On BRCA mutations

In her presentation on BRCA, medical oncologist and EMUC25 Steering Committee member Dr. Elena Castro (ES) stated that lifetime prostate cancer (PCa) risk is significantly elevated in individuals with BRCA mutations, with estimates of approximately 17% for BRCA1 carriers and up to 40% for those with BRCA2. Due to this higher risk, annual PSA screening beginning at age 40–45 is recommended for BRCA2 mutation carriers. In contrast, there is currently no clearly established screening ESMO guideline for individuals with BRCA1 mutations.

Germline BRCA2 is considered an adverse prognostic factor in PCa, while the impact of BRCA1 is less well defined. Patients with PCa who harbour BRCA1 or BRCA2 mutations benefit from close clinical monitoring. Importantly, germline BRCA1 and BRCA2 alterations sensitise tumours to PARP inhibitors.

Men with high-risk localised, locally advanced, or metastatic PCa should be offered germline genetic testing. Currently, there are no clinical characteristics to identify mutation carriers. Dr. Castro added that when a BRCA1 or BRCA2 mutation is detected in tumour tissue, germline origin should be excluded.

PRS for PCa screening

In her presentation “Polygenic risk to guide prostate cancer screening”, oncogenetics research nurse consultant Dr. Elizabeth Bancroft (GB) discussed the potential of using PRS in PCa screening.

PRS is used to estimate an individual’s genetic predisposition to developing a certain disease. However, it only provides the probability, not a prediction. A higher PRS means a higher genetic predisposition to the disease relative to others in the population, and it can be used to risk-stratify populations.

PRS is calculated by summing the effects of single nucleotide polymorphisms (SNPs), which are the most common type of genetic variation among people. There are 451 SNPs identified that are associated with PCa.

Dr. Bancroft discussed the BARCODE1 study, which evaluated the use of PRS (~130 SNPs) to identify those at the highest risk. Those participants in the top 10% were offered PSA, MRI, and prostate biopsy. The BARCODE1 study concluded that PRS found a high proportion of clinically significant PCa in men at higher genetic risk. PSA and MRI missed some significant cancers in this high-risk group.

“PRS is a one-time test using germline DNA, which is constant, unlike other tools such as PSA, which can fluctuate,” stated Dr. Bancroft.

Furthermore, the PRODICT study, which will replicate BARCODE1, was recently launched with an enriched recruitment in Black African, Black Caribbean, East Asian and South Asian populations.

Pathologist Prof. Markus Eckstein (DE), urologist Prof. Juan Gómez Rivas (ES), oncologist Dr. Pasquale Rescigno (GB), radiation oncologist Dr. Noelia Sanmamed (ES), and radiologist Prof. Harriet Thoeny (CH) spearheaded the session.

For more information, you can (re)watch the presentations via the EMUC25 Resource Centre.

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Prof. Georg Salomon (DE) and Dr. Jochen Walz (FR) chaired the session, which also covered topics on the enhancement of access to radiotheranostics for cancer care through the Oncidium initiative, as well as the different tracers for various indications in every cancer type.

In her presentation, “Current challenges of PSMA PET/CT in prostate cancer”, Assoc. Prof. Daniela Oprea-Lager (NL) cited the EAU Guidelines on Prostate Cancer, which stated PSMA PET/CT is more accurate for staging than CT and bone scan for high-risk disease but to date, no outcome data exists to inform subsequent management.

One of the recommendations of the EAU Guidelines with a “Strong” strength rating was when using PSMA PET or whole-body MRI to increase sensitivity, be aware of the lack of outcome data of subsequent treatment changes.

Assoc. Prof. Oprea-Lager concluded, “We cannot ignore modern imaging techniques and continue re(staging) and treating disease as we did in the era of conventional imaging.” She added that clinical outcomes such as overall survival, disease recurrence, and quality of life should be proven first. Learning how to interpret modern imaging properly and how to treat patients is imperative.

View the session recap and watch the full presentations on the EMUC23 Resource Centre.

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Collaborative efforts are required to drive game-changing advancements in medical research and patient care. The upcoming 15^th European Multidisciplinary Congress on Urological Cancers (EMUC23) is the perfect platform to showcase and review important GU cancer trial results and new technologies.

Plenary Session 7 on day three (Saturday, 4 November, 08:45 – 10:05) of EMUC23 will feature clinical trial presentations and multidisciplinary discussions. This “Game-changing session” will be chaired by Prof. Axel Merseburger (DE), radiotherapist Prof. Valerie Fonteyne (BE) and medical oncologist Prof. Karim Fizazi (FR).

Merseburger: “Multidisciplinary meetings in onco-urology play a pivotal role in fostering collaboration among various medical specialists dedicated to the care of GU cancer patients. The EMUC Congress excels in bringing together experts from diverse fields such as medical oncology, radiation oncology, surgical oncology, pathology, nuclear medicine, urology, and radiology. This inclusive approach cannot be overstated, as it facilitates a comprehensive and holistic evaluation of complex cases and clinical trial presentations”.

