Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the standard of care for some patients with advanced ovarian cancer. We evaluated the efficacy and safety of PARP inhibitor rechallenge. PATIENTS AND METHODS: This randomized, double-blind, multicenter trial (NCT03106987) enrolled patients with platinum-sensitive relapsed ovarian cancer who had received one prior PARP inhibitor therapy for ≥18 and ≥12 months in the BRCA-mutated and non-BRCA-mutated cohorts, respectively, following first-line chemotherapy or for ≥12 and ≥6 months, respectively, following a second or subsequent line of chemotherapy. Patients were in response following their last platinum-based chemotherapy regimen and were randomized 2 : 1 to maintenance olaparib tablets 300 mg twice daily or placebo. Investigator-assessed progression-free survival (PFS) was the primary endpoint. RESULTS: Seventy four patients in the BRCA-mutated cohort were randomized to olaparib and 38 to placebo, and 72 patients in the non-BRCA-mutated cohort were randomized to olaparib and 36 to placebo; >85% of patients in both cohorts had received ≥3 prior lines of chemotherapy. In the BRCA-mutated cohort, the median PFS was 4.3 months with olaparib versus 2.8 months with placebo [hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.37-0.87; P = 0.022]; 1-year PFS rates were 19% versus 0% (Kaplan-Meier estimates). In the non-BRCA-mutated cohort, median PFS was 5.3 months for olaparib versus 2.8 months for placebo (HR 0.43; 95% CI 0.26-0.71; P = 0.0023); 1-year PFS rates were 14% versus 0% (Kaplan-Meier estimates). No new safety signals were identified with olaparib rechallenge. CONCLUSIONS: In ovarian cancer patients previously treated with one prior PARP inhibitor and at least two lines of platinum-based chemotherapy, maintenance olaparib rechallenge provided a statistically significant, albeit modest, PFS improvement over placebo in both the BRCA-mutated and non-BRCA-mutated cohorts, with a proportion of patients in the maintenance olaparib rechallenge arm of both cohorts remaining progression free at 1 year.

Microfluidic technologies for immunotherapy studies on solid tumours.

Immunotherapy is a powerful and targeted cancer treatment that exploits the body's immune system to attack and eliminate cancerous cells. This form of therapy presents the possibility of long-term control and prevention of recurrence due to the memory capabilities of the immune system. Various immunotherapies are successful in treating haematological malignancies and have dramatically improved outcomes in melanoma. However, tackling other solid tumours is more challenging, mostly because of the immunosuppressive tumour microenvironment (TME). Current in vitro models based on traditional 2D cell monolayers and animal models, such as patient-derived xenografts, have limitations in their ability to mimic the complexity of the human TME. As a result, they have inadequate translational value and can be poorly predictive of clinical outcome. Thus, there is a need for robust in vitro preclinical tools that more faithfully recapitulate human solid tumours to test novel immunotherapies. Microfluidics and lab-on-a-chip technologies offer opportunities, especially when performing mechanistic studies, to understand the role of the TME in immunotherapy, and to expand the experimental throughput when using patient-derived tissue through its miniaturization capabilities. This review first introduces the basic concepts of immunotherapy, presents the current preclinical approaches used in immuno-oncology for solid tumours and then discusses the underlying challenges. We provide a rationale for using microfluidic-based approaches, highlighting the most recent microfluidic technologies and methodologies that have been used for studying cancer-immune cell interactions and testing the efficacy of immunotherapies in solid tumours. Ultimately, we discuss achievements and limitations of the technology, commenting on potential directions for incorporating microfluidic technologies in future immunotherapy studies.

OVPSYCH2: A randomized controlled trial of psychological support versus standard of care following chemotherapy for ovarian cancer.

