Daniel F Hayes

Concordia University–Ann Arbor, Ann Arbor, Michigan, United States

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Publications (324)3052.88 Total impact

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    ABSTRACT: Purpose: Endocrine therapy (ET) fails to induce a response in one-half of patients with hormone receptor (HR) positive metastatic breast cancer (MBC) and almost all will eventually become refractory to ET. Circulating Tumor Cells (CTC) are associated with worse prognosis in MBC patients, but enumeration alone is insufficient to predict the absolute odds of benefit from any therapy, including ET. We developed a multi-parameter CTC-Endocrine Therapy Index (CTC-ETI), which we hypothesize may predict resistance to ET in patients with HR positive MBC. Experimental Design: The CTC-ETI combines enumeration and CTC expression of four markers: estrogen receptor (ER), B-cell lymphoma 2 (BCL-2), Human Epidermal Growth Factor Receptor 2 (HER2), and Ki67. The CellSearch® System and reagents were used to capture CTC and measure protein expression by immunofluorescent staining on CTC. Results: The feasibility of determining CTC-ETI was initially established in vitro and then in a prospective single-institution pilot study in MBC patients. CTC-ETI was successfully determined in 44/50 (88%) patients. Eighteen (41%), 9 (20%), and 17 (39%) patients had low, intermediate, and high CTC-ETI scores, respectively. Inter-observer concordance of CTC-ETI determination was 94-95% (Kappa statistic 0.90-0.91). Inter- and cell-to-cell intra-patient heterogeneity of expression of each of the CTC-markers was observed. CTC biomarker expression was discordant from both primary and metastatic tissue. Conclusions: CTC expression of ER, BCL-2, HER2, and Ki67 can be reproducibly measured with high analytical validity using the CellSearch® System. The clinical implications of CTC-ETI, and of the heterogeneity of CTC-biomarker expression, are being evaluated in an ongoing prospective trial.
    Clinical Cancer Research 11/2014; · 8.19 Impact Factor
  • N Lynn Henry, Anne F Schott, Daniel F Hayes
    Journal of Clinical Oncology 09/2014; · 17.88 Impact Factor
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    ABSTRACT: The aim of this study is to use functional magnetic resonance imaging (fMRI) to prospectively examine pre-treatment predictors of post-treatment fatigue and cognitive dysfunction in women treated with adjuvant chemotherapy for breast cancer. Fatigue and cognitive dysfunction often co-occur in women treated for breast cancer. We hypothesized that pre-treatment factors, unrelated to chemotherapy per se, might increase vulnerability to post-treatment fatigue and cognitive dysfunction. Patients treated with (n = 28) or without chemotherapy (n = 37) and healthy controls (n = 32) were scanned coincident with pre- and one-month post-chemotherapy during a verbal working memory task (VWMT) and assessed for fatigue, worry, and cognitive dysfunction. fMRI activity measures in the frontoparietal executive network were used in multiple linear regression to predict post-treatment fatigue and cognitive function. The chemotherapy group reported greater pre-treatment fatigue than controls and showed compromised neural response, characterized by higher spatial variance in executive network activity, than the non-chemotherapy group. Also, the chemotherapy group reported greater post-treatment fatigue than the other groups. Linear regression indicated that pre-treatment spatial variance in executive network activation predicted post-treatment fatigue severity and cognitive complaints, while treatment group, age, hemoglobin, worry, and mean executive network activity levels did not predict these outcomes. Pre-treatment neural inefficiency (indexed by high spatial variance) in the executive network, which supports attention and working memory, was a better predictor of post-treatment cognitive and fatigue complaints than exposure to chemotherapy per se. This executive network compromise could be a pre-treatment neuromarker of risk, indicating patients most likely to benefit from early intervention for fatigue and cognitive dysfunction.
    Breast Cancer Research and Treatment 08/2014; · 4.47 Impact Factor
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    ABSTRACT: Increased circulating tumor cells (CTCs; five or more CTCs per 7.5 mL of whole blood) are associated with poor prognosis in metastatic breast cancer (MBC). A randomized trial of patients with persistent increase in CTCs tested whether changing chemotherapy after one cycle of first-line chemotherapy would improve the primary outcome of overall survival (OS).
