Early-stage Breast Cancer, Estrogen-receptor-positive Breast Cancer
Conditions
Keywords
Surgery, Inflammation, Breast cancer, Neuronal features, Ketorolac, Pregabalin, Adiposity, Neurotransmitter, Nerves
Brief summary
Out of all proportion to its short duration, the perioperative period is critical in determining the long-term outcome of cancer. To contribute to a better understanding of the neural and inflammatory mechanisms underlying this issue, we aim to implement a novel intervention based on the preoperative use of non-steroidal anti-inflammatory drugs (NSAIDs) with or without an anti-epileptic drug. Our goal is to understand and transform the perioperative window from being a facilitator of metastatic progression to arresting and/or eliminating residual disease using repurposing drugs
Detailed description
The perioperative period presents a unique window of therapeutic opportunities to counteract minimal residual growth and dormancy escape of cancer cells. The main physiological disturbances induced by the surgery, that enhance the tumoral growth in the perioperative period, are due to the neuronal and inflammatory signaling. We propose a therapeutic modelling of the inflammatory and neurological pathways in a phase II trial using ketorolac and pregabalin, alone or in combination. Ketorolac, a non-selective NSAIDs will target cyclooxygenase (COX)-enzymes, while pregabalin, an anti-epileptic drug will regulates the release of neurotransmitters. Moreover, both drugs have an effect on the postoperative pain and pregabalin has anxiolytic property. Thanks to this study, and through specific blockade, we want to understand how nervous and inflammatory systems remodel the tumour and systemic characteristics. To ensure an integrative analysis of those factors, patient's adiposity as well as other confounding variable will be taken into account.
Interventions
Core-needle biopsy of the breast (pre-treatment), surgical sample collection (post-treatment), extra collection of blood samples (pre- and post-treatment), measurements of adiposity, lifestyle questionaire
Patients will receive 10 mg film-coated tablets of ketorolac tromethamine three times a day, for five days before the surgery
DRUGPregabalin 75mg
Patients will receive 75 mg of pregabalin hard capsule twice a day, for seven days before the surgery
Patients will receive 20 mg of omeprazole once a day on an empty stomach, for five days before the surgery
Sponsors
KU Leuven
Jules Bordet Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Subjects must meet all of the following criteria in order to be eligible for this study: 1. Age ≥ 18 years and ≤ 70 years old 2. Female 3. Weight ≥ 35 kg 4. Histological diagnosis of invasive breast adenocarcinoma that is estrogen receptor positive as per the updated American Society of Clinical Oncology (ASCO) - College of American Pathologists (CAP) guidelines according to local testing with ER-positive is defined as having an immunohistochemistry (IHC) of 1% or more and/or Allred score of 3 or more 5. Tumour size ≥ 1.5 cm, determined by diagnostic ultrasound or MRI/CT scan. 6. Stage I, II or III disease (non-metastatic) 7. In case of multifocal, multicentric unilateral or bilateral breast: Adenocarcinoma tumours are allowed provided that all foci are ER+ according to local testing 8. Subject scheduled for a primary breast cancer surgery 9. Subject is willing to provide plasma/blood and tumour samples for translational research. 10. Subject is willing to provide tissue from a newly obtained core or excisional biopsy of the tumour that should be evaluable for central histological characterization and future molecular testing 11. Subject is willing to take omeprazole and has no contraindication to omeprazole. 12. Have an HEMSTOP score\<2 and conventional coagulation screening test within normal limits such as activated partial thromboplastin time (21.6\< aPTT \>28.7), international normalised ratio (1.31\<INR) and platelet count (\>100.10³/ml) 13. Women of childbearing potential must agree to use of one highly effective method of contraception prior study entry, during the course of the study and at least one months after the last administration of study treatment. 14. Negative serum pregnancy test for women of childbearing potential (within 30 days before start of treatment) 15. Subject is willing and able to provide written informed consent for the trial
Exclusion criteria
Subjects meeting one of the following criteria are not eligible for this study: 1. Subject planned for intraoperative radiotherapy 2. Subject planned for immediate reconstruction 3. Neoadjuvant BC therapy 4. Allergy to any NSAID or gabapentinoïd 5. Known hypersensitivity reactions to the investigational treatments, or any excipients or auxiliary medicinal products or concomitant medications. Hypersensitive to peanut or soya (related to propofol contraindications) 6. Current use of the antidiabetic agent thiazolidinedione (related to interaction with pregabalin), lithium salts, probenecid, pentoxifylline or intensive diuretic therapy. 7. Current NSAID (\> twice a week the year prior to diagnosis) or pregabalin use 8. Previous malignant pathology within 5 years prior to inclusion or currently undergoing maintenance therapy. Exceptions include basal cell carcinoma or squamous cell carcinoma of the skin that have undergone potentially curative therapy or in situ cervical cancer. 