Identification and validation of Protein biomarkers of response to neoadjuvant platinum chemotherapy in muscle invasive urothelial carcinoma

Alexander S. Baras, Nilay Gandhi, Enrico Munari, Sheila Faraj, Luciana Shultz, Luigi Marchionni, Mark P. Schoenberg, Noah Hahn, Mohammad Hoque, David Berman, Trinity J. Bivalacqua, George Netto

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Abstract

Background: The 5-year cancer specific survival (CSS) for patients with muscle invasive urothelial carcinoma of the bladder (MIBC) treated with cystectomy alone is approximately 50%. Platinum based neoadjuvant chemotherapy (NAC) plus cystectomy results in a marginal 5-10% increase in 5-year CSS in MIBC. Interestingly, responders to NAC (<ypT2) have a 5-year CSS of 90% which is in stark contrast to the 30-40% CSS for those whose MIBC is resistance to NAC. While the implementation of NAC for MIBC is increasing, it is still not widely utilized due to concerns related to delay of cystectomy, potential side-effects, and inability to predict effectiveness. Recently suggested molecular signatures of chemoresponsiveness, which could prove useful in this setting, would be of considerable utility but are yet to be translated into clinical practice. Methods: mRNA expression data from a prior report on a NAC-treated MIBC cohort were re-analyzed in conjunction with the antibody database of the Human Protein Atlas (HPA) to identify candidate protein based biomarkers detectable by immunohistochemistry (IHC). These candidate biomarkers were subsequently tested in tissue microarrays derived from an independent cohort of NAC naive MIBC biopsy specimens from whom the patients were treated with neoadjuvant gemcitabine cisplatin NAC and subsequent cystectomy. The clinical parameters that have been previously associated with NAC response were also examined in our cohort. Results: Our analyses of the available mRNA gene expression data in a discovery cohort (n = 33) and the HPA resulted in 8 candidate protein biomarkers. The combination of GDPD3 and SPRED1 resulted in a multivariate classification tree that was significantly associated with NAC response status (Goodman-Kruskal γ = 0.85 p<0.0001) in our independent NAC treated MIBC cohort. This model was independent of the clinical factors of age and clinical tumor stage, which have been previously associated with NAC response by our group. The combination of both these protein biomarkers detected by IHC in biopsy specimens along with the relevant clinical parameters resulted in a prediction model able to significantly stratify the likelihood of NAC resistance in our cohort (n = 37) into two well separated halves: low-26% n = 19 and high-89% n = 18, Fisher's exact p = 0.0002). Conclusion: We illustrate the feasibility of translating a gene expression signature of NAC response from a discovery cohort into immunohistochemical markers readily applicable to MIBC biopsy specimens in our independent cohort. The results from this study are being characterized in additional validation cohorts. Additionally, we anticipate that emerging somatic mutations in MIBC will also be important for NAC response prediction. The relationship of the findings in this study to the current understanding of variant histologic subtypes of MIBC along with the evolving molecular subtypes of MIBC as it relates to NAC response remains to be fully characterized.

Original languageEnglish (US)
Article numbere0131245
JournalPLoS One
Volume10
Issue number7
DOIs
StatePublished - Jul 31 2015

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platinum
Chemotherapy
Biomarkers
Platinum
drug therapy
carcinoma
Muscle
biomarkers
Carcinoma
Drug Therapy
Muscles
muscles
Proteins
proteins
Cystectomy
Biopsy
neoplasms
biopsy
Survival
Atlases

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Identification and validation of Protein biomarkers of response to neoadjuvant platinum chemotherapy in muscle invasive urothelial carcinoma. / Baras, Alexander S.; Gandhi, Nilay; Munari, Enrico; Faraj, Sheila; Shultz, Luciana; Marchionni, Luigi; Schoenberg, Mark P.; Hahn, Noah; Hoque, Mohammad; Berman, David; Bivalacqua, Trinity J.; Netto, George.

In: PLoS One, Vol. 10, No. 7, e0131245, 31.07.2015.

Research output: Contribution to journalArticle

Baras, AS, Gandhi, N, Munari, E, Faraj, S, Shultz, L, Marchionni, L, Schoenberg, MP, Hahn, N, Hoque, M, Berman, D, Bivalacqua, TJ & Netto, G 2015, 'Identification and validation of Protein biomarkers of response to neoadjuvant platinum chemotherapy in muscle invasive urothelial carcinoma', PLoS One, vol. 10, no. 7, e0131245. https://doi.org/10.1371/journal.pone.0131245
Baras, Alexander S. ; Gandhi, Nilay ; Munari, Enrico ; Faraj, Sheila ; Shultz, Luciana ; Marchionni, Luigi ; Schoenberg, Mark P. ; Hahn, Noah ; Hoque, Mohammad ; Berman, David ; Bivalacqua, Trinity J. ; Netto, George. / Identification and validation of Protein biomarkers of response to neoadjuvant platinum chemotherapy in muscle invasive urothelial carcinoma. In: PLoS One. 2015 ; Vol. 10, No. 7.
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