Pan-cancer whole-genome analyses of metastatic solid tumours.

Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106× and 38×, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer.

A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in patients with advanced solid tumours.

BACKGROUND: Gartisertib is an oral inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), a key kinase of the DNA damage response. We aimed to determine the safety and tolerability of gartisertib ± carboplatin in patients with advanced solid tumours. METHODS: This phase I open-label, multicenter, first-in-human study comprised four gartisertib cohorts: A (dose escalation [DE]; Q2W); A2 (DE; QD/BID); B1 (DE+carboplatin); and C (biomarker-selected patients). RESULTS: Overall, 97 patients were enroled into cohorts A (n = 42), A2 (n = 26), B1 (n = 16) and C (n = 13). The maximum tolerated dose and recommended phase II dose (RP2D) were not declared for cohorts A or B1. In cohort A2, the RP2D for gartisertib was determined as 250 mg QD. Gartisertib was generally well-tolerated; however, unexpected increased blood bilirubin in all study cohorts precluded further DE. Investigations showed that gartisertib and its metabolite M26 inhibit UGT1A1-mediated bilirubin glucuronidation in human but not dog or rat liver microsomes. Prolonged partial response (n = 1 [cohort B1]) and stable disease >6 months (n = 3) did not appear to be associated with biomarker status. Exposure generally increased dose-dependently without accumulation. CONCLUSION: Gartisertib was generally well-tolerated at lower doses; however, unexpected liver toxicity prevented further DE, potentially limiting antitumour activity. Gartisertib development was subsequently discontinued. CLINICALTRIALS: GOV: NCT02278250.

A Phase I Trial of the Dual MET Kinase/OCT-2 Inhibitor OMO-1 in Metastatic Solid Malignancies Including MET Exon 14 Mutated Lung Cancer.

INTRODUCTION: Targeted therapy in non-small cell lung cancer (NSCLC) patients with mesenchymal epithelial transition (MET) exon 14 skipping mutations (METex14) and MET amplifications has improved patients' outcomes. The development of more potent MET kinase inhibitors could further benefit these patients. The aim of this trial is to determine the safety and recommended phase 2 dose (RP2D) of OMO-1 (an oral dual MET kinase/OCT-2 inhibitor) and to assess preliminary clinical efficacy in METex14-positive NSCLC and other MET-positive solid tumors. MATERIALS AND METHODS: This was a first-in-patient, open-label, multicenter study of OMO-1 in patients with locally advanced or metastatic solid malignancies. A standard 3 + 3 dose escalation design was utilized starting at a dose level of 100 mg BID continuously. Preliminary efficacy was investigated in patients with METex14-positive NSCLC, and MET amplified NSCLC and other solid tumors (MET basket). RESULTS: In the dose-escalation part, 24 patients were included in 5 dose levels ranging from 100 mg twice daily (BID) to 400 mg BID. Most common adverse events (≥ 20%) were nausea, fatigue, vomiting, increased blood creatinine, and headache. The RP2D was determined at 250 mg BID. In the expansion cohorts, 15 patients were included (10 in METex14-positive NSCLC cohort and 5 in MET basket cohort) and received either 200 or 250 mg BID. Eight out of the 10 patients with METex14 positive NSCLC had stable disease as the best response. CONCLUSION: OMO-1 was tolerated at the dose of 250 mg BID and shows initial signs of MET inhibition and anti-tumor activity in METex14 mutated NSCLC patients.

A blood-based immune marker for resistance to pembrolizumab in patients with metastatic urothelial cancer.

PD1 inhibition is effective in patients with metastatic urothelial cancer (mUC), yet a large fraction of patients does not respond. In this study, we aimed to identify a blood-based immune marker associated with non-response to facilitate patient selection for anti-PD1. To this end, we quantified 18 immune cell populations using multiplex flow cytometry in blood samples from 71 patients with mUC (as part of a biomarker discovery trial; NCT03263039, registration date 28-08-2017). Patients were classified as responder (ongoing complete or partial response, or stable disease; n = 25) or non-responder (progressive disease; n = 46) according to RECIST v1.1 at 6 months of treatment with pembrolizumab. We observed no differences in numbers of lymphocytes, T-cells, granulocytes, monocytes or their subsets between responders and non-responders at baseline. In contrast, analysis of ratios of immune cell populations revealed that a high mature neutrophil-to-T-cell ratio (MNTR) exclusively identified non-responders. In addition, the survival of patients with high versus low MNTR was poor: median overall survival (OS) 2.2 vs 8.9 months (hazard ratio (HR) 6.6; p < 0.00001), and median progression-free survival (PFS) 1.5 vs 5.2 months (HR 5.6; p < 0.0001). The associations with therapy response, OS, and PFS for the MNTR were stronger than for the classical neutrophil-to-lymphocyte ratio (HR for OS 3.5, and PFS 3) and the PD-L1 combined positivity score (HR for OS 1.9, and PFS 2.1). In conclusion, the MNTR distinctly and uniquely identified non-responders to treatment and may represent a novel pre-treatment blood-based immune metric to select patients with mUC for treatment with pembrolizumab.