9. Active or history of peptic ulcer disease or gastro-intestinal bleeding or perforation 10. Pregnancy or lactating women 11. Chronic inflammatory disease as rheumatoid arthritis, uncontrolled asthma, chronic heart failure, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory myopathies (e.g., idiopathic polymyositis, dermatomyositis, inclusion body myositis), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), McArdle's disease, multiple sclerosis, lupus, chronic inflammatory demyelinating polyneuropathy, psoriasis, autoimmune thyroiditis as Graves' disease or Hashimoto's thyroiditis (unless previous surgical ablation), myasthenia gravis, vasculitis. 12. Complete or partial nasal polyposis syndrome, Quincke's oedema, bronchospasm, asthma 13. Known chronic infectious disease as active hepatitis B (defined as positive serology for Ac anti-HBc and IgM anti HBc OR Ac anti HBc and Ag HBs), active hepatitis C (defined as positive serology for anti-VHC and positive PCR-VHC) or active tuberculosis (included under treatment) 14. Uncontrolled HIV infection (defined as detectable viral loads by standard clinical assays) or controlled HIV infection (defined undetectable HIV viral loads by standard clinical assays) treated by one of following drugs: Nelfinavir, Atazanavir or Saquinavir (related to interaction with omeprazole). 15. Infection currently treated with one of the following drugs: posaconazole, voriconazole, ketoconazole and rifampicin, unless discontinuation of treatment is planned at least 10 days prior to the start of study treatment AND with complete resolution according to expert opinion (related to interaction with omeprazole) 16. Inadequate liver function (defined as total serum bilirubin ≥ 2 x upper limit of normal (ULN\<1.2 mg/dl) - unless documented Gilbert syndrome- AND Alanine Aminotransferase (ALT) ≥ 2 x ULN (ULN \<32 UI/l and ULN \<33 UI/l, respectively) AND Alkaline phosphatase (ALP) ≥ 2.5 x ULN (ULN=104 UI/l)) 17. Cirrhosis or severe hepatitis. 18. Renal impairment (defined as GFR\<90ml/min/1.73m² or serum creatinine \> 442 μmol/l or \> 5 mg/dL) or single kidney or previous renal surgery 19. Subject with history of (severe) renal toxicity with an NSAID 20. Subject with a recent history of operations associated with a high risk of bleeding 21. Previous, ongoing or suspected cardiovascular disease defined as history of ischemic heart disease or heart failure or uncontrolled high blood pressure (Systolic ≥160mmHg and/or diastolic ≥100mmHg) or peripheral arterial disease or cerebrovascular disease 22. Subject with a recent history of surgery associated with a high risk of bleeding 23. Hemostasis disorder as haemophilia, Von Willebrand disease, constitutional thrombopathies or thrombocytopenia (defined as platelet count \< 100 000/mm³), current /planned anticoagulant or anti-platelet therapy. 24. Inadequate bone marrow function (defined as absolute neutrophil count \<1000/μL and platelet count \<100'000/μL) 25. Systemic immunosuppressive treatment (defined as systemic corticotherapy or anti-rejection treatment or interferon therapy) within the 2-years prior diagnosis 26. Psychiatric disease or antipsychotic/ antidepressant use 27. Epilepsy or any current anti-epileptic drug use 28. Obstructive sleep apnea 29. ASA≥3
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in systemic neurotransmitters at surgery from baseline | At surgery | Plasma multiplex technology using cytometric bead arrays |
| Change in tumoral immune cells recruitment at surgery from baseline | At surgery | Characterization of Tumour-infiltrating leukocyte subpopulations using RNA sequencing analysis from fresh frozen tissue sections |
| Change in tumoral neurogenesis at surgery from baseline | At surgery | Level of neurogenesis markers using RNA sequencing analysis from fresh frozen tissue section |
| Change in tumoral neurotransmitters level at surgery from baseline | At surgery | Using RNA sequencing analysis from fresh frozen tissue sections |
| Change in Peripheral Blood Mononuclear Cells at surgery from baseline | At surgery | Fluorescence activated cell sorting (FACS) analysis |
| Change in systemic neuro-inflammatory mediators at surgery from baseline | At surgery | Plasma multiplex technology using cytometric bead arrays |
| To detect a reduced increase in systemic inflammation (from baseline to up to 24 hours after surgery) using peri-operative ketorolac | Up to 24 hours after surgery | Plasma multiplex technology using cytometric bead arrays |
| To detect a reduced increase in systemic neurotransmitters (from baseline to up to 24 hours after surgery) using peri-operative pregabalin | Up to 24 hours after surgery | Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS) |
| Change in biomarkers of metastasis at surgery from baseline | At surgery | Transcriptome profile and bioinformatic analysis |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in anxiety level at surgery from baseline | At surgery | Generalized Anxiety Disorder - 7 (GAD - 7) Anxiety score (natural number, range\[0 - 21\]. A score comprised between 0 - 4 indicates a minimal anxiety, 5-9 a mild anxiety, 10-14 a moderate anxiety and a 15-21 in a severe anxiety. |
| Post-operative pain | Up to 48 hours after surgery | Consumption of morphine delivered by a programmable patient-controlled analgesia (PCA) infusion pump (number of requested and effectively delivered bolus/ 24h) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Body composition | The day before surgery | Calculated from multiple frequency bio-impedance measurements (in %, range \[0 - 100\]) |
| Waist-to-hip ratio | The day before surgery | Waist circumference (cm) divided by hip circumference (cm) |
| Body Mass Index | The day before surgery | Calculated: body mass (kg) divided by height squared (m²) |
Countries
Belgium
Contacts
Primary ContactImane Bachir, MD
Backup ContactMarion Maetens, PhD
Outcome results
None listed