“Each specialist contributes unique insights based on their expertise, allowing for a thorough analysis of treatment options and potential challenges. This collaborative strategy helps prevent tunnel vision. It ensures that all available options, from surgery to radiation to systemic therapies and supportive care, are considered in the context of the patient’s overall well-being.”

GU cancer trials to be discussed at EMUC23

Urologist Prof. Maxine Tran (GB) will present on nephron sparing treatment (NEST) for small renal masses: A feasibility cohort-embedded randomised controlled trial (RCT) comparing percutaneous cryoablation (passing small needles through the skin to freeze the kidney tumour) and robot-assisted partial nephrectomy. This RCT is of significant interest due to the lack of high-level evidence on small renal mass (SRM) management, with previous classical RCTs failing to meet accrual targets.

Prof. Stephen Freedland (US) will share the latest progress on the phase 3 EMBARK trial, whereby trial data has shown that adding enzalutamide to leuprolide cuts the risk of metastasis or death by 50% in patients.

Prof. Merseburger: “This is a hot topic right now as the FDA granted priority review of enzalutamide for nmCSPC with high-risk biochemical recurrence. The FDA decision is expected in Q4 of this year for the new drug application that has been supported by data from this phase 3 EMBARK trial. Discussion remains on the value of PSMA-PET in this situation.”

Medical oncologist Dr. Yohann Loriot (FR) will present details on the THOR study reinforcing the activity of erdafitinib as personalised therapy for metastatic urothelial patients with FGFR mutations. Erdafitinib is included in the current EAU bladder cancer guidelines. The THOR study leads to precision medicine in advanced bladder cancer for 3^rd line treatment for patients with EGFR alterations. All metastatic urothelial patients should be tested for FGFR3/2 alterations.

Other trial results that will be presented and discussed by the multidisciplinary panel include TALAPRO-2 and PROpel, as well as an update on PSMA targeting.

Uniting medical experts for innovation and progress

The EMUC23 congress is a collaboration of the European Society for Medical Oncology (ESMO), the European SocieTy for Radiotherapy and Oncology (ESTRO) and the European Association of Urology (EAU). Other sessions that will take place in conjunction with EMUC23 include the EMUC Symposium on Genitourinary Pathology and Molecular Diagnostics (ESUP), the Meeting of the EAU Section of Urological Imaging (ESUI), European School of Urology (ESU courses and Hands-on Training) and the Young Academic Urologists Meeting (YAU).

If you register by 19 October (23:59 CEST) you will benefit from some registration savings. Don’t miss your opportunity to participate within this collaborative learning environment! Browse the full scientific programme.

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In the lecture “Are MRI-targeted and systematic biopsies still a roadmap for therapy?”, Radiologist Dr. Andreas Hötker (CH) stated that MRI-targeted biopsy outperforms TRUS-biopsy alone with more csPCa (clinically significant prostate cancer), and less cisPCa (clinically insignificant prostate cancer) being detected (in both biopsy-naïve and repeat-biopsy). “MRI has the potential to offer significant benefits as part of the MRI pathway with the avoidance of biopsy in ca. 30% of patients and the lower number of cisPCa detected.”

But Dr. Hötker looked a step further to whether MR-targeted biopsy alone is sufficient and pointed out that the benefits and risks of the decision to biopsy have to be balanced out, depending on patient counselling and further risk stratification.

According to Dr. Hötker, “Only 1% of missed csPCa was GS>4+3, and PCa that is not visible on MRI may be less aggressive. The value of additional systematic biopsy is low in patients with PI-RADS 5 or prior negative biopsy. However, PCa is multifocal and small lesions may not be visible on MRI. Multifocality may be important for surgical planning, focal therapy and prognosis”.

“The approach seems safe if an appropriate safety net is in place. Clinical parameters and PSA density may be used as a risk stratification strategy for patients. The 2022 EAU Guidelines suggest that when MRI is negative (i.e. PI-RADS <2), and clinical suspicion of PCa is low (e.g. PSA density < 0.15ng/mL), you can omit biopsy based on shared decision-making with the patient.”

Looking ahead

The reproductivity of prostate MRI/PI-RADS scores were mentioned by Dr. Hötker as a point that needs further work in the future: “Improved standardisation of technical parameters, lesion scoring and reporting is required. Reading certification for radiologists has begun and DMT meetings are in larger centres, but not everywhere. Further work is required on image quality and it’s assessment with the inclusion of scores into the standardised report (PI-QUAL, PSHS), as well as making use of technical advances, such as artificial intelligence (AI).”

“We aim for the best possible diagnostic performance” began urological surgeon Dr. Jochen Walz (FR) in his presentation about the added value of biopsy approaches and risk stratification. “The EAU-EANM-ESTRO-SIOG guidelines all recommend when MRI is positive (i.e. PI-RADS > 3), to combine targeted and systematic biopsy.”

In his opinion, “Not only presence of the disease is relevant, but also the extent of the disease. This is useful to predict extra prostatic extension, seminal vesicle invasion and lymph node invasion, which are all important in risk stratification for surgery. New tools based on imaging and targeted cores need to be validated. Complications are not a reason to skip the increased diagnostic options”.

