Thymidine kinase as a proliferative marker: clinical relevance in 1,692 primary breast cancer patients.

PURPOSE: To assess the prognostic value of thymidine kinase (TK), an enzyme involved in the DNA synthesis salvage pathway, relative to other prognostic factors in primary breast cancer. PATIENTS AND METHODS: This retrospective study involved 1,692 patients with operable breast cancer treated in six institutions (median follow-up, 82 months). Among the 857 node-negative patients, 135 received adjuvant chemotherapy (fluorouracil, doxorubicin, cyclophosphamide [FAC] or fluorouracil, etoposide, and cisplatin [FEC]). TK was assayed in cytosol with a quantitative radioenzymatic technique. Disease-specific survival (DSS), local recurrence-free interval (LRI), and distant-relapse-free interval (DRI) were investigated. RESULTS: High TK levels were associated with large tumor size, high histologic grade, and steroid hormone receptor negativity. Univariate analysis of the entire data set showed that high TK levels were related to shorter DSS (P < 10(-5)), LRI (P < 10(-3)), and DRI (P < 10(-5)). In time-dependent Cox models, high TK levels remained an independent predictor of the three outcomes, both in the overall population and in node-negative patients, although its prognostic value decreased over time. In node-negative patients, the introduction of an interaction term in multivariate analysis suggested that chemotherapy was more efficacious for patients who had tumors with high TK contents. In node-positive patients, high TK levels were related only to an increased risk of LRI. CONCLUSION: High TK values are an important risk factor in node-negative patients and seem to be associated with a beneficial effect of adjuvant FAC or FEC in patients who received adjuvant chemotherapy. The rationale of chemotherapy for patients with slowly proliferating tumors has to be discussed from a risk-benefit point of view.

Prognostic value of uPA and p53 accumulation measured by quantitative biochemical assays in 1245 primary breast cancer patients: a multicentre study.

The purpose of this retrospective multicentre study was to assess the prognostic value of urokinase plasminogen activator (uPA) and p53 levels in a large series of primary breast cancer, using an automatic quantitative luminometric method. Samples of 1245 operable breast tumours were collected from seven French institutions and patients were followed for a median of 75 months. The median uPA and p53 levels assayed in cytosols by means of the immunoluminometric technique (LIA) were 0.31 and 0.20 ng mg(-1) of protein respectively. In univariate analysis, high levels of uPA and p53 were associated with shorter disease-specific survival, disease-free interval, and distant recurrence-free interval. The 5-year survival rates were 95.5% among patients with uPA values below the 20th percentile, and 77.5% in those with values above the 80th percentile. The 5-year survival rates were 91.0% in patients with p53 values below the 20th percentile, and 77.6% in those with values above the 80th percentile. In multivariate analysis, the risk of disease-related death increased with uPA levels after adjustment for tumour size, histological grade, lymph node involvement, and estrogen receptor status. A high level of uPA was also related to a shorter disease-free interval and distant recurrence-free interval. In node-negative patients, a high level of uPA remained strongly related to the three outcomes. When adjusted for other prognostic factors, p53 was no longer significantly related to the outcomes. Given its rapidity and simple application to routinely prepared cytosols, this LIA may be useful for evaluating the prognostic impact of uPA in primary breast cancer, particularly in node-negative patients. According to our results, the prognostic value of p53 accumulation is limited when uPA is included in multivariate analysis.

[Long-term prognostic role of steroid receptors in cancer of the breast]. / Rôle pronostique à long terme des récepteurs stéroïdiens dans le cancer du sein.

We screened for the prognostic value of estrogen receptor (ER) and progesterone receptor (PR) through a multicentric study of 2,257 operable breast cancer patients who did not received adjuvant therapy. Three hundred and seven local-regional recurrences, 105 metachronous contralateral breast cancer, 589 metastases and 537 deaths from cancer had been diagnosed with a median follow-up of 8.5 years. A total of 69% of the tumors were ER positive and 54% PR positive. For statistical analysis, 1,665 patients were studied because of complete clinical and biological data. In univariate analysis, ER and PR status were of prognostic value for the metastases-free interval (MFI) and the overall survival (OS). In multivariate analysis (Cox proportional hazard model), only the ER status showed a significant difference between positive and negative groups regarding the MFI and OS. By using Cox regression model with time-dependent covariates, we show that the predictive value of ER status of the primary tumor decreases by approximately 20% per year, losing its significance after 8 years of follow-up. These results show that ER and PR status have a relatively limited predictive value and their major interest remain in the domain of therapeutic decision.

Prognostic value of steroid receptors after long-term follow-up of 2257 operable breast cancers.

