Daniel F Hayes

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

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Publications (383)3851.21 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the estrogen receptor-alpha (ER) gene, ESR1, have been identified in breast cancer metastases after progression on endocrine therapies. Due to limitations of metastatic biopsies, the reported frequency of ESR1 mutations may be underestimated. Here, we show a high frequency of ESR1 mutations using circulating plasma tumor DNA (ptDNA) from metastatic breast cancer patients. We retrospectively obtained plasma samples from eight patients with known ESR1 mutations and three patients with wild type ESR1 identified by next generation sequencing (NGS) of biopsied metastatic tissues. Three common ESR1 mutations were queried for using droplet digital polymerase chain reaction (ddPCR). In a prospective cohort, metastatic tissue and plasma were collected contemporaneously from eight ER-positive and four ER-negative patients. Tissue biopsies were sequenced by NGS and ptDNA ESR1 mutations were analyzed by ddPCR. In the retrospective cohort, all corresponding mutations were detected in ptDNA, with two patients harboring additional ESR1 mutations not present in their metastatic tissues. In the prospective cohort, three ER-positive patients did not have adequate tissue for NGS, and no ESR1 mutations were identified in tissue biopsies from the other nine patients. In contrast, ddPCR detected seven ptDNA ESR1 mutations in six of twelve patients (50%). We show that ESR1 mutations can occur at a high frequency and suggest that blood can be used to identify additional mutations not found by sequencing of a single metastatic lesion. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 08/2015; DOI:10.1158/1078-0432.CCR-15-0943 · 8.19 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):5489-5489. DOI:10.1158/1538-7445.AM2015-5489 · 9.28 Impact Factor
  • Daniel F Hayes
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    ABSTRACT: Adjuvant endocrine therapy (ET) reduces the odds of distant recurrence and mortality by nearly one-half in women with hormone receptor (HR) positive early stage breast cancer. While the risk of recurrence is lower for HR positive than negative patients during the first 5-7 years, HR positive patients suffer ongoing recurrences between 0.5 and 2% year over subsequent years. Extended adjuvant ET further reduces recurrence during this late phase of follow-up. ET is associated with post-menopausal side effects (hot flashes, sexual dysfunction, mood changes, and weight gain), and occasional major toxicities (thrombosis and endometrial cancer with tamoxifen; bone mineral loss and possibly heart disease with AIs) persist throughout therapy. Accurate and reliable estimates of the risk of recurrence after five years of ET for women with prior HR positive breast cancer would permit appropriate extended ET decisions. The risk of long-term relapse is related to lymph node status and size of tumor, but these are relatively crude. Several groups have investigated whether multi-parameter tumor biomarker tests might identify those patients whose risk of recurrence is so low that extended ET is not justified. These assays include IHC4, the 21-gene "OncotypeDX", the 12-gene "Endopredict," the PAM50, and the 2-gene "Breast Cancer Index (BCI)" assays. The clinical validity of all these tests for this use context have been established, with at least one paper for each that shows a statistically significant difference in risk of distant recurrence during the 5-10 years after the initial five years of adjuvant endocrine therapy. However, the stakes are high, and although each of these represents a "prospective retrospective" study, they require further validation in subsequent datasets before they should be considered to have "clinical utility" and are used to withhold potentially life-saving treatment. Perhaps more importantly, the clinical breast cancer community, and especially the patient, need to determine how low the risk of late recurrence needs to be to forego the toxicities and side effects of extended adjuvant ET. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Breast (Edinburgh, Scotland) 07/2015; DOI:10.1016/j.breast.2015.07.002 · 2.58 Impact Factor
