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1.
J Clin Oncol ; 23(24): 5542-51, 2005 Aug 20.
Article in English | MEDLINE | ID: mdl-16110015

ABSTRACT

PURPOSE: This randomized, controlled, multicenter, open-label, phase III study compared docetaxel versus paclitaxel in patients with advanced breast cancer that had progressed after an anthracycline-containing chemotherapy regimen. PATIENTS AND METHODS: Patients (n = 449) were randomly assigned to receive either docetaxel 100 mg/m2 (n = 225) or paclitaxel 175 mg/m2 (n = 224) on day 1, every 21 days until tumor progression, unacceptable toxicity, or withdrawal of consent. RESULTS: In the intent-to-treat population, both the median overall survival (OS, 15.4 v 12.7 months; hazard ratio [HR], 1.41; 95% CI, 1.15 to 1.73; P = .03) and the median time to progression (TTP, 5.7 months v 3.6 months; HR, 1.64; 95% CI, 1.33 to 2.02; P < .0001) for docetaxel were significantly longer than for paclitaxel, and the overall response rate (ORR, 32% v 25%; P = .10) was higher for docetaxel. These results were confirmed by multivariate analyses. The incidence of treatment-related hematologic and nonhematologic toxicities was greater for docetaxel than for paclitaxel; however, quality-of-life scores were not statistically different between treatment groups over time. CONCLUSION: Docetaxel was superior to paclitaxel in terms of OS and TTP. ORR was higher for docetaxel. Hematologic and nonhematologic toxicities occurred more frequently in the docetaxel group. The global quality-of-life scores were similar for both agents over time.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents, Phytogenic/therapeutic use , Breast Neoplasms/drug therapy , Paclitaxel/therapeutic use , Taxoids/therapeutic use , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Chi-Square Distribution , Disease Progression , Docetaxel , Female , Humans , Infusions, Intravenous , Logistic Models , Middle Aged , Proportional Hazards Models , Quality of Life , Treatment Outcome
2.
Eur J Cancer ; 38(6): 745-9, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11937306

ABSTRACT

The meta-analysis of trials of adjuvant systemic therapy for early breast cancer provides robust information on the impact of both cytotoxic chemotherapy and tamoxifen on relapse-free and overall survival to 15 years from diagnosis. These data are described in terms of relative risk reduction and are not meant to be viewed as a prescription for therapy. To translate relative risk reductions into absolute benefits for the individual patient and then trade off the gains against the long-term and short-term side-effects and toxicities is a highly complex process for the clinician, and current guidelines are formatted in such a way that they fail to use current information in a way that allows a quantitative assessment of the benefits and risks of adjuvant therapy. This review article explores current guidelines and describes some aids that may be used to help inform women about their treatment options for early breast cancer.


Subject(s)
Breast Neoplasms/drug therapy , Decision Making , Chemotherapy, Adjuvant , Drug Therapy, Computer-Assisted/methods , Female , Humans , Patient Education as Topic , Practice Guidelines as Topic , Receptors, Estrogen , Risk Assessment , Survival Analysis
3.
J Clin Oncol ; 19(4): 980-91, 2001 Feb 15.
Article in English | MEDLINE | ID: mdl-11181660

ABSTRACT

PURPOSE: The goal of the computer program Adjuvant! is to allow health professionals and their patients with early breast cancer to make more informed decisions about adjuvant therapy. METHODS: Actuarial analysis was used to project outcomes of patients with and without adjuvant therapy based on estimates of prognosis largely derived from Surveillance, Epidemiology, and End-Results data and estimates of the efficacy of adjuvant therapy based on the 1998 overviews of randomized trials of adjuvant therapy. These estimates can be refined using the Prognostic Factor Impact Calculator, which uses a Bayesian method to make adjustments based on relative risks conferred and prevalence of positive test results. RESULTS: From the entries of patient information (age, menopausal status, comorbidity estimate) and tumor staging and characteristics (tumor size, number of positive axillary nodes, estrogen receptor status), baseline prognostic estimates are made. Estimates for the efficacy of endocrine therapy (5 years of tamoxifen) and of polychemotherapy (cyclophosphamide/methotrexate/fluorouracil-like regimens, or anthracycline-based therapy, or therapy based on both an anthracycline and a taxane) can then be used to project outcomes presented in both numerical and graphical formats. Outcomes for overall survival and disease-free survival and the improvement seen in clinical trials, are reasonably modeled by Adjuvant!, although an ideal validation for all patient subsets with all treatment options is not possible. Additional speculative estimates of years of remaining life expectancy and long-term survival curves can also be produced. Help files supply general information about breast cancer. The program's Internet links supply national treatment guidelines, cooperative group trial options, and other related information. CONCLUSION: The computer program Adjuvant! can play practical and educational roles in clinical settings.


Subject(s)
Breast Neoplasms/therapy , Chemotherapy, Adjuvant , Software , Actuarial Analysis , Breast Neoplasms/mortality , Decision Making , Female , Humans , Prognosis , Survival Analysis
4.
J Natl Cancer Inst Monogr ; (30): 80-4, 2001.
Article in English | MEDLINE | ID: mdl-11773297

ABSTRACT

Data from several large adjuvant breast cancer chemotherapy trials suggest that anthracycline-based chemotherapies relative to non-anthracycline-based adjuvant therapies are particularly effective in patients whose tumors overexpress Her2. Most trials show some evidence of this effect, but the interaction generally has not been confirmed statistically, perhaps because the trials are underpowered. In addition, there have been a multiplicity of Her2 immunohistochemistry techniques used in these studies, which are clearly not of equivalent utility in detecting this effect. Thus, while there is good evidence that further work in this area will be of value, at this time the results are inconclusive and not ready for clinical application.


Subject(s)
Anthracyclines/therapeutic use , Breast Neoplasms/diagnosis , Breast Neoplasms/drug therapy , Receptor, ErbB-2/metabolism , Biomarkers/analysis , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Chemotherapy, Adjuvant , Genetic Predisposition to Disease , Humans , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Receptor, ErbB-2/genetics , Risk Factors , Survival Rate
6.
Semin Oncol ; 26(4 Suppl 12): 117-23, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10482203

ABSTRACT

Several recent publications have re-opened the question of whether HER2 status should be determined for all patients with newly diagnosed breast cancer. The barrier in the past to the use of HER2 has been the nonstandardization of HER2 status determination, which is the major caveat to its use today. Two test kits have been recently approved by the Food and Drug Administration for HER2 testing, one for determining HER2 amplification by fluorescence in situ hybridization and the other for measuring HER2 overexpression by immunohistochemistry. Neither of these tests, nor any of the other myriad tests used for HER2 determinations, has been validated in all the potential arenas for the use of HER2: refinement of estimates of prognosis of untreated low-risk patients, selection among treatment options for adjuvant therapy, and selection of patients for treatment with trastuzumab (Herceptin; Genentech, San Francisco, CA). The nonstandardization of testing has led to conflicting results and controversy as to the value of HER2 in evaluating breast cancer patient prognosis and the selection among therapeutic options. Thus, testing for HER2 is not yet routine for patients with newly diagnosed breast cancer, although it is of value for patients who develop metastatic disease and who need to know if they are candidates for trastuzumab.


Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Receptor, ErbB-2/metabolism , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/genetics , Gene Expression , Humans , Prognosis , Receptor, ErbB-2/genetics , Trastuzumab
7.
Semin Oncol ; 26(3 Suppl 9): 20-3, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10426455

ABSTRACT

The need for improved adjuvant chemotherapy programs for breast cancer patients is emphasized by the 1998 overview analysis of adjuvant trials, which demonstrates that although there has been substantial incremental advances in adjuvant therapy, relapse and death are prevented in less than half of women with micrometastatic disease. Because both docetaxel (Taxotere; Rhône-Pouleuc Rorer, Collegeville, PA) and paclitaxel have substantial non-cross-resistance with anthracyclines and therefore activity in anthracycline-resistant breast cancer, defining their roles in the adjuvant therapy of breast cancer is an area of great interest and active clinical investigation. The results of the adjuvant trials using docetaxel assume a particular importance because of the two taxanes in clinical use at this time, docetaxel may be the more active agent in the treatment of metastatic breast cancer, as demonstrated in the results from phase II and III randomized trials. Ongoing or soon-to-open adjuvant trials are evaluating the impact of docetaxel added to conventional adjuvant anthracyclines regimens, substituted for anthracyclines, used in combination with anthracyclines, and in direct comparison to paclitaxel. The results of these ongoing adjuvant trials will define the role of docetaxel in adjuvant chemotherapy programs for the management of patients with breast cancer and are eagerly awaited.


Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Breast Neoplasms/drug therapy , Paclitaxel/analogs & derivatives , Taxoids , Anthracyclines/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/pathology , Chemotherapy, Adjuvant , Clinical Trials as Topic , Docetaxel , Female , Humans , Neoplasm Metastasis , Paclitaxel/administration & dosage , Paclitaxel/therapeutic use
8.
Clin Cancer Res ; 5(12): 4133-9, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10632351

ABSTRACT

Tumor-node-metastasis (TNM) staging is the standard system for the estimation of prognosis of breast cancer patients. However, this system does not exploit information yielded by markers of the biological aggressiveness of breast cancer and is clearly unsatisfactory for optimal-treatment decision-making and for patient counseling. We have developed a prognostic model, based on a few routinely evaluated prognostic variables, that produces quantitative estimates for risk of relapse of individual breast cancer patients. We used data concerning 2441 of 2990 consecutive breast cancer patients to develop an artificial neural network (ANN) for the prediction of the probability of relapse over 5 years. The prognostic variables used were: patient age, tumor size, number of axillary metastases, estrogen and progesterone receptor levels, S-phase fraction, and tumor ploidy. Performances of the model were evaluated in terms of discrimination ability and quantitative precision. Predictions were validated on an independent series of 310 patients from an institution in another country. The ANN discriminated patients according to their risk of relapse better than the TNM classification (P = 0.0015). The quantitative precision of the model's estimates was accurate and was confirmed on the series from the second institution. The 5-year relapse risk yielded by the model varied greatly within the same TNM class, particularly for patients with four or more nodal metastases. The model discriminates prognosis better than the TNM classification and is able to identify patients with strikingly different risks of relapse within each TNM class.


Subject(s)
Breast Neoplasms/pathology , Models, Statistical , Adult , Aged , Aged, 80 and over , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Disease-Free Survival , Humans , Middle Aged , Models, Biological , Neoplasm Staging , Neural Networks, Computer , Predictive Value of Tests , Prognosis , Reproducibility of Results , Risk Factors
9.
J Clin Oncol ; 16(10): 3362-8, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9779713

ABSTRACT

PURPOSE: To evaluate the efficacy and safety of docetaxel in patients with paclitaxel-resistant metastatic breast cancer (MBC). PATIENTS AND METHODS: Docetaxel (100 mg/m2) was administered every 3 weeks to 46 patients registered at four centers. Patients had previously received < or = two chemotherapy regimens for MBC. All patients had progressive disease while receiving paclitaxel therapy. Treatment was repeated until there was evidence of disease progression or for a maximum of three cycles after best response. RESULTS: Objective responses were seen in eight of 44 assessable patients (18.1%; 95% confidence interval [CI], 6.7% to 29.5%). Seven patients had partial responses and one patient responded completely. Response rates were not significantly different by previously received paclitaxel dose or resistance. No responses were seen in 12 patients who had previously received paclitaxel by 24-hour infusion, but the response rate in 32 patients who had received paclitaxel by 1- to 3-hour infusion was 25%. The median response duration was 29 weeks and the median time to disease progression was 10 weeks. Median survival was 10.5 months. Clinically significant (severe) adverse events included neutropenic fever (24% of patients), asthenia (22%), infection (13%), stomatitis (9%), neurosensory changes (7%), myalgia (7%), and diarrhea (7%). CONCLUSION: Docetaxel is active in patients with paclitaxel-resistant breast cancer, particularly in those who failed to respond to brief infusions of paclitaxel. Response rates were comparable to or better than those seen with other therapies for patients with paclitaxel-resistant MBC. This confirms preclinical studies, which indicated only partial cross-resistance between paclitaxel and docetaxel.


Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Breast Neoplasms/drug therapy , Paclitaxel/analogs & derivatives , Taxoids , Adult , Aged , Antiemetics/administration & dosage , Antineoplastic Agents, Phytogenic/adverse effects , Breast Neoplasms/pathology , Dexamethasone/administration & dosage , Docetaxel , Drug Administration Schedule , Drug Resistance, Neoplasm , Edema/chemically induced , Female , Fever/etiology , Humans , Middle Aged , Nervous System Diseases/chemically induced , Neutropenia/chemically induced , Paclitaxel/adverse effects , Paclitaxel/therapeutic use
10.
Cell Motil Cytoskeleton ; 39(4): 273-85, 1998.
Article in English | MEDLINE | ID: mdl-9580378

ABSTRACT

Tubulin, the subunit protein of microtubules, is an alpha/beta heterodimer. In many organisms, both alpha and beta consist of various isotypes. Although the isotypes differ in their tissue distributions, the question of whether the isotypes perform different functions in vivo is unanswered. In mammals, the betaI and betaIV isotypes are quite widespread, and betaII is less so, while betaIII and betaVI have narrow distributions and betaV distribution is unknown. As a tool for localizing the isotypes, we report the preparation of a monoclonal antibody specific for betaI, to add to our previously described monoclonal antibodies specific for betaII, betaIII, and betaIV [Banerjee et al., J. Biol. Chem. 263:3029-3034, 1988; 265:1794-1799, 1990; 267:5625-5630, 1992]. In order to prepare this antibody, we have purified betaI-rich rat thymus tubulin. We have used our battery of antibodies to localize the beta isotypes in four human tissues: oviduct, skin, colon, and pancreas. We have found striking differences in their tissue distributions. There is little or no betaIII in these tissues, except for the columnar epithelial cells of the colon. BetaII is restricted to very few cells, except in the skin, where it is concentrated in the stratum granulosum. BetaI is widespread in all the epithelia. In the skin it is found in the entire stratum malpighii. In the oviduct, betaI is found largely in the nonciliated epithelial cells. In the exocrine pancreas, betaI occurs only in the centroacinar cells and not in the acinar cells; the latter do not stain with any of these antibodies. BetaIV is present at very low levels in skin and pancreas. By contrast, it is prominent in the colon and also in the oviduct, where it occurs in all the epithelial cells, especially in the ciliated cells, with the highest concentrations in the cilia themselves. These results suggest that the regulation of the expression and localization of isotypes in tissues is very complex.


Subject(s)
Antibodies, Monoclonal/isolation & purification , Antibody Specificity , Tubulin/immunology , Animals , Antibodies, Monoclonal/chemistry , Colon/chemistry , Fallopian Tubes/chemistry , Female , Humans , Immunoblotting , Immunohistochemistry , Organ Specificity/immunology , Pancreas/chemistry , Rats , Skin/chemistry , Thymus Gland/chemistry , Tubulin/isolation & purification
11.
J Clin Oncol ; 16(5): 1655-60, 1998 May.
Article in English | MEDLINE | ID: mdl-9586875

