The purpose of this Notice is to encourage currently funded NCI extramural investigators to apply for administrative supplements to conduct systematic evidence reviews assessing the state of the science on the clinical utility (CU) of cancer-site specific polygenic risk scores (PRS) for cancer risk assessment and inform future trials and research directions for clinical translation and implementation. The goals of this supplement opportunity are to 1) identify the potential for CU of cancer-site specific PRS for cancer risk assessment; 2) describe the state of the science in terms of cancer-site specific PRS development and evaluation; 3) assess the current evidence for efficacy and/or effectiveness of PRS CU and potential benefits and harms of their clinical use (including consideration of available screening and prevention interventions based on risk); and 4) propose criteria and optimal study designs and methods for which PRS are candidates for evaluation of CU through clinical trials.
The development of PRS for cancer risk assessment has the potential to clarify risk assessment and improve preventive care and risk management. Here we are referring to PRS as mathematical models that use germline genetic information to estimate cancer risk. Prior to the development of PRS, risk models were based on family history and other known risk factors. Studies have been conducted to assess the validity of PRS as estimates of risk, comparing PRS to other models of risk, and examining the validity of models combining PRS with other risk factors. Models have been developed for a variety of different types of cancers, including breast, prostate, ovarian, lung, colorectal, pancreatic, head and neck, kidney, and melanoma. The development, evaluation, and implementation of PRS alone or combined with other risk models for cancer risk assessment are complex and it is critical that these models are thoroughly evaluated prior to implementation to ensure that they can be effectively used in clinical practice to improve patient outcomes.
While PRS have the potential to improve cancer risk assessment and preventive care, additional research is needed to understand issues related to evaluation and establishment of CU prior to clinical implementation. The determination of CU involves the identification of the clinical benefits and harms of the use of PRS in terms of patient outcomes, ideally evaluated in randomized controlled trials. Before clinical use, the validity of the scores must be established. Factors to consider for validity include sensitivity, specificity, and discriminatory value to identify those at risk. Clinical utility considers whether the use of PRS guides appropriate clinical management and the benefits and harms of clinical use. Implementation of PRS, once CU is established, may consider additional factors such as positive and negative predictive value. A clear understanding of the CU of PRS would allow for the development of guideline-driven care that is linked to a specific threshold of risk and appropriate intervention.
The research objective of this NOSI is to conduct a systematic evidence review on the CU of cancer-site specific PRS for cancer risk assessment. (PRS for cancer prognosis should not be included in the systematic reviews.) The review should include a detailed description and discussion of cancer-site-specific PRS with respect to their development and validation and describe what is known about the efficacy and/or effectiveness of their application for guiding risk management, and potential harms and benefits associated with the clinical use of PRS. In addition, the review should propose criteria for which PRS are candidates for evaluation of CU through clinical trials and discuss the optimal study designs and methods to assess efficacy and effectiveness. The review should emphasize issues and challenges as it relates to evaluating the CU of PRS for significant clinical and public health outcomes including descriptions of ongoing and proposed research studies.
Each proposal should include a systematic review of PRS for two or more cancer-specific sites, excluding breast, prostate, and colorectal cancers, and address the following:
- Describe the state of the science in terms of cancer-site specific PRS development and evaluation;
- Assess the current evidence for the efficacy and/or effectiveness of the CU of PRS and potential benefits and harms of their clinical use (including consideration of available screening and prevention interventions based on risk); and
- Propose criteria and optimal study designs and methods for which PRS are candidates for evaluation of CU through clinical trials.
Questions that should be addressed and discussed include:
- What PRS are ready for clinical trials to inform risk and clinical management? What are the limitations and challenges of current PRS in establishing CU and subsequent clinical implementation?
- To what extent does integration of PRS with non-PRS based risk models improve cancer risk prediction?
- What types of studies, including design and methods, should be conducted to generate the evidence to determine the efficacy and effectiveness of PRS? What are appropriate comparison groups to determine the CU of an integrated-risk-score-based approach?
