Platinum-based Chemotherapy In Ovarian Cancer Research Articles

Comprehensive analysis for the immune related biomarkers of platinum-based chemotherapy in ovarian cancer

BackgroundOvarian cancer (OC) is one of the most lethal gynecological malignancies. This study aimed to identify biomarkers that were sensitive to platinum-based chemotherapeutic agents and can be used in immunotherapy and explore the importance of their mechanisms of action. MethodsRNA-seq profiles and clinicopathological data for OC samples were obtained from The Cancer Genome Atlas (TCGA) and cBioPortal platform, respectively. Platinum-sensitive and platinum-resistant OC samples in the TCGA cohort were selected based on the clinical information. RNA-seq data for 70 OC samples withSingle-sample gene set enrichment analysis (ssGSEA) and unsupervised clustering were used to classify OC patients from the TCGA cohort into clusters with different proportions of infiltrating immune cells. ESTIMATE analysis was used to assess the immune landscape among clusters. Differential expression, univariate Cox regression, and LASSO regression analyses were performed to construct prognostic model. Spearman correlation analysis was conducted to investigate the correlations among immune checkpoint inhibitors (ICIs) and risk score, half-maximal drug inhibitory concentration (IC50) and risk score. ResultsUsing ssGSEA and unsupervised clustering, OC samples were divided into two clusters with different immune cell infiltration. Then, 1715 differentially expressed immune-related genes (DEIRGs) were identified between two clusters, 984 differentially expressed platinum-sensitive related genes (DEPSRGs) between 149 platinum-sensitive and 63 platinum-resistant OC samples were identified, and 5384 differentially expressed genes (DEGs) between 380 OC and 194 normal samples were detected from the TCGA cohort. Six biomarkers (GMPPB, SRPK1, STC1, PRSS16, HPDL, and SPTSSB) were detected to establish a prognostic model. The OC patients in the TCGA cohort were classified into high- and low-risk groups. The receive operating characteristic (ROC) curve was plotted and demonstrated that the prognostic model performed well with the area under ROC curve (AUC) greater than 0.6. The expressions of 5 ICIs, including CD200, TNFRSF18, CD160, CD200R1, and CD274 (PD-L1), were significantly different between two risk groups, and the risk score was significant negative associated with CTLA4, TNFRSF4, TNFRSF18, and CD274. Moreover, there were significant differences in IC50 of 10 chemo drugs between two risk groups, patients in the high-risk group could be more resistant to po0tinib, dasatinib, and neratinib. ConclusionIn summary, this study constructed a novel prognostic model based on six prognostic biomarkers, including GMPPB, SRPK1, STC1, PRSS16, HPDL, and SPTSSB, which can be utilized for predicting the prognosis of OC patients. These biomarkers were the potential therapeutic targets.

Abstract 5957: Chemotherapy-induced extracellular matrix remodeling in HGSOC

Abstract In this study we explored the effects of chemotherapy on the extracellular matrix of high-grade serous ovarian cancer metastasis (HGSOC) at structural-textural protein level and transcriptionally, in order to identify the microenvironmental features that accompany a successful response. We studied two murine orthotopic, transplantable syngeneic models of HGSOC, one that displays excellent response to carboplatin/paclitaxel (60577) and one that is resistant to treatment (HGS2)1. Using immunohistochemistry, we stained omental tumors from both models for the ECM components fibronectin (FN1), collagen 1A1 (COL1A1) and versican (VCAN), also using Masson’s Trichrome to stain for collagen. We analyzed their abundance, textural features (Haralick features) and structure with the image analysis softwares, QuPath and TWOMBLI respectively. A compilation of 44 ECM metrics, which we named the “structure index”, correlated with response to chemotherapy, as measured by reduction in omental tumor weight. In parallel, we performed RNAseq on the omental tumors, identifying clusters of genes that change over time with chemotherapy treatment of the responsive model 60577, while the chemoresistant model HGS2 displayed limited alteration of gene expression. We integrated RNAseq and ECM structure and texture data, and showed the structure index was correlated with 144 core matrisome genes. To identify potential therapeutic targets, we then focused our study on genes that remained highly expressed in resistant tumors post chemotherapy, but were originally low or decreased with treatment in the sensitive tumors. Members of the LOX and P4HA family were found amongst these genes. We confirmed by immunohistochemical analysis that expression of LOX, LOXL2, P4HA1 and P4HA2 was downregulated by chemotherapy in the 60577 chemo-sensitive tumors while their levels remained relatively unaffected in the resistant HGS2 tumors. This study refines our understanding of the mechanisms of microenvironmental chemoresistance in HGSOC, highlighting putative therapeutic targets to increase the efficacy of platinum-based chemotherapy in ovarian cancer. 1 Maniati, E. et al. Mouse Ovarian Cancer Models Recapitulate the Human Tumor Microenvironment and Patient Response to Treatment. Cell Rep 30, 525-540.e527, doi:10.1016/j.celrep.2019.12.034 (2020). Citation Format: Panoraia Kotantaki, Florian Laforêts, Eleni Maniati, Chiara Berlato, Anna Malliouri, Michael John Devlin, Beatrice Malacrida, Samar Elorbany, Ranjit Manchanda, Frances R. Balkwill. Chemotherapy-induced extracellular matrix remodeling in HGSOC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5957.

