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Biomedical subjects

M Piccart

Publications and source records attributed to M Piccart.

At least 55 records · Page 3Linked to original sources
PubMed2001

Closing remarks and treatment guidelines.

The human epidermal growth factor receptor HER2 or C-erbB-2/neu is a tyrosine kinase membrane receptor, which when activated, induces a phosphorylation cascade in cytoplasmic kinases leading to increased protein transcription and cellular growth. HER2 plays an important role in the biology of breast cancer, an observation that has led to the selection of HER2 as a potential target for breast cancer treatment. Trastuzumab (Herceptin(R)) is the first anti-HER2 monoclonal antibody that has shown a survival benefit in metastatic breast cancer patients with HER2-positive tumours (Norton et al., Proc ASCO 2000 18, 127a (abstract 483)). Tumour HER2 status should no longer be ignored because of its direct implications for the optimal management of breast cancer patients. A high priority for future research is to refine and standardise HER2 testing in order to minimise false-negative results. Furthermore, this procedure would overcome current issues relating to test reproducibility between pathology laboratories and definitions of HER2 positivity. In the meantime, a HER2-positive status on testing using any approved technique has implications for clinical practice (Fig. 1). The treatment algorithm given in Fig. 1 considers the lack of level 1, evidence-based studies that demonstrate convincingly the value of HER2 as a predictive marker for resistance or sensitivity to classic forms of breast cancer therapy (Piccart et al., Eur J Cancer 2000, 36, 1755-1761). In addition, the algorithm incorporates the available data from 1999-2000, which were generated from prospective trials exploring the value of trastuzumab both as a single agent and in combination with chemotherapy.

Journal Article↗
PubMed2001

An overview of HER2.

HER2 is a transmembrane growth factor receptor found in normal and malignant breast epithelial cells. Phosphorylation of the intracellular tyrosine kinase results in intracellular signaling and activation of genes involved in cell growth. Overexpression of HER2 has independent prognostic significance in early breast cancer and may also predict response to hormonal and cytotoxic therapies, although this latter role is less well studied. Prospective stratification of HER2 status in current clinical trials may more accurately delineate these roles. Anti-HER2 therapy, using a humanized monoclonal antibody, has enhanced survival when given with chemotherapy compared with chemotherapy alone in patients with metastatic HER2-overexpressing breast cancer. A potential limitation to its use in the adjuvant setting is the increased incidence of cardiotoxicity in patients treated either concurrently or previously with anthracyclines; carefully designed prospective adjuvant trials are currently being launched. HER2 is a relatively new prognostic marker and holds promise for predicting response to various therapies and for target-specific therapy.

Animals↗
PubMed2000

Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study.

BACKGROUND: Surgical or medical castration and antiestrogenic treatment with tamoxifen are common endocrine treatments for premenopausal women with breast cancer. However, tamoxifen therapy induces high levels of plasma estradiol, with unknown long-term effects. In this study, we investigated the effect of combining estrogen suppression with the luteinizing hormone-releasing hormone agonist buserelin and estradiol receptor blockade with tamoxifen to determine whether the high estradiol levels induced by tamoxifen could be reduced and whether the antitumor effects would be better. METHODS: In a three-arm, randomized, prospective trial, from 1988 through 1995, a total of 161 premenopausal patients with advanced breast cancer were randomly assigned to treatment with buserelin, tamoxifen, or both. Patients with steroid receptor-negative tumors or with tumors of unknown receptor status who had a disease-free interval of less than 2 years were excluded. The median follow-up was 7.3 years, during which 76% of the patients died, all of breast cancer. Patient and tumor characteristics were well balanced among treatment groups. All P values are from two-sided tests. RESULTS: Combined treatment with buserelin and tamoxifen was superior to treatment with buserelin or tamoxifen alone by objective response rate (48%, 34%, and 28% of patients who could be evaluated, respectively; P =.11 [chi(2) test]), median progression-free survival (9.7 months, 6.3 months, and 5.6 months; P =.03), and overall survival (3.7 years, 2.5 years, and 2.9 years; P =.01). Actuarial 5-year survival percentages were 34.2% (95% confidence interval [CI] = 20.4%-48.0%), 14.9% (95% CI = 3.9%-25.9%), and 18.4% (95% CI = 7.0%-29.8%), respectively. No differences in antitumor effects were observed between single-agent treatment groups. During combined treatment or treatment with buserelin alone, plasma estradiol levels were suppressed equally; in contrast, during treatment with tamoxifen alone, plasma estradiol levels increased threefold to fourfold over pretreatment levels. CONCLUSION: Combined treatment with buserelin and tamoxifen was more effective and resulted in longer overall survival than treatment with either drug alone.

