Precision Medicine Test Research Articles

S440 Clinical Utility of an AI-driven Precision Medicine Test for Barrett’s Esophagus: Results From a Randomized Controlled Trial

S440 Clinical Utility of an AI-driven Precision Medicine Test for Barrett’s Esophagus: Results From a Randomized Controlled Trial

936P Analysis of different EGFR mutations affecting the efficacy of postoperative adjuvant therapy for resectable non-small cell lung cancer

The ADAURA study opens the door for precision medicine and biomarker testing to enter the early stage of non-small cell lung cancer (NSCLC), that is, the precise decision-making of postoperative adjuvant therapy for early-stage. As previously reported, NSCLC patients with different EGFR mutants display heterogeneous clinical course and their different response to EGFR-TKIs, but weather their responses to adjuvant chemotherapy are various is still unclear.

Ethical Considerations in Precision Medicine and Genetic Testing in Internal Medicine Practice: A Position Paper From the American College of Physicians.

This American College of Physicians position paper aims to inform ethical decision making for the integration of precision medicine and genetic testing into clinical care. Although the positions are primarily intended for practicing physicians, they may apply to other health care professionals and can also inform how health care systems, professional schools, and residency programs integrate genomics into educational and clinical settings. Addressing the challenges of precision medicine and genetic testing will guide ethical and responsible implementation to improve health outcomes.

Evidence Threshold for a Precision Medicine Test that Predicts Optimal Response to a Biologic Agent in Patients With Psoriasis: A Consensus Panel.

Precision medicine approaches are receiving increased attention in dermatology, including inflammatory skin diseases. In psoriasis, a precision medicine treatment paradigm could temper the rapid increase in pharmacy costs that have resulted from a tremendous expansion in the number of available biologic drug options. However, without a clear and agreed upon proof of clinical utility in a real-world setting, costly new pharmacotherapies are often burdened with barriers to coverage by payers and ultimately, routine patient care. This panel was assembled to discuss the evidence threshold required to demonstrate the clinical utility of a precision medicine diagnostic that predicts the biologic therapeutic class for treating psoriasis patients. The panel reviewed clinical utility study designs and economic impact study designs aimed at delineating net savings and waste reduction. A psoriasis biologic precision medicine test could optimize pharmacotherapy management of psoriasis patients. The consensus opinion of this panel was that positive results from the study described here would prove the clinical utility of this precision medicine test. J Drugs Dermatol. 2022;21(6):630-636. doi:10.36849/JDD.6864.

Precision Medicine Testing and Disparities in Health Care for Individuals With Non-Small Cell Lung Cancer: A Narrative Review

Precision medicine initiatives provide opportunities for optimal targeted therapy in individuals with non-small cell lung cancer. However, there are barriers to these initiatives that reflect social determinants of health. MEDLINE®, CINAHL®, PsycINFO®, Embase®, and Google ScholarTM databases were searched for articles published in English in the United States from 2016 to 2020. Data that were collected included individual demographic information, specific diagnosis, status of targeted genomic testing, and receipt of targeted therapy. All studies were retrospective and involved database review of insurance claims or medical records. Individuals with non-small cell lung cancer received less genetic testing and targeted therapy if they were of a lower socioeconomic status, had public health insurance or no health insurance, were Black, or lived in rural communities. Social determinants of health affect health equity, including in precision medicine initiatives for individuals with lung cancer. Gaining an understanding of this impact is the first step in mitigating inequities.

Precision Medicine Landscape of Genomic Testing for Patients With Cancer in the National Institutes of Health All of Us Database Using Informatics Approaches.

The rapid growth of biomedical data ecosystems has catalyzed research for oncology and precision medicine. We leverage federal cloud-based precision medicine databases and tools to better understand the current landscape of precision medicine and genomic testing for patients with cancer. Retrospective observational study of genomic testing for patients with cancer in the National Institutes of Health All of Us Research Program, with the cancer cohort defined as having at least two documented or reported cancer diagnoses. There were 5,678 (1.8%) All of Us participants in the cancer cohort, with a significant difference between cancer status by age category, sex, race, and ethnicity (P < .001 for all). There were 295 (5.2%) patients with cancer who received genomic testing compared with 6,734 (2.2%) of noncancer patients, with 752 genomic tests commonly focused on gene mutations (primarily pharmacogenomics), molecular pathology, or clinical cytogenetic reports. Although not yet ubiquitous, diverse clinical genomic analyses in oncology can set the stage to grow the practice of precision medicine by integrating research patient data repositories, cancer data ecosystems, and biomedical informatics.