- What are appropriate screening and preventive interventions for those identified to be at risk? What evidence exists for thresholds of risk that may warrant different interventions? To the extent possible, address age as a threshold for interventions.
- What are the potential benefits and harms for implementing PRS into clinical practice?
- What outcomes will need to be measured to demonstrate efficacy and effectiveness?
The completed systematic review must be submitted for publication in an open-access, peer-reviewed journal.
Application and Submission Information
Applications for this initiative must be submitted using the following opportunity or its subsequent reissued equivalent.
- PA-20-272 - Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
All instructions in the SF424 (R&R) Application Guide and PA-20-272 must be followed, with the following additions:
- Application Due Date: Submissions must be received by April 21, 2023, at 5:00 PM local time of applicant organization for FY 2023 funding.
- For funding consideration, applicants must include NOT-CA-23-046 in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.
- Applicants should begin the supplement application abstract by stating This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-046 .
Eligibility and Eligible Individuals (Program Director/Principal Investigator)
- Administrative supplement applications are limited to currently funded R01, R37, P01, P30, U01, UM1, UG1, U2C, UH3, U19 projects supported by NCI. Requests for no-cost extensions on the parent grant to accommodate a supplement will not be permitted.
- PDs/PIs must hold an active award supported through NCI with sufficient time (minimum 1 year) left to complete the study proposed after the supplement has been awarded within the existing project period.
- The proposed project for supplemental funding is required to be within the scope of the parent award and be a logical extension of the original aims.
- For supplements to parent awards that include multiple PDs/PIs, the supplement may be requested by any or all of the PDs/PIs (in accordance with the existing leadership plan) and submitted by the awardee institution of the parent award.
- The budget should not exceed $150,000 in total costs.
- At least one full year on the parent grant must remain at the time of funding (September 2023). The application budget is limited to 1 year only.
- If an applicant anticipates a balance of 50% or more of the current total costs for the parent grant, please contact the scientific research contact prior to submitting an application.
- Only one supplement application per grant will be accepted for consideration through this NOSI.
- Requests must reflect the actual needs of the proposed project. Administrative supplements can be used to cover cost increases that are associated with achieving certain new research objective as long as the research objectives are within the original scope of the peer-reviewed and approved project (i.e., award), or the cost increases are for unanticipated expenses within the original scope of the project.
- Permitted for 1 year of support only; the earliest anticipated start date is September 1, 2023.
- For administrative supplements to grants and cooperative agreements, supplement requests must be submitted electronically in accordance with the parent program announcement PA-20-272. NOTE: Administrative supplement requests (application) for support of clinical trials will not be accepted and/or considered in response to this NOSI.
- Applicants should begin the supplement application abstract by stating This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-046.
- For funding consideration, applicants must include NOT-CA-23-046 in the Agency Routing Identifier field (box 4b) of the SF424 R&R form. Applications without this information in box 4b will not be considered for this initiative.
- In order to facilitate efficient processing of the request, applicants are strongly encouraged to notify the assigned NCI Program Official for the parent award that a request has been submitted in response to this NOSI.
Page limits – these sections have the following limits:
- Project Summary/Abstract: 30 lines of text
- Project Narrative: 3 sentences
- Research Strategy: 5 pages
- Biographical Sketch: for Senior/Key Personnel and Significant Contributors only
Review and Selection Process
NCI Program staff will evaluate applications taking into consideration the following factors:
- Does the administrative supplement reasonably allow for the proposed project to be completed, given the time and budget requested?
- Does the proposed project address two or more site-specific cancers, excluding breast, prostate, and colorectal cancers?
- Does the proposed project address the CU of cancer-site specific polygenic risk scores for cancer risk assessment?
- Are the proposed research methods appropriate for developing a critical and reproducible summary of the literature?
- Are the proposed activities relevant to the parent grant and original work scope?
- Does the applicant demonstrate satisfactory progress towards achieving the aims of the parent grant, as appropriate to the current stage of the project?
Applicants are strongly encouraged to discuss their application with the scientific/research contact listed below prior to submission to ensure responsiveness and facilitate processing of the application.