Adult↗
PubMed2000

Summary measures and statistics in the analysis of quality of life data: an example from an EORTC-NCIC-SAKK locally advanced breast cancer study.

Quality of Life (QL) is now included as an endpoint in many phase III cancer clinical trials. Numerous statistical techniques have been presented in the literature to analyse QL data but there is still no agreement as to what is the optimal approach of analysis. In this paper we, therefore, present and compare various techniques which have all appeared in the literature and which may be globally described as summary measures and summary statistics. These techniques are illustrated using data from an EORTC clinical trial in locally advanced breast cancer (EORTC trial 10921). It is also explained in this paper how and when these techniques may be used in other cancer settings. For EORTC trial 10921, it is shown that by choosing different techniques different conclusions may be drawn concerning the QL outcome. This highlights the importance of choosing an appropriate primary statistical method and for describing it a priori in the protocol and analysis plan. In this paper, we show the importance of performing sensitivity or supportive analysis to support conclusions drawn from the primary analysis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Randomised trial of paclitaxel versus doxorubicin as first-line chemotherapy for advanced breast cancer: quality of life evaluation using the EORTC QLQ-C30 and the Rotterdam symptom checklist.

The aim of the study was to compare the quality of life (QL) of patients treated with single-agent paclitaxel versus doxorubicin as first-line chemotherapy for advanced breast cancer. 331 patients with advanced breast cancer were randomised, with 294 eligible for analysis. Patients completed both the EORTC QLQ-C30 questionnaire and the Rotterdam Symptom Checklist (RSCL) with six additional items, at baseline and after the third, fifth and seventh cycles of chemotherapy. A significant difference in progression-free survival in favour of doxorubicin caused a bias in the data with differences in expected completion rates of questionnaires beyond cycle three. Therefore, statistical comparisons were performed only for the first three cycles. Baseline compliance was 64% and 61% for the QLQ-C30 and RSCL questionnaires, respectively. Doxorubicin was associated with significantly more nausea/vomiting (P=0.001), loss of appetite (P=0.010) and a greater burden of disease and treatment (P=0.044), but with less bone pain (P=0.042) and rash (P=0.045) than paclitaxel. Both treatments were associated with improved emotional function and reduction in psychological distress at cycle 3. Longitudinal data suggested that doxorubicin was associated with less pain, specifically bone pain. Doxorubicin was more active but may have had more side-effects during the first three cycles. Long-term QL outcomes could not be assessed.

Antineoplastic Agents↗
PubMed2000

Identification and interpretation of clinical and quality of life prognostic factors for survival and response to treatment in first-line chemotherapy in advanced breast cancer.

The aim of the project was to identify clinical and quality of life (QL) factors that together predict survival and response to chemotherapy in advanced breast cancer. Potential prognostic factors were studied in 187 women with baseline QL data from a trial of paclitaxel versus doxorubicin as first-line chemotherapy. Demographic and clinical factors studied were age, performance status, dominant site of disease and preceding disease-free interval (DFI). Factors from the EORTC QLQ-C30 were all function scales, fatigue, nausea/vomiting, pain, dyspnoea, insomnia, loss of appetite and global QL. The proportional hazards regression model with stratification for treatment, and the logistic regression model adjusting for treatment arm were used for univariate and multivariate analyses of survival and response to treatment, respectively. For survival, multiple sites of visceral disease, pain, global QL and fatigue were significant prognostic factors in the univariate analysis. The final multivariate model predicted poor survival with multiple sites of visceral disease (P=0.003), DFI </=2 years (P=0.026) and pain (P=0.003). For response, age, dyspnoea, fatigue and global QL were significant predictive factors in the univariate analysis. The final multivariate model for response selected DFI (P=0.009), multiple sites of visceral disease (P=0.037) and dyspnoea (P=<0.001) using forward selection, but model instability was indicated by the inclusion of fatigue and emotional function in the final model when backward selection was used. In addition to known clinical factors, patient-assessed QL variables appear to be prognostic for survival and response to chemotherapy in women with advanced breast cancer. However, identification of prognostic factors from responses to questionnaires may be unstable, and their reliability and clinical utility should be tested prospectively.

Adolescent↗
PubMed2000

The Breast International Group. a new spirit of collaboration in breast cancer research for the new millennium.

