Adjuvant randomized trials of doxorubicin/cyclophosphamide versus doxorubicin/cyclophosphamide/tamoxifen and CMF chemotherapy versus tamoxifen in women with node-positive breast cancer.

PURPOSE: We report two randomized trials of adjuvant systemic therapy in 747 patients < or = 65 years of age with histologically proven node-positive breast cancer. PATIENTS AND METHODS: Patients were selected for the two trials on the basis of lymph node and hormone receptor status. The only stratification was based on the treating institution. In patients with a lower probability of recurrence (n = 276), a comparison between endocrine therapy (tamoxifen [Tam] 30 mg/d for 2 years) and chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [CMF] intravenously [IV], six cycles every 4 weeks) was performed. In patients with a higher risk of recurrence (n = 471), a comparison between chemotherapy alone (doxorubicin plus cyclophosphamide [AC] i.v., eight cycles every 3 weeks) and the same chemotherapy plus Tam was made. RESULTS: Overall, we found that CMF and Tam are equally effective in a subgroup of patients with a relatively good prognosis (low-risk patients). However, in the subset of women < or = 49 years old, a significantly greater disease-free survival (DFS) rate (P = .01) and overall survival (OS) rate (P = .002) was observed following therapy with CMF compared with Tam. In patients > or = 50 years old, the opposite was found, and Tam appeared to be superior to CMF (DFS, P = .003; OSm P = .5). These results must be interpreted cautiously, since a post-hoc stratification of patients by age (< or = 49, > or = 50) was performed, and significantly more younger, low-risk patients were randomized to receive chemotherapy alone and more older patients to receive Tam alone. Among patients with a relatively poor prognosis (high-risk patients), a combination of AC plus Tam was equivalent to AC and, when women were analyzed by age, this was found to be true of patients < or = 49 years as well. However, the addition of Tam to AC in women age > or 50 years resulted in a statistically significantly higher DFS (P = .01) and a trend toward better OS compared with women who received AC alone. CONCLUSION: Further trials are required to analyze the role of combined simultaneous or sequential chemoendocrine adjuvant treatment or each single therapy alone in defined risk-adapted subsets of node-negative and node-positive patients.

A case of metastasizing invasive hydatidiform mole. Is less--less good? Review of the literature with regard to adequate treatment.

BACKGROUND: Patients with invasive hydatidiform moles (IHM) have a good prognosis. Even if disease has spread, monocytostatic treatment might be sufficient if the diagnosis has been histologically confirmed. Established classifications divide gestational trophoblastic disease (GTD) including choriocarcinoma into cases with "high" and "low" risk. Without respect to histology "high-risk" cases are recommended to obtain polychemotherapy. CASE: A 40-year-old nullipara underwent hysterectomy for persistent vaginal bleeding after she had already been treated with curettage for hydatidiform mole. An IHM was pathohistologically confirmed. There were no signs of pulmonary spread or other metastases at the time of surgery. Postsurgically persistent beta-hCG levels lead to thorough staging, which revealed multiple pulmonary metastases and a vaginal metastasis. Despite metastasizing GTD with poor prognosis criteria she was treated with single agent therapy. Eight cycles of two weekly methotrexate (MTX) were administered. All sites of metastases responded and our patient is still fine after one year of follow-up. CONCLUSION: With respect to this and other reports monochemotherapy can be a reasonable primary treatment for metastatic IHM.

Endometrial carcinoma: immunohistochemically detected proliferation index is a prognosticator of long-term outcome.