ABSTRACT

PURPOSE: Adjuvant loco-regional radiation (XRT) frequently is recommended after mastectomy and adjuvant systemic therapy in patients with 10 or more positive axillary lymph nodes (ALN) to reduce the high loco-regional failure rate observed in this subset. In this study, we explored the possibility that adjuvant loco-regional radiation therapy (LR-XRT) also could decrease distant failure and improve overall survival (OS) in this subset of poor-prognosis patients. PATIENTS AND METHODS: Retrospectively, 618 breast patients with 10 or more positive ALN were studied. The median follow-up time was 7.5 years. All patients received systemic adjuvant therapy and 35% also received adjuvant radiation therapy. Loco-regional failure, distant failure, and OS analyses were adjusted for age, tumor size, number of positive ALN, and estrogen receptor (ER) status using Cox regression model. RESULTS: As expected, patients had a very high risk of loco-regional and distant failure. At 5 years, 30% of patients had loco-regional failure as a first event and 54% had distant failure. Radiation dramatically reduced loco-regional failure (hazards rate ratios [RR]=0.29; 95% confidence interval [CI], 0.19 to 0.45). The adjusted 5-year loco-regional failure rate was 13% with radiation and 38% without radiation (P=.0001). Radiation also was associated with improved distant control (RR=0.75; 95% CI, 0.58 to 0.96). The adjusted 5-year distant failure rate was 48% with radiation and 58% without radiation (P=.02). OS also improved with radiation (RR=0.68; 95% CI, 0.53 to 0.85). The adjusted 5-year OS was 56% with radiation and 42% without radiation (P=.001). CONCLUSION: In this cohort of high-risk breast cancer patients, XRT was associated with less loco-regional and distant failure and improved OS. This suggests that improved loco-regional control might decrease secondary systemic spread and improve survival.


Subject(s)
Breast Neoplasms/pathology , Breast Neoplasms/radiotherapy , Mastectomy , Adult , Aged , Aged, 80 and over , Axilla , Breast Neoplasms/mortality , Breast Neoplasms/surgery , Female , Humans , Lymphatic Metastasis , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local , Radiotherapy, Adjuvant , Regression Analysis , Retrospective Studies , Risk Factors , Survival Rate
12.
J Clin Oncol ; 16(2): 515-21, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9469335

ABSTRACT

PURPOSE: A survey of breast cancer survivors in the United States was conducted to define what they had been told about their prognosis and the value of adjuvant therapy, what they estimated their prognosis to be with and without adjuvant therapy, and what level of improvement they would have found minimally worthwhile. MATERIALS AND METHODS: Survey questionnaires were mailed to individual members and member organizations of the National Alliance of Breast Cancer Organizations (NABCO). Questionnaires were returned anonymously in prepaid mailers. Five hundred sixty-two women responded. Of these, the 318 women who received adjuvant chemotherapy were included in this analysis. RESULTS: Only 39% of the women recalled receiving quantitative estimates of their prognosis, and only 31% of women received a quantitative estimate both with and without adjuvant therapy. Sixty-eight percent of the women were able to provide a quantitative estimate for their outcome at 5 years both with and without adjuvant therapy. From these estimates, we calculated that the median estimated proportional risk reduction for recurrence that women thought they had achieved was 79%. Women were asked what degree of absolute benefit they would have found acceptable. The median acceptable extension of life expectancy was 3 to 6 months, and acceptable reduction in recurrence risk was 0.5% to 1.0%. However, there was considerable variation, with 27% of women not accepting less than 1 year and 26% not accepting a less than 5% reduction in recurrence risk. CONCLUSION: In general, American women in the surveyed population (1) do not recall being provided quantitative estimates of outcome during the process of making decisions about adjuvant therapy, (2) overestimate the value of their therapy, and (3) often will accept remarkably low degrees of net benefit. Overall, these observations can be used to support the argument that improvements in doctor/patient communication may be important to truly informed decision-making, and that flexibility for individual patients' preferences should not be superseded by rigid treatment guidelines.


Subject(s)
Breast Neoplasms/drug therapy , Patient Education as Topic , Adult , Aged , Breast Neoplasms/mortality , Breast Neoplasms/psychology , Chemotherapy, Adjuvant , Female , Humans , Middle Aged , Prognosis , Recurrence , Risk Factors , Surveys and Questionnaires
13.
J Clin Oncol ; 16(1): 187-96, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9440742

