Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2.

AIM: To investigate the efficacy and safety of gemcitabine and platinum salt, with or without trastuzumab, in patients with locally advanced or metastatic urothelial carcinoma overexpressing Her2. METHODS: The main eligibility criterion was Her2 overexpression on immunohistochemistry (IHC 2+ or 3+) of primary tumour tissue confirmed by fluorescence in situ hybridisation (FISH). Patients were randomised to Arm A: gemcitabine 1000mg/m(2) (days 1 and 8) plus either cisplatin (70mg/m(2)) or carboplatin (AUC=5) (day 1 every 3 weeks) or Arm B: added trastuzumab (8mg/kg loading dose, then 6 mg/kg every 21 days until progression). The primary end-point was progression-free survival (PFS). RESULTS: Among 563 screened patients, 75 (13.3%) were Her2 positive (IHC 2+/3+ and FISH+) and 61 met all eligibility criteria (median age, 64 years; 54/61 males; 50/61 baseline ECOG-PS 0-1; 11 locally advanced and 50 metastatic). There was no significant difference between Arms A and B in median PFS (10.2 versus 8.2 months, respectively, p=0.689), objective response rate (65.5% versus 53.2%, p=0.39), and median overall survival (15.7 versus 14.1 months, respectively, p=0.684). In an exploratory analysis, trastuzumab-treated patients receiving cisplatin rather than carboplatin-based chemotherapy fared better (PFS: 10.6 versus 8.0; OS: 33.1 versus 9.5 months). Myelosuppression was the main grade 3/4 toxicity. A case of grade 3 cardiotoxicity and one death from febrile neutropenia occurred in arm B. CONCLUSION: The unexpectedly low incidence of Her2 overexpression precluded the detection of a significant difference in efficacy on addition of trastuzumab to platinum-based chemotherapy with gemcitabine. However, the satisfactory tolerance of the combination warrants further studies, especially of the cisplatin-based combination, in well-defined patient subsets.

Comparison of fifteen immunoassays for the measurement of serum MUC-1/CA 15-3 in breast cancer patients.

BACKGROUND: Quality control results for serum MUC-1/CA 15-3 assays have always shown large discrepancies. METHODS: This multicentre study of 15 methods (labelled M1-M15) measured coded sera from 35 patients with breast cancer without recurrence (group 1), 46 patients at 1st metastasis (group 2), and 39 patients with advanced metastases (group 3). Results were compared using parametric statistics, ANOVA, principal component analysis, and receiver operating characteristic (ROC) curves. RESULTS: Mean MUC-1/CA 15-3 concentrations varied widely (75.1-303.0 U/mL, 24.8%) among methods. The false positive (FP) rate for group 1 was 8/521 (1.5%); for group 2 and group 3 false negative (FN) results were 21/680 (3.1%) and 11/583 (1.9%), respectively. Using the ROC cut-offs, we found no FPs for group 1 and no FNs for group 3. However, group 2 showed 16 FNs. All p-values for Pearson's correlation were <0.0001 between methods, except for M11. When comparing methods using different antibodies, discordance rates reached a maximum of 15.2%. Principal component analysis revealed a grouping of methods using: CanAg monoclonal antibodies (mAbs) (M2, M7 and M12); Centocor/Fujirebio mAbs (M3-M6, M8-M10, M14-M15) and Biomira mAbs (M1 and M13); and Centocor/Fujirebio mAbs (M11). CONCLUSIONS: Results were more consistent among methods using the same antibody type. Principal component analysis showed that antibody type was the strongest determinant of immunoassay results.

Serum HER-2/neu and relative resistance to trastuzumab-based therapy in patients with metastatic breast cancer.

