Precision Medicine Test Research Articles

Cardiovascular Imaging in the Era of Precision Medicine: Insights from Advanced Technologies - A Narrative Review.

Cardiovascular diseases are responsible for a high mortality rate globally. Precision medicine has emerged as an essential tool for improving cardiovascular disease outcomes. In this context, using advanced imaging exams is fundamental in cardiovascular precision medicine, enabling more accurate diagnoses and customized treatments. This review aims to provide a concise review on how advanced cardiovascular imaging supports precision medicine, highlighting its benefits, challenges, and future directions. A literature review was carried out using the Pubmed and Google Scholar databases, using search strategies that combined terms such as precision medicine, cardiovascular diseases, and imaging tests. More advanced analysis aimed at diagnosing and describing cardiovascular diseases in greater detail is made possible by tests such as cardiac computed tomography, cardiac magnetic resonance imaging, and cardiac positron emission tomography. In addition, the aggregation of imaging data with other omics data allows for more personalized treatment and a better description of patient profiles. The use of advanced imaging tests is essential in cardiovascular precision medicine. Although there are still technical and ethical obstacles, it is essential that there is collaboration between health professionals, as well as investments in technology and education to better disseminate cardiovascular precision medicine and consequently promote improved patient outcomes.

JS6-1 Cancer precision medicine and multi-gene panel testing (MGPT) overview

JS6-1 Cancer precision medicine and multi-gene panel testing (MGPT) overview

A community health worker–led intervention to improve patient knowledge and receipt of precision medicine: Updated ALCANCE randomized clinical trial findings.

181 Background: Inequitable access to precision medicine limits its impact. To address disparities, we co-developed the Addressing Latinx Cancer Care Equity Study (NCT04843332), a multi-level intervention with community stakeholders. ALCANCE was designed for low-income and Latinx adults with cancer in rural Monterey County, California. We provided annual training for clinicians about testing guidelines and precision medicine disparities. Trained CHWs educated patients about precision medicine and encouraged them to raise the topic with their oncologist. We tested whether the intervention improved patient knowledge and receipt of precision medicine. Methods: Patients with newly diagnosed or recurrent cancer, age ≥ 18 years, able to consent in English or Spanish, and who self-identified as a racial and ethnic minority OR low-income status OR were insured by public or agricultural company insurance OR uninsured and receiving cancer care at Pacific Cancer Care, a rural community oncology practice in Monterey County, were randomized 1:1 to usual care (control group) or usual care augmented with the multi-level intervention for 12 months (intervention group). The primary outcome was whether the multilevel intervention could increase patient knowledge of precision medicine using a validated 6 question survey from time of enrollment (baseline) to 6-months post-enrollment between groups. A secondary outcome was receipt of precision medicine. CHWs and clinicians completed semi-structured interviews. Results: 110 participants were randomized; 70% (n = 67) reported Spanish as their primary language; 81% (n = 89) identified as Hispanic. Median age was 55 years (55.4 ± 14.3, mean± SD); majority had annual household incomes (USD) ≤ $34,999 (59.0%, n = 46); majority obtained a high school diploma/GED or less (67.3%, n = 74). Most had gastrointestinal (35.5%, n = 39) and breast (24.5%, n = 27) cancers and were diagnosed with stage 3 or 4 (64.5%, n = 71) disease. Precision medicine knowledge was low at baseline across both the control and intervention groups (23.5 ± 19.3 versus 23.0 ± 17.7, respectively). Intervention group participants had greater precision medicine knowledge at 6-months (39.2 ± 23.0) than control group participants (24.2 ± 20.0) with greater increase in knowledge overtime than control group participants (p < 0.001). More intervention group participants (n=46, 79.3%) received precision medicine testing than control (n=34, 60.7%). Across both groups, 26 of those tested had an actionable mutation. Of those 26, 66.7% (n=6 of 9) in the control group and 94.1% (n=16 of 17) in the intervention group received targeted therapy (p=0.065). Interviews with the care team indicated the model was acceptable and has been sustained as part of usual care. Conclusions: CHW-facilitated interventions may reduce disparities in precision medicine cancer care. Clinical trial information: NCT04843332

Research advances on precision medicine testing in clinical application in colorectal liver metastasis

Research advances on precision medicine testing in clinical application in colorectal liver metastasis

Exhaustive in vitro evaluation of the 9-drug cocktail CUSP9 for treatment of glioblastoma

