Retinoblastoma protein expression and radiation response in muscle- invasive bladder cancer

Alan Pollack, Bogdan Czerniak, Gunar K. Zagars, Shi Xue Hu, Catherine S. Wu, Colin P N Dinney, Valerian Chyle, William F. Benedict

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Purpose: The retinoblastoma protein (pRB) is a key regulator of the G1 cell cycle checkpoint and has been implicated as having a role in G1 arrest and apoptosis induced by radiation damage. In this report we examine the association between pRB expression and radiation response in patients treated between 1960 and 1983 with preoperative radiotherapy (50 Gy in 25 fractions) followed 4- 6 weeks later by radical cystectomy. The correlation of pRB to patient outcome and how this relationship is complimentary to that seen with p53 staining status is also described. Methods and Materials: Immunohistochemical staining of pRB and p53 in paraffin-embedded tumor sections using WL-1 anti-RB and DO1 anti-p53 antibodies was considered adequate in 98 and 97 pretreatment tumor samples, respectively. There were 46 patients with clinical Stage T2, 28 with Stage T3a, and 24 with Stage T3b disease. The median age was 62 years and follow-up for those living was 85 months. Results: Staining for pRB was negative in 30% of the cases. Correlations were observed between pRB negativity an high pretreatment apoptosis level (p = 0.06), locally advanced clinical stage (p = 0.01) increased clinical-to-pathologic downstaging (p = 0.014), and more pathologic complete responses (Path-CRs;p = 0.019). Several other factors were tested and were not associated with pRB status, including p53 expression. RB status was the only pretreatment prognostic factor in the univariate analyses that correlated with downstaging and was independently associated with Path-CR using multivariate logistic regression. Despite these significant relationships, no correlations with patient outcome were observed when the entire cohort was analyzed. Restriction of the analyses to Stage T3b patients, however, revealed that pRB negativity predicted for enhanced distant metastasis freedom (p = 0.006, log rank) and overall survival (p = 0.02). The overexpression of p53 also correlated with distant metastasis freedom and overall survival in Stage T3b patients. Patient outcome was best when RB negative and p53 negative staining were seen. Conclusion: Our results indicate that loss of RB function as measured by immunohistochemical staining is the strongest correlate of radiation response thus far recognized. Loss of RB expression also predicted for poor outcome in Stage T3b patients, which appeared to compliment the finding of normal p53 expression. While normal RB protein expression is usually associated with better patient outcome, other series have not examined patients treated with radiotherapy. The absence of pRB may be a useful marker for selecting patients for bladder preservation with radiotherapy, particularly when wild-type p53 is present.

Original languageEnglish
Pages (from-to)687-695
Number of pages9
JournalInternational Journal of Radiation Oncology Biology Physics
Volume39
Issue number3
DOIs
StatePublished - Oct 1 1997
Externally publishedYes

Fingerprint

Retinoblastoma Protein
bladder
muscles
Urinary Bladder Neoplasms
cancer
Radiation
proteins
Muscles
radiation
staining
pretreatment
Staining and Labeling
radiation therapy
Radiotherapy
apoptosis
metastasis
tumors
Apoptosis
Neoplasm Metastasis
G1 Phase Cell Cycle Checkpoints

Keywords

  • Apoptosis
  • Bladder neoplasm
  • Immunohistochemistry
  • p53
  • pRB
  • Radiotherapy

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation

Cite this

Retinoblastoma protein expression and radiation response in muscle- invasive bladder cancer. / Pollack, Alan; Czerniak, Bogdan; Zagars, Gunar K.; Hu, Shi Xue; Wu, Catherine S.; Dinney, Colin P N; Chyle, Valerian; Benedict, William F.

In: International Journal of Radiation Oncology Biology Physics, Vol. 39, No. 3, 01.10.1997, p. 687-695.