Biomarker‑driven phase Ib clinical trial of OPB‑111077 in acute myeloid leukemia

OPB‑111077 is a novel, highly specific oral signal transducer and activator of transcription 3 inhibitor that has exhibited good efficacy against solid and blood cancers, including acute myeloid leukemia (AML), in preclinical models. In the present study, a phase 1b, two‑stage, 3+3 dose‑escalation clinical trial [dose level (DL)1 of 200 mg/day and DL2 of 250 mg/day on a once daily dose schedule in 28‑day cycles] was conducted to assess the maximum tolerated dose (MTD), safety profile and the preliminary antitumor activity of OPB‑111077 in patients with high‑risk AML. A preliminary preclinical analysis evaluated the anti‑proliferative activity of OPB‑111077 in 19 patients with AML with a Vivia Biotech <em>ex vivo</em> PharmaFlow precision medicine test. A total of 12 patients were ultimately enrolled in the trial: 5 patients (42%) were treated with DL1, and 7 (58%) were escalated to DL2 of OPB‑111077. Dose‑limiting toxicities were not observed and the MTD was not reached. In addition, the most frequently reported treatment‑emergent adverse events were nausea, vomiting and fatigue. Finally, clinical activity (overall response) was observed in 3 patients (25%). On the whole, the present study demonstrates that OPB‑111077 exhibits a good safety and tolerability profile and an acceptable clinical response in patients with high‑risk AML. A biomarker‑driven design is useful for selecting the study population upfront.

Clinical utility of therapy selection informed by predicted nonresponse to tumor necrosis factor-ɑ inhibitors: an analysis from the Study to Accelerate Information of Molecular Signatures (AIMS) in rheumatoid arthritis

ABSTRACT Background The molecular signature response classifier (MSRC) is a blood-based precision medicine test that predicts nonresponders to tumor necrosis factor-ɑ inhibitors (TNFi) in rheumatoid arthritis (RA) so that patients with a molecular signature of non-response to TNFi can be directed to a treatment with an alternative mechanism of action. Research Design and Methods This study evaluated decision choice and treatment outcomes resulting from MSRC-informed treatment selection within a real-world cohort. Results Therapy selection by providers was informed by MSRC results for 73.5% (277/377) of patients. When MSRC results were not incorporated into decision-making, 62.0% (62/100) of providers reported deviating from test recommendations due to insurance-related restrictions. The 24-week ACR50 responses in patients prescribed a therapy in alignment with MSRC results were 39.6%. Patients with a molecular signature of non-response had significantly improved responses to non-TNFi therapies compared with TNFi therapies (ACR50 34.8% vs 10.3%, p-value = 0.05). This indicates that predicted non-responders to TNFi therapies are not nonresponders to other classes of RA targeted therapy. Significant changes were also observed for CDAI, ACR20, ACR70, and for responses at 12 weeks. Conclusions Adoption of the MSRC into patient care could fundamentally shift treatment paradigms in RA, resulting in substantial improvements in real-world treatment outcomes.

Expectations and educational needs of rheumatologists, rheumatology fellows and patients in the field of precision medicine in Canada, a quantitative cross-sectional and descriptive study

BackgroundPrecision medicine, as a personalized medicine approach based on biomarkers, is a booming field. In general, physicians and patients have a positive attitude toward precision medicine, but their knowledge and experience are limited. In this study, we aimed at assessing the expectations and educational needs for precision medicine among rheumatologists, rheumatology fellows and patients with rheumatic diseases in Canada.MethodsWe conducted two anonymous online surveys between June and August 2018, one with rheumatologists and fellows and one with patients assessing precision medicine expectations and educational needs. Descriptive statistics were performed.Results45 rheumatologists, 6 fellows and 277 patients answered the survey. 78% of rheumatologists and fellows and 97.1% of patients would like to receive training on precision medicine. Most rheumatologists and fellows agreed that precision medicine tests are relevant to medical practice (73.5%) with benefits such as helping to determine prognosis (58.9%), diagnosis (79.4%) and avoid treatment toxicity (61.8%). They are less convinced of their usefulness in helping to choose the most effective treatment and to improve patient adherence (23.5%). Most patients were eager to take precision medicine tests that could predict disease prognosis (92.4%), treatment response (98.1%) or drug toxicity (93.4%), but they feared potential negative impacts like loss of insurability (62.2%) and high cost of the test (57.5%).ConclusionsOur study showed that rheumatologists and patients in Canada are overall interested in getting additional precision medicine education. Indeed, while convinced of the potential benefits of precision medicine tests, most physicians don’t feel confident in their abilities and consider their training insufficient to incorporate them into clinical practice.

Economic Evaluation of The Budget Impact of Precision Medicine Testing for The Treatment of Psoriasis

Objective: This study was a budget impact analysis based on a budget impact model (BIM) and formularies from different commercial payer types (excluding Medicare and Medicaid). The primary objective of this study was to determine the potential cost savings utilizing precision medicine testing of biologics in patients with psoriasis. The evaluation projects the predicted cost savings of multiple formulary scenarios, simulated through the BIM. Methods: A budget impact model was constructed to simulate the impact of Mind.Px, a transcriptomic predictive precision medicine test that can discriminate between psoriasis responders and non-responders, on psoriasis drug usage. This model simulated the impact of Mind.Px on different formularies and cost scenarios, considering the efficacy of individual biologics. All formularies used were acquired from the Policy Reporter database. Results: Several payers representing a spectrum of covered lives populations were used to simulate the impact of Mind.Px through the budget impact model. The budget impact model returned cost savings as low as $5,138 annually to as high as $13,141 annually. Based on the analysis of this subset of payers, the model yielded average cost savings of $8,492 annually as well as an average wasted spend savings of $16,567. All Savings are represented on an annual per patient basis. Conclusions: These savings demonstrate the potential cost savings that precision medicine testing can provide to ease the economic burden on payers, clinics/hospital systems, and patients, and may fill the need for a better method to prescribe drugs for the treatment of psoriasis.

Abstract 2618: Staged analysis of standard of care tumor molecular testing among patients with metastatic colorectal cancer in the community health system setting

Abstract Background: National Comprehensive Cancer Network guidelines have recommended metastatic colorectal cancer patients (mCRC pts) undergo BRAF, KRAS, NRAS, and microsatellite instability/mismatch repair deficiency (MSI/MMR) testing since 2015. Previous studies have reported molecular testing rates from academic and community cancer centers, but there is a lack of information on testing rates in community health systems (HS) which account for approximately half of US cancer care. Methods: Tumor molecular testing rates were assessed in a first stage analysis for pts with mCRC in HS, in order to inform a second stage analysis focused on treatment decisions and pt outcomes. For the first stage analysis, we randomly selected 200 pts (50 pts from each of 4 HS sites) diagnosed with mCRC between 1/1/2015 and 9/1/2020. The 200 pts were identified through technology-enabled curation, followed by retrospective review performed by certified tumor registrars. An anticipated cohort of 1000 evaluable pts is planned for the second stage analysis. Results: 53% of pts were tested for all four biomarkers at some point during their care (Table). Pts more likely to have been tested include those: from HS Site 1 (P = 4.2x10-5); age &amp;lt;65 years old at mCRC diagnosis (P = 0.014); and with commercial insurance (P = 0.015). Among pts tested, the median times from metastatic diagnosis to BRAF, KRAS, and NRAS testing results were 35, 33, and 34 days, respectively. Conclusion: This first stage analysis of molecular testing in mCRC pts revealed variation in testing rates by site, biomarker, and patient characteristics, which may in part be explained by the implementation of a precision medicine testing program at HS Site 1. A second stage analysis assessing the impact of biomarker testing on treatment decisions and pt outcomes will be guided by this initial characterization of testing rates and possible confounders. Biomarker testing rates among metastatic colorectal patients across four health system sitesSite 1 (n=50)Site 2 (n=50)Site 3 (n=50)Site 4 (n=50)BRAF tested43 (86%)25 (50%)24 (48%)26 (52%)Count (%)KRAS tested44 (88%)35 (70%)32 (64%)35 (70%)Count (%)NRAS tested42 (84%)23 (46%)26 (52%)30 (60%)Count (%)MSI/MMR tested49 (98%)37 (74%)44 (88%)44 (88%)Count (%)All biomarkers tested40 (80%)19 (38%)20 (40%)26 (52%)Count (%) Citation Format: Chenan Zhang, Mahder Teka, Francesca F. Coutinho, Joseph R. Burkhart, Louise E. Widmer, Ronda G. Broome, Mary T. Tran, Michael A. Thompson, Antony M. Ruggeri, Jennifer J. Godden, James L. Weese, Douglas J. Reding, Anna B. Berry, Yanina Natanzon, Thomas D. Brown. Staged analysis of standard of care tumor molecular testing among patients with metastatic colorectal cancer in the community health system setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2618.

