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Biomedical subjects

D F Hayes

Publications and source records attributed to D F Hayes.

At least 55 records · Page 3Linked to original sources
PubMed1997

Prediction of response to antiestrogen therapy in advanced breast cancer patients by pretreatment circulating levels of extracellular domain of the HER-2/c-neu protein.

PURPOSE: Overexpression of the HER-2/c-neu/c-erbB2 proto-oncogene is associated with a worse prognosis in patients with breast cancer, perhaps due to an association of the HER-2 proto-oncogene protein with resistance to hormone and/or chemotherapy. Circulating levels of the extracellular domain (ECD) of the HER-2/c-neu-related protein (NRP) are elevated in 20% to 40% of patients with metastatic breast cancer. We investigated whether pretreatment levels of NRP predict response to hormone therapy (HT). MATERIALS AND METHODS: Circulating NRP levels were determined in 94 patients who participated in a randomized trial of three different doses of the antiestrogen, droloxifene (DRO), as first-line HT for metastatic breast cancer. RESULTS: NRP levels were elevated (> or = 5,000 U/mL) in 32 of 94 patients (34%). Only three of 32 patients (9%) with elevated NRP levels responded to DRO, compared with 35 of 62 (56%) with nonelevated NRP levels (P = .00001). Low pretreatment NRP level was the most powerful predictor of response to DRO (odds ratio of response, 22.4; P = .0001). Elevated pretreatment NRP levels were also associated with a shorter time to progression (TTP) and survival duration. CONCLUSION: Pretreatment circulating NRP levels predict a low likelihood of benefit from HT, specifically DRO, in patients with estrogen receptor (ER)-positive and/or progesterone receptor (PgR)-positive or receptor-unknown metastatic breast cancer, even when adjusted for other known predictive factors, such as ER and/or PgR levels, site of disease, disease-free interval from primary treatment to recurrence, and prior adjuvant chemotherapy. These data suggest that pretreatment NRP levels may be useful in deciding whether to treat a patient who otherwise appears to be likely to respond to HT.

Aged↗
PubMed1997

High-dose toremifene vs tamoxifen in postmenopausal advanced breast cancer.

To compare the efficacy and safety of high doses (200 or 240 mg/d) of toremifene (Fareston) to standard doses (20 or 40 mg/d) of tamoxifen (Nolvadex) in postmenopausal women with estrogen receptor (ER)-positive or ER-unknown advanced breast cancer, we pooled data from two randomized, three-arm clinical trials. Of the 733 patients included in the overview, 369 were randomized to high-dose toremifene and 364, to tamoxifen. At median follow-up of 19 months, disease had progressed in over 70% of the patients. Response rates were 25.2% in the high-dose toremifene arm and 19.8% in the tamoxifen arm (P = .087). The two treatments appeared to be statistically equivalent with respect to risk for disease progression and survival. Reversible SGOT elevation was observed in 26 tamoxifen-treated patients vs 64 high-dose toremifene recipients (P < .001) and nausea in 33 vs 50 patients (P = .085). Reversible corneal keratopathy was diagnosed in two patients on tamoxifen and eight on high-dose toremifene (P = .061). Treatment had to be discontinued in 17.3% of patients in the high-dose toremifene arm and 20.1% in the tamoxifen arm. Discontinuation due to toxicity was rare, and toxicity did not differ significantly between the treatments. Toremifene, in doses up to 240 mg/d, is an effective, safe treatment for postmenopausal women with ER-positive/unknown advanced breast cancer.

Antineoplastic Agents, Hormonal↗
PubMed1996

Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers.

