Implementation Of Precision Oncology Research Articles

Implementation of Precision Oncology into the Diagnostic and Therapeutic Armamentarium: Actionable Takeaways from the 2023 Precision Oncology Summit

The 2023 Precision Oncology Summit was held in San Francisco, CA on October 7th and 8th, focusing on actionable strategies addressing personalized treatment to improve patient outcomes. This manuscript summarizes the discussion and key learning points from the precision medicine clinical science symposium in the implementation of Precision Oncology into the diagnostic and therapeutic armamentarium. This topic encompasses the advancement of molecular imaging in precision medicine and machine learning (ML) as a strategy to enhance precision oncology by individualizing patient treatments.

Molecular tumour boards - current and future considerations for precision oncology.

Over the past 15 years, rapid progress has been made in developmental therapeutics, especially regarding the use of matched targeted therapies against specific oncogenic molecular alterations across cancer types. Molecular tumour boards (MTBs) are panels of expert physicians, scientists, health-care providers and patient advocates who review and interpret molecular-profiling results for individual patients with cancer and match each patient to available therapies, which can include investigational drugs. Interpretation of the molecular alterations found in each patient is a complicated task that requires an understanding of their contextual functional effects and their correlations with sensitivity or resistance to specific treatments. The criteria for determining the actionability of molecular alterations and selecting matched treatments are constantly evolving. Therefore, MTBs have an increasingly necessary role in optimizing the allocation of biomarker-directed therapies and the implementation of precision oncology. Ultimately, increased MTB availability, accessibility and performance are likely to improve patient care. The challenges faced by MTBs are increasing, owing to the plethora of identifiable molecular alterations and immune markers in tumours of individual patients and their evolving clinical significance as more and more data on patient outcomes and results from clinical trials become available. Beyond next-generation sequencing, broader biomarker analyses can provide useful information. However, greater funding, resources and expertise are needed to ensure the sustainability of MTBs and expand their outreach to underserved populations. Harmonization between practice and policy will be required to optimally implement precision oncology. Herein, we discuss the evolving role of MTBs and current and future considerations for their use in precision oncology.

Transdifferentiation of cervical squamous cell carcinoma with ERBB2 amplification to adenocarcinoma: whole genome sequence analysis and successful control by anti-HER2 therapy

Cancer cells sometimes transdifferentiate into different histological type(s) and tumors with multiple histological types can share a common ancestor cell. However, diagnosis of the origin of multiple tumor lesions with different histological features remains a clinical challenge. A 45-year-old woman with a history of cervical squamous cell carcinoma (CeSq) presented with abdominal pain and vomiting. A surgical operation revealed an ileal tumor and a peritoneal nodule with a small amount of ascites. A histological examination of the ileal tumor demonstrated squamous cell carcinoma, which was consistent with metastasis of cervical cancer, while that of the nodule and ascites showed adenocarcinoma. Whole genome sequencing (WGS) of the CeSq, ileal squamous cell carcinoma (SiSq), and peritoneal adenocarcinoma (PeAd) demonstrated that ERBB2 was commonly amplified in all lesions. Additionally, HPV-16 genome sequences were identified at identical genomic loci in these lesions. A trajectory analysis corroborated that SiSq and PeAd had a shared origin and developed simultaneously at each metastatic site. These results indicate that a subpopulation of the CeSq had transdifferentiated into adenocarcinoma in our patient. Anti-HER2 therapy showed marked effects on the recurrent disease. Our case demonstrates the plasticity of tumor cells and reinforces the potential roles of WGS in the implementation of precision oncology.

Implementation of Precision Oncology in the National Healthcare System: A Statement Proposal Endorsed by Italian Scientific Societies.