Next-generation sequencing of homologous recombination genes could predict efficacy of platinum-based chemotherapy in non-small cell lung cancer.

With the widespread use of next-generation sequencing (NGS) in clinical practice, an increasing number of biomarkers that predict a response to anti-tumor therapy in non-small cell lung cancer (NSCLC) has been identified. However, validated biomarkers that can be used to detect a response to platinum-based chemotherapy remain unavailable. Several studies have suggested that homologous recombination deficiency (HRD) may occur in response to platinum-based chemotherapy in ovarian cancer and breast cancer. However, currently there is a lack of proven and reliable HRD markers that can be used to screen for patients who may benefit from platinum-based chemotherapy, especially in NSCLC. NGS was used to screen for gene mutations, including homologous recombination (HR) genes and common driver gene mutations in NSCLC. Cox regression analysis was performed to identify potential clinicopathological or gene mutation factors associated with survival in patients receiving platinum-based chemotherapy, while Kaplan-Meier analysis with the log-rank test was performed to assess the effect of HR gene mutations on progression-free survival (PFS). In a retrospective cohort of 129 patients with advanced NSCLC, 54 who received platinum-based chemotherapy with or without anti-angiogenic therapy were included in the analysis. Univariate and multivariate Cox proportional hazard regression analyses showed that HR gene mutations were associated with platinum-based chemotherapy sensitivity. Efficacy results indicated that the objective response rates (ORR) for patients with BRCA1/2 mutations and BRCA1/2 wild type were 75% and 30.4% (p=0.041), while the median PFS was 7.5 and 5.5 months (hazard ratio [HR], 0.52; 95% CI, 0.27-1.00; p=0.084), respectively. The ORRs of patients with HR gene mutations and HR gene wild type were 60% and 23.6% (p=0.01), and the median PFS was 7.5 and 5.2 months (HR, 0.56; 95% CI, 0.32-0.97; p=0.033), respectively. HR gene mutations show potential as promising biomarkers that may predict sensitivity to platinum-based chemotherapy in advanced and metastatic NSCLC.

COM33 suppresses carboplatin-induced epithelial-mesenchymal transition via inhibition of Twist1 in ovarian cancer.

Despite favorable responses to platinum-based chemotherapy in ovarian cancer (OC), chemoresistance is still a major cause of treatment failure. Hence, we develop a novel synthetic agent, COM33, to relieve the chemoresistance caused by carboplatin. The anti-cancerous effects of the combination of COM33 and carboplatin on OC are evaluated by cell viability, wound healing, and transwell invasion assays. A mechanistic investigation is carried out by using RNA-Seq analysis and then verified by western blot analysis and immunofluorescence microscopy. The safety and efficacy in vivo are evaluated using SKOV3 tumor-bearing nude mice. Results show that the co-administration of COM33 enhances the inhibitory effects of carboplatin on cancer cell viability, migration, and invasion in vitro and tumor growth in vivo. Furthermore, COM33 suppresses the carboplatin-induced epithelial-mesenchymal transition (EMT) by inhibiting the ERK signaling pathway. Additionally, we show that Twist1, the effector of the ERK signaling pathway, participates in carboplatin-induced EMT and is also inhibited by COM33. Our data show that the combination of carboplatin with COM33 is beneficial for chemotherapy against OC, which may be a potential novel anti-tumor strategy.

The efficacy and safety of platinum-based chemotherapy for ovarian cancer in pregnancy: A protocol for systematic review and meta-analysis.

Ovarian cancer during pregnancy is a rare event. Little is known about the treatment of this condition due to lack of high level evidence. Therefore, we performed a protocol for systematic review and meta-analysis to evaluate the efficacy and safety of platinum-based chemotherapy for the treatment of ovarian cancer during pregnancy. This systematic review has been registered in PROSPERO (CRD42022370709), which will be conducted in accordance with preferred reporting items for systematic review and meta-analysis protocols 2015 statement. We will search 7 electronic databases to identify relevant studies from inception to October, 2022, which includes PubMed, MEDLINE, Embase, Cochrane Clinical Trials Database, Web of Science, China National Knowledge Infrastructure, and Chinese Biomedical Literature Database. The Cochrane Handbook for systematic reviews of interventions will be performed to assess a broad category of biases in the included studies. The Grading of Recommendations Assessment, Development and Evaluation system will be used to judge the overall quality of evidence supporting outcomes in this work. Data are analyzed with the Review Manager Version 5.3 software. The results of this meta-analysis would be submitted to peer-reviewed journals for publication. This paper will provide high-quality synthesis to assess the efficacy and safety of platinum-based chemotherapy for ovarian cancer in pregnancy.