AIM: To test which immunohistochemically detected tumour parameters are predictive of outcome in endometrial carcinoma. METHODS: A retrospective study of 300 patients diagnosed with endometrial carcinoma between 1980 and 1985, ensuring a follow up of at least 10 years. Paraffin wax embedded tissues from 236 patients with endometrial carcinoma were evaluated in terms of histological tumour type and grade, stage of disease, and certain immunohistochemical biological parameters. These parameters included the expression of oestrogen and progesterone receptors, the expression of p53 protein, the expression of the c-erbB-2 oncoprotein, and the expression of protease cathepsin D, together with the rate of cell proliferation. RESULTS: Using univariate analysis, the following parameters correlated significantly with adjusted survival: histological type (p = 0.025), grade (p = 0.00003), FIGO stage (p < 0.00001), proliferation rate (p = 0.00002), oestrogen receptor expression (p = 0.007), progesterone receptor expression (p = 0.0092), and p53 expression (p = 0.00028). These parameters also correlated significantly with both disease free and overall survival. There was a weak correlation of cathepsin D expression with survival, but no correlation of c-erb B-2 expression with survival. Using multivariate analysis, only FIGO stage (p = 0.0021), histological grade (p = 0.005), and proliferation rate (p = 0.0007) remained statistically significant prognosticators of adjusted survival as well as of disease free and overall survival. CONCLUSIONS: In addition to conventional histological parameters, the immunohistochemical determination of proliferative activity could contribute to the identification of a high risk subgroup of endometrial carcinomas. The other parameters tested were not of significant additional predictive value.

Diagnostic value of serum VEGF in women with ovarian tumors.

BACKGROUND: Angiogenesis is necessary for growth and invasiveness of malignant tumors. Vascular endothelial growth factor (VEGF) is considered to play a key role in tumor angiogenesis. Few data are available with regard to serum levels of VEGF in patients with ovarian tumors. We investigated the diagnostic value of serum VEGF in patients with ovarian neoplasms. MATERIALS AND METHODS: 61 patients with ovarian neoplasms (41 ovarian carcinomas, 20 cystadenomas) and 20 healthy women were included into the study. VEGF serum concentrations were determined by a commercially available ELISA. RESULTS: Statistical analysis revealed significant differences in VEGF serum values of ovarian cancer patients vs. healthy controls or patients with cystadenomas. No difference could be seen between serum levels of healthy controls and women with benign ovarian tumors. For ovarian cancer patients vs. normal controls a sensitivity of 71% and a specificity of 65% resulted. The sensitivity and specificity of cancer patients vs. patients with benign neoplasms were 71% and 65%, respectively. CONCLUSION: Our results suggest that VEGF has potential as a serum marker with diagnostic relevance in ovarian neoplasms.

Prognostic relevance of serum vascular endothelial growth factor in ovarian cancer.

BACKGROUND: The vascular endothelial growth factor (VEGF) is the angiogenic growth factor most strongly implicated in tumor angiogenesis. Its special role in the pathophysiology of ovarian cancer emerges from its dual functional capability as an endothelial cell mitogen and a potent stimulator of vascular permeability, leading to the characteristic ascites accumulation in this disease. The aim of our study was to analyze the prognostic value of serum VEGF (sVEGF) as a tumor marker in ovarian cancer. PATIENTS AND METHODS: 41 patients with ovarian carcinomas were included in the study. Venous blood was taken from all patients preoperatively. From 15 patients an additional postoperative blood sample was drawn. sVEGF was measured in duplicate using a commercially available ELISA-kit. RESULTS: The mean sVEGF level for the ovarian cancer patients was 522 +/- 321 pg/ml (SD) (median: 440; range: 55-1263 pg/ml) No statistically significant correlation could be found between sVEGF concentration and age, histologic type or FIGO-stage. sVEGF values four weeks after surgery were significantly lower than those before treatment (p = 0.002). In patients after radical surgery sVEGF values dropped or stayed stable below the cut-off more often than in patients with residual disease. In the univariate analysis, improved overall survival (OS) was found for ovarian cancer patients with a sVEGF below the cut-off value of 440 pg/ml (p = 0.017). sVEGF was also tested in a multivariate analysis together with residual disease and FIGO-stage using the Cox's proportional hazard model. In the final model only residual disease had an independent influence on OS (p = 0.018). CONCLUSION: sVEGF levels decrease significantly after cytoreductive therapy and might indicate treatment efficiency. According to our study, sVEGF is not an independent prognosticator of survival for ovarian cancer.

CASA and Ca 125 in diagnosis and follow-up of advanced ovarian cancer.

