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Daniel F Hayes

Publications and source records attributed to Daniel F Hayes.

At least 37 records · Page 2Linked to original sources
PubMed2005

Comparison of HER2 status by fluorescence in situ hybridization and immunohistochemistry to predict benefit from dose escalation of adjuvant doxorubicin-based therapy in node-positive breast cancer patients.

PURPOSE: HER2 is a clinically important tumor marker in breast cancer; however, there is controversy regarding which method reliably measures HER2 status. We compared three HER2 laboratory methods: immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR), to predict disease-free survival (DFS) and overall survival (OS) after adjuvant doxorubicin-based therapy in node-positive breast cancer patients. METHODS: This is a Cancer and Leukemia Group B (CALGB) study, using 524 tumor blocks collected from breast cancer patients registered to clinical trial CALGB 8541. IHC employed CB11 and AO-11-854 monoclonal antibodies; FISH used PathVysion HER2 DNA Probe kit; PCR utilized differential PCR (D-PCR) methodology. RESULTS: Cases HER2 positive by IHC, FISH and D-PCR were 24%, 17%, and 18%, respectively. FISH and IHC were clearly related (kappa = 64.8%). All three methods demonstrated a similar relationship for DFS and OS. By any method, for patients with HER2-negative tumors, there was little or no effect of dose of adjuvant doxorubicin-based therapy. For patients with HER2-positive tumors, all three methods predicted a benefit from dose-intense (high-dose) compared with low- or moderate-dose adjuvant doxorubicin-based therapy. CONCLUSION: FISH is a reliable method to predict clinical outcome following adjuvant doxorubicin-based therapy for stage II breast cancer patients. There is a moderate level of concordance among the three methods (IHC, FISH, PCR). None of the methods is clearly superior. Although IHC-positive/FISH-positive tumors yielded the greatest interaction with dose of therapy in predicting outcome, no combination of assays tested was statistically superior.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer.

PURPOSE: Metastatic breast cancer (MBC) is incurable; its treatment is palliative. We investigated whether the presence of circulating tumor cells (CTCs) predicts treatment efficacy, progression-free survival (PFS), and overall survival (OS) in patients with newly diagnosed MBC who were about to start first-line therapy. PATIENTS AND METHODS: One hundred seventy-seven patients with measurable MBC were enrolled onto a prospective study. Eighty-three of the 177 patients were entering first-line treatment, and these patients are the focus of this analysis. CTCs from 7.5 mL of whole blood drawn before treatment initiation (baseline) and monthly thereafter for up to 6 months were isolated and enumerated using immunomagnetics. RESULTS: The mean (+/- standard deviation) follow-up time was 11.1 +/- 4.4 months (median, 12.2 months). Forty-three patients (52%) had > or = five CTCs at baseline. The median PFS was 7.2 months (95% CI, 4.9 to 9.4 months), and the median OS was more than 18 months. Patients with > or = five CTCs at baseline and at first follow-up (4 weeks) had a worse prognosis than patients with less than five CTCs (baseline: median PFS, 4.9 v 9.5 months, respectively; log-rank, P = .0014; median OS, 14.2 v > 18 months, respectively; log-rank, P = .0048; first follow-up: median PFS, 2.1 v 8.9 months, respectively; log-rank, P = .0070; median OS, 11.1 v > 18 months, respectively; log-rank, P = .0029). CTCs before and after the initiation of therapy were strong, independent prognostic factors. CONCLUSION: Detection of CTCs before initiation of first-line therapy in patients with MBC is highly predictive of PFS and OS. This technology can aid in appropriate patient stratification and design of tailored treatments.

Breast Neoplasms↗
PubMed2005

CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment.

BACKGROUND: The efficacy of tamoxifen therapy for the treatment of breast cancer varies widely among individuals. Plasma concentrations of the active tamoxifen metabolite endoxifen are associated with the cytochrome P450 (CYP) 2D6 genotype. We examined the effects of concomitant use of selective serotonin reuptake inhibitor antidepressants, which are CYP2D6 enzyme inhibitors commonly prescribed to treat hot flashes in women who take tamoxifen, and genotypes for genes that encode tamoxifen-metabolizing enzymes on plasma concentrations of tamoxifen and its metabolites. METHODS: Eighty patients with newly diagnosed with breast cancer who were beginning tamoxifen therapy (20 mg/day orally), 24 of whom were taking CYP2D6 inhibitors, were genotyped for common alleles of the CYP2D6, CYP2C9, CYP3A5, and sulfotransferase (SULT) 1A1 genes. Plasma concentrations of tamoxifen and its metabolites were measured after 1 and 4 months of tamoxifen therapy. Differences in plasma concentrations of tamoxifen and its metabolites between genotype groups were analyzed by the Wilcoxon rank sum test. All statistical tests were two-sided. RESULTS: Among all women, plasma endoxifen concentrations after 4 months of tamoxifen therapy were statistically significantly lower in subjects with a CYP2D6 homozygous variant genotype (20.0 nM, 95% confidence interval [CI] = 11.1 to 28.9 nM) or a heterozygous genotype (43.1 nM, 95% CI = 33.3 to 52.9 nM) than in those with a homozygous wild-type genotype (78.0 nM, 95%CI = 65.9 to 90.1 nM) (both P = .003). Among subjects who carried a homozygous wild-type genotype, the mean plasma endoxifen concentration for those who were using CYP2D6 inhibitors was 58% lower than that for those who were not (38.6 nM versus 91.4 nM, difference = -52.8 nM, 95% CI = -86.1 to -19.5 nM, P = .0025). The plasma endoxifen concentration was slightly reduced in women taking venlafaxine, a weak inhibitor of CYP2D6, whereas the plasma endoxifen concentration was reduced substantially in subjects who took paroxetine (a potent inhibitor of CYP2D6). Genetic variations of CYP2C9, CYP3A5, or SULT1A1 had no statistically significant associations with plasma concentrations of tamoxifen or its metabolites. CONCLUSION: Interactions between CYP2D6 polymorphisms and coadministered antidepressants and other drugs that are CYP2D6 inhibitors may be associated with altered tamoxifen activity.

Adult↗
PubMed2005

Clinical and radiologic assessments to predict breast cancer pathologic complete response to neoadjuvant chemotherapy.

PURPOSE: To prospectively compare the ability of clinical examination, mammography, vascularity-sensitive ultrasound, and magnetic resonance imaging (MRI) to determine pathologic complete response (CR) in breast cancer patients undergoing neoadjuvant chemotherapy. PATIENTS AND METHODS: Participants were women with primary measurable, operable invasive breast cancer (Stages I-III) who presented to the University of Michigan Breast Care Center. Eligibility criteria were based on clinical need for chemotherapy as part of the overall treatment plan. The chemotherapy consisted of doxorubicin and docetaxel administered every 3 weeks for four cycles. Tumor size measurements by physical examination and by the three imaging modalities were performed before chemotherapy was initiated and after its completion, prior to definitive surgery. Response criteria were pre-specified in this prospective design, and study radiologists analyzed the mammographic, sonographic and MRI image sets blinded to information from the other modalities and blinded to final histological diagnosis. The pathologic CR rate obtained by the clinical and imaging modalities was compared to pathologic CR as determined pathologically. RESULTS: 41 of 43 enrolled patients had a determination of pathologic response, and 4 patients had a pathologic CR to this chemotherapy (9.8%). The accuracy of physical examination, mammography, ultrasound, and MRI in determining pathologic CR was 75, 89, 82, and 89% respectively (NS). CONCLUSION: Biopsy after neoadjuvant chemotherapy remains absolutely necessary to determine pathologic CR to neoadjuvant chemotherapy, as the accuracy of current imaging modalities is insufficient to make this determination. The accuracy of mammography, vascularity-sensitive ultrasound, and MRI were not observed to be significantly different.

Adult↗
PubMed2005

A multicenter randomized clinical trial evaluating interleukin-2 activated hematopoietic stem cell transplantation and post-transplant IL-2 for high risk breast cancer patients.

