Prospective, randomized, open label, two arms,, phase 0 clinical trial. HER2-negative breast cancer patients recently diagnosed will be screened for trial participation.

A biopsy will be scheduled the week prior to or the same day as the FDG PET. Paraffin-embedded tumor samples will be used to evaluate the stainings of Ki67, cleaved caspase-3 and microvessels, and frozen tumor samples will be used to evaluate SDH staining.

The FDG-PET will be followed by the bevacizumab dose (15 mg/kg IV, single dose). After one week, the PET will be repeated in order to detect the patients that have experienced FDG uptake decay.

Right after, treatment with ME-344 (arm 1) or no treatment (arm 2) will start. ME-344 will be administered at 10 mg/kg on day 8, 15 and 22. Surgery will be performed on day 28 (thus, 4 weeks after the bevacizumab dose, which is considered a safe window for antiangiogenics).

Fragments of the surgical specimen will be collected. Paraffin-embedded tumor sample will be used to repeat (and compare) the stainings of Ki67, cleaved caspase-3 and microvessels, and frozen tumor sample will be used to repeat (and compare) SDH staining.

Patients will come off trial in case of consent withdrawal, unequivocal disease progression is observed, unacceptable toxicity occurs, or in case of intercurrent disease or any other condition deemed incompatible with continuation in the clinical trial by the investigator.

Antiangiogenic agents are the most widely used biologic agents in oncology and are approved by the Food and Drug Administration (FDA) for use against many different malignancies based on the results of several randomized phase III trials. However, acquired resistance to antiangiogenics is a major problem in cancer therapeutics.

Some signaling nodes have been implicated in therapeutic resistance in preclinical studies. However, a global tumor-reprogramming interrogation based on changes in the delivery of oxygen and nutrients has not been undertaken. The findings link acquired resistance to a powerful anticancer drug class with aberrant cancer metabolism. Under selective pressure, tumor plasticity allows sustained tumor growth in the long term despite exposure to antiangiogenic TKIs, and it renders mitochondrial metabolism essential for survival When one energy source (glycolysis) is pharmacologically limited, the tumors become vulnerable to the inhibition of the other (mitochondrial metabolism). Pharmacological blockers of the nutritional stress regulators can abrogate mitochondrial respiration and tumor growth in this situation, which the investigators have termed "metabolic synthetic lethality".

The investigators hypothesized that in cases in which antiangiogenics lead to hypoxia normalization, chronic high-rate glycolysis is offset and tumors might switch to an alternative metabolic source. If this source is essential for tumor survival, it would open a therapeutic opportunity.

The administration of ME-344 in animals where antiangiogenics have induced a mitochondrial phenotype seems promising. The investigators aim to extend these observations in humans. However, several questions remain, prior to launch a large trial:

• Which percentage of patients experience a mitochondrial shift when exposed to a given antiangiogenic.
• In case this happens, whether it is possible to trace this response accurately.
• What is the benefit of adding ME-344 in those cases showing the mitochondrial shift, and what is the benefit, if any, of adding it in the remainder cases.

For that purpose, investigators will conduct a pilot randomized phase 0 trial, where a cohort of patients will be treated with a single bevacizumab dose prior to surgery and a second cohort with bevacizumab plus ME-344.

The purpose of this clinical trial is to evaluate if the addition of ME-344 to antiangiogenic agents in the cases where the mitochondrial phenotype has been induced will enhance antitumor activity.

Inclusion Criteria:

1. Women older than 18 year-old.

2. Treatment-naïve diagnosed early (stage I-III) HER2-negative (histologically confirmed) breast cancer not candidates for neoadjuvant therapy.

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

4. Signed informed consent obtained from the subject prior to performing any protocol-related procedures.

5. Negative pregnancy test, or confirmed menopause.

6. Adequate organ function, according to the following parameters:

   • Haemoglobin ≥ 9.0 g/dL.
   • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 / mm3).
   • Platelet count ≥ 100 x 109/L (>100000 / mm3).
   • Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
   • AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal.
   • Serum creatinine < 1.5 x institutional upper limit of normal (ULN).

7. Cardiac ejection fraction above 45%.

8. Life expectancy superior to 6 months.

9. Willingness to undergo trial procedures.

Exclusion Criteria:

1. Neuropathy of any kind.
2. Diabetes mellitus.
3. Presence of intercurrent uncontrolled diseases, including untreated hypertension.
4. Participation in another clinical study with an investigational product during the last 4 weeks.
5. Patients with presence of concurrent or active malignant disease (other than disease under study) within the last 12 months with the exception of adequately treated in situ carcinomas, basal or squamous cell carcinoma, or nonmelanomatous skin cancer.
6. Female subjects who are pregnant, breast-feeding or of reproductive potential who are not employing an effective method of birth control.
7. Uncontrolled infection or systemic disease.
8. Clinically significant cardiac disease not well controlled with medication (e.g., congestive heart failure, symptomatic coronary artery disease e.g. angina, and cardiac arrhythmias) or myocardial infarction within the last 12 months.
9. No concurrent systemic chemotherapy or biologic therapy is allowed.
10. Known hypersensitivity to any components of ME-344 or bevacizumab.
11. Known human immunodeficiency virus (HIV) or Hepatitis B or C (active, previously treated or both).
12. History of solid organ transplantation.
13. Psychiatric disorder or social or geographic situation that would preclude study participation.
14. Inability to comply with the study and follow-up procedures (e.g. tumor biopsies).
15. Any other condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.