    Journal of Clinical Oncology 06/2014; · 17.88 Impact Factor
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    ABSTRACT: BACKGROUND Aromatase inhibitor (AI) therapy results in substantial survival benefits for patients with hormone receptor-positive breast cancer. The rates of poor adherence and discontinuation of AI therapy are high, primarily because of treatment-related toxicities like musculoskeletal pain. Although pain-related symptoms may worsen during AI therapy, the authors hypothesized that nonpersistence with AI therapy was associated with symptoms that were present before treatment initiation.METHODS Postmenopausal women initiating AI therapy who were enrolled in a prospective clinical trial completed questionnaires at baseline to assess sleep, fatigue, mood, and pain. Reasons for treatment discontinuation during the first year of treatment were recorded. Associations between baseline patient-reported symptoms and treatment discontinuation because of toxicity were identified using logistic regression.RESULTSFour hundred forty-nine patients were evaluable. The odds of treatment discontinuation were higher in patients who reported a greater number of symptoms before AI initiation. Baseline poor sleep quality was associated with early treatment discontinuation, with an odds ratio (OR) of 1.91 (95% confidence interval [CI], 1.26-2.89; P = .002). Baseline presence of tired feeling and forgetfulness had similar ORs for discontinuation (tired feeling: OR, 1.76; 95% CI, 1.15-2.67; P = .009; forgetfulness: OR, 1.66; 95% CI, 1.11-2.48; P = .015). An increasing total number of baseline symptoms was associated with an increased likelihood of treatment discontinuation, with an OR of 1.89 (95% CI, 1.20-2.96; P = .006) for 3 to 5 symptoms versus 0 to 2 symptoms.CONCLUSIONS Symptom clusters in breast cancer survivors that are present before the initiation of adjuvant AI therapy may have a negative impact on a patient's persistence with therapy. Interventions to manage these symptoms may improve breast cancer outcomes and quality of life. Cancer 2014. © 2014 American Cancer Society.
    Cancer 05/2014; · 5.20 Impact Factor
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    Journal of Clinical Oncology 04/2014; · 17.88 Impact Factor
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    ABSTRACT: Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. The NCCN Guidelines specific to management of large clinical stage II and III tumors are discussed in this article. These guidelines are the work of the members of the NCCN Breast Cancer Panel. Expert medical clinical judgment is required to apply these guidelines in the context of an individual patient to provide optimal care. Although not stated at every decision point of the guidelines, patient participation in prospective clinical trials is the preferred option of treatment for all stages of breast cancer.
    Journal of the National Comprehensive Cancer Network: JNCCN 04/2014; 12(4):542-90. · 4.24 Impact Factor
  • Cancer Research 03/2014; 73(24 Supplement):P1-04-01-P1-04-01. · 9.28 Impact Factor
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    ABSTRACT: Evidence-based guidelines for long-term follow-up of early-stage breast cancer patients developed by oncology societies in the United States and Europe recommend that breast cancer survivors undergo regular evaluation with history and physical examination, as well as annual mammography. Routine blood tests, circulating tumor markers, and/or surveillance imaging studies beyond mammography are not recommended in the absence of concerning symptoms or physical examination findings because of lack of supportive clinical evidence. Despite these guidelines, studies have shown that 20% to 40% of oncologists assess serum tumor markers as part of routine monitoring of early-stage breast cancer patients. As part of efforts to both address the financial challenges confronting the health-care system and optimize patient outcomes, the American Society of Clinical Oncology's Cost of Care Task Force identified adherence to breast cancer surveillance guidelines as an opportunity to improve care and reduce cost. However, these recommendations are based on trials done in an era of outdated technology and limited therapeutic options. It is possible that recent improvements in diagnostics and treatments could make earlier detection of recurrent disease important for improving both survival and quality of life outcomes. Research is necessary to further inform optimal breast cancer follow-up strategies, which could impact these recommendations. At this time, outside of well-conducted clinical trials, there is no role for ordering routine serial blood or imaging tests in monitoring for recurrence in early-stage breast cancer patients.
    CancerSpectrum Knowledge Environment 03/2014; · 14.07 Impact Factor
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    ABSTRACT: Aromatase inhibitors (AI), which are used to treat breast cancer, inhibit estrogen production in postmenopausal women. AI-associated musculoskeletal symptoms (AIMSS) occur in approximately half of treated women, and lead to treatment discontinuation in 20-30%. The etiology may be due in part to estrogen deprivation. In premenopausal women, lower estrogen levels have been associated with increased pain, as well as with impairment of descending pain inhibitory pathways, which may be a risk factor for developing chronic pain. We prospectively tested whether AI-induced estrogen deprivation alters pain sensitivity, thereby increasing the risk of developing AIMSS. Fifty postmenopausal breast cancer patients underwent pressure pain testing and conditioned pain modulation (CPM) assessment prior to AI initiation and after 3 and 6 months. At baseline, 26 of 40 (65%) assessed patients demonstrated impaired CPM, which was greater in those who had previously received chemotherapy (p=0.006). No statistically significant change in pressure pain threshold or CPM was identified following estrogen deprivation. In addition, there was no association with either measure of pain sensitivity and change in patient-reported pain with AI therapy. AIMSS are not likely due to decreased pain threshold or impaired CPM prior to treatment initiation, or to effects of estrogen depletion on pain sensitivity. Clinicaltrials.gov NCT01814397. This article presents our findings of the effect of estrogen deprivation on objective measures of pain sensitivity. In postmenopausal women, medication-induced estrogen depletion did not result in an identifiable change in pressure pain threshold or conditioned pain modulation. Impaired conditioned pain modulation may be associated with chemotherapy.
