TY - JOUR
T1 - Frequent upregulation of HER2 protein in hormone-receptor-positive HER2-negative breast cancer after short-term neoadjuvant endocrine therapy
AU - Chaudhary, Lubna N.
AU - Jorns, Julie M.
AU - Sun, Yunguang
AU - Cheng, Yee Chung
AU - Kamaraju, Sailaja
AU - Burfeind, John
AU - Gonyo, Mary Beth
AU - Kong, Amanda L.
AU - Patten, Caitlin
AU - Yen, Tina
AU - Cortina, Chandler S.
AU - Carson, Ebony
AU - Johnson, Nedra
AU - Bergom, Carmen
AU - Tsaih, Shirng Wern
AU - Banerjee, Anjishnu
AU - Wang, Yu
AU - Chervoneva, Inna
AU - Weil, Elizabeth
AU - Chitambar, Christopher R.
AU - Rui, Hallgeir
N1 - Funding Information:
Lubna N, Chaudhary has received consultant and advisory boards honoraria Puma Biotechnology, Seattle Genetics, Gilead Oncology, AstraZeneca, and Novartis Advisory as well as grant from Regeneron Pharmaceuticals outside the submitted work. Other authors have no financial interests to disclose.
Funding Information:
Investigator Initiated clinical trial (NCT03219476) supported by Rock River Foundation and the Medical College of Wisconsin Cancer Center. Effort for this project was supported by the National Center for Advancing Translational Sciences, National Institutes of Health Awards KL2TR001438, R03 CA259594 I, and R01 CA267549 (HR).
Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2023/10
Y1 - 2023/10
N2 - Background: Endocrine resistant metastatic disease develops in ~ 20–25% of hormone-receptor-positive (HR+) breast cancer (BC) patients despite endocrine therapy (ET) use. Upregulation of HER family receptor tyrosine kinases (RTKs) represent escape mechanisms in response to ET in some HR+ tumors. Short-term neoadjuvant ET (NET) offers the opportunity to identify early endocrine escape mechanisms initiated in individual tumors. Methods: This was a single arm, interventional phase II clinical trial evaluating 4 weeks (± 1 week) of NET in patients with early-stage HR+/HER2-negative (HER2-) BC. The primary objective was to assess NET-induced changes in HER1-4 proteins by immunohistochemistry (IHC) score. Protein upregulation was defined as an increase of ≥ 1 in IHC score following NET. Results: Thirty-seven patients with cT1-T3, cN0, HR+/HER2- BC were enrolled. In 35 patients with evaluable tumor HER protein after NET, HER2 was upregulated in 48.6% (17/35; p = 0.025), with HER2-positive status (IHC 3+ or FISH-amplified) detected in three patients at surgery, who were recommended adjuvant trastuzumab-based therapy. Downregulation of HER3 and/or HER4 protein was detected in 54.2% of tumors, whereas HER1 protein remained low and unchanged in all cases. While no significant volumetric reduction was detected radiographically after short-term NET, significant reduction in tumor proliferation rates were observed. No significant associations were identified between any clinicopathologic covariates and changes in HER1-4 protein expression on multivariable analysis. Conclusion: Short-term NET frequently and preferentially upregulates HER2 over other HER family RTKs in early-stage HR+/HER2- BC and may be a promising strategy to identify tumors that utilize HER2 as an early endocrine escape pathway. Clinical trial registry: Trial registration number: NCT03219476.
AB - Background: Endocrine resistant metastatic disease develops in ~ 20–25% of hormone-receptor-positive (HR+) breast cancer (BC) patients despite endocrine therapy (ET) use. Upregulation of HER family receptor tyrosine kinases (RTKs) represent escape mechanisms in response to ET in some HR+ tumors. Short-term neoadjuvant ET (NET) offers the opportunity to identify early endocrine escape mechanisms initiated in individual tumors. Methods: This was a single arm, interventional phase II clinical trial evaluating 4 weeks (± 1 week) of NET in patients with early-stage HR+/HER2-negative (HER2-) BC. The primary objective was to assess NET-induced changes in HER1-4 proteins by immunohistochemistry (IHC) score. Protein upregulation was defined as an increase of ≥ 1 in IHC score following NET. Results: Thirty-seven patients with cT1-T3, cN0, HR+/HER2- BC were enrolled. In 35 patients with evaluable tumor HER protein after NET, HER2 was upregulated in 48.6% (17/35; p = 0.025), with HER2-positive status (IHC 3+ or FISH-amplified) detected in three patients at surgery, who were recommended adjuvant trastuzumab-based therapy. Downregulation of HER3 and/or HER4 protein was detected in 54.2% of tumors, whereas HER1 protein remained low and unchanged in all cases. While no significant volumetric reduction was detected radiographically after short-term NET, significant reduction in tumor proliferation rates were observed. No significant associations were identified between any clinicopathologic covariates and changes in HER1-4 protein expression on multivariable analysis. Conclusion: Short-term NET frequently and preferentially upregulates HER2 over other HER family RTKs in early-stage HR+/HER2- BC and may be a promising strategy to identify tumors that utilize HER2 as an early endocrine escape pathway. Clinical trial registry: Trial registration number: NCT03219476.
KW - Breast cancer
KW - Endocrine resistance
KW - Estrogen receptor
KW - Short-term neoadjuvant endocrine treatment
UR - http://www.scopus.com/inward/record.url?scp=85164922339&partnerID=8YFLogxK
U2 - 10.1007/s10549-023-07038-3
DO - 10.1007/s10549-023-07038-3
M3 - Article
C2 - 37460683
AN - SCOPUS:85164922339
SN - 0167-6806
VL - 201
SP - 387
EP - 396
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 3
ER -