A Compendium of AR Splice Variants in Metastatic Castration-Resistant Prostate Cancer.

Treatment-induced AR alterations, including AR alternative splice variants (AR-Vs), have been extensively linked to harboring roles in primary and acquired resistance to conventional and next-generation hormonal therapies in prostate cancer and therefore have gained momentum. Our aim was to uniformly determine recurrent AR-Vs in metastatic castration-resistant prostate cancer (mCRPC) using whole transcriptome sequencing in order to assess which AR-Vs might hold potential diagnostic or prognostic relevance in future research. This study reports that in addition to the promising AR-V7 as a biomarker, AR45 and AR-V3 were also seen as recurrent AR-Vs and that the presence of any AR-V could be associated with higher AR expression. With future research, these AR-Vs may therefore harbor similar or complementary roles to AR-V7 as predictive and prognostic biomarkers in mCRPC or as proxies for abundant AR expression.

Personalised selection of experimental treatment in patients with advanced solid cancer is feasible using whole-genome sequencing.

BACKGROUND: Biomarker-guided therapy in an experimental setting has been suggested to improve patient outcomes. However, trial-specific pre-screening tests are time and tissue consuming and complicate the personalised treatment of patients eligible for early-phase clinical trials. In this study the feasibility of whole-genome sequencing (WGS) as a one-test-for-all for guided inclusion in early-phase trials was investigated. METHODS: Phase I Molecular Tumor Board (MTB) at the Erasmus MC Cancer Institute reviewed patients with advanced cancer without standard-of-care treatment (SOC) options for a 'fresh-frozen' (FF) tumour biopsy for WGS based on clinical-pathological features. Clinical grade WGS was performed by Hartwig Medical Foundation. MTB matched the patient with a trial, if available. RESULTS: From September 2019-March 2021, 31 patients with highly diverse tumour types underwent a tumour biopsy for WGS. The median turnaround time (TAT) was 15 days [10-42 days]. At least one actionable event was found in 84% of the patients (26/31). One-third of the patients (11/31) received matched experimental treatment. CONCLUSIONS: WGS on fresh FF biopsies is a feasible tool for the selection of personalised experimental therapy in patients with advanced cancer without SOC options. WGS is now possible in an acceptable TAT and thus could fulfil the role of a universal genomic pre-screening test.

A Phase I, First-in-Human Study of GSK2849330, an Anti-HER3 Monoclonal Antibody, in HER3-Expressing Solid Tumors.

BACKGROUND: GSK2849330, an anti-HER3 monoclonal antibody that blocks HER3/Neuregulin 1 (NRG1) signaling in cancer cells, is engineered for enhanced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase I, first-in-human, open-label study assessed the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of GSK2849330 in patients with HER3-expressing advanced solid tumors. PATIENTS AND METHODS: Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression. In the dose-escalation phase, patients received GSK2849330 1.4-30 mg/kg every 2 weeks, or 3 mg/kg or 30 mg/kg weekly, intravenously (IV). In the dose-expansion phase, patients received 30 mg/kg GSK2849330 IV weekly. RESULTS: Twenty-nine patients with HER3-expressing cancers, of whom two expressed NRG1, received GSK2849330 (dose escalation: n = 18, dose expansion: n = 11). GSK2849330 was well tolerated. No dose-limiting toxicities were observed. The highest dose, of 30 mg/kg weekly, expected to provide full target engagement, was selected for dose expansion. Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. The most common AEs were diarrhea (66%), fatigue (62%), and decreased appetite (31%). Dose-proportional plasma exposures were achieved, with evidence of HER3 inhibition in paired tissue biopsies. Of 29 patients, only 1 confirmed partial response, lasting 19 months, was noted in a patient with CD74-NRG1-rearranged non-small cell lung cancer (NSCLC). CONCLUSION: GSK2849330 demonstrated a favorable safety profile, dose-proportional PK, and evidence of target engagement, but limited antitumor activity in HER3-expressing cancers. The exceptional response seen in a patient with CD74-NRG1-rearranged NSCLC suggests further exploration in NRG1-fusion-positive cancers. IMPLICATIONS FOR PRACTICE: This first-in-human study confirms that GSK2849330 is well tolerated. Importantly, across a variety of HER3-expressing advanced tumors, prospective selection by HER3/NRG1 expression alone was insufficient to identify patients who could benefit from treatment with this antibody-dependent cell-mediated cytotoxicity- and complement-dependent cytotoxicity-enhanced anti-HER3 antibody. The only confirmed durable response achieved was in a patient with CD74-NRG1-rearranged lung cancer. This highlights the potential utility of screening for NRG1 fusions prospectively across tumor types to enrich potential responders to anti-HER3 agents in ongoing trials.

