Breast cancer survival and in vitro tumor response in the extreme drug resistance assay.

PURPOSE: To determine whether in vitro extreme drug resistance (EDR) assay results for patients with breast carcinoma were associated with clinical outcome after chemotherapy. PATIENTS AND METHODS: EDR assays were performed on tumor tissue obtained from 103 newly diagnosed breast cancer cases. EDR scores of 2 for low, 1 for intermediate, or 0 for extreme drug resistance were determined for each agent tested. In vitro EDR scores for 4-hydroxycyclophosphamide (4HC) and doxorubicin were summed for patients treated with AC, or for 4HC and 5-FU for patients treated with CMF. Treatment selection was blinded to assay results. RESULTS: Median time to progression was significantly shorter for patients with extreme or intermediate in vitro resistance (n = 55, 48 months), compared to patients with low in vitro resistance, (n = 41, 100 months, p = 0.022). Patients demonstrating extreme to intermediate drug resistance also showed poorer survival than the low resistance group (49.5 months vs. not reached, median follow-up 48 months, p =0.011). Summed EDR scores, stage, and number of lymph nodes were significantly associated with survival in univariate and multivariate analysis. Compared to EDR scores of 4, summed EDR scores of 0-1 and summed EDR scores of 2-3 were associated with a relative risk of death of 3.09 (95%, CI 1.05-9.06, Cox proportional hazards model, p = 0.040) and 2.35 (95%, CI 1.07-5.15, Cox proportional hazards model, p = 0.033), respectively. CONCLUSION: Extreme drug resistance testing identified patients with individual patterns of drug resistance prior to therapy. In this cohort of breast cancer patients treated with chemotherapy, summed EDR scores were significantly associated with time to tumor progression and overall survival. EDR results may offer a method for optimizing treatment selection.

Biomarker conservation in primary and metastatic epithelial ovarian cancer.

PURPOSE: The aim of this study was to compare the overexpression of specific biomarkers in primary advanced and recurrent epithelial ovarian cancers. METHODS: Biomarker expression by epithelial ovarian cancer specimens from primary and metastatic sites was examined by immunohistochemistry and flow cytometry. Biomarker expression by subpopulations of tissues consisting of matched pairs of synchronous and metachronous lesions was also studied. RESULTS: A total of 3173 epithelial ovarian cancer specimens were retrieved from women with FIGO Stage III/IV disease. These included lesions from 1036 primary and 2137 metastatic sites. The percentages of biomarker expression for primary and metastatic lesions, respectively, were MDR1, 12 and 10%; p53, 55 and 60%; HER2, 12 and 11%; EGF-R, 26 and 33%; increased microvessel counts (CD31), 21 and 36%. Approximately 73% of both primary and metastatic specimens were aneuploid, and approximately 57% of both sets had an S-phase fraction >7%. Only EGF-R and CD31 expression were found to be significantly different between the primary and metastatic tumors (P < 0.05). Of the paired synchronous cases (n = 48) evaluated, 88% of aneuploid primary lesions were associated with aneuploid metastases. Similarly, the distributions for MDR1, HER2, and p53 expression did not vary significantly between primary and metastatic sites. Pairings of metachronous cases (n = 66) revealed that nearly 80% of primary aneuploid tumors (n = 39) retained their aneuploid status at the time of relapse. Furthermore, there were no significant changes in MDR1, p53, or HER2 expression at relapse. CONCLUSIONS: With the exception of EGF-R and CD31, clonal divergence of the biomarkers evaluated in this study probably does not play a significant role in imparting clinical heterogeneity during the advanced and recurrent stages of epithelial ovarian cancer. These particular genes likely undergo alterations early in the tumorigenesis process before metastases have become established.

Inhibition of Candida albicans--induced lymphocyte proliferation by lymphocytes and sera from women with recurrent vaginitis.

To investigate whether there was an immunologic basis for recurrent Candida albicans-induced vaginitis, peripheral blood lymphocytes were isolated from six women with this disorder and from six healthy control women. No differences were observed in the proliferative responses of peripheral blood lymphocytes to mitogens. However, only the control peripheral blood lymphocytes proliferated in response to a C. albicans extract. Furthermore, patients' lymphocytes or serum suppressed the proliferative response of control lymphocytes to C. albicans but not to mitogens. Women with recurrent C. albicans vaginitis appear to produce Candida-specific suppressor lymphocytes which block the cellular immune response to this organism.

Humoral immune responses in healthy heterosexual, homosexual and vasectomized men and in homosexual men with the acquired immune deficiency syndrome.

In homosexual men, the acquired immune deficiency syndrome (AIDS) is associated with sexual promiscuity and the appearance of circulating immune complexes (CICs) and antibodies to spermatozoa which crossreact with lymphoid cells. A comparative study was initiated to determine whether similar humoral responses existed in 38 heterosexual men lacking sperm antibodies, 13 heterosexuals with sperm antibodies, 42 heterosexual vasectomized men, 22 healthy homosexual men, 26 homosexuals with lymphadenopathy and 16 with AIDS or Kaposi's sarcoma (KS). Sperm antibodies were detected in 12% of the vasectomized heterosexual men, 23% of the healthy homosexuals, 35% of the lymphadenopathy patients and 44% of the men with KS-AIDS. IgG reactive with peripheral blood T lymphocytes was present in only 3% of heterosexuals lacking sperm antibody and 5% of vasectomized men. In contrast, 23% of heterosexuals with sperm antibody, 36% of healthy homosexuals, 31% of men with lymphadenopathy and 62% of KS-AIDS patients were positive in this assay. Antibodies to the neutral glycolipid asialo GM1 were found in none of the vasectomized men, 3% of the heterosexuals without and 8% with sperm antibodies, 17% of healthy homosexuals and 38% and 31% in patients with lymphadenopathy or KS-AIDS, respectively. Lastly, the incidence of CICs, determined by the Raji cell assay, was 0% in vasectomized men, 3% in heterosexuals lacking sperm antibody, 31% in heterosexuals with sperm antibody, 69% in healthy homosexuals, 81% in lymphadenopathy patients and 87% in KS-AIDS. In the homosexuals with lymphadenopathy and KS-AIDS, levels of CICs, T cell-reactive IgG and asialo GM1 antibody were positively correlated (p less than 0.01). Sperm antibody levels were negatively correlated (p less than 0.01) with CICs levels and T cell reactive IgG in heterosexuals and lymphadenopathy and KS-AIDS patients. The results demonstrate that vasectomized men do not manifest at all, and that non-vasectomized heterosexuals with sperm antibodies manifest to a much lesser extent the range of humoral immune responses exhibited by the three homosexual groups. Thus, the route of sperm immunization and/or exposure to autologous vs. heterologous spermatozoa may be of critical importance for eliciting specific immune responses.