Introduction of tumor markers into routine clinical practice has been poorly controlled, with few criteria or guidelines as to how such markers should be used. We propose a Tumor Marker Utility Grading System (TMUGS) to evaluate the clinical utility of tumor markers and to establish an investigational agenda for evaluation of new tumor markers. A Tumor Marker Utility Grading Worksheet has been designed. The initial portion of this worksheet is used to clarify the precise characteristics of the marker in question. These characteristics include the marker designation, the molecule and/or substance and the relevant alteration from normalcy, the assay format and reagents, the specimen type, and the neoplastic disease for which the marker is being evaluated. To determine the clinical utility of each marker, one of several potential uses must be designated, including risk assessment, screening, differential diagnosis, prognosis, and monitoring clinical course. For each of these uses, associations between marker assay results and expected biologic process and end points must be determined. However, knowledge of tumor marker data should contribute to a decision in practice that results in a more favorable clinical outcome for the patient, including increased overall survival, increased disease-free survival, improvement in quality of life, or reduction in cost of care. Semiquantitative utility scales have been developed for each end point. The only markers recommended for use in routine clinical practice are those that are assigned utility scores of "++" or " " on a 6-point scale (ranging from 0 to ) in the categories relative to more favorable clinical outcomes. Each utility score assignment should be supported by documentation of the level of evidence used to evaluate the marker. TMUGS will establish a standardized analytic technique to evaluate clinical utility of known and future tumor markers. It should result in improved patient outcomes and more cost-efficient investigation and application of tumor markers.

Biomarkers, Tumor↗
PubMed1996

Recombinant human stem cell factor (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo.

Stem cell factor (SCF), also known as mast cell growth factor, kit ligand, and steel factor, is the ligand for the tyrosine kinase receptor (SCFR) that is encoded by the c-kit proto-oncogene. We analyzed the effects of recombinant human SCF (r-hSCF, 5-50 micrograms/kg/day, injected subcutaneously) on mast cells and melanocytes in a phase I study of 10 patients with advanced breast carcinoma. A wheal and flare reaction developed at each r-hSCF injection site; by electron microscopy, most dermal mast cells at these sites exhibited extensive, anaphylactic-type degranulation. A 14-d course of r-hSCF significantly increased dermal mast cell density at sites distant to those injected with the cytokine and also increased both urinary levels of the major histamine metabolite, methyl-histamine, and serum levels of mast cell alpha-tryptase. Five subjects developed areas of persistent hyperpigmentation at r-hSCF injection sites; by light microscopy, these sites exhibited markedly increased epidermal melanization and increased numbers of melanocytes. The demonstration that r-hSCF can promote both the hyperplasia and the functional activation of human mast cells and melanocytes in vivo has implications for our understanding of the role of endogenous SCF in health and disease. These findings also indicate that the interaction between SCF and its receptor represents a potential therapeutic target for regulating the numbers and functional activity of both mast cells and cutaneous melanocytes.

Anaphylaxis↗
PubMed1996

The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer.

BACKGROUND: Patients with early-stage breast cancer who are at substantial risk for systemic metastases are increasingly treated with breast-conserving therapy and adjuvant chemotherapy. However, the optimal sequencing of chemotherapy and radiation therapy is not clear. METHODS: Two hundred forty-four patients with stage I or II breast cancer who were at substantial risk for distant metastases were randomly assigned to receive a 12-week course of chemotherapy either before or after radiation therapy. All had had breast-conserving surgery. The median length of follow-up in surviving patients was 58 months (range, 10 to 124). RESULTS: The five-year actuarial rates of cancer recurrence at any site and of distant metastases in the radiotherapy-first group and the chemotherapy-first group were 38 percent and 31 percent (P = 0.17) and 36 percent and 25 percent (P = 0.05), respectively. Overall survival was 73 percent and 81 percent (P = 0.11), respectively. The five-year crude rates of first recurrence according to site in the radiotherapy-first and chemotherapy-first groups, respectively, were 5 percent and 14 percent for local recurrence and 32 percent and 20 percent for distant or regional recurrence or both. This difference in the pattern of recurrence was of borderline statistical significance (P = 0.07). CONCLUSIONS: This study suggests that for patients ar substantial risk for systemic metastases, it is preferable to give a 12-week course of chemotherapy followed by radiation therapy, rather than radiation therapy followed by chemotherapy.

Actuarial Analysis↗
PubMed1996

Serum (circulating) tumor markers for breast cancer.

