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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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/9c0763f670574156a633837d6c948965
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spelling	oai:doaj.org-article:9c0763f670574156a633837d6c9489652021-12-02T15:00:58ZNeratinib plus trastuzumab is superior to pertuzumab plus trastuzumab in HER2-positive breast cancer xenograft models10.1038/s41523-021-00274-02374-4677https://doaj.org/article/9c0763f670574156a633837d6c9489652021-05-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00274-0https://doaj.org/toc/2374-4677Abstract 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.Jamunarani VeeraraghavanCarolina GutierrezVidyalakshmi SethunathSepideh MehravaranMario GiulianoMartin J. SheaTamika MitchellTao WangSarmistha NandaResel PereiraRobert DavisKristina GoutsouliakLanfang QinCarmine De AngelisIrmina DialaAlshad S. LalaniChandandeep NagiSusan G. HilsenbeckMothaffar F. RimawiC. Kent OsborneRachel SchiffNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 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
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.
format	article
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
title	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_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_sort	neratinib plus trastuzumab is superior to pertuzumab plus trastuzumab in her2-positive breast cancer xenograft models
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/9c0763f670574156a633837d6c948965
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Neratinib plus trastuzumab is superior to pertuzumab plus trastuzumab in HER2-positive breast cancer xenograft models

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