Evidence-based Precision Medicine Research Articles

Impact of the integration of remote clinical oncology pharmacists into routine precision medicine workflows on biomarker testing rates within The US Oncology Network community-based practices.

e13813 Background: The US Oncology Network implemented a centralized, remote clinical oncology pharmacist review program (ClinReview) into select community-based practices. Initially, pharmacists were integrated into a precision medicine workflow process to increase biomarker testing rates among patients receiving adjuvant treatment for non-small cell lung cancer, with recommendations achieving a 100% acceptance rate. Following this success, metastatic prostate cancer patients were incorporated into the established workflow, following updated guideline recommendations for both germline and somatic testing and the 2023 approvals of PARP inhibitors in the first-line treatment setting. With previously reported testing rates only reaching 60%, we sought to evaluate the impact of the pharmacist integration into the precision medicine workflow on biomarker testing in metastatic prostate patients. Methods: Over a 4-month period, ClinReview remotely identified patients with metastatic prostate cancer during normal order review. The EMR was reviewed to assess germline and somatic testing status. If testing was not ordered, the pharmacist sent a recommendation to the treating provider. Initial testing rates for germline and somatic testing, BRCA+ status and provider acceptance rates for testing recommendations were collected. Additional data was collected utilizing a de-identified database. While additional data collection is ongoing, descriptive statistics were utilized to analyze data and the impact of the pharmacists’ interventions. Results: Across 9 practices, 142 patients were initiated on treatment for metastatic prostate cancer. At the time of initial assessment, germline and somatic testing was not ordered in 50% and 37% of patients, respectively. Pharmacists recommended additional testing in 61 patients (43%) with a 73% provider acceptance rate. Findings showed equitable testing rates across racial demographics. Pharmacist workflow integration enhanced combined germline and somatic testing rates, demonstrating an improvement from a baseline of 57% up to 77% currently. Conclusions: Community oncology practices seek to provide high-value care, including offering the most current evidence-based precision medicine testing. These findings highlight the continued need for improved somatic and germline testing in metastatic prostate cancer. However, the implemented precision medicine pharmacist workflow demonstrates the positive impact a clinical pharmacist can have on both testing rates and the potential to improve therapeutic offerings within this growing treatment space. [Table: see text]

A review of pharmacogenetic studies in the Bangladeshi population.

Pharmacogenetics (PGx)-guided prescribing is an evidence-based precision medicine strategy. Although the past two decades have reported significant advancements in both the quality and quantity of PGx research studies, they are seldom done in developing countries like Bangladesh. This review identified and summarized PGx studies conducted in the Bangladeshi population by searching PubMed and Google Scholar. Additionally, a quality evaluation of the identified studies was also carried out. Eleven PGx studies were identified that looked at the effects of genetic variants on blood thinners (CYP2C9, VKORC1, and ITGB3), cancer drugs (TPMT, MTHFR, DPYD, ERCC1, GSTP1, XPC, XRCC1, TP53, XPD, and ABCC4), statins (COQ2, CYP2D6, and CYP3A5), and prednisolone (ABCB1, CYP3A5, and NR3C1) inthe Bangladeshi population. Most studies were of low tomoderate quality. Although the identified studies demonstrated the potential for PGx testing, the limited PGx literature in the Bangladeshi population poses a significant challenge in the widespread implementation of PGx testing in Bangladesh.

P32: a sex- and gender-sensitive model for evidence-based precision medicine: from knowledge generation to implementation in the field of kidney transplantation

Precision medicine emerged as a promising approach to identify suitable interventions for individual patients with a particular health concern and at various time points. Technology can enable the acquisition of increasing volumes of clinical and "omics" data at the individual and population levels and support advanced clinical decision making. However, to keep pace with evolving societal realities and developments, it is important to systematically include sex- and gender-specific considerations in the research process, from the acquisition of knowledge to implementation. Building on the foundations of evidence-based medicine and existing precision medicine frameworks, we propose a novel evidence-based precision medicine framework in the form of the P32model, which considers individual sex-related (predictive [P1], preventive [P2], and personalized [P3] medicine) and gender-related (participatory [P4], psychosocial [P5], and percipient [P6] medicine) domains and their intersection with ethnicity, geography, and other demographic and social variables, in addition to population, community, and public dimensions (population-informed [P7], partnered with community [P8], and public-engaging [P9] medicine, respectively). Through its ability to contextualize and reflect on societal realities and developments, our model is expected to promote consideration of diversity, equity, and inclusion principles and, thus, enrich science, increase reproducibility of research, and ensure its social impact.

