Faculty Bibliography

PURPOSE: To identify the role of p53 pathway alteration(s) as predictors of treatment outcome in patients with advanced, resectable, squamous cell carcinoma (SCC) of the larynx and pharynx treated with larynx preservation (LP) intent. PATIENTS AND METHODS: Seventy-one patients treated on two consecutive LP protocols were studied based on availability of representative tissues. We analyzed the expression pattern of p53, its upstream regulator mdm2, and downstream transcriptional target p21/WAF1 by immunohistochemistry. Positive phenotype was defined as >or= 20% of tumor cells showing nuclear immunoreactivity. Results were correlated with treatment outcomes. RESULTS: Positive phenotype was observed in 35 (49%) of 71 cases for p53, in 52 (74%) of 70 for mdm2, and in 37 (54%) of 68 for p21. There was no correlation between p53 phenotype and p21 nuclear accumulation. The mdm2-negative phenotype was most predictive of major response at the primary tumor site (P =.088). p53-positive phenotype was associated with worse local control with LP (LCLP; 49% v 23%, P =.053) and inferior overall survival (OS; 51% v 29%, P =.017) at 5 years. On Cox regression analysis, p53-positive phenotype predicted inferior OS (P =.033) and showed a trend for worse LCLP (P =.102). When analyzed in a multivariate model as continuous variables, p53 showed a stronger correlation with inferior OS (P <.01), and mdm2 was associated with worse OS (P <.01). CONCLUSION: Among the three markers studied, our data support p53 phenotype as the most informative predictor of unfavorable outcomes in the LP setting, and suggest a role for mdm2 phenotype that requires further exploration. Our analysis does not support a p53-dependent mechanism for p21 expression. Prospective and larger studies are necessary before integration of these molecular markers as part of molecular staging and predictors for organ preservation or other outcomes

OBJECTIVES: To correlate the abnormalities on computed tomography, magnetic resonance imaging, and bone scan with fluorinated deoxyglucose positron emission tomography (FDG-PET) in patients with progressive metastatic prostate cancer, using a lesion-by-lesion analysis, and to preliminarily explore post-treatment changes in standard uptake value (SUV) with changes in prostate-specific antigen (PSA). METHODS: A lesional analysis compared abnormalities on FDG-PET with those on CT/MRI or bone scan. Patients had rising PSA levels and progressive disease according to the imaging findings. Changes in the SUV were compared with the PSA changes in patients who had serial scans after treatment. RESULTS: One hundred fifty-seven lesions in 17 patients were examined; 134 osseous lesions were evident on PET and/or bone scan, 95 lesions (71%) were evident on both, 31 (23%) were seen only on bone scan, and 8 (6%) were seen only on PET (adjusted McNemar's chi-square = 8.32, P = 0.004). All but one of the lesions seen only on bone scan were 'stable' compared with the previous bone scans. All lesions seen only on PET proved to be active disease on subsequent bone scans. Twenty-three soft-tissue lesions were present on CT/MRI or PET, or both; 9 (39%) lesions were evident on both and 14 (61%) were evident only on one imaging modality. In 9 (75%) of 12 cases in which serial PET scans were available, the SUV changed in parallel with the PSA level. CONCLUSIONS: FDG-PET can discriminate active osseous disease from scintigraphically quiescent lesions in patients with progressive metastatic prostate cancer, but it is limited in detecting soft-tissue metastases. Post-treatment changes in the SUV tend to correlate with changes in PSA

