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Background: The possible link between psychological factors and length of cancer survival has generated a literature of contradictory findings. Associations usually have not been found when general psychological symptoms are assessed. Associations usually have been found for predictors related to expressive versus repressive emotional coping (e.g., depression, 'fighting spirit,' hostility, and type C personality); however, even these associations have been relatively small, when compared with those for medical factors. Yet few studies have adequately controlled for medical and treatment-related factors. Purpose: Within a Cancer and Leukemia Group B (CALGB) national clinical trial of four adjuvant therapy regimens for stage 11 breast cancer (CALGB 8082), this study prospectively examined the contribution of potential psychological predictors to length of disease-free and overall survival over a 15-year period. Methods: Subjects were 280 women with stage 11 breast cancer, out of a total of 899, who were randomly assigned to receive CMFVP (cyclophosphamide-methotrexate-fluorouracil-vincristine-prednisone) for two 6-week cycles or six 4-week cycles, then subsequently randomly assigned to receive or not to receive VATH (vinblastine-doxorubicin-thiotepa-fluoxymesterone). Subjects were recruited during the period between October 1980 and August 1984, inclusive, and followed until January 1996. Prior to chemotherapy, psychological symptoms were assessed using the Symptom Check List-90-Revised (SCL-90-R). SCL-90-R scores were trichotomized into categories representing high, medium, and low distress. Basic base-line sociodemographic data (including age, ethnicity, education, and marital status) and medical data (including lymph node status, estrogen receptor status, menopausal status, and performance status) were collected. Subjects with psychosocial data differed from those without psychosocial data solely in their higher percentage of classification in the mild limitation category of the Zubrod (Eastern Cooperative Oncology Group) performance status rating (subjects with psychosocial data: 14%; subjects without psychosocial data: 8%). Results: In stepwise Cox regression analyses that controlled for sociodemographic and medical variables, there was no significant predictive effect of the level of distress (as measured by the SCL-90-R trichotomized scores) on length of disease-free and overall survival of the study subjects. Risk ratios for low versus high distress were 1.01 (95% confidence interval [CI] = .62-1.66) for disease-free survival and 1.03 (95% CI = 0.58-1.82) for overall survival. Conclusions: This study failed to provide evidence that psychological factors contributed to length of disease-free or overall survival of women who received adjuvant chemotherapy (either CMFVP alone or CMFVP followed by VATH) for treatment of stage 11 breast cancer. Implications: In the context of far more potent medical factors, the contribution of psychological factors to disease-free and overall survival is likely to be relatively small. Future research should focus on specific theory-driven predictors rather than on general psychological symptoms. Moreover, it should be based on clinical studies using a controlled, prospective design, in which the effects of medical factors may be distinguished and psychological predictors are clear antecedents of survival outcomes.

Background. Chemotherapy is most effective when applied during the biologically active stage of tumor cells. According to the authors' previous tumor marker kinetic study, methotrexate plus 5-fluorouracil (MF) was found to yield either a cytolytic effect in an MF-sensitive tumor cell population or a cytostatic effect in an MF-resistant population. In the latter, the suppressive effect was transient and the biologic activity resumed in one week after MF administration. Methods. Based on this marker kinetic study, an alternating chemotherapy program was designed to study its antitumor and side effects. Methotrexate (M) (200 mg/ m[.sup.2]) and 5-fluorouracil (F) (500 Mg/m[.sup.2]) were administered intravenously on day 1 followed 24 hours later by leucovorin (L) (10 mg/m[.sup.2] orally every 6 hours for 6 doses). Cyclophosphamide (C) 300 (mg/m[.sup.2]), doxorubicin (A) (50 mg/ m[.sup.2]), and vincristine (V) (1 mg/m[.sup.2]) were given on day 8. The MFL/CAV was given every 4 weeks. Results. Forty-nine patients with metastatic breast cancer were enrolled; 41 were eligible. There were 5 complete and 23 partial remissions, producing a total response rate of 68%. In 15 patients with liver metastases, the response rate was 73% and the median survival 13.7 months, results superior to those previously reported for this subgroup of patients. Side effects were manageable. Conclusions. This regimen, which can be given safely in an outpatient setting, yielded encouraging response and survival rates in patients with visceral-dominant disease with poor prognoses.

