Prognostic significance of insulin-like growth factor 1 receptors in human breast cancer.

Overall survival (OS) and relapse free survival (RFS) were studied in 297 patients according to the presence of insulin-like growth factor 1 receptors (IGF1-R). All the patients were surgically treated for locoregional disease in the same institution from January 1986. The median duration of follow-up was 40 months. RFS was better in patients with IGF1-R in their tumors as assessed by actuarial survival (P = 0.014) as well as Cox analysis (P = 0.016). OS was better in IGF1-R positive tumors studied by actuarial (P = 0.007) as well as Cox analysis (P = 0.010). By Cox analysis the other prognostic factors on RFS were estrogen receptor (P = 0.002), progesterone receptor (P = 0.002), axillary node metastases (P = 0.032), histoprognostic grading (GHP) according to the standard of Scarff and Bloom (P = 0.004), and tumor diameter (P = 0.019). The other prognostic factors on OS (Cox analysis) were estrogen receptor (P = 0.001), axillary node metastases (P = 0.010), GHP (P = 0.009), progesterone receptor (P = 0.012), and tumor diameter (P = 0.007). When combining IGF1-R, GHP, and axillary node metastases, it appeared that IGF1-R, GHP, and axillary node metastases had independent prognostic significance. In this prospective study IGF1-R had a prognostic significance on RFS as well as on OS studied by actuarial as well as Cox analysis.

Prognostic significance of prolactin receptors in human breast cancer.

Overall survival and relapse free survival (RFS) were studied in 547 patients according to the presence of prolactin receptors (PRL-R), either free or total (after 3 M MgCl2 desaturation). All these patients were surgically treated for locoregional disease in the same institution between 1978 and 1984. In actuarial survival studies, RFS was higher in total PRL-R positive patients in the whole population (P less than 0.02). When the population was divided into two groups, according to either the presence or the absence of node metastasis or the presence or absence of estradiol receptor, the higher RFS was restricted to node positive (P less than 0.001) and to estradiol receptor positive patients (P less than 0.01). The Cox analysis on RFS showed that free PRL-R alone was a significant prognostic factor in estradiol receptor positive patients; total PRL-R alone was never significant; when considered together with steroid receptors, free as well as total PRL-Rs were significant prognostic factors in some subgroups of patients.

Insulin-like growth factor 1 receptors in human breast cancer and their relation to estradiol and progesterone receptors.

Insulin-like growth factor 1 (IGF1) binding sites were characterized in breast cancer. We demonstrate the presence of one high affinity binding site. Chemical cross-linking of 125I-IGF1 to breast cancer membranes in reducing condition and sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed one band with an apparent molecular weight of 130,000. The specificity of the binding was studied. IGF2 was a good competitor whereas insulin competed with a potency lower than 1/100 that of IGF1. This IGF1 binding corresponded to the previously described type 1 IGF receptor (IGF1-R). IGF1-R was determined in 76 human breast cancer biopsies. Ninety-three % of the tumors were positive. The specific binding range was 0-16.4%; the geometric IGF1-R mean level was 3.9%. There was a relation (chi 2 test) between IGF1-R and progesterone receptor positivity rates (P = 0.002). The IGF1-R concentrations were correlated (Spearman test) with those of estradiol receptor (P = 0.0018) and progesterone receptor (P = 0.0011). A positive linear correlation existed between IGF1-R and estradiol receptor (P = 0.006) and between IGF1-R and progesterone receptor (P = 0.003). Our demonstration of the presence of IGF1-R in human breast cancer biopsies suggests that IGF1, acting either via the endocrine, paracrine, or autocrine pathways, could stimulate tumor growth.

Type I insulin-like growth factor receptors in human colorectal cancer.

