to assess the safety and efficacy of paclitaxel and navicixizumab in platinum-resistant ovarian cancer patients who received at least 3 prior therapies and/or bevacizumab.

Targeting glutaminase 1 to sensitize platinum-resistant BRCAwt ovarian cancer to PARP inhibitors

Objective: In the past 5 years, there have been several FDA approvals for utilization of PARPi in ovarian cancer, although the usage is still limited to either patients with BRCA mutations or those with platinum-sensitive disease. However, 80% of patients with ovarian cancer do not have a BRCA mutation, and the vast majority will eventually become platinum-resistant. The objective of this study was to investigate whether the usage of poly(ADP-ribose) polymerase inhibitor (PARPi) could be expanded to BRCAwt platinum-resistant patients by using a synergistic combination approach that exploits metabolic vulnerability present in ovarian cancer.

Immunotherapy Breakthroughs in the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

Simple SummaryHead and neck squamous cell carcinoma (HNSCC), in the locally advanced setting, relapses in more than 50% of cases after surgery and/or chemo-radiotherapy. Prognosis is then very poor with platinum-based chemotherapy yielding a median survival of 10 months and a 2-year survival rate of less than 20%. In recent years, immunotherapy, has changed treatment and prognosis of several tumor types. Given their inflammatory profile and high mutational burden, HNSCC is a good candidate for immunotherapy. This review describes the major therapeutic breakthrough worked by Immune Checkpoint Inhibitors (ICIs) blocking the PD-1/PD-L1 axis. These monoclonal antibodies have doubled the 2-year survival rate thanks to long lasting responses with a favorable toxicity profile. Further progress is expected with new immunotherapeutic agents having a different mechanism of action combined with anti-PD(L)1, chemotherapy or targeted therapies.Head and neck squamous cell carcinoma (HNSCC) in the recurrent or metastatic (R/M) setting is a devastating disease with a poor prognosis. Until recently, the reference first line treatment was the EXTREME protocol, which yields a 10.1 months median survival, and almost no effective treatment are available in second line. Immune checkpoint inhibitors (ICIs) have changed the prognosis of several metastatic solid tumors. Given their inflammatory profile and high mutational burden, HNSCC is a good candidate for ICIs treatments. First, a strong pembrolizumab efficacy signal was shown in the Keynote-012 Phase Ib study. Then, the phase III Checkmate-141 study validated the efficacy of nivolumab in platinum-resistant patients. Finally, the first line conquest is acquired since the final results of the keynote-048 phase III study that demonstrated the superiority of pembrolizumab versus EXTREME in CPS ≥ 1 patients, and with the addition of platinum and 5FU in all patients. However, the first line treatment landscape is not frozen. Two studies (Checkmate-651 and Kestrel) are investigating the efficacy of the combination of antibodies raised against CTLA-4 and PD-(L)1. Results are impatiently awaited. Further progress needs the use of new immunotherapeutic agents such as monalizumab or ICOS agonist rather in combination with an anti-PD(L)1. New associations of ICIs and chemotherapeutic or targeted therapeutic agents are also actively investigated. Finally, ICIs has to be studied in the locally advanced setting where there is a chance of cure. Several trials are testing the potential synergistic combination of ICIs with radiotherapy and platinum or cetuximab, or ICIs used in a neoadjuvant setting.