Breaking Barriers to Rapid Whole Genome Sequencing in Pediatrics: Michigan's Project Baby Deer.

The integration of precision medicine in the care of hospitalized children is ever evolving. However, access to new genomic diagnostics such as rapid whole genome sequencing (rWGS) is hindered by barriers in implementation. Michigan's Project Baby Deer (PBD) is a multi-center collaborative effort that sought to break down barriers to access by offering rWGS to critically ill neonatal and pediatric inpatients in Michigan. The clinical champion team used a standardized approach with inclusion and exclusion criteria, shared learning, and quality improvement evaluation of the project's impact on the clinical outcomes and economics of inpatient rWGS. Hospitals, including those without on-site geneticists or genetic counselors, noted positive clinical impacts, accelerating time to definitive treatment for project patients. Between 95-214 hospital days were avoided, net savings of $4155 per patient, and family experience of care was improved. The project spurred policy advancement when Michigan became the first state in the United States to have a Medicaid policy with carve-out payment to hospitals for rWGS testing. This state project demonstrates how front-line clinician champions can directly improve access to new technology for pediatric patients and serves as a roadmap for expanding clinical implementation of evidence-based precision medicine technologies.

PM-Search: State-of-the-art Evidence Retriever for Precision Medicine: Algorithm Development and Validation.

Under the paradigm of Precision Medicine (PM), patients with the same disease can receive different personalized therapies according to their clinical and genetic features. These therapies are determined by the totality of all available clinical evidence, including results from case reports, clinical trials, and systematic reviews. However, it is increasingly difficult for physicians to find such evidence from scientific publications, whose size is growing at an unprecedented pace. In this work, we propose the PM-Search system to facilitate the retrieval of clinical literature that contains critical evidence for or against giving specific therapies to certain cancer patients. The PM-Search system combines a Baseline Retriever that selects document candidates at a large scale and an Evidence Re-ranker that finely reorders the candidates based on their evidence quality. The Baseline Retriever uses query expansion and keyword matching with the Elasticsearch retrieval engine, and the Evidence Re-ranker fits pre-trained language models to expert annotations that are derived from an active learning strategy. The PM-Search system achieves the best performance in the retrieval of high-quality clinical evidence at the TREC PM Track 2020, outperforming the second-ranking systems by large margins (0.4780 vs. 0.4238 for standard NDCG@30 and 0.4519 vs. 0.4193 for exponential NDCG@30). We present PM-Search, a state-of-the-art search engine to assist the practicing of evidence-based PM. PM-Search uses a novel BioBERT-based active learning strategy that models evidence quality and improves the model performance. Our analyses show that evidence quality is a distinct aspect from general relevance, and specific modeling of evidence quality beyond general relevance is required for a PM search engine.

Community health workers and precision medicine: A randomized controlled trial

BackgroundPrecision cancer care has reduced cancer-related mortality. However, minorities remain less likely to receive precision medicine than White populations with cancer due to language and system-level barriers. Precision medicine knowledge increases involvement in treatment decisions and receipt of such treatment. Few interventions exist that seek to improve precision medicine knowledge among low-income and racial and ethnic minorities with cancer. MethodsWe designed a randomized controlled trial to evaluate the effectiveness of a community health worker (CHW)-delivered intervention on patients' knowledge of precision medicine in partnership with a community oncology clinic in Monterey County, California. Eligibility includes adults with newly diagnosed, progression or recurrence of cancer, low-income, or racial and ethnic minorities, or uninsured, insured by Medicaid or by a local agricultural employer. We will randomize 110 patients with cancer to the intervention or usual cancer care. The intervention group will be assigned to a CHW who will deliver culturally tailored and personalized education on precision medicine and advance care planning, screen for social determinants of health barriers and connect patients to community resources. The primary outcome is precision medicine knowledge measured by a 6-item survey adapted from Davies at baseline, 3-, 6- and 12-months post-enrollment. Exploratory outcomes include patient satisfaction with decision, activation, health care utilization, and receipt of evidence-based precision medicine care. ConclusionThis trial will assess whether the CHW-led intervention can increase knowledge of precision medicine as well as several exploratory outcomes including receipt of evidence-based cancer care among low-income and racial and ethnic minority adults with cancer.ClinicalTrials.gov Registration # NCT04843332

From precision of the evidence to the evidence for precision: An intriguing odyssey!

