In this study, the authors assess gene profile expression of 133 cisplatin-resistant BC patients to answer just that question. Matched pre-chemotherapy samples were available in 116 cases, allowing for a comparison. In addition, the former tumor bed (non-neoplastic scar tissue) of 21 post-NAC RC specimens with complete pathologic response was profiled.
Unsupervised consensus clustering yielded four distinct consensus clusters (CC) or subtypes. Two CC’s expressed genes known from previously described molecular subtypes of chemotherapy naïve BC: CC1 and 2 expressed genes consistent with a basal-like (KRT5/6, KRT14) and a luminal-like (GATA3, PPARG) phenotype and were called, CC1 basal and CC2 luminal, respectively. CC3 expressed a strong T-cell signature, markers for T-cell receptor signaling, chemokines and checkpoint molecules (CTLA4, CD80) and was therefore called CC3 immune. CC4 was associated with wound healing/scarring (MYH11, CNN1). This ‘scar-like’ character of CC4 was highly consistent with the scar samples (n=21). Consequently, CC4 was called CC4 scar-like.
In terms of comparisons, CC1 basal showed lower expression of immune related genes compared to CC3 immune (but still had evidence of expression), while CC2 luminal showed almost no expression of immune related markers. IHC for KRT5/6, CD44, GATA3, PPARg, KI67 and CD8 confirmed the biological characteristics of the CC.
Despite being pathological non-responders, patients in CC4 had favorable prognosis compared to patients in CC1-3. On MV analysis, CC4 (HR 0.36) and CC1 (HR 0.46) had improved survival compared to CC3. CC2 was not significantly different than CC3. As CC1 matches closest with basal subtype, this is consistent with current literature.
When comparing pre- and post-chemo samples, both basal- and luminal-like pre-NAC BC showed similar rates of tumors that remained in the same subtype. Moreover, the rate of tumors with increase in immune infiltration (CC3) after NAC was similar in pre-NAC basal- and luminal-like BC. Luminal-like pre-NAC tumors showed a significant enrichment for becoming CC4 scar-like (p=0.006). Basal-like pre-NAC tumors showed more frequently a switch to CC2 luminal, while switching from luminal-like to CC1 basal was rare (p<0.001).
Based on this, the authors conclude the following:
1. Existing molecular subtypes for MIBC are not applicable for post-chemotherapy bladder cancer.
2. Four CC or subtypes in cisplatin-resistant bladder cancer may have therapeutic consequences
3. CC3 and CC4 lack basal and luminal gene expression.
4. Due to immune infiltration in CC3 immune and CC1 basal, checkpoint inhibition may be promising in these cohorts. Targeted therapies seem to be more appropriate for CC2 luminal.
5. The good prognosis of CC4 scar-like suggests that these tumors showed at least a partial response to cisplatin and questions immediate adjuvant treatments.
However, these strategies need to be tested in clinical trials.
Of note, IHC and gene expression findings don’t always correlate to clinical response. This is demonstrated by the fact that ICI trials in bladder cancer have not had a good biomarker for response, as IHC for the ICI targets have not correlated to response. Hence, the CC3 cluster findings of immune infiltration gene upregulation may not translate to improved response.
Speaker: R. Seiler
Co-Authors: Gibb E., Wang N.Q., Oo H.Z., Lam H-M., Takhar M., Erho N., Van Kessel K., Winters B., Douglas J., Lopez F.V., Crabb S., Van Rhijn B., Fransen Van De Putte E., Zwarthoff E., Sjödahl G., Thalmann G., Davicioni E., Boormans J., Dall'Era M., Van Der Heijden M., Wright J., Black P.
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd, at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark