Dataset Information

Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer.

ABSTRACT: I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY's prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.

SUBMITTER: Yee D

PROVIDER: S-EPMC8492731 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer.

Yee Douglas D Isaacs Claudine C Wolf Denise M DM Yau Christina C Haluska Paul P Giridhar Karthik V KV Forero-Torres Andres A Jo Chien A A Wallace Anne M AM Pusztai Lajos L Albain Kathy S KS Ellis Erin D ED Beckwith Heather H Haley Barbara B BB Elias Anthony D AD Boughey Judy C JC Kemmer Kathleen K Yung Rachel L RL Pohlmann Paula R PR Tripathy Debu D Clark Amy S AS Han Hyo S HS Nanda Rita R Khan Qamar J QJ Edmiston Kristen K KK Petricoin Emanuel F EF Stringer-Reasor Erica E Falkson Carla I CI Majure Melanie M Mukhtar Rita A RA Helsten Teresa L TL Moulder Stacy L SL Robinson Patricia A PA Wulfkuhle Julia D JD Brown-Swigart Lamorna L Buxton Meredith M Clennell Julia L JL Paoloni Melissa M Sanil Ashish A Berry Scott S Asare Smita M SM Wilson Amy A Hirst Gillian L GL Singhrao Ruby R Asare Adam L AL Matthews Jeffrey B JB Hylton Nola M NM DeMichele Angela A Melisko Michelle M Perlmutter Jane J Rugo Hope S HS Fraser Symmans W W Van't Veer Laura J LJ Berry Donald A DA Esserman Laura J LJ

NPJ breast cancer 20211005 1

I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic compl ...[more]

PMID: 34611148

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Project description:The proliferative capacity of residual breast cancer (BC) disease indicates the existence of partial treatment resistance and higher probability of tumor recurrence. We explored the therapeutic potential of adding neoadjuvant metformin as an innovative strategy to decrease the proliferative potential of residual BC cells in patients failing to achieve pathological complete response (pCR) after pre-operative therapy. We performed a prospective analysis involving the intention-to-treat population of the (Metformin and Trastuzumab in Neoadjuvancy) METTEN study, a randomized multicenter phase II trial of women with primary, non-metastatic (human epidermal growth factor receptor 2) HER2-positive BC evaluating the efficacy, tolerability, and safety of oral metformin (850 mg twice-daily) for 24 weeks combined with anthracycline/taxane-based chemotherapy and trastuzumab (arm A) or equivalent regimen without metformin (arm B), before surgery. We centrally evaluated the proliferation marker Ki67 on sequential core biopsies using visual assessment (VA) and an (Food and Drug Administration) FDA-cleared automated digital image analysis (ADIA) algorithm. ADIA-based pre-operative values of high Ki67 (≥20%), but not those from VA, significantly predicted the occurrence of pCR in both arms irrespective of the hormone receptor status (p = 0.024 and 0.120, respectively). Changes in Ki67 in residual tumors of non-pCR patients were significantly higher in the metformin-containing arm (p = 0.025), with half of all patients exhibiting high Ki67 at baseline moving into the low-Ki67 (<20%) category after neoadjuvant treatment. By contrast, no statistically significant changes in Ki67 occurred in residual tumors of the control treatment arm (p = 0.293). There is an urgent need for innovative therapeutic strategies aiming to provide the protective effects of decreasing Ki67 after neoadjuvant treatment even if pCR is not achieved. Metformin would be evaluated as a safe candidate to decrease the aggressiveness of residual disease after neoadjuvant (pre-operative) systemic therapy of BC patients.

Dataset Information

Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer.

Publications

Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer.

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