The imprecise promise of the Precision Medicine Initiative (PMI): Where we got it wrong and how can we fix it?

e15102 Background: Over the last several years, science has taken strides in how we understand and treat cancer. We have learned that each person’s cancer is unique, in part because it is influenced by a patient’s biological characteristics, environmental exposures, lifestyle and epigenetic influence. There is excitement about the potential of PMI to transform healthcare delivery and improve population health. Targeted therapies developed based on specific mutations can result in improved outcomes and reduced toxicities. Limited knowledge of cancer biology and the genomic underpinnings of cancer in racial and ethnic minorities diminishes the potential of PMI. Previous efforts of obtaining biospecimens from institutional or local biobanks presents a challenge of inadequate representation of racial and ethnic diversity. This can result in exacerbation in the therapies efficaciousness. Methods: Numerous research studies have surfaced indicating that PMI has resulted in widening racial and ethnic health care disparities since state-of-the art diagnostic and treatment options are unequally distributed across the entire cancer population. A literature review highlighted the racial inequalities and disparities. Results: A report examining the racial diversity of samples in TCGA found that whites were overrepresented in the U.S. population while Asian and Hispanic patients were underrepresented at a 5 percent frequency. In the BATTLE study, 82 percent of participants were white, and only 6% were African American (AA). The NCI-MATCH trial preliminary numbers show that AAs accounted for about 10 percent of patients. Therefore, it should not be assumed that the response rates or clinical effectiveness of the therapeutics tested in these trials will generalize to all racial and ethnic groups. The underrepresentation of racial and ethnic minorities in cancer clinical trials and prevention research, along with the documented challenges to enrolling these individuals into studies pose a barrier for the implementation of precision medicine in these populations. Collectively, these challenges can slow the pace of medical innovation, decrease the generalizability of research findings, lead to incorrect interpretations, and limit our full understanding of precision medicine. Conclusions: It is imperative we develop solutions to solve for issues identified related to precision medicine testing and treatment development. We have developed a framework to address disparities in PMI through community-based initiatives. A two-step solution could be considered to address this unmet need. Through the development of a registry and biospecimen banking as well as just in time trials that include pharmacogenomics, we can follow the patient journey to identify unique characteristics by race and/or socioeconomic status to begin solving for the disparities across the population.

Precision medicine testing in ovarian cancer: The growing inequity between patients with commercial vs medicaid insurance