    The journal of pain: official journal of the American Pain Society 01/2014; · 4.22 Impact Factor
  • Costanza Paoletti, Daniel F Hayes
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    ABSTRACT: Tumor biomarker tests are critical to implementation of personalized medicine for patients at risk for or affected by breast cancer. A tumor biomarker test must have high analytical validity and clinical utility to be used to guide clinical care in standard practice. Few tumor biomarkers meet these high standards. These include germline DNA single-nucleotide polymorphisms in the BRCA1 and -2 genes to determine high risk in unaffected women, selected tissue-based markers to determine prognosis and predict benefit from therapy, and circulating MUC1, CEA and perhaps tumor cells to monitor patients with metastatic disease. Efforts to discover biomarkers that predict therapeutic toxicity are promising but not yet successful. Further research is needed to enhance the number of tumor biomarker tests so that patients with breast cancer can get the correct treatment at the appropriate time.
    Annual review of medicine 01/2014; 65:95-110. · 9.94 Impact Factor
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    ABSTRACT: Personalized medicine is increasingly being employed across many areas of clinical practice, as genes associated with specific diseases are discovered and targeted therapies are developed. Mobile apps are also beginning to be used in medicine with the aim of providing a personalized approach to disease management. In some areas of medicine, patient-tailored risk prediction and treatment are applied routinely in the clinic, whereas in other fields, more work is required to translate scientific advances into individualized treatment. In this forum article, we asked specialists in oncology, neurology, endocrinology and mobile health technology to discuss where we are in terms of personalized medicine, and address their visions for the future and the challenges that remain in their respective fields.
    BMC Medicine 01/2014; 12(1):37. · 7.28 Impact Factor
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    ABSTRACT: Reproductive-aged women frequently receive both chemotherapy and endocrine therapy as part of their treatment regimen for early stage hormone receptor-positive breast cancer. Chemotherapy results in transient or permanent ovarian failure in the majority of women. The difficulty in determining which patients will recover ovarian function has implications for adjuvant endocrine therapy decision making. We hypothesized that pretreatment serum anti-Müllerian hormone (AMH) and inhibin B concentrations would predict for ovarian function following chemotherapy.Methods.Pre- and perimenopausal women aged 25-50 years with newly diagnosed breast cancer were enrolled. Subjects underwent phlebotomy for assessment of serum AMH, inhibin B, follicle-stimulating hormone, and estradiol prior to chemotherapy and 1 month and 1 year following completion of treatment. Associations among hormone concentrations, clinical factors, and biochemically assessed ovarian function were assessed.Results.Twenty-seven subjects were evaluable for the primary endpoint. Median age was 41. Twenty subjects (74.1%) experienced recovery of ovarian function within 18 months. Of the 26 evaluable subjects assessed prior to chemotherapy, 19 (73.1%) had detectable serum concentrations of AMH. The positive predictive value of a detectable baseline serum AMH concentration for recovery of ovarian function was 94.7%, and the negative predictive value was 85.7%. On univariate analysis, younger age and detectable serum AMH concentration at chemotherapy initiation were predictive of increased likelihood of recovery of ovarian function.Conclusion.Prechemotherapy assessment of serum AMH may be useful for predicting postchemotherapy ovarian function. This finding has implications for decision making about adjuvant endocrine therapy in premenopausal women treated with chemotherapy.