Research output: Contribution to journalArticle

Pollack, Alan ; Czerniak, Bogdan ; Zagars, Gunar K. ; Hu, Shi Xue ; Wu, Catherine S. ; Dinney, Colin P N ; Chyle, Valerian ; Benedict, William F. / Retinoblastoma protein expression and radiation response in muscle- invasive bladder cancer. In: International Journal of Radiation Oncology Biology Physics. 1997 ; Vol. 39, No. 3. pp. 687-695.
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abstract = "Purpose: The retinoblastoma protein (pRB) is a key regulator of the G1 cell cycle checkpoint and has been implicated as having a role in G1 arrest and apoptosis induced by radiation damage. In this report we examine the association between pRB expression and radiation response in patients treated between 1960 and 1983 with preoperative radiotherapy (50 Gy in 25 fractions) followed 4- 6 weeks later by radical cystectomy. The correlation of pRB to patient outcome and how this relationship is complimentary to that seen with p53 staining status is also described. Methods and Materials: Immunohistochemical staining of pRB and p53 in paraffin-embedded tumor sections using WL-1 anti-RB and DO1 anti-p53 antibodies was considered adequate in 98 and 97 pretreatment tumor samples, respectively. There were 46 patients with clinical Stage T2, 28 with Stage T3a, and 24 with Stage T3b disease. The median age was 62 years and follow-up for those living was 85 months. Results: Staining for pRB was negative in 30{\%} of the cases. Correlations were observed between pRB negativity an high pretreatment apoptosis level (p = 0.06), locally advanced clinical stage (p = 0.01) increased clinical-to-pathologic downstaging (p = 0.014), and more pathologic complete responses (Path-CRs;p = 0.019). Several other factors were tested and were not associated with pRB status, including p53 expression. RB status was the only pretreatment prognostic factor in the univariate analyses that correlated with downstaging and was independently associated with Path-CR using multivariate logistic regression. Despite these significant relationships, no correlations with patient outcome were observed when the entire cohort was analyzed. Restriction of the analyses to Stage T3b patients, however, revealed that pRB negativity predicted for enhanced distant metastasis freedom (p = 0.006, log rank) and overall survival (p = 0.02). The overexpression of p53 also correlated with distant metastasis freedom and overall survival in Stage T3b patients. Patient outcome was best when RB negative and p53 negative staining were seen. Conclusion: Our results indicate that loss of RB function as measured by immunohistochemical staining is the strongest correlate of radiation response thus far recognized. Loss of RB expression also predicted for poor outcome in Stage T3b patients, which appeared to compliment the finding of normal p53 expression. While normal RB protein expression is usually associated with better patient outcome, other series have not examined patients treated with radiotherapy. The absence of pRB may be a useful marker for selecting patients for bladder preservation with radiotherapy, particularly when wild-type p53 is present.",
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AU - Pollack, Alan

AU - Czerniak, Bogdan

AU - Zagars, Gunar K.

AU - Hu, Shi Xue

AU - Wu, Catherine S.

AU - Dinney, Colin P N

AU - Chyle, Valerian

AU - Benedict, William F.

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N2 - Purpose: The retinoblastoma protein (pRB) is a key regulator of the G1 cell cycle checkpoint and has been implicated as having a role in G1 arrest and apoptosis induced by radiation damage. In this report we examine the association between pRB expression and radiation response in patients treated between 1960 and 1983 with preoperative radiotherapy (50 Gy in 25 fractions) followed 4- 6 weeks later by radical cystectomy. The correlation of pRB to patient outcome and how this relationship is complimentary to that seen with p53 staining status is also described. Methods and Materials: Immunohistochemical staining of pRB and p53 in paraffin-embedded tumor sections using WL-1 anti-RB and DO1 anti-p53 antibodies was considered adequate in 98 and 97 pretreatment tumor samples, respectively. There were 46 patients with clinical Stage T2, 28 with Stage T3a, and 24 with Stage T3b disease. The median age was 62 years and follow-up for those living was 85 months. Results: Staining for pRB was negative in 30% of the cases. Correlations were observed between pRB negativity an high pretreatment apoptosis level (p = 0.06), locally advanced clinical stage (p = 0.01) increased clinical-to-pathologic downstaging (p = 0.014), and more pathologic complete responses (Path-CRs;p = 0.019). Several other factors were tested and were not associated with pRB status, including p53 expression. RB status was the only pretreatment prognostic factor in the univariate analyses that correlated with downstaging and was independently associated with Path-CR using multivariate logistic regression. Despite these significant relationships, no correlations with patient outcome were observed when the entire cohort was analyzed. Restriction of the analyses to Stage T3b patients, however, revealed that pRB negativity predicted for enhanced distant metastasis freedom (p = 0.006, log rank) and overall survival (p = 0.02). The overexpression of p53 also correlated with distant metastasis freedom and overall survival in Stage T3b patients. Patient outcome was best when RB negative and p53 negative staining were seen. Conclusion: Our results indicate that loss of RB function as measured by immunohistochemical staining is the strongest correlate of radiation response thus far recognized. Loss of RB expression also predicted for poor outcome in Stage T3b patients, which appeared to compliment the finding of normal p53 expression. While normal RB protein expression is usually associated with better patient outcome, other series have not examined patients treated with radiotherapy. The absence of pRB may be a useful marker for selecting patients for bladder preservation with radiotherapy, particularly when wild-type p53 is present.

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KW - Bladder neoplasm

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