IntroductionPrecision medicine technologies have significant impact in the care of patients with ovarian cancer. Compared to affluent patients, socioeconomically vulnerable patients are less likely to have access to this testing. There is little data that demonstrate this inequity over time. MethodsWe used the IBM Truven Health MarketScan Research Database to identify patients in the United States who underwent surgery for ovarian cancer between 2011 and 2017. The presence of claims for precision medicine testing within six months of surgery was assessed for each patient. Precision medicine testing included both molecular genetic testing (BRCA limited or full sequencing, somatic and germline testing) as well as ancillary pathology tests (immunohistochemistry, microsatellite instability). Demographic data was extracted. ResultsWe identified 27,181 patients who met eligibility. Of these, 88.6% had commercial insurance, and 11.4% had Medicaid. While the proportion of patients who underwent precision medicine testing increased over time for both cohorts (47.0% to 66.6% for commercially insured, 41.4% to 57.6% for Medicaid insured, p < 0.0001), the inequity in testing rates widened (5.6% disparity to 9.0%, p < 0.0001). This was driven by growing inequity in germline and somatic genetic testing (7.6% disparity to 21.3%, p < 0.0001). ConclusionsThere is widening inequity in precision medicine testing rates between commercially insured and Medicaid insured poate patients with ovarian cancer.

Abstract PS9-28: Patient knowledge, attitudes and perceptions regarding breast cancer biomarkers, testing, and quality of life

Abstract Background: Precision medicine and molecular testing for specific biomarkers to inform treatment selection has evolved to become the standard of care for advanced breast cancer. Although there is widespread education for health care practitioners, there is less education available for patients. Two surveys from the oncology literature (Pinheiro 2017, Ciardiello 2016), reported that 90% of physicians worldwide utilize biomarkers and patients would like to understand how testing informs treatment. The objective of this survey was to gain a greater understanding of patient familiarity with biomarker testing, specifically ESR1 mutation testing, and willingness to request information and testing. Patients were also surveyed about other areas of education of greatest interest, including quality of life (QOL) issues. Methods: A 10 question on-line survey was sent to patients through 2 patient advocacy organizations: CURE’s CURExtra e-newsletter, and METAvivor’s social media channels; METAvivor’s survey included 2 additional questions to determine if respondents had metastatic disease and were currently on treatment. The survey asked about side effects impacting quality of life, satisfaction with information received about QOL issues, and knowledge about biomarkers (specifically ESR1), as well as willingness to request ESR1 testing. Results: A total of 343 completed responses were received: 177 from CURE and 166 from METAvivor, 82.5% from patients, 11% from patients who were patients and advocates, 2.3% from advocates, and 4.3% other. Disease subgroups included ER+/HER2- (53%), ER+/HER2+ (16%), TNBC (12%) and ER-/HER2+ (11%). The mean and median times from diagnosis were 8.25 and 6 years. 22% of patients surveyed were familiar with or aware of biomarker testing; only 12% were familiar with ESR1 mutations and biomarker testing. In contrast, 75% of respondents were very likely (52%) or likely (23%) to ask their provider about ESR1 mutations if this would aid in tailoring treatment, with METAvivor respondents more likely to than CURE respondents (78 vs 70%). 71% were very likely (49%) or likely (22%) to request ESR1 mutation testing. Survey respondents identified 3 areas of greatest interest: new treatments in development, QOL, and management of side effects. Joint (62%) and bone pain (48%) were identified as negatively impacting QOL followed by sexual intimacy and recurrent urinary tract infections (52%). 51% reported that GI disturbances were concerns. 55% were very satisfied or satisfied with the QOL information that they were receiving from their provider and 54% looked to their providers as their primary source of information, with 27% citing the internet and medical journals as additional sources of information. Conclusion: The results of this survey indicate knowledge gaps in patients with breast cancer, specifically regarding genomic testing to tailor therapy, and the role of ESR1. In addition, QOL of life issues remain an area of unmet need. The results from this survey underscores breast cancer patients’ desire for information related to new treatments in development, discussions with their provider specific to QOL, and how to manage side effects from therapy. Providing patient education tools for providers and patient advocacy organizations that includes information on tumor genomics, treatment options, and side effect management is of utmost importance. Support: Sermonix Pharmaceuticals Citation Format: Hope S. Rugo, Kelly Shanahan, Elizabeth Attias, Miriam Portman, Jenna Gencarelli. Patient knowledge, attitudes and perceptions regarding breast cancer biomarkers, testing, and quality of life [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-28.

