Personalized Medicine Program Research Articles

Abstract B047: Inhibition of the polyamine pathway: a novel therapeutic approach to treat aggressive pediatric medulloblastoma

Abstract Medulloblastoma is the most common pediatric malignant brain tumor. Polyamines, critical intracellular polycations governing key cell processes such as DNA replication, translation, and cell proliferation, are frequently upregulated in cancer. We previously showed that the polyamine pathway is critical to the growth and survival of pediatric diffuse midline gliomas and MYC amplified neuroblastoma. Given the activity of polyamine inhibition in DMG, and given the critical role of MYC in medulloblastoma, we sought to investigate the potential of polyamine pathway inhibition as a therapeutic approach for medulloblastoma. We compared the expression of regulators of the polyamine pathway in a cohort of pediatric medulloblastoma tumors from patients enrolled in the Zero Childhood Cancer (ZERO) Personalized Medicine Program and found significant over-expression compared with normal fetal brain samples. Analysis of Cavalli dataset of 763 medulloblastoma samples, found that high expression of polyamine biosynthetic genes predicted poor overall survival, and low expression of catabolic flux genes significantly correlated with better outcomes. We next treated medulloblastoma cells treated with a polyamine synthesis inhibitor, DFMO, and found that led to a compensatory increase in polyamine transporter protein expression. Conversely, treatment with the polyamine transport inhibitor AMXT 1501 led to compensatory increase in ODC1, the key polyamine synthetic enzyme. Dual targeting of the polyamine pathway, (DFMO and AMXT 1501) showed a potent and synergistic inhibition of cell proliferation and reduced the clonogenic potential of medulloblastoma cells in soft agar clonogenic assays. Flow cytometric analysis of Annexin V-stained cells showed that treatment with DFMO and AMXT 1501 in combination led to induction of apoptosis. Furthermore, we found that dual polyamine inhibition potently sensitized medulloblastoma cells, particularly Group 3, to the chemotherapeutic agent SN-38, leading to complete eradication of medulloblastoma cells in both cytotoxicity assays and clonogenic assays at nanomolar chemotherapeutic concentrations. We are currently validating this treatment strategy in aggressive orthotopic medulloblastoma models. Our findings suggest that inhibiting both polyamine synthesis and uptake holds promise for sensitizing highly aggressive pediatric medulloblastoma tumors to chemotherapy. Currently, AMXT 1501 combined with DFMO is undergoing evaluation in a Phase I clinical trial for adults (NCT05500508). Building on these promising results, we are developing a Phase I/II clinical trial for children with aggressive brain tumors through the international CONNECT consortium. Citation Format: Aaminah Khan, Anjana Gopalakrishnan, Jie Liu, Mark R. Burns, Maria Tsoli, David S. Ziegler. Inhibition of the polyamine pathway: a novel therapeutic approach to treat aggressive pediatric medulloblastoma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B047.

From the identification of actionable molecular targets to the generation of faithful neuroblastoma patient-derived preclinical models

BackgroundNeuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Although the overall survival of patients with NB has improved in the last years, more than 50% of high-risk patients still undergo a relapse. Thus, in the era of precision/personalized medicine, the need for high-risk NB patient-specific therapies is urgent.MethodsWithin the PeRsonalizEd Medicine (PREME) program, patient-derived NB tumors and bone marrow (BM)-infiltrating NB cells, derived from either iliac crests or tumor bone lesions, underwent to histological and to flow cytometry immunophenotyping, respectively. BM samples containing a NB cells infiltration from 1 to 50 percent, underwent to a subsequent NB cells enrichment using immune-magnetic manipulation. Then, NB samples were used for the identification of actionable targets and for the generation of 3D/tumor-spheres and Patient-Derived Xenografts (PDX) and Cell PDX (CPDX) preclinical models.ResultsEighty-four percent of NB-patients showed potentially therapeutically targetable somatic alterations (including point mutations, copy number variations and mRNA over-expression). Sixty-six percent of samples showed alterations, graded as “very high priority”, that are validated to be directly targetable by an approved drug or an investigational agent. A molecular targeted therapy was applied for four patients, while a genetic counseling was suggested to two patients having one pathogenic germline variant in known cancer predisposition genes. Out of eleven samples implanted in mice, five gave rise to (C)PDX, all preserved in a local PDX Bio-bank. Interestingly, comparing all molecular alterations and histological and immunophenotypic features among the original patient’s tumors and PDX/CPDX up to second generation, a high grade of similarity was observed. Notably, also 3D models conserved immunophenotypic features and molecular alterations of the original tumors.ConclusionsPREME confirms the possibility of identifying targetable genomic alterations in NB, indeed, a molecular targeted therapy was applied to four NB patients. PREME paves the way to the creation of clinically relevant repositories of faithful patient-derived (C)PDX and 3D models, on which testing precision, NB standard-of-care and experimental medicines.