Precision oncology (PO) promises positive results for patients. To date, in Italy, the effort to implement PO has been made autonomously by regional health institutions in a top-down fashion. This approach is not very efficient and jeopardizes patients' equal access to PO. Similar outcomes have been recorded in other Western countries. We tested a method of collaboration among professionals, scientific societies, and government institutions to facilitate the delivery of PO innovation to patients' bedsides. We designed an organizational research project on the basis of a bottom-up approach. We started by observing PO-related activities in five health care authorities (HCAs) in one Italian region. We then compared the issues that emerged with those of three additional HCAs in other Italian regions. Using the results of the initial observation and adopting validated multiple-step consensus methods, we finally derived 14 statements that were approved by the four main scientific societies of oncology and pathology at the national level. The 14 statements addressed the main issues linked to the implementation of PO in clinical practice. The strong professional consensus advocated for prompt adoption within the national healthcare system. The consensus on the statements that were obtained shows the importance of a synergistic effort among professionals, scientific societies, and health care institutions in defining homogeneous solutions for innovation implementation within the health care system.

Consensus Statements on Precision Oncology in the China Greater Bay Area.

Next-generation sequencing comprehensive genomic panels (NGS CGPs) have enabled the delivery of tailor-made therapeutic approaches to improve survival outcomes in patients with cancer. Within the China Greater Bay Area (GBA), territorial differences in clinical practices and health care systems and strengthening collaboration warrant a regional consensus to consolidate the development and integration of precision oncology (PO). Therefore, the Precision Oncology Working Group (POWG) formulated standardized principles for the clinical application of molecular profiling, interpretation of genomic alterations, and alignment of actionable mutations with sequence-directed therapy to deliver clinical services of excellence and evidence-based care to patients with cancer in the China GBA. Thirty experts used a modified Delphi method. The evidence extracted to support the statements was graded according to the GRADE system and reported according to the Revised Standards for Quality Improvement Reporting Excellence guidelines, version 2.0. The POWG reached consensus in six key statements: harmonization of reporting and quality assurance of NGS; molecular tumor board and clinical decision support systems for PO; education and training; research and real-world data collection, patient engagement, regulations, and financial reimbursement of PO treatment strategies; and clinical recommendations and implementation of PO in clinical practice. POWG consensus statements standardize the clinical application of NGS CGPs, streamline the interpretation of clinically significant genomic alterations, and align actionable mutations with sequence-directed therapies. The POWG consensus statements may harmonize the utility and delivery of PO in China's GBA.

Temporal trends of atypical drug access at an academic oncology unit: The Verona University Hospital experience.

e13651 Background: In Italy, patient (pt) access to oncological drugs is almost exclusively provided by the NHS, following authorization by the European Medicines Agency (EMA) and negotiation with the Italian Medicines Agency (AIFA) for specific indications. However, regulatory delays (with respect to the availability of scientific evidence) and the need for rapid access to innovative drugs, particularly in the context of orphan and rare diseases, have prompted the utilization of atypical drug access pathways. In addition to enrollment in clinical trials, atypical drug access pathways are expected to be increasingly used in the context of a Precision Oncology practice. Methods: We explored trends in atypical drug access at the Oncology Section of the Verona University and Hospital Trust, by interrogating Oncology and Pharmacy databases and regional registries of rare diseases and reviewing AIFA registries records. Data on atypical drug access were also correlated with the use of NGS-based molecular profiling. Results: Between January 2016 and December 2022, a total of 355 atypical drug access requests for the treatment of cancer pts were recorded, with a peak in 2017 and no discernible temporal trend. Over this period, the two most common atypical access schemes were compassionate (including named patient and early access programs, 61%) and off-label (21%) use. The latter steadily increased over time (from 8% in 2017 to 39% in 2021). Overall, the type of drugs requested through atypical access were almost equally distributed between classical cytotoxic agents (CHT, 36%), immuno-oncology drugs (IO, 29%) and molecularly targeted agents (TT, 35%). Temporal trends in the usage of different classes of drugs are shown. Interestingly, TT requests decreased between 2016 and 2018 and stabilized at approximately 50% of total requests since 2019. Between 2019 and 2021, atypical drug access requests triggered by NGS-based extended molecular profiling significantly increased from 2.8% to 23.1% (p=0.0007). Conclusions: Although atypical drug access did not increase overall during the observation period, a trend towards increased off-label use of TT was identified, especially from 2019 onwards; figures for 2022 are being analyzed and will be presented at the Meeting. Since 2019, NGS-informed requests have significantly increased to constitute almost 1/4 of all atypical drug access requests, clearly identifying a trend towards implementation of Precision Oncology in routine clinical practice and evolving towards the implementation of Molecular Tumor Board case discussions. [Table: see text]

The Maine Cancer Genomics Initiative: Implementing a Community Cancer Genomics Program Across an Entire Rural State.