The CUSP9 protocol is a polypharmaceutical strategy aiming at addressing the complexity of glioblastoma by targeting multiple pathways. Although the rationale for this 9-drug cocktail is well-supported by theoretical and in vitro data, its effectiveness compared to its 511 possible subsets has not been comprehensively evaluated. Such an analysis could reveal if fewer drugs could achieve similar or better outcomes.We conducted an exhaustive in vitro evaluation of the CUSP9 protocol using COMBImageDL, our specialized framework for testing higher-order drug combinations. This study assessed all 511 subsets of the CUSP9v3 protocol, in combination with temozolomide, on two clonal cultures of glioma-initiating cells derived from patient samples. The drugs were used at fixed, clinically relevant concentrations, and the experiment was performed in quadruplicate with endpoint cell viability and live-cell imaging readouts. Our results showed that several lower-order drug combinations produced effects equivalent to the full CUSP9 cocktail, indicating potential for simplified regimens in personalized therapy. Further validation through in vivo and precision medicine testing is required.Notably, a subset of four drugs (auranofin, disulfiram, itraconazole, sertraline) was particularly effective, reducing cell growth, altering cell morphology, increasing apoptotic-like cells within 4–28 h, and significantly decreasing cell viability after 68 h compared to untreated cells.This study underscores the importance and feasibility of comprehensive in vitro evaluations of complex drug combinations on patient-derived tumor cells, serving as a critical step toward (pre-)clinical development.

Clinical validation of image-based AI predictive biomarkers for precision neoadjuvant triple-negative breast cancer treatment (PEAR-TNBC).

TPS627 Background: Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancer subtypes, with a 5-year recurrence rate of 30% in patients with localized disease. Pathological Complete Response (pCR) strongly predicts the risk of recurrence and death, which are reduced by approximately 80% in patients who achieve a pCR following neoadjuvant treatment. There are multiple treatment regimens available for TNBC patients in the neoadjuvant setting but no biomarkers to match patients to treatments. Giving ineffective treatment leads to worse outcomes for patients and additional burden on healthcare systems. Pear Bio has developed a functional precision medicine test coupling an organ-on-a-chip with a computer vision (CV) pipeline through which an individual patient’s response to different treatments can be monitored simultaneously ex vivo. Each microtumor’s response is monitored using time-lapse 3D microscopy. A proprietary CV pipeline quantifies the responses (e.g. tumor cell viability, culture size). Lab test responses are correlated to the clinical outcomes of the patients to identify biomarkers with high predictive accuracy. This generates multiple CV-based biomarkers with potential predictive value. PEAR-TNBC (NCT05435352) is a prospective, observational UK-wide trial aimed at assessing the test’s accuracy in predicting pCR in TNBC patients in the neoadjuvant setting. The study recruits patients with early TNBC (N=54) who are willing to undergo an additional core needle biopsy prior to starting neoadjuvant therapy. The assay is run in parallel with the patient’s treatment and the treating oncologist is blind to the results of the Pear Bio test. Methods: The study has 2 cohorts (A and B), each recruiting at least 20 evaluable patients. To be eligible, patients need to have ≥10mm tumor, stage I-III, TNBC, with planned neoadjuvant treatment followed by surgery and be willing to undergo a study-specific core needle biopsy procedure. Cohort B also requires a 40mL blood sample. To be evaluable, eligible patients’ samples must be successfully cultured in the 3D ex vivo assay and they must complete at least 4 cycles of neoadjuvant chemotherapy prior to surgery. Cohort A recruitment began on 05/27/22 and has recruited 20 evaluable patients, through 5 sites. Cohort B accrual will begin upon completion of Cohort A. The primary endpoint is the accuracy of the Pear test in predicting pCR, defined as specificity, with secondary outcomes as sensitivity, and positive and negative predictive values. Novel aspects include a focus on specificity (i.e. accurately predicting patients who will not achieve pCR) combined with the use of Receiver-operating characteristic curves to define optimal cutoffs for the CV biomarkers. Future trials will aim to run the test prior to therapy selection, guiding the choice of regimen to assess the test’s ability to increase pCR rates. Clinical trial information: NCT05435352 .

The effect of a multilevel community health worker-led intervention on patient knowledge and receipt of precision medicine: Updated findings from a randomized clinical trial.

