Michael Kelley

Overview:

1.     A major theme throughout my career has been the biology of and improving outcomes for patients with lung cancer.  Early publications examined the relationship between specific genetic alterations in lung cancer and clinically relevant applications including differential drug sensitivity, differentiation of metastases from second primary cancers, and application of patient-specific mutations as epitopes for immunotherapy.  Correlation of alteration of p16 with drug sensitivity led to identification of a class of CDK4 inhibitor. I served as the primary investigator or co-investigator in all of these studies.  I led a study that demonstrated that tubulin mutations are uncommon in lung cancer and described the artifactual detection of pseudogenes as the origin of a prior report claiming association of tubulin mutation with taxane sensitivity, thus correcting the scientific record. 

2.   A second area of continuing interest in lung cancer is the conduct of therapeutic and prevention clinical trials.  These trials have primarily been translation of hypotheses derived primarily from laboratory-based biological observations including the GRP autocrine growth factor in small cell lung cancer, a phase I study of a pulmonary toxin in non-small cell lung cancer, mutation-specific immunotherapy, and a putative chemopreventive agent for smokers.  More recently, I have been an active member of the Respiratory Committee of CALGB/Alliance including serving as principal investigator on a trial testing the addition of irinotecan to treatment of patients with small cell lung cancer. 

3.  Through my clinical practice, I identified a large family with the May-Hegglin anomaly, an autosomal dominant platelet condition characterized as thrombocytopenia, leukocyte inclusions, and giant platelets.  While the condition had been described in the early 1900s, the genetic basis was unknown.  I conceptualized and led a project to identify the underlying molecular basis of this frequently misdiagnosed disorder through classical genetics.  I then extended that observation to related genetic conditions (now known as MYH9-assocaited disorders) characterized by varying degrees of hematological abnormalities, hearing loss and renal disease.  Analysis of the spectrum of observed mutations and phenotypes resulted in identification of a genotype-phenotype association for the most medically significant aspects of the disorders.  Working with Dan Kiehart’s lab, we described the effect of commonly observed mutations of MYH9 on assembly of non-muscle myosin.  An animal model of the most common MYH9 mutation was created in my lab and demonstrated hematological abnormalities similar to those found in humans. 

4.  I described genetic linkage for a rare familial cancer syndrome characterized by very high penetrance of chordoma.  Subsequent linkage analysis resolved a phenotype mis-assignment and resulted in identification of germline gene duplication of the T-box gene, Brachyury in about half of affected families.  I then confirmed another groups report that a common coding region SNP of the Brachyury gene as well as additional genetic variants are associated with an increased risk for development of chordoma independent of amplification of the Brachyury gen.   To study the biology of chordoma, I established the origin of existing putative chordoma cell lines and working criteria for identification of possible new chordoma cell lines.  Using two confirmed chordoma cell lines, I screened all regulatory-approved drugs for anti-growth activity to determine whether any could be repurposed for clinical use in patients. 

5.  Beginning in 2007, I began to transition my career to a leadership position within the Department of Veterans Affairs as the National Program Director for Oncology.  This led to opportunities to utilize the vast and detailed clinical data sets of nearly 1 million patients with cancer to address questions that have been difficult to study either through randomized trials or in less robust datasets.  The use of surgery to treat early stage non-small cell lung cancer is a standard treatment for which I observed a racial disparity.  The lower rate of use of surgery among African Americans was not explained by association with comorbidity.  In another study, I described the rate of use of adjuvant chemotherapy as having increased temporally after publication of randomized trials showing a modest benefit to its use.  I showed that initially this chemotherapy was primarily carboplatin-based, despite all positive trials having used cisplatin.  Cisplatin use has subsequently increased though there is not a demonstrable improvement is survival associated with its use.  I also showed that survival overall, regardless of use of chemotherapy, has improved suggesting that the application of clinical trial data for adjuvant chemotherapy is improving outcome.  In a related study, I found that elderly patients benefit as much as younger patients from adjuvant chemotherapy.  Patients with stage III non-small cell lung cancer are frequently treated with concurrent chemoradiotherapy, for which there are two commonly used chemotherapy regimens: cisplatin-etoposide and carboplatin-paclitaxel.  I examined the outcome and toxicity of patients treated with these two regimens and found that while there was no significant difference in survival, there was more toxicity associated with cisplatin-etoposide.  This finding may impact one current clinical guideline recommendation that favors cisplatin-etoposide over carboplatin-paclitaxel.  Finally, in stage IV disease, a similar observation was made that cisplatin-based chemotherapy is associated with greater toxicity but not improved survival. 