The Maine Cancer Genomics Initiative (MCGI) aimed to overcome patient- and provider-level barriers to using genomic tumor testing (GTT) in rural practices by providing genomic tumor boards (GTBs), clinician education, and access to comprehensive large-panel next-generation sequencing to all patients with cancer in Maine. This paper describes the successful implementation of the initiative and three key services made operative between 2016 and 2020. A community-inclusive, hub-and-spoke approach was taken to implement the three program components: (1) a centralized GTB program; (2) a modular online education program, designed using an iterative approach with broad clinical stakeholders; and (3) GTT free of charge to clinicians and patients. Implementation timelines, participation metrics, and survey data were used to describe the rollout. The MCGI was launched over an 18-month period at all 19 oncology practices in the State. Seventy-nine physicians (66 medical oncologists, 5 gynecologic oncologists, 1 neuro-oncologist, and 7 pediatric oncologists) enrolled on the study, representing 100% of all practicing oncologists in Maine. Between July 2017 and September 2020, 1610 patients were enrolled. A total of 515 cases were discussed by 47 (73%) clinicians in 196 GTBs. Clinicians who participated in the GTBs enrolled significantly more patients on the study, stayed in Maine, and reported less time spent in clinical patient care. The MCGI was able to engage geographically and culturally disparate cancer care practices in a precision oncology program using a hub-and-spoke model. By facilitating access to GTT, structured education, and GTBs, we narrowed the gap in the implementation of precision oncology in one of the most rural states in the country.

Global Challenges in Access to and Implementation of Precision Oncology: TheHealth Care Manager and HealthEconomistPerspective.

Precision medicine changes the landscape of oncology practices by offering the opportunity to optimize care through a more targeted, personalized approach of managing cancer treatments. However, precision oncology is costly and does not benefit all patients with cancer, making it critically important to consider the tradeoff between costs and health benefits. Here, we discuss the global challenges in implementing precision oncology from the perspective of health care management and health economics and emphasize the different challenges for high-income compared with low- and middle-income countries. For health care managers making resource allocation decisions, the decision to adopt, implement, and finance precision oncology must consider opportunity costs, and the allocation must be proportional to the system's capacity. The standard approach of health technology assessment is inadequate because it fails to consider the capacity to pay. From an economic perspective, global implementation of precision oncology must confront the issues of accessibility, affordability, and system readiness. Low- and middle-income countries often have no or delayed access to novel targeted-therapy agents, find these drugs cost-prohibitive, and struggle to build the infrastructure with sufficient workforce and adequate testing and computing facilities to capitalize the benefit of precision oncology. Although high-income countries are better equipped to implement precision oncology, the challenges there lie in implementing strategies to maximize the value of precision oncology through promoting appropriate use while limiting inappropriate applications. The recent rollout of COVID-19 vaccines internationally highlights the importance of information uncertainty and offers valuable insights on global access to and implementation of precision oncology.

Uniting Latin America Through Research: How Regional Research Can Strengthen Local Policies, Networking, and Outcomes for Patients With Lung Cancer.

Lung cancer represents a considerable global health threat, leading the list in terms of cancer-related deaths worldwide. An important proportion of lung cancer cases occur within Latin America, and current projections show that over the next decade, the number of deaths due to lung cancer will double in the region, underscoring the need to implement evidence-based interventions to improve outcomes. Several challenges have limited the progress in lung cancer research in Latin America for many years, though recently the surge of multidisciplinary, transnational, and transcultural research groups have overcome many of these limitations. The increase in region-specific knowledge has improved cancer care in the area, providing clinicians with a specific demographic and molecular profile for Hispanic patients with lung cancer; as a result, the implementation of precision oncology has benefited from a profound knowledge of the patient profile. Nonetheless, there are still challenges to improve research in Latin America, including stabilizing funding sources to continue independent research, supporting mentoring programs and an early immersion in clinical research for early career fellows, and overcoming barriers for publishing.

