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

Preference Tx for Sequencing in NSCLC

Administered By
Duke Clinical Research Institute
Awarded By
AstraZeneca Pharmaceuticals, LP
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

Publications:

Chemoradiation treatment patterns among United States Veteran Health Administration patients with unresectable stage III non-small cell lung cancer.

BACKGROUND: The Veterans Health Administration (VHA) is the largest integrated health care system in the United States (US). Among VHA patients, the rate of use of concurrent chemoradiation therapy (CCRT) among those with unresectable, stage III non-small cell lung cancer (NSCLC) is unknown. The objective was to report recent CCRT treatment patterns in VHA patients and identify characteristics associated with receipt of CCRT. METHODS: Using Department of Veteran Affairs (VA) Cancer Registry System data linked to VA electronic medical records, we determined rates of CCRT, sequential CRT (SCRT), radiation therapy (RT) only, chemotherapy (CT) only, and neither treatment. RESULTS: Among 4054 VHA patients who met study criteria, CCRT rates slightly increased from 44 to 50% between 2013 and 2017. Factors associated with decreased odds of CCRT receipt compared to any other treatment included increasing age (adjusted odds ratio [aOR] per 10 years = 0.67; 95% CI: 0.60-0.76) and Charlson-Deyo comorbidity score (aOR = 0.94; 95% CI: 0.91-0.97). White race was associated with increased odds of CCRT receipt (aOR = 1.24; 95% CI: 1.004-1.53). In a chart review sample of 200 patients, less than half (n = 85) had a documented reason for not receiving CCRT. Among these, 29% declined treatment, and 71% did not receive CCRT due to "not being a candidate" for reasons related to frailty or lung nodules being too far apart for radiation therapy. CONCLUSIONS: CCRT rates among VHA patients with unresectable, stage III NSCLC slightly increased from 2013 to 2017; however in 2017, only half were receiving CCRT. Older patients and those with multiple comorbidities were less likely to receive CCRT and even when controlling for these factors, non-white patients were less likely to receive CCRT.
Authors
Hung, A; Lee, KM; Lynch, JA; Li, Y; Poonnen, P; Efimova, OV; Hintze, BJ; Buckingham, T; Yong, C; Seal, B; Kelley, MJ; Reed, SD
MLA Citation
Hung, Anna, et al. “Chemoradiation treatment patterns among United States Veteran Health Administration patients with unresectable stage III non-small cell lung cancer.Bmc Cancer, vol. 21, no. 1, July 2021, p. 824. Pubmed, doi:10.1186/s12885-021-08577-y.
URI
https://scholars.duke.edu/individual/pub1488945
PMID
34271861
Source
pubmed
Published In
Bmc Cancer
Volume
21
Published Date
Start Page
824
DOI
10.1186/s12885-021-08577-y

Transportation as a barrier to colorectal cancer care.

BACKGROUND: Transportation barriers limit access to cancer care services and contribute to suboptimal clinical outcomes. Our objectives were to describe the frequency of Veterans reporting and the factors associated with transportation barriers to or from colorectal cancer (CRC) care visits. METHODS: Between November 2015 and September 2016, Veterans with incident stage I, II, or III CRC completed a mailed survey to assess perceived barriers to recommended care. Participants who reported difficulty with transportation to or from CRC care appointments were categorized as experiencing transportation barriers. We assessed pairwise correlations between transportation barriers, transportation-related factors (e.g., mode of travel), and chaotic lifestyle (e.g., predictability of schedules), and used logistic regression to examine the association between the reporting of transportation difficulties, distance traveled to the nearest Veterans Affairs (VA) facility, and life chaos. RESULTS: Of the 115 Veterans included in this analysis, 18% reported experiencing transportation barriers. Distance to the VA was not strongly correlated with the reporting of transportation barriers (Spearman's ρ = 0.12, p = 0.19), but chaotic lifestyle was both positively and significantly correlated with experiencing transportation barriers (Spearman's ρ = 0.22, p = 0.02). Results from the logistic regression model modestly supported the findings from the pairwise correlations, but were not statistically significant. CONCLUSIONS: Transportation is an important barrier to or from CRC care visits, especially among Veterans who experience greater life chaos. Identifying Veterans who experience chaotic lifestyles would allow for timely engagement in behavioral interventions (e.g., organizational skills training) and with support services (e.g., patient navigation).
Authors
Jazowski, SA; Sico, IP; Lindquist, JH; Smith, VA; Bosworth, HB; Danus, S; Provenzale, D; Kelley, MJ; Zullig, LL
MLA Citation
Jazowski, Shelley A., et al. “Transportation as a barrier to colorectal cancer care.Bmc Health Serv Res, vol. 21, no. 1, Apr. 2021, p. 332. Pubmed, doi:10.1186/s12913-021-06339-x.
URI
https://scholars.duke.edu/individual/pub1478718
PMID
33849524
Source
pubmed
Published In
Bmc Health Services Research
Volume
21
Published Date
Start Page
332
DOI
10.1186/s12913-021-06339-x

