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We assessed both non- and peptide-specific immune responses in prostate cancer patients before and after immunotherapy with dendritic cells exogenously pulsed with the prostate-specific membrane antigen-derived peptides, PSM-P1 and PSM-P2. For all subjects, we observed that clinical responses were strongly associated with two indicators of immunocompetence: skin test responses to recall antigens and cytokine secretion by T cells after nonspecific stimulation. In a subset of responders, we observed cytokine secretion or cytotoxicity against the immunizing peptides or an immunodominant epitope from an influenza recall antigen. The clinical results support the use of monitoring for overall immunocompetence to help determine why a patient has or has not responded to therapy. Moreover, it could be useful as an inclusion criterion to select those more likely to benefit from treatment.

Few molecular genetic alterations have been identified in endometrial cancers that are associated with poor clinical outcome. Overexpression of HER-2/neu, transforming growth factor alpha, and p53 proteins have all been associated with poor prognosis in women with endometrial cancer. In this study, the level of HER-2/neu gene amplification and expression was characterized in 92 endometrial cancers. Fluorescence in situ hybridization (FISH) was used to characterize HER-2/neu gene copy number, and immunohistochemistry was used to characterize expression. Forty-seven of the 90 (52%) endometrial cancers were characterized as showing moderate or high immunostaining. HER-2/neu gene amplification was detected in 17 of 81 (21%) cases. Immunohistochemical staining and FISH results were both available for 80 cases. Fourteen of these cases showed both moderate or high immunostaining and gene amplification. Clinical follow-up information was available for 76 women in this study. Women whose endometrial cancer exhibited HER-2/neu gene amplification by FISH had a shorter overall survival than women whose endometrial cancer lacked amplification (P = 0.018). Likewise, tumors with moderate or high HER-2/neu immunostaining were associated with a lower cumulative overall survival than tumors with low immunostaining by log rank analysis (P < 0.0001). Multivariate analysis of survival rates revealed HER-2/neu overexpression to be an independent predictor of overall survival (P = 0.0163). Among those patients with HER-2/neu overexpression, adjuvant chemotherapy or radiation therapy was associated with an improved overall survival (P = 0.039). However, among those women whose tumor lacked overexpression, overall survival was not improved by adjuvant treatment.

Conventional cytosol estrogen receptor analysis is not a significant prognostic variable in serous ovarian carcinoma. Although the use of immunocytochemical receptor analysis for estrogen does provide prognostically useful information in enhanced accuracy of predicting survival in patients with ovarian cancer, its usefulness can still be improved. Surgical samples from ovarian carcinomas are heterogeneous in tissue composition. Immunocytochemical receptor analysis allows for the specific assessment of the tumorous portions of a histological specimen. However, it is limited by its dependence on staining intensity as the determining factor. Biochemical receptor analysis does provide objective information concerning the number of receptor molecules present in a given sample, but the value is not adjusted for histological composition of the tumor section. Therefore, we have attempted to combine the advantages of both methods. By adjusting the conventional receptor analysis for the percentage of tumor present in the specimen, we have eliminated the tissue heterogeneity as a confounding variable. The resulting value is named Composition Adjusted Receptor Level or CARL. A prospective study was performed on the estrogen receptor concentrations in 61 ovarian cancers. Minimum follow-up was 8 years. For the percentage of tumor in the specimen, a highly significant correlation of the assessment of the two pathologists was observed. Stage (P < 0.05) and grade (P < 0.05) as well as cell type (P < 0.05) were found to be significant prognostic variables. In an attempt to eliminate the confounding influences of these variables, the CARL of the estrogen receptor was assessed with regard to its prognostic significance in 32 grade 2 and 3 serous carcinomas of the ovary, stage III and IV. A linear correlation between CARL and survival was found above a threshold estrogen receptor concentration of 15 fmol/mg cytosol protein using a correlation of the Cox proportional hazards model (P < 0.02). Our data suggest that (a) the assessment of the percentage of tumor in a given sample is not significantly observer dependent, (b) CARL is a significant predictor of survival in serous ovarian carcinoma, and (c) a CARL should be determined for the analysis of any cytosol receptor in solid tumors.

Serum was collected at intervals from postmenopausal breast cancer patients to determine the effects of tamoxifen adjuvant therapy and a low-fat dietary intervention, alone and in combination, on sex hormone-binding globulin (SHBG) concentrations and circulating estradiol bioavailability. Serum corticosteroid-binding globulin and follicle-stimulating hormone were also assayed as indicators of patient compliance to tamoxifen therapy. The immunoreactive SHBG concentration was higher (P less than 0.001) in 22 patients who had been treated with tamoxifen for 6-36 weeks when first sampled, compared with 27 who were not receiving tamoxifen therapy. Tamoxifen also produced a reduction in the percentage non-protein-bound estradiol (P less than 0.001) and percentage albumin-bound estradiol (P less than 0.01), the two biologically available fractions, and a corresponding increase in the percentage SHBG-bound estradiol (P less than 0.01). A longitudinal study of 7 patients showed significant reductions in the percentage of albumin-bound estradiol and an increased percentage of SHBG-bound estradiol, after 3-6 months of tamoxifen; after 12-18 months there was also a significant decrease in the non-protein-bound estradiol fraction. We conclude that in postmenopausal breast cancer patients the redistribution of circulating estradiol, with reduced bioavailability, provides an additional mechanism to those demonstrated previously for the therapeutic activity of tamoxifen. Another 12 patients receiving tamoxifen and 8 who were not were followed for 6-12 months on a low-fat diet (fat comprised 20% of the total calories). The dietary intervention had no effect on the serum SHBG concentration or the estradiol distribution. Although tamoxifen increased the serum corticosteroid-binding globulin and partially suppressed the follicle-stimulating hormone concentrations, the responses obtained were less consistent compared with those of the SHBG levels.

