npj Breast Cancer (Dec 2022)
Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer
- Julie E. Lang,
- Andres Forero-Torres,
- Douglas Yee,
- Christina Yau,
- Denise Wolf,
- John Park,
- Barbara A. Parker,
- A. Jo Chien,
- Anne M. Wallace,
- Rashmi Murthy,
- Kathy S. Albain,
- Erin D. Ellis,
- Heather Beckwith,
- Barbara B. Haley,
- Anthony D. Elias,
- Judy C. Boughey,
- Rachel L. Yung,
- Claudine Isaacs,
- Amy S. Clark,
- Hyo S. Han,
- Rita Nanda,
- Qamar J. Khan,
- Kristen K. Edmiston,
- Erica Stringer-Reasor,
- Elissa Price,
- Bonnie Joe,
- Minetta C. Liu,
- Lamorna Brown-Swigart,
- Emanuel F. Petricoin,
- Julia D. Wulfkuhle,
- Meredith Buxton,
- Julia L. Clennell,
- Ashish Sanil,
- Scott Berry,
- Smita M. Asare,
- Amy Wilson,
- Gillian L. Hirst,
- Ruby Singhrao,
- Adam L. Asare,
- Jeffrey B. Matthews,
- Michelle Melisko,
- Jane Perlmutter,
- Hope S. Rugo,
- W. Fraser Symmans,
- Laura J. van ‘t Veer,
- Nola M. Hylton,
- Angela M. DeMichele,
- Donald A. Berry,
- Laura J. Esserman
Affiliations
- Julie E. Lang
- University of Southern California
- Andres Forero-Torres
- University of Alabama at Birmingham
- Douglas Yee
- University of Minnesota
- Christina Yau
- University of California San Francisco
- Denise Wolf
- University of California San Francisco
- John Park
- University of California San Francisco
- Barbara A. Parker
- University of California San Diego
- A. Jo Chien
- University of California San Francisco
- Anne M. Wallace
- University of California San Francisco
- Rashmi Murthy
- University of Texas MD Anderson Cancer Center
- Kathy S. Albain
- Loyola University Chicago Stritch School of Medicine
- Erin D. Ellis
- Swedish Cancer Institute
- Heather Beckwith
- University of Minnesota
- Barbara B. Haley
- University of Texas Southwestern
- Anthony D. Elias
- University of Colorado
- Judy C. Boughey
- Mayo Clinic Rochester
- Rachel L. Yung
- University of Washington
- Claudine Isaacs
- University of Georgetown
- Amy S. Clark
- University of Pennsylvania
- Hyo S. Han
- Moffitt Cancer Center
- Rita Nanda
- University of Chicago
- Qamar J. Khan
- University of Kansas
- Kristen K. Edmiston
- Inova Health System
- Erica Stringer-Reasor
- University of Alabama at Birmingham
- Elissa Price
- University of California San Francisco
- Bonnie Joe
- University of California San Francisco
- Minetta C. Liu
- Mayo Clinic Rochester
- Lamorna Brown-Swigart
- University of California San Francisco
- Emanuel F. Petricoin
- George Mason University
- Julia D. Wulfkuhle
- George Mason University
- Meredith Buxton
- University of California San Francisco
- Julia L. Clennell
- University of California San Francisco
- Ashish Sanil
- Berry Consultants, LLC
- Scott Berry
- Berry Consultants, LLC
- Smita M. Asare
- Quantum Leap Healthcare Collaborative
- Amy Wilson
- Quantum Leap Healthcare Collaborative
- Gillian L. Hirst
- University of California San Francisco
- Ruby Singhrao
- University of California San Francisco
- Adam L. Asare
- Quantum Leap Healthcare Collaborative
- Jeffrey B. Matthews
- University of California San Francisco
- Michelle Melisko
- University of California San Francisco
- Jane Perlmutter
- Gemini Group
- Hope S. Rugo
- University of California San Francisco
- W. Fraser Symmans
- University of Texas MD Anderson Cancer Center
- Laura J. van ‘t Veer
- University of California San Francisco
- Nola M. Hylton
- University of California San Francisco
- Angela M. DeMichele
- University of Pennsylvania
- Donald A. Berry
- Berry Consultants, LLC
- Laura J. Esserman
- University of California San Francisco
- DOI
- https://doi.org/10.1038/s41523-022-00493-z
- Journal volume & issue
-
Vol. 8,
no. 1
pp. 1 – 10
Abstract
Abstract HSP90 inhibitors destabilize oncoproteins associated with cell cycle, angiogenesis, RAS-MAPK activity, histone modification, kinases and growth factors. We evaluated the HSP90-inhibitor ganetespib in combination with standard chemotherapy in patients with high-risk early-stage breast cancer. I-SPY2 is a multicenter, phase II adaptively randomized neoadjuvant (NAC) clinical trial enrolling patients with stage II-III breast cancer with tumors 2.5 cm or larger on the basis of hormone receptors (HR), HER2 and Mammaprint status. Multiple novel investigational agents plus standard chemotherapy are evaluated in parallel for the primary endpoint of pathologic complete response (pCR). Patients with HER2-negative breast cancer were eligible for randomization to ganetespib from October 2014 to October 2015. Of 233 women included in the final analysis, 140 were randomized to the standard NAC control; 93 were randomized to receive 150 mg/m2 ganetespib every 3 weeks with weekly paclitaxel over 12 weeks, followed by AC. Arms were balanced for hormone receptor status (51–52% HR-positive). Ganetespib did not graduate in any of the biomarker signatures studied before reaching maximum enrollment. Final estimated pCR rates were 26% vs. 18% HER2-negative, 38% vs. 22% HR-negative/HER2-negative, and 15% vs. 14% HR-positive/HER2-negative for ganetespib vs control, respectively. The predicted probability of success in phase 3 testing was 47% HER2-negative, 72% HR-negative/HER2-negative, and 19% HR-positive/HER2-negative. Ganetespib added to standard therapy is unlikely to yield substantially higher pCR rates in HER2-negative breast cancer compared to standard NAC, and neither HSP90 pathway nor replicative stress expression markers predicted response. HSP90 inhibitors remain of limited clinical interest in breast cancer, potentially in other clinical settings such as HER2-positive disease or in combination with anti-PD1 neoadjuvant chemotherapy in triple negative breast cancer. Trial registration: www.clinicaltrials.gov/ct2/show/NCT01042379