Systematic analysis of actionable gene fusions by NGS-based in pancancer for precision oncology in China.

e15072 Background: Detection of gene fusions with NGS is widely used for clinical diagnosis and drug development. To deeply understand clinically actionable gene fusions for implementation of precision oncology, we systematically analyzed the distribution of tumor types of each fused driver gene, and other mutation types in the same sample which were accompanied. Methods: Samples were performed with NGS based 450 tumor genes panel assay. Genomic alterations, including single nucleotide variations (SNV), short and long insertions/deletions (InDels), copy number variations and gene fusions were analyzed using a published algorithm. Results: We collected 1740 patients with 1478 known fusions and 338 novel fusions. Of all the patients, 48.5% were male, 6.5% were TMB-H (≥ 10 muts/Mb) and 0.6% were MSI-H. We found that breast carcinoma (BRCA) accounts for 28.6% of the ERBB2 fusions, intrahepatic cholangiocarcinoma (ICC) accounts for 60.4% of FGFR2 fusions, non-small cell lung cancer (NSCLC) accounts for 45.5% of FGFR1, 41.5% of FGFR3, and 87.3% of ALK fusions, respectively, renal cell carcinoma (RCC) accounts for 65.9% of TFE3 fusions, the soft tissue sarcoma (STS) accounts for 30.3% of NTRK1 fusions, 70.6% of PDGFB fusions, and 75.6% of SS18 fusions, respectively. We identified EGFR fusions in specific tumor types such as colorectal carcinoma (CRC) and Glioma (GBM), MET fusions in gallbladder carcinoma (GBC), PDGFRA fusions in NSCLC, BRAF fusions in ICC and FGFR3 fusions in urothelial carcinoma (UC). About novel fusions, many of them were detected in multiple tumor types, for example, PHF20-NTRK1 was detected in CRC, NSCLC and ovarian carcinoma (OC), FGFR2-INA was found in ICC and NSCLC, FGFR2-PAWR was detected in BRCA and ICC. Some partner genes were shared by multiple driver genes. For example, TTC28 presented as partner of FGFR2 in ICC, of NRG1 in ICC, of NTRK3 in hepatocellular carcinoma (HCC). Some novel fusions were found more than twice in one tumor type, for example, CMAHP-ALK was detected twice in NSCLC and EHBP1-MET was detected three times in ICC. These novel fusions are helpful to drug development and molecular diagnosis. Some co-occurring variations with fusions often existed in same patient. For example, patients with ALK fusion were also detected SNV of ALK such as L1196, F1174, and G1202. In addition, amplification of ERBB2 and EGFR were both 1.7% in patients with fusions, and CDKN2A/B deletion occupied 5.1% often with EML4-ALK and FGFR3-TACC3. Conclusions: In our study, many new novel fusions and known fusion in new tumor type were revealed. The regular pattern of co-occurring variations of fusion helps to improve the fusion detection rate and clinical application. This simultaneous detection of multiple meaningful variants is the advantage of NGS methods over other traditional methods. All of the above will helpful for improving the clinical benefit rate and accelerating target drug development.

Molecular tests and target therapies in oncology: recommendations from the Italian workshop.

Next-generation sequencing (NGS) and liquid biopsy are new technologies that can allow overall tumor profiling in a single analysis and play an important role in the implementation of precision oncology. However, the lack of guidelines in this setting has limited the development of precision oncology in Italy. This articlesummarizes recommendations for the appropriate use of NGS in tumor gene profiling, as well asaccess to tests and target drugs, that were prepared by a group of key opinion leaders and relevant stakeholders. In particular, the need to create laboratory networks capable of carrying out NGS tests in Italy ishighlighted. It also appears necessary to establish an adequate reimbursement system for NGS tests. However, the expert panel recommendsthat the use of NGS tests in clinical practice should be limited to specific tumor types, based on the number and complexity of biomarkers and the availability of treatments.