1609 Background: Inequitable access to precision medicine limits its impact. To address disparities, we co-developed a 2-part multi-level intervention with community stakeholders, called the Addressing Latinx CANcer Care Equity Study (NCT04843332). The intervention was designed for low-income and Latinx adults with cancer in rural Monterey County, California. We provided annual training for clinicians about testing guidelines and precision medicine disparities. Trained community health workers educated patients about precision medicine and encouraged them to raise the topic with their oncologist. We tested whether the intervention improved patient knowledge and receipt of precision medicine. Methods: Patients with newly diagnosed or recurrent cancer, age ≥ 18 years, able to consent in English or Spanish, and who self-identified as a racial and ethnic minority OR low-income status OR were insured by public or agricultural company insurance OR uninsured and receiving cancer care at Pacific Cancer Care, a rural community oncology practice in Monterey County, were randomized 1:1 to usual care (control group) or usual care augmented with the multi-level intervention for 12 months (intervention group). The primary outcome was whether the multilevel intervention could increase patient knowledge of precision medicine using a validated 6-question survey from the time of enrollment (baseline) to 6 months post-enrollment between groups. A secondary outcome was the receipt of precision medicine. Patients were followed for 12 months. Results: 110 participants were randomized; 70% (n = 67) reported Spanish as their primary language; 81% (n = 89) identified as Hispanic. The median age was 55 years (55.4 ± 14.3, mean± SD); the majority had annual household incomes (USD) ≤ $34,999 (59.0%, n = 46); the majority obtained a high school diploma/GED or less (67.3%, n = 74). Most had gastrointestinal (35.5%, n = 39) and breast (24.5%, n = 27) cancers and were diagnosed with stage 3 or 4 (64.5%, n = 71) disease. Precision medicine knowledge was low at baseline across both the control and intervention groups (23.5 ± 19.3 versus 23.0 ± 17.7, respectively). Intervention group participants had greater precision medicine knowledge at 6 months (39.2 ± 23.0) than control group participants (24.2 ± 20.0) with a greater increase in knowledge over time than control group participants (p < 0.001).More intervention group participants (n=46, 79.3%) received precision medicine testing than control (n=34, 60.7%). Across both groups, 26 of those tested had an actionable mutation. Of those 26, 66.7% (n=6 of 9) in the control group and 94.1% (n=16 of 17) in the intervention group received targeted therapy (p=0.065). Conclusions: CHW-facilitated interventions may reduce disparities in precision medicine cancer care. Clinical trial information: NCT04843332 .

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]

Abstract PO1-20-12: CD8+ Tumor Infiltrating Lymphocytes Turn a Cold Tumor Hot in Metastatic Breast Cancer

Abstract Introduction: Turning “cold” tumors “hot” is considered essential for immune-oncology therapies to be effective. Bria-IMT is an allogenic human cancer cell line with antigen presenting cell activity (SV-BR-1-GM) designed to overcome the immune-suppressive tumor microenvironment. However, until now there has not been proof that “cold” tumors can become “hot” with this therapy. Using Zr-89 crefmirlimab berdoxam, a zirconium-89 labelled truncated antibody specific to human CD8α and developed for CD8 ImmunoPET, we image before and after Bria-IMT therapy administration to assess the baseline status as well as changes in CD8 cell presence after initiation of therapy. Here we present the first evidence that cold tumors can become hot on treatment with Bria-IMT combined with an anti-PD-1 checkpoint inhibitor (CPI), showing CD8+ cells increased over baseline using CD8 ImmunoPET. Case: After informed consent, a 61 year-old Hispanic female, enrolled in the ongoing randomized phase 2 Bria-IMT trial in advanced heavily pretreated metastatic breast cancer (MBC) (NCT03328026). Her history included MBC in May 2020, ductal type, grade 3, triple negative breast cancer (TNBC) with 6 prior lines of therapy including a Trop-2-directed antibody-drug conjugate and 6 lines of chemotherapy. Precision medicine testing identified no actionable targets. All prior therapies had progressive disease as their best response. The subject was randomized to start the CPI after 2 cycles of Bria-IMT to “train” the host immune system before proceeding with combination immune-oncology therapy. Baseline testing revealed the subject to be anergic to candida and SV-BR-1-GM inoculation. However, by cycle 3 delayed-type hypersensitivity to SV-BR-1GM developed. Interestingly the subject matched SV-BR-1-GM at 2 HLA loci: DRB3*02:02 and DRB1*11:04 which in previous publications is associated with greater clinical benefit. Tumor markers were stable or decreased slightly including CEA (25% decrease) and CA 15-3 (43% decrease). Circulating Tumor Cells (CTCs) and Cancer Associated Macrophage Like cells (CAMLs) also improved. Standard imaging at baseline showed 3 main sites of disease including a large right breast mass, multiple right axillary lymph nodes and a right lower lobe mass with CD8 ImmunoPET uptake in these areas similar to the blood pool. On the follow-up CT imaging, all of these lesions increased in size with newly appreciated pulmonary nodules. The right lower lobe mass showed increased CD8 ImmunoPET accumulation with an SUV of 5.8 (close to the liver background) as compared to an SUV of 2.2 at baseline. The lesions in the right breast and right axilla remained at blood pool levels. There was an increase in CD8 ImmunoPET uptake in bilateral inguinal lymph nodes reaching an SUV of 4.8 as compared to SUV 2.2 at baseline. In addition, there were non-enlarged lymph nodes in bilateral axillary regions that also showed increased radio-tracer accumulation reaching an SUV of 9.5 as compared to SUV 4.9 at baseline. Conclusion: This subject demonstrated a mixed response of metastatic lesions on CD8 ImmunoPET with encouraging changes in peripheral blood tumor markers and CTCs. The nonspecific nodal localization of CD8 ImmunoPET may indicate a systemic activation of CD8 positive lymphoid cells. This shows the value of CD8 ImmunoPET in identifying lesions that are progressing on treatment versus pseudo progression. It also provides support that the Bria-IMT + CPI combination immune-based therapy can result in an increase of CD8+ tumor infiltrating lymphocytes in breast cancer metastatic sites as well as an increase in lymphoid organs. This advance may aid in triaging patients, adjudicating pseudo-progression and predicting clinical benefit of immune based therapies. Citation Format: Russ Kuker, Frances Valdes-Albini, Giuseppe Del Priore, Aazim Arif, Kristin Schmiedehausen, Carmen Calfa. CD8+ Tumor Infiltrating Lymphocytes Turn a Cold Tumor Hot in Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-12.

