Learning Objectives
After completing this course, the reader will be able to:
Explain the role of the androgen axis in the development of ovarian cancer.
Discuss the potential compounds with ...anti‐androgen activity that can be assessed for the treatment of patients with ovarian cancer.
This article is available for continuing medical education credit at CME.TheOncologist.com
Androgen receptors are frequently expressed in epithelial ovarian cancer (EOC). Their role in the development of EOC is not fully understood. In the present review we first discuss the epidemiological data linking a hyperandrogen state to a higher risk for ovarian cancer, second describe in vitro studies of the role of androgens in influencing the growth of EOC, and finally review the completed clinical trials with compounds that exploit the androgen axis in patients with ovarian cancer. The therapeutic approaches that inhibit androgen signaling have so far produced only modest response rates. In the light of new data regarding the role of androgen stimulation in the evolution of EOC and the emergence of new compounds used for the treatment of other hormone‐driven malignancies, such as prostate and breast cancer, we provide suggestions for new studies of antiandrogen therapeutics in the treatment of EOC. A specific example is the new agent abiraterone. In addition, we propose a panel of molecules that could be assessed as potential biomarkers that may aid patient selection for this approach in the future.
摘要
雄激素受体常表达于上皮性卵巢癌（EOC），但其在EOC发展中的作用尚未完全阐明。本综述首先讨论雄激素亢进状态和卵巢癌高风险相联系的流行病学资料，其次描述雄激素影响EOC生长的体外研究，最后回顾作用于卵巢癌患者雄激素轴的化合物的已完成临床试验。迄今为止，雄激素抑制疗法仅获得中等缓解率。根据雄激素刺激在EOC演进中的相关新资料以及其他激素驱动性恶性肿瘤（例如前列腺癌和乳腺癌）治疗所用新型化合物，本文提议进行新的抗雄激素治疗EOC研究。新药阿比特龙即为其中一个特例。此外，本文提出一组可作为评估标准的分子生物标志，有助于未来该疗法患者的选择。
The epidemiological data linking a hyperandrogen state to a higher risk for ovarian cancer are reviewed, in vitro studies of the role of androgens in influencing the growth of epithelial ovarian cancer are described, and completed clinical trials with compounds that exploit the androgen axis in patients with ovarian cancer are reviewed.
BackgroundData suggest that immunomodulation induced by DNA hypomethylating agents can sensitize tumors to immune checkpoint inhibitors. We conducted a phase 1 dose-escalation trial (NCT02998567) of ...guadecitabine and pembrolizumab in patients with advanced solid tumors. We hypothesized that guadecitabine will overcome pembrolizumab resistance.MethodsPatients received guadecitabine (45 mg/m2 or 30 mg/m2, administered subcutaneously on days 1–4), with pembrolizumab (200 mg administered intravenously starting from cycle 2 onwards) every 3 weeks. Primary endpoints were safety, tolerability and maximum tolerated dose; secondary and exploratory endpoints included objective response rate (ORR), changes in methylome, transcriptome, immune contextures in pre-treatment and on-treatment tumor biopsies.ResultsBetween January 2017 and January 2020, 34 patients were enrolled. The recommended phase II dose was guadecitabine 30 mg/m2, days 1–4, and pembrolizumab 200 mg on day 1 every 3 weeks. Two dose-limiting toxicities (neutropenia, febrile neutropenia) were reported at guadecitabine 45 mg/m2 with none reported at guadecitabine 30 mg/m2. The most common treatment-related adverse events (TRAEs) were neutropenia (58.8%), fatigue (17.6%), febrile neutropenia (11.8%) and nausea (11.8%). Common, grade 3+ TRAEs were neutropaenia (38.2%) and febrile neutropaenia (11.8%). There were no treatment-related deaths. Overall, 30 patients were evaluable for antitumor activity; ORR was 7% with 37% achieving disease control (progression-free survival) for ≥24 weeks. Of 12 evaluable patients with non-small cell lung cancer, 10 had been previously treated with immune checkpoint inhibitors with 5 (42%) having disease control ≥24 weeks (clinical benefit). Reduction in LINE-1 DNA methylation following treatment in blood (peripheral blood mononuclear cells) and tissue samples was demonstrated and methylation at transcriptional start site and 5’ untranslated region gene regions showed enriched negative correlation with gene expression. Increases in intra-tumoural effector T-cells were seen in some responding patients. Patients having clinical benefit had high baseline inflammatory signature on RNAseq analyses.ConclusionsGuadecitabine in combination with pembrolizumab is tolerable with biological and anticancer activity. Reversal of previous resistance to immune checkpoint inhibitors is demonstrated.
Remarkable progress in molecular analyses has improved our understanding of the evolution of cancer cells toward immune escape
. However, the spatial configurations of immune and stromal cells, which ...may shed light on the evolution of immune escape across tumor geographical locations, remain unaddressed. We integrated multiregion exome and RNA-sequencing (RNA-seq) data with spatial histology mapped by deep learning in 100 patients with non-small cell lung cancer from the TRACERx cohort
. Cancer subclones derived from immune cold regions were more closely related in mutation space, diversifying more recently than subclones from immune hot regions. In TRACERx and in an independent multisample cohort of 970 patients with lung adenocarcinoma, tumors with more than one immune cold region had a higher risk of relapse, independently of tumor size, stage and number of samples per patient. In lung adenocarcinoma, but not lung squamous cell carcinoma, geometrical irregularity and complexity of the cancer-stromal cell interface significantly increased in tumor regions without disruption of antigen presentation. Decreased lymphocyte accumulation in adjacent stroma was observed in tumors with low clonal neoantigen burden. Collectively, immune geospatial variability elucidates tumor ecological constraints that may shape the emergence of immune-evading subclones and aggressive clinical phenotypes.
