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 e...
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-05-01
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| Series: | npj Breast Cancer |
| Online Access: | https://doi.org/10.1038/s41523-021-00274-0 |
| _version_ | 1797641159477035008 |
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| author | Jamunarani Veeraraghavan Carolina Gutierrez Vidyalakshmi Sethunath Sepideh Mehravaran Mario Giuliano Martin J. Shea Tamika Mitchell Tao Wang Sarmistha Nanda Resel Pereira Robert Davis Kristina Goutsouliak Lanfang Qin Carmine De Angelis Irmina Diala Alshad S. Lalani Chandandeep Nagi Susan G. Hilsenbeck Mothaffar F. Rimawi C. Kent Osborne Rachel Schiff |
| author_facet | Jamunarani Veeraraghavan Carolina Gutierrez Vidyalakshmi Sethunath Sepideh Mehravaran Mario Giuliano Martin J. Shea Tamika Mitchell Tao Wang Sarmistha Nanda Resel Pereira Robert Davis Kristina Goutsouliak Lanfang Qin Carmine De Angelis Irmina Diala Alshad S. Lalani Chandandeep Nagi Susan G. Hilsenbeck Mothaffar F. Rimawi C. Kent Osborne Rachel Schiff |
| author_sort | Jamunarani Veeraraghavan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T13:41:33Z |
| format | Article |
| id | doaj.art-9c0763f670574156a633837d6c948965 |
| institution | Directory Open Access Journal |
| issn | 2374-4677 |
| language | English |
| last_indexed | 2024-03-11T13:41:33Z |
| publishDate | 2021-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Breast Cancer |
| spelling | doaj.art-9c0763f670574156a633837d6c9489652023-11-02T11:40:22ZengNature Portfolionpj Breast Cancer2374-46772021-05-017111110.1038/s41523-021-00274-0Neratinib plus trastuzumab is superior to pertuzumab plus trastuzumab in HER2-positive breast cancer xenograft modelsJamunarani Veeraraghavan0Carolina Gutierrez1Vidyalakshmi Sethunath2Sepideh Mehravaran3Mario Giuliano4Martin J. Shea5Tamika Mitchell6Tao Wang7Sarmistha Nanda8Resel Pereira9Robert Davis10Kristina Goutsouliak11Lanfang Qin12Carmine De Angelis13Irmina Diala14Alshad S. Lalani15Chandandeep Nagi16Susan G. Hilsenbeck17Mothaffar F. Rimawi18C. Kent Osborne19Rachel Schiff20Lester and Sue Smith Breast Center, Baylor College of MedicineLester and Sue Smith Breast Center, Baylor College of MedicineLester and Sue Smith Breast Center, Baylor College of MedicineDepartment of Pathology, Baylor College of MedicineLester and Sue Smith Breast Center, Baylor College of MedicineLester and Sue Smith Breast Center, Baylor College of MedicineLester and Sue Smith Breast Center, Baylor College of MedicineLester and Sue Smith Breast Center, Baylor College of MedicineLester and Sue Smith Breast Center, Baylor College of MedicineLester and Sue Smith Breast Center, Baylor College of MedicineLester and Sue Smith Breast Center, Baylor College of MedicineLester and Sue Smith Breast Center, Baylor College of MedicineLester and Sue Smith Breast Center, Baylor College of MedicineLester and Sue Smith Breast Center, Baylor College of MedicinePuma Biotechnology Inc.Puma Biotechnology Inc.Lester and Sue Smith Breast Center, Baylor College of MedicineLester and Sue Smith Breast Center, Baylor College of MedicineLester and Sue Smith Breast Center, Baylor College of MedicineLester and Sue Smith Breast Center, Baylor College of MedicineLester and Sue Smith Breast Center, Baylor College of MedicineAbstract 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.https://doi.org/10.1038/s41523-021-00274-0 |
| spellingShingle | Jamunarani Veeraraghavan Carolina Gutierrez Vidyalakshmi Sethunath Sepideh Mehravaran Mario Giuliano Martin J. Shea Tamika Mitchell Tao Wang Sarmistha Nanda Resel Pereira Robert Davis Kristina Goutsouliak Lanfang Qin Carmine De Angelis Irmina Diala Alshad S. Lalani Chandandeep Nagi Susan G. Hilsenbeck Mothaffar F. Rimawi C. Kent Osborne Rachel Schiff Neratinib plus trastuzumab is superior to pertuzumab plus trastuzumab in HER2-positive breast cancer xenograft models npj Breast Cancer |
| title | Neratinib plus trastuzumab is superior to pertuzumab plus trastuzumab in HER2-positive breast cancer xenograft models |
| title_full | Neratinib plus trastuzumab is superior to pertuzumab plus trastuzumab in HER2-positive breast cancer xenograft models |
| title_fullStr | Neratinib plus trastuzumab is superior to pertuzumab plus trastuzumab in HER2-positive breast cancer xenograft models |
| title_full_unstemmed | Neratinib plus trastuzumab is superior to pertuzumab plus trastuzumab in HER2-positive breast cancer xenograft models |
| title_short | Neratinib plus trastuzumab is superior to pertuzumab plus trastuzumab in HER2-positive breast cancer xenograft models |
| title_sort | neratinib plus trastuzumab is superior to pertuzumab plus trastuzumab in her2 positive breast cancer xenograft models |
| url | https://doi.org/10.1038/s41523-021-00274-0 |
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