Today I will start a new small series: Uropathology for urologists and uro-oncologists.
@urotoday
@OncoAlert
@imedverse
Let us start with my favorite topic: Urothelial Cancer!
You will often hear urothelial cancer is a heterogeneous disease, but why ?
We are happy to share our new study published today
@JCO_ASCO
(👉 ) on the role of NECTIN4 amplifications to predict responses to Enfortumab Vedotin treatment in metastatic urothelial cancer.
With a huge contribution of our multinational team we uncovered
Today I will start a new small series: Uropathology for urologists and uro-oncologists.
@urotoday
@OncoAlert
@imedverse
Let us start with my favorite topic: Urothelial Cancer!
You will often hear urothelial cancer is a heterogeneous disease, but why ?
It is incredible how fast the landscape of 🎯 targeted chemotherapies evolves🏄♂️. Antibody drug conjugates came to stay!
➡️ exciting times to study the tumor cellular surfaceome 🏄♂️ ‼️
➡️ Multiple new predictive tests für ADCs will enter pathological testing soon opening a whole
FGFR3 mutations are frequent alterations in urothelial cancer, but 🚨:
➡️ NMIBC: ~50% are mutated
➡️ MIBC: ~10% are mutated
➡️ UTUC stage independent: ~ 30% are mutated
➡️ mUC (=bc + UTUC): ~15-20 % are mutated
Fusions are very rare throughout all entities! Frequency is ~1%‼️
🚨🚨 EV-302 data finally published
@NEJM
! Such a breakthrough for
#metastatic
#urothelial
#cancer
with doubling in OS and „insane ORR“.
👉 First
#therapy
improving OS massively by doubling overall survival of frontline metastatic patients‼️
👉 All subgroups show huge benefits‼️
Really honored that our paper has been selected as best translational paper published
@EUplatinum
#EAU24
☺️. Highlights the importance of assessing biomarkers in the right tissue specimen especially for immune biomarkers 🎯. Thanks so much to all contributors
@niklas_kluemper
It‘been a while, but 🎉🔬 The 17th episode is out.
The last entity we tackled was the „incarnation“ of hot/inflamed urothelial carcinomas🔥🔥🔥🔥
But what do you know about PD-L1 testing ?
Today
@MattGalsky
presented important data of CheckMate274 at
#EAU24
. PD-L1 positive
🔬 After years of relentless dedication two incredible minds have achieved a major scientific award
@dgukongress
! Their journey in testis and urothelial cancer research is a testament to the power of collaboration and perseverance.
@niklas_kluemper
@tim_nestler
@urotoday
Final results from
#ASCENT
in
@JCO_ASCO
. SG demonstrates huge OS benefits in patients with triple negative
#breast
#cancer
. Although benefit present in all subgroups, there is an incremental benefit dependent on TROP2 surface expression 🏄♂️!
👉 another piece of the puzzle‼️🎯
🎉🔬 The 18th episode is out.
Trastuzumab-Deruxtecan approved by FDA two days ago! Agnostic approval including bladder cancer
🚨‼️🎯 But only for Her2neu 3+ positive tumors!
👉 but what does 3+ actually mean?
Similar to PD-L1 testing different assays and algorithms exist
Our latest paper ist out in
@Histo_Journal
! We comprehensively studied the membranous protein expression of the two important
#ADC
targets TROP2 and NECTIN4 (surfaceome 🏄♂️). it is the first paper on protein expression in a large cohort of over 200 muscle-invasive and metastic
🎉🔬 The 13th episode is out.
➡️ What is the difference between nested and large nested urothelial carcinoma ? 🤓
➡️Large 🪺🪺 nested urothelial carcinoma (LNUC) is a very particular subtype of
#urothelial
#cancer
that is rare but biologically (🧬🧬) very interesting🏄♂️‼️
➡️
Really honored to receive this funding by
@EKFStiftung
! It is a great opportunity to push our group‘s effort to develop novel (immunotherapy) approaches for
#urothelial
#cancer
patients!
Sacituzumab + Pembro is efficacious in metastic urothelial cancer following progress on platinum based chemotherapy !! Very interesting study by
@PGrivasMDPhD
and
@y_loriot
and team that unfortunately comes late. Is there still a place for this regimen after EV302 results ?
But
Long term update on he predictive value of MIBC response to NAC molecular subtypes presented by
@djmcconkey
at
#AACRBladder
@AACR
. Some inconsistencies, but seems that certain luminal tumors respond better - but mixed with prognostic impacts as well - difficult.