Type I insulin-like growth factor (IGF) receptors have been recently characterised in human colorectal cancers. The aim of this study was to determine whether type I IGF receptor concentration may be related to prognostic variables in colorectal cancers. Saturation experiments with [125I]IGF-I were performed on membrane preparations of 46 frozen specimens (20 tumours, 26 controls) and analysed according to the Scatchard method. In all the studied cases, we found a single class of high affinity binding sites in both normal and malignant colorectal tissues (median 0.17 and 0.15 nmol/l, respectively). Using paired analysis, we found no significant difference in terms of type I IGF receptor concentration between malignant and normal colorectal tissues. There was also no relationship between type I IGF receptors and any of the tumour characteristics studied. This study does not support a critical role of the type I IGF receptors in the clinical management of colorectal cancers.

Plasma insulin-like growth factor-1 (IGF-1) concentrations in human breast cancer.

Insulin-like growth factor-1 (IGF-1) is capable of stimulating breast cancer cell growth in vitro and the presence of IGF-1 receptors has been demonstrated in primary breast cancers. We determined plasma IGF-1 in a primary breast cancer population and in a control population. Radioimmunoassays were performed either directly on plasma, IGF-1 (NE), or after an acid-ethanol extraction of the plasma, IGF-1 (E). We demonstrated an inverse correlation between age and IGF-1: for this reason, only results obtained in females of the same age range (> 35 years) were compared. Median concentrations of IGF-1 were significantly higher in primary breast cancers [IGF-1 (E) = 152 ng/ml, IGF-1 (NE) = 26 ng/ml, n = 44] than in controls [IGF-1 (E) = 115 ng/ml, IGF-1 (NE) = 20 ng/ml, n = 92]. To our knowledge such a growth factor increase has never been described in breast cancer. We conclude that IGF-1 could be an important factor involved in the development of breast cancer and that treatment reducing IGF-1 levels could be beneficial for patients.

Expression of ps2 and cathepsin-d in breast-cancer.

Cytosolic levels of pS2 and Cathepsin D (Cath D) were compared in 145 primary breast cancer patients using the immunoradiometric (IRMA) assays ELSA-pS2-degrees and ELSA-Cath. D-degrees of Cis biointernational. The mean values were 20.04 +/- 41.75 ng pS2/mg of cytosol protein (cp) and 49.94 +/- 33.71 pmol Cath D/mg cp. The pS2 level was significantly associated with Estrogen Receptor (ER), Progesterone Receptor (PgR) and Cath D levels. Significant associations were also found between Log (pS2) or Log (Cath. D) and differentiation grade (SBR), between Log (pS2) and ER (+,-) or PgR (+,-), between Log (Cath. D) and PgR (+,-). No correlations were noted between Log (pS2) or Log (Cath D) and menopausal status, tumor size (T) and lymph node involvement (N), between pS2 and age, between Cath D and age, ER and PgR, between Log (Cath D) and ER (+,-). Contrary to Cath D, pS2 was strongly linked to steroid receptors.

Drug resistance in oncology: from concepts to applications.

The complex problem of drug resistance is discussed with respect to host toxicity, to tumor characteristics (kinetic resistance, heterogeneity of cell subpopulations, hypoxia, mutation and gene amplification), and to the medication itself (pharmacokinetic and pharmacodynamic resistance: cell membrane, intracellular metabolism, intracellular target). After detailing each type of resistance, the possibilities of fighting against drug resistance are explored (dealing with host toxicity, tumor characteristics and drugs--intensifying therapy, multiple drug therapy, biochemical modulation, particular modalities of drug administration). Finally, perspectives of research and development of new drugs are summarized.

Biological and clinical aspects of prolactin receptors (PRL-R) in human breast cancer.