Impact of panel design and cut-off on tumour mutational burden assessment in metastatic solid tumour samples.

Tumour mutational burden (TMB) has emerged as a promising biomarker to predict immune checkpoint inhibitors (ICIs) response in advanced solid cancers. However, harmonisation of TMB reporting by targeted gene panels is lacking, especially in metastatic tumour samples. To address this issue, we used data of 2841 whole-genome sequenced metastatic cancer biopsies to perform an in silico analysis of TMB determined by seven gene panels (FD1CDx, MSK-IMPACT™, Caris Molecular Intelligence, Tempus xT, Oncomine Tumour Mutation Load, NeoTYPE Discovery Profile and CANCERPLEX) compared to exome-based TMB as a golden standard. Misclassification rates declined from up to 30% to <1% when the cut-point for high TMB was increased. Receiver operating characteristic analysis demonstrated that, for correct classification, the cut-point for each gene panel may vary more than 20%. In conclusion, we here demonstrate that a major limitation for the use of gene panels is inter-assay variation and the need for dynamic thresholds to compare TMB outcomes.

Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer.

Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with docetaxel for uptake by the drug transporter OATP1B3. Irrespective of docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by docetaxel treatment in vivo. These results indicate that to optimise docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with docetaxel in CRPC.

Phase 1 study of the pan-HER inhibitor dacomitinib plus the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutation-positive colorectal, non-small-cell lung and pancreatic cancer.

BACKGROUND: Mutations in KRAS result in a constitutively activated MAPK pathway. In KRAS-mutant tumours existing treatment options, e.g. MEK inhibition, have limited efficacy due to resistance through feedback activation of epidermal growth factor receptors (HER). METHODS: In this Phase 1 study, the pan-HER inhibitor dacomitinib was combined with the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutant colorectal, pancreatic and non-small-cell lung cancer (NSCLC). Patients received escalating oral doses of once daily dacomitinib and twice daily PD-0325901 to determine the recommended Phase 2 dose (RP2D). (Clinicaltrials.gov: NCT02039336). RESULTS: Eight out of 41 evaluable patients (27 colorectal cancer, 11 NSCLC and 3 pancreatic cancer) among 8 dose levels experienced dose-limiting toxicities. The RP2D with continuous dacomitinib dosing was 15 mg of dacomitinib plus 6 mg of PD-0325901 (21 days on/7 days off), but major toxicity, including rash (85%), diarrhoea (88%) and nausea (63%), precluded long-term treatment. Therefore, other intermittent schedules were explored, which only slightly improved toxicity. Tumour regression was seen in eight patients with the longest treatment duration (median 102 days) in NSCLC. CONCLUSIONS: Although preliminary signs of antitumour activity in NSCLC were seen, we do not recommend further exploration of this combination in KRAS-mutant patients due to its negative safety profile.

Phase Ib Study of Combination Therapy with MEK Inhibitor Binimetinib and Phosphatidylinositol 3-Kinase Inhibitor Buparlisib in Patients with Advanced Solid Tumors with RAS/RAF Alterations.