Clinical Correlation of a Precision Medicine Test with Treatment Outcome in Acute Myeloid Leukemia Patients

Introduction: Precision Medicine (PM) by measuring the pharmacological activity of drug combination treatments in patient samples by flow cytometry is a new field. This approach has been validated in an observational study of 236 Acute Myeloid Leukemia (AML) patients from Spain and China. Patients were treated with commonly administered chemotherapeutic regimens in AML, and the PM test generated a ranking of the activity of alternative treatments in each patient sample to support personalizing treatments in clinical practice. Material and Methods: Results were processed from an observational study collecting 236 bone marrow samples from AML adult patients from hospitals in China (113) and Spain (123). Most were de novo patients (223) with 13 relapse-refractory patients. The PM test was carried out in the laboratories of Hosea Precision Medical (China) or Vivia Biotech (Spain). Whole bone marrow samples maintaining their Native Environment were incubated for 48h or 72h in well plates containing 23 treatments (Tx) representing the most common drugs and drug combinations used in induction treatments with AML patients. The PM test activity was calculated by the percentage of the maximum Area Under the Curve (AUC) from curve functions models fitted to dose-response experiments results. Besides that, the test includes a measurement of synergy in drug combinations estimated by the application of surface interaction models. The predicted sensitivities of alternative treatments for each individual patient are ranked in five 20% categories following a traffic lights color code, from most sensitive 80-100% green to most resistant 0-20% red. Statistical analysis by response frequency on the predicted green (most sensitive) patients with a target frequency of 85% responders in the green group and a target error of 10% required N=236 total samples. Results: The clinical % CR (Complete Remission) correlates with the predicted responses, decreasing from green to orange to red categories (Figure). PM Test predicts well 85.5% CR for green Tx. 70% of all patient samples have ≥1 green Tx among these 23 Tx. For these 70% patients, the analysis and projection of these observed prediction frequencies suggest that the use of the PM Test might achieve 85.5% CR vs the clinical 62.0%, a 23.5% increase. Within the remaining 30% samples without any green Tx, 17% have at least 1 dark orange Tx (60-80%), with a good prediction CR rate of 68.4%. An additional 8% have ≥1 orange Tx, without any Green or Dark Orange Txs, and these patients have a low clinical 22.2% CR, consistent with being multiresistant to most 23 drug treatments in PM Test. PM Test might increase CR rates from 22.2 to 40%, an increase of 17.8% CR in very difficult patients. If we include all patient samples, PM Test might increase CR from 54.9% to 71.8%, 16.9% more patients achieving CR. Results from Chinese or Spanish patients were consistent with each other. Conclusions: Ranking each treatment across all patient samples in a database, and ranking the alternative treatments that can be administered to a new patient, generates a new Precision Medicine test that might help selecting the optimal treatment for each individual patient. This should be validated by a prospective, two-arms, study. Disclosures Wang: Hosea Precision Medical Technology Co., Ltd: Current Employment. Ge:Hosea Precision Medical Technology Co., Ltd: Current Employment. Zhou:Hosea Precision Medical Technology Co., Ltd: Current Employment. Gorrochategui:VIVIA BIOTECH: Current Employment. Primo:Vivia Biotech: Current Employment. Ballesteros:Vivia Biotech: Current Employment. Martinez-López:Janssen, BMS, Sanofi, Novartis, Incyte, F. Hoffmann-La Roche and Amgen: Honoraria, Other: Advisory boards; Hosea and Altum: Membership on an entity's Board of Directors or advisory committees; Janssen, Novartis, BMS, Incyte: Consultancy.

Clinical Molecular Marker Testing Data Capture to Promote Precision Medicine Research Within the Cancer Research Network.

