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
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.