Dear Editor, Evidence-based medicine (EBM), described as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients” is the expected modus operandi of delivering health care in the 21st century.[1] However, the original connotation has been probably lost in transition with the increasing incorporation of perioperative guidelines and protocols, promoting pertinent concerns on the impact on physician autonomy, individualized clinical judgement, and the implications of practice variability which are being increasingly debated by the fraternity.[2-4] Interestingly, while a number of factors such as physician awareness of and compliance to the ever-increasing research volume are often cited as reasons precluding the EBM practice, the precision of the evidence continues to be an important contemplation. The spectrum consists of controversies over highly cited randomized controlled trials, medical reversal phenomenon, and the inherent biases involved.[2] Nevertheless, the wise words of Prof Ioannidis: “EBM has been hijacked and has been transformed into guidelines-based medicine” highlight the underlying inexorable transition process in the EBM domain.[3] This is heralded by the fact that the guidelines are often only EBM in concept, prone to biases emanating from institutional support, conflicts of interest, etc. Moreover, they are peculiarly “rigid”, designed for an average subset, demonstrating an inherent lack of sensitivity for the clinical and individual context.[4] The discussion is further accentuated by the various practitioners emphasizing the need for befitting evidence as per the context-appropriateness considering the elucidation of the detrimental effect of various clinical pathways in particular scenarios.[567] Alongside the continuing deliberation on the precision of the evidence that is worth practice changing, the concept of precision medicine has dawned almost inevitably. The precision medicine slogan: “One-size-does-not-fit-all” embraces the commonplace heterogeneity observed in the treatment effects, perioperative complications and associated outcomes.[89] The proponents of the notion opine that EBM by nature regards treatment at a population level with minimal individualistic considerations and highlight the importance of personalizing clinical medicine. Nevertheless, the overarching premise to make precision medicine evidence-based is substantially challenging given a patient is much more than a set of covariates and incurs multipronged difficulties in the terms of investigation, knowledge-acquisition, education, interpretation, and dissemination of multilevel data, from cellular level to environment and lifestyle, for the ever-diversifying patient population. To conclude, much or most of the practice variability in clinical medicine stems from the subtle differences among the patients.[789] Therefore, personalized management is appreciated well even in the era of EBM aimed at improving patient outcomes as it does not annihilate intuition, clinical expertise, and reasoning physiology as the ground for decision-making while accounting for the systematic evaluation of the evidence. In fact, distant from the dogma of EBM and precision medicine being dichotomous, an intuitive “open-mind” can complement both to practice evidence-based precision medicine in a unified pluralistic health care model, particularly relevant in the perioperative management of high-risk surgical cohort. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Automatic Identification of High Impact Relevant Articles to Support Clinical Decision Making Using Attention-Based Deep Learning

To support evidence-based precision medicine and clinical decision-making, we need to identify accurate, appropriate, and clinically relevant studies from voluminous biomedical literature. To address the issue of accurate identification of high impact relevant articles, we propose a novel approach of attention-based deep learning for finding and ranking relevant studies against a topic of interest. For learning the proposed model, we collect data consisting of 240,324 clinical articles from the 2018 Precision Medicine track in Text REtrieval Conference (TREC) to identify and rank relevant documents matched with the user query. We built a BERT (Bidirectional Encoder Representations from Transformers) based classification model to classify high and low impact articles. We contextualized word embedding to create vectors of the documents, and user queries combined with genetic information to find contextual similarity for determining the relevancy score to rank the articles. We compare our proposed model results with existing approaches and obtain a higher accuracy of 95.44% as compared to 94.57% (the next best performer) and get a higher precision by about 14% at P@5 (precision at 5) and about 12% at P@10 (precision at 10). The contextually viable and competitive outcomes of the proposed model confirm the suitability of our proposed model for use in domains like evidence-based precision medicine.

ARtPM: Article Retrieval for Precision Medicine.