The Breast International Group (B.I.G.-aisbl), an official non-profit organisation since 1999, is an association whose members are well established clinical breast cancer research groups located around the world. Inspired by the American 'Intergroup' model, B.I.G. functions as a 'consortium of consortia': it is a partnership among independent co-operative groups, each with its own extensive network of affiliated centres, hospitals, laboratories and investigators. Through B.I.G., groups draw on combined resources to reduce the wasteful duplication of efforts and to achieve results in breast cancer research impossible for any individual group in a comparable period of time. International collaboration through a mechanism like B.I.G. will become increasingly frequent in the future, especially as we move towards exploring therapies targeted at subgroups of patients with specific tumour molecular profiles.

Breast Neoplasms↗
PubMed2000

EORTC 10941: A phase II study of liarozole in postmenopausal patients with 'chemotherapy-resistant' or 'potentially hormone sensitive' metastatic breast cancer.

Liarozole is an imidazole compound that inhibits enzymes involved in steroid hormone aromatisation and retinoid metabolism. The IDBBC branch of the EORTC has performed a series of phase II studies of the agent in four groups of postmenopausal women with metastatic breast cancer. This paper reports the results of the first two groups: 'Chemotherapy Resistant' (unrestricted ER status, 1 or 2 prior chemotherapy regimens, 0-2 prior hormonal therapies) and 'Potentially Hormone Sensitive' (ER positive or unknown, 1 or 2 prior hormonal therapies with a substantial disease free interval or progression free survival, and no history of chemotherapy for metastatic disease). Liarozole was administered at 150-300 mg orally bid. The objective response rate was 12% in the 'Chemotherapy Resistant' group (n = 34), and 22% in the 'Potentially Hormone Sensitive' group (n = 37), with median response durations of 9 and 14 months, respectively. Median time to treatment failure was only 2 months in both groups, due largely to the significant percentage (24%) of patients who ceased treatment following excessive mucocutaneous and gastrointestinal toxicity. This adverse event profile will limit its use in breast cancer. Results of the 'ER negative' and 'Tamoxifen Refractory' groups will be reported in a future paper.

Adult↗
PubMed2000

The contribution of molecular markers to the prediction of response in the treatment of breast cancer: a review of the literature on HER-2, p53 and BCL-2.

BACKGROUND: The selection of therapies for breast cancer is today based on prognostic features (chemotherapy, radiotherapy), hormone receptor status (hormonal therapy) and HER-2 status (trastuzumab therapy). HER-2, p53 and BCL-2 are tumour-related proteins that have the potential to further improve individualisation of patient management, by predicting response to chemotherapy, hormonal therapy and radiotherapy. MATERIALS AND METHODS: This paper reviews the rationale for the use of these proteins as predictive factors, as well as the published literature addressing the use of each one to predict response to hormonal therapy, chemotherapy and radiotherapy. RESULTS: HER-2, p53 and BCL-2 remain inadequately assessed as predictive factors in breast cancer. HER-2 evaluation is required for the selection of patients for trastuzumab (Herceptin) therapy, as trials of this therapy have been limited to HER-2 overexpressors. HER-2 overexpression may be predictive of resistance to hormonal therapy. Anthracyclines are effective therapy for breast cancer regardless of HER-2 status, but patients whose tumours overexpress HER-2 appear to receive the greatest relative benefit from this therapy. Studies of HER-2 as a predictor of response to CMF and to radiotherapy are inconclusive at this time. No data yet exist to support the use of p53 or BCL-2 as predictive factors in the therapy of breast cancer. CONCLUSIONS: At this point in time, there is inadequate evidence to support the use of HER-2, p53 or BCL-2 to guide the selection of hormonal therapy, chemotherapy or radiotherapy for breast cancer.

Anthracyclines↗
PubMed2000

Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organization for Research and Treatment of Cancer Randomized Study with cross-over.

PURPOSE: To compare the efficacy of paclitaxel versus doxorubicin given as single agents in first-line therapy of advanced breast cancer (primary end point, progression-free survival ¿PFS) and to explore the degree of cross-resistance between the two agents. PATIENTS AND METHODS: Three hundred thirty-one patients were randomized to receive either paclitaxel 200 mg/m(2), 3-hour infusion every 3 weeks, or doxorubicin 75 mg/m(2), intravenous bolus every 3 weeks. Seven courses were planned unless progression or unacceptable toxicity occurred before the seven courses were finished. Patients who progressed within the seven courses underwent early cross-over to the alternative drug, while a delayed cross-over was optional for the remainder of patients at the time of disease progression. RESULTS: Objective response in first-line therapy was significantly better (P =.003) for doxorubicin (response rate ¿RR, 41%) than for paclitaxel (RR, 25%), with doxorubicin achieving a longer median PFS (7.5 months for doxorubicin v 3.9 months for paclitaxel, P <.001). In second-line therapy, cross-over to doxorubicin (91 patients) and to paclitaxel (77 patients) gave response rates of 30% and 16%, respectively. The median survival durations of 18.3 months for doxorubicin and 15.6 months for paclitaxel were not significantly different (P =.38). The doxorubicin arm had greater toxicity, but this was counterbalanced by better symptom control. CONCLUSION: At the dosages and schedules used in the present study, doxorubicin achieves better disease and symptom control than paclitaxel in first-line treatment. Doxorubicin and paclitaxel are not totally cross-resistant, which supports further investigation of these drugs in combination or in sequence, both in advanced disease and in the adjuvant setting.

