High-throughput molecular assays for inclusion in personalised oncology trials – State-of-the-art and beyond

In the last decades, the development of high-throughput molecular assays has revolutionised cancer diagnostics, paving the way for the concept of personalised cancer medicine. This progress has been driven by the introduction of such technologies through biomarker-driven oncology trials. In this review, strengths and limitations of various state-of-the-art sequencing technologies, including gene panel sequencing (DNA and RNA), whole-exome/whole-genome sequencing and whole-transcriptome sequencing, are explored, focusing on their ability to identify clinically relevant biomarkers with diagnostic, prognostic and/or predictive impact. This includes the need to assess complex biomarkers, for example microsatellite instability, tumour mutation burden and homologous recombination deficiency, to identify patients suitable for specific therapies, including immunotherapy. Furthermore, the crucial role of biomarker analysis and multidisciplinary molecular tumour boards in selecting patients for trial inclusion is discussed in relation to various trial concepts, including drug repurposing. Recognising that today's exploratory techniques will evolve into tomorrow's routine diagnostics and clinical study inclusion assays, the importance of emerging technologies for multimodal diagnostics, such as proteomics and in vivo drug sensitivity testing, is also discussed. In addition, key regulatory aspects and the importance of patient engagement in all phases of a clinical trial are described. Finally, we propose a set of recommendations for consideration when planning a new precision cancer medicine trial.imag

High-throughput molecular assays for inclusion in personalised oncology trials – State-of-the-art and beyond

In the last decades, the development of high-throughput molecular assays has revolutionised cancer diagnostics, paving the way for the concept of personalised cancer medicine. This progress has been driven by the introduction of such technologies through biomarker-driven oncology trials. In this review, strengths and limitations of various state-of-the-art sequencing technologies, including gene panel sequencing (DNA and RNA), whole-exome/whole-genome sequencing and whole-transcriptome sequencing, are explored, focusing on their ability to identify clinically relevant biomarkers with diagnostic, prognostic and/or predictive impact. This includes the need to assess complex biomarkers, for example microsatellite instability, tumour mutation burden and homologous recombination deficiency, to identify patients suitable for specific therapies, including immunotherapy. Furthermore, the crucial role of biomarker analysis and multidisciplinary molecular tumour boards in selecting patients for trial inclusion is discussed in relation to various trial concepts, including drug repurposing. Recognising that today's exploratory techniques will evolve into tomorrow's routine diagnostics and clinical study inclusion assays, the importance of emerging technologies for multimodal diagnostics, such as proteomics and in vivo drug sensitivity testing, is also discussed. In addition, key regulatory aspects and the importance of patient engagement in all phases of a clinical trial are described. Finally, we propose a set of recommendations for consideration when planning a new precision cancer medicine trial.imag

Ten-year survival after High-Dose-Rate Brachytherapy combined with External Beam Radiation Therapy in high-risk prostate cancer: A comparison with the Norwegian SPCG-7 cohort