BACKGROUND: Previous reports based on small patient numbers suggested that changes in serum HER-2/neu levels may predict response or lack of response to trastuzumab-based therapies in metastatic breast cancer (MBC). The objectives of this study were to pool data from 307 patients with MBC from 7 medical institutions to validate that the serum HER-2/neu profile predicts patient resistance to trastuzumab and to establish a clinically relevant cutoff. METHODS: This was an international, multicenter, retrospective analysis of individual pooled data from 307 patients with MBC who were treated with first-line trastuzumab-based therapy. Serum was collected at baseline and 30 to 120 days after the initiation of trastuzumab therapy. A serum HER-2/neu decrease >or=20% (receiver operating curve analysis) was defined as a significant HER-2/neu change. RESULTS: Of the 307 patients with MBC, 191 patients (62%) had a significant decline (>20%) in serum HER-2/neu and 116 patients (38%) did not. The objective response rate was 57% for patients who achieved this decline in serum HER-2/neu (>20%) compared with 28% for patients who did not. Patients who achieved this decline in serum HER-2/neu also had a significantly longer time to disease progression (320 days vs 180 days; P < .0001), longer duration of response (369 days vs 230 days; P = .008), and longer overall survival (898 days vs 593 days; P < .018). CONCLUSIONS: In this pooled analysis of 307 patients with MBC, individuals who did not achieve a significant decline (>or=20%) in serum HER-2/neu levels had decreased benefit from trastuzumab-based therapy, and these patients should be considered for clinical trials evaluating additional HER-2/neu-targeted interventions.

Variations of soluble fas and cytokeratin 18-Asp 396 neo-epitope in different cancers during chemotherapy.

Soluble Fas (sFas) and cytokeratin 18-Asp396 neoepitope (CK18-NE) were measured by ELISA in serial samples from 42 patients with different cancers under chemotherapy and were compared with pharmacokinetic results. Baseline sFas (median 6146 pg/ml, range 3123-16294 pg/ml) was higher in cancer patients than in normal subjects (median 4954 pglml, range 2595-10565 pg/ml, n =95) (p <0.01) and increased with the number of previous chemotherapy lines (p =0.008). During pharmacokinetics, the median sFas response differed significantly with tumour histology (p<0.001) and was correlated to 5-Fluorouracil (rho=0.366, p=0.015, n=45) or cisplatin (rho=0.509, p=0.025, n=21) concentrations but not to anthracyclines or oxazaphosphorine. By Kaplan-Meier analysis, patients with baseline sFas <6146 pg/ml had a longer survival probability (p=0.002). The median baseline CK18-NE did not differ from normal subjects, but its maximum increase differed according to histology (p=0.007) and to drug type (p=0.028). Patients with a maximum increase >67.5% (median) during chemotherapy had a better univariate overall survival (p=0.021). As measured by sFas concentration, chemotherapy induces an anti-apoptotic response of differing intensity according to tumour types and drugs, which has a prognostic value for survival. A CK18-NE elevation, indicative of chemotherapy-induced apoptosis, is linked to good prognosis.

A soluble lymphocyte activation gene-3 (sLAG-3) protein as a prognostic factor in human breast cancer expressing estrogen or progesterone receptors.

In contrast to the long-held belief that breast cancer is a weakly immunogenic tumor, accumulating evidence indicates an immune infiltrate is an invariable finding in breast cancers, raising hopes that immunotherapy for breast cancers may succeed in targeted patients, specifically those with either regional or minimal residual disease. However, no immunologically related prognostic factor has yet been established that may help to define subsets of patients who are more prone to respond to immunotherapy. High levels of soluble LAG-3 protein (sLAG-3) in sera has previously been shown to be associated, as a Th1 marker, to resistance to tuberculosis in large series of patients. We therefore hypothesized that, if cell-mediated immune mechanisms are indeed important for improved prognosis, high levels of sLAG-3 might be correlated with improved survival in some subsets of breast cancer patients. Studying a cohort of 246 patient's sera collected in 1994 at time of first diagnosis, we found that both disease-free and overall survival rates were greater in patients with estrogen or progesterone receptor positive tumor cells who had detectable levels of sLAG-3 at diagnosis versus patients with undetectable sLAG-3 levels. These results indicate that sLAG-3 may be a valuable marker for prognosis in some subsets of breast cancers and, more importantly, that cell-mediated mechanisms such as Th1 responses do have an impact on survival, a pre-requisite before the setting-up of immunotherapy protocols as a form of adjuvant therapy for breast cancer.