But clinical
Really grateful that
@joostboormans
highlighted our study on membranous NECTIN4 expression which is related to EV response/resistance published recently in
@CCR_AACR
@AACR
. Rising Star
@niklas_kluemper
first author also gave a great presentation on
#EAU2023
on the full abstract.
Thank you
@EUplatinum
for highlighting our recently published paper on the predictive value of spatial immune microenvironment composition for immune checkpoint inhibition in metastatic urothelial cancer! Twittorial follows!
Spatial Immunephenotypes of Distant Metastases but not Matched Primary UC Predict Response to ICI
Erlmeier,
@Markuseckstein3
et al
"MET immunephenotypes & MHC-I status show potential to predict chemo & durable ICI responses, while PRIM TIME does not"
🎉🔬 The 15th episode is out.
👉 Last Episode tackled FGFR3 testing
#urothelial
#cancer
👉
🚨🚨 But which tissue would you use/request for testing? 🚨🚨
👉Primary tumor ?
👉Metastatic Biopsy ?
👉Liquid Biopsy ?
This is extremely important, maybe
FGFR3 mutations are frequent alterations in urothelial cancer, but 🚨:
➡️ NMIBC: ~50% are mutated
➡️ MIBC: ~10% are mutated
➡️ UTUC stage independent: ~ 30% are mutated
➡️ mUC (=bc + UTUC): ~15-20 % are mutated
Fusions are very rare throughout all entities! Frequency is ~1%‼️
🎉🔬 The 16th episode is out.
We are still in the middle of
#subtype
#urothelial
#cancer
histologies.
👉 what is the prime example of an inflamed UC with high checkpoint expression 🤓? 🔥🔥🔥🔥
👉 How would you call the histology below on the picture below ?
@niklas_kluemper
following
@pcvblack
giving a detailed overview on NECTIN-4 ADC development in urothelial cancer.
Critical talk on the potential role of NECTIN4 being an important. Membranous expression is heterogenous among histologies and molecular subtypes (absent in basal
In the first part we tried to understand the architecture of regular urothelium and key markers expressed in different layers of it. This important to understand why urothelial cancer can appear with multiple molecular and histological subtypes.
Today I will start a new small series: Uropathology for urologists and uro-oncologists.
@urotoday
@OncoAlert
@imedverse
Let us start with my favorite topic: Urothelial Cancer!
You will often hear urothelial cancer is a heterogeneous disease, but why ?
Long Term results from PROFOUND out. Clearly showing the tremendous (🧪) predictive potential of deleterious BRCA alterations for PARP inhibitor Olaparib in metastatic castration resistant
#prostatecancer
!!
Although certainly not powered for that: ‼️ germline BRCA patients tend
Really nice paper demonstrating that tumor cell subtype lineages stay stable during metastatic evolution of upper urinary tract
#urothelial
#cancer
! Confirms our results from Cox et al, 2023 for bladder urothelial cancer
Congrats Bishoy for this elegant
ctDNA profiling seems to have severe blind spots depending on metastasis location🤯. More pathogenic variants identified by tissue sequencing.
🧬🧪👉 What does this mean for targetable alterations? We likely miss some in ctDNA…
@OncoAlert
@imedverse
@urotoday
@niklas_kluemper
Very pleased to share our latest work: Molecular Urothelial Tumor Cell Subtypes Remain Stable During Metastatic Evolution published in
@EUPlatinum
- -
@niklas_kluemper
@markuseckstein3
. Follow our tweetorial about these clinically relevant data 1/9
Great talk by
@niklas_kluemper
on the emerging role of NECTIN4 and related biomarkers to predict EV responses. Timely at background of groundbreaking EV302! Huge potential for true precision oncology with smart chemotherpies.
@Uroweb
@urotoday
@OncoAlert
#EMUC2023
Really delighted that our novel pattern based grading approach for pT1 urothelial carcinomas is published
@BJUIjournal
‼️
👉 Growth and Invasive patterns
👉combined with tumor budding
Outperform conventional grading systems and risk classification.
👉Assessment can be done via
🎉🔬 The 3d episode of my Uropathology series tailored for Urologists & Oncologists is OUT NOW! Dive into the world of genitourinary cancers and enhance your expertise 🌟🩺 Featuring insights for
@AmerUrological
,
@Uroweb
,
@ASCO
,
@PathSoc
. Don't miss out!