Information curation and literature surveillance efforts that synthesize the current knowledge about the impact of genetic variability on disease states and drug responses are vitally important for the practise of evidence-based precision medicine. For these efforts, finding the relevant and comprehensive set of articles from the ever growing scientific literature is a challenge. We have designed and developed Article Retrieval for Precision Medicine (ARtPM), an end-to-end article retrieval system that employs multi-stage architecture to retrieve and rank relevant articles for a given medical case summary (genetic variants, disease, demographic, and other medical conditions). We compared ARtPM with five baselines, including PubMed Best Match, the improved search functionality recently introduced by PubMed. The differences in the performance of ARtPM and five baselines were statistically significant for four metrics that quantify different aspects of search effectiveness (P-values for P@10, R-prec, infNDCG, Recall@1000 were <.001, <.001,.003,.009, respectively). Pairwise systems' comparisons show that ARtPM is comparable or better than the best performing baseline on three metrics (R-prec: 0.324 vs 0.299, P-value=.06; infNDCG: 0.556 vs 0.465, P-value=.08; R@1000: 0.665 vs 0.572, P-value=.007), but performance in P@10 (0.603 vs 0.630, P-value:.64) needs to improve. The recall-focused phase of the ARtPM is effective at retrieving more relevant articles. The precision-focused ranking phase performs well at deeper ranks but needs further work on early ranks (e.g., richer feature set). Overall, the ARtPM system effectively facilitates evidence-based precision medicine practice, and provides a robust search framework for further work in this direction.

PTEN-opathies: from biological insights to evidence-based precision medicine.

The tumor suppressor phosphatase and tensin homolog (PTEN) classically counteracts the PI3K/AKT/mTOR signaling cascade. Germline pathogenic PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), featuring various benign and malignant tumors, as well as neurodevelopmental disorders such as autism spectrum disorder. Germline and somatic mosaic mutations in genes encoding components of the PI3K/AKT/mTOR pathway downstream of PTEN predispose to syndromes with partially overlapping clinical features, termed the "PTEN-opathies." Experimental models of PTEN pathway disruption uncover the molecular and cellular processes influencing clinical phenotypic manifestations. Such insights not only teach us about biological mechanisms in states of health and disease, but also enable more accurate gene-informed cancer risk assessment, medical management, and targeted therapeutics. Hence, the PTEN-opathies serve as a prototype for bedside to bench, and back to the bedside, practice of evidence-based precision medicine.

Electroencephalogram (EEG) for children with autism spectrum disorder: evidential considerations for routine screening.

Routine electroencephalograms (EEG) are not recommended as a screen for epileptic discharges (EDs) in current practice guidelines for children with autism spectrum disorder (ASD). However, a review of the research from the last three decades suggests that this practice should be reevaluated. The significant comorbidity between epilepsy and ASD, its shared biological pathways, risk for developmental regression, and cognitive challenges demand increased clinical investigation requiring a proactive approach. This review highlights and explains the need for screening EEGs for children with ASD. EEG would assist in differentiating EDs from core features of ASD and could be included in a comprehensive assessment. EEG also meets the demand for evidence-based precision medicine and focused care for the individual, especially when overlapping processes of development are present.

Evidence-Based Precision Medicine is Needed to Move Toward General Internal Precision Medicine.

Evidence-Based Precision Medicine is Needed to Move Toward General Internal Precision Medicine.

Reconciling evidence-based medicine and precision medicine in the era of big data: challenges and opportunities.

This era of groundbreaking scientific developments in high-resolution, high-throughput technologies is allowing the cost-effective collection and analysis of huge, disparate datasets on individual health. Proper data mining and translation of the vast datasets into clinically actionable knowledge will require the application of clinical bioinformatics. These developments have triggered multiple national initiatives in precision medicine—a data-driven approach centering on the individual. However, clinical implementation of precision medicine poses numerous challenges. Foremost, precision medicine needs to be contrasted with the powerful and widely used practice of evidence-based medicine, which is informed by meta-analyses or group-centered studies from which mean recommendations are derived. This “one size fits all” approach can provide inadequate solutions for outliers. Such outliers, which are far from an oddity as all of us fall into this category for some traits, can be better managed using precision medicine. Here, we argue that it is necessary and possible to bridge between precision medicine and evidence-based medicine. This will require worldwide and responsible data sharing, as well as regularly updated training programs. We also discuss the challenges and opportunities for achieving clinical utility in precision medicine. We project that, through collection, analyses and sharing of standardized medically relevant data globally, evidence-based precision medicine will shift progressively from therapy to prevention, thus leading eventually to improved, clinician-to-patient communication, citizen-centered healthcare and sustained well-being.