BACKGROUND: The clinical effects of targeting HER-2 in prostate carcinoma are not known. This study explored the feasibility of molecular profiling to determine the correlation between HER-2 expression, hormonal sensitivity, and the antitumor effects of trastuzumab and paclitaxel in patients with prostate carcinoma. METHODS: Patients with progressive androgen dependent (AD) and androgen independent (AI) prostate carcinoma were eligible to participate in the study. HER-2 expression was assessed on pretreatment tissue specimens, and patients were then assigned to one of four treatment groups: AD HER-2 positive, AD HER-2 negative, AI HER-2 positive, and AI HER-2 negative. They were treated with weekly trastuzumab at a dose of 2 mg/kg (after a 4 mg/kg loading dose) until they experienced disease progression, when weekly paclitaxel at 100 mg/m(2) was added. RESULTS: The authors screened 130 patients for HER-2 expression. In total, 23 patients were treated. Six eligible patients had HER-2 positive disease; therefore, only the AI HER-2 negative arm accrued to completion. All patients (100%) experienced disease progression on trastuzumab alone at or before the first 12 weeks of treatment. Fifteen patients received combined therapy: Seven patients (47%) experienced disease progression, 5 patients (33%) had stable disease, and 3 patients (20%) had a decline > or = 50% in prostate specific antigen PSA level or in soft tissue disease. HER-2 overexpression was found in significant proportions only in AI metastatic tissue samples (42% HER-2 positive; 95% confidence interval, 14-60%). In three of nine matched pairs, the AD prostate biopsy was HER-2 negative, and the AI metastatic sample was HER-2 positive. CONCLUSIONS: Trastuzumab is not effective as a single agent for the treatment of patients with AI HER-2 negative tumors. HER-2 expression varies by clinical state in patients with prostate carcinoma: Accurate HER-2 profiling requires sampling metastatic tissue in patients with metastatic disease. Further development of trastuzumab for the treatment of patients with metastatic prostate carcinoma is not feasible until more reliable and practical methods of sampling metastatic disease are developed to identify patients with HER-2 positive tumors

Metastatic prostate cancer may respond initially to hormone suppression, with involution of tumor sites, but ultimate tumor progression is inevitable. Our aim was to detect the proportion of bone and soft-tissue lesions that represent metabolically active tumor sites in patients with progressive metastatic prostate cancer. METHODS: In a prospective study, we compared 18F-FDG and L-methyl-11C-methionine (11C-methionine) PET with conventional imaging modalities (CIM), which included the combination of 99mTc-methylene diphosphonate scintigraphy, CT, or MRI. Twelve patients with prostate cancer, increasing levels of prostate-specific antigen (PSA), and at least 1 site (index lesion) with new or increasing disease on CIM were studied. The total numbers of soft-tissue and bone-tissue lesions, in a site-by-site comparison, were calculated for all imaging modalities. RESULTS: The sensitivities of 18F-FDG PET and 11C-methionine PET were 48% (167/348 lesions) and 72.1% (251/348 lesions), respectively, with CIM being used as the 100% reference (348/348). 11C-Methionine PET identified significantly more lesions than 18F-FDG PET (P < 0.01). All 12 patients with progressive metastatic prostate cancer had at least 1 lesion site of active metabolism for 18F-FDG or 11C-methionine, which could be used as an index lesion to monitor the metabolic response to therapy. A significant proportion of lesions (26%) had no detectable metabolism of 18F-FDG or 11C-methionine. Although technical factors cannot be totally excluded, we believe that metabolically inactive sites may be necrotic or dormant. More than 95% (251/258) of metabolically active sites (72% of the total number of lesions detected by CIM) metabolize 11C-methionine. 18F-FDG uptake is more variable, with 65% of metabolically active sites (48% of the total number of lesions detected by CIM). CONCLUSION: These findings reflect the different biologic characteristics of the lesions in a heterogeneous tumor such as prostate cancer and suggest that a time-dependent metabolic cascade may occur in advanced prostate cancer, with initial uptake of 11C-methionine in dormant sites followed by increased uptake of 18F-FDG during progression of disease

