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Response to Commentary

The Potential for Precision Oncology to Enhance Cancer Detection, Diagnosis, and Treatment for Veterans

The VA Precision Oncology Initiative integrates clinical and research domains with the aim of transforming VA into a System of Excellence for oncology care; the Initiative both provides individualized cancer treatment to Veterans based on the characteristics of their tumors and creates a learning healthcare system for oncology care. The National Precision Oncology Program (NPOP) has provided Veterans with centralized molecular testing for their cancers and genetic counseling is available from the Clinical Cancer Genetics Service. NPOP provides molecular testing (somatic and germline) of advanced cancers at over 90 percent of VA medical centers and provides expert consultation service to assist oncologists with interpretation and therapeutic decision making. These capabilities along with a robust data, informatics, and analytic infrastructure offer signature components for a system where the generation of data and use of evidence are critical to providing Veterans with high quality oncology care.

To further the creation of this system, the Office of Research and Development (ORD) and the National Oncology Program Office (NOPO), both parts of the Veterans Health Administration within VA, have partnered to establish multiple synergistic care and research networks. For example, the Prostate Cancer Analysis for Therapy Choice (PATCH) network works with the Precision Oncology Program for Cancer of the Prostate (POPCaP) and genitourinary (GU) sites to increase the number of VA facilities involved in clinical trials. In turn, the number and diversity of Veteran participants in clinical trials of precision therapies for prostate cancer can be increased. Appropriate studies developed from within the PATCH network by VA investigators allow Veterans with prostate cancer to participate in biomarker stratified basket trials in which they are assigned to one of the treatments based on the genetic changes identified in their tumors, thereby providing Veterans with the most advanced clinical trials. PATCH provides a coordinated effort to perform a range of multi-site studies focused on targetable molecular alterations for Veterans with prostate cancer. Simultaneously, similar efforts are being developed for lung cancer through the Lung Precision Oncology Program (LPOP) to carry out a robust set of biomarker studies in which “on-” and “off-label” Food and Drug Administration-approved therapies are paired with specific mutations identified in advanced cancer.

It is important to note that POPCaP, GU, and LPOP are part of a larger set of networks, coordinated and managed by the VA Cooperative Studies Program (CSP), that include the Network of Dedicated Enrollment Sites (non-cancer specific studies) and the National Cancer Institute (NCI) VA Interagency Group to Accelerate Trials Enrollment (specific to NCI-supported trials). Under this umbrella, these groups have undertaken a pilot program aimed at engaging rural VA medical centers interested in enrolling Veterans in clinical trials called Advancing Capacity for Clinical Research through Engagement and Strategic Sites. By developing capabilities to run clinical trials across multiple therapeutic areas, these groups can share and disseminate best practices to build expertise and to focus efforts on novel ways of reaching out to Veterans and building rapport with them across the VA enterprise. 

Despite the success of molecular targeted therapy, the benefit for patients has been modest since only some patient populations show significant improvement in their response to targeted treatment and survival. It remains to be seen if additional genomic signatures apart from driver mutations can be utilized to further expand targeted therapeutic efforts. More specifically, it is uncertain if these signatures can predict response to treatment. Identifying such biomarkers will require deep whole genome sequencing of tumors, matched controls, and bioinformatic analyses to identify potential mutational signatures involved in cancer development. ORD is supporting investigations in this area of research with initial pan-cancer studies. This effort also has the potential to shed light on the effects of environmental exposure, epigenetic changes, and other mutational processes in the genome.

Similarly, immunotherapy has shown durable benefit in some cancers and more so in lung cancer where it is effective in approximately 20 percent of patients. However, in most cancers, there is resistance and/or no benefit from immunotherapy due to immune checkpoint blockade. Efforts are under way through ORD funded research to examine the combination of immunotherapy with other treatment modalities (chemotherapy, radiation, etc.) to potentiate anti-tumor immune response, thereby increasing the efficacy of immunotherapy (i.e., enhance the efficacy of checkpoint inhibitors). Since resistance to treatment and recurrence continue to be major problems for cancer patients, ORD is investing in the development of novel molecular and immune biomarkers and molecular diagnostic assays to monitor treatment response and recurrence in real time. These assays utilize protein profiles, ctDNA, microRNAs, circulating tumor cells, and other tumor fragments circulating in plasma. If successful, these assays would be less invasive and could be impactful in clinical management of patients.

