DIRECT-2: Fasting mimicking Diet Program to ImpRovE ChemoTherapy in HR+, HER2- breast cancer

In preclinical research, short-term fasting (STF) protects tumor-bearing mice
against the toxic effects of chemotherapy, improves the CD8+ effector T-cell
intratumor infiltration, while enhancing the chemotherapy efficacy. Short-term
use of a "fasting-mimicking diet" (FMD) caused a major increase in the efficacy
of cancer treatment in mice comparable to STF. In humans, we recently performed
a multicenter randomized phase II trial showing that patients with Human
Epidermal growth factor Receptor 2 (HER2) negative breast cancer treated with
neoadjuvant chemotherapy and FMD displayed a better radiological response and a
better pathological response (90-100% vs <90% tumor cell reduction) than
patients treated with chemotherapy without FMD. Therefore the goal is validate
the effect of an FMD during neoadjuvant chemotherapy in a phase 3 trial. That
is why we hypothesize that FMD during neoadjuvant chemotherapy for hormone
receptor positive, HER2 negative breast cancer improves pathological response
rate and quality of life including cognition, potentially due to improved local
immunity.

To improve the pathological response rate according to Miller and Payne
To improve quality of life including cognition
To determine the effect of FMD on local tumor immunity

DIRECT-2 will be a multicenter, randomized, open label, phase III trial
coordinated by the Dutch Breast Cancer Research Group (BOOG) for patients with
hormone receptor positive and HER2-negative breast cancer with an indication
for neoadjuvant chemotherapy consisting of 2-weekly dose dense adriamycine and
cyclophosphamide (ddAC) for 4 cycles followed by 12 times weekly paclitaxel
(T). Participants will be randomized to receive an FMD 3 days prior to and the
day of chemotherapy administration, every 4 weeks during chemotherapy (2x
during ddAC and 3x during T) or their regular diet. Histopathological response
will be assessed on the surgical tumor specimen. Additionally, an extra tumor
biopsy will be obtained after 4 ddAC cycles for investigation of tumor-immunity
modulation. Clinical response will be evaluated by MRI after 4 cycles ddAC and
at the end of chemotherapy. Quality of Life will be measured at baseline, 1-2
weeks after the last ddAC, 2-3 weeks after the end of chemotherapy and 6 months
after surgery. Cognition will be determined at baseline, 2-3 weeks after the
end of chemotherapy and 6 months after surgery.

Fasting mimicking diet by L-Nutra, a 4-day low caloric, low protein, vegetarian
diet 3 days prior to and the day of neoadjuvant chemotherapy administration.
The FMD will take place every 4 weeks, thus in total 5 times (2x during ddAC,
3x during Paclitaxel) during the neoadjuvant chemotherapy. The control arm will
follow regular diet.

Participating patients have to be willing to follow the 4-day FMD diet every 4
weeks during chemotherapy (5 times in total) and extra blood sampling during
routine. A relative risk for participating patients regarding the 4-day FMD
includes mild side-effects such as: feelings of hunger, headache, nausea, lack
of energy. After 4 ddAC cycles, an additional tumor biopsy will be obtained.
There is also extra burden for the online quality of life and cognition
questionnaires up until six months after surgery. Ample experience with a much
more extensive test battery for cognition in many patient populations has
indicated that such a procedure is feasible. The neuropsychological examination
(online test battery) to assess cognition does not pose any risk for patients,
albeit it takes around 50 minutes to complete.