BACKGROUND: Fear of disease progression (FOP) is a rational concern for women with Ovarian Cancer (OC) and depression is also common. To date there have been no randomized trials assessing the impact of psychological intervention on depression and FOP in this patient group. PATIENTS AND METHODS: Patients with primary or recurrent OC who had recently completed chemotherapy were eligible if they scored between 5 and 19 on the PHQ-9 depression and were randomized 1:1 to Intervention (3 standardized CBT-based sessions in the 6-12 weeks post-chemotherapy) or Control (standard of care). PHQ-9, FOP-Q-SF, EORTC QLQ C30 and OV28 questionnaires were then completed every 3 months for up to 2 years. The primary endpoint was change in PHQ-9 at 3 months. Secondary endpoints were change in other scores at 3 months and all scores at later timepoints. RESULTS: 182 patients registered; 107 were randomized; 54 to Intervention and 53 to Control; mean age 59 years; 75 (70%) had completed chemotherapy for primary and 32 (30%) for relapsed OC and 67 patients completed both baseline and 3-month questionnaires. Improvement in PHQ-9 was observed for patients in both study arms at three months compared to baseline but there was no significant difference in change between Intervention and Control. A significant improvement on FOP-Q-SF scores was seen in the Intervention arm, whereas for those in the Control arm FOP-Q-SF scores deteriorated at 3 months (intervention effect = -4.4 (-7.57, -1.22), p-value = 0.008). CONCLUSIONS: CBT-based psychological support provided after chemotherapy did not significantly alter the spontaneously improving trajectory of depression scores at three months but caused a significant improvement in FOP. Our findings call for the routine implementation of FOP support for ovarian cancer patients.

A phase II randomised, placebo-controlled trial of low dose (metronomic) cyclophosphamide and nintedanib (BIBF1120) in advanced ovarian, fallopian tube or primary peritoneal cancer.

BACKGROUND: We investigated the safety and efficacy of a combination of the oral tyrosine kinase inhibitor, nintedanib (BIBF 1120) with oral cyclophosphamide in patients with relapsed ovarian cancer. PATIENTS AND METHODS: Patients with relapsed ovarian, fallopian tube or primary peritoneal cancer received oral cyclophosphamide (100 mg o.d.) and were randomised (1,1) to also have either oral nintedanib or placebo. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), response rate, toxicity, and quality of life. RESULTS: 117 patients were randomised, 3 did not start trial treatment, median age 64 years. Forty-five (39%) had received ≥5 lines chemotherapy. 30% had received prior bevacizumab. The median OS was 6.8 (nintedanib) versus 6.4 (placebo) months (hazard ratio 1.08; 95% confidence interval 0.72-1.62; P = 0.72). The 6-month PFS rate was 29.6% versus 22.8% (P = 0.57). Grade 3/4 adverse events occurred in 64% (nintedanib) versus 54% (placebo) of patients (P = 0.28); the most frequent G3/4 toxicities were lymphopenia (18.6% nintedanib versus 16.4% placebo), diarrhoea (13.6% versus 0%), neutropenia (11.9% versus 0%), fatigue (10.2% versus 9.1%), and vomiting (10.2% versus 7.3%). Patients who had received prior bevacizumab treatment had 52 days less time on treatment (P < 0.01). 26 patients (23%) took oral cyclophosphamide for ≥6 months. There were no differences in quality of life between treatment arms. CONCLUSIONS: This is the largest reported cohort of patients with relapsed ovarian cancer treated with oral cyclophosphamide. Nintedanib did not improve outcomes when added to oral cyclophosphamide. Although not significant, more patients than expected remained on treatment for ≥6 months. This may reflect a higher proportion of patients with more indolent disease or the higher dose of cyclophosphamide used. CLINICAL TRIAL REGISTRATION: Clinicaltrials.govNCT01610869.

Correction: Safety and utility of image-guided research biopsies in relapsed high-grade serous ovarian carcinoma-experience of the BriTROC consortium.

This article was originally published under a CC BY NC SA License, but has now been made available under a CC BY 4.0 License.

Routine germline BRCA1 and BRCA2 testing in patients with ovarian carcinoma: analysis of the Scottish real-life experience.

OBJECTIVE: To determine the rates of germline BRCA1 and BRCA2 mutations in Scottish patients with ovarian cancer, before and after a change in testing policy. DESIGN: Retrospective cohort study. SETTING: Four cancer/genetics centres in Scotland. POPULATION: Patients with ovarian cancer undergoing germline BRCA1 and BRCA2 (gBRCA1/2) sequencing before 2013 (under the 'old criteria', with selection based solely on family history), after 2013 (under the 'new criteria', with sequencing offered to newly presenting patients with non-mucinous ovarian cancer), and in the 'prevalent population' (who presented before 2013, but were not eligible for sequencing under the old criteria but were sequenced under the new criteria). METHODS: Clinicopathological and sequence data were collected before and for 18 months after this change in selection criteria. MAIN OUTCOME MEASURES: Frequency of germline BRCA1, BRCA2, RAD51C, and RAD51D mutations. RESULTS: Of 599 patients sequenced, 205, 236, and 158 were in the 'old criteria', 'new criteria', and 'prevalent' populations, respectively. The frequency of gBRCA1/2 mutations was 30.7, 13.1, and 12.7%, respectively. The annual rate of gBRCA1/2 mutation detection was 4.2 before and 20.7 after the policy change. A total of 48% (15/31) 'new criteria' patients with gBRCA1/2 mutations had a Manchester score of <15 and would not have been offered sequencing based on family history criteria. In addition, 20 patients with gBRCA1/2 were identified in the prevalent population. The prevalence of gBRCA1/2 mutations in patients aged >70 years was 8.2%. CONCLUSIONS: Sequencing all patients with non-mucinous ovarian cancer gives a much higher annual gBRCA1/2 mutation detection rate, with the frequency of positive tests still exceeding the 10% threshold upon which many family history-based models operate. TWEETABLE ABSTRACT: BRCA sequencing all non-mucinous cancer patients increases mutation detection five fold.

Safety and utility of image-guided research biopsies in relapsed high-grade serous ovarian carcinoma-experience of the BriTROC consortium.

BACKGROUND: Investigating tumour evolution and acquired chemotherapy resistance requires analysis of sequential tumour material. We describe the feasibility of obtaining research biopsies in women with relapsed ovarian high-grade serous carcinoma (HGSC). METHODS: Women with relapsed ovarian HGSC underwent either image-guided biopsy or intra-operative biopsy during secondary debulking, and samples were fixed in methanol-based fixative. Tagged-amplicon sequencing was performed on biopsy DNA. RESULTS: We screened 519 patients in order to enrol 220. Two hundred and two patients underwent successful biopsy, 118 of which were image-guided. There were 22 study-related adverse events (AE) in the image-guided biopsies, all grades 1 and 2; pain was the commonest AE. There were pre-specified significant AE in 3/118 biopsies (2.5%). 87% biopsies were fit-for-purpose for genomic analyses. Median DNA yield was 2.87 µg, and was higher in biopsies utilising 14 G or 16 G needles compared to 18 G. TP53 mutations were identified in 94.4% patients. CONCLUSIONS: Obtaining tumour biopsies for research in relapsed HGSC is safe and feasible. Adverse events are rare. The large majority of biopsies yield sufficient DNA for genomic analyses-we recommend use of larger gauge needles and methanol fixation for such biopsies, as DNA yields are higher but with no increase in AEs.

Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG): clinical trial design for rare ovarian tumours.

