Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial

Groot, Stefanie de; Lugtenberg, Rieneke T.; Cohen, Daniëlle; Welters, Marij J.P.; Ehsan, Ilina; Vreeswijk, Maaike P.G.; Smit, Vincent T.H.B.M.; Graaf, Hiltje de; Heijns, Joan B.; Portielje, Johanneke E.A.; Wouw, Agnès J. van de; Imholz, Alex L.T.; Kessels, Lonneke W.; Vrijaldenhoven, Suzan; Baars, Arnold; Kranenbarg, Elma Meershoek-Klein; Carpentier, Marjolijn Duijm-de; Putter, Hein; Hoeven, J.J.M. van der; Nortier, J.W.R.; Longo, Valter D.; Pijl, Hanno; Kroep, Judith R.

doi:10.1038/s41467-020-16138-3

Cited by 229 publications

(276 citation statements)

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“…Unfortunately, the study was prematurely interrupted because a pre-planned interim analysis showed a lower-than-anticipated pCR rate in the study population, as well as poor patient adherence to the proposed FMD regimen 1 . In addition, the FMD did not provide evident clinical advantages, neither in terms of reduction of AEs (the primary endpoint of the phase II trial) nor in terms of increased pCR rates (the primary endpoint of the phase III trial) 1 . Of note, triple-negative breast cancer (TNBC) patients, who are much more likely to undergo pCR during preoperative ChT 6 , were significantly more represented in the FMD arm than in the control arm (21.5% vs. 10.9%).…”

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confidence: 99%

“…The main cause of lack of adherence to the experimental diet was dislike of specific components of the FMD, which consisted of a plant-based, standardized kit providing~1200 kcal on day 1 and~200 kcal on days 2-4 1 . Alternative FMD regimens, including schemes containing fresh foods, could be associated with better patient compliance, thus potentially resulting in higher antitumor activity 10 .…”

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Fasting-mimicking diet plus chemotherapy in breast cancer treatment

et al. 2020

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A clinical trial published in Nature Communications examined the effect of fastingmimicking diet (FMD) during chemotherapy in breast cancer patients. The overall negative study results highlight the need for ameliorating future trial design and investigating alternative FMD-based therapeutic combinations. The "DIRECT" trial In a study recently published in Nature Communications, de Groot et al. reported the results of the phase II trial "DIRECT", in which experimental cyclic fasting-mimicking diet (FMD) in combination with standard anthracycline-taxane preoperative chemotherapy (ChT) failed to reduce ChT-related adverse events and to improve the rate of pathological complete responses (pCR) in patients with stage II-III HER2-negative breast cancer (BC) 1. However, some study findings, such as the possibility to avoid dexamethasone use during doxorubicincyclophosphamide ChT and the reduction of ChT-induced DNA damage to circulating lymphocytes in patients undergoing the FMD, are of potential interest. While highlighting the importance of publishing results of clinical trials even when they are negative for their primary endpoint, findings of the DIRECT trial indicate the necessity to ameliorate patient adherence to the FMD and to improve clinical trial designs to fully exploit the therapeutic potentialities of calorie-restricted dietary interventions. In tumor-bearing mice, cycles of fasting or calorie-restricted, low-carbohydrate, low-protein diets, collectively referred to as FMDs, synergize with cytotoxic ChT or other antitumor therapies to slow down tumor growth 2,3. At the same time, fasting/FMD protect normal tissues from ChTinduced toxicity 4,5 and boosts ChT-induced CD8+ T cell intratumor infiltration 2. These effects are mainly mediated by fasting/FMD-induced reduction of blood glucose, insulin and insulinlike growth factor 1 (IGF-1) concentration 4,5. Notably, murine models of BC are exquisitely sensitive to the FMD when compared to other tumor types 2,3. Therefore, the DIRECT trial, which investigated the FMD efficacy in reducing ChT-induced toxicities and in increasing pCR rates in HER2-BC patients, was timely and based on solid preclinical evidence. In addition, the study was conducted in early-stage BC patients, who are at low risk of undergoing malnutrition and cachexia,. Finally, this was a randomized phase II/III trial with sufficient power to provide evidence of a clinical benefit of the FMD in a selected population of cancer patients. For these