The prognostic value of oestrogen receptor (ER) and progesterone receptor (PR) was estimated through a multicentric study of 2257 operable breast cancer patients followed up for a median of 8.5 years. None of the patients had received adjuvant therapy. The series included 33.3% stage I patients, 57.1% stage II, 5.7% stage IIIa and 2.4% stage IIIb. At the end point of the study 589 metastases and 537 deaths from cancer were recorded. Receptor measurements were performed by radiolgand assay according to a uniform protocol. A total of 68.8% of the tumous were ER positive and 54.0% PR positive ( > or = 10 fmol mg-1 cytosol protein). In univariate analysis, ER and PR status (positive/negative) were of prognostic value (P < 0.001) for the disease-free interval (DFI), the metastases-free interval (MFI) and the overall survival (OS). The OS of the patients after a first metastasis was also significantly different between ER-positive and -negative tumours (P < 0.001). In multivariate analysis (Cox proportional hazard model, 1665 patients), only the ER status showed a significant difference (P < 0.01) between positive and negative groups regarding the DFI, MFI and OS. By using Cox non-proportional, time-dependent models, we show that the predictive value of ER status of the primary tumour decreases by approximately 20% per year, losing its significance after 8 years of follow-up. Overall, when compared with TNM and histological grading, ER and PR status have a low prognostic value, their major interest remaining solely in the domain of therapeutic decision.

Epidermal growth factor receptors in breast cancer: comparison of radioligand and immunocytochemical assays.

Epidermal growth factor receptors (EGFR) are part of second generation biological factors that clinicians caring for breast cancer patients wish to evaluate for their prognostic value. This aim requires the standardization of methods: the radioligand assay (RLA) for the quantification of EGF binding sites was performed on membrane pellets from 261 breast cancer samples (ligand binding and hydroxylapatite separation as recommended by the EORTC Receptor Study Group); the immunocytochemical assay (ICA) for the staining of EGFR antigenic sites was performed on fine needle aspiration (FNA) cytology or touch imprints from 97 surgical specimens. The percentage of EGFR positivity by RLA (specific binding higher than 1% of total radioactivity) and the EGFR positive rate by ICA (more than 5% of stained cells) were respectively 43% and 38%. For 61 cases assayed on the same patient both methods revealed a concordance of 85%. Our results show that both methods are complementary and give quantitative data and information on tumor heterogeneity when they are performed in parallel. The next step of this study will be to determine the prognostic value of EGFR in these subpopulations of tumors for the adjustment of adjuvant treatment.

Inhibition of collagenolytic activity in human leukemic K562 cells by tamoxifen.

Presence of a collagenolytic activity has been demonstrated in the human leukemic cell line K562. Among various effectors studied, tamoxifen, a well-known antiestrogenic compound, exhibited a strong inhibitory effect. After 3 days of culture in the presence of 10(-7) M of tamoxifen, 75% of the collagenolytic activity was inhibited. Hydroxytamoxifen and N-desmethyltamoxifen were equally potent inhibitors though devoid of the direct cytotoxic effect. Cis-tamoxifen was less efficient. K562 cells have no binding sites for estrogens but they possess high affinity binding sites for 3H-tamoxifen (295 fmol/mg of proteins, KD = 0.25 x 10(-9) M). Tamoxifen had no effect on cellular differentiation or enzyme secretion. Anticollagenolytic activity of tamoxifen (10(-7)-10(-6) M) could be related to its inhibitory action on plasmin and plasminogen activator.

[Retinoid receptors in epidermoid carcinoma of the ORL sphere]. / Recepteurs de rétinoïdes dans les carcinomes épidermoïdes de la sphère ORL.

Head and neck tumors from 20 patients were investigated for the presence and the level of retinoid binding proteins (cellular retinoic acid binding protein or CRABP, cellular retinol binding protein or CRBP). A binding assay-gel filtration technic was used. CRABP were found in all tumors and in the adjacent normal tissues. A decreased level was associated with poor prognostic factors. CRBP were only found in some tumors and were absent from the adjacent normal tissue and from benign tumors. These results are discussed as regards their interest in prognostic evaluation and therapeutic orientation.

Phagocytosis of the streptococcal preparation OK-432 (picibanil) by non-phagocytic human leukemia K 562 cells and its modulation by tumor cell differentiation.

OK-432, an inactivated and lyophilized preparation of a low-virulence strain of Streptococcus pyogenes induced a phagocytosis process in human erythroleukemic K 562 cells. This process seems to be specific to the cell line, known however as non-phagocytic, and specific to the bacterial preparation. Transmission and scanning electron microscopy confirmed phagocytosis. Increased lysosomal activity was also demonstrated by cytochemical and biochemical criteria. The induction of phagocytosis required an intact cell surface membrane and sialo-glycoproteins seemed to be implied. The phagocytosis was inversely correlated with the erythroid differentiation of the K 562 cell. Hemin-treated K 562 cells and the markedly erythroid K 562 clone showed a decreased level of phagocytosis. The phagocytosis level in a K 562 clone expressing Fc (IgG) receptors was not altered by OK-432. In addition, a weak erythroid K 562 clone expresses the same level of phagocytosis as the total population.

[Metabolism of vitamin A and retinoids]. / Métabolisme de la vitamine A et des rétinoïdes.

Dietary vitamin A is stored in the liver as ester derivatives; after hydrolysis it is transported through the organism bound to a Retinol Binding Protein-Prealbumin complex. Intracellular metabolism is complex and involves the binding to specific receptors for retinol (CRBP) and retinoic acid (CRABP) followed by a nuclear translocation. In addition, retinol can be phosphorylated and implicated in glycosylation processes. Retinoids are characterized by their action on cellular growth and differentiation. Such properties result in anticancer activities which have been clearly put in evidence in vitro and begin to be applied in human oncology. Nevertheless there is always a need for a better comprehension on fundamental mechanisms of natural or synthetic retinoids.