Grant Number:	5R00CA207872-05 Interpret this number
Primary Investigator:	Ryser, Marc
Organization:	Duke University
Project Title:	The Mathematics of Breast Cancer Overtreatment: Improving Treatment Choice Through Effective Communication of Personalized Cancer Risk
Fiscal Year:	2020

Project Summary/Abstract This Career Development Application provides targeted coursework and mentored research to enable pro- gression to independent research in the highly cross-disciplinary areas of mathematical modeling and person- alized breast cancer care. Every year, close to 60,000 women in the US undergo radical surgery after diagno- sis with screen-detected breast carcinoma in situ (BCIS), yet as many as 45,000 of these are treated for be- nign lesions that would not progress to invasive breast cancer in their lifetime. The resulting overtreatment of non-progressive BCIS lesions can cause substantial harms and significantly reduce the patient's quality of life without reducing breast cancer mortality. Although the widespread overtreatment of women with BCIS is well documented at the population level, its prevention at the patient level is hindered by the current treatment par- adigm, which dictates that virtually all patients undergo immediate treatment. This in turn perpetuates the lack of data needed for the evaluation of management strategies other than immediate treatment, such as active surveillance. To resolve this conundrum, randomized controlled trials on active surveillance have been initiated, but only recently and only in Europe. It is anticipated that these trials, even if successful, will not yield clinically actionable data for at least 10 years. At the same time, however, there is a wealth of existing clinical and bio- logical data on BCIS that is dispersed across a large number of data and knowledge sources. In the absence of quantitative models that enable the integration of these dispersed sources, the bulk of the existing data re- mains inaccessible to patients. Thus, to enable informed decision making among patients with BCIS, there is a critical need (i) to develop predictive models that integrate available patient- and tumor-specific data to make personalized risk and uncertainty projections for different management strategies, and (ii) to effectively com- municate these personalized projections to patients. In the absence of tools for the quantification and commu- nication of personalized risk projections, it remains difficult for patients and physicians to weigh the trade-offs associated with different management strategies and to make an informed, evidence-based decision that re- duces the risk of potentially harmful overtreatment of BCIS. The long-term goal is to develop personalized de- cision aids that maximize informed decision-making and minimize overtreatment in patients with BCIS. The overall objective of this proposal comprises the first three steps towards this goal: (i) to develop personalized risk projection models for different management strategies of BCIS, (ii) to use these projections to develop a personalized decision aid, and (iii) to evaluate its impact in in a test cohort of women without a history of breast cancer. Our central hypothesis is that communication of model-based personalized risk projections leads to an improved understanding of the trade-offs associated with different management strategies for BCIS. The ra- tionale for the proposed research is that with personalized outcome estimates, patients gain access to the in- formation needed for an evidence-based decision that is aligned with their personal risk tolerance. The specific aims for the mentored (K) and independent (R) research phases of this K99/R00 are as follows. Aim K1: Discover data and knowledge sources that are relevant for personalized risk projections in BCIS pa- tients, and curate them into a harmonized data store and knowledge base, respectively. Aim K2: Develop mathematical models that use the data store and knowledge base to compute personalized risk projections for different BCIS management strategies, including active surveillance. Aim K3: Design a two-stage study to develop, refine and evaluate a model-based personalized decision aid for BCIS patients through cognitive interviews (Stage 1) and a RCT (Stage 2). Aim R1: Perform model validation and uncertainty quantification to maximize model confidence. Aim R2: Stage 1: Conduct cognitive interviews to develop and refine an interactive decision aid for the effec- tive communication of personalized risk projections in BCIS patients. Aim R3: Stage 2: Implement a RCT to test the main hypothesis that the use of personalized decision aids leads to (i) an increase in the proportion of women who would consider active surveillance as a viable management strategy for BCIS, and (ii) an increase in knowledge of the associated risk trade-offs. The deliverables will include a data-driven mathematical modeling framework, expected to yield the best pos- sible patient-specific risk projections for different management strategies of BCIS. The interactive decision aid is expected to provide an intuitive understanding of the risks and uncertainties that are associated with different BCIS management strategies. Moreover, this approach will have widespread application in other screen- detected lesions of unknown progression risk, such as those increasingly diagnosed in the prostate, thyroid and lung. The applicant has completed graduate studies in physics (MSc) and mathematics (PhD) and has ini- tiated projects with the primary mentor who has extensive experience in early stage breast cancer, including BCIS. Based on his history of successful collaborative research with clinicians, the applicant is in the unique position to bridge the divide between mathematical modeling and personalized cancer care.




