TMPRSS2 gene fusions with ETS transcription factor family members ERG, ETV1, or ETV4 have been recently discovered as a common molecular event in prostate cancer. Much attention has been focused on exploring their clinical application as a genetic tumor marker for the diagnosis, prognosis, and prediction of response to therapy. Although several studies have been done, the clinical utility of TMPRSS2 genetic alterations as biomarkers for prostate carcinoma remains indeterminate. In this study, we examined adenocarcinomas, prostatic intraepithelial neoplasia (PIN), and normal epithelium of the prostate retrieved from radical prostatectomy specimens to determine the frequency, specificity, tissue heterogeneity, and prognostic value of TMPRSS2 genetic alterations using a direct-labeled TMPRSS2 dual-color break-apart fluorescence in situ hybridization (FISH) probe cocktail designed to detect all known TMPRSS2-associated deletions or translocations. Seventy-one patients (161 samples) with normal prostate tissue, 60 patients (153 samples) with PIN, and 61 patients (142 samples) with carcinoma in formalin-fixed paraffin-embedded tissue microarrays were tested. None of the 161 normal prostate samples showed TMPRSS2 translocation or deletion. Sixty-two percent patients of prostate carcinomas demonstrated TMPRSS2 gene alterations, including 39% with translocation, 16% with deletion, and 7% with a mixed pattern. Tissue heterogeneity for TMPRSS2 gene alterations was identified in 28% of prostate carcinomas. No difference in the frequency of TMPRSS2 gene alterations was found between Gleason 6 and 7 tumors. Seventeen percent of PIN had TMPRSS2 gene alterations and showed the same FISH patterns as in the carcinomas from respective prostatectomy specimens. The TMPRSS2 dual-color break-apart FISH probe cocktail provides a simple and reliable method for the detection of TMPRSS2-related genetic alterations in formalin-fixed paraffin-embedded tissue. TMPRSS2 genetic alterations detectable by this method are strictly restricted in prostate neoplasia, and can be identified in the majority of prostate carcinomas. Tissue heterogeneity for TMPRSS2 alterations is common, and it should be considered when sampling and evaluating biopsy specimens.
6572 Background: Optimal treatment of older adults with AML remains challenging. While AML tends to be a disease of older adults, this population experiences greater treatment-related toxicity and worse overall survival than younger patients. Only fit older adults enter clinical trials and thus the results may not apply to the entire population. Methods: We conducted a retrospective analysis of patients > 60 years with AML (APL excluded) diagnosed prior to 2008 with IRB approval. The association of clinical factors (age, sex, comorbidities, prior chemotherapy), leukemia (prior myelodysplastic syndrome or myeloproliferative neoplasm, cytogenetics, WBC count), and therapy (induction chemotherapy, palliative chemotherapy, and best supportive care) as they relate to overall survival was evaluated using bivariate and multivariate regression analyses. Results: Of 87 patients (median age 73), 45% were male, 58% had high risk cytogenetics, 38% had prior MDS/MPD, 92% were chemotherapy naive, and 21% were in the high/very high Charlson risk class. The majority (67%) received standard dose induction chemotherapy (IC), 9% received (palliative intent) low-dose chemotherapy (LDC), and 24% received best supportive care (BSC). The median overall survival (OS) of the entire cohort was 2.5 months. On bivariate analysis high WBC (>50,000 at presentation) was negatively associated (1.0 vs 2.7 months p <0.01) with survival. OS for IC, LDC, and BSC were 3.1, 2.8, and 0.7 months, respectively (p=0.001). On multivariable analysis, IC conferred longer survival when compared to LDC and BSC combined (OR 0.33 CI 0.2-0.6, p<0.001). High WBC was associated with a decreased survival time (OR 2.96 CI 1.6-5.5, p=0.02). Mortality during induction or consolidation chemotherapy was 38%. At 5-year follow-up, only 4 patients were alive. Conclusions: In a non-clinical trial setting, OS of older adults with AML remains dismal. While IC offers a chance of longer survival, mortality with IC is unacceptably high. Further studies are required to identify and validate tools for risk stratification in older adults with AML as well as to utilize therapies with an improved toxicity profile.
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