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    ABSTRACT: Cancer pharmacogenetic studies use archival tumor samples as a DNA source when germline DNA is unavailable. Genotyping DNA from formalin-fixed paraffin embedded tumors (FFPE-T) may be inaccurate due to FFPE storage, genetic aberrations, and/or insufficient DNA extraction. Our objective was to assess the extent and source of genotyping inaccuracy from FFPE-T DNA and demonstrate analytical validity of FFPE-T genotyping of candidate single nucleotide polymorphisms (SNPs) for pharmacogenetic analyses. Cancer pharmacogenetics SNPs were genotyped by Sequenom MassARRAYs in DNA harvested from matched FFPE-T, FFPE lymph node (FFPE-LN), and whole blood leukocyte samples obtained from breast cancer patients. No- and discordant-call rates were calculated for each tissue type and SNP. Analytical validity was defined as any SNP with <5% discordance between FFPE-T and blood and <10% discordance plus no-calls. Matched samples from 114 patients were genotyped for 247 SNPs. No-call rate in FFPE-T was greater than FFPE-LN and blood (4.3% vs. 3.0% vs. 0.5%, p < 0.001). Discordant-call rate between FFPE-T and blood was very low, but greater than that between FFPE-LN and blood (1.1% vs. 0.3%, p < 0.001). Samples with heterozygous genotypes were more likely to be no- or discordantly-called in either tissue (p < 0.001). Analytical validity of FFPE-T genotyping was demonstrated for 218 (88%) SNPs. No- and discordant-call rates were below concerning thresholds, confirming that most SNPs can be accurately genotyped from FFPE-T on our Sequenom platform. FFPE-T is a viable DNA source for prospective-retrospective pharmacogenetic analyses of clinical trial cohorts. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
    Molecular oncology 07/2015; DOI:10.1016/j.molonc.2015.07.002 · 5.94 Impact Factor
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    ABSTRACT: To provide recommendations on the appropriate use of breast tumor biomarker assay results to guide decisions on systemic therapy for metastatic breast cancer. A literature search and prospectively defined study selection identified systematic reviews, meta-analyses, randomized controlled trials (RCTs), prospective-retrospective studies, and prospective comparative observational studies published from 2006 through September 2014. The literature search revealed 17 articles that met criteria for further review: 11 studies reporting discordances between primary tumors and metastases in expression of hormone receptors or human epidermal growth factor receptor 2 (HER2), one RCT that addressed the use of a biomarker to decide whether to change or continue a treatment regimen, and five prospective-retrospective studies that evaluated the clinical utility of biomarkers. In patients with accessible metastases, biopsy for confirmation of disease process and retesting of estrogen receptor, progesterone receptor, and HER2 status should be offered, but evidence is lacking to determine whether changing anticancer treatment on the basis of change in receptor status affects clinical outcomes. With discordance of results between primary and metastatic tissues, the Panel consensus is to use preferentially the estrogen receptor, progesterone receptor, and HER2 status of the metastasis to direct therapy if supported by the clinical scenario and patient's goals for care. Carcinoembryonic antigen, cancer antigen 15-3, and cancer antigen 27-29 may be used as adjunctive assessments, but not alone, to contribute to decisions regarding therapy. Recommendations for tumor rebiopsy and use of circulating tumor markers are based on clinical experience and Panel informal consensus in the absence of studies designed to evaluate the clinical utility of the markers. As such, it is also reasonable for clinicians to not use these markers as adjunctive assessments. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 07/2015; DOI:10.1200/JCO.2015.61.1459 · 18.43 Impact Factor
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    ABSTRACT: Cardiomyopathy is a known complication of anthracycline-based adjuvant chemotherapy and is more commonly reported in population-based studies of breast cancer survivors than in clinical trials. This study prospectively evaluated the prevalence of elevated cardiac biomarkers in unselected patients who had been treated with doxorubicin for early-stage breast cancer and the prevalence of reduced LVEF in patients with an elevated biomarker. All participants underwent an examination, symptom inventory, medical record review, and biomarker analysis for BNP, troponin, and plasma and urine NT-proBNP. Patients who had one or more elevated biomarkers were referred for echocardiogram; systolic dysfunction was defined as LVEF less than 55 %. Multivariable logistic regression was used to determine the associations between age, BMI, cumulative dose of doxorubicin, diabetes, hypertension, and left-sided radiation therapy and the risk of reduced LVEF. Among the 269 patients who underwent lab testing (mean age 56 years, mean time since completion of doxorubicin-based chemotherapy 6 years), 192 (72 %) had one or more elevated biomarker. Among the 166 patients who completed an echocardiogram, 11.5 % had a LVEF < 55 %. After adjusting for covariates known to affect cardiac function, multivariable logistic regression revealed plasma NT-proBNP to be the only measured cardiac biomarker associated with systolic dysfunction. There is a relationship between NT-proBNP and the frequency of reduced LVEF in women treated with doxorubicin for curative intent; further study of NT-proBNP as a potential biomarker for subclinical cardiac dysfunction after exposure to anthracyclines is warranted.
