CUOS 2019: Neoadjuvant Chemotherapy for All Muscle-Invasive Bladder Cancer

Toronto, Ontario ( Dr. Nimira Alimohamed presented her opinion of the question in debate: neoadjuvant chemotherapy for all muscle-invasive bladder cancer versus neoadjuvant chemotherapy guided by molecular subtyping.  Dr. Alimohamed believes all medically fit patients with muscle-invasive bladder cancer should be offered neoadjuvant chemotherapy before radical cystectomy. Furthermore, she strongly believes that neoadjuvant chemotherapy should not be guided by molecular subtyping at this point. Neoadjuvant chemotherapy has been shown to confer a survival benefit with a difference of more than 30 months (77 vs. 46 months).1 There are, however, still several unresolved issues with the current standard of care:

  1. The standard regimen has not been defined yet (Gemcitabine and cisplatin vs. dense dose methotrexate, vinblastine, doxorubicin, and cisplatin).
  2. The rate of non-responders is considerably high with up to 60% of patients having invasive muscle disease following neoadjuvant chemotherapy, with no apparent downstaging.
  3. Patient selection is quite important – even though great progress has been made in precision oncology, it is still not ready for “prime-time.”
Next, Dr. Alimohamed discussed why molecular subtyping is still not ready to be used in a standardized way. Firstly, it continues to be refined, and there is considerable intratumoral heterogeneity, making the concept of molecular subtyping quite difficult. Second, the availability/accessibility of testing is still problematic. Lastly, there is a lack of prospective validation data.

There are four main molecular classification systems that have emerged during the years, including the Lund, MDA, UNC, and TCGA. Figure 1 demonstrates some attributes of these different classification systems. Using the single-sample genome classifier, investigators analyzed the impact of these different subtyping methods on patient response to neoadjuvant chemotherapy.2 For this study, transcriptome-wide microarray analysis was conducted on TURBT samples from 223 patients. The genomic classifier was trained to predict four subtypes: Claudin-low, basal, luminal-infiltrated, and luminal. The results showed that luminal tumors have the best overall prognosis, independent of whether patients received neoadjuvant chemotherapy. Basal tumors had the greatest improvement in overall survival with neoadjuvant chemotherapy compared to radical cystectomy alone. Claudin-low tumors had the worst overall survival regardless of the treatment regimen. Lastly, the single-sample genomic classifier was better at assigning patients to a definitive subtype. The limitations of this study include its retrospective design and the fact that the patient cohorts are from different samples.

Recently, the bladder cancer taxonomy group has issued a new classification system with six consensus classes (luminal papillary, luminal non-specified, luminal unstable, stroma-rich, basal/squamous and neuroendocrine like).

Figure 1- The Different Classification Systems:
UroToday CUOS19 The Different Classification Systems

The next topic discussed was whether specific gene mutations are associated with an improved response to neoadjuvant chemotherapy. Mutations in the ERCC2 and ERBB2 mutations have shown such an association. Moreover, defects in DNA repair genes have demonstrated an association with heightened response to neoadjuvant chemotherapy.3 The mutations in ATM, RB1, and FANCC have predicted such a response with 100% specificity. In a prospective study evaluating neoadjuvant chemotherapy given as dense dose gemcitabine and cisplatin, a total of 49 patients were analyzed.4 Neoadjuvant chemotherapy resulted in downstaging in 57% of patients, and the presence of DNA damage response gene alteration was associated with chemosensitivity. However, most responders did not harbor these mutations.

Dr. Alimohamed moved on to discuss intra-tumoral heterogeneity. In a recently published study, intratumoral heterogeneity was demonstrated in 39% of cases with multiple tumor histology.5 This finding means that we need to worry about sampling error because if we do not account for intra-tumor heterogeneity, this could have a significant effect on our decision to administer neoadjuvant chemotherapy, based on molecular subtype.

The last topic discussed was the varying accessibility of testing, and the length of time it takes to get molecular subtyping results. Additionally, the timing of when neoadjuvant chemotherapy is given is most important. Patients starting neoadjuvant chemotherapy more than eight weeks after being diagnosed with muscle-invasive bladder cancer had an odds ratio of upstaging of 1.27, p-0.031).6

In conclusion, molecular subtyping continues to be refined. Intratumor heterogeneity is an important concept and must be incorporated when relying on molecular subtyping to help decide which patient should receive neoadjuvant chemotherapy. Lastly, the availability of testing for molecular subtyping needs to improve, and we need more prospective validated data to ascertain its true impact.

Presented by: Nimira Alimohamed, MD, FRCPC, Medical Advisory Board, University of Calgary, Calgary, Alberta, Canada

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter: @GoldbergHanan at the CUOS – Canadian Uro-Oncology Summit 2019, #CUOS19 January 10-12, 2019 Westin Harbour Castle, Toronto, Ontario, Canada

1. Grossman et al. NEJM 2003
2. Seiler R et al. Eur Urol 2017
3. Plimack et al. Eur Urol 2015
4. Gopa  et al. JCO 2018
5. Warrick J. et al. Eur Urol 2018
6. Audenet F et al. Urol Oncol 2019

Further Related Content:
Neoadjuvant Chemotherapy Guided by Molecular Subtyping