NCALD as a potential predictive biomarker for the efficacy of platinum-based chemotherapy in ovarian cancer.

Aim: Since reliable response predictors to platinum-based chemotherapy in ovarian cancer (OC) are scarce, we characterize NCALD as apredictive biomarker. Materials & methods: NCALD mRNA (n=100) and protein (n=102) expression was analyzed in OC samples and associated with patient outcome. A stable OC cell line knockdown was generated and cellular response to platinum was explored. Results: High NCALD mRNA and protein expression was significantly associated with longer overall patient survival (p=0.037/0.002). Knockdown experiments revealed a significant association between cisplatin sensitivity and NCALD expression. Conclusion: Low NCALD expression was associated with reduced sensitivity to platinum-based chemotherapy. NCALD may be a new biomarker candidate to identify patients who might benefit from platinum-based chemotherapy.

ATHENA–MONO (GOG-3020/ENGOT-ov45): A randomized, double-blind, phase 3 trial evaluating rucaparib monotherapy versus placebo as maintenance treatment following response to first-line platinum-based chemotherapy in ovarian cancer.

LBA5500 Background: While PARP inhibitors have shown efficacy as first-line (1L) maintenance treatment for patients (pts) with ovarian cancer (OC), questions remain about the pt population that may benefit from their use. ATHENA (NCT03522246) was designed to test if rucaparib may be effective as 1L maintenance treatment in a broad pt population, including those without BRCA mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. Here we report results from the ATHENA–MONO comparison of rucaparib vs placebo. Methods: Pts with stage III–IV high-grade OC who had completed cytoreductive surgery (R0 permitted) and 4–8 cycles of 1L platinum-doublet (bevacizumab allowed with chemotherapy) with a response were randomized 4:1 to oral rucaparib 600 mg BID or placebo. Pts were stratified by HRD status (as determined by FoundationOne CDx), residual disease status after chemotherapy, and timing of surgery. The primary endpoint of investigator-assessed PFS per RECIST was assessed in a step-down procedure first in the HRD population (BRCA mutant or BRCA wild-type/loss of heterozygosity [LOH] high carcinoma) and then in the intent-to-treat (ITT) population. Blinded independent central review (BICR)–assessed PFS was a stand-alone, secondary endpoint. PFS in BRCA mutant and HRD-negative pts (BRCA wild-type/LOH low) were exploratory endpoints. Results: As of Mar 23, 2022 (visit cutoff), 427 and 111 pts were randomized to rucaparib monotherapy or placebo (median time on treatment, 14.7 and 9.9 mo). PFS data are shown in the Table. Most common grade ≥3 TEAEs were anemia (rucaparib, 28.7% vs placebo, 0%), neutropenia (14.6% vs 0.9%), and ALT/AST increased (10.6% vs 0.9%). Rucaparib dose reduction, interruption, and discontinuation due to TEAEs occurred in 49.4%, 60.7%, and 11.8% of pts. Conclusions: Rucaparib monotherapy is effective as 1L maintenance with significant benefit vs placebo observed in the ITT and HRD populations, as well as the non-nested subgroup of pts without known HRD. Clinical trial information: NCT03522246. [Table: see text]

Evaluating patient-reported symptoms and late adverse effects following completion of first-line chemotherapy for ovarian cancer using the MOST (Measure of Ovarian Symptoms and Treatment concerns)

ObjectivesKnowledge on the course of symptoms patients with ovarian cancer experience is limited. We documented the prevalence and trajectories of symptoms after first-line chemotherapy using the Measure of Ovarian Symptoms and Treatment concerns (MOST). MethodsA total of 726 patients who received platinum-based chemotherapy for ovarian cancer were asked to complete the MOST every 3 months, beginning 6 months post-diagnosis and continuing for up to 4 years. We used descriptive statistics to examine temporal changes in MOST-S26 index scores for disease or treatment-related (MOST-DorT), neurotoxicity (MOST-NTx), abdominal (MOST-Abdo), and psychological (MOST-Psych) symptoms, and wellbeing (MOST-Wellbeing) and selected individual symptoms. We used group-based trajectory models to identify groups with persistently poor symptoms. ResultsThe median MOST-Abdo, MOST-DorT and MOST-Wellbeing score were worst at chemotherapy-end but improved and stabilised by 1, 3 and 12 months after treatment, respectively. The median MOST-NTx score peaked at 1 month after treatment before improving, while the median MOST-Psych score did not change substantially over time. Long-term moderate-to-severe fatigue (32%), trouble sleeping (31%), sore hands and feet (21%), pins and needles (20%) and anxiety (18%) were common. Trajectory models revealed groups of patients with persistent symptoms had MOST-DorT scores above 30 and MOST-NTx scores above 40 at treatment-end. ConclusionsAlthough many patients report improvements in symptoms by 3 months after first-line chemotherapy for ovarian cancer, patients who score > 30/100 on MOST-S26-DorT or > 40/100 on MOST-S26-NTx at the end of chemotherapy are likely to have persistent symptoms. The MOST could triage this at-risk subset for early intervention.