Background The survival benefit of dose-escalation with High-Dose-Rate brachytherapy (HDR-BT) boost combined with External Beam Radiotherapy (EBRT) for the treatment of high-risk prostate cancer (PCa) remains debatable. We investigated 10-year PCa-specific mortality (PCSM) and overall mortality (OM) in high-risk patients treated with HDR-BT/EBRT (calculated EQD2 = 102 Gy) compared to EBRT alone (70 Gy). Methods HDR-BT boosts (10 Gy × 2) were given 2 weeks apart followed by 50 Gy conformal EBRT (2 Gy × 25) to the prostate and seminal vesicles. The HDR-BT/EBRT group (N:325) received Androgen Deprivation Therapy for a median duration of 2 years. The historical control group (N:296), received a median dose of 70 Gy (2 Gy × 35) to the prostate and seminal vesicles with lifelong Anti-Androgen Treatment. For each treatment group PCSM and OM were established by competing-risk analyses and Kaplan–Meier analyses respectively. Differences were evaluated by the logrank test. Independent associations were established by Cox regression analyses. Significance level set to p < 0.05. Results Median follow-up was 104 and 120 months for the HDR-BT/EBRT and the EBRT group respectively. A 3.6-fold decreased risk of PCSM (p < 0.01) and a 1.6-fold decreased risk of OM (p = 0.02) in the HDR-BT/EBRT cohort compared to the EBRT-only group were revealed. Ten-year OM and PCSM rates were 16% and 2.5% in the HDR-BT/EBRT group versus 23% and 8.2% in the EBRT-only group respectively. Both treatment modality (HR = 3.59, 95%CI 1.50–8.59) and Gleason score (HR = 2.48, 95%CI 1.18–5.21) were associated with PCSM. Only treatment modality (HR = 1.63, 95%CI = 1.08–2.44) was significantly associated with OM. Conclusions Men with high-risk PCa have a significantly reduced PCSM and OM rates when treated with dose-escalated radiotherapy achieved by HDR-BT/EBRT compared to EBRT alone (70 Gy). A Gleason score of 8–10 was independently associated with increased risk of PCSM. Randomized studies are warranted. Summary Observational study of 10-year survival in high-risk Prostate Cancer (PCa) after High-Dose-Rate brachytherapy combined with External Beam Radiation Therapy (HDR-BT/EBRT) compared to EBRT alone. The combined HDR-BT/EBRT treatment was found to give a 3.6-fold decrease in Prostate Cancer Specific Mortality (PCSM) and a 1.6-fold decrease in Overall Mortality (OM). Gleason score and type of treatment strongly influenced PCSM whereas only treatment modality was associated with OM. The observed benefits of dose-escalation warrant future randomized trials

Ten-year survival after High-Dose-Rate Brachytherapy combined with External Beam Radiation Therapy in high-risk prostate cancer: A comparison with the Norwegian SPCG-7 cohort

Background: The survival benefit of dose-escalation with High-Dose-Rate brachytherapy (HDR-BT) combined with External Beam Radiotherapy (EBRT) for the treatment of high-risk prostate cancer (PCa) remains debatable. We investigated 10-year PCa-specific mortality (PCSM) and overall mortality (OM) in high-risk patients treated with HDR-BT/EBRT compared to EBRT alone. Methods: HDR-BT boosts were given followed by 50 Gy conformal EBRT to the prostate and seminal vesicles. The HDR-BT/EBRT group (N:325) received Androgen Deprivation Therapy for median 2 years. The historical control group (N:296), received a median dose of 70 Gy to the prostate and seminal vesicles with lifelong Anti-Androgen Treatment. For each treatment group, PCSM and OM were calculated using competing-risk and Kaplan-Meier analyses, respectively. Differences were assessed with the logrank test. OM and PCSM were computed using Cox and Fine & Grey regression. Significance level set to p<0.05. Patient-measured (PM) toxicity were assessed by EPIC-26 questionnaire at 5 years. Results: Median follow-up was 104 and 120 months for the HDR-BT/EBRT and the EBRT group respectively. A 3.6-fold decreased risk of PCSM (p<0.01) and a 1.6-fold decreased risk of OM (p=0.02) in the HDR-BT/EBRT cohort compared to the EBRT-only group were revealed. Ten year OM and PCSM rates were 16 % and 2.5% in the HDR-BT/EBRT group versus 23% and 8.2% in the EBRT-only group respectively. Treatment modality (SHR=3.58, 95%CI 1.40-9.14) and Gleason score (SHR=2.58, 95%CI 1.15 5.78) were associated with PCSM. Only treatment modality (HR=1.63, 95%CI=1.08-2.44) was significantly associated with OM. Conclusions: Men with high-risk PCa have a significantly reduced PCSM and OM rates when treated with dose-escalated radiotherapy achieved by HDR-BT/EBRT compared to EBRT alone (70 Gy). PM toxicity scores were acceptable and similar to the ProtecT study. A Gleason score of 8-10 was independently associated with increased risk of PCSM. Randomized studies in men with high-risk disease treated with dose-escalation are warranted