Implementation of precision oncology in the Veterans Health Administration (VHA).

<jats:p> 6507 </jats:p><jats:p> Background: VHA is the US’s largest integrated healthcare system providing care to over 6 million Veterans (~40% in rural areas). Precision Oncology offers the promise of effective, low-toxicity targeted therapies tailored to individual tumor genomics but is unequally available to patients in the US. As part of the Cancer Moonshot, VHA is implementing a system-wide Precision Oncology Program (POP) including patients in rural areas, where specialty oncology care has historically had limited availability. Methods: Patients tested with multigene NGS tumor sequencing through 1 of 2 contracted vendors were identified from POP records and cancer characteristics were extracted from POP and medical records. Drug use data was obtained from the VA Corporate Data Warehouse. NGS testing results and annotations were extracted from POP records. Results: A total of 978 tumor samples were sent for NGS testing since program inception in 2015. The most common diagnoses are lung (464: adeno 314, squamous 107), GI (87), LN (75), liver (56), H&amp;N (52), and prostate (43). The rate of sample test requests increased rapidly after national implementation in July 2016 (mean 23 samples/month prior to implementation to mean 126 samples/month 3 months later) as did the number of participating facilities (mean 8/month to 27/month). Sequencing success rate increased from 68% to 71% over the same interval while mean turn around time remained similar at 19.7 and 19.1 d, respectively. NGS results are available for a cohort of 344 patients including: lung 200 (adeno 138, squamous 51), skin 28, LN 20, liver 19, GI 16. 979 variants were found including TP53 278, KRAS 106, STK11, APC 38, PIK3CA 38, and CDKN2A 37. 228 patients had actionable results (on-label drug 24, off-label drug 165, clinical trial 213). To date, 8 patients received a recommended drug outside a clinical trial between 11 and 288 d after testing (median 82 d); 4 additional patients had received an NGS-recommended drug prior to testing. Conclusions: Implementation of tumor NGS testing as part of Precision Oncology Program in a US distributed healthcare system is feasible. Further program implementation and provision of appropriate targeted drugs both on and off study will be necessary to impact patient outcomes. </jats:p>
Authors
Kelley, MJ; Duffy, J; Hintze, BJ; Williams, CD; Spector, NL
MLA Citation
Kelley, Michael J., et al. “Implementation of precision oncology in the Veterans Health Administration (VHA).Journal of Clinical Oncology, vol. 35, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2017, pp. 6507–6507. Crossref, doi:10.1200/jco.2017.35.15_suppl.6507.
URI
https://scholars.duke.edu/individual/pub1470305
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
35
Published Date
Start Page
6507
End Page
6507
DOI
10.1200/jco.2017.35.15_suppl.6507

Barriers to Prescribing Targeted Therapies for Patients With NSCLC With Highly Actionable Gene Variants in the Veterans Affairs National Precision Oncology Program.

