First-Line Herceptin&lt;sup&gt;®&lt;/sup&gt; Monotherapy in Metastatic Breast Cancer

Vogel, Charles L.; Cobleigh, Melody A.; Tripathy, Debasish; Gutheil, John; Harris, Lyndsay N.; Fehrenbacher, Louis; Slamon, Dennis J.; Murphy, Maureen; Novotny, William; Burchmore, Michael; Shak, Steven; Stewart, Stanford J.

doi:10.1159/000055400

Cited by 193 publications

(114 citation statements)

References 12 publications

(15 reference statements)

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“…[5][6][7] Although it is tolerated very well, trastuzumab confers a risk of cardiotoxicity. 7 Thus, accurate determination of HER-2 status is crucial for increasing the potential clinical benefit of trastuzumab and for avoiding toxic effects in inappropriately selected patients.…”

Section: Discussionmentioning

confidence: 99%

“…Amplification of the HER-2 gene or overexpression of the HER-2 protein has been identified in 10 -34% of primary breast carcinomas and is associated with adverse clinical outcomes and drug resistance in patients with breast carcinoma. [1][2][3][4] Trastuzumab is a high-affinity, humanized, anti-HER-2 antibody for the treatment of advanced breast carcinoma, especially metastasis, 5,6 and its efficacy is associated directly with the HER-2 status of the tumor. 5,7 Although therapy targets metastases, to our knowledge there is no agreement on whether HER-2 status should be assessed in primary tumors or metastases, because controversy exists among previous studies regarding the stability of HER-2 status in breast carcinoma throughout the course of the disease.…”

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confidence: 99%

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Comparison of HER‐2 status determined by fluorescence in situ hybridization in primary and metastatic breast carcinoma

Gong

Booser

Sneige

2005

Cancer

144

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BACKGROUNDAccurate assessment of HER‐2 status is necessary prior to anti‐HER‐2 antibody (trastuzumab) therapy for metastatic breast carcinoma. However, controversy exists regarding whether to assess HER‐2 status in the primary tumor or in metastatic lesions. It is also unclear whether HER‐2 status can change during disease progression or after chemotherapy.METHODSBreast carcinoma samples from 60 women with known HER‐2 status in both primary tumors and paired metastases (locoregional disease, n = 43 patients; distant disease, n = 17 patients) were reviewed retrospectively. Thirty‐two patients underwent chemotherapy before their metastatic lesions were sampled, including 18 patients who received neoadjuvant chemotherapy and 14 patients who received adjuvant chemotherapy. The HER‐2 gene was examined by fluorescence in situ hybridization either in paraffin‐embedded tissue samples (48 primary tumors and 9 metastatic tumors) or in fine‐needle aspirates (12 primary tumors and 51 metastatic tumors). HER‐2 gene amplification was defined as a HER‐2:chromosome 17 signal ratio ≥ 2.0.RESULTSThe HER‐2 status of primary and metastatic tumors agreed in 58 of 60 patients (97%), including 18 (30%) amplified tumors and 40 (67%) nonamplified tumors. A discrepancy in HER‐2 status was observed in specimens from two patients in which HER‐2 amplification was detected in the primary tumor but not the metastatic tumors. In one patient, three foci of tumor nodules were found in the same breast; the HER‐2 status was assessed in only one of them, which showed amplification; however, HER‐2 amplification was not detected in the axillary lymph node metastasis. In another patient, the HER‐2 gene was amplified in the primary tumor but not in the liver metastasis. No metastases showed HER‐2 amplification without amplification in the primary tumor. Locoregional and distant metastases demonstrated similar concordance rates with their corresponding primary tumors (98% and 94%, respectively). Complete concordance of HER‐2 status was found between primary tumors prior to chemotherapy and metastases that were sampled after chemotherapy.CONCLUSIONSThe HER‐2 status in breast carcinoma generally was stable during metastasis, whether to locoregional or distant sites. Chemotherapy did not modify the HER‐2 status in metastatic lesions. Therefore, HER‐2 amplification can be evaluated reliably in material from either primary or metastatic tumors in most patients. Further study with larger series is warranted to elucidate the significance of discordant results. Cancer 2005. © 2005 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Comparison of HER‐2 status determined by fluorescence in situ hybridization in primary and metastatic breast carcinoma