Prognostic Significance of SLFN11 Methylation in Plasma Cell-Free DNA in Advanced High-Grade Serous Ovarian Cancer.

Simple SummaryIn the present study, we examined the methylation status of six gene promoters (BRCA1, CST6, MGMT, RASSF10, SLFN11 and USP44) in high-grade serous ovarian cancer (HGSOC). We evaluated the prognostic significance of DNA methylation of these six gene promoters in primary tumors (FFPEs) and plasma cfDNA samples from patients with early, advanced and metastatic HGSOC. We report for the first time that the DNA methylation of SLFN11 in plasma cfDNA was significantly correlated with worse PFS (p = 0.045) in advanced stage HGSOC. Our results strongly indicate that SLFN11 epigenetic inactivation could serve as a potential prognostic DNA methylation biomarker and a predictor of resistance to platinum-based chemotherapy in ovarian cancer.Background: Epigenetic alterations in ctDNA are highly promising as a source of novel potential liquid biopsy biomarkers and comprise a very promising liquid biopsy approach in ovarian cancer, for early diagnosis, prognosis and response to treatment. Methods: In the present study, we examined the methylation status of six gene promoters (BRCA1, CST6, MGMT, RASSF10, SLFN11 and USP44) in high-grade serous ovarian cancer (HGSOC). We evaluated the prognostic significance of DNA methylation of these six gene promoters in primary tumors (FFPEs) and plasma cfDNA samples from patients with early, advanced and metastatic HGSOC. Results: We report for the first time that the DNA methylation of SLFN11 in plasma cfDNA was significantly correlated with worse PFS (p = 0.045) in advanced stage HGSOC. Conclusions: Our results strongly indicate that SLFN11 epigenetic inactivation could be a predictor of resistance to platinum drugs in ovarian cancer. Our results should be further validated in studies based on a larger cohort of patients, in order to further explore whether the DNA methylation of SLFN11 promoter could serve as a potential prognostic DNA methylation biomarker and a predictor of resistance to platinum-based chemotherapy in ovarian cancer.

Efficacy and Safety of Platinum-Based Chemotherapy for Ovarian Cancer During Pregnancy: A Systematic Review and Meta-Analysis.

IntroductionBased on the available data on ovarian cancer during pregnancy, we performed a review and meta-analysis to evaluate the efficacy and safety of platinum-based chemotherapy against ovarian cancer during pregnancy.MethodsWe systematically searched three databases including the PubMed, Embase, and Cochrane Library databases for articles published from January 1986 to December 2020 using the following terms: “ovarian tumors OR ovarian carcinoma OR adnexal masses OR ovarian cancer” AND “pregnancy” AND “chemotherapy.” Two authors (Yaping Pei and Yuanfeng Gou) independently searched the literature and extracted data from each eligible study. The outcome measures were overall survival (OS) and progression-free survival (PFS). The OS and PFS of all patients were estimated by Kaplan–Meier survival curves and log-rank tests.ResultsA total of 43 studies including 55 cases of ovarian cancer during pregnancy were selected. Forty-eight patients were comprehensively staged using the International Federation of Gynecology and Obstetrics (FIGO) staging system. Twenty-six of the 48 patients (54.17%) were diagnosed with early-stage disease, while the remaining had advanced stages (II, III, and IV). The mean age at diagnosis was 29.31 years. The majority of patients in this meta-analysis were diagnosed at a mean gestational age of 16.05 weeks. The mean GA at chemotherapy administration was 17.42 weeks. Overall, 55 women gave birth to 56 newborns, including a pair of twins. At the end of follow-up (median 10 months, range 0–73 months), all the children were healthy, except for one child who died 5 days after delivery due to a congenital abnormality. During 2–204 months of follow-up, there were five cases of recurrence, with no evidence of recurrence in the remaining cases. Unfortunately, one patient died 29 months after diagnosis. Neither median overall survival nor median progression-free survival was obtained.ConclusionPlatinum-based chemotherapy may be a good choice for pregnant women with ovarian cancer who want to continue their pregnancy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40487-021-00179-9.