PURPOSE: This Phase III randomized multicenter trial compared progression-free (PFS) and overall survival (OS) for autologous peripheral blood stem cell (aPBSC) transplantation with or without immunotherapy in high-risk breast cancer patients. METHODS: Eligible patients had American Joint Committee on Cancer (AJCC) 5th Edition Stage II/IIIA with > or = 4 axillary nodes, Stage IIIB, or chemotherapy-sensitive or stable Stage IV disease. Following treatment with cyclophosphamide, thiotepa and carboplatin (STAMP V), patients were randomized to aPBSC transplant with or without immunotherapy. Patients on immunotherapy received cells that were incubated in interleukin-2 (IL-2) for 24 h followed by parenteral IL-2 for 5 days then 2 days of rest for 4 weeks. RESULTS: Fifty-nine patients were treated (35 Stage II/IIIA; 13 Stage IIIB; 11 Stage IV), 30 patients were randomized to immunotherapy and 29 patients to no immunotherapy. Neutrophils engrafted a median of 10 days post-transplant in both groups. The median times to platelet engraftment were 9 and 10 days after transplant in the no-immunotherapy and immunotherapy groups, respectively (p = 0.03). There was no statistical evidence (p = 0.61) of a difference in progression-free and surviving (PFS) at 3 years for patients receiving immunotherapy (53%) compared with no immunotherapy (48%). There was some evidence of superiority in overall survival (OS) at 3 years for patients receiving immunotherapy (83%) compared with no immunotherapy (69%), but the difference between survival curves was not statistically significant (p = 0.08). Also, there was some evidence that patients developing acute graft versus host disease (aGVHD) had superior PFS (p = 0.02) but not OS (p = 0.19) than patients not developing aGVHD. Toxicities were transient and similar between groups, with no treatment-related deaths. CONCLUSIONS: This phase III study of high-risk breast cancer patients randomized to immunotherapy or no immunotherapy demonstrated that a well-tolerated immunotherapy regimen added to aPBSC transplant did not improve PFS, but there was some improvement in OS, but not by an amount that was statistically significant (p = 0.08).

Adolescent↗
PubMed2005

Breast cancer.

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Antineoplastic Agents↗
PubMed2004

A pilot study to establish a clinical model to perform phase II studies of breast cancer chemopreventive agents in women at high risk with biomarkers as surrogate endpoints for activity.

PURPOSE: Use of surrogate end point biomarkers in phase II trials may help select agents that appear to have activity and might be evaluated in future phase III definitive trials of breast cancer prevention. We performed a pilot clinical trial to establish the logistics for a clinical model to perform phase II studies of breast cancer chemopreventive agents in women at high risk with novel imaging techniques and candidate surrogate end point biomarkers for activity. We chose tamoxifen to establish proof of principal with a known effective agent. EXPERIMENTAL DESIGN: Women at a high risk of developing a new breast cancer and for whom tamoxifen was recommended were eligible. The women underwent baseline and 3 and 6 months mammogram and magnetic resonance imaging (MRI) of one breast to identify areas of water-like intensity (epithelial) and to determine the changes over time and MRI-directed core breast biopsies of these areas for surrogate end point biomarkers analysis. RESULTS: From August 1999 to March 2001, 26 women underwent baseline imaging and core biopsies. Sixteen women took tamoxifen and 10 chose not to. Overall, 79% of the samples contained glandular tissue evaluable for histology, but only 66% of the samples were evaluable for marker analysis. Only 12 patients had specimens with glandular tissue sufficient for marker analysis both at baseline and in at least one follow-up. Because of the small number of women with matched samples, marker analysis was not informative. CONCLUSIONS: This study shows the feasibility of obtaining serial core breast biopsies from women at a high risk of developing a new breast cancer. Patient participation in this model is satisfactory, and such a model may provide indication of drug activity. MRI-directed biopsy did not provide a high yield of evaluable samples, and additional work on adequate collection of epithelial tissue for surrogate end point biomarker analysis is thus necessary.

Adult↗
PubMed2004

A pilot surrogate end point biomarker trial of perillyl alcohol in breast neoplasia.