    The Oncologist 12/2013; · 4.54 Impact Factor
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    Archives of pathology & laboratory medicine 11/2013; 138(5). · 2.88 Impact Factor
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    ABSTRACT: In breast cancer, immunohistochemical assessment of proliferation using the marker Ki67 has potential use in both research and clinical management. However, lack of consistency across laboratories has limited Ki67's value. A working group was assembled to devise a strategy to harmonize Ki67 analysis and increase scoring concordance. Toward that goal, we conducted a Ki67 reproducibility study. Eight laboratories received 100 breast cancer cases arranged into 1-mm core tissue microarrays-one set stained by the participating laboratory and one set stained by the central laboratory, both using antibody MIB-1. Each laboratory scored Ki67 as percentage of positively stained invasive tumor cells using its own method. Six laboratories repeated scoring of 50 locally stained cases on 3 different days. Sources of variation were analyzed using random effects models with log2-transformed measurements. Reproducibility was quantified by intraclass correlation coefficient (ICC), and the approximate two-sided 95% confidence intervals (CIs) for the true intraclass correlation coefficients in these experiments were provided. Intralaboratory reproducibility was high (ICC = 0.94; 95% CI = 0.93 to 0.97). Interlaboratory reproducibility was only moderate (central staining: ICC = 0.71, 95% CI = 0.47 to 0.78; local staining: ICC = 0.59, 95% CI = 0.37 to 0.68). Geometric mean of Ki67 values for each laboratory across the 100 cases ranged 7.1% to 23.9% with central staining and 6.1% to 30.1% with local staining. Factors contributing to interlaboratory discordance included tumor region selection, counting method, and subjective assessment of staining positivity. Formal counting methods gave more consistent results than visual estimation. Substantial variability in Ki67 scoring was observed among some of the world's most experienced laboratories. Ki67 values and cutoffs for clinical decision-making cannot be transferred between laboratories without standardizing scoring methodology because analytical validity is limited.
    CancerSpectrum Knowledge Environment 11/2013; · 14.07 Impact Factor
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    ABSTRACT: Breast cancer is the most prevalent cancer in women, and over two-thirds of cases express estrogen receptor-α (ER-α, encoded by ESR1). Through a prospective clinical sequencing program for advanced cancers, we enrolled 11 patients with ER-positive metastatic breast cancer. Whole-exome and transcriptome analysis showed that six cases harbored mutations of ESR1 affecting its ligand-binding domain (LBD), all of whom had been treated with anti-estrogens and estrogen deprivation therapies. A survey of The Cancer Genome Atlas (TCGA) identified four endometrial cancers with similar mutations of ESR1. The five new LBD-localized ESR1 mutations identified here (encoding p.Leu536Gln, p.Tyr537Ser, p.Tyr537Cys, p.Tyr537Asn and p.Asp538Gly) were shown to result in constitutive activity and continued responsiveness to anti-estrogen therapies in vitro. Taken together, these studies suggest that activating mutations in ESR1 are a key mechanism in acquired endocrine resistance in breast cancer therapy.
    Nature Genetics 11/2013; · 29.65 Impact Factor
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    ABSTRACT: Circulating tumor cells (CTCs) are shed from the primary tumor into the peripheral blood. CTCs are emerging as important biomarkers with high clinical relevance. Enumeration of CTCs may have several clinical uses, including determination of prognosis in patients with established malignancy, or even detection of previously undiagnosed cancer. However, due to the limitation of sensitivity and specificity of current technologies for CTC isolation, the full potential of CTCs has yet to be realized. Emerging microfluidic technologies are promising for isolating CTCs with a high yield; however, these platforms often have three-dimensional structures, thus lacking the advantages of traditional planar surface and limiting further characterization and expansion of cells on the chip. Here we describe a new approach to more effectively isolate CTCs incorporating the nanomaterial, graphene oxide (GO). Using self-assembly of GO on a patterned gold surface, we create islands of nano-arms for sensitive CTC capture without the aid of three dimensional posts or structures. The capture is truly planar and we demonstrate the isolation of cells with high sensitivity even at low frequency of target cells (75.22% ±29.46 at 5 cells/mL spiked in blood). This 2D planar GO-chip provides a maximum recovery rate of 95% and a stable mean capture efficiency of 82% up to 3 mL/hr sample processing rate. The cells are specifically captured on the planar islands of nano-arms and are able to proliferate after capture when placed in culture conditions in the chip. We further show that the GO-chip is able to capture CTCs from blood samples collected from pancreatic, breast and lung cancer patients. In summary, we present here a novel integrated nano microfluidic technology using GO for sensitive planar capture of CTCs.