Complete List of Published Work in MyBibliography:   http://www.ncbi.nlm.nih.gov/sites/myncbi/michael.kelley.1/bibliography/43511621/public/?sort=date&direction=descending

Positions:

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1985

University of Michigan, Ann Arbor

Medical Resident, Medicine

Duke University

Grants:

Measurement of Hypoxia in Non-Small Cell Lung Carcinoma

Administered By
Medicine, Medical Oncology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Quit-smoking program for lung cancer patients' families

Administered By
Duke Cancer Institute
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

IPA - Bradley Hintze

Administered By
Medicine, Medical Oncology
Awarded By
Durham Veterans Affairs Medical Center
Role
Principal Investigator
Start Date
End Date

Chordoma Foundation Brachyury Mouse Model Project

Administered By
Medicine, Medical Oncology
Awarded By
Chordoma Foundation
Role
Principal Investigator
Start Date
End Date

Chordoma Genetically Engineered Mouse Model

Administered By
Medicine, Medical Oncology
Awarded By
Chordoma Foundation
Role
Principal Investigator
Start Date
End Date

Publications:

Comparison of annotation services for next-generation sequencing in a large-scale precision oncology program

© 2020 by American Society of Clinical Oncology PURPOSE Next-generation sequencing (NGS) multigene panel testing has become widespread, including the Veterans Affairs (VA), through the VA National Precision Oncology Program (NPOP). The interpretation of genomic alterations remains a bottleneck for realizing precision medicine. We sought to examine the concordance for pathogenicity determination and clinical actionability of annotation services in NPOP. METHODS Unique gene variants were generated from NGS gene panel results using two sequencing services. For each unique gene variant, annotations were provided through N-of-One (NoO), IBM Watson for Genomics (WfG), and OncoKB. Annotations for pathogenicity (all three sources) and actionability (WfG and OncoKB) were examined for concordance. Cohen’s kappa statistic was calculated to measure agreement between annotation services. RESULTS Among 1,227 NGS results obtained between 2015 and 2017, 1,388 unique variants were identified in 117 genes. The genes with the largest number of variants included TP53 (270), STK11 (92), and CDKN2A (81). The most common cancer type was lung adenocarcinoma (440), followed by colon adenocarcinoma (113). For pathogenic and likely pathogenic variants, there was 30% agreement between WfG and NoO (kappa, −0.26), 76% agreement between WfG and OncoKB (kappa, 0.22), and 42% agreement between NoO and OncoKB (kappa, −0.07). For level 1 drug actionability of gene variant–diagnosis combinations, there was moderate agreement between WfG and OncoKB (96.9%; kappa, 0.44), with 27 combinations identified as level 1 by both services, 58 by WfG alone, and 6 variants by OncoKB alone. CONCLUSION There is substantial variability in pathogenicity assessment of NGS variants in solid tumors by annotation services. In addition, there was only moderate agreement in level 1 therapeutic actionability recommendations between WfG and OncoKB. Improvement in the precision of NGS multigene panel annotation is needed.
Authors
Katsoulakis, E; Duffy, JE; Hintze, B; Spector, NL; Kelley, MJ
MLA Citation
Katsoulakis, E., et al. “Comparison of annotation services for next-generation sequencing in a large-scale precision oncology program.” Jco Precision Oncology, vol. 3, Jan. 2019, pp. 212–21. Scopus, doi:10.1200/PO.19.00118.
URI
https://scholars.duke.edu/individual/pub1448457
Source
scopus
Published In
Jco Precision Oncology
Volume
3
Published Date
Start Page
212
End Page
221
DOI
10.1200/PO.19.00118

Genomic analysis of metastatic solid tumors in veterans: Findings from the VHA national precision oncology program

© 2019 by American Society of Clinical Oncology. PURPOSE The Veterans Health Administration (VHA) is the largest cancer care provider in the United States, with the added challenge of serving more than twice the percentage of patients with cancer in rural areas than the national average. The VHA established the National Precision Oncology Program in 2016 to implement and standardize the practice of precision oncology across the diverse VHA system. METHODS Tumor or peripheral blood specimens from veterans with advanced solid tumors who were eligible for treatment were submitted for next-generation sequencing (NGS) at two commercial laboratories. Annotated results were generated by the laboratories and independently using IBM Watson for Genomics. Levelsof- evidence treatment recommendations were based on OncoKB criteria. RESULTS From July 2016 to June 2018, 3,698 samples from 72 VHA facilities were submitted for NGS testing, of which 3,182 samples (86%) were successfully sequenced. Most samples came from men with lung, prostate, and colorectal cancers. Thirty-four percent of samples were from patients who lived in a rural area. TP53, ATM, and KRAS were among the most commonly mutated genes. Approximately 70% of samples had at least one actionable mutation, with clinical trials identified as the recommended option in more than 50%. Mutations in genes associated with a neuroendocrine prostate cancer phenotype were expressed at increased frequency among veterans than in the general population. The most frequent therapies prescribed in response to NGS testing were immune checkpoint inhibitors, EGFR kinase inhibitors, and PARP inhibitors. CONCLUSION Clinical implementation of precision oncology is feasible across the VHA health care system, including rural sites. Veterans have unique occupational exposures that might inform the nature of the mutational signatures identified here. Importantly, these results underscore the importance of increasing clinical trial availability to veterans.
Authors
Poonnen, PJ; Duffy, JE; Hintze, B; Shukla, M; Brettin, TS; Conrad, NR; Yoo, H; Guertin, C; Looney, JA; Vashistha, V; Kelley, MJ; Spector, NL
MLA Citation
Poonnen, P. J., et al. “Genomic analysis of metastatic solid tumors in veterans: Findings from the VHA national precision oncology program.” Jco Precision Oncology, vol. 3, Jan. 2019. Scopus, doi:10.1200/PO.19.00075.
URI
https://scholars.duke.edu/individual/pub1448458
Source
scopus
Published In
Jco Precision Oncology
Volume
3
Published Date
DOI
10.1200/PO.19.00075