Biomarker-Driven DNA-Functionalized Colloidal Programmed Simultaneous Assembly and Disassembly in Cells.

Complex structures and devices, both natural and artificial, can often undergo assembly and disassembly. Assembly and disassembly allow multiple stimuli to initiate, for example, the assembly and disassembly of primary cilia under the control of E3 ubiquitin ligases and deubiquitinases. Although biology relies on such schemes, they are rarely available in materials science. Here, we demonstrate a DNA-functionalized colloidal Au response to endogenous biomarkers to trigger simultaneous assembly and disassembly techniques. Colloidal Au is initially inert because the starting DNA strands are paired and prehybridized. TK1 mRNA competes to bind one of the paired strands and release its complement. The released complement binds to the next colloidal Au to initiate assembly, and APE1 can shear the colloidal Au assembly binding site to initiate disassembly. Our strategy provides temporal and spatial logic control during colloidal Au assembly and disassembly, and this simultaneous assembly and disassembly process can be used for sequential detection and cellular imaging of two biomarkers, effectively reducing signal false-positive results and shortening detection time. This work highlights biomarker-controlled colloidal Au simultaneous assembly and disassembly in ways that are simple and versatile, with the potential to enrich the application scope of DNA nanotechnology and provide an idea for the application of precision medicine testing.

Abstract 4960: PIONEER initiative: Providing patient access to functional precision medicine

Abstract Eighty-five percent of patients receive medical care in cancer centers without National Cancer Institute (NCI) designation or significant ongoing research. The ability to access fresh tumor tissue for immediate functional testing is now available with appropriate logistical coordination. Cryopreservation of these tissues also allows testing to be done at a later date. We hypothesize that patient access to and ownership of each individual's tissues will facilitate personalized testing, thus bridging the chasm between research and the clinical cancer care for the individual patient. The PIONEER Initiative stands for Precision Insights On N-of-1 Ex vivo Effectiveness Research. In this Initiative we save cancerous tissue for any patient at any location, with subsequent cryopreservation and functional testing as needed and as able within an environment in which neither are standard. Our endpoint was to determine if this process serves to alter care for individual patients, and to what degree. The SpeciCare PIONEER Initiative: Precision Insights On N-of-1 Ex Vivo Effectiveness Research Based on Individual Tumor Ownership Trial (MYCT001) received human subjects IRB approval (Approval Number: 33943/1) from Quorum Review. The PIONEER Initiative is our lead clinical trial designed to provide the foundation for subsequent adaptive trials. Our mission with this trial was to demonstrate the utility of carrying out functional precision medicine in that cohort of patients who receive local cancer care at institutions that do not have significant research capabilities or are not NCI-designated cancer centers. Most cancer patients (~85%) are in this category. It is imperative to open the possibility of the best-in-class functional precision medicine testing to these patients. Core aspects of the PIONEER Initiative involve scaling up this process to approximately 200 patients, showing that our proof of concept in a more limited set of patients can ultimately scale to arbitrarily large numbers of patients. We see this capacity filling an important unmet need within the cancer community. The primary endpoint was the return of actionable information to positively impact care as assessed by the patient's clinical team and the patient. The underlying basic assumption of the PIONEER Initiative is that the ability to receive the best in cancer care should not come with restriction as to location, age, or medical condition. The PIONEER Initiative design facilitates inclusion of subjects across all these divides, thus providing beneficence to all participants. Among the 60 patients whose tumors had ex vivo drug testing performed, none of the data was included in the clinical decision making of the healthcare team. We conclude that physicians are not adequately prepared to use ex vivo drug testing data and the more likely acceptance of molecular characterization is primarily driven by genomic sequencing. Citation Format: Ken Dixon, Jared James Barrott, David Booker. PIONEER initiative: Providing patient access to functional precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4960.