ABSTRACT

PURPOSE: The population pharmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and investigate systemic exposure as a prognostic factor for clinical outcome. PATIENTS AND METHODS: PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules. Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention. PK/PD analysis was conducted using logistic and Cox multivariate regression models. RESULTS: PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients). First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151). Docetaxel CL was a strong independent predictor (P < .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P < .0001) of the time to onset of fluid retention (n = 631). However, the duration of exposure over 0.20 micromol/L (0.16 microg/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication. CONCLUSION: First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity. A starting dose of 75 mg/m2 is currently being evaluated in this population. Prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacokinetics , Neoplasms/blood , Paclitaxel/analogs & derivatives , Taxoids , Adult , Aged , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Agents, Phytogenic/therapeutic use , Area Under Curve , Bayes Theorem , Breast Neoplasms/blood , Breast Neoplasms/drug therapy , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/drug therapy , Docetaxel , Edema/chemically induced , Female , Humans , Lung Neoplasms/blood , Lung Neoplasms/drug therapy , Male , Middle Aged , Neoplasms/drug therapy , Neutropenia/chemically induced , Paclitaxel/adverse effects , Paclitaxel/pharmacokinetics , Paclitaxel/therapeutic use , Prospective Studies
15.
Recent Results Cancer Res ; 152: 86-93, 1998.
Article in English | MEDLINE | ID: mdl-9928549

ABSTRACT

Since the 1995 St. Gallen conference the standard prognostic and predictive variables have not changed. Good treatment planning (and clinical trial entry and stratification) can be made on the basis of TNM staging, age, and ER and menopausal status. Three years from now, in 2001, this situation will have changed enormously. This will be achieved by better designs for prognostic studies, studies of predictive factors with definitive data from large, statistically powerful cooperative group trials, and perhaps simple computer-based tools to make projections and present data clearly. These advances will lead to still better-individualized selection of adjuvant therapy for breast cancer patients.


Subject(s)
Breast Neoplasms/diagnosis , Biomarkers, Tumor , Female , Humans , Meta-Analysis as Topic , Predictive Value of Tests , Prognosis , Risk Factors , Treatment Outcome
16.
Breast Cancer Res Treat ; 52(1-3): 227-37, 1998.
Article in English | MEDLINE | ID: mdl-10066085

ABSTRACT

Some prognostic factors, such as steroid receptors, appear strongly related to outcome in early studies with short follow-up, but as follow-up matures the relationships appear to weaken. We investigated this phenomenon for several factors (tumor size, axillary lymph nodes, S-phase fraction, estrogen receptor (ER) status, and adjuvant therapy) in a large sample of breast cancer cases (N=2,873) with up to 17 years of follow-up for disease-free survival (DFS). Subjects in the study were identified from patients who had hormone receptor assays performed in our laboratory. Analysis of DFS included fitting a multivariate Cox proportional hazards model, testing for nonproportionality, and examining diagnostic plots. The assumption of proportional hazards was violated for several factors including ER, tumor size, and S-phase fraction. For ER, the hazard ratio was initially less than 1.0, indicating a good effect on prognosis, but increased at later times to values greater than 1.0, indicating a bad effect on prognosis. In contrast, the hazard ratios for tumor size and S-phase were initially high and decreased asymptotically toward 1.0 over time. Analysis of p53 expression in a subset of cases yielded qualitatively similar results. We conclude that several standard prognostic factors (ER, tumor size, S-phase fraction) and possibly other investigational factors have important but nonproportional effects on hazard. It is likely that violation of proportional hazards is common and not limited to breast cancer. Failure to recognize violations of proportional hazards can lead to both over- and under-estimation of the effects of important prognostic factors.


Subject(s)
Breast Neoplasms/mortality , Adult , Aged , Breast Neoplasms/pathology , Disease-Free Survival , Female , Humans , Middle Aged , Prognosis , Proportional Hazards Models , Receptors, Estrogen/analysis , S Phase , Time Factors , Tumor Suppressor Protein p53/analysis
17.
Semin Oncol ; 24(4 Suppl 10): S10-18-S10-21, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9275002