A comprehensive understanding of cancer in which genomic, molecular, and clinical data are integrated is critically important to enable discovery and opportunities to translate those discoveries into the clinic.  Data that are curated, cleaned, validated, and optimized for system-wide access by clinicians and researchers are crucial to realizing the power of VA data to drive innovation and advance therapies more quickly to benefit Veterans and the public. Data integration, combined with a data governance framework that applies across the enterprise, is necessary for sharing data and knowledge, and for fostering collaborations, partnerships, and cross-disciplinary approaches to operationalize findings into care.

ORD and NOPO are actively working to harmonize data systems that organize and integrate various pieces of genomic, phenotypic, imaging, and clinical data combined with bioinformatics and other technologies such as artificial intelligence and machine learning to enhance cancer detection, diagnosis, and treatment and to improve patient outcomes by optimizing clinical trials for appropriate patient populations and research. Together this effort can support new investigations (whether or not funded by VA), development of novel biomarkers, and targeted and immunotherapy approaches; increase the use of technologies to improve the analysis of data that informs precision oncology; and make it possible to translate discoveries into clinical care.

With respect to data, VA is also partnering with the NCI in the Big Data Scientist Training Enhancement Program and providing access to data as part of training the next generation of experts for using large, complex datasets that VA expects to continue to generate. ORD is also working with the University of Chicago Center for Translation and Data Science and the Precision Oncology Data Repository to provide access to and share de-identified data with the research community to enable rapid advances for Veterans. In addition, ORD supports the development of the Computer Vision and Machine Learning in Precision Oncology (CoMPL) hub within LPOP to accelerate the development of computer vision and machine learning (CVML) tools to address cancer diagnosis, prognosis, risk stratification, prediction of treatment response, and improving outcomes in the VA population. These tools are regulated as software as a medical device and are the future for cost-effective, precision treatment. CoMPL serves as a resource for building and expanding the community for CVML precision oncology research within the VA through collaborative efforts. Critical to this effort will be the development of a repository of curated, de-identified, and annotated high quality data with clinical information from all cancer types to be available to researchers to develop, test, and validate algorithms that can be used in healthcare. CoMPL leverages expertise from the Million Veteran Program and CSP, which were instrumental in developing GenHub and Genesis data analytics platforms. ORD has been building these platforms as enterprise resources to enable investigators to perform high computational analyses in a secure environment. Since its phased implementation in 2022, CoMPL is bringing VA investigators together and fostering collaborative multidisciplinary studies in prostate, lung, head and neck, and other cancers.

To exemplify the power of partnerships that leverage these resources, bioinformatics, and data science capabilities, VA has made a centerpiece of its participation in the Cancer Moonshot relaunch. Specifically, data from Applied Proteogenomics Organizational Learning and Outcomes (APOLLO), a tri-agency partnership among VA, Department of Defense, and NCI, will be made available through the Genomic Data Commons, Proteomic Data Portal and Cancer Imaging Archive of the NCI. APOLLO is focused on advanced genomic and protein analyses of high-quality tumor samples from service members and Veterans to identify potentially actionable therapeutic molecular targets and determine whether and how protein expression predicts patient response to treatment. The goal is to enable a continual learning process involving data obtained from trials and clinical care to inform Veteran care that builds upon experiences from each case.

Together, these efforts within the precision oncology initiative have positioned VA to leverage its resources, expertise, human capital, and diverse patient population to become a leader in developing and advancing clinical evidence for care. More importantly, they enable VA to improve cancer outcomes for Veterans and their loved ones.