Patient-Derived Xenograft Models for Translational Prostate Cancer Research and Drug Development.

Patient-derived xenografts (PDXs) are a valuable preclinical research platform generated through transplantation of a patient's resected tumor into an immunodeficient or humanized mouse. PDXs serve as a high-fidelity avatar for both precision medicine and therapeutic testing against the cancer patient's disease state. While PDXs show mixed response to initial establishment, those that successfully engraft and can be sustained with serial passaging form a useful tool for basic and translational prostate cancer (PCa) research. While genetically engineered mouse (GEM) models and human cancer cell lines, and their xenografts, each play beneficial roles in discovery science and initial drug screening, PDX tumors are emerging as the gold standard approach for therapeutic proof-of-concept prior to entering clinical trial. PDXs are a powerful platform, with PCa PDXs shown to represent the original patient tumor cell population and architecture, histopathology, genomic and transcriptomic landscape, and heterogeneity. Furthermore, PDX response to anticancer drugs in mice has been closely correlated to the original patient's susceptibility to these treatments in the clinic. Several PDXs have been established and have undergone critical in-depth characterization at the cellular and molecular level across multiple PCa tumor subtypes representing both primary and metastatic patient tumors and their inherent levels of androgen responsiveness and/or treatment resistance, including androgen-sensitive, castration resistant, and neuroendocrine PCa. Multiple PDX networks and repositories have been generated for the collaborative and shared use of these vital translational cancer tools. Here we describe the creation of a PDX maintenance colony from an established well-characterized PDX, best practice for PDX maintenance in mice, and their subsequent application in preclinical drug testing. This chapter aims to serve as a go to resource for the preparation and adoption of PCa PDX models in the research laboratory and for their use as a valuable preclinical platform for translational research and therapeutic agent development.

Biomarker-triggered, spatiotemporal controlled DNA nanodevice simultaneous assembly and disassembly.

Despite many advances in the use of DNA nanodevices as assembly or disassembly modules to build various complex structures, the simultaneous assembly and disassembly of DNA structures in living cells remains a challenge. In this study, we present a modular engineering approach for assembling and disassembling DNA nanodevices in response to endogenous biomarkers. As a result of pairwise prehybridization of original DNA strands, the DNA nanodevice is initially inert. In an effort to bind one of the paired strands and release its complement, nucleolin competes. Assembly of the DNA nanodevice is initiated when the released complement binds to it, and disassembly is initiated when APE1 shears the assembled binding site of the DNA nanodevice. Spatial-temporal logic control is achieved through our approach during the assembly and disassembly of DNA nanodevices. Furthermore, by means of this assembly and disassembly procedure, the sequential detection and imaging of two tumor markers can be achieved, thereby effectively reducing false-positive signal results and accelerating the detection time. This study emphasizes the simultaneous assembly and disassembly of DNA nanodevices controlled by biomarkers in a simple and versatile manner; it has the potential to expand the application scope of DNA nanotechnology and offers an idea for the implementation of precision medicine testing.

Clinical Evaluation of a Functional Combinatorial Precision Medicine Platform to Predict Patient-Specific Treatment Outcomes in Acute Myeloid Leukemia

