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:

Homologous Recombination Repair Gene Variants and Outcomes Among Patients With Prostate Cancer Treated With Poly (ADP-ribose) Polymerase Inhibitors.

PURPOSE: Poly ADP-ribose polymerase inhibitors (PARPi) are used for patients with advanced prostate cancer bearing alterations in homologous recombination repair (HRR) genes. We sought to characterize HRR gene variants and describe real-world outcomes for patients on PARPi. METHODS: The US Department of Veterans Affairs' National Precision Oncology Program's database was reviewed to identify patients who underwent somatic DNA sequencing and were prescribed a PARPi before May 15, 2020. Somatic and germline variants within HRR genes were reported, and pathogenicity was reviewed via OncoKB. In patients treated with PARPi for > 4 weeks, the rate of those achieving a 30% decrease in prostate-specific antigen (PSA30) and composite progression-free survival (PFS) were compared between patients bearing pathogenic variants of BRCA2 and patients without these variants using Mann-Whitney and log-rank tests, respectively. RESULTS: Forty-eight patients bearing 67 total HRR gene variants were prescribed PARPi for prostate cancer. Twenty-one patients (43.8%) were found to have at least one pathogenic HRR gene variant. Eight (16.6%) were referred to genetic counseling, and five (10.4%) were ultimately confirmed with germline variants. The median PFS was 4.0 months, and PSA30 was 25.6% (11 of 43) for all 43 evaluable patients. Patients with pathogenic BRCA2 variants (n = 13) had higher PSA30 (69.2% v 4.0%; P < .001) and longer PFS (7.2 v 2.8 months; P = .0291) than those without. CONCLUSION: In a real-world setting, heavily pretreated patients with prostate cancer and pathogenic BRCA2 variants have a significant PSA response rate and a PFS > 7 months with PARPi. This work emphasizes the importance of determining pathogenicity and origin of HRR alterations to better inform clinical treatment decisions and highlights the need for provider education and other decision support tools.
Authors
Price, MJ; Vashistha, V; Winski, D; Kelley, MJ; Bitting, RL; Montgomery, B
MLA Citation
Price, Meghan J., et al. “Homologous Recombination Repair Gene Variants and Outcomes Among Patients With Prostate Cancer Treated With Poly (ADP-ribose) Polymerase Inhibitors.Jco Precis Oncol, vol. 6, Apr. 2022, p. e2100461. Pubmed, doi:10.1200/PO.21.00461.
URI
https://scholars.duke.edu/individual/pub1519395
PMID
35476551
Source
pubmed
Published In
Jco Precision Oncology
Volume
6
Published Date
Start Page
e2100461
DOI
10.1200/PO.21.00461

Metastatic bulk to predict subclonal heterogeneity by ctDNA in RAS/RAF-wildtype colorectal cancer.

