Description:
Triple-negative breast cancer is a subtype of breast cancer that is clinically negative for
expression of estrogen and progesterone receptors (ER/PR) and HER2 protein. It is
characterized by its unique molecular profile, aggressive behavior, distinct patterns of
metastasis, and lack of targeted therapies. Although not synonymous, the majority of
triple-negative breast cancers carry the "basal-like" molecular profile on gene expression
arrays.
Although sensitive to chemotherapy, early relapse is common and these cancers show a
predilection for visceral metastasis, including brain metastasis. Targeted agents, including
epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and poly
(ADP-ribose) polymerase (PARP) inhibitors, are currently in clinical trials and hold promise
in the treatment of this aggressive disease.
Multiple independent data sets have revealed that the triple negative type of breast cancer
carries a poor prognosis. It is unclear whether the poor prognosis of triple negative breast
cancer is due to poor therapy options or inherent aggressiveness. Given their triple negative
receptor status, these tumors are not amenable to conventional targeted therapies for breast
cancer, such as endocrine therapy or trastuzumab, leaving only chemotherapy in the
therapeutic armamentarium.
Patients on metformin showed a 30-40% protection against all forms of cancer. Recent pilot
studies carried out using population registries raise the possibility that metformin may
reduce cancer risk and/or improve cancer prognosis. One showed an unexpectedly lower risk of
a cancer diagnosis among diabetics using metformin compared with a control group of diabetics
using other treatments ; another showed lower cancer-specific mortality among subjects with
diabetes using metformin compared with diabetics on other treatments. Metformin is a
biguanide known to be an insulin sensitizing agent which promotes reduced circulating insulin
and glucose levels in hyper-glycaemic and hyper-insulinaemic patients. Metformin activates
the AMP dependent kinase, attenuates insulin and IGF-1 stimulated proliferation in breast
cancer cells and a general decrease in protein synthesis in vitro. Western blot analysis
indicated that metformin stimulates AMPK phosphorylation in a dose-dependent manner. AMPK
activation is associated with decreased phosphorylation of mTOR and S6 kinase. While
metformin reduces breast carcinoma cell proliferation both in vitro and in vivo, the
activation of AMPK leads to significant VEGF production, angiogenesis and tumor progression.
This must be taken into consideration when it is applied in as a therapeutic regimen.
Title
- Brief Title: A Randomized Controlled Trial of Neoadjuvant Weekly Paclitaxel Versus Weekly Paclitaxel Plus Weekly Carboplatin In Women With Large Operable or Locally Advanced, Triple Negative Breast Cancer
- Official Title: A Randomized Controlled Trial of Neoadjuvant Weekly Paclitaxel Versus Weekly Paclitaxel Plus Weekly Carboplatin In Women With Large Operable or Locally Advanced, Triple Negative Breast Cancer
Clinical Trial IDs
- ORG STUDY ID:
CTRI/2012/07/002802
- NCT ID:
NCT03168880
Conditions
- Triple Negative Breast Cancer
Interventions
| Drug | Synonyms | Arms |
|---|
| Paclitaxel + Carboplatin | | B |
| Paclitaxel only | | A |
Purpose
Triple-negative breast cancer is a subtype of breast cancer that is clinically negative for
expression of estrogen and progesterone receptors (ER/PR) and HER2 protein. It is
characterized by its unique molecular profile, aggressive behavior, distinct patterns of
metastasis, and lack of targeted therapies. Although not synonymous, the majority of
triple-negative breast cancers carry the "basal-like" molecular profile on gene expression
arrays.
Although sensitive to chemotherapy, early relapse is common and these cancers show a
predilection for visceral metastasis, including brain metastasis. Targeted agents, including
epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and poly
(ADP-ribose) polymerase (PARP) inhibitors, are currently in clinical trials and hold promise
in the treatment of this aggressive disease.
Multiple independent data sets have revealed that the triple negative type of breast cancer
carries a poor prognosis. It is unclear whether the poor prognosis of triple negative breast
cancer is due to poor therapy options or inherent aggressiveness. Given their triple negative
receptor status, these tumors are not amenable to conventional targeted therapies for breast
cancer, such as endocrine therapy or trastuzumab, leaving only chemotherapy in the
therapeutic armamentarium.
Patients on metformin showed a 30-40% protection against all forms of cancer. Recent pilot
studies carried out using population registries raise the possibility that metformin may
reduce cancer risk and/or improve cancer prognosis. One showed an unexpectedly lower risk of
a cancer diagnosis among diabetics using metformin compared with a control group of diabetics
using other treatments ; another showed lower cancer-specific mortality among subjects with
diabetes using metformin compared with diabetics on other treatments. Metformin is a
biguanide known to be an insulin sensitizing agent which promotes reduced circulating insulin
and glucose levels in hyper-glycaemic and hyper-insulinaemic patients. Metformin activates
the AMP dependent kinase, attenuates insulin and IGF-1 stimulated proliferation in breast
cancer cells and a general decrease in protein synthesis in vitro. Western blot analysis
indicated that metformin stimulates AMPK phosphorylation in a dose-dependent manner. AMPK
activation is associated with decreased phosphorylation of mTOR and S6 kinase. While
metformin reduces breast carcinoma cell proliferation both in vitro and in vivo, the
activation of AMPK leads to significant VEGF production, angiogenesis and tumor progression.
This must be taken into consideration when it is applied in as a therapeutic regimen.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| A | Active Comparator | weekly Paclitaxel chemotherapy at the dose of 100 mg/m2/week for 8 weeks as a 1-hour infusion and AC/EC (60/600 or 90/600) / 3 weekly. | |
| B | Experimental | weekly Paclitaxel at 100mg /m2/week + weekly Carboplatin AUC-2 as an infusion over 60 minutes and AC/EC (60/600 or 90/600)/ 3 weekly. | |
Eligibility Criteria
Inclusion Criteria:
1. Age 18-70 years
2. All patients with baseline clinical staging T4, N0-3, M0 or T1-4, N2-3, M0 and T3, N1,
M0 with triple negative hormone status.
3. Patients with adequate baseline marrow function defined as ANC > 1500/mm3 and Platelet
count > 1, 00,000/mm3.
4. Patients with acceptable liver function tests (normal bilirubin and AST/ALT < 2 times
the upper limit of normal) and normal renal function tests at baseline
5. Patients willing to provide informed consent
6. Patients fit for chemotherapy
Exclusion Criteria:
1. Prior excision biopsy
2. Metastatic breast cancer
3. Women with inflammatory breast cancer
4. Poor cardiac function at baseline with LVEF <40%
5. Patients with a prior history of a malignancy
6. Pregnant or lactating women.
| Maximum Eligible Age: | 70 Years |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | Female |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | DFS |
| Time Frame: | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months |
| Safety Issue: | |
| Description: | Disease free survival |
Details
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | Tata Memorial Hospital |
Last Updated
April 1, 2021