Medical oncologists' perspectives of the Veterans Affairs National Precision Oncology Program.

BACKGROUND: To support the rising need for testing and to standardize tumor DNA sequencing practices within the U.S. Department of Veterans Affairs (VA)'s Veterans Health Administration (VHA), the National Precision Oncology Program (NPOP) was launched in 2016. We sought to assess oncologists' practices, concerns, and perceptions regarding Next-Generation Sequencing (NGS) and the NPOP. MATERIALS AND METHODS: Using a purposive total sampling approach, oncologists who had previously ordered NGS for at least one tumor sample through the NPOP were invited to participate in semi-structured interviews. Questions assessed the following: expectations for the NPOP, procedural requirements, applicability of testing results, and the summative utility of the NPOP. Interviews were assessed using an open coding approach. Thematic analysis was conducted to evaluate the completed codebook. Themes were defined deductively by reviewing the direct responses to interview questions as well as inductively by identifying emerging patterns of data. RESULTS: Of the 105 medical oncologists who were invited to participate, 20 (19%) were interviewed from 19 different VA medical centers in 14 states. Five recurrent themes were observed: (1) Educational Efforts Regarding Tumor DNA Sequencing Should be Undertaken, (2) Pathology Departments Share a Critical Role in Facilitating Test Completion, (3) Tumor DNA Sequencing via NGS Serves as the Most Comprehensive Testing Modality within Precision Oncology, (4) The Availability of the NPOP Has Expanded Options for Select Patients, and (5) The Completion of Tumor DNA Sequencing through the NPOP Could Help Improve Research Efforts within VHA Oncology Practices. CONCLUSION: Medical oncologists believe that the availability of tumor DNA sequencing through the NPOP could potentially lead to an improvement in outcomes for veterans with metastatic solid tumors. Efforts should be directed toward improving oncologists' understanding of sequencing, strengthening collaborative relationships between oncologists and pathologists, and assessing the role of comprehensive NGS panels within the battery of precision tests.
Authors
Vashistha, V; Poonnen, PJ; Snowdon, JL; Skinner, HG; McCaffrey, V; Spector, NL; Hintze, B; Duffy, JE; Weeraratne, D; Jackson, GP; Kelley, MJ; Patel, VL
MLA Citation
Vashistha, Vishal, et al. “Medical oncologists' perspectives of the Veterans Affairs National Precision Oncology Program.Plos One, vol. 15, no. 7, 2020, p. e0235861. Pubmed, doi:10.1371/journal.pone.0235861.
URI
https://scholars.duke.edu/individual/pub1452610
PMID
32706774
Source
pubmed
Published In
Plos One
Volume
15
Published Date
Start Page
e0235861
DOI
10.1371/journal.pone.0235861

Statin Use is Associated With Increased Overall Survival in Patients With Colorectal Cancer: Findings From a Cohort of 29,498 United States Veterans

Authors
Melloni, C; Kimmick, GG; Oyekunle, T; Zullig, LL; Khouri, MG; Howard, L; Kelley, MJ; Dent, SF
URI
https://scholars.duke.edu/individual/pub1443696
Source
wos-lite
Published In
Circulation
Volume
140
Published Date

Association of NGS mutational pattern with immune checkpoint inhibitor clinical benefit in solid tumors.

Authors
Kaufman, J; Duffy, J; Xu, J; Huettner, CS; Xue, S; Michelini, VV; Harvey, SJ; Guertin, CM; Hintze, BJ; Spector, NL; Kelley, MJ
MLA Citation
Kaufman, Jacob, et al. “Association of NGS mutational pattern with immune checkpoint inhibitor clinical benefit in solid tumors.Journal of Clinical Oncology, vol. 36, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2018, pp. e24274–e24274. Crossref, doi:10.1200/jco.2018.36.15_suppl.e24274.
URI
https://scholars.duke.edu/individual/pub1448986
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
36
Published Date
Start Page
e24274
End Page
e24274
DOI
10.1200/jco.2018.36.15_suppl.e24274