<jats:p> 186 </jats:p><jats:p> Background: Distinct molecular subgroups of colorectal cancer (CRC) have been afforded with use of next-generation sequencing (NGS) as standard in clinical practice for advanced disease. We have previously demonstrated that disease bulk predicts clinical resistance to EGFR inhibition in RAS/RAF-wildtype (WT) CRC. We hypothesized bulky disease would predict advanced subclonal heterogeneity by circulating tumor DNA (ctDNA) in RAS/RAF<jats:sup>WT</jats:sup> CRC. Methods: Following IRB-approval, a retrospective review of molecular profiles in advanced CRC (n = 965) were compiled from the Veteran Administration’s (VA) National Precision Oncology Program (NPOP) and University of Wisconsin Precision Medicine Molecular Tumor Board (MTB). Disease bulk was defined as the longest diameter of metastatic disease or short axis for advanced lymphadenopathy. Molecular profiling was performed using commercially available platforms including Strata Oncology (MTB) and FoundationOne (NPOP). Bulky was compared as categorical (&gt; 35 cm) and continuous variable against the count of pathologic variants. Results: The population was largely representative of advanced CRC with alterations in TP53 (80.5%), KRAS (44.8%), PIK3CA (22.0%) and BRAF (12.8%). Veterans had increased frequency of alterations in PIK3CA (22.7% v. 13.0%, p &lt; 0.02) and BRAF (13.3% v. 6.9%, p &lt; 0.05). There was no difference in metastatic bulk at the time of NGS for tissue biopsy between MTB and NPOP populations (t = 0.80). Disease bulk did not predict the number of pathologic variants from tissue sampling in RAS/RAF<jats:sup>WT</jats:sup> CRC (n = 96, t = 0.24). RAS/RAF<jats:sup>MT</jats:sup> cancers had increased frequency of subclonal alterations by ctDNA (9.1±4.0) v. RAS/RAF<jats:sup>WT</jats:sup> (4.5±3.4, p &lt; 0.0001). Using ctDNA, bulky disease in RAS/RAF<jats:sup>MT</jats:sup> CRC was not predictive of increased pathologic variants (8.8±3.5 v. 9.5±4.8, t = 0.62). Bulky disease (&gt; 35mm) in RAS/RAF<jats:sup>WT</jats:sup> CRC predicted increased subclonal variants (6.2±3.6 v. 3.5±2.9, p &lt; 0.02). As a continuous variable, disease bulk predicted the number of pathologic variants in RAS/RAF<jats:sup>WT</jats:sup> CRC (R = 0.51). Conclusions: These data indicate that metastatic bulk is a predictor of subclonal heterogeneity by ctDNA in RAS/RAF<jats:sup>WT</jats:sup> CRC. Molecular profiling of tissue alone did not predict differences in subclonal heterogeneity when stratified by disease bulk in RAS/RAF<jats:sup>WT</jats:sup> CRC. Limited subclonal heterogeneity in non-bulky cancers support ongoing prospective investigations to select non-bulky cancers for early incorporation of anti-EGFR inhibition (NCT04587128). </jats:p>
Authors
Kratz, JD; Lubner, SJ; LoConte, NK; Patel, MA; Uboha, NV; Lesnik, DM; Ahmed, S; Kelley, MJ; Lemmon, K; Bassetti, MF; Sanger, C; Deming, DA
MLA Citation
Kratz, Jeremy D., et al. “Metastatic bulk to predict subclonal heterogeneity by ctDNA in RAS/RAF-wildtype colorectal cancer.Journal of Clinical Oncology, vol. 40, no. 4_suppl, American Society of Clinical Oncology (ASCO), 2022, pp. 186–186. Crossref, doi:10.1200/jco.2022.40.4_suppl.186.
URI
https://scholars.duke.edu/individual/pub1518004
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
40
Published Date
Start Page
186
End Page
186
DOI
10.1200/jco.2022.40.4_suppl.186

Integration of Patient-Reported Outcome Measures in the Electronic Health Record: The Veterans Affairs Experience.

PURPOSE: There are growing efforts to integrate patient-reported outcome (PRO) data into electronic health records (EHRs) to bring together disparate sources of patient information and improve medical care. PRO measures can be used to assess cancer symptom presence and severity. Integrating PRO tools in EHRs can alert providers to address symptoms, which is an essential component of comprehensive oncology care. METHODS: We modified a PRO used to measure cancer and end-of-life symptoms, the Edmonton Symptom Assessment System to create the Veteran Symptom Assessment System (VSAS). VSAS was implemented as an integrated PRO as part of the Veterans Administration EHR system and was used at hematology-oncology clinics in Veteran Administration (VA) medical centers in the Southeast. RESULTS: From 2013 to 2014, VSAS was introduced, underwent usability testing and modifications, and was finally implemented in the EHR. Between 2015 and 2019, VSAS was administered 43,883 times in 9,058 patients. Eighty-nine percent of Veterans were male, 11% were female, 52% identified as non-Hispanic White, and 43% identified as African American. Fatigue, shortness of breath with exertion, and pain were most frequently reported initially (68%, 48%, and 45%, respectively) and were most frequently rated as severe (27%, 16%, and 17%, respectively). In patients diagnosed with stage IV cancer, higher symptom burden was significantly associated with shorter overall survival. The majority of Veterans with longitudinal measurements experienced improvement in symptoms, most frequently in severe symptoms. CONCLUSION: To our knowledge, this is the first large-scale implementation of a PRO system, integrated in the VA EHR, in ambulatory patients with cancer and blood disorders. The integration of VSAS within the VA EHR is a significant demonstration and a necessary requirement for current and future systemic initiatives in cancer symptom management.
Authors
Friedman, DR; Patil, V; Li, C; Rassmussen, KM; Burningham, Z; Hamilton-Hill, S; Kelley, MJ; Halwani, AS
MLA Citation
Friedman, Daphne R., et al. “Integration of Patient-Reported Outcome Measures in the Electronic Health Record: The Veterans Affairs Experience.Jco Clin Cancer Inform, vol. 6, Feb. 2022, p. e2100086. Pubmed, doi:10.1200/CCI.21.00086.
URI
https://scholars.duke.edu/individual/pub1512651
PMID
35290072
Source
pubmed
Published In
Jco Clinical Cancer Informatics
Volume
6
Published Date
Start Page
e2100086
DOI
10.1200/CCI.21.00086

Real World Outcomes versus Clinical Trial Results of Durvalumab Maintenance in Veterans with Stage III Non-Small Cell Lung Cancer.