Abstract 169: Ephesus - A curated content knowledgebase for the clinical interpretation of genomic variants

Abstract Accurate and comprehensive interpretation of genomic variants has become a bottleneck in clinical sequencing applications due to the implementation of precision oncology and the growth of biomedical findings. We therefore were motivated to build Ephesus, a framework enabling curation of predictive, prognostic and diagnostic evidence for clinical biomarkers in somatic cancers. Currently Ephesus is the primary content source for Roche NAVIFY Mutation Profiler (RUO). The Ephesus' data model ensures adherence to best practices in the field of clinical genomic content curation. Somatic variant classification followed the AMP guidelines. Approvals and recommendations from regulatory agencies and clinical practice guidelines were applied on a regional basis. The data model is mapped to a set of relational tables. Strategies such as data normalization according to standard ontologies, a submit-review-approval workflow with change logs, and biologically relevant data constraints are adopted to enforce data integrity. Ephesus is deployed as a web application whose UI allows users to conduct edits, sorting, filtering, and bulk operations on entities attributes. In order to minimize the manual effort and maximize content coverage, a number of inference rules are applied before the content is ingested into NMP. Currently Ephesus is developed to guide data collection, browsing and summarizing related to primary entities such as Biomarkers, Evidence items, Genes, Variants, Variant groups, and Drugs. The content from 10/28/20 snapshot contains 233k biomarker profiles (including biomarker combinations), in the context of 17 major cancer types. To evaluate the clinical reporting value of the curated knowledge, ~60k clinical cancer patient samples from the AACR GENIE project were queried against Ephesus. Compared our results against those from 3 other major knowledgebases (snapshotted at the same time as Ephesus), we see the performance of Ephesus/NMP exceeds all these knowledgebases. Patients% with at least one interpretation (numbers in parenthesis include matching by inferences)KnowledgebaseVariantVariant & diseaseTier I variant & diseaseEphesus53 (91)40 (89)19 (25)CGI3573CIViC402215ClinVar452313 Citation Format: Jian Li, Lili Niu, Fnu Kinshuk, Bernie Chu, John Mu, Nicole Greene, Vivian Douglas, Caitlin Schartner, Kalpana Kannan, Priyanka Rao, Shuba Krishna. Ephesus - A curated content knowledgebase for the clinical interpretation of genomic variants [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 169.

Ephesus: A curation workflow tool for the clinical interpretation of genomic variants.

e14074 Background: Accurate and comprehensive interpretation of genomic variants has become a bottleneck in clinical sequencing applications due to the accelerated implementation of precision oncology and the rapid growth of relevant biomedical findings. We therefore are motivated to build Ephesus, a framework enabling curation of clinical evidence for biomarkers in somatic cancers. Currently Ephesus is the primary content source for Roche NAVIFY Mutation Profiler (NMP). Methods: Ephesus’ data model ensures adherence to best practice in clinical genomic content curation. Variant classification followed the AMP guidelines for somatic variant interpretation. Approvals and recommendations from regulatory agencies and organizations (FDA, NCCN, etc.) are applied on a regional basis. The data model is mapped to a set of PostgreSQL relational tables. Strategies such as data normalization according to standard ontologies, a submit-review-approval workflow with change logs, and biologically relevant datatype constraints are adopted to enforce data integrity. Ephesus is deployed as a web application, of which the UI allows users to conduct edits, filtering, sorting and bulk operations on entities by attributes. To maximize curation efficiency, a number of inference rules are applied before the content is ingested into NMP. Results: Currently Ephesus is developed to guide data collection, browsing and summarizing related to these primary entities: Biomarkers, Evidence items, Genes, Variants, Variant groups, and Drugs. The content exported on 2020/01/27 contains > 170K biomarker profiles (including combinations), in the context of 13 major cancer types. To evaluate the clinical reporting value of the curated knowledge, more than 60k real clinical cancer patient samples from the AACR GENIE project were queried against Ephesus. We compared the results to the latest content from several major knowledgebases. We see that the performance of Ephesus/NMP excels the others. Conclusions: We have developed Ephesus, a practical content curation framework which provides a highly structured and user-friendly environment for clinically relevant somatic biomarkers. The framework improved the productivity and quality of the manual curation, met clinical interpretation scope and complexity, and assures data integrity and auditability. [Table: see text]

Genomic analysis of metastatic solid tumors in veterans: Findings from the VHA National Precision Oncology Program.