To evaluate health care systems for the availability of population-level data on the frequency of use and results of clinical molecular marker tests to inform precision cancer care. We assessed cancer-related molecular marker test data availability across 12 US health care systems in the Cancer Research Network. Overall, these systems provide care to a diverse population of more than 12 million people in the United States. We performed qualitative analyses of test data availability for five blood-based protein, nine germline, and 14 tissue-based tumor marker tests in each health care system's electronic health record and tumor registry using key informants, test code lists, and manual review of data types and output. We then performed quantitative analyses to estimate the proportion of patients with cancer with test utilization data and results for specific molecular marker tests. Health systems were able to systematically capture population-level data on all five blood protein markers, six of 14 tissue-based tumor markers, and none of the nine germline markers. Successful, systematic data capture was achievable for tests with electronic data feeds for test results (blood protein markers) or through prior manual abstraction by tumor registrars (select tumor-based markers). For test results stored in scanned image files (particularly germline and tumor marker tests), information on which test was performed and test results was not readily accessible in an electronic format. Even in health care systems with sophisticated electronic health records, there were few codified data elements available for evaluating precision cancer medicine test use and results at the population level. Health care organizations should establish standards for electronic reporting of precision medicine tests to expedite cancer research and facilitate the implementation of precision medicine approaches.

A dropout-regularized classifier development approach optimized for precision medicine test discovery from omics data

BackgroundModern genomic and proteomic profiling methods produce large amounts of data from tissue and blood-based samples that are of potential utility for improving patient care. However, the design of precision medicine tests for unmet clinical needs from this information in the small cohorts available for test discovery remains a challenging task. Obtaining reliable performance assessments at the earliest stages of test development can also be problematic. We describe a novel approach to classifier development designed to create clinically useful tests together with reliable estimates of their performance. The method incorporates elements of traditional and modern machine learning to facilitate the use of cohorts where the number of samples is less than the number of measured patient attributes. It is based on a hierarchy of classification and information abstraction and combines boosting, bagging, and strong dropout regularization.ResultsWe apply this dropout-regularized combination approach to two clinical problems in oncology using mRNA expression and associated clinical data and compare performance with other methods of classifier generation, including Random Forest. Performance of the new method is similar to or better than the Random Forest in the two classification tasks used for comparison. The dropout-regularized combination method also generates an effective classifier in a classification task with a known confounding variable. Most importantly, it provides a reliable estimate of test performance from a relatively small development set of samples.ConclusionsThe flexible dropout-regularized combination approach is able to produce tests tailored to particular clinical questions and mitigate known confounding effects. It allows the design of molecular diagnostic tests addressing particular clinical questions together with reliable assessment of whether test performance is likely to be fit-for-purpose in independent validation at the earliest stages of development.

Accounting for Capacity Constraints in Economic Evaluations of Precision Medicine: A Systematic Review.

Background and ObjectivePrecision (stratified or personalised) medicine is underpinned by the premise that it is feasible to identify known heterogeneity using a specific test or algorithm in patient populations and to use this information to guide patient care to improve health and well-being. This study aimed to understand if, and how, previous economic evaluations of precision medicine had taken account of the impact of capacity constraints.MethodsA meta-review was conducted of published systematic reviews of economic evaluations of precision medicine (test–treat interventions) and individual studies included in these reviews. Due to the volume of studies identified, a sample of papers published from 2007 to 2015 was collated. A narrative analysis identified whether potential capacity constraints were discussed qualitatively in the studies and, if relevant, which quantitative methods were used to account for capacity constraints.ResultsA total of 45 systematic reviews of economic evaluations of precision medicine were identified, from which 222 studies focusing on test–treat interventions, published between 2007 and 2015, were extracted. Of these studies, 33 (15%) qualitatively discussed the potential impact of capacity constraints, including budget constraints; quality of tests and the testing process; ease of use of tests in clinical practice; and decision uncertainty. Quantitative methods (nine studies) to account for capacity constraints included static methods such as capturing inefficiencies in trials or models and sensitivity analysis around model parameters; and dynamic methods, which allow the impact of capacity constraints on cost effectiveness to change over time.ConclusionsUnderstanding the cost effectiveness of precision medicine is necessary, but not sufficient, evidence for its successful implementation. There are currently few examples of evaluations that have quantified the impact of capacity constraints, which suggests an area of focus for future research.Electronic supplementary materialThe online version of this article (10.1007/s40273-019-00801-9) contains supplementary material, which is available to authorized users.

The Clinical Utility of a Precision Medicine Blood Test Incorporating Age, Sex, and Gene Expression for Evaluating Women with Stable Symptoms Suggestive of Obstructive Coronary Artery Disease: Analysis from the PRESET Registry.