Introduction: Acute myeloid leukemia (AML) is an aggressive form a leukemia that remains difficult to treat, often with rapid and frequent disease relapse due to drug-resistant clonal selection. A range of combination therapies have been designed to overcome this hurdle, however, identifying the most appropriate combination therapy at each line of treatment remains a challenge. Functional precision medicine platforms that use ex vivo drug sensitivity data from primary patient samples have shown potential to guide treatments in a range of cancers. We have recently developed an ex vivo combinatorial drug sensitivity platform, quadratic phenotypic optimization platform (QPOP), that analyses a predesigned array of 155 test combinations performed on a primary patient sample to rank and compare all possible therapeutic combinations from a 12-drug set. In this study, we evaluated the use of QPOP to predict treatment outcomes in an AML cohort treated with a variety of combination therapies. Furthermore, we also explored QPOP's combination therapy ranking function to identify novel or under-utilized combinations that may benefit larger groups of AML patients when appropriately guided. Methods: Prospective clinical feasibility study of QPOP in AML was performed at National University Hospital (NUH) in Singapore. Peripheral blood or bone marrow aspirations were collected from AML patients, recruited between 26 th November 2019 and June 15 th 2023. Following CD34+ cell selection, the enriched malignant blast population was subjected to an array of 155 test combinations derived from an orthogonal array composite design. Phenotypic cell viability data from this test was subsequently used by QPOP to derive drug combination scores and rankings for all possible combinations. Median turnaround time for QPOP patient-specific reports was 8 (±2.1) days. Patients were treated with current standard of care options as guided by the clinician. The primary outcomes of this study were to determine the concordance between treatment outcomes as guided by clinicians and QPOP drug combination scores and rankings. Secondary outcomes of this study were to identify high-ranking, potentially effective combinations that may be nover or under-utilized for future studies. Results: 40 patients were recruited to the study with 49 samples analyzed by QPOP. Samples collected until 21 January 2022 were also used to refined ex vivo drug dosing levels for 12-drug, 3-level test combination arrays. Excluding patients diagnosed as non-AML and patient without available clinical concordance data, QPOP response concordance was evaluable for 19 patients. A 75% positive predictive value (PPV) and a 72.7% negative predictive value (NPV) was determined for a QPOP normalized cell viability (NCV) cutoff of 0.65. The area under the curve of the receiver operator curve, AUC = 0.75, suggesting acceptable predictivity. Concordance analysis of with samples (n = 10) collected after 21January 2022 demonstrated an 80% PPV, 80% NPV, AUC = 0.80 for an NCV cutoff of 0.62, suggesting that current ex vivo dosage settings for test array can further improve test accuracy. Combination therapy with the BCL2 inhibitor venetoclax and hypomethylating agent azacytidine is standard-of-care for AML. QPOP NCV cutoff of 0.62 also exhibited 100% concordance (5/5) with venetoclax+azacytidine treatment further demonstrating the accuracy of QPOP to predict treatment outcomes in AML. Amongst top ranked QPOP-derived combinations, venetoclax/fludarabine was amongst the most frequently reoccurring top-ranked combinations. With appropriate functional combinatorial precision medicine testing, patients who may benefit from addition of venetoclax to fludarabine-based chemotherapy regimens, such as fludarabine/busulfan reduced-intensity conditioning chemotherapy, may be accurately identified. Conclusions: This clinical study demonstrates the feasibility of QPOP to predict treatment outcomes and accurately identify both response and resistance to combination therapy. Following platform workflow optimization, initial concordance analysis suggests excellent predictivity. Expansion of this clinical study is needed to confirm these results. This study also suggests that underutilized combinations may be effective across a larger population of AML patients with appropriate ex vivo drug testing and deserve further clinical interrogation.

Enhancing precision medicine testing process in a breast cancer population of a community oncology practice: Use of oncology patient navigators (OPN) and a molecular processing team (MPT) to improve germline testing.

559 Background: In 2021, universal germline testing was recommended to breast cancer patients. Historically, germline testing has been ordered using manual paper requisition forms or via molecular vendor portal input with no capabilities of follow-up to ensure timely results. There are few reports of how to optimize universal germ line testing; we endeavored to determine benefit of OPN and a MPT in a breast cancer population in the private practice setting. Methods: For the baseline population, using the Electronic Health Record (EHR), a report was generated to identify breast cancer patients seen that were eligible for germline testing. The patient records from the report were manually reviewed to identify germline testing completed. In the intervention arm, OPN would review provider schedules in real time to identify any newly diagnosed breast cancer pts. Concurrently the pts were offered the opportunity for germline testing along with education by providers during their visit. Certified Medical Assistants (CMAs) placed all orders via vendor portals using OPN supplied templates completed by providers. The MPT would follow orders placed to confirm specimen procurement, receipt by vendor and collaboratively resolve any delays in specimen processing, insurance challenges and test selection revisions. Tracking activities were implemented within the EHR to document all progress in testing and to quantify the volume of tests. Results: For the baseline population, between 1/1/21-3/31/21, 29 (24%) of 120 breast cancer patients received germ line testing. Post intervention, between 1/1/22-3/31/22, 70 (45%) of 155 patients had germline testing. The mean turnaround time (TAT) for germline results for the baseline population was 12 days, and 44% percent were over 11 days. In the intervention arm, the mean TAT was 10 days and 20% were over 11 days. Conclusions: Our results illustrate the early benefit of OPN and a MPT in expediting result obtainment and increasing utilization of germline testing. Enhancing cohesion with the vendors and our MPT and more automated use of the EHR will further improve utilization. Continued practice wide education of providers in the necessity of germline testing in a breast cancer population is also essential.

Integrating Early-Stage Drug Development with Clinical Networks; Challenges and Opportunities: The City of Hope Developing Experience.

Recent data suggest that patients with advanced cancer who participate in biomarker/genomically informed early-stage clinical trials experience clinical benefit. While most early-stage clinical trials are conducted in major academic centers, the majority of cancer patients in the United States are treated in community practices. Here, we describe ongoing efforts at the City of Hope Cancer Center to integrate our network community oncology clinical practices into our academic, centralized biomarker/genomic-driven, early-stage clinical trial program to build an understanding of the approaches that provide the benefits of early-stage clinical trial participation to community patients. Our efforts include three key initiatives: the development of a virtual "Refractory Disease" phase 1 trial matching televideo clinic, the construction of infrastructure to support the expansion of phase 1 clinical trials to a distant regional clinical satellite hub, and the implementation of an enterprise-wide precision medicine, germline, and somatic testing program. Our work at City of Hope may serve as an example to facilitate similar efforts at other institutions.