    Breast Cancer Research and Treatment 06/2015; DOI:10.1007/s10549-015-3454-8 · 4.20 Impact Factor
  • Cancer Research 05/2015; 75(9 Supplement):P6-08-50-P6-08-50. DOI:10.1158/1538-7445.SABCS14-P6-08-50 · 9.28 Impact Factor
  • Cancer Research 05/2015; 75(9 Supplement):P6-03-08-P6-03-08. DOI:10.1158/1538-7445.SABCS14-P6-03-08 · 9.28 Impact Factor
  • Cancer Research 05/2015; 75(9 Supplement):OT2-1-01-OT2-1-01. DOI:10.1158/1538-7445.SABCS14-OT2-1-01 · 9.28 Impact Factor
  • Cancer Research 05/2015; 75(9 Supplement):P3-11-16-P3-11-16. DOI:10.1158/1538-7445.SABCS14-P3-11-16 · 9.28 Impact Factor
  • Erin F Cobain · Daniel F Hayes
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    ABSTRACT: Breast cancer is a heterogeneous disease. While breast cancer mortality has dropped substantially over the past three decades due to early detection and adjuvant systemic therapy (AST), the risk of recurrence is highly dependent upon numerous factors including tumor size, involvement of regional lymph nodes, histologic grade, expression of hormone receptors (estrogen and progesterone), and human epidermal growth factor receptor 2 (HER2) amplification. We use these factors to determine which early breast cancer (EBC) patients should be treated with AST, including endocrine therapy (ET), chemotherapy, and HER2-directed treatments. While these factors aid in this determination, it remains challenging to identify those patients unlikely to benefit from adjuvant chemotherapy, resulting in over-treatment of patients. Given this dilemma, there has been great interest in the development of prognostic and predictive gene expression profiles. The most extensively studied profile, the 21-gene recurrence score (Oncotype Dx®), estimates 10-year risk of breast cancer recurrence in patients with estrogen receptor (ER)-positive, HER2-negative, node-negative EBC and is likely predictive of chemotherapy benefit. This assay has established analytic validity, clinical validity, and clinical utility for this patient group and, therefore, is indicated in this patient population to help inform decisions regarding administration of adjuvant chemotherapy. Several other assays may have utility in this clinical context or perhaps to identify patients who do not require extended adjuvant ET. These assays include the following: PAM 50 Risk of Recurrence (ROR) Score (Prosigna™), Breast Cancer Index, and EndoPredict®.
    Current Treatment Options in Oncology 05/2015; 16(5):340. DOI:10.1007/s11864-015-0340-x · 3.24 Impact Factor
  • Daniel F Hayes · Anne F Schott
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    ABSTRACT: Neoadjuvant chemotherapy has several appealing potential benefits compared with classic adjuvant chemotherapy. Of these, the only proven benefit is to facilitate the surgical approach, either by converting an inoperable cancer to one that is operable, or by converting a patient who is felt to be a candidate for mastectomy to one who might be treated successfully with breast conserving therapy. Randomized trials comparing neoadjuvant chemotherapy with postoperative chemotherapy have failed to demonstrate prolongation of overall survival. The benefits of monitoring apparent response during neoadjuvant chemotherapy have not been proven. Conduct of phase II drug development trials in the neoadjuvant setting may be advantageous compared with performing such trials in the metastatic setting. However, such trials raise concerns that are not unavoidable but need to be addressed. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    JNCI Monographs 05/2015; 2015(51):36-9. DOI:10.1093/jncimonographs/lgv004
  • Anne F Schott · Charles M Perou · Daniel F Hayes
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    ABSTRACT: This is an exciting time to be in cancer medicine. New technologies, such as next-generation sequencing (NGS), have increased our understanding of the molecular aberrations that define cancer. This, in turn, has led to the identification of cancer-specific molecular targets and potential drugs to confront these targets. As these new technologies move toward clinical application, a new vocabulary of "genome medicine" has been introduced to the field of oncology. Unfortunately, unclear or incorrect use of the new terminology has led to semantic misunderstandings that impair communication between the basic research and clinical practice arenas. These misunderstandings have led to assumptions regarding the clinical application of NGS and other technologies that may or may not be true. For example, some organizations that perform NGS testing on clinical samples have endorsed use of the results of such tests to direct specific therapies based on laboratory hypotheses, but without clinical testing of the hypotheses to show utility for these potential predictive claims. Here, we review some simple, and hopefully universally acceptable, definitions, concepts, and trial designs so that laboratory researchers and clinicians can move closer toward speaking the same language. Cancer Res; 75(10); 1-6. ©2015 AACR. ©2015 American Association for Cancer Research.
