GENe EXpression After Regional or General ANesthesia in Patients Undergoing Breast Cancer Surgery

Study Overview
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Brief Summary
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Breast cancer is the most commonly diagnosed cancer in females and the second leading cause of death from cancer in women. It was estimated that 2 million new cases have occurred in 2018 worldwide 1. Standard anesthetic procedures for the surgery of breast cancer include general and regional anesthesia 2. Growing preclinical and clinical data support the hypothesis that anesthetic choice may affect cancer-related outcomes. Recurrence in breast cancer was reduced to four-fold in a retrospective study with a 2.5 to 4 year follow up 3. Recurrence and metastasis-free survival, with multivariate analysis, was 94% (95% CI 87,100) versus 82% (74, 91) at 24 months, and 94 (87, 100) versus 77 (68, 87) at 36 months in the paravertebral and general anesthesia patients, respectively, (p=0.013). Currently large confirmatory randomized trials evaluating breast cancer recurrence in patients operated with general or regional anesthesia are yet undergoing 4.

Detailed Description
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Background: Exposure to general or regional anesthesia, can modulate differently breast cancer biology through a direct activity on cancer cells or indirectly through modifications in host response (immune system, angiogenesis, nervous system). Alterations occur both systemically and locally on the surgical site and is supposed that can affect cancer-related outcomes after months or years. It is not known whether the action of this short exposure to anesthetics on the host and cancer biology is driven by epigenetic alterations in gene and protein expression during the immediate to early post-anesthesia period. An altered gene and protein expression profile may affect the response of the immune system, angiogenesis and the nervous system and induce more or less propitious conditions to tumor progression. Data from studies in animals and humans show that gene expression may change in the brain and heart after only a short exposure to general anesthesia and that changes may persist for several weeks. Methods: The GENEXAN is a randomized, controlled, monocentric, genomic trial aiming to test the hypothesis that regional (paravertebral) anesthesia, compared to general anesthesia, would elicit a differential gene and protein expression pattern in cancer tissue and normal surgical microenvironment after breast cancer surgery in women. Discussion: This research will serve to map gene and protein expression profile after surgery with different anesthetics and elucidate which genes specific to biological systems may affect tumor biology in the immediate operative period. The findings may also address further research depending on the tissue specificity of the up or down-regulated genes.

Official Title
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GENe EXpression in Tissues From Operating Field After Regional or General ANesthesia in Patients Undergoing Breast Cancer Surgery. The GENEXAN Randomized Controlled Genomic Trial

Conditions
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Breast Cancer Female

Intervention / Treatment
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* Procedure: General anesthesia
* Procedure: Regional anesthesia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women 18-85 years old No undergoing pregnancy ASA Score I-IV Patients scheduled for breast surgery No contraindications (including surgical) to regional (paravertebral) anesthesia No previous breast surgery No known hereditary or familial cancer syndromes No previous cancer anamnesis, radio o chemiotherapy Primary breast cancer with Tumor classification 1-3, Nodes 0-2 as determined according to the NCI stage definitions (Primary breast cancer without known extension beyond the breast and axillary nodes) Free from pain in preoperative period Patients who don't use analgesic drugs before surgery Patients without cognitive impairment or mental retardation Exclusion Criteria: Women > 18, < 85 years old Pregnancy ASA Score > IV Previous breast surgery Contraindications to regional anesthesia Known hereditary or familial cancer syndromes Previous cancer anamnesis, radio or chemiotherapy Tumor classification > 3, Nodes > 2, M > 0 as determined according to the NCI stage definitions Pain in preoperative period Use of analgesic drugs before surgery Cognitive impairment or mental retardation Patients who did not gave a written informed consent Undergoing therapy with alpha (doxazosin) or beta blockers.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: General anesthesia<br>Breast cancer surgery (Tumor Stage 1-3, Nodes 0-2 as determined according to the NCI stage definitions http://www.cancer.gov/cancertopics/pdq/treatment/breast/HealthProfessional/page3/print) | Procedure: General anesthesia<br>* Sevoflurane and morphine<br>|
| Experimental: Regional anesthesia<br>Breast cancer surgery (Tumor Stage 1-3, Nodes 0-2 as determined according to the NCI stage definitions http://www.cancer.gov/cancertopics/pdq/treatment/breast/HealthProfessional/page3/print) | Procedure: Regional anesthesia<br>* Paravertebral block<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Whole genome expression by microarray | tumor, biopsy, normal wound tissue | before tumor excision | 
| Whole genome expression by mircoarray | tumor, wound tissue | during surgery (just after tumor excision) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune progenitors (MDBCs, GMPs, HPSCs), Natural Killer, T regulatory Lymphocytes, PentraxinIII | in blood | before tumor excision | 
| cancer recurrence | local or distant metastasis | each 6 months for up to 7 years | 
| survival from cancer | death | each 6 months for up to 7 years | 
| Immune progenitors (MDBCs, GMPs, HPSCs), Natural Killer, T regulatory Lymphocytes, PentraxinIII | in blood | at the end of surgery | 
| Immune progenitors (MDBCs, GMPs, HPSCs), Natural Killer, T regulatory Lymphocytes, PentraxinIII | in blood | at 24 hours | 
| Immune progenitors (MDBCs, GMPs, HPSCs), Natural Killer, T regulatory Lymphocytes, PentraxinIII | in blood | at 168 hours |