HER2 discordance between primary breast cancer and its paired metastasis: tumor biology or test artefact? Insights through meta-analysis

Houssami, Nehmat; Macaskill, Petra; Balleine, Rosemary L.; Bilous, Michael; Pegram, Mark D.

doi:10.1007/s10549-011-1632-x

Cited by 113 publications

(75 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…There are several indications for various types of tumors that in cases where the expression of members of the epidermal growth factor receptor (EGFR) family is high in the primary tumor, it may also be high in the metastases (2)(3)(4). The reason for this may be that the receptor-expressing tumor cells require the growth factor-receptor interactions for growth stimulation.…”

Section: Introductionmentioning

confidence: 99%

Tendencies for higher co-expression of EGFR and HER2 and downregulation of HER3 in prostate cancer lymph node metastases compared with corresponding primary tumors

et al. 2012

View full text Add to dashboard Cite

Abstract. The epidermal growth factor receptor (EGFR) family members are potential targets for therapy using extracellular domain receptor binding agents, such as the antibodies trastuzumab and cetuximab, or antibodies labeled with therapeutically useful radionuclides or toxins. This is especially the case when the tumor cells are resistant to chemotherapy and tyrosine kinase inhibitors. Studies concerning the expression of these receptors in prostate cancer vary in the literature, possibly due to differences in patient inclusion, sample preparations and scoring criteria. In our study, EGFR, HER2 and HER3 expression was analyzed in prostate cancer samples from primary tumors and corresponding lymph node metastases from 12 patients. The expression of HER2 and EGFR was scored from immunohistochemical preparations and the HercepTest criteria (0, 1+, 2+ or 3+), while HER3 expression was scored as no, weak or strong staining. There were 5 EGFR-positive (2+ or 3+) primary tumors and 6 EGFR-positive lymph node metastases, and there was EGFR upregulation in one metastasis. Only 4 of the 12 patients had marked HER2 expression (2+ or 3+) in their primary tumors and there was one downregulation and 5 cases of upregulation in the metastases. Thus, a total of 8 out of 12 analyzed metastases were HER2-positive. Of the 12 primary tumors, 9 expressed HER3 while only 2 of the lymph node metastases expressed recognizable HER3 staining, so 7 metastases appeared to have downregulated HER3 expression.In one of the primary tumors there was positive co-expression of EGFR and HER2, while this co-expression was observed in 4 of the metastases. Thus, there were tendencies for upregulation of HER2, increased co-expression of EGFR and HER2 and downregulation of HER3 in the prostate cancer lymph node metastases in comparison to the primary tumors. The results are encouraging for studies involving more patients. Possible strategies for EGFR-and HER2-targeted therapy are briefly discussed in the present study, especially with regard to the expression and co-expression of EGFR and HER2 in metastases.

show abstract

Section: Introductionmentioning

confidence: 99%

Tendencies for higher co-expression of EGFR and HER2 and downregulation of HER3 in prostate cancer lymph node metastases compared with corresponding primary tumors

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Disparities in HER2 expression of primary breast cancer and metastases have been reported. Metaanalysis of 26 studies including 2,520 patients revealed discordance in HER2 expression between the primary tumor and local lymph node metastases in the range of 2.4%-7.2% and discordance with distant metastases in the range of 6.9%-18.6%, with an absolute variation for all studies in the range of 0%-40% (12). A recent symposium publication including 2,845 patients reported absolute variations in the same range (13).…”

mentioning

confidence: 96%

First-in-Human Molecular Imaging of HER2 Expression in Breast Cancer Metastases Using the ¹¹¹In-ABY-025 Affibody Molecule

