Estrogen-independent proliferation is present in estrogen-receptor HER2-positive primary breast cancer after neoadjuvant letrozole.

Abstract

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.

• Authors: Matthew J Ellis, Yu Tao, Oliver Young, Sharon White, Alan D Proia, Julliette Murray, Lorna Renshaw, Dana Faratian, Jeremy Thomas, Mitch Dowsett, Andreas Krause, Dean B Evans, William R Miller, J Michael Dixon
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 24 Issue 19 Pg. 3019-25 (Jul 01 2006) ISSN: 1527-7755 [Electronic] United States
• PMID: 16754938 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Nitriles
• Receptors, Estrogen
• Triazoles
• Letrozole
• Receptor, ErbB-2

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Agents (therapeutic use)
• Biomarkers, Tumor (analysis)
• Breast Neoplasms (drug therapy, physiopathology)
• Cell Proliferation (drug effects)
• Female
• Gene Amplification
• Genes, erbB-1
• Humans
• Immunohistochemistry
• In Situ Hybridization, Fluorescence
• Letrozole
• Middle Aged
• Neoadjuvant Therapy
• Nitriles (therapeutic use)
• Receptor, ErbB-2 (genetics)
• Receptors, Estrogen (analysis)
• Treatment Outcome
• Triazoles (therapeutic use)