PRL has a definite activity in the induction and promotion of mouse and in the growth of rat mammary tumors. We and others have found that human PRL or growth hormone (GH) had a growth promoting effect on human mammary cancer cells. It has been shown that prolactin receptors (PRL-R) which are specific for all lactogenic hormones (hPRL, hGH, hPL) are present on mammary cancer cells in long-term tissue culture and also in tumor biopsies. We found that 43% of the tumors had free PRL-R (FPRL-R) and that 72% had total PRL-R (TPRL-R) which have been desaturated in vitro. A significant correlation (Spearman test) was found between PRL-R (especially TPRL-R) on the one hand, estradiol (P less than 0.001) and progesterone receptors (P less than 0.01) on the other. The demonstration of PRL-induced proteins (PIP) might be a better sign of PRL sensitivity than the existence or PRL-R; PIP have been found by Northern blot analysis in 47% of 70 breast cancers. Overall survival (OS) and relapse-free survival (RFS) analysis with a median duration of follow-up of 5.3 yr showed that TPRL-R had a significant prognostic value only in node positive patients (chi 2 = 5.61, P = 0.02). Neither FPRL-R or TPRL-R were a significant prognostic factor when studied by Cox analysis. This confirms our previous results. Since at least some human mammary cancers appear to be PRL-dependent we carried out a multicenter randomized trial comparing as the first hormonal treatment tamoxifen (TAM) (30 mg/day) + bromocriptine (B) (5 mg/day) vs TAM + placebo. 171 patients entered this trial. No difference was observed between the two groups in response rates, duration of response or survival. Recent studies are thus in favor of a role of lactogenic hormones during the course of breast cancer. However no improvement in therapy has been observed yet. The combination of drugs to achieve a total anti-lactogenic treatment, the use of anti-PRL-R antibodies are interesting areas of research; the recent cloning of PRL-R and GH receptors may open new clinical perspectives.

Basic fibroblast growth factor (bFGF): mitogenic activity and binding sites in human breast cancer.

We investigated binding characteristics of basic fibroblast growth factor (bFGF) on membranes prepared from 4 human breast cancer cell lines and 38 primary BC biopsies. Competitive binding experiments were performed and analyzed using the "Ligand" program. Furthermore bFGF mitogenic activity was measured by [3H]thymidine incorporation into DNA from breast cancer cell lines. The presence of high-affinity binding sites was demonstrated in each cell type (MCF-7: Kd = 0.60 nM; T-47D: Kd = 0.55 nM; BT-20: Kd = 0.77 nM; MDA-MB-231: Kd = 0.34 nM). The presence of these high-affinity binding sites was confirmed with saturation experiments. A second class of low-affinity binding sites was detected in the 2 hormone-independent cells (BT-20: Kd = 2.9 nM; MDA-MB-231: Kd = 2.7 nM). bFGF stimulated the proliferation of MCF-7, T-47D, BT-20 but not MDA-MB-231 cell lines. With competition experiments, binding sites were detectable in 36/38 breast cancers; high-affinity binding sites (Kd less than 1 nM) were present in 19/36 cases and low-affinity binding sites (Kd greater than 2 nM) were present in 29/36 cases (the two classes of binding sites were present in 12 breast cancers). No relation between bFGF binding sites and node involvement, histologic type or grading of the tumor was evidenced. There were negative correlations (Spearman test) between total bFGF binding sites and estradiol receptor (P = 0.05) or progesterone receptor (P = 0.009). The demonstration of (1) bFGF specific binding sites in breast cancer membranes, and (2) bFGF growth stimulation of some breast cancer cell lines indicates that this factor may be involved directly in the growth of some breast cancers.

Insulin-like growth factor 1 receptors (IGF1-R) and IGF1 in human breast tumors.

To appreciate the IGF1 sensitivity of breast tumors we detected IGF1-R with a biochemical assay (RRA). We then localized and quantified IGF1-R on frozen tissue sections by histo-autoradiographic analysis (HAA). In some cases, the IGF1 and IGF1-R mRNA expression were studied by Northern blot analysis. We also studied the IGF1 plasma concentration in primary breast cancers compared to controls. IGF1-R (RRA) were found in 87% (n = 297) of the breast cancers. The mean geometric value was 3.87% (specific binding as percentage of total radioactivity); we found a highly significant correlation between IGF1-R and ER on the one hand (P = 0.0001) and PgR on the other (P = 0.0001) (Spearman test). The presence of IGF1-R was associated with a better prognosis, either on relapse-free survival (actuarial analysis: P = 0.004; Cox analysis: P = 0.005) or overall survival (respectively P = 0.003; P = 0.005). The median duration of follow-up was 30 months. By Cox analysis IGF1-R was a better prognostic factor than ER and PgR. In a series of 77 cases of benign breast disease only 47% (36/77) were positive; the mean geometric level was 1.8%. The HAA IGF1-R quantification in 20 breast carcinomas and 12 cases of benign breast disease confirmed the RRA results and demonstrated that the labeling was localized on the epithelial component. In four breast cancers, we did not detect IGF1 mRNA; IGF1-R probe demonstrated two major mRNAs of 11 and 7 kB. Finally we found that IGF1 plasma level was higher in breast cancer patients than in healthy controls of the same age. These results show that IGF1 is implicated in breast cancer growth and suggest that anti-IGF1 treatment might be useful in human breast cancer: for this reason, we and others carried out a phase II clinical trial with somatostatin.