Background: Evaluating women with symptoms suggestive of coronary artery disease (CAD) remains challenging. A blood-based precision medicine test yielding an age/sex/gene expression score (ASGES) has shown clinical validity in the diagnosis of obstructive CAD. We assessed the effect of the ASGES on the management of women with suspected obstructive CAD in a community-based registry.Materials and Methods: The prospective PRESET (A Registry to Evaluate Patterns of Care Associated with the Use of Corus® CAD in Real World Clinical Care Settings) Registry (NCT01677156) enrolled 566 patients presenting with symptoms suggestive of stable obstructive CAD from 21 United States primary care practices from 2012 to 2014. Demographics, clinical characteristics, and referrals to cardiology or further functional and/or anatomical cardiac studies after ASGES testing were collected for this subgroup analysis of women from the PRESET Registry. Patients were followed for 1-year post-ASGES testing.Results: This study cohort included 288 women with a median age 57 years. The median body mass index was 29.2, with hyperlipidemia and hypertension present in 48% and 43% of patients, respectively. Median ASGES was 8.5 (range 1–40), with 218 (76%) patients having low (≤15) ASGES. Clinicians referred 9% (20/218) low ASGES versus 44% (31/70) elevated ASGES women for further cardiac evaluation (odds ratio 0.14, p < 0.0001, adjusted for patient demographics and clinical covariates). Across the score range, higher ASGES were associated with a higher likelihood of posttest cardiac referral. At 1-year follow-up, low ASGES women experienced fewer major adverse cardiac events than elevated ASGES women (1.3% vs. 4.2% respectively, p = 0.16).Conclusions: Incorporation of ASGES into the diagnostic workup demonstrated clinical utility by helping clinicians identify women less likely to benefit from further cardiac evaluation.

Abstract P5-11-11: A preliminary assessment of knowledge, attitudes, and awareness surrounding ESR1 mutations and biomarker testing amongst medical oncologists

Abstract Background: Estrogen receptor gene (ESR1) mutations present in breast cancer patients are associated with resistance to endocrine therapy and worse patient outcomes. Recent findings suggest ESR1 mutations are present in up to 40% of metastatic breast cancer (mBC) patients' tumors. The objective of this study was to evaluate the perceptions of precision medicine and biomarker testing specific to ESR1 mutations among medical oncologists. Methods: Ten 60-minute web-assisted, telephone interviews were conducted with medical oncologists. Each physician was prescreened prior to being interviewed to ensure board certification and practice experience between 2 and 35 years. Each participant spent greater than 30% of their time on direct patient care and managed the treatment of more than 30 different cancer patients per month, with a minimum of 15 breast cancer patients, including at least five who had metastatic breast cancer and at least one patient with an ESR1 mutation. Results: A 10-20% prevalence of ESR1 mutation was estimated by the oncologists. However, the practitioners did accept the possibility of a 40% prevalence. Physician knowledge of ESR1 mutations included the relationship between ESR1 mutations and efficacy of endocrine therapies and its association with poorer outcomes. None of the medical oncologists interviewed were highly satisfied with the existing armamentarium of treatments for patients with an ESR1 mutation. In general, the interview participants were highly comfortable ordering ESR1 companion diagnostics to test for an ESR1 mutation, pending viable treatment options are available. Nonetheless, most physicians will wait until the patient has progression of disease before ordering a biomarker test. Several areas of unmet need in the mBC arena were offered by the survey participants, including more efficacious hormonal options for later-line therapies, better durability of remission, improved drug tolerability profiles, and lower treatment costs. Conclusion: Most oncologists acknowledged that personalized treatment is beneficial because it allows for better efficacy than a “one size fits all” approach. The study results also suggest that there are few barriers and drawbacks to the use of personalized medicine in the mBC arena, as most physicians expect precision medicine to account for the majority of advances in breast cancer treatments in the foreseeable future. Support: Sermonix Pharmaceuticals Citation Format: Goldfarb SB, Goetz MP, Plourde PP, Attias E, Portman DJ. A preliminary assessment of knowledge, attitudes, and awareness surrounding ESR1 mutations and biomarker testing amongst medical oncologists [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-11-11.