TPS8600
Background: Malignant mesothelioma is a universally lethal cancer that has been increasing over the last three decades. No treatment has been licenced for patients with relapsed mesothelioma ...after receipt of licenced systemic anti-cancer therapy in the UK. A previous single-arm phase IIa trial (MiST1) evaluated the efficacy of Poly (ADP-ribose) polymerase (PARP) inhibition in mesothelioma, which met its primary endpoint with 15% of patients having durable responses exceeding 1 year. Therefore, there is a need to evaluate PARP inhibitors in a randomised trial in relapsed mesothelioma patients. NERO is currently in progress in this setting. Methods: Co-ordinated by the CRUK Southampton Clinical Trials Unit, NERO is a multicentre, two arm, open-label UK randomised phase II trial comparing niraparib + Active Symptom Control (ASC) versus ASC alone in mesothelioma patients who have relapsed after previously receiving platinum-based systemic therapy. NERO is not restricted by line of therapy and treatment allocation ratio is 2:1 (niraparib + ASC:ASC), stratified by histology and response to prior platinum-based therapy. Participants will receive either niraparib + ASC or ASC alone for a period of 24 weeks. Participants will be treated until disease progression, withdrawal, death or development of significant treatment limiting toxicity. Participants randomised to niraparib will receive 200/300 mg every day in a 21-day cycle. The primary endpoint is progression-free survival, where progression is determined by modified RECIST or RECIST 1.1; investigator reported progression; or death from any cause, whichever comes first. Time to event data will be analysed and presented using Kaplan-Meier curves according to the intention to treat principle, with treatment-related intercurrent events handled using the treatment strategy policy, and study withdrawal following the “while on study” strategy. A Cox proportional hazards model will be used to calculate the Hazard Ratio, 95% CIs and p-value adjusted for stratification factors. Median PFS and 6 and 12 month PFS will also be reported. Secondary endpoints include overall survival, best overall response, 12 and 24 week disease control, duration of response, treatment compliance and safety/tolerability. Patients consent to provide mandatory diagnostic tissue blocks, blood samples and an optional stool sample for translational research. These will be used to interrogate homologous recombination deficiency and its association with response in NERO, translational research comprising multi-omic analysis with multiplex immune landscape phenotyping will be analysed and correlated with clinical outcome using machine learning. NERO opened in July 2022 and will be run in approximately 10 UK secondary care hospitals with the aim of recruiting 84 evaluable patients (recruitment is currently 24 on 11-Jan-2023). Clinical trial information: NCT05455424 .
AT13148 is an oral AGC kinase inhibitor, which potently inhibits ROCK and AKT kinases. In preclinical models, AT13148 has been shown to have antimetastatic and antiproliferative activity.
The trial ...followed a rolling six design during dose escalation. An intrapatient dose escalation arm to evaluate tolerability and a biopsy cohort to study pharmacodynamic effects were later added. AT13148 was administered orally three days a week (Mon-Wed-Fri) in 28-day cycles. Pharmacokinetic profiles were assessed using mass spectrometry and pharmacodynamic studies included quantifying p-GSK3β levels in platelet-rich plasma (PRP) and p-cofilin and p-MLC2 levels in tumor biopsies.
Fifty-one patients were treated on study. The safety of 5-300 mg of AT13148 was studied. Further, the doses of 120-180-240 mg were studied in an intrapatient dose escalation cohort. The dose-limiting toxicities included hypotension (300 mg), pneumonitis, and elevated liver enzymes (240 mg), and skin rash (180 mg). The most common side effects were fatigue, nausea, headaches, and hypotension. On the basis of tolerability, 180 mg was considered the maximally tolerated dose. At 180 mg, mean
and AUC were 400 nmol/L and 13,000 nmol/L/hour, respectively. At 180 mg, ≥50% reduction of p-cofilin was observed in 3 of 8 posttreatment biopsies.
AT13148 was the first dual potent ROCK-AKT inhibitor to be investigated for the treatment of solid tumors. The narrow therapeutic index and the pharmacokinetic profile led to recommend not developing this compound further. There are significant lessons learned in designing and testing agents that simultaneously inhibit multiple kinases including AGC kinases in cancer.
Purpose
Metastatic breast cancer (mBC) patients with
DPYD
genetic variants linked to loss of dihydropyrimidine dehydrogenase (DPD) activity are at risk of severe capecitabine-associated toxicities. ...However, prospective
DPYD
genotyping has not yet been implemented in routine clinical practice. Following a previous internal review in which two patients underwent lengthy hospitalisations whilst receiving capecitabine, and were subsequently found to be DPD deficient, we initiated routine
DPYD
genotyping prior to starting capecitabine. This study evaluates the clinical application of routine
DPYD
screening at a large cancer centre in London.
Methods
We reviewed medical records for consecutive patients with mBC who underwent DPYD genotyping before commencing capecitabine between December 2014 and December 2017. Patients were tested for four
DPYD
variants associated with reduced DPD activity.
Results
Sixty-six patients underwent
DPYD
testing. Five (8.4%) patients were found to carry
DPYD
genetic polymorphisms associated with reduced DPD activity; of these, two received dose-reduced capecitabine. Of the 61 patients with
DPYD
wild-type, 14 (23%) experienced grade 3 toxicities which involved palmar–plantar erythrodysesthesia (65%), and gastrointestinal toxicities (35%); no patient was hospitalised due to toxicity.
Conclusions
Prospective
DPYD
genotyping can be successfully implemented in routine clinical practice and can reduce the risk of severe fluoropyrimidine toxicities.
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