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Fasting-mimicking diet plus chemotherapy in breast cancer treatment

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“…La evidencia reportada está basada en diseños de estudios de baja evidencia científica: reportes y series de casos, estudios observacionales y pocos estudios clínicos. El tamaño de la muestra es pequeño en la mayoría de los casos, desde 1 persona hasta 129 pacientes, y con diferentes objetivos en la implementación de la DC (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39) . Un punto a resaltar es la dificultad de la adherencia a la dieta, así como los periodos de seguimiento.…”

Section: Evidencia Del Uso De La Dieta Cetogénica En Pacientes Con Cáunclassified

“…En los tres casos no reportan efectos adversos. La evidencia más basta surge de tres estudios clínicos realizados en glioblastoma, tumores ginecológicos y cáncer de mama (31,38,39) . De estos, 17 de 20 pacientes con glioblastoma accedieron a realizar la DC entre 6 y 8 semanas.…”

Section: Tabla 2 Estudios En Humanos Que Reportan El Efecto De La DIunclassified

“…Los resultados indican que los pacientes con la dieta tipo DIEA no presentaron diferencias en toxicidad a la QT, pese a que en este grupo no se utilizó tratamiento paralelo con glucocorticoides. Además de esto presentaron mayor tolerancia a la RT, acompañado del aumento de los cuerpos cetónicos, disminución de los niveles de glucosa, IGF-1 e insulina (39) .…”

Section: Tabla 2 Estudios En Humanos Que Reportan El Efecto De La DIunclassified

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Dieta cetogénica en cáncer: revisión de la literatura

Alvarez-Altamirano

Bejarano-Rosales

Rosas-Gonzalez

et al. 2020

Rev. Nutr. Clin. Metab.

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A “Valve‐Closing” Starvation Strategy for Amplification of Tumor‐Specific Chemotherapy

Jiang

Wang

et al. 2022

Advanced Science

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Starvation‐dependent differential stress sensitization effect between normal and tumor cells provides a potentially promising strategy to amplify chemotherapy effects and reduce side effects. However, the conventional starvation approaches such as glucose oxidase (Gox)‐induced glucose depletion and nanomedicine‐enabled vascular embolism usually suffer from aggravated tumor hypoxia, systemic toxicity, and unpredictable metabolic syndrome. Herein, a novel “valve‐closing” starvation strategy is developed to amplify the chemotherapy effects via closing the “valve” of glucose transported into tumor cells, which is accomplished by a glucose transporters 1 (GLUT1, valve of glucose uptake) inhibitor (Genistein, Gen) and chemotherapeutic agent (Curcumin, Cur) coloaded hybrid organosilica‐micelles nanomedicine (designated as (Gen + Cur)@FOS) with controllable stability. In vitro and in vivo results demonstrate that (Gen + Cur)@FOS can effectively reduce glucose/adenosine triphosphate levels in tumor cells by inhibiting GLUT1 expression (i.e., “valve‐closing”) to induce the starvation of tumor cells, thus weakening the resistance of tumor cells to apoptosis caused by chemotherapy, and consequently contributing to the remarkably improved antitumor efficiency and minimized side effects based on the stress sensitization effect mediated by GLUT1 inhibition‐induced starvation. This “valve‐closing” starvation strategy provides a promising paradigm for the development of novel nanotherapeutics with amplified chemotherapy effect.

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Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial

Cited by 229 publications

References 24 publications

Fasting-mimicking diet plus chemotherapy in breast cancer treatment

Fasting-mimicking diet plus chemotherapy in breast cancer treatment

Dieta cetogénica en cáncer: revisión de la literatura

A “Valve‐Closing” Starvation Strategy for Amplification of Tumor‐Specific Chemotherapy

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