The search for a hormonal marker in breast cancer has centered on estrogens and their metabolites. However, direct measurements of total amounts of these steroids have shown no convincing or consistent differences between normal women and women with breast cancer. The purpose of this study was to measure the percentages of non-protein-bound estradiol (%NPBE) and of estradiol bound to albumin (%ABE) and the levels of sex hormone-binding globulin (SHBG) both in women with breast cancer and in those free of disease. Serum was collected and analyzed within 2 weeks, using an isodialysis method. The mean %NPBE and %ABE were significantly higher in 32 women with breast cancer (1.73 and 64.0%, respectively) than in 32 matched disease-free women (1.43 and 48.6%, respectively) (P less than 0.001). No significant difference was observed in the levels of plasma albumin when the above matched groups were compared. However, plasma levels of SHBG were significantly lower in the women with breast cancer than in either the control population or matched controls. In this finding we differ from previous studies which reported no significant differences in the mean plasma levels of SHBG. In our study, the increased %NPBE and %ABE in some patients with breast cancer may be related to a lower level of plasma SHBG; other factors, too, may affect the distribution of estradiol. Our results support the hypothesis than an increase in %NPBE and %ABE or both may indicate an increased risk of breast cancer.

Neonatal female BALB/cCrgl mice (mammary tumor virus unexpressed) were given a daily injection of estradiol and/or progesterone for 5 days, beginning within 36 hr after birth. About one-half of each group was ovariectomized when 40 days old, and all mice were killed when between 18.5 and 26 months of age. Neonatal progesterone leads to ovary-dependent persistent vaginal cornification and hyperplasia. In addition, 16 of the 24 progesterone-treated mice had genital tract lesions, and 4 of these showed predominantly glandular features. No such lesions were observed in either oil-treated or untreated mice. Lesions were also observed in both intact and ovariectomized mice treated with estrogen-progesterone combinations, but most of the lesions were not as severe as those seen in mice treated neonatally with progesterone alone, and they were predominantly squamous in appearance. Although mammary tumors were not observed in either the control or the neonatally steroid-treated intact mice, many in the latter groups possessed hyperplastic alveolar-like mammary nodules and other abnormalities.

Twenty-eight cervicovaginal tracts from approximately 2-year-old female BALB/cCrgl mice neonatally exposed to ovarian steroids were cut into small segments and transplanted into syngeneic hosts. Within six months, six of 28 host animals developed tumors. Three tumors were from progesterone-exposed mice, two were from estrogen-exposed mice, and one was from estrogen-progesterone-exposed mice. These tumors have been maintained by serial transplantation for approximately two years. The progesterone-induced tumors are mixed tumors with both squamous cell and glandular components. The estrogen-induced tumors are squamous cell carcinomas. The estrogen-progesterone-induced tumor was originally a squamous cell carcinoma, which now resembles a basal cell carcinoma. The other tumors have maintained their original morphological characteristics. All tumors have proven to be hormone independent. No control cervicovaginal tracts developed tumors after transplantation, even after 24 months in the host animals.

Neonatal female mice of the BALB/cfC3H strain were given 5 daily injections of 17beta-estradiol and progesterone alone and in combination, beginning within 36 hr after birth. Half of the mice in each group were ovariectomized at 40 days of age, and all were killed at tumor age of at 12 months of age. Mice receiving progesteron (100 mug daily) alone showed ovary-dependent persistent vaginal cornification. When neonatal progesterone and estradiol were given concurrently, the occurrence of persistent vaginal cornification was significantly lower than in mice receiving neonatal estradiol treatment alone. Progesterone alone produced hyperplastic downgrowths and lesions of both vaginal and cervical epithelia, but to a lesser degree than occurred in mice treated neonatally with estrogen. When progesterone was given concurrently with 17beta-estradiol, the incidence of lesions was lower but their severity was greater. The low doses of 17beta-estradiol and progesterone each resulted in an earlier age of onset and a higher incidence of mammary tumors; this also occurred after both combined estrogen-progesterone treatments. In treated mice ovariectomized on Day 40, normal mammary development did not occur and mammary tumors failed to appear, regardless of neonatal treatment. The data indicate a clear effect of neonatal progesterone exposure on both the genital tract and the mammary apparatus of female mice.