BACKGROUND: This multicenter, open-label, phase Ib study investigated the safety and efficacy of binimetinib (MEK inhibitor) in combination with buparlisib (phosphatidylinositol 3-kinase [PI3K] inhibitor) in patients with advanced solid tumors with RAS/RAF alterations. MATERIALS AND METHODS: Eighty-nine patients were enrolled in the study. Eligible patients had advanced solid tumors with disease progression after standard therapy and/or for which no standard therapy existed. Evaluable disease was mandatory, per RECIST version 1.1 and Eastern Cooperative Oncology Group performance status 0-2. Binimetinib and buparlisib combinations were explored in patients with KRAS-, NRAS-, or BRAF-mutant advanced solid tumors until the maximum tolerated dose and recommended phase II dose (RP2D) were defined. The expansion phase comprised patients with epidermal growth factor receptor (EGFR)-mutant, advanced non-small cell lung cancer, after progression on an EGFR inhibitor; advanced RAS- or BRAF-mutant ovarian cancer; or advanced non-small cell lung cancer with KRAS mutation. RESULTS: At data cutoff, 32/89 patients discontinued treatment because of adverse events. RP2D for continuous dosing was buparlisib 80 mg once daily/binimetinib 45 mg twice daily. The toxicity profile of the combination resulted in a lower dose intensity than anticipated. Six (12.0%) patients with RAS/BRAF-mutant ovarian cancer achieved a partial response. Pharmacokinetics of binimetinib were not altered by buparlisib. Pharmacodynamic analyses revealed downregulation of pERK and pS6 in tumor biopsies. CONCLUSION: Although dual inhibition of MEK and the PI3K pathways showed promising activity in RAS/BRAF ovarian cancer, continuous dosing resulted in intolerable toxicities beyond the dose-limiting toxicity monitoring period. Alternative schedules such as pulsatile dosing may be advantageous when combining therapies. IMPLICATIONS FOR PRACTICE: Because dysregulation of the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K) pathways are both frequently involved in resistance to current targeted therapies, dual inhibition of both pathways may be required to overcome resistance mechanisms to single-agent tyrosine kinase inhibitors or to treat cancers with driver mutations that cannot be directly targeted. A study investigating the safety and efficacy of combination binimetinib (MEK inhibitor) and buparlisib (PI3K inhibitor) in patients harboring alterations in the RAS/RAF pathway was conducted. The results may inform the design of future combination therapy trials in patients with tumors harboring mutations in the PI3K and MAPK pathways.

Fundamentals of liquid biopsies in metastatic prostate cancer: from characterization to stratification.

PURPOSE OF REVIEW: In this review, we provide an overview of the recent developments and prospects on the applications of blood-based liquid biopsies, including circulating tumor DNA and circulating tumor cells, in metastatic prostate cancer. RECENT FINDINGS: Guidelines and consensus statements have been formulated to standardize preanalytical conditions that affect liquid biopsy analysis. Currently, there are four FDA approved assays for the analysis of liquid biopsies and many quantitative and qualitative assays are being developed. Comprehensive analyses of cell-free tumor DNA (ctDNA) and circulating tumor cells (CTCs) demonstrate that they adequately reflect the genomic makeup of the tumor and may thus complement or even replace tumor biopsies. The assessment of genomic aberrations in ctDNA can potentially predict therapy response and detect mechanisms of resistance. CTC count is not only a strong prognosticator in metastatic prostate cancer but can also measure therapy response. SUMMARY: Liquid biopsies may provide a temporal snapshot of the biologic variables that affect tumor growth and progression in metastatic prostate cancer. Liquid biopsies could inform on prognostic, predictive, and response measures. However, prospective clinical trials need to be performed to provide definitive validation of the clinical value of the most advanced assays.

Phase I study of continuous olaparib capsule dosing in combination with carboplatin and/or paclitaxel (Part 1).