ATHENA (GOG-3020/ENGOT-ov45): a randomized, phase III trial to evaluate rucaparib as monotherapy (ATHENA–MONO) and rucaparib in combination with nivolumab (ATHENA–COMBO) as maintenance treatment following frontline platinum-based chemotherapy in ovarian cancer

BackgroundThe optimal treatment strategy for women with newly diagnosed ovarian cancer has yet to be determined. Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated substantial improvement in progression-free survival as monotherapy maintenance...

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.

N-Glycome changes reflecting resistance to platinum-based chemotherapy in ovarian cancer

A number of studies have reported aberrant glycosylation in connection with malignancy. Our investigation further expands on this topic through the examination of N-glycans, which could be associated with the resistance of advanced stage, high-grade non-mucinous ovarian cancer to platinum/taxane based chemotherapy. We used tissue samples of 83 ovarian cancer patients, randomly divided into two independent cohorts (basic and validation). Both groups involved either cases with/without postoperative tumor residue or the cases determined either resistant or sensitive to this chemotherapy. In the validation cohort, preoperative serum samples were also available. N-glycans released from tumors and sera were permethylated and analyzed by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The MS analysis yielded a consecutive detection of 68 (tissue) and 63 (serum) N-glycan spectral signals. Eight of these were found to be differentially abundant in tissues of both independent cohorts including the cases with a postoperative cancer residue. One of these glycans was detected as differentially abundant in sera of the validation cohort. No statistically significant differences in intensities due to the same N-glycans were found in the cases without postoperative macroscopic residues in either the basic or validation cohort.From the biochemical point of view, the statistically significant N-glycans correspond to the structures carrying bisecting (terminal) GlcNAc residue and tetra-antennary structures with sialic acid and/or fucose residues. Among them, six tissue N-glycans could be considered potential markers connected with a resistance to chemotherapy in ovarian cancer patients. The prediction of primary resistance to standard chemotherapy may identify the group of patients suitable for alternative treatment strategies. SignificanceDrug resistance has become a major impediment to a successful treatment of patients with advanced ovarian cancer. The glycomic measurements related to cancer are becoming increasingly popular in identification of the key molecules as potential diagnostic and prognostic indicators. Our report deals with identification of differences in N-glycosylation of proteins in tissue and serum samples from the individuals showing sensitivity or resistance to platinum/taxane-based chemotherapy. The detection sensitivity to chemotherapy is vitally important for these patients.

Bcl‑2 family: Novel insight into individualized therapy for ovarian cancer (Review).

Chemoresistance to platinum-based chemotherapy for ovarian cancer in the advanced stage remains a formidable concern clinically. Increasing evidence has revealed that apoptosis represents the terminal events of the anti-tumor mechanisms of a number of chemical drugs and has a close association with chemoresistance in ovarian cancer. The B-cell lymphoma-2 (Bcl-2) family plays a crucial role in apoptosis and has a close association with chemoresistance in ovarian cancer. Some drugs that target Bcl-2 family members have shown efficacy in overcoming the chemoresistance of ovarian cancer. A BH3 profiling assay was found to be able to predict how primed a cell is when treated with antitumor drugs. The present review summarizes the role of the Bcl-2 family in mediating cell death in response to antitumor drugs and novel drugs that target Bcl-2 family members. The application of the new functional assay, BH3 profiling, is also discussed herein. Furthermore, the present review presents the hypothesis that targeting Bcl-2 family members may prove to be helpful for the individualized therapy of ovarian cancer in clinical practice and in laboratory research.

263TiP - ATHENA (GOG-3020/ENGOT-ov45): A randomised, double-blind, placebo-controlled phase III study of the poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib + the PD-1 inhibitor nivolumab following frontline platinum-based chemotherapy in ovarian cancer

