W. Jäger

Influence of circulating c-erbB-2 serum protein on response to adjuvant chemotherapy in node-positive breast cancer patients.

This retrospective case control study investigated the therametricvalue of the circulating c-erbB-2 gene product (Her-2,NEU) as (1) an eligibility criterion for highdoses of chemotherapy and (2) response to standardadjuvant chemotherapy in node-positive breast cancer patients. Preoperativec-erbB-2 levels were measured in 211 locally advanced(> 3 nodes positive), pre- and perimenopausal breastcancer patients to determine if circulating levels ofthe gene product can assist in the determinationof appropriate therapeutic options.152 of 211 breast cancer patients received post-operativelya combination chemotherapy including the anthracycline analog mitoxantrone,while 59 patients were treated with conventional CMFtherapy. Using 120 fmol/ml as a cut-off level,elevated c-erbB-2 values were found in 26 (12.3%)patients with locally advanced breast cancer. In univariateanalysis significant survival differences were detected when c-erbB-2‘positive’ patients were compared with c-erbB-2 ‘negative’ patients.However, no significant survival differences were detected, whenc-erbB-2 ‘positive’ patients were compared according to regimenof adjuvant treatment.In multivariate analysis c-erbB-2 was an independent prognosticfactor for predicting disease-free survival, but not foroverall survival. High levels of c-erbB-2 were associatedwith low estrogen and progesterone receptor concentrations ofthe tumor cytosol. There was no correlation betweenelevated c-erbB-2 values and age, tumor size ordegree of nodal involvement. c-erbB-2 was a betterpredictor of risk of recurrence than extent ofnodal involvement or hormone receptor status.

The Prognostic Significance of c-erbB-2 Serum Protein in Metastatic Breast Cancer

The relationship between c-erbB-2 serum positivity and prognosis was evaluated in 80 patients with metastatic breast cancer. Using 120 fmol/ml as a cutoff level, elevated concentrations were found in 31 patients (38.8%) at the time of detection of metastases. Menopausal status, steroid receptor status, site of recurrence, initial tumor size, initial degree of nodal involvement as well as relapse-free interval were unrelated to c-erbB-2 serum positivity. In addition, no association could be found between adjuvant chemotherapy and positive c-erbB-2 concentrations. Patients with elevated c-erbB-2 levels showed a lower response rate (including complete remission, partial remission, no change) to first-line therapy than those with normal levels (29 vs. 59%, p < 0.01). The median survival time after relapse was 12 months (CI: 3–22 months) for the c-erbB-2-negative patients and only 6 months (CI: 3–8 months) for the c-erbB-2-positive group (p < 0.01). In the multivariate analysis, while c-erbB-2 levels at the time of primary surgery had no significant impact on survival in metastatic breast cancer, serum c-erbB-2 turned out to be the strongest factor for predicting survival after relapse.

Clinical Utility of Serial Serum c-erbB-2 Determinations in the Follow-up of Breast Cancer Patients

To evaluate the ability of serum c-erbB-2 protein to (1) indicate occult and manifest metastases and (2) reflect response to first-line therapy, serial serum c-erbB-2 measurements were performed in a retrospective series of 52 primary breast cancer patients who had developed metastatic disease during follow-up. The results were compared with CA 15-3. Preoperatively, 31% (16/52) of the primary breast cancer patients had elevated c-erbB-2 concentrations. The CA 15-3 positivity rate was 13% (7/52). After surgery, 10 of the 52 patients showed either stable but highly elevated or rising c-erbB-2 serum levels indicating serum c-erbB-2 producing minimal residual disease. Increasing CA 15-3 concentrations were seen in only three patients. Elevated serum c-erbB-2 levels predicted manifest metastases in 27 and 50% of the patients at 6 and 3 months, respectively, prior to clinical diagnosis. CA 15-3 was less sensitive. Only 16 and 32% of the patients had increased CA 15-3 serum concentrations at 6 and 3 months, respectively, prior to clinical detection. The positivity rates of c-erbB-2 and CA 15-3 were similar when metastases were clinically diagnosed. Elevated c-erbB-2 concentrations were found in 62% (32/52). The sensitivity of CA 15-3 was 56% (29/52). The association between serum profiles and response to first-line therapy was evaluated in detail for 45 patients. Serial c-erbB-2 and CA 15-3 measurements reflected disease course in 24 and 27 patients, respectively. The serum profiles of c-erbB-2 and CA 15-3 were similar in 17 patients. In summary, our results suggest that serial determinations of serum c-erbB-2 are useful to monitor breast cancer patients.