    13 AIChE Annual Meeting; 11/2013
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    ABSTRACT: Background:Change in breast density may predict outcome of women receiving adjuvant hormone therapy for breast cancer. We performed a prospective clinical trial to evaluate the impact of inherited variants in genes involved in oestrogen metabolism and signalling on change in mammographic percent density (MPD) with aromatase inhibitor (AI) therapy.Methods:Postmenopausal women with breast cancer who were initiating adjuvant AI therapy were enrolled onto a multicentre, randomised clinical trial of exemestane vs letrozole, designed to identify associations between AI-induced change in MPD and single-nucleotide polymorphisms in candidate genes. Subjects underwent unilateral craniocaudal mammography before and following 24 months of treatment.Results:Of the 503 enrolled subjects, 259 had both paired mammograms at baseline and following 24 months of treatment and evaluable DNA. We observed a statistically significant decrease in mean MPD from 17.1 to 15.1% (P<0.001), more pronounced in women with baseline MPD 20%. No AI-specific difference in change in MPD was identified. No significant associations between change in MPD and inherited genetic variants were observed.Conclusion:Subjects with higher baseline MPD had a greater average decrease in MPD with AI therapy. There does not appear to be a substantial effect of inherited variants in biologically selected candidate genes.British Journal of Cancer advance online publication, 1 October 2013; doi:10.1038/bjc.2013.587 www.bjcancer.com.
    British Journal of Cancer 10/2013; · 5.08 Impact Factor
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    ABSTRACT: The spread of cancer throughout the body is driven by circulating tumour cells (CTCs). These cells detach from the primary tumour and move from the bloodstream to a new site of subsequent tumour growth. They also carry information about the primary tumour and have the potential to be valuable biomarkers for disease diagnosis and progression, and for the molecular characterization of certain biological properties of the tumour. However, the limited sensitivity and specificity of current methods for measuring and studying these cells in patient blood samples prevents the realization of their full clinical potential. The use of microfluidic devices is a promising method for isolating CTCs. However, the devices are reliant on three-dimensional structures, which limits further characterization and expansion of cells on the chip. Here we demonstrate an effective approach to isolating CTCs from blood samples of pancreatic, breast and lung cancer patients, by using functionalized graphene oxide nanosheets on a patterned gold surface. CTCs were captured with high sensitivity at a low concentration of target cells (73 ± 32.4% at 3-5 cells per ml blood).
    Nature Nanotechnology 09/2013; · 31.17 Impact Factor

Publication Stats

19k Citations
3,052.88 Total Impact Points


  • 2001–2014
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • Washington DC VA Medical Center
      Washington, Washington, D.C., United States
  • 2012
    • American Society of Clinical Oncology
      Alexandria, Virginia, United States
  • 2009–2012
    • National Cancer Institute (USA)
      • Biometrics Research Branch
      Maryland, United States
    • University of Sydney
      • School of Public Health
      Sydney, New South Wales, Australia
    • University Center Rochester
      Rochester, Minnesota, United States
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • Loyola University Medical Center
      Maywood, Illinois, United States
    • Brigham and Women's Hospital
      • Department of Pathology
      Boston, MA, United States
  • 2011
    • Saint Barnabas Medical Center
      Livingston, New Jersey, United States
    • Breakthrough Breast Cancer
      Londinium, England, United Kingdom
  • 2009–2011
    • Roswell Park Cancer Institute
      Buffalo, New York, United States
  • 2005–2011
    • Indiana University-Purdue University Indianapolis
      • Department of Medicine
      Indianapolis, IN, United States
    • Stanford Medicine
      • Stanford Emergency Department (Hospitals and Clinics)
      Stanford, California, United States
    • University of North Carolina at Chapel Hill
      • Lineberger Comprehensive Cancer Center
      Chapel Hill, NC, United States
  • 2002–2011
    • University of Michigan
      • • Comprehensive Cancer Center
      • • Department of Internal Medicine
      • • Division of Hematology and Oncology
      • • Medical School
      Ann Arbor, MI, United States
  • 2010
    • University of Utah
      Salt Lake City, Utah, United States
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 1989–2010
    • University of Miami Miller School of Medicine
      • Division of Hospital Medicine
      Miami, FL, United States
  • 2006–2009
    • Johns Hopkins Medicine
      • Department of Medicine
      Baltimore, Maryland, United States
  • 2007
    • Fred Hutchinson Cancer Research Center
      Seattle, Washington, United States
  • 1997–2007
    • Georgetown University
      • • Lombardi Cancer Center
      • • Department of Oncology
      • • Department of Medicine
      Washington, Washington, D.C., United States
  • 2004
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 2000–2002
    • North Shore Medical Center
      Salem, Massachusetts, United States
  • 1986–1999
    • Dana-Farber Cancer Institute
      • • Department of Biostatistics and Computational Biology
      • • Department of Radiation Oncology
      • • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 1993–1996
    • Beth Israel Deaconess Medical Center
      • Department of Radiation Oncology
      Boston, Massachusetts, United States
  • 1990–1993
    • Harvard Medical School
      • • Department of Pathology
      • • Department of Radiation Oncology
      Boston, Massachusetts, United States