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Estrogen-independent proliferation is present in estrogen-receptor HER2-positive primary breast cancer after
Matthew J Ellis1, Yu Tao, Oliver Young
1Siteman Comprehensive Cancer Center,, Washington University School of Medicine, Campus Box 8056, 660 S Euclid Ave, St Louis, MO 63110, USA. mellis@wustl.edu
Purpose:
To investigate the impact of human epidermal growth factor receptor (HER) 1 and HER2 gene amplification on endocrine therapy responsiveness, a fluorescence in situ hybridization (FISH) study was conducted on tumor samples from 305 postmenopausal patients with stage II and III estrogen receptor (ER) -positive (ER > or = 10%) breast cancers treated on two independent neoadjuvant endocrine therapy trials.
Patients And Methods:
FISH analysis focused on HER1 and/or HER2 immunohistochemistry (IHC) -positive patients and a random selection of HER1/2 IHC-negative patients. HER2 FISH status was correlated with response and changes in the proliferation marker Ki67.
Results:
HER1 was rarely amplified (< 1%), and HER2 amplification was observed in 9.2% of patients. Letrozole response by clinical measurement (71% HER2 FISH positive v 71% HER2 FISH negative), mammogram (44% HER2 FISH positive v 47% HER2 FISH negative), or ultrasound (47% HER2 FISH positive v 54% HER2 FISH negative) was not impaired by HER2 FISH-positive status. In contrast, HER2 FISH-positive tumors showed higher histologic grade (P = .009), higher pretreatment Ki67 (P = .005), and less Ki67 suppression after letrozole when compared with HER2 FISH-negative tumors (P = .0001). Similar observations regarding Ki67 were made in a smaller cohort of tamoxifen-treated tumors.
Conclusion:
Neoadjuvant letrozole is clinically effective in ER-positive HER2 FISH-positive tumors, indicating sensitivity to short-term estrogen deprivation. However, continued proliferation despite ongoing letrozole or tamoxifen treatment in the majority of ER-positive HER2 FISH-positive samples (88%) could imply therapeutic resistance that may manifest later in the clinical course of the disease. Discordance between clinical and biomarker findings in this study serves to emphasize the need for surrogate end point validation in neoadjuvant endocrine trials through correlation with information on long-term outcomes.
Insights
Human epidermal growth factor receptor 2 (HER2) gene amplification did not affect clinical response to neoadjuvant letrozole in estrogen receptor-positive breast cancer. However, HER2 amplification was linked to higher tumor grade and proliferation, suggesting potential later therapeutic resistance.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Estrogen receptor (ER)-positive breast cancer is often treated with endocrine therapy.
- Human epidermal growth factor receptor (HER) family genes, including HER1 and HER2, play roles in breast cancer development and progression.
- Gene amplification of HER family members can influence treatment response.
Purpose of the Study:
- To evaluate the impact of HER1 and HER2 gene amplification on the effectiveness of neoadjuvant endocrine therapy in ER-positive breast cancer.
- To correlate HER2 gene amplification status with clinical response and proliferation markers.
Main Methods:
- Fluorescence in situ hybridization (FISH) was used to assess HER1 and HER2 gene amplification in tumor samples from 305 postmenopausal patients with ER-positive breast cancer.
- Patients were treated with neoadjuvant endocrine therapy (letrozole or tamoxifen).
- HER2 FISH status was correlated with clinical response (e.g., mammogram, ultrasound) and changes in the Ki67 proliferation marker.
Main Results:
- HER1 amplification was rare (<1%), while HER2 amplification occurred in 9.2% of patients.
- HER2 FISH-positive status did not impair clinical response to letrozole based on clinical measurements, mammography, or ultrasound.
- HER2 FISH-positive tumors exhibited higher histologic grade, increased pretreatment Ki67 levels, and reduced Ki67 suppression after letrozole treatment compared to HER2 FISH-negative tumors.
Conclusions:
- Neoadjuvant letrozole is effective in ER-positive, HER2 FISH-positive tumors, demonstrating sensitivity to short-term estrogen deprivation.
- Persistent proliferation in a majority of ER-positive, HER2 FISH-positive tumors despite endocrine therapy suggests potential for later therapeutic resistance.
- Validation of surrogate endpoints in neoadjuvant trials is crucial, emphasizing the need to correlate biomarker findings with long-term clinical outcomes.
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