This manuscript reports the consensus statements on designing clinical trials in rare ovarian tumours reached at the fifth Ovarian Cancer Consensus Conference (OCCC) held in Tokyo, November 2015. Three important questions were identified concerning rare ovarian tumours (rare epithelial ovarian cancers (eOC), sex-cord stromal tumours (SCST) and germ cell tumours (GCT)): (i) What are the research and trial issues that are unique to rare ovarian tumours? There is a lack of randomised phase III data defining standards of care which makes it difficult to define control arms, but identifies unmet needs that merit investigation. Internationally agreed upon diagnostic criteria, expert pathological review and translational research are crucial. (ii) What should be investigated in rare eOC, GCT and SCST? Trials dedicated to each rare ovarian tumour should be encouraged. Nonetheless, where the question is relevant, rare eOC can be included in eOC trials but with rigorous stratification. Although there is emerging evidence suggesting that rare eOC have different molecular profiles, trials are needed to define new type-specific standards for each rare eOC (clear cell, low grade serous and mucinous). For GCTs, a priority is reducing toxicities from treatment while maintaining cure rates. Both a robust prognostic scoring system and more effective treatments for de novo poor prognosis and relapsed GCTs are needed. For SCSTs, validated prognostic markers as well as alternatives to the current standard of bleomycin/etoposide/cisplatin (BEP) should be identified. (iii) Are randomised trials feasible? Randomised controlled trials (RCT) should be feasible in any of the rare tumours through international collaboration. Ongoing trials have already demonstrated the feasibility of RCT in rare eOC and SCST. Mucinous OC may be considered for inclusion, stratified, into RCTs of non-gynaecological mucinous tumours, while RCTs in high risk or relapsed GCT may be carried out as a subset of male and/or paediatric germ cell studies.

A randomised, phase II trial of the DNA-hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in combination with carboplatin vs carboplatin alone in patients with recurrent, partially platinum-sensitive ovarian cancer.

BACKGROUND: Our previous laboratory and clinical data suggested that one mechanism underlying the development of platinum resistance in ovarian cancer is the acquisition of DNA methylation. We therefore tested the hypothesis that the DNA hypomethylating agent 5-aza-2'-deoxycytodine (decitabine) can reverse resistance to carboplatin in women with relapsed ovarian cancer. METHODS: Patients progressing 6-12 months after previous platinum therapy were randomised to decitabine on day 1 and carboplatin (AUC 6) on day 8, every 28 days or carboplatin alone. The primary objective was response rate in patients with methylated hMLH1 tumour DNA in plasma. RESULTS: After a pre-defined interim analysis, the study closed due to lack of efficacy and poor treatment deliverability in 15 patients treated with the combination. Responses by GCIG criteria were 9 out of 14 vs 3 out of 15 and by RECIST were 6 out of 13 vs 1 out of 12 for carboplatin and carboplatin/decitabine, respectively. Grade 3/4 neutropenia was more common with the combination (60% vs 15.4%) as was G2/3 carboplatin hypersensitivity (47% vs 21%). CONCLUSIONS: With this schedule, the addition of decitabine appears to reduce rather than increase the efficacy of carboplatin in partially platinum-sensitive ovarian cancer and is difficult to deliver. Patient-selection strategies, different schedules and other demethylating agents should be considered in future combination studies.

Does body mass index affect progression-free or overall survival in patients with ovarian cancer? Results from SCOTROC I trial.

BACKGROUND: Previous studies have indicated an association between obesity and poor survival in several tumour types, including ovarian cancer. We sought to test the hypothesis that obesity reduces survival in a large, well-characterised and relatively homogeneous cohort of ovarian cancer patients. PATIENTS AND METHODS: The relationship between body mass index (BMI) and overall survival (OS) and progression-free survival (PFS) in 1067 patients participating in the Scottish Randomised Trial in Ovarian Cancer I trial was assessed. All patients received first-line carboplatin/taxane chemotherapy. The dose of carboplatin was determined by a measured glomerular filtration rate (GFR), ensuring accurate dosing in all categories of BMI and the dose of taxane was not capped. Patients were assigned to one of four categories: underweight (BMI < 18.5), ideal weight (BMI 18.5-24.9), overweight (BMI 25-29.9) or obese (BMI >or= 30). RESULTS: There were neither statistically significant differences in PFS or OS between these four groups nor were there any differences in taxane or carboplatin dose intensity. Furthermore, there was no association between BMI and tumour stage or grade at presentation, or completeness of debulking surgery. CONCLUSIONS: Obese patients with epithelial ovarian cancer do not have a poorer prognosis, provided that they receive optimal doses of chemotherapy based on measured GFR and actual body weight.