Background The PARP inhibitor olaparib has shown acceptable toxicity at doses of up to 400 mg twice daily (bid; capsule formulation) with encouraging signs of antitumor activity. Based on its mode of action, olaparib may sensitize tumor cells to DNA-damaging agents. This Phase I trial (NCT00516724) evaluated the safety, pharmacokinetics (PK) and preliminary efficacy of olaparib combined with carboplatin and/or paclitaxel. Methods Patients with advanced solid tumors received olaparib (capsule bid) plus carboplatin (Part A), carboplatin and paclitaxel (Part B), or paclitaxel (Part C). In each part of the study, different drug doses were given to define the most appropriate dose/drug combination to use in further studies. Safety assessments included evaluation of dose-limiting toxicities (DLTs; cycle 1 only), adverse events (AEs) and physical examinations. PK assessments of olaparib, carboplatin and paclitaxel were performed. Tumor responses (RECIST) were assessed every two cycles. Results Fifty-seven patients received treatment. DLTs were reported in two patients (both receiving olaparib 100 mg bid and carboplatin AUC 4; Part A, cohort 2): grade 1 thrombocytopenia with grade 2 neutropenia lasting for 16 days, and grade 2 neutropenia lasting for 7 days. Non-hematologic AEs were predominantly grade 1-2 and included fatigue (70%) and nausea (40%). Bone marrow suppression, mainly neutropenia (51%) and thrombocytopenia (25%), frequently led to dose modifications. Conclusions Olaparib in combination with carboplatin and/or paclitaxel resulted in increased hematologic toxicities, making it challenging to establish a dosing regimen that could be tolerated for multiple cycles without dose modifications.

Phase I study of intermittent olaparib capsule or tablet dosing in combination with carboplatin and paclitaxel (part 2).

Background In the first part of this extensive phase I study (NCT00516724), continuous olaparib twice daily (bid) with carboplatin and/or paclitaxel resulted in myelosuppression and dose modifications. Here, we report the safety, tolerability, and efficacy of intermittent olaparib dosing combined with carboplatin and paclitaxel. Methods Patients with advanced solid tumors (part D) and enriched for ovarian and breast cancer (part E) received olaparib (capsule and tablet formulations) using intermittent schedules (2 to 10 days of a 21-day cycle) combined with carboplatin/paclitaxel. Safety assessments included evaluation of dose-limiting toxicities (DLTs; cycle 1 only), adverse events (AEs), and physical examinations. Pharmacokinetic assessments of olaparib capsule and tablet combined with carboplatin/paclitaxel were performed. Tumor responses (RECIST) were assessed every 2 cycles. Results In total, 132 heavily pre-treated patients were included. One DLT of grade 3 elevated alanine aminotransferase lasting for 8 days was reported (olaparib tablet 100 mg bid days 3-12, carboplatin area under the curve 4 and paclitaxel 175 mg/m2). The most common hematological AEs were neutropenia (47%) and thrombocytopenia (39%), which frequently led to dose modifications. Non-hematological AEs were predominantly grade 1-2, including alopecia (89%) and fatigue (84%). Overall objective response rate was 46%. Conclusions Discontinuous dosing of olaparib resulted in significant myelosuppression leading to dose interruptions and/or delays. Anti-tumor activity was encouraging in patients enriched with BRCA-mutated breast and ovarian cancer. The most appropriate olaparib tablet dose for use in further studies evaluating olaparib in combination with carboplatin and paclitaxel is 50 mg bid (days 1-5).

Effects of prednisone on docetaxel pharmacokinetics in men with metastatic prostate cancer: A randomized drug-drug interaction study.

AIMS: Docetaxel has been approved for the treatment of metastatic prostate cancer in combination with prednisone. Since prednisone is known to induce the cytochrome P450 iso-enzyme CYP3A4, which is the main metabolizing enzyme of docetaxel in the liver, a potential drug-drug interaction may occur. In this prospective randomized pharmacokinetic cross-over study we investigated docetaxel exposure with concomitant prednisone, compared to docetaxel monotherapy in men with metastatic prostate cancer. METHODS: Patients scheduled to receive at least 6 cycles of docetaxel (75 mg/m2 ) and who gave written informed consent were randomized to receive either the 1st 3 cycles, or the last 3 consecutive cycles with prednisone (twice daily 5 mg). Pharmacokinetic blood sampling was performed during cycle 3 and cycle 6. Primary endpoint was difference in docetaxel exposure, calculated as area under the curve (AUC0-inf ) and analysed by means of a linear mixed model. Given the cross-over design the study was powered on 18 patients to answer the primary, pharmacokinetic, endpoint. RESULTS: Eighteen evaluable patients were included in the trial. Docetaxel concentration with concomitant prednisone (AUC0-inf 2784 ng*h/mL, 95% confidence interval 2436-3183 ng*h/mL) was similar to the concentration of docetaxel monotherapy (AUC0-inf 2647 ng*h/mL, 95% confidence interval 2377-2949 ng*h/mL). Exploratory analysis showed no toxicity differences between docetaxel monotherapy and docetaxel cycles with prednisone. CONCLUSION: No significant difference in docetaxel concentrations was observed. In addition, we found similar toxicity profiles in absence and presence of prednisone. Therefore, from a pharmacokinetic point of view, docetaxel may be administrated with or without prednisone.

