The primary objective of the study is to assess metabolic plasma markers of insulin resistance in patients with early-stage HER2-negative breast cancers receiving dapagliflozin concomitant with neoadjuvant therapy.
This is a single arm, open label trial that will evaluate changes in plasma markers of insulin resistance, namely, fasting glucose and insulin, measured as the HOMA-IR score, as well as the safety of the addition of dapagliflozin to neoadjuvant treatment in hyperinsulinemic women with newly diagnosed early stage HER2-negative breast cancers who are candidates for neoadjuvant therapy. Hypotheses are: (i) the SGLT2 inhibitor, dapagliflozin, administered concomitantly with weekly neoadjuvant therapy in hyperinsulinemic women with newly diagnosed HER2-negative breast cancers will lead to a decrease in fasting plasma insulin and glucose and thus, a downregulation in downstream insulin signaling in the tumor as measured by Protein kinase B (PKB)/AKT phosphorylation. (ii) that dapagliflozin can be safely coadministered at full dose with multiagent chemotherapy or chemo-immunotherapy. Routine, standard of care neoadjuvant chemotherapy, with or without immunotherapy, will be given together with the investigational product. Acceptable chemotherapy regimens include: 1) weekly paclitaxel x12 treatments followed by every two-week doxorubicin, cyclophosphamide (ddAC) x 4 treatments (ddAC-T; ); 2) pembrolizumab every 3 weeks (Q3W), with carboplatin + weekly paclitaxel (cycles 1-4) x12 weeks followed by ddAC x 4 treatments (cycles 5-8) (KEYNOTE-522 regimen; only for participants with stage II-III ER/PR and HER-negative breast cancer); 3) docetaxel plus cyclophosphamide and 4) docetaxel plus carboplatin. The primary objective of the study is to assess metabolic plasma markers of insulin resistance in participants with early-stage HER2-negative breast cancers receiving dapagliflozin concomitant with neoadjuvant therapy. Secondary objectives are to assess tissue expression of insulin signaling intermediates and SGLT2 by immunohistochemistry (IHC) on pre- and post-treatment tissue samples. Outcomes will be assessed before treatment and 12 weeks post treatment (after completion of all neoadjuvant therapy but before surgery). Registration (including outcome measures) was updated to reflect current protocol July 2024.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
20
10 mg tablets for oral administration daily throughout chemotherapy treatment
Yale Cancer Center Smilow Cancer Hospital
New Haven, Connecticut, United States
RECRUITINGChange in Homeostasis Model Assessment-Insulin Resistance (HOMA-IR)
Change in HOMA-IR (calculated as fasting insulin (μU/ml) x fasting glucose (mmol/l) divided by 22.5.
Time frame: baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy
Change in Fasting glucose concentration
Fasting plasma glucose concentration will be assessed following an overnight fast at baseline and 12 weeks post treatment
Time frame: baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy
Change in Fasting insulin concentration
Fasting plasma insulin concentration will be assessed at baseline and 12 weeks post treatment
Time frame: baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy
Total and phosphorylated PKB/AKT
Immunohistochemistry (IHC) staining for expression of Total and phosphorylated PKB/AKT in breast cancer tissue, before and after (in participants with residual cancer) treatment. For quantification of IHC, sections will be scored manually by a pathologist using the Allred system, a clinical instrument based on the percentage of cells that stain by immunohistochemistry for PKB/AKT (on a scale of 0 to 5) and the intensity of that staining (on a scale of 0 to 3, for a possible maximum total score of 8. The lower the number the less staining.
Time frame: baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy
Total and phosphorylated insulin receptor
Immunohistochemistry (IHC) staining for expression of Total and phosphorylated insulin receptor in breast cancer tissue, before and after (in participants with residual cancer) treatment. For quantification of IHC, sections will be scored manually by a pathologist using the Allred system, a clinical instrument based on the percentage of cells that stain by immunohistochemistry for PKB/AKT (on a scale of 0 to 5) and the intensity of that staining (on a scale of 0 to 3, for a possible maximum total score of 8. The lower the number the less staining.
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Time frame: baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy
Total and phosphorylated insulin-like growth factor-1 receptor (IGF1R)
Immunohistochemistry (IHC) staining for expression of Total and phosphorylated insulin-like growth factor-1 receptor (IGF1R) in breast cancer tissue, before and after (in participants with residual cancer) treatment. For quantification of IHC, sections will be scored manually by a pathologist using the Allred system, a clinical instrument based on the percentage of cells that stain by immunohistochemistry for PKB/AKT (on a scale of 0 to 5) and the intensity of that staining (on a scale of 0 to 3, for a possible maximum total score of 8. The lower the number the less staining.
Time frame: baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy
Total and phosphorylated insulin receptor substrate (IRS) 1
Immunohistochemistry (IHC) staining for expression of Total and phosphorylated insulin receptor substrate (IRS) 1 in breast cancer tissue, before and after (in participants with residual cancer) treatment. For quantification of IHC, sections will be scored manually by a pathologist using the Allred system, a clinical instrument based on the percentage of cells that stain by immunohistochemistry for PKB/AKT (on a scale of 0 to 5) and the intensity of that staining (on a scale of 0 to 3, for a possible maximum total score of 8. The lower the number the less staining.
Time frame: baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy
Sodium-glucose cotransporter-2 (SGLT2)
Immunohistochemistry (IHC) staining for expression of SGLT2 in breast cancer tissue, before and after (in participants with residual cancer) treatment. For quantification of IHC, sections will be scored manually by a pathologist using the Allred system, a clinical instrument based on the percentage of cells that stain by immunohistochemistry for PKB/AKT (on a scale of 0 to 5) and the intensity of that staining (on a scale of 0 to 3, for a possible maximum total score of 8. The lower the number the less staining.
Time frame: baseline, post paclitaxel treatment at week 12, and 2 weeks post neoadjuvant therapy