#Uropathology
In the first part we tried to understand the architecture of regular urothelium and key markers expressed in different layers of it. This important to understand why urothelial cancer can appear with multiple molecular and histological subtypes.
Final Results of POUT Trial out
@ASCO
#JCO
! Adjuvant platinum-based chemotherapy 🧪 increases disease free survival increase for upper urinary tract
#urothelial
#cancer
patients, but not overall survival 🥲.
However great study by Allison Birtle and group.
Important message
🚨🚨 EV-302 data finally published
@NEJM
! Such a breakthrough for
#metastatic
#urothelial
#cancer
with doubling in OS and „insane ORR“.
👉 First
#therapy
improving OS massively by doubling overall survival of frontline metastatic patients‼️
👉 All subgroups show huge benefits‼️
Cannot agree more ! ADCs need their target to bind -> no target no action.
It is an exciting time for translational research in this field. Pathologists need to be involved as we will need to test for many indications soon likely!
oncology!
@Markuseckstein3
@PTarantinoMD
We are looking for a motivated PhD student for exciting spatial transcriptomics projects in urothelial cancer! Our lab has been involved in important clinical and translational molecular UC research in the past years. PM if you are interested to join!
🏆
#EMUC23
Best Abstract Kidney Cancer:
Prof. Viktor Grünwald (Essen, DE)
Abstract: O12 - Tumor response by baseline metastases in patients with renal cell carcinoma (RCC) treated with lenvatinib (L) plus pembrolizumab (P) vs sunitinib (S): Post hoc analysis of the CLEAR trial.
Really delighted being a Ort of this great study just published
@nature
biomedical engineering. Congratulations
@GuckLab
@JochenGuck
to this great success and looking forward to exciting projects in the future ! This methodology is exciting for rapid diagnosis on frozen sections!
Excited to share our latest paper in Nat Biomed Eng. With a
#TissueGrinder
we can dissociate biopsies and then use
#RTDC
and
#AI
to distinguish cancer from healthy tissue based on cell deformability and other physical parameters
@MPZ_PhysMed
@UniFAU
These are truly fantastic results for patients with dMMR endometrial cancer. Another impressive proof of PD-1 inhibitors being especially effective in tumors with extremely high putstive neoantigen load and antigenicity
@OncoAlert
@niklas_kluemper
Molecular Grading at Its Best! Take a look of this newly published paper
@EurUrolOncol
, led by
@Markuseckstein3
. Great honor to be part of this study
We proposed a novel, prognostically relevant, and biologically based scoring system for
#bladdercancer
@SiaLindskrog
giving a great overview on NMIBC molecular subtype work that has been done in last decade(s) mainly driven by the Aarhus Group led by
@LDyrskjot
.
It is fascinating how you and other groups moved this field to this stage! And great to hear that you are aiming for a
Our new paper plates the role of FGFR3 alterations and its influence on BCG treatment of NMIBC is out now online first in European Urology.
@EUplatinum
Prognostic and Predictive Value of Fibroblast Growth Factor Receptor Alterations in High-grade Non–muscle-invasive Bladder Cancer Treated with and Without Bacillus Calmette-Guérin Immunotherapy
@Markuseckstein3
@mahadibaig
Cool Study by
@shilpaonc
and
@BenMironMD
!
#ctDNA
is really an interesting tool for molecular disease surveillance. Guess the major benefit will be molecular follow-up when ctDNA turns out to be reliable and sequencing becomes cheaper!
#exciting
#time
! Looking forward to seeing
The urothelium consists of three different layers:
1) Basal cell layer: cells that express markers like CK5, CD44, but not GATA3 or FOXA1
2) Intermediate cell layer: differentiated cells that express CK7 (cytokeratin found in glandular epithelium!!!), GATA3, FOXA1 and PPARG.
We have a PDL-1 assessment method where there are many different antibodies and the methodology does not match exactly.
Moreover, we see significant inconsistencies between studies of the same drug on different tumors, or studies of different drugs on the same tumor.
In this
@SaraEWobker
kicking off
#AACRBladder
@AACR
on day 1 with a comprehensive overview on urothelial cancer histology including divergent and subtype histology. Important topic that cannot be reacted often enough - especially to arise awareness for the biological and clinical
Really important study by
@DanNett1980
! Congratulations and thank you for involving me.
Car-T-cells are a promising new therapeutic concept not only for liquid neoplasms. Really excited to see further data on their efficacy against urological neoplasms.