Personalized medicine in a community health system: the NorthShore experience.

Genomic and personalized medicine implementation efforts have largely centered on specialty care in tertiary health systems. There are few examples of fully integrated care systems that span the healthcare continuum. In 2014, NorthShore University HealthSystem launched the Center for Personalized Medicine to catalyze the delivery of personalized medicine. Successful implementation required the development of a scalable family history collection tool, the Genetic and Wellness Assessment (GWA) and Breast Health Assessment (BHA) tools; integrated pharmacogenomics programming; educational programming; electronic medical record integration; and robust clinical decision support tools. To date, more than 225,000 patients have been screened for increased hereditary conditions, such as cancer risk, through these tools in primary care. More than 35,000 patients completed clinical genetic testing following GWA or BHA completion. An innovative program trained more than 100 primary care providers in genomic medicine, activated with clinical decision support and access to patient genetic counseling services and digital healthcare tools. The development of a novel bioinformatics platform (FLYPE) enabled the incorporation of genomics data into electronic medical records. To date, over 4,000 patients have been identified to have a pathogenic or likely pathogenic variant in a gene with medical management implications. Over 33,000 patients have clinical pharmacogenomics data incorporated into the electronic health record supported by clinical decision support tools. This manuscript describes the evolution, strategy, and successful multispecialty partnerships aligned with health system leadership that enabled the implementation of a comprehensive personalized medicine program with measurable patient outcomes through a genomics-enabled learning health system model that utilizes implementation science frameworks.

Abstract 3407: The italian personalized medicine program PREME for high-risk neuroblastoma

Abstract Background: In the era of precision medicine, the need for high-risk neuroblastoma (NB) patient-specific therapies is crucial. Methods: From November 2018 to February 2021, the Italian PeRsonalizEd MEdicine (PREME) program has enrolled 18 NB affected patients. Tumors and bone marrow-infiltrating NB cells underwent to histological (selection panel: CD45, CD56, TH, PHOX-2B, S100) and to flow cytometry (selection panel: CD45, CD56, GD2, B7-H3) immunophenotyping, respectively. The biological material was then used for: 1) DNA extraction for subsequent DNAseq (Whole Exome Sequencing, 100X mean coverage, or Deep Targeted Gene Panel Sequencing, 1000x mean coverage, when the percentage of the neoplastic counterpart within the sample was over or down 60%, respectively); 2) RNA extraction for subsequent RNAseq (30 millions of reads per sample); 3) Development of primary NB cell culture (3D/tumor-spheres) and of Patient-Derived Xenografts (PDX) models in mice (both stored in local Bio-banks). Results: 14 out of 18 patients (77.7%) had one or more potentially actionable somatic alterations in primary tumors. Among those, 4 had also one pathogenic germline variant in known cancer predisposition genes. In 11 of the 14 cases the Molecular Tumor Board identified molecular alterations potentially targetable by an approved or investigational agent, and 4 of those received the treatment. Out of 11 tumor samples implanted in mice, 5 gave rise to PDX, all preserved in a local PDX Bio-bank. Comparing all genomic variants of the 5 tumors with developed PDX samples up to second generation, we observed a high grade of similarity among primary tumors and subsequent PDX tumor models (Pearson coefficients>0.8). Considered the allele frequency distribution, a significant increase in the PDX tumor models at first generation (G1) (median=0.008) and second generations (G2) (median=0.038) with respect to the primary tumors (G0) (median=0.034) was observed. The validity and reproducibility of our PDX models was further demonstrated from high rates of conserved somatic variants at G1 compared to G0 tumors (mean=81.93%), at G2 compared to G1 (mean=84.04%) and at G2 compared to G0 tumors (mean=78.31%). Finally, we were able to identify all the potentially actionable genetic alterations of G0 tumors in the PDX generations G1 and G2. A high grade of similarity was confirmed when the histological, the immunophenotypic and the transcriptomic profiles among primary tumors and PDX generations were compared. Also, NB cells grown as 3D demonstrated good rates of conserved somatic variants, paving the way to the creation of a Bio-bank of patient-derived tumor-spheres. The development of a bioinformatics pipeline for RNAseq data analysis is ongoing. Conclusions: Until now, PREME program has reported a large number of NB patient samples, which harbor targetable genomic alterations and has allowed the development of a Bio-banks to be used for translational research. Citation Format: Mario Capasso, Chiara Brignole, Veronica Bensa, Vito Alessandro Lasorsa, Enrico Sebastiani, Sueva Cantalupo, Angela Rita Sementa, Katia Mazzocco, Barbara Cafferata, Valerio Gaetano Vellone, Michele Cilli, Enzo Calarco, Elena Giusto, Eleonora Ciampi, Patrizia Perri, Maria Valeria Corrias, Sanja Aveic, Doriana Fruci, Alessandro Quattrone, Annalisa Tondo, Roberto Luksch, Rossella Mura, Marco Rabusin, Francesco De Leonardis, Monica Cellini, Paola Coccia, Massimo Conte, Loredana Amoroso, Alberto Garaventa, Mirco Ponzoni, Fabio Pastorino. The italian personalized medicine program PREME for high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3407.