In vitro interactions of TNO6 with human plasma.

The ability of TNO6 to react with human plasma was investigated by in vitro incubation of plasma or plasma fractions with injectable TNO6. HPLC, ultrafiltration and flameless atomic absorption spectrophotometry were used to separate the platinum-containing chemical species and to measure the platinum content. The initial concentration of TNO6 in plasma declines very rapidly. The kinetics of the loss of initial TNO6 is very different from that of cisplatin loss. Most of the TNO6 is bound more quickly to proteins, while a little is transformed to less reactive or nonreactive platinum species. The level of final nonreactive platinum species depends on the particular plasma concerned. In addition, the reactivity of TNO6 towards proteins is very sensitive to Cl- concentration. The usefulness of HPLC for the study of TNO6 kinetics is demonstrated.

Platinum concentration in human tumors of head and neck, uterine cervix, and breast following treatment with cisplatin.

Intratumoral platinum concentrations were measured in three tumor sites (head and neck, uterine cervix, and breast) 48 h after cisplatin administration according to the same protocol. The platinum levels were in the same order of magnitude in all tumors, but the concentration in breast tumors was found to be higher than that in tumors of the head and neck and of the uterine cervix.

Plasma acid and alkaline phosphatase in patients with breast cancer.

Acid and alkaline phosphatase were determined in 107 breast cancer patients to study their potential value in case of bone metastases. The patients were divided into 4 groups: A, patients without metastases (n = 34); B, metastatic patients without bone lesions (n = 37); C, patients with metastases in and outside of bones (n = 24), D, patients with bone-only metastases (n = 12). Tartrate resistant acid phosphatase (TR-ACP), and bone alkaline phosphatase (bone-ALP) were significantly higher in patients with metastases than in patients without. However, no difference in TR-ACP was observed between subgroups of metastatic patients.

Effect of the long-acting somatostatin analogue SMS 201-995 (Sandostatin) in advanced breast cancer.

Sixteen post-menopausal patients with advanced breast cancer were treated with a long acting somatostatin analogue, SMS 201-995 (Sandostatin): 0.1 mg bid sub-cutaneously. The dose was chosen on the basis of efficiency in acromegaly treatment. SMS 201-995 activity was evaluated assaying Insulin Growth Factor 1 (IGF1) plasma concentration. A merely partial IGF1 decrease was noted. To be evaluable for response, patients had to be treated for at least 30 days. Among the 14 evaluable patients, we observed no response to SMS 201-995. However, we noted tumor stabilization in 3 patients after a 90 days treatment period. Side-effects were very mild. This first report on SMS 201-995 treatment of breast cancer suggests that further studies evaluating the effect of other modes of administration or drug association should be warranted.

An evaluation of CA 549, a circulating marker of breast cancer using a procedure for comparison with CA 15.3.