BACKGROUND: CA 125 is the most important tumor marker in ovarian cancer. Due to its low specificity and the fact that some ovarian malignancies do not produce considerable amounts of CA 125 a combination with the Cancer Associated Serum Antigen (CASA) may reflect more accurately the clinical situation. MATERIALS AND METHODS: CA 125 and CASA determination was performed in sera of 78 patients with advanced ovarian cancer pre- and postoperatively, monthly during chemotherapy and during follow-up care. The cut-off values for CASA were 4 U/ml, for CA 125 35 U/ml and 65 U/ml, respectively. RESULTS: In the detection of advanced ovarian cancer a combination of both tumor markers was superior to the use of either CASA or CA 125 alone. In the follow-up situation CA 125 with the 35 U/ml cut-off showed the highest sensitivity. Both markers had similar prognostic relevance when marker levels three months after surgery were used. CONCLUSION: CA 125 and CASA have similar characteristics in preoperative diagnosis and postoperative follow-up. In clinical situations with inconclusive or negative CA 125 serum values CASA is helpful to improve management of patients with advanced ovarian cancer.

Predictive value of CEA and CA 15-3 in the follow up of invasive breast cancer.

BACKGROUND: The clinical usefulness of tumor markers in the follow-up care of invasive breast cancer is controversial. METHODS: In 1228 serum samples of 664 women with history of breast cancer, the diagnostic accuracy and predictive power of CEA and CA 15-3 for the detection of disease relapse was determined prospectively by analyzing the clinical course for at least 6 months after the measurement of the tumor markers in 1994. RESULTS: A total of 76 patients relapsed during the period of study. The diagnostic accuracy was 83% for CEA and 88% for CA 15-3. CEA and CA 15-3 had a positive predictive value of 27% and 47% as well as a negative prediction of 91% and 93%, respectively. CONCLUSIONS: The low positive predictive value and sensitivity of these tumor markers clearly limit their clinical utility. Therefore, the effectiveness of routine determinations during the follow-up seems questionable.

Prognostic relevance of p53 in node negative breast cancer.

In a retrospective study, immunohistochemical determinations of p53 were performed on paraffinised tissue sections of 243 patients with node negative breast cancer. These patients were primary treated in the years 1980-1986 at the UFK-Würzburg. A complete follow up could be performed in 92% of all cases. The median follow up is at 102 month. The results have been correlated to other prognostic criteria and to the clinical course of the patients. In 77 of the 243 cases a positive immunohistochemical staining for p53 (31.7%) could be found. In 42 (17.3%) cancer specimens the p53 expression was over 5%. A significant correlation was found between p53 and tumour size (p = 0.05), ploidy (p < 0.001) and dynamic parameters of the cell cycle (S-phase-fraction, MIB1: p < 0.001). In univariate and multivariate analysis the expression of p53 did not effect disease-free or over-all survival of patients with node negative breast cancer.

Clinical value of CYFRA 8/18 and TPS in the diagnosis and follow up of invasive breast cancer.

In a prospective study, we evaluated the diagnostic accuracy of CYFRA 8/18, TPS, CEA and CA 15-3 among 415 patients in various clinical situations of invasive breast cancer and 244 women with benign breast diseases. In comparison to TPS, the sensitivity of CYFRA 8/18 was slightly lower as well in local malignancy (25% vs. 30%) as in metastatic cancer (54% vs. 57%), but in follow up care the rate of false positive results of TPA (> or = 25%) seems to be higher than that of CYFRA 8/18 (> or = 17%). In conclusion, the clinical value of CYFRA 8/18 and TPA appears to be similar.

Evaluation of tartrate-resistant acid phosphatase (TRAP) 5b as serum marker of bone metastases in human breast cancer.