Profiling of peripheral blood B-cell transcriptome in children who developed coeliac disease in a prospective study

BackgroundIn coeliac disease (CoD), the role of B-cells has mainly been considered to be production of antibodies. The functional role of B-cells has not been analysed extensively in CoD. MethodsWe conducted a study to characterize gene expression in B-cells from children developing CoD early in life using samples collected before and at the diagnosis of the disease. Blood samples were collected from children at risk at 12, 18, 24 and 36 months of age. RNA from peripheral blood CD19+ cells was sequenced and differential gene expression was analysed using R package Limma. FindingsOverall, we found one gene, HNRNPL, modestly downregulated in all patients (logFC −0·7; q = 0·09), and several others downregulated in those diagnosed with CoD already by the age of 2 years. InterpretationThe data highlight the role of B-cells in CoD development. The role of HNRPL in suppressing enteroviral replication suggests that the predisposing factor for both CoD and enteroviral infections is the low level of HNRNPL expression. FundingEU FP7 grant no. 202063, EU Regional Developmental Fund and research grant PRG712, The Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research (SyMMyS) 2012–2017, grant no. 250114) and, AoF Personalized Medicine Program (grant no. 292482), AoF grants 292335, 294337, 319280, 31444, 319280, 329277, 331790) and grants from the Sigrid Jusélius Foundation (SJF).

Genetic Variation among Pharmacogenes in the Sardinian Population.

Pharmacogenetics (PGx) aims to identify the genetic factors that determine inter-individual differences in response to drug treatment maximizing efficacy while decreasing the risk of adverse events. Estimating the prevalence of PGx variants involved in drug response, is a critical preparatory step for large-scale implementation of a personalized medicine program in a target population. Here, we profiled pharmacogenetic variation in fourteen clinically relevant genes in a representative sample set of 1577 unrelated sequenced Sardinians, an ancient island population that accounts for genetic variation in Europe as a whole, and, at the same time is enriched in genetic variants that are very rare elsewhere. To this end, we used PGxPOP, a PGx allele caller based on the guidelines created by the Clinical Pharmacogenetics Implementation Consortium (CPIC), to identify the main phenotypes associated with the PGx alleles most represented in Sardinians. We estimated that 99.43% of Sardinian individuals might potentially respond atypically to at least one drug, that on average each individual is expected to have an abnormal response to about 17 drugs, and that for 27 drugs the fraction of the population at risk of atypical responses to therapy is more than 40%. Finally, we identified 174 pharmacogenetic variants for which the minor allele frequency was at least 10% higher among Sardinians as compared to other European populations, a fact that may contribute to substantial interpopulation variability in drug response phenotypes. This study provides baseline information for further large-scale pharmacogenomic investigations in the Sardinian population and underlines the importance of PGx characterization of diverse European populations, such as Sardinians.

