TY - JOUR
T1 - Extended adjuvant therapy with neratinib plus fulvestrant blocks ER/HER2 crosstalk and maintains complete responses of ER þ /HER2 þ breast cancers
T2 - Implications to the EXTENET trial
AU - Sudhan, Dhivya R.
AU - Schwarz, Luis J.
AU - Guerrero-Zotano, Angel
AU - Formisano, Luigi
AU - Nixon, Mellissa J.
AU - Croessmann, Sarah
AU - Gonzalez Ericsson, Paula I.
AU - Sanders, Melinda
AU - Balko, Justin M.
AU - Avogadri-Connors, Francesca
AU - Cutler, Richard E.
AU - Lalani, Alshad S.
AU - Bryce, Richard
AU - Auerbach, Alan
AU - Arteaga, Carlos L.
N1 - Funding Information:
This study was supported by NIH Breast SPORE grant P50 CA098131, Vanderbilt-Ingram Cancer Center P30 CA68485, UTSW Simmons Cancer Center P30 CA142543, CPRIT RR170061 grant, Susan G. Komen Breast Cancer Foundation grant SAC100013 (CLA), and a grant from the Breast Cancer Research Foundation (CLA). J.M. Balko was supported by Susan G. Komen Career Catalyst Grant CCR14299052 and NIH/NCI R00CA181491.
Funding Information:
A. S. Lalani is an employee of and holds ownership interest (including patents) in Puma Biotechnology, Inc. R. Bryce is an employee of and holds ownership interest (including patents) in Puma Biotechnology, Inc. A. Auerbach is an employee of and holds ownership interest (including patents) in Puma Biotechnology, Inc. C. L. Arteaga reports receiving research grants from Puma Biotechnology, Inc., Pfizer, Lilly, Bayer, Takeda, and Radius, holds ownership interest (including patents) in Provista and Y-TRAP, is a consultant/advisory board member for Novartis, Merck, Lilly, Symphogen, Daiichi Sankyo, Radius, Taiho Oncology, H3Biomedicine, OrigiMed, Puma Biotechnology, and Sanofi, and reports other remuneration from the Komen Foundation. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/1/15
Y1 - 2019/1/15
N2 - Purpose: The phase III ExteNET trial showed improved invasive disease-free survival in patients with HER2 þ breast cancer treated with neratinib versus placebo after trastuzumab-based adjuvant therapy. The benefit from neratinib appeared to be greater in patients with ER þ /HER2 þ tumors. We thus sought to discover mechanisms that may explain the benefit from extended adjuvant therapy with neratinib. Experimental Design: Mice with established ER þ /HER2 þ MDA-MB-361 tumors were treated with paclitaxel plus trastuzumab pertuzumab for 4 weeks, and then randomized to fulvestrant neratinib treatment. The benefit from neratinib was evaluated by performing gene expression analysis for 196 ER targets, ER transcriptional reporter assays, and cell-cycle analyses. Results: Mice receiving "extended adjuvant" therapy with fulvestrant/neratinib maintained a complete response, whereas those treated with fulvestrant relapsed rapidly. In three ER þ / HER2 þ cell lines (MDA-MB-361, BT-474, UACC-893) but not in ER þ /HER2 MCF7 cells, treatment with neratinib induced ER reporter transcriptional activity, whereas treatment with fulvestrant resulted in increased HER2 and EGFR phosphorylation, suggesting compensatory reciprocal crosstalk between the ER and ERBB RTK pathways. ER transcriptional reporter assays, gene expression, and immunoblot analyses showed that treatment with neratinib/fulvestrant, but not fulvestrant, potently inhibited growth and downregulated ER reporter activity, P-AKT, P-ERK, and cyclin D1 levels. Finally, similar to neratinib, genetic and pharmacologic inactivation of cyclin D1 enhanced fulvestrant action against ER þ /HER2 þ breast cancer cells. Conclusions: These data suggest that ER blockade leads to reactivation of ERBB RTKs and thus extended ERBB blockade is necessary to achieve durable clinical outcomes in patients with ER þ /HER2 þ breast cancer.
AB - Purpose: The phase III ExteNET trial showed improved invasive disease-free survival in patients with HER2 þ breast cancer treated with neratinib versus placebo after trastuzumab-based adjuvant therapy. The benefit from neratinib appeared to be greater in patients with ER þ /HER2 þ tumors. We thus sought to discover mechanisms that may explain the benefit from extended adjuvant therapy with neratinib. Experimental Design: Mice with established ER þ /HER2 þ MDA-MB-361 tumors were treated with paclitaxel plus trastuzumab pertuzumab for 4 weeks, and then randomized to fulvestrant neratinib treatment. The benefit from neratinib was evaluated by performing gene expression analysis for 196 ER targets, ER transcriptional reporter assays, and cell-cycle analyses. Results: Mice receiving "extended adjuvant" therapy with fulvestrant/neratinib maintained a complete response, whereas those treated with fulvestrant relapsed rapidly. In three ER þ / HER2 þ cell lines (MDA-MB-361, BT-474, UACC-893) but not in ER þ /HER2 MCF7 cells, treatment with neratinib induced ER reporter transcriptional activity, whereas treatment with fulvestrant resulted in increased HER2 and EGFR phosphorylation, suggesting compensatory reciprocal crosstalk between the ER and ERBB RTK pathways. ER transcriptional reporter assays, gene expression, and immunoblot analyses showed that treatment with neratinib/fulvestrant, but not fulvestrant, potently inhibited growth and downregulated ER reporter activity, P-AKT, P-ERK, and cyclin D1 levels. Finally, similar to neratinib, genetic and pharmacologic inactivation of cyclin D1 enhanced fulvestrant action against ER þ /HER2 þ breast cancer cells. Conclusions: These data suggest that ER blockade leads to reactivation of ERBB RTKs and thus extended ERBB blockade is necessary to achieve durable clinical outcomes in patients with ER þ /HER2 þ breast cancer.
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U2 - 10.1158/1078-0432.CCR-18-1131
DO - 10.1158/1078-0432.CCR-18-1131
M3 - Article
C2 - 30274983
AN - SCOPUS:85060052933
SN - 1078-0432
VL - 25
SP - 771
EP - 783
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -