Frequent upregulation of HER2 protein in hormone-receptor-positive HER2-negative breast cancer after short-term neoadjuvant endocrine therapy

Lubna N. Chaudhary, Julie M. Jorns, Yunguang Sun, Yee Chung Cheng, Sailaja Kamaraju, John Burfeind, Mary Beth Gonyo, Amanda L. Kong, Caitlin Patten, Tina Yen, Chandler S. Cortina, Ebony Carson, Nedra Johnson, Carmen Bergom, Shirng Wern Tsaih, Anjishnu Banerjee, Yu Wang, Inna Chervoneva, Elizabeth Weil, Christopher R. ChitambarHallgeir Rui

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)387-396
Number of pages10
JournalBreast Cancer Research and Treatment
Issue number3
StatePublished - Oct 2023


  • Breast cancer
  • Endocrine resistance
  • Estrogen receptor
  • Short-term neoadjuvant endocrine treatment


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