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Strategy for combining circulating tumor DNA (ctDNA) and magnetic resonance imaging (MRI) measures of tumor burden for prediction of response and outcome in neoadjuvant-treated early breast cancer

Award Number: R01CA255442
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT/PROJECT SUMMARY Neoadjuvant chemotherapy (NAC), which is treatment given before surgery, has become a standard-of-care for breast cancer patients diagnosed with locally advanced disease. NAC offers a unique opportunity for real- time monitoring of tumor response and evaluation of drug efficacy. Patients who achieve pathologic complete response (pCR) have an excellent outcome. Thus, the challenge of NAC is to bring each patient to pCR; and, among non-responders, to identify those with a high probability of recurring for additional therapy in the adjuvant setting. Biomarkers that accurately predict NAC response and metastatic recurrence are key to achieving these objectives. We hypothesize that a multimodal approach for monitoring of tumor burden during NAC—i.e., by magnetic resonance imaging (MRI)-based functional tumor volume (FTV) and liquid biopsy-based circulating tumor DNA (ctDNA) analyses—can yield robust and accurate predictors of response to NAC and metastatic recurrence; and in turn, aid in therapeutic decisions regarding escalation or de-escalation of treatment to improve patient outcomes. Here, we propose a correlative study to the neoadjuvant I-SPY 2 TRIAL, a multicenter, adaptive randomization phase II trial that evaluates the efficacy of novel therapies in combination with standard NAC. Integrated within I-SPY 2, is an ongoing study that evaluates MRI FTV as predictor of response and outcome, and an infrastructure for discovery and validation of companion diagnostic markers, including ctDNA. The proposed study aims to: (1) perform serial ctDNA profiling in patients receiving NAC; (2) combine serial ctDNA profiles with available FTV data to develop breast cancer subtype-specific predictors of pCR, and (3) build prognostic models that combine ctDNA and FTV information to improve on the predictive performance of residual cancer burden (RCB) assessed at surgery. The deliverables of this proposed study include: (1) serial ctDNA profiles in a large cohort of early breast cancer patients; (2) a prediction tool that will calculate the probability of pCR (or residual cancer burden, RCB 0) at an early time point during treatment, and (3) a prognostic tool that will provide accurate risk assessment for early metastatic recurrence in patients who have residual disease after NAC (non-pCR or RCB 1/2/3). Our ultimate goal is to use the pCR prediction tool in the clinical trial setting to identify good responders who may be eligible for early surgical treatment to reduce exposure to toxicities from unnecessary additional therapies; and poor responders who may benefit from a switch in therapy to increase the likelihood of achieving a pCR. Furthermore, we envision that the prognostic tool developed here will help guide treatment choices in the adjuvant trial setting by providing aggressive adjuvant therapies to patients who are at high-risk of early metastatic recurrence, while de-escalating or forgoing further treatment for those who were potentially cured by NAC and surgical treatment and, therefore, not likely to recur.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $603,203 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	5	11/26/2024	NON-COMPETING CONTINUATION	$603,203
														Subtotal = $603,203

Issue Date FY: 2024 ( Subtotal = $636,712 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	001	4	4/19/2024	NON-COMPETING CONTINUATION	$33,511
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	4	11/9/2023	NON-COMPETING CONTINUATION	$603,201
														Subtotal = $636,712

Issue Date FY: 2023 ( Subtotal = $656,820 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	3	11/28/2022	NON-COMPETING CONTINUATION	$603,202
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	001	3	3/17/2023	NON-COMPETING CONTINUATION	$53,618
														Subtotal = $656,820

Issue Date FY: 2022 ( Subtotal = $656,818 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	2	11/8/2021	NON-COMPETING CONTINUATION	$603,200
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	001	2	4/28/2022	NON-COMPETING CONTINUATION	$53,618
														Subtotal = $656,818

Issue Date FY: 2021 ( Subtotal = $670,223 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	1	12/3/2020	NEW	$670,223
														Subtotal = $670,223

Grand Total All Awards = $3,223,776

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Strategy for combining circulating tumor DNA (ctDNA) and magnetic resonance imaging (MRI) measures of tumor burden for prediction of response and outcome in neoadjuvant-treated early breast cancer

Award Number: R01CA255442

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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