PURPOSE: Next-generation sequencing (NGS) gene panels are frequently completed for patients with advanced non-small-cell lung cancer (NSCLC). Patients with highly actionable gene variants have improved outcomes and reduced toxicities with the use of corresponding targeted agents. We sought to identify barriers to targeted agent use within the Veterans Health Affairs' National Precision Oncology Program (NPOP). METHODS: A retrospective evaluation of patients with NSCLC who underwent NGS multigene panels through NPOP between July 2015 and February 2019 was conducted. Patients who were assigned level 1 or 2A evidence for oncogenic gene variants by an artificial intelligence offering (IBM Watson for Genomics [WfG]) and NPOP staff were selected. Antineoplastic drug prescriptions and provider notes were reviewed. Reasons for withholding targeted treatments were categorized. RESULTS: Of 1,749 patients with NSCLC who successfully underwent NGS gene panel testing, 112 (6.4%) patients were assigned level 1 and/or 2A evidence for available targeted treatments by WfG and NPOP staff. All highly actionable gene variants were within ALK, BRAF, EGFR, ERBB2, MET, RET, and ROS1. Of these, 36 (32.1%) patients were not prescribed targeted agents. The three most common reasons were (1) patient did not carry a diagnosis of metastatic disease (33.3%), (2) treating provider did not comment on the NGS results (25.0%), and (3) provider felt that patient could not tolerate therapy (19.4%). No patients were denied access to level 1 or 2A targeted drugs because of rejection of a nonformulary drug request. CONCLUSION: A substantial minority of patients with NSCLC bearing highly actionable gene variants are not prescribed targeted agents. Further provider- and pathologist-directed educational efforts and implementation of health informatics systems to provide real-time decision support for test ordering and interpretation are needed.
Authors
Vashistha, V; Armstrong, J; Winski, D; Poonnen, PJ; Hintze, B; Price, M; Snowdon, JL; Weeraratne, D; Brotman, D; Jackson, GP; Kelley, MJ
MLA Citation
Vashistha, Vishal, et al. “Barriers to Prescribing Targeted Therapies for Patients With NSCLC With Highly Actionable Gene Variants in the Veterans Affairs National Precision Oncology Program.Jco Oncol Pract, vol. 17, no. 7, 2021, pp. e1012–20. Pubmed, doi:10.1200/OP.20.00703.
URI
https://scholars.duke.edu/individual/pub1467081
PMID
33780286
Source
pubmed
Published In
Jco Oncol Pract
Volume
17
Published Date
Start Page
e1012
End Page
e1020
DOI
10.1200/OP.20.00703

Veterans Affairs Pharmacogenomic Testing for Veterans (PHASER) clinical program.

In 2019, the Veterans Affairs (VA), the largest integrated US healthcare system, started the Pharmacogenomic Testing for Veterans (PHASER) clinical program that provides multi-gene pharmacogenomic (PGx) testing for up to 250,000 veterans at approximately 50 sites. PHASER is staggering program initiation at sites over a 5-year period from 2019 to 2023, as opposed to simultaneous initiation at all sites, to facilitate iterative program quality improvements through Plan-Do-Study-Act cycles. Current resources in the PGx field have not focused on multisite, remote implementation of panel-based PGx testing. In addition to bringing large scale PGx testing to veterans, the PHASER program is developing a roadmap to maximize uptake and optimize the use of PGx to improve drug response outcomes.
Authors
Dong, OM; Bates, J; Chanfreau-Coffinier, C; Naglich, M; Kelley, MJ; Meyer, LJ; Icardi, M; Vassy, JL; Sriram, P; Heise, CW; Rivas, S; Ribeiro, M; Jacobitz, R; Rozelle, S; Chapman, JG; Voora, D
MLA Citation
Dong, Olivia M., et al. “Veterans Affairs Pharmacogenomic Testing for Veterans (PHASER) clinical program.Pharmacogenomics, vol. 22, no. 3, Feb. 2021, pp. 137–44. Pubmed, doi:10.2217/pgs-2020-0173.
URI
https://scholars.duke.edu/individual/pub1470711
PMID
33403869
Source
pubmed
Published In
Pharmacogenomics
Volume
22
Published Date
Start Page
137
End Page
144
DOI
10.2217/pgs-2020-0173