Summary Background Clonal haemopoiesis of indeterminate potential (CHIP) is an age-associated genetic event linked to increased risk of primary haematological malignancies and increased all-cause ...mortality, but the prevalence of CHIP in patients who develop therapy-related myeloid neoplasms is unknown. We did this study to investigate whether chemotherapy-treated patients with cancer who have CHIP are at increased risk of developing therapy-related myeloid neoplasms. Methods We did a nested, case-control, proof-of-concept study to compare the prevalence of CHIP between patients with cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not develop these neoplasms (controls). We identified cases from our internal biorepository of 123 357 patients who consented to participate in the Total Cancer Care biobanking protocol at Moffitt Cancer Center (Tampa, FL, USA) between Jan 1, 2006, and June 1, 2016. We included all individuals who were diagnosed with a primary malignancy, were treated with chemotherapy, subsequently developed a therapy-related myeloid neoplasm, and were 70 years or older at either diagnosis. For inclusion in this study, individuals must have had a peripheral blood or mononuclear cell sample collected before the diagnosis of therapy-related myeloid neoplasm. Controls were individuals who were diagnosed with a primary malignancy at age 70 years or older and were treated with chemotherapy but did not develop therapy-related myeloid neoplasms. Controls were matched to cases in at least a 4:1 ratio on the basis of sex, primary tumour type, age at diagnosis, smoking status, chemotherapy drug class, and duration of follow-up. We used sequential targeted and whole-exome sequencing and described clonal evolution in cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available. The primary endpoint of this study was the development of therapy-related myeloid neoplasm and the primary exposure was CHIP. Findings We identified 13 cases and 56 case-matched controls. The prevalence of CHIP in all patients (23 33% of 69 patients) was higher than has previously been reported in elderly individuals without cancer (about 10%). Cases had a significantly higher prevalence of CHIP than did matched controls (eight 62% of 13 cases vs 15 27% of 56 controls, p=0·024; odds ratio 5·75, 95% CI 1·52–25·09, p=0·013). The most commonly mutated genes in cases with CHIP were TET2 (three 38% of eight patients) and TP53 (three 38% of eight patients), whereas controls most often had TET2 mutations (six 40% of 15 patients). In most (four 67% of six patients) cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available, the mean allele frequency of CHIP mutations had expanded by the time of the therapy-related myeloid neoplasm diagnosis. However, a subset of paired samples (two 33% of six patients) had CHIP mutations that decreased in allele frequency, giving way to expansion of a distinct mutant clone. Interpretation Patients with cancer who have CHIP are at increased risk of developing therapy-related myeloid neoplasms. The distribution of CHIP-related gene mutations differs between individuals with therapy-related myeloid neoplasm and those without, suggesting that mutation-specific differences might exist in therapy-related myeloid neoplasm risk. Funding Moffitt Cancer Center.
Background
The increasing practicality of genomic sequencing technology has led to its incorporation into routine clinical practice. Successful identification and targeting of driver genomic ...alterations that provide proliferative and survival advantages to tumor cells have led to approval and ongoing development of several targeted cancer therapies. Within many major cancer centers, molecular tumor boards are constituted to shepherd precision medicine into clinical practice.
Materials and Methods
In July 2014, the Clinical Genomics Action Committee (CGAC) was established as the molecular tumor board companion to the Personalized Medicine Clinical Service (PMCS) at Moffitt Cancer Center in Tampa, Florida. The processes and outcomes of the program were assessed in order to help others move into the practice of precision medicine.
Results
Through the establishment and initial 1,400 patients of the PMCS and its associated molecular tumor board at a major cancer center, five practical lessons of broad applicability have been learned: transdisciplinary engagement, the use of the molecular report as an aid to clinical management, clinical actionability, getting therapeutic options to patients, and financial considerations. Value to patients includes access to cutting‐edge practice merged with individualized preferences in treatment and care.
Conclusions
Genomic‐driven cancer medicine is increasingly becoming a part of routine clinical practice. For successful implementation of precision cancer medicine, strategically organized molecular tumor boards are critical to provide objective evidence‐based translation of observed molecular alterations into patient‐centered clinical action. Molecular tumor board implementation models along with clinical and economic outcomes will define future treatment standards.