Realizing better doctor-patient dialogue about choices in palliative care and early phase clinical trial participation: towards an online value clarification tool (OnVaCT).

BACKGROUND: Patients with advanced cancer for whom standard systemic treatment is no longer available may be offered participation in early phase clinical trials. In the decision making process, both medical-technical information and patient values and preferences are important. Since patients report decisional conflict after deciding on participation in these trials, improving the decision making process is essential. We aim to develop and evaluate an Online Value Clarification Tool (OnVaCT) to assist patients in clarifying their values around this end-of-life decision. This improved sharing of values is hypothesized to support medical oncologists in tailoring their information to individual patients' needs and, consequently, to support patients in taking decisions in line with their values and reduce decisional conflict. METHODS: In the first part, patients' values and preferences and medical oncologists' views hereupon will be explored in interviews and focus groups to build a first prototype OnVaCT using digital communication (serious gaming). Next, we will test feasibility during think aloud sessions, to deliver a ready-to-implement OnVaCT. In the second part, the OnVaCT, with accompanied training module, will be evaluated in a pre-test (12-18 months before implementation) post-test (12-18 months after implementation) study in three major Dutch cancer centres. We will include 276 patients (> 18 years) with advanced cancer for whom standard systemic therapy is no longer available, and who are referred for participation in early phase clinical trials. The first consultation will be recorded to analyse patient-physician communication regarding the discussion of patients' values and the decision making process. Three weeks afterwards, decisional conflict will be measured. DISCUSSION: This project aims to support the discussion of patient values when considering participation in early phase clinical trials. By including patients before their first appointment with the medical oncologist and recording that consultation, we are able to link decisional conflict to the decision making process, e.g. the communication during consultation. The study faces challenges such as timely including patients within the short period between referral and first consultation. Furthermore, with new treatments being developed rapidly, molecular stratification may affect the patient populations included in the pre-test and post-test periods. TRIAL REGISTRATION: Netherlands Trial Registry number: NTR7551 (prospective; July 17, 2018).

Understanding how coping strategies and quality of life maintain hope in patients deliberating phase I trial participation.

OBJECTIVE: This study aimed to understand how hope and motivation of patients considering phase I trial participation are affected by psychological factors such as coping strategies and locus of control (LoC) and general well-being as measured by the quality of life (QoL). METHODS: An exploratory cross-sectional study was performed in patients with incurable cancer (N = 135) referred to our phase I unit for the first time. Patients were potentially eligible for phase I trial participation and participated in our study while deliberating phase I trial participation. We used questionnaires on hope, motivation to participate, coping, LoC, and QoL. To investigate the nature and magnitude of the relationships between the scales, a structural equation modeling (SEM) was fitted to the data. RESULTS: Hope significantly predicted the motivation to participate in phase I trials. Predictors of hope were a combination of flexible and tenacious goal pursuit (both P < .01), internal LoC (P < .01), and QoL (P < .01). The SEM showed an exact fit to the data, using a null hypothesis significance test: chi-square (8) = 9.30, P = .32. CONCLUSIONS: Patients considering phase I trial participation seem to use a pact of tenacious and flexible coping and control to stay hopeful. Furthermore, hope and QoL positively affected each other. The psychological pact may promote an adaptation enabling them to adjust to difficult circumstances by unconsciously ignoring information, called dissonance reduction. This mechanism may impair their ability to provide a valid informed consent. We suggest including a systematic exploration of patients' social context and values before proposing a phase I trial.

Self-reported quality of life and hope in phase-I trial participants: An observational prospective cohort study.