BACKGROUND: The osteoclast-specific active TRAP 5b isoform is detectable in serum and claimed to be a specific marker of bone resorption. The present study was undertaken to evaluate the usefulness of TRAP 5b as a serum marker of bone resorption in breast cancer patients with bone metastases. MATERIALS AND METHODS: TRAP 5b serum levels were measured in 192 samples from patients with breast cancer with and without bone metastases and in 53 healthy pre- and postmenopausal women using the enzyme immunoassay Bone-TRAP. RESULTS: Serum levels of TRAP 5b were significantly higher in patients with breast cancer and clinical signs of bone metastases before therapy than in healthy women. There was also a significant difference between patients with bone metastases before and during bisphosphonate therapy, indicating a reduction of bone alteration under this treatment. The subgroup with progression of bone metastases under bisphosphonate therapy showed the highest difference in TRAP 5b concentrations compared to patients with stable disease. CONCLUSION: Serum TRAP 5b levels are elevated in patients with bone metastases and breast cancer. The TRAP 5b levels decline under bisphosphonate therapy when no progression is detectable. When progress of the bone metastases occurs, TRAP 5b levels rise again. Therefore, active TRAP 5b seems to be a useful serum marker for bone metastases in breast cancer patients, especially to detect progressive disease under bisphosphonate treatment. Further studies with larger numbers of patients are required to confirm these data.

Correlation of the EGF-receptor with cell kinetic and classical prognostic factors in breast cancer.

SPECIFIC OBJECTIVE: The Epidermal Growth Factor Receptor (EGFR) is a specific cell membrane receptor that shows homology to the product of the oncogene c-erbB2 in human breast cancer. Growth factors bound to the EGFR are able to stimulate the growth of tumor cells in an autocrine or paracrine manner. Our objective was to examine whether there is a relationship between EGFR, cell kinetic prognostic factors (ploidy, proliferation-antigen Ki67) and classical prognostic factors (hormone receptors, menopausal status, nodal status) in breast cancer. METHODS: EGFR was assayed in tumor tissue of 55 patients with breast cancer using an ELISA, the ploidy-status was evaluated by image analysis and Ki67 was determined by immune histochemistry. Estrogen- (ER) and Progesterone-Receptor (PR)-concentrations were quantified using a radioligand assay. RESULTS: There was a significant positive correlation between the EGFR and the cell kinetic prognostic factors: EGFR positive tumors were significantly-more often aneuploid and Ki67-positive. In addition there was an inverse association between EGFR- and ER-concentration, but no association between EGFR and PR. The EGFR did not correlate with the nodal and the menopausal status. CONCLUSIONS: Our study revealed associations between EGFR, ER, Ki67 and ploidy. Whether these correlations can help to predict the course of disease, providing further information in addition to the conventional factors (nodal status, steroid hormone receptors etc.) has to be investigated by several years of clinical follow up.

The endothelial marker CD 34 in the assessment of tumour vascularisation in ovarian cancer.

OBJECTIVE: Tumour angiogenesis as well as the density of newly formed vessels are of potential prognostic relevance in the assessment of malignant neoplasia. Among other monoclonal antibodies the endothelial marker CD 34 is being increasingly investigated in the assessment of tumour vascularisation, especially in vascular tumours. The aim of this study was to determine the value of CD 34 as an immunohistochemical method to quantify tumour vascularisation in ovarian cancers. METHODS: In a preliminary study 30 solid ovarian cancers were investigated with regard to their CD 34 expression. Paraffine embedded specimens were processed immunohistochemically using the PAP-method, in a dilution of the primary antibody CD 34 of 1:50. Morphological aspects, such as tumour homogenicity and vessel distribution, as well as vessel density were analysed. RESULTS: The primary antibody CD 34 reacted positively with the endothelium of arteries, veins and capillaries, noting a more marked expression in small vessels. Furthermore, enhanced staining of those tumour sections with connective tissue was observed, very likely due to the increased vascular pattern of connective tissue. Non-homogenous distribution (e.g. "hot spots") was also seen. Overall, an excellent marking and therefore quantification of tumour vessels was achieved using CD 34. SUMMARY: In this pilot study we were able to demonstrate the ability of CD 34 to mark tumour vessels in solid cancers of the ovary. Whether this marker will be of any prognostic relevance in the future is under investigation in a larger patient cohort at present.

Prognostic relevance of the endothelial marker CD 34 in ovarian cancer.