We investigated the role of alterations of HDM2, the human homologue of murine mdm2, in the tumorigenesis and progression of cutaneous melanoma. A well-characterized cohort of 172 cases representing different points in the spectrum of melanocyte transformation (16 dysplastic nevi, 11 melanomas in situ, 107 invasive primaries, and 38 metastatic lesions), as well as 11 human melanoma cell lines were examined by immunohistochemistry and Western blotting for HDM2 protein expression, and by either Southern blotting (SB) or fluorescence in situ hybridization for HDM2 gene amplification. HDM2 overexpression, defined as >20% tumor cells showing nuclear immunoreactivity, was observed in 1 of 16 (6%) dysplastic nevi, 3 of 11 (27%) melanomas in situ, and 81 of 145 (56%) invasive primary and metastatic melanomas. Comparable frequencies of HDM2 overexpression were observed among invasive primary cases with differing tumor thicknesses as well as among the metastatic cases: 21 of 40 (53%) at < or =1.5 mm; 31 of 50 (62%) at 1.6-3.9 mm; 10 of 17 (58%) at >4 mm; and 19 of 38 (50%) metastases. HDM2 amplification was observed in 1 of 88 (1%) primary cases using fluorescence in situ hybridization, and in 0 of 12 (0%) metastatic cases that overexpressed HDM2 using SB. Melanoma cell lines expressed HDM2 protein, but there was no evidence of amplification by SB. Our data suggest that HDM2 protein overexpression is common in invasive and metastatic melanoma. Observing HDM2 overexpression in noninvasive melanoma suggests that expression of this oncogene may play an early role in melanocyte transformation. HDM2 amplification occurs infrequently, and other mechanisms that up-regulate HDM2 expression are under investigation

PURPOSE: Amplification of HER-2/neu gene and overexpression of its encoded product, the p185neu (HER-2/neu) tyrosine kinase membrane receptor, have been associated with tumor progression in certain neoplasms. We conducted this study to investigate patterns of HER-2/neu protein expression in prostate cancer, analyzing different points in the natural and treated history of the disease. EXPERIMENTAL DESIGN: Radical prostatectomy cases (83) and 20 metastatic lesions were studied for the association between HER-2/neu protein overexpression detected by immunohistochemistry and clinicopathological parameters, including time to prostate-specific antigen (PSA) relapse. RESULTS: HER-2/neu protein overexpression, defined as complete membrane staining in >10% of tumor cells using the Food and Drug Administration-approved Dako kit, was found in 9 of 45 (20%) of evaluable hormone naive primary tumors and 23 of 34 (67%) primary tumors after androgen-deprivation therapy (P = 0.0001). Of the 20 metastatic lesions, positivity was noted in 16 (80%) of the cases. On univariate analysis, HER-2/neu overexpression was associated with pretreatment PSA (P = 0.011) and time to PSA relapse (P = 0.02). After controlling for pretreatment PSA, the association between hormone treatment and HER-2/neu was still observed. No association was found between HER-2/neu overexpression and Gleason score, capsular invasion, and tumor proliferative index determined by Ki67. CONCLUSIONS: These data suggest that there is significant HER-2/neu overexpression in primary tumors that persist after androgen deprivation. It also emphasizes the importance of characterizing tumors at determined points in the natural or treated history of prostate cancer when targeting treatment to specific biological processes

Cyclin D1 is a key regulator of the G1 phase progression of the cell cycle. There is increasing evidence that deregulated cyclin D1 expression is implicated in tumorigenesis and tumor progression in certain neoplasms. Recently, it has been reported that cyclin D1 overexpression might be related to the evolution of androgen-independent disease in prostate cancer. This study was conducted to investigate patterns of cyclin D1 expression in prostate cancer samples representing different points in the natural history and treatment evolution of the disease. Association with clinical outcomes was also explored. Using immunohistochemistry, 86 radical prostatectomy specimens (53 naive and 33 after androgen deprivation) and 22 androgen-independent bone metastases were studied. We examined the difference in cyclin D1 expression in primary versus metastatic cases. In addition, we examined the association in primary cases between cyclin D1 expression and clinicopathological parameters of poor clinical outcome, including time to prostate-specific antigen relapse and Ki67 proliferative index. Cyclin D1-positive phenotype, defined as identification of positive immunoreactivity in the nuclei of > or =20% of tumor cells, was observed in 10 of 86 (11%) primary cases compared with 15 of 22 (68%) androgen-independent bone metastases (P = 0.001). There was no correlation between cyclin D1 overexpression and either Gleason score, neo-adjuvant hormone treatment, or prostate-specific antigen relapse We observed a statistical association between cyclin D1 overexpression and high Ki67 proliferative index, defined as > or =20% of positive tumor cells (P = 0.02). These data support the hypothesis that cyclin D1 overexpression may represent an oncogenic event in androgen-independent metastatic prostate cancer to the bone