Exome Sequencing of Bilateral Testicular Germ Cell Tumors Suggests Independent Development Lineages

Intratubular germ cell neoplasia, the precursor of testicular germ cell tumors (TGCTs), is hypothesized to arise during embryogenesis from developmentally arrested primordial germ cells (PGCs) or gonocytes. In early embryonal life, the PGCs migrate from the yolk sac to the dorsal body wall where the cell population separates before colonizing the genital ridges. However, whether the malignant transformation takes place before or after this separation is controversial. We have explored the somatic exome-wide mutational spectra of bilateral TGCT to provide novel insight into the in utero critical time frame of malignant transformation and TGCT pathogenesis. Exome sequencing was performed in five patients with bilateral TGCT (eight tumors), of these three patients in whom both tumors were available (six tumors) and two patients each with only one available tumor (two tumors). Selected loci were explored by Sanger sequencing in 71 patients with bilateral TGCT. From the exome-wide mutational spectra, no identical mutations in any of the three bilateral tumor pairs were identified. Exome sequencing of all eight tumors revealed 87 somatic non-synonymous mutations (median 10 per tumor; range 5-21), some in already known cancer genes such as CIITA, NEB, platelet-derived growth factor receptor α (PDGFRA), and WHSC1. SUPT6H was found recurrently mutated in two tumors. We suggest independent development lineages of bilateral TGCT. Thus, malignant transformation into intratubular germ cell neoplasia is likely to occur after the migration of PGCs. We reveal possible drivers of TGCT pathogenesis, such as mutated PDGFRA, potentially with therapeutic implications for TGCT patients

PEACE V-Salvage Treatment of OligoRecurrent nodal prostate cancer Metastases (STORM): Acute Toxicity of a Randomized Phase 2 Trial.

BACKGROUND Treatment recommendations for patients with limited nodal recurrences are lacking, and different locoregional treatment approaches are currently being used. OBJECTIVE The aim of this trial is to compare metastasis-directed therapy (MDT) with or without elective nodal pelvic radiotherapy (ENRT). DESIGN, SETTING, AND PARTICIPANTS PEACE V-Salvage Treatment of OligoRecurrent nodal prostate cancer Metastases (STORM) is an international, phase 2, open-label, randomized, superiority trial (ClinicalTrials.gov identifier: NCT03569241). Patients diagnosed with positron emission tomography-detected pelvic nodal oligorecurrence (five or fewer nodes) following radical local treatment for prostate cancer were randomized in a 1:1 ratio between arm A (MDT and 6 mo of androgen deprivation therapy [ADT]) and arm B (ENRT [25 × 1.8 Gy] with MDT and 6 mo of ADT). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We report the secondary endpoint acute toxicity, defined as worst grade ≥2 Common Terminology Criteria for Adverse Events v4.0 gastrointestinal (GI) or genitourinary (GU) toxicity within 3 mo of treatment. The chi-square test was used to compare toxicity between treatment arms. We also compare the quality of life (QoL) using the European Organisation for Research and Treatment of Cancer QLQ C30 and PR25 questionnaires. RESULTS AND LIMITATIONS Between June 2018 and April 2021, 196 patients were assigned randomly to MDT or ENRT. Ninety-seven of 99 patients allocated to MDT and 93 of 97 allocated to ENRT received per-protocol treatment. Worst acute GI toxicity proportions were as follows: grade ≥2 events in three (3%) in the MDT group versus four (4%) in the ENRT group (p = 0.11). Worst acute GU toxicity proportions were as follows: grade ≥2 events in eight (8%) in the MDT group versus 12 (13%) in the ENRT group (p = 0.95). We observed no significant difference between the study groups in the proportion of patients with a clinically significant QoL reduction from baseline for any subdomain score area. CONCLUSIONS No clinically meaningful differences were observed in worst grade ≥2 acute GI or GU toxicity or in QoL subdomains between MDT and ENRT. PATIENT SUMMARY We found no evidence of differential acute bowel or urinary side effects using metastasis-directed therapy and elective nodal radiotherapy for the treatment of patients with a pelvic lymph node recurrence