et al. 2014

View full text Add to dashboard Cite

The expression status of human epidermal growth factor receptor type 2 (HER2) predicts the response of HER2-targeted therapy in breast cancer. ABY-025 is a small reengineered Affibody molecule targeting a unique epitope of the HER2 receptor, not occupied by current therapeutic agents. This study evaluated the distribution, safety, dosimetry, and efficacy of 111 In-ABY-025 for determining the HER2 status in metastatic breast cancer. Methods: Seven patients with metastatic breast cancer and HER2-positive (n 5 5) or -negative (n 5 2) primary tumors received an intravenous injection of approximately 100 μg (∼140 MBq) of 111 In-ABY-025. Planar γ-camera imaging was performed after 30 min, followed by SPECT/CT after 4, 24, and 48 h. Blood levels of radioactivity, antibodies, shed serum HER2, and toxicity markers were evaluated. Lesional HER2 status was verified by biopsies. The metastases were located by 18 F-FDG PET/CT 5 d before 111 In-ABY-025 imaging. Results: Injection of 111 In-ABY-025 yielded a mean effective dose of 0.15 mSv/MBq and was safe, well tolerated, and without drug-related adverse events. Fast blood clearance allowed high-contrast HER2 images within 4-24 h. No anti-ABY-025 antibodies were observed. When metastatic uptake at 24 h was normalized to uptake at 4 h, the ratio increased in HER2-positive metastases and decreased in negative ones (P , 0.05), with no overlap and confirmation by biopsies. In 1 patient, with HER2-positive primary tumor, 111 In-ABY-025 imaging correctly suggested a HER2-negative status of the metastases. The highest normal-tissue uptake was in the kidneys, followed by the liver and spleen. Conclusion: 111 In-ABY-025 appears safe for use in humans and is a promising noninvasive tool for discriminating HER2 status in metastatic breast cancer, regardless of ongoing HER2-targeted antibody treatment. Today,t reatment of breast cancer is based on the biologic profile of the individual tumor. Knowledge of the human epidermal growth factor receptor type 2 (HER2) status is crucial to predict the response of HER2-targeted therapy (1). Patients with breast cancer overexpressing HER2 have improved survival when treated with HER2-targeting agents such as trastuzumab, pertuzumab, and trastuzumab emtansine (2-10).The analysis of HER2 expression is usually based on a surgical specimen of the primary tumor or, in case of neoadjuvant therapy or inoperable disease, on a biopsy sample from the tumor (11). The pathologic analysis includes immunohistochemistry and in some cases fluorescence in situ hybridization (FISH). Therapy for patients with disseminated disease is often based on histopathologic classification of the primary tumor and not of the metastases. Disparities in HER2 expression of primary breast cancer and metastases have been reported. Metaanalysis of 26 studies including 2,520 patients revealed discordance in HER2 expression between the primary tumor and local lymph node metastases in the range of 2.4%-7.2% and discordance with distant metastases in the range of 6.9%-18.6%, with an abs...

show abstract

“…Today, assessment of HER2 status is based on tumor biopsy. However, HER2 expression can vary between the primary tumor and metastases in up to 40% of cases (2,5,6) and metastatic HER2 expression can change over time, which could necessitate a change of therapy (7,8). Follow-up using biopsies cannot always be performed due to practical reasons or patient discomfort.…”

mentioning

confidence: 99%

Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule ⁶⁸Ga-ABY-025 in Breast Cancer Patients