Disease-specific survival outcomes for patients after locoregional treatment for ductal carcinoma in situ: observational cohort study.
Authors: Wang S.M. , Li Y. , Nash A. , Ren Y. , Thomas S.M. , Francescatti A.B. , Barber A. , Lynch T. , Frank E.S. , Grimm L.J. , et al. .
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PMID: 39213131
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Growth Dynamics of Ductal Carcinoma in Situ Recapitulate Normal Breast Development.
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Estimation of Breast Cancer Overdiagnosis in a U.S. Breast Screening Cohort.
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Source: Breast Cancer Research And Treatment, 2022-02-02 00:00:00.0; , .
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Ductal Carcinoma in Situ: State-of-the-Art Review.
Authors: Grimm L.J. , Rahbar H. , Abdelmalak M. , Hall A.H. , Ryser M.D. .
Source: Radiology, 2022 02; 302(2), p. 246-255.
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Long-term risk of subsequent ipsilateral lesions after surgery with or without radiotherapy for ductal carcinoma in situ of the breast.
Authors: van Seijen M. , Lips E.H. , Fu L. , Giardiello D. , van Duijnhoven F. , de Munck L. , Elshof L.E. , Thompson A. , Sawyer E. , Ryser M.D. , et al. .
Source: British Journal Of Cancer, 2021 Nov; 125(10), p. 1443-1449.
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Modeling the natural history of ductal carcinoma in situ based on population data.
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Source: Breast Cancer Research : Bcr, 2020-05-27 00:00:00.0; 22(1), p. 53.
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Minimal barriers to invasion during human colorectal tumor growth.
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Source: Nature Communications, 2020-03-09 00:00:00.0; 11(1), p. 1280.
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Growth Dynamics of Mammographic Calcifications: Differentiating Ductal Carcinoma in Situ from Benign Breast Disease.
Authors: Grimm L.J. , Miller M.M. , Thomas S.M. , Liu Y. , Lo J.Y. , Hwang E.S. , Hyslop T. , Ryser M.D. .
Source: Radiology, 2019 07; 292(1), p. 77-83.
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Response to Habel and Buist.
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Source: Journal Of The National Cancer Institute, 2019-06-14 00:00:00.0; , .
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Incidence of Ductal Carcinoma in Situ in the United States, 2000-2014.
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Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2019-06-11 00:00:00.0; , .
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Cancer Outcomes in DCIS Patients Without Locoregional Treatment.
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Source: Journal Of The National Cancer Institute, 2019-02-13 00:00:00.0; , .
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Epigenetic Heterogeneity in Human Colorectal Tumors Reveals Preferential Conservation And Evidence of Immune Surveillance.
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Source: Scientific Reports, 2018-11-23 00:00:00.0; 8(1), p. 17292.
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Identification of the Fraction of Indolent Tumors and Associated Overdiagnosis in Breast Cancer Screening Trials.
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Source: American Journal Of Epidemiology, 2018-10-16 00:00:00.0; , .
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Spatial mutation patterns as markers of early colorectal tumor cell mobility.
Authors: Ryser M.D. , Min B.H. , Siegmund K.D. , Shibata D. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2018-05-29 00:00:00.0; 115(22), p. 5774-5779.
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Role of Preoperative Variables in Reducing the Rate of Occult Invasive Disease for Women Considering Active Surveillance for Ductal Carcinoma In Situ.
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Source: Jama Surgery, 2018-03-01 00:00:00.0; 153(3), p. 290-291.
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How Low Can We Go-and Should We? Risk Reduction for Minimal-Volume DCIS.
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Estimating the frequency of indolent breast cancer in screening trials.
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Surgical Upstaging Rates for Vacuum Assisted Biopsy Proven DCIS: Implications for Active Surveillance Trials.
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Programmable assembly of pressure sensors using pattern-forming bacteria.
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Modeling of US Human Papillomavirus (HPV) Seroprevalence by Age and Sexual Behavior Indicates an Increasing Trend of HPV Infection Following the Sexual Revolution.
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