Immunogenicity and clinical efficacy of anti‐SARS‐CoV‐2 vaccination in patients with hematological malignancies: Results of a prospective cohort study of 365 patients

Immunogenicity and clinical efficacy of anti‐SARS‐CoV‐2 vaccination in patients with hematological malignancies: Results of a prospective cohort study of 365 patients

Soluble CD14 Levels in the Jackson Heart Study: Associations With Cardiovascular Disease Risk and Genetic Variants.

[Figure: see text].

The welfare state driving “me” and “we” medicine – a critical discourse analysis

This study explored the relationship between visions of personalized medicine, for-profit companies, and state governance in the context of an ongoing discussion of “me” vs. “we” medicine. It took its empirical departure in a Scandinavian welfare state, Denmark, and a discourse analysis was conducted based on interviews, documents, webpages, and media sources from vital public and private stakeholders. The analysis demonstrated how the development of a program for personalized medicine in Denmark emerges as largely driven by the state. Although for-profit companies are involved, the Danish state governs the development of the personalized medicine program single-handedly. This results in a form of personalized medicine framed in both “me” and “we” discursive terms. The analysis revealed that the welfare state plays a dominating role and controls these discourses articulating certain ideas of “me” and “we.” When compared to other studies, these results showed how the role of welfare states may still remain potent in the development of personalized medicine, and in the case of a Scandinavian welfare state, this challenges established views of a “me” vs. “we” dichotomy.

Abstract P5-12-05: Clinical outcomes in early breast cancer patients on adjuvant tamoxifen: Impact of CYP2D6 genotype and observed endoxifen concentrations