c-erbB-2 in serum of patients with breast cancer.

c-erbB-2 is an oncoprotein which is overexpressed in some breast cancers. Recently it has been established that the extracellular domain of c-erbB-2 is shed into the serum of patients with breast cancer. There appears to be no association between tumor stage and extracellular domain of c-erbB-2 (c-erbB-2/ECD): c-erbB-2/ECD seems to correlate with patient prognosis whatever the stage of disease. The data also suggest that c-erbB-2/ECD may be useful in monitoring for tumor recurrence and in predicting resistance to hormonal therapy, but not as useful in predicting response to chemotherapy. This may relate to the power of this marker to reflect disease burden, which has an overwhelmingly negative impact on outcome.

Some observations on the effect of a GnRH analog in ovarian cancer

Observations in healthy women led us to suppose that the increase of the tumor marker CA 125 observed during progression of ovarian cancer could be dependent on pituitary gonadotropins. Therefore we administered the GnRH-analog, DTrp 6-LH-RH, to 19 patients with progressive ovarian cancer and increasing CA 125 serum levels. When compared to 11 untreated patients, CA 125 levels increased at a considerably slower rate in 9 of 11 patients who were treated with the substance for more than 3 months. This was associated with stable disease, ranging from 4 to 20 months so far. The further analysis of 2 patients who developed an increase in CA 125 serum levels and a progression of disease during treatment demonstrated that FSH and LH levels had escaped suppression. The results support our assumption, that gonadotropins may be involved in the mechanisms leading to increasing CA 125 concentrations in ovarian cancer. The reduced increase of CA 125 and the observed stabilisation of disease during pituitary blockade offers a rationale for GnRH analogues in the therapeutic approach to this disease.

CA 125 production and release by ovarian cancer cells in vitro.

The antigenic determinant CA 125 is a high molecular weight glycoprotein which is elevated in more than 80% of patients with epithelial ovarian cancer. Despite its good performance as a human tumor marker, only little is known about its physiological function. According to recent publications, CA 125 production and release appear to be related to cellular growth. In order to investigate this putative relationship more closely, we analyzed the pattern of CA 125 production and release by ovarian cancer cells during exponential cell growth, during cell cycle arrest by colchicine and during inhibition of cellular protein synthesis by cycloheximide. The results were correlated with the cell cycle distribution. According to our results, the main determinant of CA 125 release into the culture supernatant is the total cell count. Although cell cycle arrest in the G2 + M phase by means of colchicine treatment resulted in the death of most cells, which was reflected by an increased release of CA 125, no differences in the intracellular production rate between colchicine treated and untreated cells were seen. In contrast, treatment of cells with cycloheximide not only resulted in decreasing cell numbers but also in a complete inhibition of CA 125 production by surviving cells.

CEA-containing immune complexes in sera of patients with colorectal and breast cancer--analysis of complexed immunoglobulin classes.

SummaryA sandwich enzyme immunoassay was developed to detect circulating immune complexes containing carcinoembryonic antigen (CEA) and immunoglobulin (Ig) G, IgA, or IgM using a nitrocellulose-bound anti-CEA antibody as the solid phase reagent. Elevated levels of CEA-containing circulating immune complexes (CEA-IC) were found in 15.4% of 117 sera from patients with colorectal cancer in a postsurgery follow-up study. Also in 24.5% of 102 sera from patients with breast cancer in different states of disease CEA-IC were found. The predominant Ig determined in CEA-IC of colorectal cancer patients was IgA, followed by IgG and IgM, whereas IgG and IgM were the most frequent Igs in CEA-IC of breast cancer patients. Elevated CEA levels were found in 12.0% of the colorectal cancer patients and in 25.4% of sera from breast cancer patients. No significance for the coincidence of elevated CEA levels and CEA-IC was recorded in all patients sera tested. In sera of patients with disease recurrence, however, both parameters were shown to be elevated (CEA 80.7% and CEA-IC 42.3%). The data presented indicate the detection of CEA-IC as an additional parameter for the identification of patients at increased risk for disease recurrence.

