TY - JOUR
T1 - Genetic profiling to determine risk of relapse-free survival in high-risk localized prostate cancer
AU - Barnett, Christine M.
AU - Heinrich, Michael C.
AU - Lim, Jeong
AU - Nelson, Dylan
AU - Beadling, Carol
AU - Warrick, Andrea
AU - Neff, Tanaya
AU - Higano, Celestia S.
AU - Garzotto, Mark
AU - Qian, David
AU - Corless, Christopher L.
AU - Thomas, George V.
AU - Beer, Tomasz M.
PY - 2014
Y1 - 2014
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.
AB - 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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U2 - 10.1158/1078-0432.CCR-13-1775
DO - 10.1158/1078-0432.CCR-13-1775
M3 - Article
C2 - 24352642
AN - SCOPUS:84895815910
SN - 1078-0432
VL - 20
SP - 1306
EP - 1312
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 5
ER -