BackgroundRucaparib has clinical activity in patients with recurrent ovarian cancer with or without homologous recombination deficiency (HRD; eg, a BRCA mutation or high genome-wide loss of heterozygosity) and is hypothesised to provide clinical benefit following frontline treatment. ATHENA (NCT03522246) is evaluating rucaparib + nivolumab as maintenance treatment following frontline platinum-based chemotherapy in patients with newly diagnosed, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The rationale for this combination includes the following: tumours with deleterious BRCA mutations or HRD express tumour-specific neoantigens, which attract PD-L1–expressing, tumour-infiltrating lymphocytes; rucaparib + anti-PD-1/PD-L1 demonstrated activity in a syngeneic ovarian cancer model; and PARP inhibitor–induced DNA damage may create a more antigenic tumour microenvironment regardless of HRD status. Trial designPatients are required to have completed cytoreductive surgery and achieved an investigator-assessed response to frontline, platinum-based doublet chemotherapy without disease progression or rising CA-125 during frontline treatment. Patients are randomised 4:4:1:1 to receive maintenance treatment in Arm A (oral rucaparib 600 mg twice daily + intravenous [IV] nivolumab 480 mg on day 1 of every 4-week cycle), Arm B (oral rucaparib + IV placebo), Arm C (oral placebo + IV nivolumab), or Arm D (oral placebo + IV placebo). Stratification factors include centrally determined tumour HRD status, posttreatment disease status, and timing of surgery. Investigator-assessed progression-free survival (RECIST v1.1; primary endpoint) will be compared among arms. Secondary endpoints include blinded independent central review of progression-free survival, overall survival, investigator-assessed objective response rate, duration of response, and safety. Enrolment is ongoing; patients (n≈1000) will be enrolled at > 270 sites worldwide. Clinical trial identificationNCT03522246. Legal entity responsible for the studyClovis Oncology, Inc. FundingClovis Oncology, Inc. DisclosureK. Fujiwara: Research grant / Funding (institution): Advanced Oncotherapy; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Chugai-Roche; Research grant / Funding (institution): Daiichi-Sankyo; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): ImmunoGen; Research grant / Funding (institution): Kaken-Seiyaku; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Shionogi; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Zeria Pharmaceutical. J-W. Kim: Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Janssen ; Research grant / Funding (institution): Genexine; Research grant / Funding (institution): GlaxoSmithKline ; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck Sharp & Dohme; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech ; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Tesaro. D.S. Tan: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Karyopharm; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech ; Advisory / Consultancy: Genmab; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Tessa Therapeutics. N. Katsumata: Honoraria (institution): AbbVie. K. Harano: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Takeda. S. Hume: Shareholder / Stockholder / Stock options, Full / Part-time employment: Clovis Oncology. E. Jones: Shareholder / Stockholder / Stock options, Full / Part-time employment: Clovis Oncology. S. Goble: Shareholder / Stockholder / Stock options, Full / Part-time employment: Clovis Oncology. L. Sullivan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Clovis Oncology. D. Shih: Shareholder / Stockholder / Stock options, Full / Part-time employment: Clovis Oncology. R.L. Coleman: Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy, Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Esperance; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Millennium; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): OncoMed; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy: Bayer; Advisory / Consultancy: GamaMabs; Advisory / Consultancy: Genmab; Advisory / Consultancy: Gradalis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Tesaro. I. McNeish: Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro. B. Monk: Advisory / Consultancy, Speaker Bureau / Expert testimony: Clovis Oncology ; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Janssen/Johnson & Johnson; Speaker Bureau / Expert testimony: Myriad; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche/Genentech; Advisory / Consultancy, Speaker Bureau / Expert testimony: Tesaro; Advisory / Consultancy: Amgen; Advisory / Consultancy: Vermillion; Advisory / Consultancy: Verastem; Advisory / Consultancy: Precision Oncology; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Perthera; Advisory / Consultancy: NuCana; Advisory / Consultancy: Merck; Advisory / Consultancy: Mateon (formally OXiGENE); Advisory / Consultancy: Insys; Advisory / Consultancy: ImmunoGen; Advisory / Consultancy: Gradalis; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy: Cerulean; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Bayer. R. Kristeleit: Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Roche; Advisory / Consultancy: Tesaro. All other authors have declared no conflicts of interest.

Abstract CT158: ATHENA (GOG-3020/ENGOT-ov45): a randomized, double-blind, placebo-controlled, Phase III study of rucaparib + nivolumab following front-line platinum-based chemotherapy in ovarian cancer

