Neratinib plus trastuzumab is superior to pertuzumab plus trastuzumab in HER2-positive breast cancer xenograft models
Abstract
Lapatinib (L) plus trastuzumab (T), with endocrine therapy for estrogen receptor (ER)+ tumors, but without chemotherapy, yielded meaningful response in HER2+ breast cancer (BC) neoadjuvant trials. The irreversible/pan-HER inhibitor neratinib (N) has proven more potent than L. However, the efficacy of N+T in comparison to pertuzumab (P) + T or L + T (without chemotherapy) remains less studied. To address this, mice bearing HER2+ BT474-AZ (ER+) cell and BCM-3963 patient-derived BC xenografts were randomized to vehicle, N, T, P, N+T, or P+T, with simultaneous estrogen deprivation for BT474-AZ. Time to tumor regression/progression and incidence/time to complete response (CR) were determined. Changes in key HER pathway and proliferative markers were assessed by immunohistochemistry and western blot of short-term-treated tumors. In the BT474-AZ model, while all N, P, T, N + T, and P + T treated tumors regressed, N + T-treated tumors regressed faster than P, T, and P + T. Further, N + T was superior to N and T alone in accelerating CR. In the BCM-3963 model, which was refractory to T, P, and P + T, while N and N + T yielded 100% CR, N + T accelerated the CR compared to N. Ki67, phosphorylated (p) AKT, pS6, and pERK levels were largely inhibited by N and N + T, but not by T, P, or P + T. Phosphorylated HER receptor levels were also markedly inhibited by N and N + T, but not by P + T or L + T. Our findings establish the efficacy of combining N with T and support clinical testing to investigate the efficacy of N + T with or without chemotherapy in the neoadjuvant setting for HER2+ BC.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 27, 2021
- Source ID
- 10.1038/s41523-021-00274-0
Entities
People
- Alshad S. Lalani
- C. Kent Osborne
- Carmine De Angelis
- Carolina Gutierrez
- Chandandeep Nagi
- Irmina Diala
- Jamunarani Veeraraghavan
- Kristina Goutsouliak
- Lanfang Qin
- Mario Giuliano
- Martin J. Shea
- Mothaffar F Rimawi
- Rachel Schiff
- Resel Pereira
- Robert F Davis
- Sarmistha Nanda
- Sepideh Mehravaran
- Susan Hilsenbeck
- Tamika Mitchell
- Tao Wang
- Vidyalakshmi Sethunath
Organizations
- Congressionally Directed Medical Research Programs
- National Institutes of Health
- The Breast Cancer Research Foundation