Many circulating markers have been proposed for breast cancer, with potential utility for identification, screening, prognosis, detection, or monitoring. Of the available markers, those with the greatest promise include circulating tumor markers that provide an indication of clinical course, such as CA15-3 and CEA, and novel markers such as BrCa1, antibodies to p53, antibodies to HER-2/neu, indicators of angiogenesis, and the extracellular domain of HER-2/neu. However, the precise clinical utilities of all of these markers have yet to be determined. It is especially important that the relative independence of the markers in relation to other available markers be determined so as to avoid the unnecessary cost and expense of redundancy. Moreover, it is important that the clinician be aware of the limitations in both sensitivity and specificity of each marker so as not to over- or under-interpret the predictive value of any test.

Antigens, Neoplasm↗
PubMed1996

Breast cancer-associated antigen, DF3/MUC1, induces apoptosis of activated human T cells.

Given the plethora of well-documented breast carcinoma-associated antigens in humans including MAGE-1, -2 and -3, mutated p53, p21ras, HER-2/neu and DF3/MUC-1, coupled with evidence that humoral and cytotoxic T-cell responses against these antigens exist, the central dilemma facing tumor immunologists is why the host immune response is so inefficient. One possibility is that tumor cells themselves are either inefficient or ineffective antigen-presenting cells (APCs). The failure of tumor cells to function as APCs may be due to their inability to process and present the antigen, the absence or insufficient numbers of adhesion and costimulatory molecules or, potentially, the secretion of inhibitory cytokines. Therefore, we sought to determine whether human breast cancer cell lines could function as APCs and, if not, to identify mechanism(s) responsible for this defect. Here, we show that human breast cancer cell lines fail to present alloantigen. This defect does not reside in their inherent capacity to present antigen but rather is due to apoptosis of activated T cells induced by exposure to the breast carcinoma-associated mucin antigen, DF3/MUC1. These results support the hypothesis that DF3/MUC1 may contribute to the paucity of clinically significant anticarcinoma-specific immune responses.

3T3 Cells↗
PubMed1995

Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer.

PURPOSE: To perform a randomized three-arm comparison of tamoxifen (TAM; 20 mg/d) and two separate doses of toremifene (TOR; 60 mg/d [TOR60] and 200 mg/d [TOR200]) in postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer. MATERIALS AND METHODS: Six hundred forty-eight patients with hormone receptor-positive or -unknown metastatic breast cancer were randomly assigned to receive TAM (n = 215), TOR60 (n = 221), or TOR200 (n = 212). RESULTS: The combined response rates (by intent to treat) were as follows;: TAM, 44%; TOR60, 50%; and TOR200, 48%. Complete and partial response rates were as follows: TAM, 19%; TOR60, 21%, and TOR200, 23% (not statistically different). Median times to progression and overall survival were not significantly different. Adverse events (lethal, serious but nonlethal, and important but non-life-threatening) were similar in all three arms, except that patients in the TOR200 arm had a statistically significantly increased rate of nausea (37% v 26% and 26% for TOR200, TAM, and TOR60, respectively; P = .027). Quality-of-life assessments were not different among the three arms. CONCLUSION: The activity, toxicity, and side effects of TOR in postmenopausal women with hormone receptor-positive or -unknown metastatic breast cancer are similar if not equivalent to those of TAM. We detected no clear evidence of a dose-response effect for TOR. TOR60 is an effective and safe agent for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and can be considered an alternative to TAM as first-line treatment for such patients.

Adult↗
PubMed1995

Worsening bone scan in the evaluation of antitumor response during hormonal therapy of breast cancer.