Abstract Background: The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib has demonstrated clinical activity in patients with ovarian cancer with or without homologous recombination (HR) deficiency (HRD; eg, a BRCA mutation or high genome-wide loss of heterozygosity [LOH high]). ATHENA (NCT03522246) is evaluating rucaparib + the anti-PD-1 antibody nivolumab as maintenance treatment following front-line platinum-based chemotherapy in patients with newly diagnosed, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The rationale for evaluating this combination includes the following: tumors with a deleterious BRCAmutation express novel, tumor-specific protein sequences (neoantigens), which can attract PD-L1-expressing, tumor-infiltrating lymphocytes; ovarian tumors with HRD have more neoantigens relative to HR-proficient tumors and may respond preferentially to immune checkpoint inhibitors; and rucaparib combined with anti-PD-1 or anti-PD-L1 demonstrated improved antitumor activity in a syngeneic ovarian cancer BrKras (BRCA1-/-; TP53-/-; MYC; KRAS-G12D; AKT) model. Furthermore, it is hypothesized that DNA damage induced by PARP inhibition may increase neoantigens regardless of HRD status. Methods: Eligible patients must have completed first-line platinum doublet chemotherapy and surgery. Patients had to have achieved an investigator-assessed response without disease progression or rising CA-125 at any time during first-line platinum doublet treatment. Cytoreductive surgery (R0 permitted) could have been completed either prior to chemotherapy (primary surgery) or following neoadjuvant chemotherapy (interval debulking). Patients will be randomized 4:4:1:1 to receive maintenance treatment in Arm A (oral rucaparib 600 mg BID + intravenous [IV] nivolumab 480 mg on day 1 of every 4-week cycle), Arm B (oral rucaparib + IV placebo), Arm C (oral placebo + IV nivolumab), or Arm D (oral placebo + IV placebo). Stratification factors include centrally determined tumor HRD status (BRCA mutant, non-BRCA mutant/LOH high, non-BRCA mutant/LOH low, or non-BRCA mutant/LOH indeterminate), posttreatment disease status (residual vs no residual disease), and timing of surgery (primary vs interval debulking). The primary endpoint of investigator-assessed progression-free survival (per RECIST version 1.1) will be evaluated in 3 independent comparisons between arms: A vs B, A vs D, and B vs D. Secondary endpoints include blinded independent central review of progression-free survival, overall survival, investigator-assessed objective response rate, investigator-assessed duration of response, and safety. Enrollment is ongoing; patients (n≈1000) will be enrolled at &amp;gt;270 sites worldwide. Citation Format: Shannon N. Westin, Rebecca S. Kristeleit, Robert L. Coleman, Keiichi Fujiwara, Amit M. Oza, David M. O’Malley, Thomas J. Herzog, Frederik Marmé, Ana Oaknin, Ramez Eskander, Domenica Lorusso, Tamar Safra, Jacob Korach, Kevin K. Lin, Danny Shih, Lisa Caunt, Sandra Goble, Stephanie Hume, Lara Maloney, Iain McNeish, Bradley J. Monk. ATHENA (GOG-3020/ENGOT-ov45): a randomized, double-blind, placebo-controlled, Phase III study of rucaparib + nivolumab following front-line platinum-based chemotherapy in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT158.

BRCA Mutation Status Is Not Associated With Increased Hematologic Toxicity Among Patients Undergoing Platinum-Based Chemotherapy for Ovarian Cancer.

Women with an inherited BRCA1 or BRCA2 mutation may have an impaired ability to repair chemotherapy-induced damage as a result of a state of haploinsufficiency and may experience greater treatment-related toxicity. The objective of this study was to compare the hematologic adverse effect profiles associated with platinum-based chemotherapy in ovarian cancer patients with and without germline BRCA mutations. We conducted a retrospective analysis of patients treated for high-grade serous ovarian cancer at Princess Margaret Cancer Center, Toronto, Ontario between January 2000 and December 2015. We included only women with known BRCA mutation status and who received first-line platinum-based chemotherapy. We compared 3 primary measures of myelosuppression (ie, hemoglobin levels, platelet counts, and neutrophil counts) before each cycle of chemotherapy in patients with and without a BRCA mutation. We included 130 BRCA mutation carriers and 302 noncarriers who met the eligibility criteria. There were no significant differences in baseline hemoglobin levels, neutrophil counts, or platelet counts between the groups (P ≥ 0.31). We found no significant difference in 3 measures of hematologic toxicity (ie, neutropenia, anemia, or thrombocytopenia) based on BRCA mutation status across all chemotherapy cycles (P ≥ 0.06). Although BRCA mutation carriers were more likely to experience an absolute neutrophil count below 1.0 × 10/L than noncarriers (P = 0.02), this did not translate to an increased frequency of dose reduction or dose delay. Among women with ovarian cancer, hematologic toxicity does not appear to be more frequent in BRCA mutation carriers than in noncarriers. This is reassuring for clinicians treating ovarian cancer patients with respect to dosing regimens. These findings do not support the hypothesis that a haploinsufficiency phenotype exists with respect to the repair of chemotherapy-induced double-strand DNA breaks in this high-risk population.