For advanced cancer patients deliberating early clinical trial participation, adequate information about expected effect on quality of life (HRQoL) and hope, may support decision making. The aim was to assess the potential relation of HRQoL to eligibility for phase-I trial participation, and to observe the variations in patient-reported outcomes. Patients completed questionnaires at preconsent (n = 124), baseline (n = 96), and after first evaluation of a phase-I trial (n = 76). The Mann-Whitney U test was used to test differences between eligible and ineligible patients. Univariate logistic regression was performed for eligibility. Factorial repeated-measures ANOVA compared the outcomes of patients continuing vs. stopping participation after first evaluation over time. Eligibility is associated with significant better global health OR = 0.946, 95% CI [0.918, 0.975], p = 0.001, physical functioning OR = 0.959, 95% CI [0.933, 0.985], p = 0.002, role functioning OR = 0.974, 95% CI [0.957, 0.991] and better appetite OR = 1.114 95% CI [1.035, 1.192]. HRQoL outcomes like global health, social functioning and appetite decline in all patients and differ between patients continuing or having to end participation. Over time, hope and tenacity decline in all patients and coping strategies alter in patients stopping participation. Trial participation influences patient-reported outcomes. Global health may predict for eligibility and trial continuation. Informing patients could affect patients' decision making.

Implementation of a Multicenter Biobanking Collaboration for Next-Generation Sequencing-Based Biomarker Discovery Based on Fresh Frozen Pretreatment Tumor Tissue Biopsies.

BACKGROUND: The discovery of novel biomarkers that predict treatment response in advanced cancer patients requires acquisition of high-quality tumor samples. As cancer evolves over time, tissue is ideally obtained before the start of each treatment. Preferably, samples are freshly frozen to allow analysis by next-generation DNA/RNA sequencing (NGS) but also for making other emerging systematic techniques such as proteomics and metabolomics possible. Here, we describe the first 469 image-guided biopsies collected in a large collaboration in The Netherlands (Center for Personalized Cancer Treatment) and show the utility of these specimens for NGS analysis. PATIENTS AND METHODS: Image-guided tumor biopsies were performed in advanced cancer patients. Samples were fresh frozen, vital tumor cellularity was estimated, and DNA was isolated after macrodissection of tumor-rich areas. Safety of the image-guided biopsy procedures was assessed by reporting of serious adverse events within 14 days after the biopsy procedure. RESULTS: Biopsy procedures were generally well tolerated. Major complications occurred in 2.1%, most frequently consisting of pain. In 7.3% of the percutaneous lung biopsies, pneumothorax requiring drainage occurred. The majority of samples (81%) contained a vital tumor percentage of at least 30%, from which at least 500 ng DNA could be isolated in 91%. Given our preset criteria, 74% of samples were of sufficient quality for biomarker discovery. The NGS results in this cohort were in line with those in other groups. CONCLUSION: Image-guided biopsy procedures for biomarker discovery to enable personalized cancer treatment are safe and feasible and yield a highly valuable biobank. The Oncologist 2017;22:33-40Implications for Practice: This study shows that it is safe to perform image-guided biopsy procedures to obtain fresh frozen tumor samples and that it is feasible to use these biopsies for biomarker discovery purposes in a Dutch multicenter collaboration. From the majority of the samples, sufficient DNA could be yielded to perform next-generation sequencing. These results indicate that the way is paved for consortia to prospectively collect fresh frozen tumor tissue.

Genomic and transcriptomic plasticity in treatment-naive ovarian cancer.

Intra-tumor heterogeneity is a hallmark of many cancers and may lead to therapy resistance or interfere with personalized treatment strategies. Here, we combined topographic mapping of somatic breakpoints and transcriptional profiling to probe intra-tumor heterogeneity of treatment-naïve stage IIIC/IV epithelial ovarian cancer. We observed that most substantial differences in genomic rearrangement landscapes occurred between metastases in the omentum and peritoneum versus tumor sites in the ovaries. Several cancer genes such as NF1, CDKN2A, and FANCD2 were affected by lesion-specific breakpoints. Furthermore, the intra-tumor variability involved different mutational hallmarks including lesion-specific kataegis (local mutation shower coinciding with genomic breakpoints), rearrangement classes, and coding mutations. In one extreme case, we identified two independent TP53 mutations in ovary tumors and omentum/peritoneum metastases, respectively. Examination of gene expression dynamics revealed up-regulation of key cancer pathways including WNT, integrin, chemokine, and Hedgehog signaling in only subsets of tumor samples from the same patient. Finally, we took advantage of the multilevel tumor analysis to understand the effects of genomic breakpoints on qualitative and quantitative gene expression changes. We show that intra-tumor gene expression differences are caused by site-specific genomic alterations, including formation of in-frame fusion genes. These data highlight the plasticity of ovarian cancer genomes, which may contribute to their strong capacity to adapt to changing environmental conditions and give rise to the high rate of recurrent disease following standard treatment regimes.