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Molecular Characterization of Residual Bladder Cancer after Neoadjuvant Pembrolizumab - Beyond the Abstract

A transurethral resection of bladder tumour (TURBT), followed by neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) is a standard-of-care therapy for muscle-invasive bladder cancer (MIBC). It is becoming increasingly apparent that systemic therapy, such as immune therapy or chemotherapy, can also induce gross changes in the biological character of a patient tumor.1-3  However, in this study we have provided evidence suggesting that the TURBT procedure can impact the tumor biology by itself. As TURBT is a surgical procedure, tissue damage occurs not only to the tumor but also to the surrounding bladder wall which can elicit a wound healing response in both host and tumor tissue.4  The nature of the tissue replenishing the wound site is likely to be some combination of scar, normal bladder, and tumor tissue.


In RC samples of a cohort treated with neoadjuvant atezolizumab, tumors were enriched with an inflamed subtype (Lund model5), which was suggested to be in response to systemic neoadjuvant therapy leading to a ‘tissue repair’ molecular signature.1 Likewise, in a cohort of residual tumor tissue after platinum-based systemic therapy, a ‘scar-like’ subtype was identified in 15% of tumors.2 In this study, half of the residual bladder tumors were defined by a scar-like subtype,6 which have consistent features with the stroma-rich subtype of the consensus bladder classifier.7  Collectively, these data suggest wound-healing or scarring in tumors represents a major response mechanism to therapeutic intervention in MIBC.

However, the underlying question remains: is a wound-healing or tissue repair signature in treated tumors response to TURBT, to systemic therapy, or to both?  Insights to this question may be found in transcriptome profiles derived from residual tumor tissue from patients who did not receive systemic therapy.  In the absence of the selective pressures imposed by systemic therapy, treatment naïve tumors should, at least in principle, represent the unchanged tumor from TURBT. In untreated tumor tissue collected at RC, we also identified a scar-like subtype which suggested that a wound-healing signature can be induced in the tumor in the absence of systemic therapy and was therefore likely in response to TURBT.6  Unfortunately, matched TURBT samples were not available for these patients.

While the scar-like subtype has been reported in the cohorts of immune and chemotherapy-treated tumors, there are some important differences in the clinical presentation. In both the NAC (chemotherapy) and PURE-01 (pembrolizumab) cohorts in this study, patients with scar-like tumors appear to have improved outcomes compared to either basal or luminal tumors, while in the untreated, RC-only cohort (UTSW) outcomes were similar for all three subtypes.6  Here, it is probably that the addition of systemic therapy improves outcomes by the control of micro-metastases, regardless of the impact of therapy on the primary tumor.


For all studies to date, there is no consistent pattern for how a given tumor subtype may respond to systemic therapy, which is a current limitation for developing predictive models.  However, there is significant potential for clinical utility in profiling treated tumor tissue to inform adjuvant treatment decisions. Importantly, there is consistency in the definitions of the molecular subtypes post-treatment, regardless of the type of therapy.  To relate these to the consensus bladder cancer model, basal tumors are consistent with the Basal/Squamous subtype and luminal tumors have similarity to the broader luminal classes, including Luminal Papillary, Luminal Unstable, and Luminal Non-specified.7  As described above, the scar-like subtype shares features with the stroma-rich subtype.7  The immune subtype, defined by very high immune infiltration and activity, is unique and appears to be limited to NAC-treated tumors as this was not reported for untreated or pembrolizumab-treated tumors.2,6

A single-sample classifier trained to identify each of these four subtypes would be essential for deploying this information to the clinic.  Each of these classes has the potential to have an improved response to selected adjuvant therapy as depicted in Figure 1.6 This represents a rationale for the development of clinical trials to test novel agents or immunotherapy drugs while taking into account the potential for alterations of primary tumor tissue due to previous therapy. There would be several advantages in proposing personalized adjuvant therapies based on molecular profiling of radical cystectomy tissue, although one of the most important would be the restricted use of expensive novel agents to patients who, only administering them to impact best for the benefit of these potentially curable patients.

We are confident that this era of personalized perioperative therapy is just around the corner.

TURBT_BTA.png


Figure 1. Molecular subtypes of tumors collected at radical cystectomy with potential targets for adjuvant therapy.

Written by: Ewan A. Gibb, PhD1 and Andrea Necchi, MD2

  1. Decipher Urologic Cancers, Veracyte Inc., Vancouver, British Columbia, Canada
  2. Vita-Salute San Raffaele University, Department of Medical Oncology, IRCCA San Raffaele Hospital and Scientific Institute, Milan, Italy

References:

  1. Powles T, Kockx M, Rodriguez-Vida A, et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med. 2019;25(11):1706-1714.
  2. Seiler R, Gibb EA, Wang NQ, et al. Divergent Biological Response to Neoadjuvant Chemotherapy in Muscle-invasive Bladder Cancer. Clin Cancer Res. 2019;25(16):5082-5093.
  3. Faltas BM, Prandi D, Tagawa ST, et al. Clonal evolution of chemotherapy-resistant urothelial carcinoma. Nat Genet. 2016;48(12):1490-1499.
  4. Patel SG, Cohen A, Weiner AB, Steinberg GD. Intravesical therapy for bladder cancer. Expert Opin Pharmacother. 2015;16(6):889-901.
  5. Sjodahl G, Lauss M, Lovgren K, et al. A molecular taxonomy for urothelial carcinoma. Clin Cancer Res. 2012;18(12):3377-3386.
  6. Necchi A, de Jong JJ, Raggi D, et al. Molecular Characterization of Residual Bladder Cancer after Neoadjuvant Pembrolizumab. Eur Urol. 2021.
  7. Kamoun A, de Reynies A, Allory Y, et al. A Consensus Molecular Classification of Muscle-invasive Bladder Cancer. Eur Urol. 2020;77(4):420-433.

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