Recovery of miR-139-5p in Ovarian Cancer Reverses Cisplatin Resistance by Targeting C-Jun

Background/Aims: In platinum-based chemotherapy for ovarian cancer, acquired drug resistance is a frequent occurrence. Because recent studies have demonstrated that dysregulation of microRNAs (miRNAs) is partly responsible for the induction of acquired drug resistance in cancers, we hypothesized that correcting the dysregulation of key miRNAs would reverse the acquired resistance to platinum-based drugs in ovarian cancer. Methods: Cisplatin-resistant SKOV3 and A2780 ovarian cancer cell lines (SKOV3-R and A2780-R, respectively) were established by long-term exposure to cisplatin. MTT assays were performed to evaluate the viability of SKOV3, SKOV3-R, A2780, and A2780-R cells. Quantitative PCR was used to examine the expression of miR-139-5p in these cell lines. The regulatory mechanism was confirmed by western blot analysis and luciferase reporter assays. After treatment with miR-139-5p and cisplatin, mitochondrial membrane potential and apoptosis were measured by using flow cytometry. Interaction with c-Jun and activating transcription factor 2 (ATF2) was evaluated by co-immunoprecipitation. Expression of B-cell lymphoma-extra large (Bcl-xl) and activation of caspase-9 and caspase-3 were detected by western blotting. Results: Expression of miR-139-5p was decreased in SKOV3-R and A2780-R cells. Recovery of miR-139-5p increased the sensitivity of SKOV3-R and A2780-R cells to cisplatin treatment, inhibited the interaction of c-Jun and ATF2, and decreased Bcl-xl expression in SKOV3-R and A2780-R cells. Expression of miR-139-5p promoted cisplatin-induced mitochondrial apoptosis through binding the 3′ untranslated region of c-Jun mRNA. Conclusion: Recovery of miR-139-5p suppressed the expression of c-Jun and thus reversed cisplatin-resistance in ovarian cancer.

High RBM3 expression is associated with an improved survival and oxaliplatin response in patients with metastatic colorectal cancer.

BackgroundHigh expression of the RNA-binding motif protein 3 (RBM3) has been shown to correlate, with prolonged survival in several malignant diseases and with the benefit of platinum-based chemotherapy in ovarian cancer. The aim of this study was to evaluate RBM3 in metastatic colorectal cancer (mCRC) as a prognostic factor for overall survival and in relation to benefit of first-line chemotherapy.MethodsImmunohistochemical staining was conducted and evaluated in tumours from 455 mCRC patients. Kaplan-Meier analysis and Cox regression proportional hazards models were used to access the impact of RBM3 expression on overall survival (OS) and progression-free survival (PFS).ResultsHigh RBM3 expression, both nuclear and cytoplasmic, was an independent prognostic factor for prolonged OS (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.50–0.90 and HR 0.66, 95% CI 0.48–0.91, respectively). PFS was significantly longer in patients with high RBM3 expression who had received first-line oxaliplatin based treatment, compared to those who had received irinotecan based treatment, both regarding nuclear and cytoplasmic expression (p-value 0.020 and 0.022 respectively).ConclusionHigh RBM3 expression is an independent predictor of prolonged survival in mCRC patients, in particular in patients treated with first-line oxaliplatin based chemotherapy.

A phase 2 study to assess olaparib by homologous recombination deficiency status in patients with platinum-sensitive, relapsed, ovarian, fallopian tube, or primary peritoneal cancer.

TPS5606 Background: The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is approved for treatment of patients (pts) with germline BRCA mutations ( BRCAm) and advanced ovarian cancer (OC). BRCA mutations are genetic alterations leading to homologous recombination deficiency (HRD) and tumor susceptibility to DNA-damaging agents, including PARP inhibitors. Loss of genetic heterozygosity, telomeric-allelic imbalance, or large-scale state transitions may identify additional pts who could benefit from PARP inhibitor therapy. Methods: LIGHT is a non-randomized, open-label, phase 2 study to assess the efficacy and safety of olaparib in patient cohorts identified by different HRD genetic tests (NCT02983799). Patients will have platinum-sensitive (progression &gt; 6 mo after the end of the last platinum-based chemotherapy), relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer; ECOG performance status 0–1; and ≥2 prior lines of platinum-based chemotherapy for OC. Key exclusion criteria include prior PARP inhibitor treatment; concomitant use of potent CYP3A4/5 inhibitors or inducers; and symptomatic uncontrolled brain metastases. Patients will be enrolled into 4 cohorts of 30 pts each based upon BRCAm or tumor HRD status determined by genetic test results: germline BRCAm; somatic BRCAm; MyChoice HRD-positive and wildtype BRCAm; MyChoice HRD-negative and wildtype BRCAm. All pts will receive 300 mg olaparib tablets twice daily until disease progression (RECIST v1.1) or unacceptable toxicity. The primary endpoint is investigator-assessed objective response rate (ORR) according to RECIST v1.1 criteria. The maximum precision of the ORR is approximately ±18.7% for 30 pts. Secondary endpoints include duration of response, cancer antigen-125 response rate, disease control rate, progression-free survival, time to any progression, overall survival, and homologous recombination repair gene panel mutation status related to clinical outcome. Planned enrollment of 120 pts at sites in the United States was initiated in December 2016. Clinical trial information: NCT02983799.