Genetic profiling to determine risk of relapse-free survival in high-risk localized prostate cancer

Christine M. Barnett, Michael Heinrich, Jeong Lim, Dylan Nelson, Carol Beadling, Andrea Warrick, Tanaya Neff, Celestia S. Higano, Mark Garzotto, Zheng (David) Qian, Christopher Corless, George Thomas, Tomasz (Tom) Beer

Research output: Contribution to journalArticle

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Abstract

Purpose: The characterization of actionable mutations in human tumors is a prerequisite for the development of individualized, targeted therapy.Weexamined the prevalence of potentially therapeutically actionable mutations in patients with high-risk clinically localized prostate cancer. Experimental Design: Forty-eight samples of formalin-fixed paraffin-embedded prostatectomy tissue from a neoadjuvant chemotherapy trial were analyzed. DNA extracted from microdissected tumor was analyzed for 643 common solid tumor mutations in 53 genes using mass spectroscopy-based sequencing. In addition, PTEN loss and erythroblast transformation-specific-related gene (ERC) translocations were examined using immunohistochemistry (IHC) in associated tissue microarrays. Association with relapse during 5 years of follow-up was examined in exploratory analyses of the potential clinical relevance of the genetic alterations. Results: Of the 40 tumors evaluable for mutations, 10% had point mutations in potentially actionable cancer genes. Of the 47 tumors evaluable for IHC, 36% had PTEN loss and 40% had ERG rearrangement. Individual mutations were not frequent enough to determine associations with relapse. Using Kaplan- Meier analysis with a log-rank test, the 16 patients who had PTEN loss had a significantly shorter median relapse-free survival, 19 versus 106 months (P = 0.01). Conclusions: This study confirms that point mutations in the most common cancer regulatory genes in prostate cancer are rare. However, the PIK3CA/AKT pathway was mutated in 10% of our samples. Although point mutations alone did not have a statistically significant association with relapse, PTEN loss was associated with an increased relapse in high-risk prostate cancer treated with chemotherapy followed by surgery.

Original languageEnglish (US)
Pages (from-to)1306-1312
Number of pages7
JournalClinical Cancer Research
Volume20
Issue number5
DOIs
StatePublished - 2014

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Prostatic Neoplasms
Recurrence
Mutation
Survival
Point Mutation
Neoplasm Genes
Neoplasms
Immunohistochemistry
Drug Therapy
Erythroblasts
Kaplan-Meier Estimate
Regulator Genes
Prostatectomy
Paraffin
Formaldehyde
Genes
Mass Spectrometry
Research Design
DNA
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Genetic profiling to determine risk of relapse-free survival in high-risk localized prostate cancer. / Barnett, Christine M.; Heinrich, Michael; Lim, Jeong; Nelson, Dylan; Beadling, Carol; Warrick, Andrea; Neff, Tanaya; Higano, Celestia S.; Garzotto, Mark; Qian, Zheng (David); Corless, Christopher; Thomas, George; Beer, Tomasz (Tom).

In: Clinical Cancer Research, Vol. 20, No. 5, 2014, p. 1306-1312.

Research output: Contribution to journalArticle

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abstract = "Purpose: The characterization of actionable mutations in human tumors is a prerequisite for the development of individualized, targeted therapy.Weexamined the prevalence of potentially therapeutically actionable mutations in patients with high-risk clinically localized prostate cancer. Experimental Design: Forty-eight samples of formalin-fixed paraffin-embedded prostatectomy tissue from a neoadjuvant chemotherapy trial were analyzed. DNA extracted from microdissected tumor was analyzed for 643 common solid tumor mutations in 53 genes using mass spectroscopy-based sequencing. In addition, PTEN loss and erythroblast transformation-specific-related gene (ERC) translocations were examined using immunohistochemistry (IHC) in associated tissue microarrays. Association with relapse during 5 years of follow-up was examined in exploratory analyses of the potential clinical relevance of the genetic alterations. Results: Of the 40 tumors evaluable for mutations, 10{\%} had point mutations in potentially actionable cancer genes. Of the 47 tumors evaluable for IHC, 36{\%} had PTEN loss and 40{\%} had ERG rearrangement. Individual mutations were not frequent enough to determine associations with relapse. Using Kaplan- Meier analysis with a log-rank test, the 16 patients who had PTEN loss had a significantly shorter median relapse-free survival, 19 versus 106 months (P = 0.01). Conclusions: This study confirms that point mutations in the most common cancer regulatory genes in prostate cancer are rare. However, the PIK3CA/AKT pathway was mutated in 10{\%} of our samples. Although point mutations alone did not have a statistically significant association with relapse, PTEN loss was associated with an increased relapse in high-risk prostate cancer treated with chemotherapy followed by surgery.",
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AU - Heinrich, Michael

AU - Lim, Jeong

AU - Nelson, Dylan

AU - Beadling, Carol

AU - Warrick, Andrea

AU - Neff, Tanaya

AU - Higano, Celestia S.

AU - Garzotto, Mark

AU - Qian, Zheng (David)

AU - Corless, Christopher

AU - Thomas, George

AU - Beer, Tomasz (Tom)

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N2 - Purpose: The characterization of actionable mutations in human tumors is a prerequisite for the development of individualized, targeted therapy.Weexamined the prevalence of potentially therapeutically actionable mutations in patients with high-risk clinically localized prostate cancer. Experimental Design: Forty-eight samples of formalin-fixed paraffin-embedded prostatectomy tissue from a neoadjuvant chemotherapy trial were analyzed. DNA extracted from microdissected tumor was analyzed for 643 common solid tumor mutations in 53 genes using mass spectroscopy-based sequencing. In addition, PTEN loss and erythroblast transformation-specific-related gene (ERC) translocations were examined using immunohistochemistry (IHC) in associated tissue microarrays. Association with relapse during 5 years of follow-up was examined in exploratory analyses of the potential clinical relevance of the genetic alterations. Results: Of the 40 tumors evaluable for mutations, 10% had point mutations in potentially actionable cancer genes. Of the 47 tumors evaluable for IHC, 36% had PTEN loss and 40% had ERG rearrangement. Individual mutations were not frequent enough to determine associations with relapse. Using Kaplan- Meier analysis with a log-rank test, the 16 patients who had PTEN loss had a significantly shorter median relapse-free survival, 19 versus 106 months (P = 0.01). Conclusions: This study confirms that point mutations in the most common cancer regulatory genes in prostate cancer are rare. However, the PIK3CA/AKT pathway was mutated in 10% of our samples. Although point mutations alone did not have a statistically significant association with relapse, PTEN loss was associated with an increased relapse in high-risk prostate cancer treated with chemotherapy followed by surgery.

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