A serum assay of CA 549 (Hybri-BREScan CA 549 degrees, Hybritech), a new tumor marker, was performed in 129 patients with breast cancer and 35 healthy women, in parallel with CA 15.3 (ELSA-CA 15.3 degrees, CIS Biointernational). Comparing 95 women with primary breast carcinoma and 35 controls, Relative (or Receiver) Operating Characteristic (ROC) analysis revealed that the Area Under ROC Curve (AUC) of CA 15.3 was significantly higher than that of CA 549, indicating that, for our population, the first marker was more effective. Parallel and series analyses were also performed using ROC AUC and revealed that the combination of these two tests did not give more information than the CA 15.3 test alone; however, they did not in any way constitute diagnostic tools. In our experience, the best field of application for CA 549 seems to be the therapeutic monitoring and early detection of breast cancer recurrences. However, further investigations on a larger scale are necessary to assess more precisely the place of CA 549 in following the clinical course of breast cancer patients.

Growth factors and oncogenes in human solid tumors: clinical aspects.

Growth factors, growth factor receptors and oncogenes have been extensively studied in human tumors for some years. The purpose of this paper is to review the clinical results obtained in human cancers and their predisposing conditions or high risk groups as well as their relation with clinical, pathological characteristics and their prognosis.

Cis-platinum complex with retained prolactin receptor specific binding.

Two complexes of prolactin and platinum have been synthetized and their biological activity was assayed by radioreceptor assay. Only the cis-platinum prolactin complex retains the capacity of native prolactin to bind to cell receptor membrane. Prolactin could be used to increase the specificity of cis-platinum to cells with prolactin receptors.

Aminoglutethimide in malignant melanoma. A phase II study.

The role of steroid hormones has been suggested in the growth of malignant melanoma, and since aromatase activity has been found in melanoma tissue, we carried out a phase II study of aminoglutethimide, an aromatase inhibitor in malignant melanoma patients. Fifteen heavily pretreated patients entered the study. No response was observed--the treatment was well tolerated. We concluded that aminoglutethimide is very unlikely to be useful in melanoma patients.

Cytarabine and cisplatin as salvage therapy in patients with metastatic colorectal cancer who failed 5-fluorouracil + folinic acid regimen. French Northern Oncology Group.

The combination of CDDP and ARA-C has shown some clinical efficiency as first-line therapy in advanced colorectal cancer. Our study was aimed to evaluate the therapeutic activity of this combination in advanced colorectal cancer who failed 5-fluorouracil (FU) and folinic acid (LV) regimen. Seventeen patients with measureable metastatic colorectal cancer who failed 5FU-LV therapy as first line (n = 14) or second line treatment (n = 3), entered the study. Three patients who recurred during adjuvant treatment with 5FU and levamisol, were also included. Median age was 59.5 (40-69). Performance status was as follows: 0 (n = 5), 1 (n = 11), 2 (n = 3), 3 (n = 1). Site of metastases included liver (n = 16), lung (n = 7), abdomen (n = 2), pelvic recurrences (n = 2), cutaneous (n = 1). Seven patients had 2 metastatic sites and two 3. The treatment was given as follows: ARA-C 75 mg/m2/day, days 1-3, followed 1 hour later by CDDP 30 mg/m2/day, days 1-3, every 28 days. The median number of cycles was 3 (range: 1-6 cycles). All patients but one were evaluable for both response and toxicity. Of these patients, 50% experienced severe hematologic toxicity and nonhematologic toxicity mainly consisted of fatigue and/or vomiting. No objective response was observed, but there were 3 stabilizations and 16 progressive diseases. Median time to progression was 10 weeks. Thus, the CDDP/ARA-C regimen is not of clinical value as salvage therapy in advanced colorectal cancer because of its toxicity and its lack of efficiency.

[Adjuvant chemotherapy of cancer: immediate costs and long-term risks]. / Chimiothérapie adjuvante des cancers: coûts immédiats et risques à long terme.

Medical, psychologic, socio-professional and economic side effects of adjuvant chemotherapy are frequent. Some of these are not easily recognized with accuracy. They influence directly the life of treated patients and perhaps later their medical future. They involve the quality of life for cancer patients, after initial curative treatments. Indications for adjuvant chemotherapy cannot be extended without comparative evaluation of their advantages and disadvantages. It is necessary to select patients with the highest probability of improvement in the duration and the quality of life and to give them so active but the least toxic treatments possible.