Bladder cancer in young patients

Dr Roland Seiler (Inselspital University Hospital of Bern, Switzerland) showed that bladder cancer morphology appears to be different in younger patients, with urothelial carcinoma being rarely observed in paediatric patients, whereas clear cell adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma are more common. The underlying hypothesis is that there are molecular aspects of bladder cancer that are unique to younger patients.

Dr Seiler explained, “We do tend to see clusters of bladder cancer in some families, but it can be difficult to discern if these are due to shared risk factors, such as environmental exposures or lifestyle choices (i.e. tobacco use), or if these are due to germline mutations within the family.”

Importantly, there are currently no guidelines about when to refer younger patients with bladder cancer to genetic counselling. Other malignancies, however, have tackled this unmet need [1], and Dr Seiler pointed out that for the time being we should adopt similar practices. In short, if a patient is <50 years of age, or if they have >3 cases of breast, ovarian, pancreatic, or prostate cancer in close relatives (per definition parents, siblings, or children), it is reasonable to offer genetic counselling.

There is scant data examining germline mutations in bladder cancer to date; one recent study sequenced a selected cancer-related gene panel in 98 bladder cancer patients [2]. Although the authors concluded that germline mutations within this cohort were related to DNA repair, this study was not genome-wide, and was inherently biased because the selected gene panel featured many genes involved in DNA repair.

Analysing the Cancer Genome Atlas Program, a few known somatic differences between older and younger patients with urothelial carcinoma have been identified. For example, inactivating mutations in canonical tumour suppressor genes RB1 and TP53 are associated with younger patients, as well as higher neoantigen loads, and higher interferon-gamma signalling and chemokine signalling. Of the known molecular subtypes of urothelial carcinoma, the luminal papillary subtype appears to be more prevalent in younger patients. Interestingly, this luminal papillary subtype has characteristically low levels of immune infiltrate that make it potentially less likely to show a favourable response to checkpoint inhibition treatment. In exciting complementary data, transcriptome profiling of 368 tumour samples from patients in the IMvigor 210 trials with platinum-refractory or cisplatin-ineligible urothelial carcinoma who were treated with the PD-L1 inhibitor atezolizumab trial revealed that the TP53 and/or RB1 mutated samples in neuronal tumours of the Lund subtype classification was associated with the best response [3].

In a video interview, Prof. Morgan Rouprêt (Pierre and Marie Curie University, France) and Prof. Fiona Burkhard (Inselspital University Hospital of Bern, Switzerland) gave insights from the plenary session at EAU19 looking at bladder cancer in the young patient and why is it important to focus on these patients [4].

1. Shuch et al. J Clin Oncol. 2014 Feb 10;32(5):431-7.
2. Na et al. BJU Int 2018 Nov;122(5):808-813.
3. Kim et al. Eur Urol. 2019 Mar 6. pii: S0302-2838(19)30160-5.
4. https://www.youtube.com/watch?v=wgGKVB_-7cA&list=PLCVO1Vai8uzXJOGRwfLw5uDBghBvjcfKe&index=8&t=0s

Posted on 21 May, 201917 March, 2021