Gong

Booser

Sneige

2005

Cancer

144

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“…Almost 25% to 30% of these tumors overexpress erbB2, which is associated with very poor prognosis (1). Only about 20% to 50% of the erbB2 overexpressing tumors are sensitive to trastuzumab (Herceptin), a humanized monoclonal antibody that binds to an extracellular domain of erbB2 adjacent to the plasma membrane (2)(3)(4)(5). The mechanism of action of trastuzumab is complex (6)(7)(8)(9)(10); thus, the possible origins of trastuzumab resistance also remain obscure.…”

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confidence: 99%

Signal transduction of erbB receptors in trastuzumab (Herceptin) sensitive and resistant cell lines: Local stimulation using magnetic microspheres as assessed by quantitative digital microscopy

et al. 2005

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Background: ErbB2 (HER-2), a member of the epidermal growth factor (EGF) receptor family, is a class I transmembrane receptor tyrosine kinase. Although erbB2 has no known physiologic ligand, it can form complexes with other members of the family and undergo transactivation of its very potent kinase activity, thereby initiating downstream signaling and cell proliferation. ErbB2 is a frequent pathologic marker in ductal invasive breast carcinomas and is targeted by using a specific humanized monoclonal antibody, trastuzumab (Herceptin). The antibody is effective in only 20% to 50% of erbB2-positive tumors, and this resistance, as yet poorly understood, constitutes a major therapeutic challenge. Methods: Magnetic microspheres coated with ligands or antibodies are widely used for separation of proteins and cells and allow localized, high intensity, and precisely timed stimulation of cells. We used EGF-and trastuzumabcovered paramagnetic microspheres, quantitative confocal laser scanning microscopy, and digital image processing to investigate the (trans)activation of and local signal propagation from erbB1 and erbB2 on trastuzumab sensitive and resistant carcinoma cell lines expressing these receptors at high levels. Results: On A431 cells expressing high levels of endogenous erbB1 and transfected erbB2-mYFP (A4-erbB2-mYFP F4 cell line), EGF-coupled-microspheres activated

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“…Trastuzumab was approved by the US Food and Drug Administration (FDA) for the treatment of breast cancer patients whose tumours overexpress HER-2/neu. Trastuzumab produced objective responses in 26% of previously untreated breast cancer patients (Vogel et al, 2001) and 15% of breast cancer patients in the second line setting (Cobleigh et al, 1999). Response rates were considerably higher when trastuzumab was combined with doxorubicin or paclitaxel (45%), and breast cancer patients treated with the combination had higher response rates and longer survival than patients treated with doxorubicin or paclitaxel alone .…”

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confidence: 99%

Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas

et al. 2002

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HER-2/neu gene amplification and cell surface overexpression are important factors in breast cancer for prognosis and prediction of sensitivity to anti-HER-2/neu monoclonal antibody therapy. In lung cancer, the clinical significance of HER-2/neu expression is currently under evaluation. We investigated 238 non-small lung carcinomas for HER-2/neu protein overexpression by immunohistochemistry using the HercepTest. We found 2+ or 3+ overexpression in 39 patients (16%), including 35% in adenocarcinomas and 20% in large cell carcinomas, but only 1% of squamous cell carcinomas. Marked (3+) overexpression was uncommon (4%). The association between protein expression and gene copy number per cell, as determined by fluorescence in situ hybridisation assay, was investigated in 51 of these NSCLC tumours. Twenty-seven tumours (53%) were negative by both tests. Marked (3+) protein expression and gene amplification were present in only 4% of samples. In 11 tumours (21%), gene gain was accompanied by chromosomal aneusomy and did not result in high protein levels while in 7 (14%) the score 2+ was associated with maximum number of signals per cell 59. The prognostic implication of HER-2/neu protein expression was studied in 187 surgically resected tumours. No statistical difference in survival was observed comparing patients with positive (2+/3+) and negative tumours (0/1+), although 3+ patients showed a tendency to shorter survival. The therapeutic implications of protein expression and gene amplification in lung cancer need to be examined in prospective clinical trials.

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First-Line Herceptin<sup>®</sup> Monotherapy in Metastatic Breast Cancer

Cited by 193 publications

References 12 publications

Comparison of HER‐2 status determined by fluorescence in situ hybridization in primary and metastatic breast carcinoma

Comparison of HER‐2 status determined by fluorescence in situ hybridization in primary and metastatic breast carcinoma

Signal transduction of erbB receptors in trastuzumab (Herceptin) sensitive and resistant cell lines: Local stimulation using magnetic microspheres as assessed by quantitative digital microscopy

Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas

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