PURPOSE: Scintigraphic flare in association with response to therapy has been well described in the medical literature. During the course of a recent breast cancer trial, it became apparent that several patients with worsening bone scan but no other clinical evidence of disease progression might have potentially benefited from continued therapy, but had therapy discontinued. A retrospective analysis of this issue was performed to assess the magnitude and scope of this problem. MATERIALS AND METHODS: A total of 648 patients with hormone receptor-positive or unknown advanced breast cancer were treated as part of a large-scale trial of first-line hormonal therapy. Patients were assessed for response to therapy, including response duration, progression-free interval (PFI), overall survival, and quality of life. The retrospective analysis presented here was performed to assess whether patients with a possible scintigraphic flare within the first 16 weeks of therapy might have had therapy discontinued prematurely due to a worsening bone scan attributable to tumor flare, rather than due to disease progression. RESULTS: Analysis of the hormonal trial showed that of 376 assessable patients 108 (29%) with bone disease had a possible scintigraphic flare by week 8 or 16 of the trial, based on data on the case report forms and radiology reports (bone scans and x-rays). Of these, 69 patients (64%) were continued on study therapy, which resulted in clinical benefit in 50 (72%) of those patients. In contrast, 39 patients (36%) with possible scintigraphic flare were removed from the trial. CONCLUSION: We conclude that changes in bone scintigraphy that mimic progressive disease early in the course of hormonal treatment of patients with breast cancer metastatic to bone may represent scintigraphic flare associated with response. Thus, clinicians must be cognizant of the phenomenon of scintigraphic flare to avoid premature discontinuation of a potentially beneficial treatment.

Bone Neoplasms↗
PubMed1995

Treatment of metastatic breast cancer: present and future prospects.

Patients with recurrent breast cancer can be divided into three categories: those with locoregional recurrence, those with distant nonvisceral recurrence, and those with visceral recurrence. Survival from time of first relapse is clearly dependent on these categories. Selection of therapeutic modality should be based on considerations of site recurrence, symptomatology, anticipated response to therapy, and expected toxicities related to the therapy. Chemotherapy is appropriate for patients who are either unlikely to respond to hormone therapy, quite symptomatic, clearly hormone refractory, or have rapidly progressive visceral disease. Previously untreated patients are likely to respond to chemotherapy, with no clear-cut marker or clinical category associated with increased or decreased likelihood of benefit. Studies are ongoing to identify markers for response to chemotherapy, with recent investigations focusing on HER-2/neu expression. Standard combination chemotherapeutic regimens, consisting of either cyclophosphamide/methotrexate/5-fluorouracil (CMF) or cyclophosphamide/doxorubicin/5-fluorouracil (CAF), are associated with response rates in untreated patients of 35% to 80% and in previously treated patients of 10% to 40%. Although CAF probably has a slightly higher response rate than CMF, the toxicity of CAF is substantially higher. Newer agents are effective in both previously untreated and treated patients with breast cancer. These include paclitaxel, docetaxel, vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France), and amonafide. Furthermore, modulation of previously existing agents, designed to overcome resistance, has been tested. Only leucovorin/5-fluorouracil has apparent clinical benefit. A number of novel approaches are being designed or are currently being used in clinical trials. These include differentiating agents, anti-angiogenesis factors, antitumor antigen-based therapy, growth factor receptor/ligand therapy, and gene therapy.

Antineoplastic Agents↗
PubMed1995

Dose escalation of N,N',N"-triethylenethiophosphoramide combined with pentoxifylline for advanced breast cancer.