Abstract IA03: Towards the next clinical option: Experience from a precision cancer medicine trial

Abstract Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low frequency mutations. We describe an evidence-based precision medicine program designed to bring whole exome sequencing (WES) into clinical practice and illustrate how this can be utilized to identify novel predictive biomarkers associated with exceptional systemic response. Metastatic and treatment-resistant cancer patients are prospectively enrolled for paired metastatic tumor and normal WES. Using a comprehensive computational pipeline, point mutations, indels and copy number alterations are detected. Mutations are categorized as Category I-III based on actionability and a report is generated and discussed in tumor board. Patients are followed prospectively for correlation of molecular information with clinical response and patient outcomes. A rapid response functional team follows on key findings to expand actionability based on the WES results. In the first year, 154 tumor-normal pairs from 97 patients were sequenced, with an average coverage of 95X of over 21,000 genes and 16 somatic alterations detected on average per patient. In total, 16 mutations were Category I, 98 were Category II, and 1474 were Category III. Tumor purity ranged from 14 to near 100%. Among unexpected findings, a prostate cancer exceptional responder was identified that harbored a somatic hemizygous deletion of the DNA repair gene FANCA and likely loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response. The establishment of a clinical program for whole exome sequencing of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response. Citation Format: Mark A. Rubin. Towards the next clinical option: Experience from a precision cancer medicine trial. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr IA03.

Abstract IA19: Towards the next clinical option: Experience from a precision cancer medicine trial

Abstract Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low frequency mutations. We describe an evidence-based precision medicine program designed to bring whole exome sequencing (WES) into clinical practice and illustrate how this can be utilized to identify novel predictive biomarkers associated with exceptional systemic response. Metastatic and treatment-resistant cancer patients are prospectively enrolled for paired metastatic tumor and normal WES. Using a comprehensive computational pipeline, point mutations, indels and copy number alterations are detected. Mutations are categorized as Category I-III based on actionability and a report is generated and discussed in tumor board. Patients are followed prospectively for correlation of molecular information with clinical response and patient outcomes. A rapid response functional team follows on key findings to expand actionability based on the WES results. In the first year, 154 tumor-normal pairs from 97 patients were sequenced, with an average coverage of 95X of over 21,000 genes and 16 somatic alterations detected on average per patient. In total, 16 mutations were Category I, 98 were Category II, and 1474 were Category III. Tumor purity ranged from 14 to near 100%. Among unexpected findings, a prostate cancer exceptional responder was identified that harbored a somatic hemizygous deletion of the DNA repair gene FANCA and likely loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response. The establishment of a clinical program for whole exome sequencing of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response. Citation Format: Mark A. Rubin. Towards the next clinical option: Experience from a precision cancer medicine trial. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr IA19.

Abstract 4745: Precision cancer medicine program for whole-exome sequencing of metastatic tumors reveals biomarkers of response

Abstract Background: Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low frequency mutations. We describe an evidence-based precision medicine program designed to bring whole exome sequencing into clinical practice and illustrate how this can be utilized to identify novel predictive biomarkers associated with exceptional systemic response. Methods: Metastatic and treatment-resistant cancer patients are prospectively enrolled under an IRB approved protocol for paired metastatic tumor and normal WES through our Precision Medicine Clinic. Using a comprehensive computational pipeline, point mutations, indels and copy number alterations are detected. Mutations are categorized as Category I-III based on actionability and a report is generated and discussed in tumor board. Patients are followed prospectively for correlation of molecular information with clinical response and patient outcomes. A rapid response functional team follows on key findings to expand actionability based on the WES results. Results: In the first year, 154 tumor-normal pairs from 97 patients were sequenced, with an average coverage of 95X of over 21,000 genes and 16 somatic alterations detected on average per patient. In total, 16 mutations were Category I, 98 were Category II, and 1474 were Category III. Tumor purity ranged from 14 to near 100%. Among unexpected findings, a prostate cancer exceptional responder was identified that harbored a somatic hemizygous deletion of the DNA repair gene FANCA and likely loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response. Conclusions: The establishment of a clinical program for whole exome sequencing of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response. Citation Format: Himisha Beltran, Kenneth Eng, Juan Miguel Mosquera, Alexandros Sigaras, Alessandro Romanel, Hanna Rennart, Myriam Kossai, Chantal Pauli, Bishoy Faltas, Jacqueline Fontugne, Brian Robinson, David M. Nanus, Scott T. Tagawa, Jenny Z. Xiang, Francesca Demichelis, David Rickman, Andrea Sboner, Olivier Elemento, Mark A. Rubin. Precision cancer medicine program for whole-exome sequencing of metastatic tumors reveals biomarkers of response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4745. doi:10.1158/1538-7445.AM2015-4745