3074 Background: Scalable next generation sequencing (NGS) technologies have enabled incorporation of precision oncology into clinical practice, informing treatment decisions based on tumor genomics. The Veterans Health Administration (VHA) is the largest integrated healthcare system in the U.S., serving a higher percentage of rural patients (36%) than the national average (14%). To implement and standardize the practice of precision oncology across a diverse healthcare system, the VHA established the National Precision Oncology Program (NPOP). Methods: Tumor or peripheral blood specimens were collected from Veterans with advanced solid tumors who were eligible for treatment with targeted or immunotherapeutic drugs. Specimens were sequenced using cancer gene panels at two commercial laboratories. Annotated results were generated by the vendors and independently using IBM Watson for Genomics. Levels of evidence treatment recommendations were based upon OncoKB criteria. Results: Between July 2016 and June 2018, 3713 samples were collected from 72 facilities; the sequencing success rate was 86%. The majority of samples came from males with lung, prostate and colorectal cancers. Thirty-four percent of samples submitted were from rural patients. The most commonly mutated genes included TP53, ATM and KRAS. Over 70% of samples sequenced had at least one actionable mutation, and clinical trials were the recommended option in over 50%. The most frequent therapies prescribed in response to NGS testing were immune checkpoint inhibitors, EGFR kinase inhibitors and PARP inhibitors. Interestingly, prostate cancers among Veterans had a higher frequency of mutations in genes associated with a neuroendocrine phenotype compared with the general population. Conclusions: Implementation of precision oncology into clinical practice is feasible across the diverse VHA system, including rural community sites. Veterans have unique occupational exposures that might inform underlying causes of distinct mutational signatures identified here. Our results highlight the importance of increasing the availability of clinical trials for Veterans.

Implementing precision cancer medicine in the genomic era.

The utilization of genomic data to direct treatment for cancer patients represents the central tenet in precision oncology, in which a patient is matched to a specific drug or therapy based on the genetic drivers detected in his or her tumor rather than the tumor's histologic classification. The expected but not always realized outcomes of molecularly matched therapies include increased response rates, more durable responses, deeper responses, and decreased number of therapy-related side effects. In this review, we will discuss different facets of utilizing genomic data to direct the increasingly complex care of cancer patients. We discuss the enlarging compendium of actionable genomic alterations and the development of novel molecular diagnostic assays for clinical application. Finally, we present an overview of the growing number of genomics-driven clinical trials and conclude with a discussion of future challenges in the implementation of precision oncology.

Abstract 998: OPeN: the oncology precision network data sharing consortium

Abstract Background: The advent of Next-Generation Sequencing (NGS), and other molecular diagnostic technologies, has enabled the use of genomic information to guide targeted treatment in cancer patients. While this precision oncology approach can yield exciting clinical outcomes, the innumerable genomic variants identified in individual tumors effectively establishes each case as a unique N=1 clinical presentation. This scenario is contrary to a basic dogma of medical practice where historical cases and treatment outcomes guide future management and therapeutic decisions. Aggregation of large data sets, on a multi-institutional basis, has the potential to overcome the N=1 paradox and yield management insights in the implementation of precision oncology. Methods: We have formed the Oncology Precision Network (OPeN), an oncology data sharing consortium, to aggregate big data sets consisting of clinical, genomic, pharmacological, and treatment response data from diverse patient cases. Data from Intermountain Healthcare, Stanford University, and Swedish Cancer Institute-Providence St. Joseph Health, as well as other institutions, comprises the database and is derived from 79 hospitals, over 800 physician clinics and more than 50,000 annual cases. Results: The OPeN database can be interrogated by variant type, specific therapeutics, clinical outcomes, and by grouped variables, in a structured data format. The overarching IT platform is a cloud based, open source, triple store precision oncology solution, Syapse. These data are yielding valuable insights, including tumor mutational burden (TMB) scores and their correlation to immunotherapy response, clinical response in various drug-gene combinations, and therapy-specific adverse events. Conclusions: We anticipate this resource will be used by the Molecular Tumor Boards of contributing institutions for clinical interpretation, and by treating providers to overcome the N=1 challenge associated with precision oncology. Citation Format: Lincoln Nadauld, Derrick Haslem, Paul D. Tittel, Mariko Tameishi, Thomas Brown, James Ford. OPeN: the oncology precision network data sharing consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 998. doi:10.1158/1538-7445.AM2017-998

Implementation of precision oncology in the Veterans Health Administration (VHA).

