The intent of the Breakthrough Award is to support promising research that has high potential to lead to or make breakthroughs in breast cancer. The critical components of this award mechanism are: Impact: Research supported by the Breakthrough Award will have the potential for a major impact and accelerate progress toward ending breast cancer. The impact may be near-term or long-term, but must be significant and move beyond an incremental advancement. Applications must articulate the pathway to making a clinical impact for individuals with, or at risk for, breast cancer, even if clinical impact is not an immediate outcome. Research Scope: Research proposed under this award mechanism may be small- to large-scale projects, at different stages of idea and research development. Two different funding levels, based on the scope of the research, are available under this Program Announcement. The current Program Announcement discusses Funding Levels 1 and 2. Funding Levels 3 and 4 are available under a different Program Announcement (W81XWH-17-BCRP-BREAKTHROUGH2-FL34). It is the responsibility of the Principal Investigator (PI) to select the funding level that is most appropriate for the research proposed. The funding level should be selected based on the scope of the research project, rather than the amount of the budget. The following are general descriptions, although not all-inclusive, of the scope of research projects that would be appropriate to propose under each funding level: • Funding Level 1: Innovative, high-risk/high-reward research that is in the earliest stages of idea development. Research with potential to yield new avenues of investigation. Proof of concept. No preliminary data required. • Funding Level 2: Research that is already supported by preliminary data and has potential to make significant advancements toward clinical translation. Partnering PI Option: The Breakthrough Award encourages applications that include meaningful and productive collaborations between investigators. The Partnering PI Option is structured to accommodate two PIs, referred to as the Initiating PI and the Partnering PI, each of whom will receive a separate award. The Initiating and Partnering PIs have different submission requirements; however, both PIs should contribute significantly to the development of the proposed research project including the Project Narrative, Statement of Work, and other required components. The PIs may have expertise in similar or disparate scientific disciplines, but each PI is expected to bring distinct contributions to the application. New collaborations are encouraged, but not required. It is the responsibility of the PIs to describe how their combined expertise will better address the research question and explain why the work should be done together rather than through separate efforts. To meet the intent of the Partnering PI Option, applicants are discouraged from submitting as a Partnering PI on multiple Breakthrough Award Levels 1 and 2 applications unless they are clearly addressing distinct research questions. Applications submitted by a mentor and his/her current postdoctoral fellow or junior investigator as Initiating and Partnering PIs do not meet the intent of the Partnering PI Option. Personnel: PIs are expected to engage and assemble an appropriate and robust research team with the combined backgrounds and breast cancer-related expertise to enable successful conduct of the project. Research involving human subjects and human anatomical substances is permitted; however, clinical trials are not allowed under this funding opportunity. PIs wishing to apply for funding for a clinical trial may consider applying under the FY17 BCRP Breakthrough Award Levels 3 and 4 Program Announcement (W81XWH-17-BCRP-BREAKTHROUGH2-FL34).