PURPOSE: Efficient strategies to screen promising agents in early phase development are essential for rapid progress in breast cancer chemoprevention. We report our experience with the natural compound perillyl alcohol (POH) administered in a short-term surrogate end point biomarker (SEB) protocol, using the "window" between diagnostic and definitive surgery. EXPERIMENTAL DESIGN: Eligible patients included those with a diagnosis of atypical ductal hyperplasia, ductal carcinoma in situ, lobular carcinoma in situ, or invasive carcinoma (<3 cm in size) that required further surgery. Thirty-seven of 267 women screened were enrolled in the study (14%). Five women received single-dose POH (1.5 g/m2) 2 days before surgery, 16 received escalating doses of POH (1.2 g/m2 to 4.8 g/m2/day) for 2 days before surgery, and 16 served as untreated controls. Exploratory SEB analysis [estrogen receptor, progesterone receptor, proliferation, apoptosis, M6P/insulin-like growth factor (IGF)-2R, IGF1, IGF2 and transforming growth factor beta] was conducted before and after POH. RESULTS: Only a small portion of the population screened entered the study. Reasons for nonparticipation included protocol ineligibility, conflict of timing of surgery, miscellaneous logistical reasons, or patient's choice. POH administration was well tolerated and did not interfere with surgical management. The power to observe changes in candidate SEB was diminished by a 44% incidence of cases in which the index lesion was not present in the definitive surgical specimen. CONCLUSIONS: Preoperative POH exposure was safe and suitable for a more definitive phase II SEB study. Further investigations must overcome logistical obstacles to accrual, and they must focus on approaches to maximize tissue collection and to incorporate genomic analysis of target lesions.

Aged↗
PubMed2004

An academic health center cost analysis of screening mammography: creating a financially viable service.

BACKGROUND: The current study sought to determine the institutional financial impact of a screening mammography (SM) program in the context of an integrated cancer center. METHODS: Using administrative databases, 10,048 women were identified as receiving screening mammograms in fiscal year 1999 and the first one-half of fiscal year 2000. The utilization of breast care resources was followed for an average of 1208 days. The University of Michigan cost accounting system was then used to determine overall margin (revenues-total costs) and contribution margin (revenues-actual costs) of the SM program, as well as other breast care services. RESULTS: The percentage of variable costs to total costs for the SM program was 24%. The overall facility losses in the breast care line were $1.7 million with a positive contribution margin of $2.0 million. The annual yield of nonscreening/diagnostic mammographic procedures was 0.9%. All types of radiologic activity failed to cover their total costs, but did provide a positive contribution margin. Overall margins for surgery procedures were approximately even, and adjuvant medical and radiotherapy services were net positive. Modeling helped to identify overhead limits necessary to achieve margin targets associated with increased activity. CONCLUSIONS: The current study showed that SM programs are unlikely to succeed financially without careful selection of those screened to increase the yield of diagnostic and therapeutic procedures. Based on favorable contribution margins, SM programs were viable when viewed as incremental business.

Adult↗
PubMed2004

Circulating tumor cells, disease progression, and survival in metastatic breast cancer.

BACKGROUND: We tested the hypothesis that the level of circulating tumor cells can predict survival in metastatic breast cancer. METHODS: In a prospective, multicenter study, we tested 177 patients with measurable metastatic breast cancer for levels of circulating tumor cells both before the patients were to start a new line of treatment and at the first follow-up visit. The progression of the disease or the response to treatment was determined with the use of standard imaging studies at the participating centers. RESULTS: Outcomes were assessed according to levels of circulating tumor cells at baseline, before the patients started a new treatment for metastatic disease. Patients in a training set with levels of circulating tumor cells equal to or higher than 5 per 7.5 ml of whole blood, as compared with the group with fewer than 5 circulating tumor cells per 7.5 ml, had a shorter median progression-free survival (2.7 months vs. 7.0 months, P<0.001) and shorter overall survival (10.1 months vs. >18 months, P<0.001). At the first follow-up visit after the initiation of therapy, this difference between the groups persisted (progression-free survival, 2.1 months vs. 7.0 months; P<0.001; overall survival, 8.2 months vs. >18 months; P<0.001), and the reduced proportion of patients (from 49 percent to 30 percent) in the group with an unfavorable prognosis suggested that there was a benefit from therapy. The multivariate Cox proportional-hazards regression showed that, of all the variables in the statistical model, the levels of circulating tumor cells at baseline and at the first follow-up visit were the most significant predictors of progression-free and overall survival. CONCLUSIONS: The number of circulating tumor cells before treatment is an independent predictor of progression-free survival and overall survival in patients with metastatic breast cancer.