Pentoxifylline potentiates the cytotoxicity of alkylating agents in preclinical models. In this study we sought to define the maximum tolerated dose (MTD) of N,N',N"-triethylenethiophosphoramide (thioTEPA) with pentoxifylline, and to estimate the antitumor response to this combination in previously treated breast cancer patients. Thirty-five previously treated advanced breast cancer patients received 70 cycles (median, 2 cycles/patient; range, 1-6) of 1600 mg of oral sustained release pentoxifylline every 8 h for 4 doses in combination with escalating doses of i.v. bolus thioTEPA 40-65 mg/m2 administered 3 h after the second dose of pentoxifylline. Thrombocytopenia was dose limiting at 65 mg/m2 of thioTEPA, and the MTD was defined as 60 mg/m2. Among 25 patients treated at the MTD, leukopenia was grade 2 in 9 patients (36%), grade 3 in 4 patients (16%), and grade 4 in 2 patients (8%); thrombocytopenia was grade 2 in 3 patients (12%), grade 3 in 4 patients (16%), and grade 4 in 3 patients (12%). No other thioTEPA-related toxicity was observed. Plasma concentrations of thioTEPA, TEPA, and pentoxifylline were measured in 6 patients. The median (range) area under the plasma concentration versus time curve for thioTEPA was 29.4 microM/h (26. 2-40.5) and for TEPA was 16.3 microM/h (9.2-21.7 microM-h). The median (range) maximal plasma concentration of pentoxifylline and major metabolites I, IV, and V were 1.2 microgram/ml (0.2-7.8), 4.0 microgram/ml (0.5-16.4), 0.4 (range 0.1-0.8), and 2.9 (1.1-5.5), respectively. No objective responses were observed among 21 evaluable patients treated at the MTD (95% confidence interval, 0-15%). The combination of pentoxifylline and thioTEPA is well tolerated but not active in previously treated advanced breast cancer patients. Further clinical trials using commercially available oral sustained release pentoxifylline as a modulator of alkylating agents are not warranted.

Administration, Oral↗
PubMed1994

Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers.

BACKGROUND: Experimental evidence supports the hypothesis that the development of blood vessels is fundamental to the growth and metastasis of solid tumors. Elevated levels of the angiogenic peptide basic fibroblast growth factor (bFGF) have been significantly correlated with the status and extent of disease in bladder cancer. PURPOSE: We measured the bFGF levels in patients with cancer in organs other than the bladder to determine whether elevated levels accompany these cancers. METHODS: Urine samples were collected from 950 patients having a wide variety of solid tumors, leukemia, or lymphoma and from a control group of 87 healthy volunteers and 198 patients with non-cancer-related diseases. Levels of bFGF in samples prepared from the urine were measured using an enzyme bioassay. RESULTS: Male control subjects had a median bFGF level of 151 pg/g and female control subjects a median of 237 pg/g, with a combined 90th percentile of 619 pg/g. An elevated level of bFGF was found in the urine of some of the patients with every type of tumor studied except cervical carcinoma. For example, patients with active local cancers had a median level of 312 pg/g. Those with active, metastatic cancers had a median level of 479 pg/g and a 90th percentile level of 14143 pg/g. After "elevated" was defined to mean higher than the 90th percentile level for controls, 31% of patients with local active and 47% of patients with metastatic active cancers showed elevated bFGF levels. Survival among cancer patients at the median follow-up time was 85%-88% for those with "normal" and 71%-72% for those with "elevated" urine bFGF levels. IMPLICATIONS: Our results suggest that bFGF in urine deserves further evaluation of its potential use as a monitor of therapy or as a predictor of outcome once a cancer has been diagnosed.

Analysis of Variance↗
PubMed1994

Healing flare in skeletal metastases from breast cancer.

PURPOSE: To identify the frequency, characteristics, and prognostic significance of scintigraphically detected healing flare in patients with breast cancer metastatic to bone. MATERIALS AND METHODS: Findings on bone scans and concomitant radiographs of 1,188 patients were reviewed. Bone metastases occurred in 426 patients. Outcomes of 101 patients (aged 21-71 years) with skeletal metastases were correlated with typical scintigraphic and radiographic features. RESULTS: Healing flare with increased radiotracer uptake and radiographically demonstrated sclerotic changes in osteolytic or mixed skeletal metastases were prospectively identified in 12% of patients with skeletal metastases. Healing flare was detected 3.2 months +/- 1.4 after initiation of hormonal treatment or chemotherapy. Skeletal metastatic activity stabilized on bone scans within 6.2 months +/- 3.0. Patients with healing flare did not survive longer than patients without healing flare but with stable metastases after treatment (3.3 years +/- 2.0 vs 3.9 years +/- 1.6). CONCLUSION: Scintigraphically detected healing flare represents a favorable response to therapy not associated with increased survival.