Integrating Precision Medicine into Medical Dermatology Clinical Practice: An Expert Consensus Panel.

Precision medicine utilizes an individual’s genomics to improve diagnosis, prognosis, and therapy. The joint American Academy of Dermatology and National Psoriasis Foundation 2019 guidelines recognized the need to identify biomarkers that can predict the optimal biologic agent for an individual patient. This paper examines the current state of precision medicine in dermatology and how its use can improve outcomes in psoriasis. A search of PubMed/MEDLINE using the terms precision medicine, personalized medicine, biomarkers, genomics, and dermatology was performed to identify relevant publications. An expert consensus panel was then convened to assign levels of evidence to each article using strength of recommendation taxonomy and create consensus statements requiring a two-thirds supermajority for agreement utilizing a modified Delphi approach. Thirteen articles met inclusion and exclusion criteria and were assigned levels of evidence. The panel created 10 consensus statements on how precision medicine can improve patient outcomes, all of which received a unanimous (6/6) vote. Choosing a biologic medication for psoriasis often relies on patient preference, provider preference, and a trial-and-error approach. Utilizing precision medicine tests such as Mind.Px can help providers identify biomarkers unique to a patient’s pathophysiology and choose the optimal medication through a targeted and evidence-based approach. Zakria D, Brownstone N, Armstrong AW, et al. Integrating precision medicine into medical dermatology clinical practice: an expert consensus panel. J Drugs Dermatol. 2023;22(6):588-593. doi:10.36849/JDD.7432.

Abstract 5500: Patient-derived organotypic cultures (PDOCs) from melanoma metastases as a precision medicine test to improve patient management

Abstract INTRODUCTION Despite significant improvements in advanced melanoma therapy, there is still a pressing need for innovative therapies. Here, we optimized a method for testing the drug sensitivity of PDOCs and evaluated whether this preclinical model could be a valid tool for rapidly determining the patient’s tumor response profile to approved and alternative therapies. METHODS PDOCs were generated from melanoma metastases (> 60 specimens) after mechanical or enzymatic dissociation. Tissue fragments (<70um) were harvested, embedded in 3D collagen beads (1.5 mg/mL type I collagen), and cultured in a 96-well plate for 6 days, maintaining tumor and stromal viability. More than 20 primary cell lines from the same samples were also stabilized. The melanoma cells or the PDOCs were left untreated or treated with the patient’s own therapy or with alternative drugs, and the efficacy of treatments was evaluated by MTT assay and flow cytometry. CD8+ T cell infiltration and cytokine secretion were also investigated. RESULTS The first experiments were set up to validate PDOCs as predictive preclinical models of patient response to therapy. We tested approved melanoma therapies (i.e., the combination of BRAF and MEK inhibitors, or anti-PD-1 antibodies) on the same melanoma specimens at the IDI and IEO institutes. More than 10 different samples were compared, finding reproducible results between the two Institutions. Furthermore, drug response in PDOCs was comparable to the clinical response of matched patients undergoing the tested therapy, demonstrating PDOCs are reliable predictive tools. Then, we used primary cell lines to screen a pool of ten different targeted agents selected through functional screening of a bioactive library of 512 compounds on patient-derived xenografts, and based on known drug resistance mechanisms in melanoma. The three best-performing compounds were subsequently studied in PDOCs as single agents or in combination with immunotherapy. We found high heterogeneity of drug efficacy in different melanoma samples with no obvious correlation to BRAF or NRAS mutations, metastasis type, or patients’ prior therapies. Of note, in some cases, the combination with an anti-PD-1 inhibitor significantly improved the efficacy of one or more of the three drugs. CONCLUSIONS We optimized and validated PDOCs as personalized preclinical models suitable for assessing the drug sensitivity/resistance profile of individual patient-derived melanomas. By retaining tumor stromal components and heterogeneity, PDOCs could be used to predict patients’ clinical response to currently approved agents, helping oncologists expedite decision-making when several treatment options are possible. Furthermore, the model could be used to evaluate the effectiveness of alternative treatments on tumors resistant to approved therapies, and to explore new drug combinations. Citation Format: Antonella Bresin, Fiorenza Lotti, Lauretta Levati, Pier F. Ferrucci, Francesca Ricci, Francesco Scicchitano, Zorika C. Di Rocco, Giandomenico Russo, Luisa Lanfrancone. Patient-derived organotypic cultures (PDOCs) from melanoma metastases as a precision medicine test to improve patient management. [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 5500.