Abstract Background: Tamoxifen is widely used in patients with hormone sensitive breast cancer in the adjuvant setting to decrease risk of recurrence and metastasis. 5-10 years of tamoxifen has demonstrated a near 50% reduction in recurrence risk. Despite marked interpatient variation in the metabolism of tamoxifen to its active metabolite endoxifen, all patients are prescribed 20 mg daily dose of tamoxifen. Current evidence suggests that patients are at risk for suboptimal benefit if measured endoxifen concentration is below 5.9 ng/ml (~15nM). However, there have been conflicting data on the clinical utility of CYP2D6 genotype testing, and measuring endoxifen plasma concentration as a predictor of breast cancer recurrence. The goal of this prospective study was to determine the impact of endoxifen levels and CYP2D6 genetic variations to clinical outcome among patients with early breast cancer. Methods: Since 2010, as part of Personalized Medicine Program in Oncology, our team has been prospectively enrolling patients on tamoxifen therapy. To date 950 patients have been enrolled and preliminary analysis has been completed in 429. After initial CYP2D6 genotype testing, plasma concentration of tamoxifen and its metabolites were quantified using liquid chromatography-tandem mass spectrometry during each clinic visit. Baseline characteristic are outlined in table 1. Primary outcome assessed was invasive disease-free survival (IDFS) defined as time since start of tamoxifen therapy till an event of interest such as loco-regional recurrence, distant metastasis, new contralateral primary breast cancer, death due to breast cancer and other causes. Patients were censored at their last encounter at our institution (London Health Sciences Centre). Results: IDFS data for 426 patients were obtained. Outcome was stratified by CYP2D6 phenotypes (ultra-rapid, extensive, intermediate and poor metabolizers) and endoxifen levels (>5.9ng/ml or <5.9ng/ml). CYP2D6 phenotype did not demonstrate a significant association for IDFS. However, Kaplan Meier analysis stratified for endoxifen concentration >vs< 5.9 ng/ml showed a clear trend towards lower IDFS (hazard ratio = 2.4, (95%CI,1.26-4.77) P=0.0002) among those with endoxifen < 5.9 ng/ml. We note this preliminary data analysis was unadjusted and will undergo further in-depth statistical analysis. Conclusion: Preliminary finding suggests endoxifen concentration, but not CYP2D6 phenotype, may be a predictor of risk for suboptimal benefit during tamoxifen therapy. Detailed statistical analysis is planned for the full cohort, including adjustment for covariates including tumor stage, menopausal status, drug interactions, and use of aromatase inhibitors. To our knowledge, this is the first study of its type to prospectively collect multiple plasma samples for tamoxifen and endoxifen level in real-world patients during tamoxifen therapy, with sufficient sample size and follow-up period for primary clinical outcome. Table 1: Baseline Characteristics of PatientsCharacteristicsCYP2D6-Phenotypes, n=429 (%)Endoxifen concentration, n=429 (%)UM/EMIMPM>5.9ng/ml(~15nm)<5.9ng/ml(~15nm)n= 256n= 153n= 20n=376n= 53Age at DiagnosisMean5049485048Range24-8928-7928-8324-8427-88SexMale3 (1)7(5)08(2)2(4)Female253 (99)146(95)20(100)368(98)51(96)Tumor statusT1121(47)70(46)9(45)177(47)23(43)T297(38)58(38)10(50)142(38)23(43)T318(7)16(10)1(5)30(8)5(9)T412(5)4(3)016(4)0unknown8(3)5(3)011(3)2(4)Nodal statusN0124(97)71(46)10(50)179(48)26(49)N195 (37)53(35)9(45)144(38)13(24)N217(7)18(12)1(5)28(7)8(15)N313(5)5(3)015(4)3(6)Unknown7(3)6(4)010(3)3(6)HistologyIDC205(80)128(84)16(80)303(81)48(91)ILC28(11)14(9)3(15)41(11)3(6)other5(2)2(1)06(2)0unknown18(7)9(6)1(5)26(7)2(4)Grade154(21)24(16)3(15)78(21)3(6)2139(54)84(55)13(65)202(54)34(64)354(21)39(25)4(20)84(3)13(24)unknown9(4)6(4)012(3)3(6)ER+251(98)151(99)20(100)369(98)53(100)-5(2)2(1)07(2)0unknown00000PR+232(90)142(93)20(100)343(91)51(96)-24(9)11(7)033(9)2(4)unknown00000Her2+55(21)25(16)5(25)75(20)10(19)-200(78)127(84)15(75)299(80)43(81)unknown1102(1)0Breast SurgeryMastectomy149(58)84(55)11(55)214(57)30(57)Lumpectomy105(41)68(44)9(45)159(42)23(43)Unknown2(1)103(1)0Axillary SurgerySLNB137(54)80(52)12(60)204(54)25(47)ALND113(44)70(46)8(40)165(44)26(49)Unknown6(2)3(2)07(2)2(4)Chemotherapy190(74)108(71)16(80)277(74)37(70)Radiation Therapy213(83)126(82)17(85)310(82)46(87)Herceptin57(22)23(15)6(30)77(16)9(17) Citation Format: Veera Durga Sravanthi Panuganty, Denise Keller, Wendy A Teft, John Gordon Lenehan, Kylea Raijann Potvin, Jawaid Younus, Theodorus Anthony Vandenberg, Diane Mary Logan, Karin Hahn, Muriel Brackstone, Phillip Stanley Blanchette, Francisco Perera, Yun-Hee Choi, Richard Brian Kim. Clinical outcomes in early breast cancer patients on adjuvant tamoxifen: Impact of CYP2D6 genotype and observed endoxifen concentrations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-05.

Patient selection for a developmental therapeutics program using whole genome and Transcriptome analysis.

Introduction Given the high level of uncertainty surrounding the outcomes of early phase clinical trials, whole genome and transcriptome analysis (WGTA) can be used to optimize patient selection and study assignment. In this retrospective analysis, we reviewed the impact of this approach on one such program. Methods Patients with advanced malignancies underwent fresh tumor biopsies as part of our personalized medicine program (NCT02155621). Tumour molecular data were reviewed for potentially clinically actionable findings and patients were referred to the developmental therapeutics program. Outcomes were reviewed in all patients, including those where trial selection was driven by molecular data (matched) and those where there was no clear molecular rationale (unmatched). Results From January 2014 to January 2018, 28 patients underwent WGTA and enrolled in clinical trials, including 2 patients enrolled in two trials. Fifteen patients were matched to a treatment based on a molecular target. Five patients were matched to a trial based upon single-gene DNA changes, all supported by RNA data. Ten cases were matched on the basis of genome-wide data (n = 4) or RNA gene expression only (n = 6). With a median follow-up of 6.7months, the median time on treatment was 8.2weeks. Discussion When compared to single-gene DNA-based data alone, WGTA led to a 3-fold increase in treatment matching. In a setting where there is a high level of uncertainty around both the investigational agents and the biomarkers, more data are needed to fully evaluate the impact of routine use of WGTA.