Implications for Practice
It is clear that the increasing practicality of genetic tumor sequencing technology has led to its incorporation as part of routine clinical practice. Subsequently, many cancer centers are seeking to develop a personalized medicine services and/or molecular tumor board to shepherd precision medicine into clinical practice. This article discusses the key lessons learned through the establishment and development of a molecular tumor board and personalized medicine clinical service. This article highlights practical issues and can serve as an important guide to other centers as they conceive and develop their own personalized medicine services and molecular tumor boards.
Genomic‐driven cancer medicine is increasingly becoming a part of routine clinical practice. For successful implementation of precision cancer medicine, strategically organized molecular tumor boards are critical to provide objective evidence‐based translation of observed molecular alterations into patient‐centered clinical action. Molecular tumor board implementation models along with clinical and economic outcomes will define future treatment standards.
Abstract Dysregulation of growth factor cell signaling is a major driver of most human cancers. This has led to development of numerous drugs targeting protein kinases, with demonstrated efficacy in ...the treatment of a wide spectrum of cancers. Despite their high initial response rates and survival benefits, the majority of patients eventually develop resistance to these targeted therapies. This review article discusses examples of established mechanisms of drug resistance to anticancer therapies, including drug target mutations or gene amplifications, emergence of alternate signaling pathways, and pharmacokinetic variation. This reveals a role for pharmacogenomic analysis to identify and monitor for resistance, with possible therapeutic strategies to combat chemoresistance.
In this era of precision-based medicine, for optimal patient care, results reported from commercial next-generation sequencing (NGS) assays should adequately reflect the burden of somatic mutations ...in the tumor being sequenced. Here, we sought to determine the prevalence of clonal hematopoiesis leading to possible misattribution of tumor mutation calls on unpaired Foundation Medicine NGS assays.
This was a retrospective cohort study of individuals undergoing NGS of solid tumors from two large cancer centers. We identified and quantified mutations in genes known to be frequently altered in clonal hematopoiesis (
) that were returned to physicians on clinical Foundation Medicine reports. For a subset of patients, we explored the frequency of true clonal hematopoiesis by comparing mutations on Foundation Medicine reports with matched blood sequencing.
Mutations in genes that are frequently altered in clonal hematopoiesis were identified in 65% (1,139/1,757) of patients undergoing NGS. When excluding
, which is often mutated in solid tumors, these events were still seen in 35% (619/1,757) of patients. Utilizing paired blood specimens, we were able to confirm that 8% (18/226) of mutations reported in these genes were true clonal hematopoiesis events. The majority of
mutations (64%, 7/11) and minority of
mutations (4%, 2/50) were clonal hematopoiesis.
Clonal hematopoiesis mutations are commonly reported on unpaired NGS testing. It is important to recognize clonal hematopoiesis as a possible cause of misattribution of mutation origin when applying NGS findings to a patient's care.
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Levels of genetic diversity can be used to determine haplotype frequency, population size and patterns of invasive species distribution. In this study, we sought to investigate the genetic structure ...of the invasive marine mussel Mytella charruana and compare variation from invasive populations with variation found within three native populations. Invaded areas in the USA (Florida, Georgia); native areas in Ecuador, Colombia and Brazil. We sequenced 722 bp of the mitochondrial COI gene from 83 M. charruana samples from four invasive populations (USA) and 71 samples from two natural populations (Ecuador, Columbia). In addition, we sequenced 31 individuals of a congeneric species, Mytella guyanensis, from Salvador, Brazil. We constructed the phylogenetic relationship among all haplotypes and compared diversity measures among all populations. We found significantly higher levels of nucleotide diversity in invasive populations than in native populations, although the number of haplotypes was greater in the native populations. Moreover, mismatch distribution analyses resulted in a pattern indicative of population admixture for the invasive populations. Conversely, mismatch distributions of native populations resulted in a pattern indicative of populations in static equilibrium. Our data present compelling evidence that the M. charruana invasion resulted from admixture of at least two populations, which combined to form higher levels of genetic diversity in invasive populations. Moreover, our data suggest that one of these populations originated from the Caribbean coast of South America. Overall, this study provides an analysis of genetic diversity within invasive populations and explores how that diversity may be influenced by the genetic structure of native populations and how mass dispersal may lead to invasion success.