et al. 2016

View full text Add to dashboard Cite

68 Ga-ABY-025 is a radiolabeled Affibody molecule for in vivo diagnosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer tumors with PET. The aim of the present work was to measure the biodistribution and estimate the radiation dosimetry of 68 Ga-ABY-025 for 2 different peptide mass doses in a single group of patients using dynamic and serial whole-body PET/CT. Methods: Eight patients with metastatic breast cancer were included. Each patient underwent an abdominal 45-min dynamic and 3 whole-body PET/CT scans at 1, 2, and 4 h after injection of a low peptide dose (LD) and a high peptide dose (HD), with approximately the same amount of radioactivity, in separate investigations 1 wk apart. As input to the absorbed dose calculations, volumes of interest were drawn on all clearly identifiable source organs: liver, kidneys, spleen, descending aorta, and upper large intestine. Absorbed doses were calculated using OLINDA/EXM, version 1.1. Results: Of the major organs, the highest radionuclide uptake at 1, 2, and 4 h after injection was observed in the kidneys and liver. The highest absorbed organ doses were seen in the kidneys, followed by the liver for both LD and HD 68 Ga-ABY-025. Absorbed doses to liver and kidneys were slightly but significantly higher for LD. Total effective dose was 0.030 ± 0.003 mSv/MBq for LD and 0.028 ± 0.002 mSv/MBq for HD. Conclusion: The effective dose for a typical 200-MBq administration of 68 Ga-ABY-025 is 6.0 mSv for LD and 5.6 mSv for HD. Therefore, from a radiation dosimetry point of view, HD is preferred for PET/CT evaluation of HER2-expressing breast cancer tumors. These effective doses are somewhat higher than earlier published values for other 68 Ga-labeled tracers, such as 0.021 ± 0.003 mSv/MBq for 68 Ga-DOTATATE and 68 Ga-DOTATOC, mainly because of higher uptake in liver and kidney. Forwomen,br east cancer is currently the most common cancer.Human epidermal growth factor receptor 2 (HER2) is overexpressed in about 1 of 6 cases (1-3) at initial diagnosis and is associated with poor survival (1,3). Treatments targeted to HER2, such as with the anti-HER2 antibody trastuzumab, have considerably improved overall survival (1,3,4). Today, assessment of HER2 status is based on tumor biopsy. However, HER2 expression can vary between the primary tumor and metastases in up to 40% of cases (2,5,6) and metastatic HER2 expression can change over time, which could necessitate a change of therapy (7,8). Follow-up using biopsies cannot always be performed due to practical reasons or patient discomfort.Molecular imaging using SPECT and PET might be a noninvasive, whole-body-based way to evaluate HER2 expression quantitatively. One such approach is the use of trastuzumab labeled with 111 In (half-time, 2.8 d) (9) or 89 Zr (3.3 d) (10) for use with SPECT and PET, respectively, but the slow kinetics of antibodies require imaging several days after administration. One promising method of fast, safe, and accurate imaging that specifically binds to a site on the receptor not occu...

show abstract

HER2 discordance between primary breast cancer and its paired metastasis: tumor biology or test artefact? Insights through meta-analysis

Cited by 113 publications

References 54 publications

Tendencies for higher co-expression of EGFR and HER2 and downregulation of HER3 in prostate cancer lymph node metastases compared with corresponding primary tumors

Tendencies for higher co-expression of EGFR and HER2 and downregulation of HER3 in prostate cancer lymph node metastases compared with corresponding primary tumors

First-in-Human Molecular Imaging of HER2 Expression in Breast Cancer Metastases Using the ¹¹¹In-ABY-025 Affibody Molecule

Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule ⁶⁸Ga-ABY-025 in Breast Cancer Patients

Contact Info

Product

Resources

About

HER2 discordance between primary breast cancer and its paired metastasis: tumor biology or test artefact? Insights through meta-analysis

Cited by 113 publications

References 54 publications

Tendencies for higher co-expression of EGFR and HER2 and downregulation of HER3 in prostate cancer lymph node metastases compared with corresponding primary tumors

Tendencies for higher co-expression of EGFR and HER2 and downregulation of HER3 in prostate cancer lymph node metastases compared with corresponding primary tumors

First-in-Human Molecular Imaging of HER2 Expression in Breast Cancer Metastases Using the 111In-ABY-025 Affibody Molecule

Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule 68Ga-ABY-025 in Breast Cancer Patients

Contact Info

Product

Resources

About

First-in-Human Molecular Imaging of HER2 Expression in Breast Cancer Metastases Using the ¹¹¹In-ABY-025 Affibody Molecule

Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule ⁶⁸Ga-ABY-025 in Breast Cancer Patients