BACKGROUND: Tumour angiogenesis and microvessel density are of prognostic significance in several human neoplasia. To investigate how tumour vascularity correlates with disease-free survival microvessel density was assessed in 38 patients with ovarian cancer using the highly specific endothelial marker CD 34. METHODS: Representative specimens were obtained and stained using monoclonal CD 34 antibodies. The microvessels were quantified at 200x and 400x magnification in the most active areas of neovascularisation. Degree of angiogenesis was correlated with histologic tumour type, grading, and tumour stage. Furthermore, survival was calculated using Kaplan-Meier analysis and results again correlated with the microvessel count. RESULTS: No correlation was found between microvessel density, histologic type, grading, and FIGO stage. Patients with a vessel count more than 40 (200x magnification) had a statistically significant lower overall survival (p = 0.022). CONCLUSION: Our results indicate that CD 34 is a useful marker in determining tumour neovascularisation which might be of prognostic relevance in patients with ovarian cancer.

The correlation of c-erbB-2 oncoprotein and established prognostic factors in human breast cancer.

BACKGROUND: The c-erbB-2 (HER2/neu) receptor is a transmembrane phosphoglycoprotein associated with multiple signal transduction pathways. Its overexpression in breast cancer tissue has been correlated with poor prognosis. We report preliminary data of an ongoing study in invasive breast cancer patients exploring c-erbB-2 protein overexpression in relation to established tumor characteristics of prognostic value. MATERIALS AND METHODS: In primary breast carcinoma samples from 115 women undergoing surgery in our department in 1999, a polyclonal rabbit antibody to human c-erbB-2 oncoprotein was used for immunohistochemical assessment of the c-erbB-2 expression in formalin-fixed paraffin-embedded material. The data were statistically correlated with classical histopathological parameters. RESULTS: In the studied collective of mainly postmenopausal women (75%) with a high rate of early stage breast cancer (88% pT1 + 2), there was no significant relation between c-erbB-2 overexpression, classified as positive in 42% of the samples, and lymph node involvement, tumor size and grade, or hormone receptor status. CONCLUSION: Using the presented highly sensitive method, no association between c-erbB-2 expression and established prognostic factors was found. These data are in line with reports that the value of HER2/neu determination is not fully clarified for the preadjuvant evaluation of newly diagnosed breast cancer patients.

Simultaneous interdisciplinary counseling in German breast/ovarian cancer families: first experiences with patient perceptions, surveillance behavior and acceptance of genetic testing.

As part of a multicenter study supported by the German Mildred Scheel foundation we have established an interdisciplinary counseling setting for members of breast and/or ovarian cancer families. We offer simultaneous counseling by a team consisting of a geneticist, a gynecologist and a psycho-oncologist. Here we describe our counseling protocol and our first short-term experience with this interdisciplinary approach. Preliminary data on patient perceptions and behaviors in the context of DNA testing are reported. Overall, our counseling approach was perceived as beneficial both by the counselors and the consultants. A marked overestimation of the risk to develop breast and/or ovarian cancer was noted in the group of unaffected individuals from medium to low risk breast cancer families in contrast to an appropriate risk perception in members from high risk families. All participants shared many of the same expectations about genetic testing and counseling and appeared to base their decision-making about testing on the risk classification given by the genetic counselor. The reported participation in gynecological cancer prevention programs was high in all families at risk, but was less sufficient in unaffected as compared to affected persons. Although current data on BRCA1/BRCA2 mutation analyses render testing in medium to low risk individuals questionable, our findings emphasize the importance of genetic counseling and education in all risk categories of breast and/or ovarian cancer families.

[Cathepsin D in primary breast cancer in correlation with various prognostic factors]. / Kathepsin D beim primären Mammakarzinom in Korrelation zu verschiedenen Prognosefaktoren.

The concentration of total cathepsin D, which is regarded as an additional prognostic factor, was measured in 87 patients with primary breast cancer by a radioimmunoassay in tumour cytosol. The distribution of values was approximately log normal with a median value of 49 pmol/mg protein. Relating the level of cathepsin D to other prognostic factors, no significant association to the patients' age, menopausal status, tumour size, axillary lymph node involvement, distant metastases, type of tumour, histological grading or hormone receptor status could be established. Therefore, cathepsin D seems to be independent from other established prognostic criteria, which is a prerequisite for this protease to be useful as an additional prognostic marker.