248P - Targeting triple-negative breast cancer metabolism with neoadjuvant chemotherapy plus fasting-mimicking diet plus/minus metformin: The BREAKFAST trial

Background

Cyclic fasting or fasting-mimicking diets (FMDs) enhanced the antitumor activity of chemotherapy (CT) in TNBC mouse models, while the combination of fasting and metformin resulted in impressive antitumor activity in several preclinical tumor models. The BREAKFAST study was designed to investigate if cyclic FMD, plus/minus metformin, improves the antitumor activity of neoadjuvant CT in patients (pts) with localized TNBC.

Methods

BREAKFAST is a randomized, non-comparative, phase II trial originally designed to enrol 90 stage I-III (cT>1cm) TNBC pts candidate to receive neoadjuvant doxorubicin-cyclophosphamide q3w for 4 cycles, followed by weekly paclitaxel for 12 cycles. Pts were randomized 1:1 to receive: CT + triweekly 5-day FMD cycles (arm A), or CT + FMD + daily metformin (1700 mg) (arm B). The primary study objective was to investigate if one or both experimental treatments were able to increase pCR rates when compared to anthracycline-taxane CT alone according to historical data.

Results

We enrolled 30 pts between June 2020 and February 2022, when the study was prematurely interrupted after the introduction of chemo-immunotherapy (CT-IO) as a standard neoadjuvant therapy for early stage TNBC. Of these pts, 13 were randomized to arm A and 17 to arm B; 73.3% of enrolled pts completed the maximum of 8 FMD cycles, with an average number of 6.9 completed FMD cycles. The observed pCR rate was 56.6%, i.e., significantly higher than pCR rates previously reported with CT alone in phase II/III trials (26-39%), and with no significant differences among treatment arms (OR 1.67, 95% CI 0.39-7.43; p=0.49). RNA-seq analysis in tumor specimens revealed higher pCR probability in pts undergoing precocious enhancement of tumor infiltration by activated T and NK cells, as well as precocious downmodulation of glycolysis and oxidative mitochondrial metabolism pathways.

Conclusions

Preoperative CT plus cyclic FMD (plus/minus metformin) results in excellent pCR rates in early TNBC pts. Based on these findings, we recently initiated a phase II, randomized, multicentric trial, namely BREAKFAST-2, to investigate if adding cyclic FMD to neoadjuvant CT-IO increases pCR rates in stage II-III TNBC pts.

Clinical trial identification

NCT04248998.

Editorial acknowledgement

Legal entity responsible for the study

Fondazione IRCCS Istituto Nazionale dei Tumori.

Funding

Fondazione IRCSS Istituto Nazionale dei Tumori; AIRC.

Disclosure

F. Ligorio: Financial Interests, Personal, Other, Travel/accomodation: Eli Lilly, Istituto Gentili; Financial Interests, Personal, Invited Speaker: Novartis. R. Lobefaro: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, AstraZeneca; Financial Interests, Personal, Speaker, Consultant, Advisor: Pfizer; Financial Interests, Personal, Other, Travel/accomodation: Eli Lilly. G.V. Bianchi: Financial Interests, Personal, Advisory Board: Novartis, Eli Lilly, Daiichi Sankyo, AstraZeneca, Roche, MSD, Seagen. G. Pruneri: Financial Interests, Personal, Advisory Role: Roche, Bayer; Financial Interests, Personal, Advisory Board: AstraZeneca. F.G.M. De Braud: Financial Interests, Personal, Advisory Board: Roche, EMD Serono, NMS Nerviano Medica Science, Sanofi, MSD, Novartis, Incyte, BMS, Menarini, AstraZeneca, Pierre Fabre, Mattioli 1885 , MCCann Health, Taiho, IQVIA; Financial Interests, Personal, Speaker’s Bureau: BMS, Healthcare Research & Parmacoepidemiology, Merck Group, MSD, Pfizer, Servier, Sanofi, Roche, AMGEN, Incyte, Dephaforum, Seagen, Nadirex, Ambrosetti, Itanet; Financial Interests, Personal and Institutional, Sponsor/Funding: Novartis, F.Hoffmann-LaRoche Ltd, BMS, Ignyta Operating INC, Merck Sharp & Dohme Spa, Kymab, Pfizer, Tesaro, MSD, MedImmune LCC, Exelixis Inc., LOXO Oncology Incorporated, Daiichi Sankyo, Basilea Pharmaceutica International AG, Janssen-Cilag Internationa NV, Merck KGAA. C. Vernieri: Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Lilly, Daiichi Sankyo, Novartis, Lilly, Istituto Gentili; Financial Interests, Institutional, Research Grant: Roche. All other authors have declared no conflicts of interest.