One year of durvalumab following concurrent chemoradiotherapy improves progression-free (PFS) and overall survival (OS) for patients with stage III non-small cell lung cancer (NSCLC). However, the real-world efficacy of durvalumab has not been determined. We conducted a multi-center observational cohort study across the Veterans Health Administration, including patients with stage III NSCLC who received concurrent chemoradiotherapy and durvalumab, compared to patients who received concurrent chemoradiotherapy alone. Kaplan-Meier and Cox regression approaches were used to identify factors associated with PFS and OS. We calculated a hazard ratio and efficacy-effectiveness factor to compare OS of veterans to the referenced clinical trial population. A total of 1006 patients with stage III NSCLC who received concurrent chemoradiotherapy and at least one dose of durvalumab from November 2017 to April 2021 were compared to 989 patients who received concurrent chemoradiotherapy alone from January 2015 to December 2016. Adjuvant durvalumab was associated with higher PFS (HR 0.62, 95% CI 0.55-0.70, p < 0.001) and OS (HR 0.57, 95% CI 0.50-0.66, p < 0.001). OS was shorter in veterans compared to PACIFIC (HR 1.24, 95% CI 1.03-1.48, p = 0.02: EE gap 0.73). OS of veterans with stage III NSCLC treated with adjuvant durvalumab is improved compared to a modern comparator but is reduced compared to the PACIFIC population.
Authors
Sankar, K; Bryant, AK; Strohbehn, GW; Zhao, L; Elliott, D; Moghanaki, D; Kelley, MJ; Ramnath, N; Green, MD
MLA Citation
Sankar, Kamya, et al. “Real World Outcomes versus Clinical Trial Results of Durvalumab Maintenance in Veterans with Stage III Non-Small Cell Lung Cancer.Cancers (Basel), vol. 14, no. 3, Jan. 2022. Pubmed, doi:10.3390/cancers14030614.
URI
https://scholars.duke.edu/individual/pub1507486
PMID
35158881
Source
pubmed
Published In
Cancers
Volume
14
Published Date
DOI
10.3390/cancers14030614

Evaluation of the Veterans Affairs Pharmacogenomic Testing for Veterans (PHASER) clinical program at initial test sites.

Aim: The first Plan-Do-Study-Act cycle for the Veterans Affairs Pharmacogenomic Testing for Veterans pharmacogenomic clinical testing program is described. Materials & methods: Surveys evaluating implementation resources and processes were distributed to implementation teams, providers, laboratory and health informatics staff. Survey responses were mapped to the Consolidated Framework for Implementation Research constructs to identify implementation barriers. The Expert Recommendation for Implementing Change strategies were used to address implementation barriers. Results: Survey response rate was 23-73% across personnel groups at six Veterans Affairs sites. Nine Consolidated Framework for Implementation Research constructs were most salient implementation barriers. Program revisions addressed these barriers using the Expert Recommendation for Implementing Change strategies related to three domains. Conclusion: Beyond providing free pharmacogenomic testing, additional implementation barriers need to be addressed for improved program uptake.
Authors
Dong, OM; Roberts, MC; Wu, RR; Voils, CI; Sperber, N; Gavin, KL; Bates, J; Chanfreau-Coffinier, C; Naglich, M; Kelley, MJ; Vassy, JL; Sriram, P; Heise, CW; Rivas, S; Ribeiro, M; Chapman, JG; Voora, D
MLA Citation
Dong, Olivia M., et al. “Evaluation of the Veterans Affairs Pharmacogenomic Testing for Veterans (PHASER) clinical program at initial test sites.Pharmacogenomics, vol. 22, no. 17, Nov. 2021, pp. 1121–33. Pubmed, doi:10.2217/pgs-2021-0089.
URI
https://scholars.duke.edu/individual/pub1500433
PMID
34704830
Source
pubmed
Published In
Pharmacogenomics
Volume
22
Published Date
Start Page
1121
End Page
1133
DOI
10.2217/pgs-2021-0089