Personalized Medicine Program in Myelodysplastic Syndromes

Personalized Medicine Program in Myelodysplastic Syndromes

Paradigm changes for diagnosis: using big data for prediction.

Due to profound changes occurring in biomedical knowledge and in health systems worldwide, an entirely new health and social care scenario is emerging. Moreover, the enormous technological potential developed over the last years is increasingly influencing life sciences and driving changes toward personalized medicine and value-based healthcare. However, the current slow progression of adoption, limiting the generation of healthcare efficiencies through technological innovation, can be realistically overcome by fostering convergence between a systems medicine approach and the principles governing Integrated Care. Implicit with this strategy is the multidisciplinary active collaboration of all stakeholders involved in the change, namely: citizens, professionals with different profiles, academia, policy makers, industry and payers. The article describes the key building blocks of an open and collaborative hub currently being developed in Catalonia (Spain) aiming at generation, deployment and evaluation of a personalized medicine program addressing highly prevalent chronic conditions that often show co-occurrence, namely: cardiovascular disorders, chronic obstructive pulmonary disease, type 2 diabetes mellitus; metabolic syndrome and associated mental disturbances (anxiety-depression and altered behavioral patterns leading to unhealthy life styles).

Implementing a personalized medicine program in a community health system.

The implementation of a de novo personalized medicine program in a rural community health system serving an underserved population is described. Focusing on the safe use of drugs impacted by genetic variations in the non-oncology setting, we first addressed drug-gene pairs designated by the US FDA in black-box warnings (codeine, clopidogrel, abacavir, carbamazepine). The program's first success was a policy change to remove codeine from the pediatric formulary, rather than a testing recommendation. Pilot studies were then conducted with primary care providers to get them familiar with pharmacogenetic testing, and a consultative outpatient clinic for patients was developed. The assessment, planning, implementation, challenges, successes and lessons learned are described.

Pharmacogenomics Guided-Personalization of Warfarin and Tamoxifen.

The use of pharmacogenomics to personalize drug therapy has been a long-sought goal for warfarin and tamoxifen. However, conflicting evidence has created reason for hesitation in recommending pharmacogenomics-guided care for both drugs. This review will provide a summary of the evidence to date on the association between cytochrome P450 enzymes and the clinical end points of warfarin and tamoxifen therapy. Further, highlighting the clinical experiences that we have gained over the past ten years of running a personalized medicine program, we will offer our perspectives on the utility and the limitations of pharmacogenomics-guided care for warfarin and tamoxifen therapy.

Analysis of reimbursement (R) for next generation sequencing (NGS) on patients' tumors in the context of a personalized medicine program.

6506 Background: R policies for NGS testing vary widely among private and public insurers. While drug costs are the greatest challenge in personalized or precision medicine, cost and R are substantial barriers to genomic profiling with NGS. We examined variation in coverage and R for a cohort of cancer patients (pts) treated at a tertiary oncology center. Methods: An Institutional Review Board approved prospective registration protocol was activated with the objective of establishing a centralized longitudinal clinical, molecular phenotypic, and research data repository for pts diagnosed with cancer. Based on provider assessment of medical necessity, mutations in 68 cancer associated genes were analyzed. Evaluation of R for NGS was performed from Sept, 2014 through Jan, 2017, with use of CPT code 81455. R was analyzed based on: payer type; pt age; localized vs. metastatic disease; and actionability of data. Results: 588 pts with evaluable analytic cases, and NGS testing, with R results shown in the table below. For groups with >= 10 pts: R frequency was highest in managed care programs, either private or Medicare, and least frequent in non-HMO Medicare (p<.001). In pts receiving R, payments by private HMOs were highest (p<.02). NGS results with labelled drug indications were associated with less frequent R (26% vs. 35%; p<.05), and lower payments (mean of $358 vs. $567; p<.02) compared to other NGS results. Younger age was associated with more frequent R (38% in pts <60 years, 24% in pts >= 60 years; p<.005). Neither cancer diagnosis nor stage were significantly associated with R. Conclusions: One third of pts received some R for NGS testing. R was more frequent and higher in managed care programs, both private and Medicare. R was more likely for younger age pts, while actionable NGS results were associated with lower R. These data demonstrate the need for rational, transparent, and consistent R policies, along with a value-based R model for NGS across all payer groups. [Table: see text]

Institutional profile: University of Florida Health Personalized Medicine Program.