6507 Background: VHA is the US’s largest integrated healthcare system providing care to over 6 million Veterans (~40% in rural areas). Precision Oncology offers the promise of effective, low-toxicity targeted therapies tailored to individual tumor genomics but is unequally available to patients in the US. As part of the Cancer Moonshot, VHA is implementing a system-wide Precision Oncology Program (POP) including patients in rural areas, where specialty oncology care has historically had limited availability. Methods: Patients tested with multigene NGS tumor sequencing through 1 of 2 contracted vendors were identified from POP records and cancer characteristics were extracted from POP and medical records. Drug use data was obtained from the VA Corporate Data Warehouse. NGS testing results and annotations were extracted from POP records. Results: A total of 978 tumor samples were sent for NGS testing since program inception in 2015. The most common diagnoses are lung (464: adeno 314, squamous 107), GI (87), LN (75), liver (56), H&N (52), and prostate (43). The rate of sample test requests increased rapidly after national implementation in July 2016 (mean 23 samples/month prior to implementation to mean 126 samples/month 3 months later) as did the number of participating facilities (mean 8/month to 27/month). Sequencing success rate increased from 68% to 71% over the same interval while mean turn around time remained similar at 19.7 and 19.1 d, respectively. NGS results are available for a cohort of 344 patients including: lung 200 (adeno 138, squamous 51), skin 28, LN 20, liver 19, GI 16. 979 variants were found including TP53 278, KRAS 106, STK11, APC 38, PIK3CA 38, and CDKN2A 37. 228 patients had actionable results (on-label drug 24, off-label drug 165, clinical trial 213). To date, 8 patients received a recommended drug outside a clinical trial between 11 and 288 d after testing (median 82 d); 4 additional patients had received an NGS-recommended drug prior to testing. Conclusions: Implementation of tumor NGS testing as part of Precision Oncology Program in a US distributed healthcare system is feasible. Further program implementation and provision of appropriate targeted drugs both on and off study will be necessary to impact patient outcomes.

AB169. Engaging the genetic counsellor in the implementation of precision oncology in Singapore

Cancer is a genetic condition driven by a series of both inherited (germline) and tumour specific (somatic) mutations. The analysis of tumour to identify somatic alterations and generate a genetic profile has given rise to a personalised approach for treating oncology patients, guiding optimal therapy. Next generation sequencing (NGS) technology is now routinely utilised in oncology to screen for both genes known to be associated with improving treatment response, as well as, genes of uncertain significance to contribute to new findings in cancer treatment. In the development of genome wide mutation analysis of tumour tissue, germline DNA has also been routinely collected for comparative analysis in order to identity tumour specific mutations. As the identification of germline mutations is secondary to the main purpose of tumour testing for targeted treatment, the management of germline findings has been extensively debated, in particular, around if and when to communicate these findings to patients. The role of the genetic counsellor in this process has been pertinent to these discussions. Clinical practice, however, is shifting towards a preference of sequencing tumour tissue alone to characterise its molecular profile for reasons such as reducing cost and facilitating logistics of sample collection. This method raises the question of how the testing of tumour alone contributes to the identification of germline mutations. The laboratory at POLARIS, Singapore, has generated genomic data of 130 colon tumours using a panel of 84 genes, including 29 germline susceptibility genes associated with known inherited syndromes. The analysis of this data has given an insight into the proportion of mutations that are potentially germline, which in turn will impact how patients are consented for tumour profiling and the delivery of the results. In generating these findings, however, the analysis process has demonstrated a number of the complexities in interpreting the pathogenicity of the variants, as well as, determining the somatic or germline origin of the variant. The challenges in interpreting germline mutations from tumour next generation data, the importance of conveying a germline finding to the patient and the integration of the genetic counsellor in this process will be discussed.