    Cancer Research 04/2015; 75(10). DOI:10.1158/0008-5472.CAN-15-0174 · 9.28 Impact Factor
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    ABSTRACT: Biomarkers are playing increasingly important roles in the detection and management of patients with cancer. Despite an enormous number of publications on cancer biomarkers, few of these biomarkers are in widespread clinical use. In this review, we discuss the key steps in advancing a newly discovered cancer candidate biomarker from pilot studies to clinical application. Four main steps are necessary for a biomarker to reach the clinic: analytical validation of the biomarker assay, clinical validation of the biomarker test, demonstration of clinical value from performance of the biomarker test, and regulatory approval. In addition to these 4 steps, all biomarker studies should be reported in a detailed and transparent manner, using previously published checklists and guidelines. Finally, all biomarker studies relating to demonstration of clinical value should be registered before initiation of the study. Application of the methodology outlined above should result in a more efficient and effective approach to the development of cancer biomarkers as well as the reporting of cancer biomarker studies. With rigorous application, all stakeholders, and especially patients, would be expected to benefit. © 2015 American Association for Clinical Chemistry.
    Clinical Chemistry 04/2015; 61(6). DOI:10.1373/clinchem.2015.239863 · 7.77 Impact Factor
  • Journal of Clinical Oncology 04/2015; 33(14). DOI:10.1200/JCO.2014.60.5519 · 18.43 Impact Factor
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    ABSTRACT: Circulating Tumor cells (CTC) are prognostic in metastatic breast cancer (MBC). We tested whether EpCAM based capture system (CellSearch®) is effective in patients with triple negative (TN) MBC, and whether CTC-apoptosis and clustering enhances the prognostic role of CTC. CTC enumeration and apoptosis was determined using the CXC CellSearch® kit at baseline and days 15 and 29 in blood drawn from TN MBC patients who participated in a prospective randomized phase II trial of nanoparticle albumin-bound paclitaxel (nab-PAC) with or without tigatuzumab (TIG). Association between levels of CTC and patient outcomes was assessed using logistic regression, Kaplan Meier curves, and Cox proportional hazards modeling. Nineteen of 52 (36.5%), 14/52 (26.9%), and 13/49 (26.5%) patients who were evaluable had elevated CTC (≥5CTC/7.5 ml WB) at baseline, days 15 and 29, respectively. Patients with elevated vs. not elevated CTC at each time point had worse progression free survival (PFS) (p=0.005, 0.0003, 0.0002, respectively). The odds of clinical benefit response for those who had elevated vs. low CTC at baseline and days 15 and 29 were 0.25 (95% CI: 0.08-0.84, p=0.024), 0.19 (95% CI: 0.05-0.17, p=0.014), and 0.06 (95% CI: 0.01-0.33, p=0.001), respectively. There was no apparent prognostic effect comparing CTC-apoptosis vs. non-apoptosis. Presence of CTC-cluster at day 15, and day 29 was associated with shorter PFS. CTC were detected using CellSearch® assay in approximately one-third of TN MBC patients. Elevated CTC at baseline and days 15 and 29 were prognostic, and reductions in CTC levels reflected response. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 03/2015; 21(12). DOI:10.1158/1078-0432.CCR-14-2781 · 8.19 Impact Factor
  • Journal of Clinical Oncology 03/2015; 33(11). DOI:10.1200/JCO.2014.59.7559 · 18.43 Impact Factor
  • Source
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    ABSTRACT: Although an important biomarker in breast cancer, Ki67 lacks scoring standardization, which has limited its clinical use. Our previous study found variability when laboratories used their own scoring methods on centrally stained tissue microarray slides. In this current study, 16 laboratories from eight countries calibrated to a specific Ki67 scoring method and then scored 50 centrally MIB-1 stained tissue microarray cases. Simple instructions prescribed scoring pattern and staining thresholds for determination of the percentage of stained tumor cells. To calibrate, laboratories scored 18 'training' and 'test' web-based images. Software tracked object selection and scoring. Success for the calibration was prespecified as Root Mean Square Error of scores compared with reference <0.6 and Maximum Absolute Deviation from reference <1.0 (log2-transformed data). Prespecified success criteria for tissue microarray scoring required intraclass correlation significantly >0.70 but aiming for observed intraclass correlation ≥0.90. Laboratory performance showed non-significant but promising trends of improvement through the calibration exercise (mean Root Mean Square Error decreased from 0.6 to 0.4, Maximum Absolute Deviation from 1.6 to 0.9; paired t-test: P=0.07 for Root Mean Square Error, 0.06 for Maximum Absolute Deviation). For tissue microarray scoring, the intraclass correlation estimate was 0.94 (95% credible interval: 0.90-0.97), markedly and significantly >0.70, the prespecified minimum target for success. Some discrepancies persisted, including around clinically relevant cutoffs. After calibrating to a common scoring method via a web-based tool, laboratories can achieve high inter-laboratory reproducibility in Ki67 scoring on centrally stained tissue microarray slides. Although these data are potentially encouraging, suggesting that it may be possible to standardize scoring of Ki67 among pathology laboratories, clinically important discrepancies persist. Before this biomarker could be recommended for clinical use, future research will need to extend this approach to biopsies and whole sections, account for staining variability, and link to outcomes.Modern Pathology advance online publication, 20 February 2015; doi:10.1038/modpathol.2015.38.