Happy to share a collaborative work where I was involved as „immunopathologist“
@NatureMedicine
! Beside my oncology hobby we provide services for tissue monitoring therapy responses to autoimmune diseases.
Led by
@grieshaber
and Georg Schett our study shows
👉 that
🎉🔬 The 3d episode of my Uropathology series tailored for Urologists & Oncologists is OUT NOW! Dive into the world of genitourinary cancers and enhance your expertise 🌟🩺 Featuring insights for
@AmerUrological
,
@Uroweb
,
@ASCO
,
@PathSoc
. Don't miss out!
#Uropathology
Really nice to see that there is growing interest in deep profiling of penile cancer - a hard treat aggressive cancer entity that has been widely neglected in the last decades !
@OncoAlert
@ASCO
@urotoday
#GU24
Excited to unveil the biological landscape of penile cancer at
@ASCO
#GU24
. Stop by poster board E7 for a journey into the penile cancer single-cell RNA sequencing wonderland 🧬🔬
Big shoutout to
@MaartenAlbersen
for all the guidance 🙏🏼
Last generation sequencing 🤓 - Sanger Sequencing:
Do not underestimate these techniques🚨 they are ancient but very powerful! Nothing beats Sanger sequencing sensitivity‼️
👉 there is a nice snapshot multiplex PCR approach for FGFR3 (see below).
Advantage:
👉 Highly
We are extremely grateful for our new collaborative grant by the IZKF Erlangen to study chemotherapy and immunotherapy resistance together with
@Engel_FB_Lab
! Two PhD positions are open!
The Engel lab is highly grateful for new funding by the IZKF (interdisciplinary center for clinical research) Erlangen for studying
#ferroptosis
and chemo-/immunotherapy resistance in
#urothelial
carcinoma in collaboration with
@Markuseckstein3
(two PhD positions).
Thanks
@urotoday
for highlighting our article on CRP kinetics predicting response to immune checkpoint inhibitor treatment of patients with metastatic urothelial cancer!
Exploring the profound implications of pinpointing ADC targets across a multicancer landscape, this study sheds light on novel therapeutic pathways and target expression of
#ADCtargets
. Highly valuable pper for an exciting era of
#precisiononcology
.
#CancerResearch
.
Great paper by Bosi et al: Pan-cancer analysis of antibody-drug conjugate targets and putative predictors of treatment response🎯Co-expression of various ADC targets (e.g. NECTIN4) again highlights potential for agnostic ADC therapy
@OncoAlert
@urotoday
Really nice results from the Rotterdam Team
@AlbertoNakauma
@NatureComms
! Confirms the results we published 2023 in
@EUplatinum
➡️
Thank you for also confirming that METASTATIC tissue samples are highly predictive for immunetherapy. Another hint for poor
New short correspondence out
@JAMAOnc
by
@montypal
and team.
Astonishing ORR for metastatic
#prostatecancer
with TMB >=10 Mut/mb. Mutation rates are however in stark contrast to much larger series reported before in mCRPC! (>95% of PC with TMB <1-2 Mut/mb). What is the MSI
Liquid biopsies: In principle these assays are ultra deep NGS sequencing assays, so see ☝️!
➡️ Careful: Liquid biopsies are often hyped by oncologists, but have severe limitations!
➡️ Liquid biopsies have severe blind spots, especially if tumors are not shedding ctDNA to the
This was thought as episode 14 ;-) the epilogue is missing:
🎉🔬 The 14th episode is out.
👉 Last Episode was on large nested urothelial cancer, the prototype of fgfr3 mutant
#urothelial
#cancer
👉Thus here an excursion to FGFR3 testing which very important as Erdafitinib -
FGFR3 mutations are frequent alterations in urothelial cancer, but 🚨:
➡️ NMIBC: ~50% are mutated
➡️ MIBC: ~10% are mutated
➡️ UTUC stage independent: ~ 30% are mutated
➡️ mUC (=bc + UTUC): ~15-20 % are mutated
Fusions are very rare throughout all entities! Frequency is ~1%‼️
Thank you
@EUplatinum
for highlighting our recently published paper on the predictive value of spatial immune microenvironment composition for immune checkpoint inhibition in metastatic urothelial cancer! Twittorial follows!
Studying metastatic biology rather than primary site biology (eg archival tissue) is urgently needed. But different tumors will remain different at metastatic sites based on their primary site traits. Primary biology and evolution drives metastasis not the host organ!