Adenocarcinoma↗
PubMed2000

Sensitivity of HER-2/neu antibodies in archival tissue samples of invasive breast carcinomas. Correlation with oncogene amplification in 160 cases.

Overexpression and amplification of the HER-2 oncogene in patients with breast cancer has correlated with early onset of metastasis, resistance to hormonal therapy and some forms of chemotherapy, and shortened survival. Therefore, evaluation of this putative prognostic or predictive factor seems critical. Because different antibodies are used for the detection of the 185-kd HER-2 oncoprotein, we studied the sensitivity of 3 frequently used antibodies. Immunohistochemistry results were correlated with gene amplification level as assessed by fluorescence in situ hybridization. Protein overexpression was found in 17.2% and 12.5% of cases using antibodies against the external (TAB250) and internal (CB11) domains of the protein, respectively, and in 38.0% of cases using a rabbit polyclonal antibody. Fluorescence in situ hybridization was successful in all 160 tumors, and amplification was found in 37 tumors (23.1%). The monoclonal antibody TAB250 had the lowest misclassification rate, 9.6% (sensitivity, 67%; specificity, 97.5%).

Antibodies↗
PubMed2000

A study of the value of p53, HER2, and Bcl-2 in the prediction of response to doxorubicin and paclitaxel as single agents in metastatic breast cancer: a companion study to EORTC 10923.

This study assesses the potential value of the tumor markers p53, HER2, and Bcl-2 in predicting the clinical response to doxorubicin and paclitaxel as single agents in the treatment of metastatic breast cancer. The primary tumors of 114 patients in the European Organization for Research and Treatment of Cancer 10923 trial were assessed by immunohistochemistry using monoclonal antibodies; the results were correlated with clinical response to therapy. HER2 was positive in 24% of patients, p53 was positive in 25% of patients, and Bcl-2 was positive in 49% of patients. There was no correlation between the expression of any of the markers and the clinical response to either agent. Although methodologically limited, this study does not support the use of p53, HER2, or Bcl-2 to assist the selection of anthracycline versus taxane in metastatic breast cancer.

Adult↗
PubMed2000

Promising results with exemestane in the first-line treatment of metastatic breast cancer: a randomized phase II EORTC trial with a tamoxifen control.

Because tamoxifen (TAM), a nonsteroidal antiestrogen, is routinely used in the adjuvant setting, other hormone therapies are needed as alternatives for first-line treatment of metastatic breast cancer (MBC). Currently, exemestane (EXE) and other antiaromatase agents are indicated for use in patients who experience failure of TAM. In this multicenter, randomized, open-label, TAM-controlled (20 mg/day), phase II trial, we examined the activity and tolerability of EXE 25 mg/day for the first-line treatment of MBC in postmenopausal women. Exemestane was well tolerated and demonstrated substantial first-line antitumor activity based on intent-to-treat analysis of peer-reviewed responses. In the EXE arm, values for complete, partial, and objective response, clinical benefit, and time to tumor progression (TTP) exceeded those reported for TAM although no statistical comparison was made. Based on these encouraging results, a phase III trial will compare EXE and TAM.

Administration, Oral↗
PubMed2000

A phase I and pharmacokinetic study of docetaxel administered in combination with continuous intravenous infusion of 5-fluorouracil in patients with advanced solid tumors.