Adult↗
PubMed1994

Relationship of patient age to pathologic features of the tumor and prognosis for patients with stage I or II breast cancer.

PURPOSE: This analysis was performed to clarify the relationship of young age at diagnosis to the pathologic features of the tumor and prognosis in patients with early-stage breast cancer. PATIENTS AND METHODS: We retrospectively analyzed data from 1,398 patients with American Joint Committee on Cancer Staging stage I or II breast cancer treated by breast-conserving therapy between 1968 and 1985. One hundred seven patients were younger than 35 years at the time of diagnosis. The median follow-up duration for the 1,032 survivors was 99 months. RESULTS: Patients younger than 35 years had a significantly higher overall recurrence rate (P = .002), as well as a greater risk for developing distant metastases (P = .03), when compared with older patients. The cancers in younger patients more commonly showed factors associated with a worse prognosis (including grade 3 histology, lymphatic vessel invasion [LVI], necrosis, and estrogen receptor [ER] negativity) as compared with older patients. In a proportional hazards model that included clinical and treatment-related variables, as well as these pathologic features, age younger than 35 years remained a significant predictor for time to recurrence (relative risk [RR], 1.70), time to distant failure (RR, 1.60), and overall mortality (RR, 1.50). CONCLUSION: Breast cancer patients younger than 35 years have a worse prognosis than older patients. This difference is only partially explained by a higher frequency of adverse pathologic factors seen in younger patients.

Actuarial Analysis↗
PubMed1994

Angiogenesis and breast cancer.

Antiangiogenesis is an appealing therapeutic modality for the treatment of a number of clinically important diseases, including human malignancies and specifically breast cancer. For years, such an approach has remained little more than good theory. However, recent studies have suggested that specific antiangiogenic agents might be effective and safe, and preliminary clinical trials are now being planned to test these drugs. Although early studies will be designed to test the safety of these agents, it seems most likely that they will have their greatest efficacy early in the course of the disease, for example, in the adjuvant setting. Moreover, they will almost certainly be most active when used in combination, both with other antiangiogenic agents and with other modalities such as classic chemotherapy or endocrine therapies or both. Given the potential for monitoring tissue neovascularization and circulating angiogenic factors, one might also speculate that therapies might be chosen based on specific, individual characteristics, not unlike the current use of tumor steroid hormone receptor content to determine the appropriate use of endocrine therapy. In fact, individual responses to antiangiogenic molecules may be important. For example, one group of investigators investigated antiangiogenic activity of a large, polyglycosylated lipid, maltose tetrapalmitate (MTP). They found that the genetic ability of inbred mice to respond to MTP is specifically related to the antiangiogenic and antitumor effects of MTP. Mice genetically unable to respond to MTP were not protected from tumor-graft growth by MTP, whereas responders survived for long periods of time. Although the clinical field of antiangiogenic therapy remains in its infancy, physicians in the future may be as concerned about the "angiogenic profile" of individual patients as they are today about clinical staging and ER status.

Breast Neoplasms↗
PubMed1994

Tumor markers for breast cancer. Current utilities and future prospects.

Tumor-associated markers have potential utility in identification, screening, prognosis, detection, or monitoring breast cancer. Of the available markers, those with the greatest promise in 1994 include the yet-to-be-cloned BrCa1, the p53 tumor suppressor gene, tissue-associated prognostic factors such as HER-2/neu, cathepsin-D, and indicators of angiogenesis, and circulating tumor markers that provide an indication of clinical course, such as CA15-3 and CEA. Unfortunately, the precise clinical utilities of all of these markers remain imprecise. It is especially important that the relative independence of the markers in relation to other available markers be determined so as to avoid the unnecessary cost and expense of redundancy. Moreover, it is important that the clinician be aware of the limitations in both sensitivity and specificity of each marker so as not to over- or underinterpret the predictive value of any test. With these caveats in mind, judicial application of germline, tissue, and soluble tumor markers can improve clinical care of patients at risk for and with breast cancer.

Biomarkers, Tumor↗