Daan De Maeseneer

Battling resistance mechanisms in antihormonal prostate cancer treatment: Novel agents and combinations

Prostate cancer (PCa) is a hormone-sensitive disease. Androgen deprivation therapy lowers serum testosterone levels (castration) or blocks the androgen receptor (AR) ligand-binding domain. Especially in metastatic disease, hormonal therapy has been able to delay disease progression, reduce symptoms, and improve overall survival. Despite subsequent disease progression and development of castration resistance, PCa remains AR driven. Secondary hormonal treatments such as abiraterone acetate or enzalutamide have demonstrated increased overall survival. However, new resistance mechanisms to these agents have been identified, and systemic chemotherapy is still needed especially in fast-progressing castration-resistant PCa. Several promising androgen synthesis inhibitors (orteronel and galeterone), AR inhibitors (ARN-509, EPI-001, AZD3514, and ODM-201), and heat shock protein modulators (AT11387, 17-DMAG, STA-9090, and OGX-427) are currently under investigation. The wide variety in upcoming systemic agents underlines the molecular heterogeneity of castration-resistant PCa. This article reviews antihormonal therapy in PCa and resistance mechanisms and focuses on novel and upcoming agents currently in clinical testing.

18-FLUORODEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY AS A TOOL FOR RESPONSE PREDICTION IN SOLID TUMOURS

Abstract Current response guidelines for the treatment of solid tumours are based on CT criteria. Over the last decades new techniques have emerged to evaluate cancer therapy. FDG-PET scanning is a more functional imaging technique, which can measure differences in metabolic activity. Although it has a low specificity, studies show that it can outperform classical CT scanning criteria. Especially in lung, breast and oesophageal cancer it can predict response earlier in the neo-adjuvant setting. This could reduce the use of ineffective cancer therapies, reducing costs and patient toxicity, and direct patients sooner towards effective therapy. The main problem with FDG-PET remains the difficulty in defining thresholds for response, as there is clearly a lack in large prospective randomized studies validating the use of FDG-PET in response guidelines. We give an overview of data on response prediction in solid tumours by the application of PET.

Pembrolizumab for the treatment of bladder cancer

ABSTRACT Introduction: Until recently, patients with locally advanced or metastatic urothelial carcinoma after progression on cisplatin-containing chemotherapy had limited systemic treatment options with no significant survival benefit and poor tolerability. Advances in the field of immunotherapy with the introduction of checkpoint inhibitors have led to paradigm shifts in the treatment of various malignancies. Areas covered: The current review will summarize the clinical evidence of checkpoint inhibitors in bladder cancer, with a focus on pembrolizumab. Expert commentary: Category 1 evidence indicates that the checkpoint inhibitor pembrolizumab improves overall survival in patients with locally advanced or metastatic urothelial carcinoma who progressed after or during cisplatin-containing therapy as compared to current standard of care chemotherapy. Phase 1 and 2 evidence also indicates that checkpoint inhibitors are active in first line in patients who are ineligible for cisplatin-containing chemotherapy.

Checkpoint inhibition : new treatment options in urologic cancer

Both urothelial (UC) and renal cell cancer (RCC) are highly immunogenic tumours. Recent advances in cellular immunity understanding have resulted in a successful new class of therapeutic agents. Interaction between the programmed cell death 1 (PD1) on regulatory T-cells (Treg) and programmed cell death 1 ligand (PDL1) on cancer cells inhibits an effective immune response and is an important mechanism for cancer cells to evade the immune system. Monoclonal anti-PD1 and anti-PDL1 antibodies inhibit this interaction and are called checkpoint inhibitors. As in non-small lung cancer and melanoma, these agents have shown to be highly active agents in UC and RCC. In metastatic or inoperable UC, no good second line therapy exists and checkpoint inhibitors have shown to be active. Multiple Randomized Clinical Trials (RCT) are underway both in second line and adjuvant settings which could change daily practice. In RCC, an anti-PD1 antibody, Nivolumab, has already proven to be effective in prolonging overall survival, and is included in current guidelines in metastatic RCC in second and third line. RCTs with other anti-PD1 and anti-PDL1 antibodies are ongoing both in metastatic and adjuvant setting. Checkpoint inhibitors have breathed new life into immunotherapy in urologic cancers and are rapidly being included in practice guidelines.

Cell motility and breast cancer metastasis

Motility and invasion of breast cancer cells are the result of the concerted action of a number of cell activities: directional migration underpinned by the dynamic organisation of cytoskeletal components (actin micro-filaments and microtubules), establishment and disruption of cell-matrix and homotypic/heterotypic cell-cell adhesions, and extracellular proteolysis. Metastasis formation is not only related to cancer cell motility, but also necessitates the collaboration of other, coined “host” cells. Newly discovered ligand-receptor interactions between cancer cells and these host elements offer a molecular explanation for Paget’s “seed and soil” hypothesis, and indicate new targets for possible anti-metastatic therapeutic agents

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

Background There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. Methods A combination of targeted- and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. Results ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first line mCRPC therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥0.1 ctDNA fraction). Sequencing of non-repetitive intronic- and exonic regions of PTEN, RB1 and TP53 detected biallelic inactivation in 47.5%, 20.3% and 44.1% of samples with ≥0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. Conclusions ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenge the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.

Circulating tumor cells and survival in abiraterone- and enzalutamide-treated patients with castration-resistant prostate cancer

The outcome to treatment administered to patients with metastatic castration‐resistant prostate cancer (mCRPC) greatly differs between individuals, underlining the need for biomarkers guiding treatment decision making.

Evaluating the Current Place of Radiotherapy as Treatment Option for Patients With Muscle Invasive Bladder Cancer in Belgium

Introduction: There is a gap between optimal and actual use of radiotherapy (RT) in muscle‐invasive bladder cancer (MIBC). We investigated the opinions of radiation‐oncologists, urologists, and medical oncologists on use of RT in different cases. Barriers and facilitators for applying guidelines were examined. Material and Methods: A web‐based survey was developed at Ghent University Hospital and conducted from November 18, 2016 to July 17, 2017. The place of primary, adjuvant, and palliative RT was evaluated. Additional questions assessed the use of guidelines, barriers, and facilitators. Results: In total, 126 physicians (57 radiation oncologists, 41 urologists, and 28 medical oncologists) completed the survey. Significant differences in use of RT in the primary and adjuvant setting were observed between radiation oncologists and urologists. Younger age and presence of hydronephrosis are perceived as contraindications for RT in the primary setting. In the adjuvant setting, RT was mainly considered in case of positive surgical margins. All radiation oncologists and 96% of medical oncologists considered palliative RT for patients with painful bone metastases, whereas 21% of urologists did not (P < .001). Clinical decisions are mainly based on EAU guidelines. The most important reason for nonadherence to guidelines is external barriers (18%). One strategy to improve awareness of guidelines is a summary of guidelines on the website of national organizations (54%). Conclusion: There is controversy regarding the place of RT in MIBC, with a clear variation between professionals. Barriers and facilitators to use RT should be addressed, seeing the gap in RT utilization and predicted increase in patients requiring RT for MIBC.

TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer

Purpose: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi). Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC (n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan–Meier analysis, and independent associations were determined using multivariable Cox regression models. Results: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18–3.00; P = 0.008], and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; P < 0.0001), which was validated in an independent mCRPC cohort (n = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; P < 0.0001). Conclusions: In an all-comer cohort, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis. See related commentary by Rebello et al., p. 1699