    Modern Pathology 02/2015; 28(6). DOI:10.1038/modpathol.2015.38 · 6.36 Impact Factor
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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; 21(11). DOI:10.1158/1078-0432.CCR-14-1913 · 8.19 Impact Factor
  • Daniel F Hayes
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    ABSTRACT: A tumor biomarker is a molecular or process-based change that reflects the status of an underlying malignancy. A tumor biomarker may be identified and measured by one or more assays, or tests, for the biomarker. Increasingly, tumor biomarker tests are being used to drive patient management, either by identifying patients who do not require any, or any further, treatment, or by identifying patients whose tumors are so unlikely to respond to a given type of treatment that it will cause more harm than good. A tumor biomarker assay should only be used to guide management if it has analytical validity, meaning that it is accurate, reproducible, and reliable, and if it has been shown to have clinical utility. The latter implies that high levels of evidence are available that demonstrate that application of the tumor biomarker test for a given use context results in better outcomes, or similar outcomes with less cost, than if the assay were not applied. Use contexts include risk categorization, screening, differential diagnosis, prognosis, prediction of therapeutic activity or monitoring disease course. Very few tumor biomarker tests have passed these high bars for routine clinical application. However, if tumor biomarker tests are going to be used to drive patient care, than an understanding, and careful assessment, of these concepts are essential, since "A Bad Tumor Biomarker Test Is as Bad as a Bad Drug." Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
    Molecular Oncology 10/2014; 9(5). DOI:10.1016/j.molonc.2014.10.004 · 5.94 Impact Factor

Publication Stats

24k Citations
3,851.21 Total Impact Points

Institutions

  • 2002–2015
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2001–2014
    • University of Michigan
      • • Department of Internal Medicine
      • • Division of Hematology and Oncology
      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
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
  • 2010
    • University of Utah
      Salt Lake City, Utah, United States
    • University of Milan
      Milano, Lombardy, Italy
  • 2004–2010
    • Indiana University-Purdue University Indianapolis
      • • Department of Medicine
      • • Division of Clinical Pharmacology
      Indianapolis, Indiana, United States
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 2009
    • Brigham and Women's Hospital
      • Department of Pathology
      Boston, MA, United States
    • National Cancer Institute (USA)
      • Biometrics Research Branch
      Maryland, United States
  • 2007
    • Johns Hopkins University
      Baltimore, Maryland, United States
    • Fred Hutchinson Cancer Research Center
      Seattle, Washington, United States
  • 2005–2007
    • Duke University
      Durham, North Carolina, United States
    • Stanford Medicine
      • Stanford Emergency Department (Hospitals and Clinics)
      Stanford, California, United States
  • 2002–2007
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
  • 1998–2007
    • Georgetown University
      • Lombardi Cancer Center
      Washington, Washington, D.C., United States
  • 2006
    • Washington University in St. Louis
      San Luis, Missouri, United States
    • Johns Hopkins Medicine
      • Department of Medicine
      Baltimore, Maryland, United States
  • 1986–2001
    • Dana-Farber Cancer Institute
      • • Lank Center for Genitourinary Oncology
      • • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 1996
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States
  • 1990–1993
    • Harvard Medical School
      • • Department of Pathology
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 1987
    • University of Massachusetts Boston
      Boston, Massachusetts, United States