Radiation oncologist Prof. Peter Hoskin (GB) stated that “MRI-targeted and systematic biopsies are still the roadmap for radiotherapy because of the dose escalation that can be given to the DIL (dominant intraprostatic lesions), sparing of negative glands and reduced toxicity, as well as individualisation of treatment through the molecular analysis of tumour heterogeneity.”

A higher resolution

Focal therapist oncologist Ass. Prof. Clement Orczyk (GB) shared his thought-provoking lecture about the resolution detail required in diagnosis to treat a tumour selectively within the gland. “It is all about resolution. There is a lack of 3D resolution from systematic biopsy to make a good plan, for example: no spatial resolution. The roadmap for a patient-centred treatment in the form of focal therapy needs systematically mpMRI.”

In his opinion, resolution of mpMRI enables the definition of Target for Complete Ablation. “Resolution of standard systematic biopsy is low as it doesn’t detect all foci. Resolution of MRI visibility phenomena is set to detect truly significant disease linked to molecular features. Resolution of mpMRI enables oncological control with focal therapy and can be optimised.”

This followed with the lecture “Should PSMA + MRI guide treatment algorithm in high-risk prostate cancer?”, debated by Nuclear medicine physician Prof. Valentina Garibotto (CH) and Oncologist Dr. Alberto Bossi (FR) and “Biomarkers to guide active surveillance”, presented by Assoc. Prof. Gianluca Ingrosso.

Watch the full presentations from Plenary Session 1 via the EMUC22 Resource Centre.

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The programme launched with Plenary Session 01 “Prostate cancer management: Implementation without good evidence?” which was chaired by Prof. J. Oldenburg (GB), Prof. Dr. Kerstin Junker (DE), Prof. James N’Dow (GB) and Dr. Bradley Pieters (NL).

In his lecture “Functional imaging for recurrent disease”,  Dr. Stefano Fanti (IT) emphasised the relevance of performing more randomised and multi-centre studies to produce and procure more quality and robust data.

As he showed the model of the levels of the evidence pyramid, he said “You don’t have to take into account only  expert opinion;  you have to go through systematic reviews, randomised control trials, multi-centre trials as these are absolutely fundamental.”

As an example, he stated that data from his team’s study “PET/CT with ¹¹C-choline for evaluation of prostate cancer patients with biochemical recurrence: meta-analysis and critical review of available data” was incorporated into the EAU Guidelines. “It’s not only the matter of the final diagnostic accuracy but the fact that study has robust, validated data and better than the competitors’,” said Dr. Fanti. “We provide good images, as well as, good evidence.”

Digital slides
“Information, diagnostic and therapeutic approaches resulting from Digital GU Pathology can be more accurate with less uncertainty when sources are evaluated separately and/or individually. It requires knowledge of previous studies that contributed to the current utilisation and role of virtual slides and quantitative tissue analysis. An ability to integrate data from diverse tests will be required,” stated Prof. Rodolfo Montironi (IT) in his lecture “Digital GU pathology”.

Digital Pathology, also known as whole slide imaging (WSI), refers to the high-resolution digitization and storage of entire glass slides as digital (virtual) slides. The advantages of using these include image sharing, interactive publication, quantitative image analysis, and information fusion.

Image sharing can be used for teaching, consultation, remote interpretation, and quality assurance. A digital pathology platform allows instant sharing of WSI in review cases, as multiple pathologists can review the same case in parallel.

With regard to interactive publication, Prof. Montironi said “When we submit data to a journal, we like to include the images of the histology. So we upload the virtual slides. This means that the readers that can see the slide and all the details.”

Quantitative image analysis (computational pathology) is used for prostate cancer detection and grading; location and identification of High-Grade Prostatic Intraepithelial Neoplasia (HGPIN); malignancy-associated changes; and biomarker expression in individual cells.

Information Fusion is direct integration with data derived, for instance, from surgery and other imaging techniques, such as mpMRI.

Prof. Montironi also stated that the performance of digital pathology is equivalent to glass slide microscopy [Snead, et al 2016].

Sequencing of novel therapies
In his lecture “Sequencing of novel therapies in urogenital malignancies”, Dr. Sergio Bracarda (GB) stated that at present, Abiraterone (ABI) or docetaxel (DCT) plus androgen deprivation therapy (ADT) are the new standards of care for cases presenting with high-risk metastatic castration-sensitive prostate cancer (HR-mCSPC), but which is better is not yet known. He added that radiotherapy may be evaluated in cases presenting with LV (oligometastatic?) disease.

Dr. Bracarda said that immediate sequencing between ABI and Enzalutamide (ENZA) should be discouraged, while AR-V7 possibly remains only a prognostic tool; and asked about the relevance and role of Radium-223 (Ra-223).

He foresees that non-androgen receptor (AR) novel targeted therapies such as P13K/AKT or poly-ADP ribose polymerase (PARP) inhibitors, and other new agents, such as checkpoint inhibitors will enter the prescription (Rx) scenario. “These new agents, after being tested in biologically designed Phase III studies, will modify the actual clinical sequencing in a genome-based, step-by-step verified sequencing. The future is here!”

To know more, access the EMUC18 Resource Centre.

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