Abstract
SJS and TEN are extremely rare (approximately 2-7 cases per million per year) hypersensitivity reactions most commonly attributed to medications. The life-threatening nature of SJS/TEN ...necessitates early diagnosis and immediate identification and withdrawal of causative agents. Some of the most commonly associated culprits include sulfonamide antibiotics, aromatic anticonvulsants (phenytoin, carbamazepine, lamotrigine), -oxicam NSAIDs (e.g., meloxicam), allopurinol, and nevirapine. Individual case reports of SJS/TEN have been associated with anti-cancer agents, but a comprehensive assessment has not been performed. A large-scale retrospective analysis of the prevalence of SJS/TEN in cancer patients treated at Moffitt Cancer Center (MCC) between Jan 1, 2002 - Dec 31, 2014 was conducted. A total of 104,917 cancer patients were screened for SJS/TEN-related ICD-9 codes in the MCC health research informatics database. SJS/TEN diagnoses were identified in 121 patients. Manual chart review of physician, dermatology, and pathology notes confirmed SJS/TEN in 47 patients (in-patient + historical) and possible SJS/TEN in an additional 17 patients, corresponding to an overall prevalence of 0.06%. Confirmed in-patient cases of SJS/TEN were more common in hematologic malignancies compared to solid tumors (n = 12 vs. n = 7, respectively). Notably, 5 of the 19 (26.3%) confirmed cases were observed in patients with acute myeloid leukemia. Physician-reported culprits for SJS/TEN diagnoses included antibiotics, immunomodulators, anticonvulsants, and anti-cancer agents. The observed prevalence of SJS/TEN was higher in cancer patients than previous reports from the general USA population. There were 19 confirmed in-patient diagnoses of SJS/TEN and an additional 45 historical and possible cases of SJS/TEN in 104,917 cancer patients, corresponding to an overall prevalence of 0.018% to 0.06%, an approximately 90-fold increase when compared to the general population. Possible explanations for increased risk in cancer patients include increased exposure to culprit medications, cancer disease process, immunocompromised state, or synergy between risk factors. A thorough understanding of the factors that increase risk to SJS/TEN in cancer patients is critical to facilitate culprit withdrawal and maximize patient outcomes and survival.
Citation Format: Nancy K. Gillis, Gillian C. Bell, Howard L. McLeod, Amy J. Brandt. Prevalence and triggers of drug-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in a cancer patient cohort. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4304.
Introduction
Moffitt Cancer Center's Personalized Medicine Clinical Service (PMCS) reviews somatic next‐generation sequencing (NGS) assay results, provides interpretations, and identifies potential ...therapeutic options. The number of individuals reviewed by our clinical service who are eligible for on‐label or off‐label drug therapy based on genetic test results has previously not been quantitated. We determined the number of patients harboring an actionable mutation that would qualify a patient for an on‐label drug or consideration for off‐label drug treatment.
Methods
The Food and Drug Administration (FDA) Table of Pharmacogenomic Biomarkers in Drug Labeling was utilized to identify anticancer agents containing genomic markers in the Indications and Usage section of the drug label. A database containing discrete NGS patient data was queried retrospectively for those drugs and associated genomic mutations included in this study. On‐label was defined as those patients who were eligible for a drug based on harboring a targetable mutation in the FDA‐approved cancer type. Off‐label was defined as those patients who may be considered for a drug based on harboring a targetable mutation in a non–FDA‐approved cancer type.
Results
A total of 1072 patients and 1131 NGS results were eligible for study inclusion. Fifty‐two patients (4.9%) had results for more than one NGS assay. Seventeen drugs targeting ALK, BRAF, BRCA1/BRCA2, EGFR, or ERBB2 mutations met the study inclusion criteria. Of the entire patient population, 92 (8.6%) unique patients were eligible for at least one on‐label drug; off‐label use of at least one drug could be considered in 103 (9.6%) unique patients.
Conclusion
Combining both on‐label and off‐label opportunities, 175 (16.3%) unique patients had actionable mutations in six genes. Because most patients reviewed by our PMCS have previously treated advanced disease with limited treatment options, identifying additional lines of therapy is of clinical utility.
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