Encouraged by preclinical synergism between docetaxel and 5-fluorouracil (5FU), we conducted a Phase I study of docetaxel in combination with continuous i.v. infusion of 5FU in patients with advanced solid tumors to determine the maximum tolerated dose, the recommended dose for Phase II studies, and the safety and pharmacokinetic profiles of this combination. Forty-two patients with advanced solid tumors, most of whom had been previously treated, received docetaxel on day 1 as a 1-h i.v. infusion, immediately followed by a 5-day continuous i.v. infusion of 5FU, every 3 weeks without hematopoietic growth factor support. All patients were premedicated with methylprednisolone. Dose levels of docetaxel/SFU studied were (daily dose, in mg/m2) 60/300, 75/300, 75/500, 75/750, 85/750, 85/1000, and 75/1000. Forty-one patients were assessable for toxicity. The maximum tolerated dose determined during the first cycle was 1000 mg/m2/day for 5 days of 5FU with either 75 or 85 mg/m2 docetaxel. Dose-limiting toxicities at these dose levels were reversible secretory diarrhea (4 of 12 evaluable patients), stomatitis (2 patients), and febrile neutropenia (2 patients). Overall, grade 3/4 neutropenia and febrile neutropenia were seen in 63.4% and 9.8% of the patients, respectively. Four patients experienced grade 3/4 infection, which led to toxic death in one of them. There were five early deaths: (a) one was clearly treatment related; (b) two others were possibly treatment related or remotely treatment related; and (c) two deaths were not related to the study drugs. Partial responses were documented in 5 of 39 evaluable patients. Pharmacokinetic results of both drugs were consistent with those from single-agent studies. The recommended dose of this combination, which showed acceptable toxicity and antitumoral activity at various dose levels, is 85 mg/m2 docetaxel given as a 1-h i.v. infusion on day 1 immediately followed by a 5-day continuous i.v. infusion of 5FU (750 mg/m2/day). This study has been extended by adding cisplatin on day 1 of the combination of docetaxel and 5FU.

Adult↗
PubMed1999

Tumor-infiltrating dendritic cells in adenocarcinomas of the breast: a study of 143 neoplasms with a correlation to usual prognostic factors and to clinical outcome.

Dendritic cells (DC) are the most potent antigen-presenting cells, and induce antigen-specific immune responses. Infiltration of tumors by DC is thought to reflect the interaction between the host immune system and tumor cells. Tumor-infiltrating DC (TIDC) are believed to evolve into tumor-antigen pulsed cells and then to migrate to local lymph nodes, where they activate anti-tumor immune responses. Indirect clinical evidence supporting this theory is provided by studies showing that high TIDC densities are associated with favorable prognosis in some tumor types. In the present study, we evaluated 143 primary breast adenocarcinomas for the presence of DC, using immunohistochemistry with the anti-S100 protein antibody. We analyzed the relationship between the degree of infiltration by S100+ TIDC and the usual prognostic factors and clinical outcome. The results show that 42% of breast adenocarcinomas contain S100 TIDC. The number of S100+ TIDC varies according to the grade of tumors as follows: GRIII > GRII > GRI. A relationship is also found between S100+ TIDC and tumor size, lymph-node involvement, estrogen/progesterone receptor status and age. However, the presence of S100+ TIDC, even at the highest density, was not correlated with metastasis-free survival or overall survival.

Adenocarcinoma↗
PubMed1999

The third-generation non-steroidal aromatase inhibitors: a review of their clinical benefits in the second-line hormonal treatment of advanced breast cancer.

Three new aromatase inhibitors have recently completed phase III evaluation as treatment of metastatic breast cancer in post-menopausal women whose disease has progressed despite tamoxifen therapy: anastrozole (ARIMIDEX, Zeneca), letrozole (FEMARA, Novartis) and vorozole (RIVIZOR, Janssen). All belong to the third generation of non-steroidal aromatase inhibitors, and each is superior to previous generations in terms of potency and selectivity. The trials that have been performed compare each agent to megestrol acetate, and letrozole and vorozole to aminoglutethimide. Although the studies are not directly comparable due to differing study designs and patient populations, it has been demonstrated each of these drugs provides single agent, once-daily, oral palliation of hormone-responsive, post-menopausal metastatic breast cancer. Letrozole is clearly more effective than megestrol acetate, and anastrozole and vorozole are possibly so. All three are better tolerated than the progestin, particularly in terms of weight gain. Both letrozole and vorozole are significantly more effective, and better tolerated than aminoglutethimide. Overall, this most recent generation of aromatase inhibitors is a clear improvement on our current standard second-line therapies. In 1999, tamoxifen remains the first choice in the hormonal therapy of breast cancer. Following tamoxifen failure, the optimal second-line hormonal therapy remains undefined, but aminoglutethimide and megestrol acetate are no longer optimal therapy in this setting. The third-generation non-steroidal aromatase inhibitors must now be compared to each other, to the steroidal aromatase inhibitors, to the pure anti-oestrogens, and to tamoxifen.

Aged↗