The University of Florida (UF) Health Personalized Medicine Program launched in 2012 with CYP2C19 genotyping for clopidogrel response at UF Health Shands Hospital. We have since expanded CYP2C19 genotyping to UF Health Jacksonville and established the infrastructure at UF Health to support clinical implementation for five additional gene-drug pairs: TPMT-thiopurines, IFNL3 (IL28B)-PEG IFN-α-based regimens, CYP2D6-opioids, CYP2D6/CYP2C19-antidepressants and CYP2C19-proton pump inhibitors. We are contributing to the evidence based on outcomes with genotype-guided therapy through pragmatic studies of our clinical implementations. In addition, we have developed a broad array of educational programs for providers, trainees and students that incorporate personal genotype evaluation to enhance participant learning.

Avoidable drug-gene conflicts and polypharmacy interactions in patients participating in a personalized medicine program.

Determine the ability of a pharmacogenetic service, PRIMER, to identify drug-gene (DGI) and drug-drug interactions (DDI) in patients across multiple conditions. PRIMER consists of patient selection criteria, a gene panel and actionable guidance for DGIs and DDIs. The average patient was prescribed 12 medications. PRIMER identified significant DGIs in 73% of patients tested, with 43% having more than one DGI. DDIs were found in 87% of patients. The most common actionable DGIs were for opioid, psychotropic and cardiovascular medications. The pairing of patient selection criteria, a multigene panel with evidence-based interpretation and review of DDIs maximizes the patients tested who have actionable benefit and alerts physicians to potentially critical adjustments needed for the patient's medication regimen.

Initiative for Molecular Profiling and Advanced Cancer Therapy and challenges in the implementation of precision medicine

In the last decade, breakthroughs in technology have improved our understanding of genomic, transcriptional, proteomic, epigenetic aberrations and immune mechanisms in carcinogenesis. Genomics and model systems have enabled the validation of novel therapeutic strategies. Based on these developments, in 2007, we initiated the IMPACT (Initiative for Molecular Profiling and Advanced Cancer Therapy) study, the first personalized medicine program for patients with advanced cancer at The University of Texas MD Anderson Cancer Center. We demonstrated that in patients referred for Phase I clinical trials, the use of tumor molecular profiling and treatment with matched targeted therapy was associated with encouraging rates of response, progression-free survival and overall survival compared to non-matched therapy. We are currently conducting IMPACT2, a randomized study evaluating molecular profiling and targeted agents in patients with metastatic cancer. Optimization of innovative biomarker-driven clinical trials that include targeted therapy and/or immunotherapeutic approaches for carefully selected patients will accelerate the development of novel drugs and the implementation of precision medicine.

Personalized medicine as a model of care to improve patient outcomes, communication, and reduce cost.

e270 Background: Cancer treatment based on an individual’s tumor profiling has been associated with increased time to progression. Despite this, adoption has been impeded by various technical, financial, legislative, and ethical issues. Implementation of a personalized medicine program into a healthcare system with a goal of improving patient outcomes includes clinician and patient education, increased tumor profiling of patients, data sharing/analysis, expanded research, and billing/reimbursement practices. Methods: A personalized medicine program was implemented at a hospital system. Measures of physician practice included attendance at genomic medicine education sessions, utilization of genetic/genomic tests, enrollment of patients into clinical trials, modifications in billing practices, and submission of data for analysis. Reimbursement of off-label pharmaceutical agents as well as use of aggregate data to inform treatment and enrollment in biomarker-based clinical trials was recorded. Frequency of genetic and/or genomic tests relative to physician and patient education and access to research opportunities was also assessed. Early patient outcomes, overall costs of care, access to clinical trials, and changes in knowledge and communication are also being monitored. Results: Although analysis is ongoing, the initial assessment indicates an increased utilization of genetic and genomic tests, clarity in billing practices, improved reimbursement for off label therapies, and consumption of educational opportunities from clinicians to patients/caregivers. Analysis of the first year implementation will be reported, including evaluation of preliminary results relative to quality of life and survivorship. Conclusions: Preliminary analysis of data from implementation of a personalized medicine program indicates that utilizing relevant education, research, aggressive billing and reimbursement processes, and IT infrastructure, can provide patients with the individual therapies which reduce cost and improve survivorship.