Commentary on Cohen et al.: Role of Clinical Factors in Precision Medicine Test to Predict Nonresponse to TNFi Therapies in Rheumatoid Arthritis.

A 2021 study described the development and validation of a blood-based precision medicine test called the molecular signature response classifier (MSRC) that uses 23 features to identify rheumatoid arthritis (RA) patients who are likely nonresponders to tumor necrosis factor-α inhibitor (TNFi) therapy. Both the gene expression features and clinical components (sex, body mass index, patient global assessment, and anti-cyclic citrullinated protein) included in the MSRC were statistically significant contributors to MSRC results. In response to continued inquiries on this topic, we write this letter to provide additional insights into the contribution of clinical components to the MSRC on the Network-004 validation cohort.

Current Testing Practices for t(11;14) Rearrangements in Patients with Newly Diagnosed Multiple Myeloma in the United States

Background: Despite an improvement in the awareness and use of precision medicine and molecular testing in hematological cancers, there are still significant disparities in biomarker testing. This ultimately leads to inequality in molecular testing access and can lead to suboptimal medical care for some patients, who do not receive the most appropriate and effective therapy. Venetoclax is a selective BCL-2 inhibitor and has shown promising antimyeloma activity in patients with t(11;14) multiple myeloma (MM). t(11;14) is the most frequent chromosomal translocation in MM reported in approximately 15-20% of newly diagnosed MM patients (NDMM) (Kumar et al. Blood 2017). In this study, we assessed current t(11;14)(q13;q32) testing practices in patients with NDMM in the United States (US) to gain insights on challenges for biomarker testing and equitable access to precision medicine. Methods: A retrospective, real-world evidence study was conducted between January and December 2021 using the Diaceutics DXRX Data Repository database. DXRX is a patient-level claims- and laboratory-linked dataset covering more than 4000 laboratories and 360 million patient lives between 2011 and 2022 in the US. Eligible patients were identified using International Classification of Disease (ICD) codes for NDMM (ICD-10 code C90.0). A 2-year lookback was utilized to ensure patients were not in remission or relapse (ICD-10 codes C90.01, C90.02). Percentages were used to describe study population characteristics. t(11;14) and plasma cell enrichment (PCE) testing rates were estimated using descriptive statistics for the entire cohort as well as for race/ethnicity subgroups. PCE testing was considered as it contributes to increasing sensitivity of testing. Results: We identified 27,586 eligible patients with NDMM. The median age at diagnosis was 70 years (interquartile range: 65-75) and 45% were female. Among the eligible patients, 69% (n=19,034) specifically received t(11;14) testing, within 1 month from diagnosis to testing. Fluorescence in situ hybridization (FISH; dual color, dual fusion probe and immunoglobin [IG] break apart) was the most commonly utilized technology (89%; n=16,940) for detecting t(11;14); next-generation sequencing panels were limited (<1%) in utilization. Confirmatory reflex testing with a t(11;14) dual probe following positive IG break apart was not performed in 17% (n=3235) of patients. In patients who were tested with the t(11;14) dual probe FISH assay, less than half (40.9%) were tested for t(11;14) with PCE. Results of the FISH assay were available for 4941 patients. A lower positivity rate was observed with non-PCE testing (13.1%; n=647) compared with those utilizing PCE (16.8%; n=830), p=0.494. Testing rates of t(11;14) in an academic setting were 72% (n=10,659) vs 64% (n=8374) in the community setting, p<0.0001. PCE was performed on only 24.9% (n=2093) of patients in a community setting vs 61% (n=6502) of samples in an academic setting, p<0.0001. For the subgroup analysis, race/ethnicity data were available for 9245 patients with NDMM; 75.7% were White, 15.9% were Black, 2.6% were Asian, 2% were Hispanic, and 3.2% were classified as other. t(11;14) testing rates were higher for patients who were White (72.8%) compared with the minority groups (66.9% for patients who were Black, 68.8% for patients who were Asian, and 65.7% for patients who were Hispanic). The t(11;14) testing setting for minority group patients was community (62%) vs academic (38%). Conclusions: Notable variations in t(11;14) testing patterns were observed among patients with NDMM in different care settings and racial/ethnic groups. There is a clear unmet need for standardization across academic and community settings to mitigate suboptimal testing methodologies that could impact treatment decision-making and patient outcomes. From our study, there is a clear need to improve t(11;14) testing rates as the clinical utility changes from a prognostic to predictive biomarker with the availability of personalized healthcare options. Education of PCE utilization for physicians, especially community-based pathologists and laboratories, will be essential to reduce false negatives and inequalities in optimal testing, especially PCE in ethnic minorities in the US.