[FDG (18 fluorodeoxyglucose) positron emission tomography and breast cancer]. / Tomographie par emission de positons (TEP) au FDG et cancer du sein.

Positron emission tomography (PET) is a metabolic radionuclide imaging method in which a tracer labeled with a positron emitter is detected with a dedicated system. 18F-fluorodeoxyglucose (FDG) accumulates in tumor cells because of their increased glycolytic activity, and is thus widely used as a tracer in oncology. This increased metabolic activity precedes morphologic modifications, making FDG-PET a very useful tool for detecting and staging cancer. It can also be used to characterize morphologic changes, differentiating not only between benign and malignant lesions, but also between viable tumor cells and areas of necrosis and/or fibrosis induced by treatments. Being a whole-body examination, it allows malignancies to be staged in a single procedure. Systems combining PET and CT (computed tomography) offer improved performance, providing both metabolic and anatomical data. This technique appears to be useful for initial breast cancer staging, especially of locally advanced forms and suspected recurrences (increase of isolated tumor marker). Early studies of PET evaluation of responses to hormonal and/or cytotoxic therapies have also given very promising results. However, this technique does not seem sufficiently sensitive to be included in the initial screening or diagnosis of primary tumors, owing to its limited resolution (about 5 mm) and its restricted availability. This approach is poorly sensitive when used for axillary assessment, but offers good specificity.

Longitudinal changes in serum HER-2/neu oncoprotein levels in trastuzumab-treated metastatic breast cancer patients.

BACKGROUND: To evaluate longitudinal variations of serum HER-2/neu extracellular domain (sHER-2) in metastatic breast cancer patients receiving combined trastuzumab treatment. PATIENTS AND METHODS: Thirty-three patients were monitored by serial sHER-2 ELISA (Oncogene Science). Results were compared to time to progression (TTP) and survival from treatment initiation. Non parametric statistical tests were used. RESULTS: Median sHER-2 before first injection was 41.37 ng/ml (range 7.54-1597.00 ng/ml, n=32). Mean sHER-2 levels differed significantly between responders (n=20) and non responders (n=13) (p<0.0001). Median TTP (266 days, range 35-1000 days) was unrelated to clinico-biological variables at diagnosis or number and site of metastases before treatment. Patients with pre-treatment sHER-2 levels < or = 30 ng/ml (n=14) had a significantly longer TTP than the group with sHER-2 > 30 ng/ml (n=18) (p=0.0346) and sHER-2 levels were of prognostic value for overall survival from first injection (p=0.0150). CONCLUSION: Our results show that monitoring serum HER-2/neu levels during metastatic breast cancer can provide a real time assessment of a woman's HER-2/neu status and can provide important information for therapeutic decisions.

Serum HER-2 extracellular domain (ECD) before the first metastasis in 128 breast cancer patients.

We studied the serum HER-2 extracellular domain (sHER-2) before the first metastases in 128/701 breast cancer patients diagnosed and followed-up in our institution who developed metastases as the first relapse. sHER-2 was measured by an enzyme-linked immnunosorbent assay and CA 15.3 by an immunoradiometric assay. Non-parametric statistics were used. sHER-2 and CA 15.3 before and after primary treatment were measured in a previous part of the study. Before first metastases, 45% of the samples were over 12 microg/l of sHER-2 (cut-off) and were significantly related to sHER-2 values before and after primary treatment (P = 0.0350 and P < 0.0001 respectively). Concordance with CA 15.3 was 56.25 % (weak correlation, rho = 0.263). sHER-2 levels differed according to the sites of the metastases (P = 0.0199), the highest levels were found in liver and lung metastases. A median sHER-2 lead time of 254 days was found for 18/28 (64.3 %) patients before first metastasis. Pre-metastatic sHER-2 levels showed strong univariate (Kaplan-Meier method, P = 0.0014) and multivariate prognostic values (Cox model, P < 0.0001) for survival after first metastasis. In recurrent breast cancer, elevated levels of sHER-2 enabled an early detection of occult metastases and the identification of patients with a high probability of shortened survival.