Great perspective from
@FAndreMD
&
@BenjaminBesseMD
@Nature
: The community urgently needs to shift from using organ-based classifications of cancer to using molecular-based ones -> Tumor-agnostic targeted therapies (e.g. ADC) will be important for rapid implementation
@OncoAlert
Great summary of urothelial cancer highlights at ESMO!
@sonpavde
! Exciting times for urothelial cancer patients and their families. Hope that similar breakthroughs will be seen for early stages (curative settings)! Also time for precise biomarkers !
@urotoday
@OncoAlert
Happy to share our work: Membranous NECTIN-4 expression frequently decreases during metastatic spread of urothelial carcinoma and is associated with enfortumab vedotin resistance
@CCR_AACR
Follow our tweetorial about this clinically important data 1/12
Cannot agree more! Aiming without a target being present does not make biological sense!
We need detailed analyses of clinical trials to learn which patients are really responding based on target protein expression. Everything else is contradictory to precision medicine!
HER2 heterogeneity is important for HER2-ADC response. ADC response depends on its target gene expression🎯
EV response depends on NECTIN4 (PMID: 36534531) but heterogeneous NECTIN4 in mUC has not yet been systematically investigated!
@OncoAlert
@urotoday
Take Home:
➡️ TROP2 widely expressed on cell membranes of UC except neuroendocrine and sarcomatoid!
➡️ NECTIN4 membranous expression is heterogenous and clearly linked to luminal UC! Low or negative on membranes in Basal squamous‼️
➡️Membranous NECTIN4 protein expression
The companion diagnostic assay approved for FGFR3 alteration detection in conjunction with Erdafitinib is the Therascreen assay from Quiagen:
➡️ This assay requires RNA‼️ from FFPE or liquid biopsies‼️
➡️ … and detects mutation or fusion specific transcripts via a RT-qPCR‼️
➡️
Great work by
@niklas_kluemper
et al. finding that 24% of mUC have Nectin4 ampl, which predicts ⬆️ORR (96% vs 32%) & ⬆️OS with the ADC
#EV
. Excited to see EV data for MBC presented at ASCO by
@antgiorda
& to study this biomarker in breast cancer. Congrats!
Cannot agree more, great news for patients with no more therapy options but high expression of Her2neu! This is an important approval, which is expanding the landscape of ADCs🎯. Exciting times, and more precise biomarker work for us pathologists !
@AmerUrological
,
@Uroweb
,
Great news again! First agnostic ADC approval for anti HER2
#TDXd
based on DESTINY-PanTumor02!
@US_FDA
Approval based on HER2-biomarker-selection, only HER2 IHC3+ solid tumors with no satisfactory alternative treatment options
-> ADC targetability matters!
Great news for
These data are huge for RCC patients. Long-term plateau really underlines the role of Nivo IPI as current SOC. It would be so nice to see pathological (eg sarcomatoid histology) and biomarker subgroup analysis!!
#GU24
@ASCO
@urotoday
@OncoAlert
🔎 Conclusion
NECTIN4 amplifications serve as effective genomic predictors for both EV response and long-term survival in mUC patients.
🧐 Significance
This finding could guide personalized treatment strategies in mUC patients and potentially other cancers with NECTIN4
Our latest paper ab predicting survival of muscle invasive urothelial Cancer patients after curative cystectomy and adjuvant chemotherapy based on a cytotoxic T-cell related gene expression signature just went online today in JITC! Thanks to all contributors, a great effort!
New
#JITC
article: Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy
@Markuseckstein3
🎉🔬 The 2nd episode of my Uropathology series tailored for Urologists & Oncologists is OUT NOW! Dive into the world of Genitourinary pathology and enhance your expertise 🌟🩺 Featuring insights for
@AmerUrological
,
@Uroweb
,
@ASCO
,
@PathSoc
. Don't miss out!
#Uropathology
In the first part we tried to understand the architecture of regular urothelium and key markers expressed in different layers of it. This important to understand why urothelial cancer can appear with multiple molecular and histological subtypes.
Urothelial cancer is considered to arise from the urothelium of the renal pelvis, the ureter, the urinary bladder and the urethra. Importantly, urothelium is a specialized epithelium that has both features of glandular and squamous epithelium!
📊 Results
High Frequency: NECTIN4 amplifications frequent in bladder cancer (17% in TCGA data; 26% in study cohorts).
Positive Response: 96% objective response rate in mUC-EV patients with NECTIN4 amplifications versus 32% in those without.
Survival Benefit: NECTIN4