Breast Neoplasms↗
PubMed2003

Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine.

BACKGROUND: Tamoxifen, a selective estrogen receptor modulator (SERM), is converted to 4-hydroxy-tamoxifen and other active metabolites by cytochrome P450 (CYP) enzymes. Selective serotonin reuptake inhibitors (SSRIs), which are often prescribed to alleviate tamoxifen-associated hot flashes, can inhibit CYPs. In a prospective clinical trial, we tested the effects of coadministration of tamoxifen and the SSRI paroxetine, an inhibitor of CYP2D6, on tamoxifen metabolism. METHODS: Tamoxifen and its metabolites were measured in the plasma of 12 women of known CYP2D6 genotype with breast cancer who were taking adjuvant tamoxifen before and after 4 weeks of coadministered paroxetine. We assessed the inhibitory activity of pure tamoxifen metabolites in an estradiol-stimulated MCF7 cell proliferation assay. To determine which CYP isoforms were involved in the metabolism of tamoxifen to specific metabolites, we used CYP isoform-specific inhibitors. All statistical tests were two-sided. RESULTS: We separated, purified, and identified the metabolite 4-hydroxy-N-desmethyl-tamoxifen, which we named endoxifen. Plasma concentrations of endoxifen statistically significantly decreased from a mean of 12.4 ng/mL before paroxetine coadministration to 5.5 ng/mL afterward (difference = 6.9 ng/mL, 95% confidence interval [CI] = 2.7 to 11.2 ng/mL) (P =.004). Endoxifen concentrations decreased by 64% (95% CI = 39% to 89%) in women with a wild-type CYP2D6 genotype but by only 24% (95% CI = 23% to 71%) in women with a variant CYP2D6 genotype (P =.03). Endoxifen and 4-hydroxy-tamoxifen inhibited estradiol-stimulated MCF7 cell proliferation with equal potency. In vitro, troleandomycin, an inhibitor of CYP3A4, inhibited the demethylation of tamoxifen to N-desmethyl-tamoxifen by 78% (95% CI = 65% to 91%), and quinidine, an inhibitor of CYP2D6, reduced the subsequent hydroxylation of N-desmethyl-tamoxifen to endoxifen by 79% (95% CI = 50% to 108%). CONCLUSIONS: Endoxifen is an active tamoxifen metabolite that is generated via CYP3A4-mediated N-demethylation and CYP2D6-mediated hydroxylation. Coadministration of paroxetine decreased the plasma concentration of endoxifen. Our data suggest that CYP2D6 genotype and drug interactions should be considered in women treated with tamoxifen.

Adult↗
PubMed2003

Clinicopathologic features of metastasis in nonsentinel lymph nodes of breast carcinoma patients.

BACKGROUND: In breast carcinoma patients with a positive sentinel lymph node (SN), the value of complete axillary lymph node dissection has been questioned. Multiple published reports have attempted to identify clinicopathologic characteristics of the primary tumor and SN that are associated with an increased likelihood of positive nonsentinel lymph nodes (NSN). Because of differences in lymph node evaluation techniques and limited patient numbers in each study, the authors performed a meta-analysis to assess the regularity and relative strength of association between various characteristics and the risk of NSN metastasis. METHODS: A MEDLINE search identified 15 candidate studies, 11 of which met the criteria for analysis. General elements of the studies, the pathologic characteristics evaluated, and the results for selected characteristics were compared. Original data were abstracted from each study and used to calculate odds ratios. The Mantel-Haenszel common odds ratios were calculated to determine the relative strength of the associations. RESULTS: Despite methodologic differences, the correlation between positive NSNs and certain pathologic characteristics was found to be remarkably similar among studies. The 5 individual characteristics found to be associated with the highest likelihood of NSN metastasis are SN metastasis > 2 mm in size, extranodal extension in the SN, tumor size > 2 cm, > 1 positive SN, and lymphovascular invasion in the primary tumor. CONCLUSIONS: There is general concordance among studies regarding the association between pathologic characteristics and NSN metastasis in breast carcinoma patients with a positive SN. The pooled analysis identified those factors with the strongest associations that should be evaluated routinely in SN specimens and included in prospective databases for the development of a predictive model.

Adult↗