Background: Amplification and over-expression of the HER-2/neu oncogene (also known as c-erbB-2) occurs in 20%-30% of invasive breast carcinomas. The extent to which HER-2/neu expression changes over time in association with tumor progression or is heterogeneous at different metastatic sites has received only limited study. Purpose: Our purpose was to determine whether primary tumors differ from metastases in HER-2/neu protein content or whether metastases are heterogeneous in regard to HER-2/neu expression. Methods: In a retrospective study, we examined tumor tissue obtained at autopsy from two to five metastatic organ sites in each of 30 patients who died with metastatic breast carcinoma. Using an immunoperoxidase technique, we stained archival formalin-fixed, paraffin-embedded tissue sections with a monoclonal antibody to the 185-kilodalton protein product (p185) of the HER-2/neu gene. Results: The tissue from eight of 30 patients showed strong diffuse reactivity for p185 at all metastatic sites examined. Tissues from six patients showed faint staining and tissues from 15 were negative, again with a congruent staining pattern. A single case showed discordant staining, in that two of four metastases showed faint staining, whereas the other two showed strong immunoreactivity. In 14 cases, we were able to obtain paraffin blocks from the original biopsy or surgical resection of the primary breast lesion. For these 14 patients, the average length of time between initial diagnosis and death was 4 years (range, 2-9). There was good correlation between results from autopsy and original surgical tissues. Conclusions: Expression of HER-2/neu appears to be relatively stable over time and is generally congruent at different metastatic sites. Implications: The fact that p185 immunoreactivity is rarely heterogeneous is encouraging, both for the potential use of HER-2/neu-related proteins as serum tumor markers and for innovative therapies targeted at p185 expression. [J Natl Cancer Inst 85:1230-1235, 1993]

Tumor markers are protein antigens which are preferentially expressed by tumor cells rather than by normal tissues. Frequently, traces of these molecules may be found in the circulation, and their potential clinical value may lie in using these circulating markers to evaluate the response to therapy in cancer patients. Unfortunately, the method is not without its problems. Not all tumors express these antigens or release them into the circulation. Furthermore, reports have indicated that in some patients the circulating markers behave paradoxically; that is, the marker levels rise in patients experiencing documented tumor regression and decrease in patients showing signs of tumor progression. It is clear why investigators hoping for a simple test to evaluate treatment success have been disappointed. Thirty patients with advanced breast cancer were closely followed in order to observe the kinetics of change of two tumor markers. Carcinoembryonic antigen (CEA), which was among the first markers found and the most widely studied, and CA15-3, another marker, were measured at least four times in the first month after chemotherapy and afterwards as schedules permitted. Four distinct kinetic patterns of circulating marker levels were identified. Two followed the expected patterns, in which rising marker levels accompany continued tumor growth and falling markers indicate tumor regression. The remaining two patterns were paradoxical. It appears that continued tumor growth may result in a transient reduction in marker levels, which then begin to rise again and continue to rise along with tumor progression. Tumor marker levels may also rise paradoxically during the early stages of tumor regression, but fall thereafter. One possible explanation for the rise in marker levels among patients with regressing tumor is that the dying cells may release large amounts of marker into the blood. An explanation for the falling of tumor markers in some patients with progressing tumors is somewhat more elusive. However, there is some evidence from tissue culture experiments that chemotherapeutic agents inhibit the release of CEA from the cells, though there is no inhibition of its synthesis. The cells simply accumulate larger amounts of carcinoembryonic antigen. Although the paradoxical effects may occur with many tumor markers, in this study the kinetics of CEA and CA15-3 were similar but not identical. This raises the possibility that two or more markers may be used together to get a better picture of the clinical response to cancer treatment. (Consumer Summary produced by Reliance Medical Information, Inc.)