352Tip Neoadjuvant Chemo-Immunotherapy Plus/minus Fasting-Like Approach in Stage II-III Triple-Negative Breast Cancer Patients: the Phase II Randomized BREAKFAST-2 Trial

Despite remarkable improvements in early-stage Triple-Negative Breast Cancer (TNBC) treatment with neoadjuvant chemoimmunotherapy (CT-IO), a considerable proportion of TNBC patients (pts) still experience tumor relapse after surgery. Preclinical studies indicate that TNBC is exquisitely sensitive to fasting-like approaches (FLAs), and we have recently shown that cyclic FLA boosts systemic and intratumor immunity in cancer patients. We hypothesize that combining FLA with preoperative CT-IO can increase pathologic complete response (pCR) rates in pts with stage II-III TNBC. BREAKFAST-2 (NCT05763992) is an open-label, multicentric, randomized, phase 2 trial aimed at investigating the antitumor activity of experimental FLA in combination with standard preoperative CT-IO in pts with treatment-naïve, localized (T1c and N1-2, or T2-4 and N0-2) TNBC. Pts will be randomized in a 1:1 ratio to: a) control arm (standard CT-IO), consisting of 12 administrations of weekly paclitaxel + carboplatin concomitant with 4 triweekly cycles of Pembrolizumab, followed by 4 triweekly cycles of doxorubicin/epirubicin + cyclophosphamide + Pembrolizumab every three weeks; b) experimental arm, consisting of CT-IO + 5-day FLA every three weeks, up to 8 FLA cycles. Then pts will undergo surgery. Key eligibility criteria are: age of 18-75 years, ECOG PS 0-1, BMI > 19 kg/m2, absence of malnutrition, diabetes, uncontrolled autoimmune disorders, or severe comorbidities. The primary study endpoint is pCR. Hypothesizing that the experimental treatment is able to increase the pCR rate from 65% (historical data with CT-IO alone) to 85%, and assuming an α error of 5% and a power of 85%, a total of 145 patients will be enrolled. Secondary endpoints include: safety and tolerability, compliance, Event-Free Survival (EFS) and Overall Survival (OS). We will combine plasma metabolomics and bulk/single cell RNA-seq analyses to explore the impact of the experimental treatment on systemic and intratumor immunometabolic pathways, as well as to assess the association between immunometabolic changes and clinical outcomes. The trial has started to enroll pts on May 2nd, 2023. NCT05763992. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. Giuliani Foundation – Fondazione Gianmaria e Sabrina Giuliani; Fondazione IRCCS Istituto Nazionale dei Tumori; AIRC.