Influence of Human Luteinizing Hormone on Cell Growth and CA125 Secretion of Primary Epithelial Ovarian Carcinomas in vitro

In the present study, the influence of human luteinizing hormone(hLH) on the growth and the CA 125 secretion of primary ovarian carcinoma cell cultures derived from 11 previously untreated patients was investigated. Two different patterns of in vitro growth of unstimulated ovarian carcinoma cells could be detected: 5 cell cultures in which no changes of cell number were observed during an incubation period of 6 days (group A) and 6 cell cultures which grew without any hormonal support (group B). All tumors of group A showed enhanced cell proliferation when hLH was added to the culture medium, reaching a maximum at dosages of 100 mIU/ml on day 2 after incubation, while such an effect was not observed in group B. In most cases, no positive correlation was found between hLH-induced cell growth and CA 125 release. Our findings demonstrated a dose-dependent hLH-induced stimulation of epithelial ovarian tumors in vitro.

Gonadotropin levels in ovarian cyst fluids : a predictor of malignancy?

Gonadotropins can stimulate ovarian cancer growth in cell cultures. Corresponding LH/hCG receptors have been demonstrated in ovarian cancer. However, reduction of elevated serum gonadotropins by GnRH analogs in ovarian cancer patients did not lead to growth restriction, which means that serum levels of gonadotropins may not play the most important role in ovarian cancer. We therefore analyzed the LH and FSH concentrations in cyst fluids of ovarian cancer. Patients with preoperatively diagnosed cystic ovarian tumors were eligible for the study. Serum samples of the patients were obtained during surgery, while the fluids within the cysts were aspirated after surgical removal of the tumor. FSH and LH levels in serum and cyst fluids were measured using single antibody EIA (Boehringer Mannheim GmbH, Germany). Cyst fluids and sera of 108 patients were evaluated. While there were no significant differences in the FSH and LH serum concentrations, highly significant differences in the FSH and LH levels in cyst fluids were found. Only cancer cysts contained FSH and LH, while the corresponding concentrations in benign cysts were always below the measuring range of the assays. This clear division between high gonadotropin levels in cysts of serous ovarian cancer and low or absent concentrations in benign ovarian tumors further supports the hypothesis that FSH and LH may play a role in ovarian cancer; however, explanations for this surprising finding are still lacking.

Effect of timing of surgery during the menstrual cycle of premenopausal breast cancer patients

AbstractBackground. In 1989 it was suggested that the timing of surgery during follicular or corpus luteum phase of the menstrual cycle could substantially influence the survival time in premenopausal breast-cancer patients [1]. Several researchers analysed their data, but in general they could not confirm this observation. Nevertheless, two other reports in that series found some influence of the time of surgery during menstrual cycle on prognosis, although, they suggested different time periods as favourable [8, 9]. Purpose. The purpose of this study was to investigate the effect of timing of surgery in a study population which was much larger than the previous studies. Method. All premenopausal patients with primary breast cancer who had been operated at one clinic between 1st of January 1980 and 31st of December 1990 were considered eligible for the study. Based on the day of surgery during the menstrual cycle all patients were grouped according to three proposed categories and to an additional one which consisted of the favourable days from the three proposed categories. We investigated the effects of several prognostic factors and of the timing of surgery on three endpoints: recurrence free survival, distant disease free survival, and overall survival. Results. The traditional prognostic factors had effects in agreement with the literature. Of the different categories for timing of surgery none had a significant influence; the strongest in univariate analysis had a p-value of 0.10 and the trend was in the opposite direction to the one proposed in the literature. These results did not change in multivariate analysis with the Cox model. Conclusions. Timing of surgery does not have an important effect on the prognosis of breast cancer patients. Incorporating other results from the literature, we conclude that it has at most a weak effect. Implications. At present there is no need to incorporate the day of menstrual cycle in the planning of surgery for premenopausal breast cancer patients.