About half of the patients treated with docetaxel in the setting of metastatic castration-resistant prostate cancer (CRPC) are non-responders. Therefore, a marker of response would be beneficial for clinical decision-making. We evaluated class III β-tubulin (βIII-tubulin) expression as a predictor of resistance in this setting, which previously has been correlated with lack of response to taxanes in other cancers. Patients with CRPC were included if they were treated with at least 3 cycles of docetaxel between 1990 and 2011. βIII-tubulin expression was assessed by immunostaining, which was performed in tissue samples obtained either via biopsy or prostatectomy at the time of diagnosis. Rates of prostate-specific antigen (PSA) response and overall survival (OS) following docetaxel treatment were compared between patients with high (2+ or 3+ staining) vs. low (0 or 1+ staining) βIII-tubulin expression. Of 73 patients, 26 (35%) had a high expression of βIII-tubulin. A PSA decline of 10% or greater occurred in 65% of patients with a high βIII-tubulin expression vs. 89% with a low βIII-tubulin expression (p = 0.0267). The median OS for patients with a high βIII-tubulin expression was 17.4 (95% CI 8.7–21.0) months vs. 19.8 (95% CI 16.6–23.6) months for patients with a low expression (p = 0.039). Our results show that a high βIII-tubulin expression is a negative prognostic factor in metastatic CRPC patients treated with docetaxel.
e15174 Background: Docetaxel is a tubulin-targeting cytotoxic that remains first-line therapy in metastatic castrate-resistant prostate cancer (mCRPC) patients (pts) even though half of pts are reported to be non-responders. A predictive marker to identify those who will benefit from docetaxel-therapy will assist clinical decision making. High βIII-tubulin (TUBB3) expression has previously been reported to correlate with lack of response to taxanes in other cancers. We evaluated TUBB3 expression as a predictor of docetaxel-resistance in mCRPC. Methods: mCRPC pts treated with at least 3 cycles of docetaxel between 1990 and 2011 were identified retrospectively. TUBB3 immunostaining was performed on archival formalin-fixed, paraffin-embedded tissue. Stain intensity was scored from 0 to 3; 2 and 3 were interpreted as positive. Rates of PSA response were compared between pts with positive (+) and negative (-) TUBB3 expression. Two definitions of PSA response were evaluated (any PSA decline and at least 50% decline). Overall survival (OS) distribution between TUBB3+ and TUBB3- pts was estimated by the Kaplan-Meier method. Results: Of 73 pts, 26 (35%) expressed TUBB3. At diagnosis, the mean age was 65.7 years and the median Gleason score was 8. At the time of docetaxel therapy, the mean age was 71.2 years, the median PSA level was 70.9 (range, 0.2-5253) and 76% had ECOG performance status ≤1. The median number of docetaxel cycles was 7 (range, 3-18). The total dose of docetaxel was not different between groups (p=0.705). The median OS was 19.2 mo. TUBB3 expression was not correlated with any clinical or pathological characteristic (age, Gleason score, stage, ECOG, PSA, LDH, alkaline phosphatase, hemoglobin, visceral disease or chemotherapy before docetaxel). 65% of TUBB3+ pts had any PSA decline compared to 89% of pts with TUBB3- (p=0.0267). 52% of TUBB3+ pts had a PSA decline of ≥ 50% compared to 70% of TUBB3- pts (p=0.0144). Median OS for TUBB3+ pts was 16.8 mo compared to 20.4 mo in TUBB3- pts (p=0.039). Conclusions: High TUBB3 expression was associated with shorter OS and lower PSA response rates in mCRPC pts treated with docetaxel. These findings need to be validated prospectively.
4659 Background: Patients with a bleeding diathesis remain a diagnostic challenge in medicine. Many healthy individuals consider their bleeding and bruising excessive, whereas patients with mild to moderate abnormalities may not recognize subtle symptoms as abnormal. Distinguishing between these two groups of patients requires skill and experience and often cannot be done with certainty. On the other hand, patients with profound coagulation disorders and obviously abnormal bleeding symptoms may not volunteer information unless specifically questioned. A few standardized bleeding assessment instruments and disease-specific scales have been developed, but few attempts have been made to assess their clinical usefulness and hence are not widely used. In addition, laboratory tests for screening for hemostatic abnormalities lack sensitivity and specificity. The purpose of this study is to describe the initial approach, consultation behavior and outcome in patients with a suspected bleeding diathesis in a tertiary care center. Methods: A 5-year retrospective analysis of adult patients with new and/or unexplained bleeding history referred to the hematology service of the Henry Ford Hospital. Patients were excluded it they were younger than 18 years, had a previous diagnosis of a bleeding disorder, or had been referred because of an abnormal hemostatic screening test without a history of bleeding. Data were collected for demographics, presenting symptoms, initial work up prior to consultation, hematologist’s work up and final diagnosis. Results: A total of 103 patients were included in the study. 75.7% (78) were female, and the median age of presentation was 41 years (range 18 to 85). The most common bleeding symptom was easy bruising (62.7%), followed by menorrhagia (37.3%), bleeding after tooth extraction or a surgical procedure (15.6%), and epistaxis (13.6%). The initial work up was mostly done by the primary care physician and in a few cases by the gynecologist. In 58% of cases the initial work up consisted of a complete blood count and a PT/PTT; in 32.3% no work up was done; in 5.7% the work up included a PFA-100; and in 4% a von Willebrand screening test was carried out. Work up by the consulting hematologist consisted of PFA-100, von Willebrand screen (and associated specialized tests), platelet aggregation studies, and electron microscopy when appropriate. Von Willebrand disease was diagnosed in 36.4% of patients, a platelet function disorder was found in 8.4%, a coagulation factor deficiency was found in 3.9% (2 patients with factor iX, 1 patient with factor VIII and 1 patient with factor VII). After complete work up, a bleeding diathesis could not be confirmed in 36.4% of patients, while in 14.9% of patients the etiology was secondary to a systemic illness or medication related. Among patients diagnosed with von Willebrand disease, 76.9% were female, with menorrhagia being reported in 70% of them, followed by easy bruising in 44.4%. In cases where a bleeding diathesis could not be confirmed, 79.5% were female. Of those, menorrhagia was reported in 31.25% of cases. Conclusions: Easy bruising was the most common presenting symptom for which patients were referred to hematology. Overall, a third of patients complained of menorrhagia, and we found that it was the most common complaint among those with von Willebrand disease. Our study describes the difficulty in attaining a definite diagnosis in patients with a suspected bleeding diathesis since a diagnosis could not be confirmed in about one third of the patients. This addresses the limitations of current diagnostic assays. Additionally, should these patients truly not have a bleeding diathesis, it stresses the need for standardized bleeding scores and instruments to discriminate between healthy individuals and patients with a true bleeding diathesis. Disclosures: No relevant conflicts of interest to declare.
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