ABSTRACT

Until the introduction of the taxoids, docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) and paclitaxel (Taxol; Bristol-Myers Squibb Oncology, Princeton, NJ), in the 1990s, anthracyclines were widely recognized as the best single agents for the treatment of breast cancer. However, even when anthracyclines are used in combination regimens with response rates of over 50%, including complete responses in 17% of patients, few women (3%) with metastatic disease remain disease free at 5 years after treatment. The low level of sustained responses is largely due to the phenomenon of drug resistance. Anthracycline resistance often involves multidrug resistance efflux mechanisms, but also can involve factors affecting topoisomerase II and apoptosis. When combining other cytotoxic agents with anthracyclines, it is of value to use non-cross-resistant drugs so that the induction of anthracycline-resistance mechanisms does not also affect the efficacy of other agents in the combination therapy. Clinical studies have shown that docetaxel, which is highly active against metastatic breast cancer as a single agent, has a high level of non-cross-resistance with anthracyclines. The overall response rate to docetaxel monotherapy in patients with anthracycline-resistant or refractory metastatic disease has been shown to be 41%. The response rate to first-line docetaxel monotherapy for metastatic breast cancer has been shown to be 61%, suggesting that two thirds of the activity of docetaxel is retained in anthracycline-resistant disease. Treatment with a simultaneous combination of docetaxel and doxorubicin has been found to be very active, with a response rate of 89%, and trials to exploit the lack of cross-resistance between these agents, in sequential regimens and adjuvant therapies, are under way.


Subject(s)
Anthracyclines/therapeutic use , Antineoplastic Agents, Phytogenic/therapeutic use , Breast Neoplasms/drug therapy , Paclitaxel/analogs & derivatives , Taxoids , Docetaxel , Drug Resistance, Neoplasm , Drug Therapy, Combination , Female , Humans , Paclitaxel/therapeutic use , Treatment Outcome
18.
Eur J Cancer ; 33 Suppl 7: S7-10, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9486096

ABSTRACT

Anthracyclines play a central role in the treatment of breast cancer. They are perhaps the most active single agents available for the treatment of this disease. For patients with primary breast cancer for whom chemotherapy would be appropriate, anthracyclines are often incorporated in adjuvant regimens. For patients with endocrine-therapy-resistant metastatic disease, anthracyclines are nearly always included in the first or second-line therapeutic regimes. Unfortunately, despite the fact that anthracyclines and anthracycline-containing regimens can achieve impressive objective response rates, this impressive activity has not translated into a great improvement in disease-free survival for patients with early stage breast cancer or overall survival for patients with metastatic disease. The addition of anthracyclines to adjuvant therapy regimens in general only modestly improves their efficacy and the use of anthracyclines in metastatic disease does not cure these patients. The clinical utility of anthracyclines would be greatly improved if we could predict which patients would be anthracycline resistant, interfere with the development or expression of anthracycline resistance and predict which anticancer agents would be non-cross-resistant with anthracyclines. Some progress is being made in all these areas. Preclinical studies have identified several intracellular processes that are perturbed by anthracyclines, or that may modulate anthracycline sensitivity of cells. These processes include topoisomerase II activity, drug and toxin transmembrane pumps, intracellular detoxification systems (such as that related to gluatathione), stress-related proteins and apoptotic mechanisms. Although measurement of the components of these systems has not yet shown clinical utility in breast cancer, some preclinical work and exploratory studies with small numbers of patients suggest that we may in the future be able to predict which patients will respond or be resistant to anthracyclines. An important avenue of work is the identification of anticancer agents that are non-cross-resistant with anthracyclines in breast cancer patients. These agents would be particularly valuable in patients with metastatic disease who had progressed while on anthracyclines. In general, such patients have a very poor prognosis with a median survival of less than 1 year. Also of importance in non-cross-resistant agents is that they might be used in combination with anthracyclines in regimens with very high response rates. Recently completed work suggests that taxoids might be such agents. This finding opens up exciting possibilities in the treatment of metastatic disease and, even more importantly, in the adjuvant arena. The identification of agents that clinically are non-cross-resistant with anthracyclines depends on the careful interpretation of clinical trial data. Unfortunately, a number of definitions of anthracycline resistance have been used in the medical literature. These range from very weak definitions, which include many patients with only prior anthracycline exposure (for example, in an adjuvant regimen), to more biologically and clinically appropriate definitions, such as documented progression while receiving an anthracycline. This distinction is very important because it is clear that many patients who have relapsed after an anthracycline-based adjuvant therapy will respond to anthracyclines for metastatic disease and are, therefore, not truly anthracycline resistant. In this regard, the recently completed trials with docetaxel in patients with rigorously defined anthracycline resistance are particularly provocative. These trials show that docetaxel maintains much of its excellent first-line levels of efficacy in patients with anthracycline-resistant breast cancer. Agents with this type of maintenance of efficacy in anthracycline-resistant tumours may find immediate utility in this clinical scenario as single agents but, more importantly, have gr


Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Antineoplastic Agents, Phytogenic/therapeutic use , Breast Neoplasms/drug therapy , Paclitaxel/analogs & derivatives , Taxoids , Clinical Trials as Topic , Docetaxel , Drug Resistance, Neoplasm , Female , Humans , Paclitaxel/therapeutic use
19.
Cancer Lett ; 116(2): 177-83, 1997 Jun 24.
Article in English | MEDLINE | ID: mdl-9215861

ABSTRACT

The value of cathepsin D determinations done on tumor cytosols in evaluating the prognosis of breast cancer patients has been debated in the literature. Our previous work suggested that cathepsin D determinations were not of prognostic value, but in that study we used immunoblotting and immunohistochemical methods rather than the more widely used double antibody immunoradiometric (IRMA) assay for measuring cathepsin levels. Here we report our results determining cathepsin D using components of a commercially available IRMA system on a large patient sample (n = 1984). Reagents from a commercially available IRMA kit were used to analyze cathepsin D levels in the cytosols of 1984 patients with breast cancer. All patients had invasive breast cancer with known tumor size and with some axillary nodes pathologically examined. Only patients with T1 and T2 tumor sizes were included. Median follow-up was 37 months. The hypothesis that high cathepsin D levels correlated with poorer outcome (poorer DFS or OS) was not confirmed, either in all patients, or in node-positive or node-negative subsets. Only in patients treated with adjuvant therapy were higher cathepsin D levels correlated with negative outcome (worsened OS, but not DFS), although given the large number of subsets analyzed this correlation may be spurious. Multivariate analyses using interaction terms did not support the concept that high cathepsin D levels correlate with resistance to adjuvant therapy. In this study evaluating the value of cathepsin D using components from a kit widely used for measuring cathepsin D levels, we conclude that cathepsin D is of doubtful value in predicting risk of early relapse or death for patients with newly diagnosed invasive breast cancer.


Subject(s)
Breast Neoplasms/mortality , Cathepsin D/analysis , Adult , Aged , Breast Neoplasms/drug therapy , Breast Neoplasms/enzymology , Disease-Free Survival , Female , Humans , Middle Aged , Prognosis
20.
Oncology (Williston Park) ; 11(3 Suppl 2): 38-42, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9110341

ABSTRACT

The extensively studied agent docetaxel (Taxotere) has shown marked clinical activity in the treatment of anthracycline-resistant breast cancer. Phase I trials indicate that toxicities, such as mucositis and neutropenia, limit the administration of docetaxel to shorter perfusion schedules. Pharmacokinetic studies have shown that docetaxel's clearance by hepatic metabolism is correlated with a marked increase in risk of toxicity in patients with impaired liver function. Nevertheless, studies of docetaxel as front-line therapy for breast cancer were initiated because of its good activity against tumors in early studies and its close relationship to paclitaxel (Taxol), an agent with proven efficacy. Phase II studies have demonstrated excellent activity for docetaxel as a single agent, with an overall response rate of 61% in trials of a 100-mg/m2 dose. A phase III study is currently comparing docetaxel with paclitaxel as single-agent therapy. Docetaxel is expected to provide a better response rate but a higher incidence of neutropenia. The agent shows promise in adjuvant therapy, with very high response rates in anthracycline-resistant patients. Preliminary results of tests using docetaxel in combination with doxorubicin show high objective response rates but low complete response rates; early results suggest that this combination may have some advantages over paclitaxel/doxorubicin.


Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Breast Neoplasms/drug therapy , Paclitaxel/analogs & derivatives , Taxoids , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Combined Chemotherapy Protocols , Clinical Trials as Topic , Docetaxel , Drug Resistance, Neoplasm , Female , Humans , Paclitaxel/pharmacology , Paclitaxel/therapeutic use
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