Epigenetics as a mechanism driving polygenic clinical drug resistance.

Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such 'one gene:one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance.

A phase I/II study of oral uracil/tegafur (UFT), leucovorin and irinotecan in patients with advanced colorectal cancer.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose (MTD), toxicity profile and response rate of the oral 5-fluorouracil prodrug UFT (tegafur/uracil) and leucovorin (LV) in combination with irinotecan in patients with advanced or metastatic colorectal cancer. PATIENTS AND METHODS: Patients with histologically proven advanced or metastatic colorectal adenocarcinoma received first-line chemotherapy comprising UFT 250 mg/m(2)/day and LV 90 mg/day given on days 1 to 14, with escalating doses of irinotecan (200-300 mg/m(2)) administered intravenously on day 1 of a three-weekly cycle. Eligibility criteria were standard. The MTD was defined as the dose at which >33% of six patients experienced a dose-limiting toxicity (DLT) during cycle 1. RESULTS: A total of 32 patients were studied. Initially, six patients were treated at each of the irinotecan dose levels (200, 250 and 300 mg/m(2)) combined with UFT 250 mg/m(2)/day and LV 90 mg/day. DLTs consisting of grade 3 or 4 diarrhoea and febrile neutropenia were observed in one of 20 patients at 250 mg/m(2) and three of six patients at the 300 mg/m(2) irinotecan dose level. Having defined the MTD, the 250 mg/m(2) dose level was established as the recommended dose (RD) and expanded to 20 patients in whom treatment was generally well tolerated. The overall response rate was 19%, with five patients having a partial response (PR) and 18 stable disease (SD) out of 32 response-evaluable patients. CONCLUSION: UFT and LV can be safely combined with irinotecan. The RDs for future studies are UFT 250 mg/m(2)/day and LV 90 mg/day given on days 1-14, with irinotecan 250 mg/m(2) administered on day 1, every 3 weeks. This combination is well tolerated and active. Further investigation of UFT and LV in combination with irinotecan is warranted in patients with colorectal cancer.

Telomerase-specific suicide gene therapy vectors expressing bacterial nitroreductase sensitize human cancer cells to the pro-drug CB1954.

Telomerase activation is considered to be a critical step in cancer progression due to its role in cellular immortalization. The prevalence of telomerase expression in human cancers makes it an attractive candidate for new mechanism-based targets for cancer therapy. The selective killing of cancer cells can be achieved by gene-directed enzyme pro-drug therapy (GDEPT). In this study we have tested the feasibility of using the transcriptional regulatory sequences from the hTERT and hTR genes to regulate expression of the bacterial nitroreductase enzyme in combination with the pro-drug CB1954 in a suicide gene therapy strategy. hTERT and hTR promoter activity was compared in a panel of 10 cell lines and showed a wide distribution in activity; low activity was observed in normal cells and telomerase-negative immortal ALT cell lines, with up to 300-fold higher activity observed in telomerase positive cancer lines. Placing the nitroreductase gene under the control of the telomerase gene promoters sensitized cancer cells in tissue culture to the pro-drug CB1954 and promoter activity was predictive of sensitization to the pro-drug (2-20-fold sensitization), with cell death restricted to lines exhibiting high levels of promoter activity. The in vivo relevance of these data was tested using two xenograft models (C33a and GLC4 cells). Significant tumour reduction was seen with both telomerase promoters and the promoter-specific patterns of sensitization observed in tissue culture were retained in xenograft models. Thus, telomerase-specific suicide gene therapy vectors expressing bacterial nitroreductase sensitize human cancer cells to the pro-drug CB1954.