The evaluation of new therapies in prostate cancer requires unique end points for agents with diverse mechanisms of action. Because retinoic acid may have a confounding effect on prostate-specific antigen, we incorporated a pathological end point into the outcome assessment of two sequential clinical trials using all-trans-retinoic acid (ATRA) and the combination of 13-cis-retinoic acid and IFN-2a (cRA inverted question markIFN). Pre- and posttherapy tumor biopsy specimens were studied for histological changes, apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling assay), and proliferation index (Ki67). Prostate-specific membrane antigen (PSMA) expression was also evaluated using two different monoclonal antibodies to its intracellular domain (Cytogen 7E11 and Hybritech PM2). Fourteen patients with androgen-independent disease were treated with ATRA (50 mg/m2 p.o. every 8 h daily) and 16 androgen-independent and 4 androgen-dependent patients were treated with cRA inverted question markIFN (10 mg/kg/day cRA plus 3, 6, or 9 million units daily IFN). Both therapies were well tolerated, with fatigue and cheilitis being the most common adverse events. Clinical activity, assessed by radiographs and serum prostate-specific antigen, was minimal, and the majority of patients progressed within 3 months. One patient with androgen-dependent disease had prolonged stabilization for >1 year. The majority of cases (95%) showed no gross histological changes and no difference in apoptotic or proliferative indices. Increased PSMA immunoreactivity was seen in seven of nine (78%) cases using PM2 antibody and in two of nine (22%) cases using the 7E11 antibody. Although antitumor effects were modest, the results suggest a role for retinoids in modulating the expression of PSMA on prostate cancer cells

To determine the potential role of p53 inactivation in prostate cancer, we studied a well characterized cohort of 86 patients treated with radical prostatectomy. We analyzed patterns of p53, mdm2, and p21/WAF1 expression by immunohistochemistry. Results were then correlated with clinicopathological parameters of poor outcome, including time to PSA relapse. In addition, data were also correlated with proliferative index, as assessed by Ki67 antigen detection. p53-positive phenotype, defined as identification of nuclear immunoreactivity in > 20% of tumor cells, was observed in 6 of 86 cases (7%). An association was observed between p53-positive phenotype and decreased time to PSA relapse (P < 0.01). mdm2-positive phenotype, defined as > or = 20% of tumor cells displaying nuclear immunoreactivity, was observed in 28 of 86 cases (32.5%). mdm-2-positive phenotype was found to be associated with advanced stage (P = 0.009). p21-positive phenotype, defined as > 5% of tumor cells with nuclear immunoreactivity, was observed in 28 of 86 cases (32.5%). An association was observed between p21-positive phenotype and high Ki67 proliferative index (P = 0.002). Patients with p21-positive phenotype had a significant association with decreased time to PSA relapse (P = 0.0165). In addition, a significant association was found between p21-positive phenotype and coexpression of mdm2 (P < 0.01). Forty-three of 86 cases (50%) were found to have one or more alterations, and patients with any alteration were found to have a higher rate of PSA relapse (P < 0.01). It is our hypothesis that a pathway of prostate cancer progression involves p53 inactivation caused by mdm2 overexpression and that p21 transactivation in this setting is due to an alternative signaling system, rather than through a p53-dependent mechanism