Telomerase and cancer: time to move from a promising target to a clinical reality.

The past 25 years have seen unparalleled advances in our understanding of the molecular basis of cancer. As a result, novel molecular targets have been identified that provide great potential for the development of new cancer diagnostics and therapies. Four key features of cancer cells distinguish them from their normal counterparts: loss of cell-cycle regulation, loss of control over invasion and metastasis, failure of apoptotic mechanisms, and bypass of senescence. This review examines our understanding of the bypass of senescence and the process of immortalization during carcinogenesis. In addition, the realistic opportunities for telomerase in cancer diagnostics and the challenges faced in clinical trial design for telomerase therapeutics are discussed.

Matrix metalloproteinase inhibitors: past lessons and future prospects in breast cancer.

The matrix metalloproteinases (MMPs) play a central role in invasion and metastasis. However, despite striking activity in preclinical models, the clinical development of the matrix metalloproteinase inhibitors (MMPIs) has been difficult. The results of important phase III trials are now emerging and it is therefore opportune to review the current state of the MMPIs. In this article the evidence for the role of MMPs in the progression of breast cancer, the development of the MMPIs and the recent phase III results are discussed. Despite the problems encountered it is hoped that the MMPIs may yet provide another mechanism for the long-term control of micrometastatic disease. Furthermore, important lessons can be learnt from their development that are relevant to the development of other biological agents.

Clinical imaging of cancer metastasis.

Tumour imaging is an essential part of the practice of oncology, with a crucial role in screening programmes and in diagnosis and staging of established disease. Furthermore, the assessment of tumour size by imaging, usually with computer tomography (CT) scanning, is a key component in determining the tumour response to therapy both in clinical trials and in daily oncology practice. Techniques such as CT, ultrasound (US) and magnetic resonance imaging (MRI) provide high resolution anatomical images with detailed structural information. However, these imaging modalities yield limited functional information on the tumour tissues and often cannot distinguish residual disease from non-viable or necrotic tumour masses, nor can they detect minimal residual disease. In contrast, radiopharmaceutical imaging and, in particular, positron emission tomography (PET) can give some functional information about the underlying tissues. The possibility of refining these techniques and also the emergence of newer imaging modalities that can detect changes in cancers at the physiological, cellular or molecular levels, gives rise to the notion that these methods will have implications for drug development strategies and also future clinical management. In this review, we briefly discuss the current role of imaging in clinical practice, describe some of the advances in imaging modalities currently undergoing evaluation, and speculate on the future role of these techniques in developmental therapeutics programmes.

Activation of telomerase rna gene promoter activity by NF-Y, Sp1, and the retinoblastoma protein and repression by Sp3.

Expression of the human telomerase RNA component gene, hTERC is essential for telomerase activity. The hTERC gene is expressed during embryogenesis and then downregulated during normal development, leaving most adult somatic cells devoid of hTERC expression. During oncogenesis, however, hTERC is re-expressed consequently contributing to the unrestricted proliferative capacity of many human cancers. Thus the identification of the molecular basis for the regulation of the telomerase RNA component gene in normal cells and its deregulation in cancer cells is of immediate interest. We have previously cloned the hTERC promoter and in this study have identified several transcription factors that modulate the expression of hTERC. We demonstrate that NF-Y binding to the CCAAT region of the hTERC promoter is essential for promoter activity. Sp1 and the retinoblastoma protein (pRb) are activators of the hTERC promoter and Sp3 is a potent repressor. These factors appear to act in a species-specific manner. Whereas Sp1 and Sp3 act on the human, bovine, and mouse TERC promoters, pRb activates only the human and bovine promoter, and NF-Y is only essential for the human TERC gene.