Trastuzumab

Boekhout, Annelies H.; Beijnen, Jos H.; Schellens, Jan H.M.

doi:10.1634/theoncologist.2010-0035

Cited by 95 publications

(71 citation statements)

References 53 publications

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“…Mechanistically, trastuzumab's antitumor activity is unclear, but may involve disruption of HER2 homodimerization and prevention of cleavage of the extracellular domain (ECD) generating the active truncated receptor p95HER2 (20). In the clinical setting, secondary effector functions may also be involved.…”

Section: Introductionmentioning

confidence: 99%

Targeting Three Distinct HER2 Domains with a Recombinant Antibody Mixture Overcomes Trastuzumab Resistance

Pedersen

Jacobsen

Koefoed

et al. 2015

Molecular Cancer Therapeutics

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HER2 plays an important role in the development and maintenance of the malignant phenotype of several human cancers. As such, it is a frequently pursued therapeutic target and two antibodies targeting HER2 have been clinically approved, trastuzumab and pertuzumab. It has been suggested that optimal inhibition of HER2 is achieved when utilizing two or more antibodies targeting nonoverlapping epitopes. Superior clinical activity of the trastuzumab plus pertuzumab combination in metastatic breast cancer supports this hypothesis. Because trastuzumab and pertuzumab were not codeveloped, there may be potential for further optimizing HER2 targeting. The study herein evaluated functional activity of anti-HER2 antibody combinations identifying optimal epitope combinations that provide efficacious HER2 inhibition. High-affinity antibodies to all four extracellular domains on HER2 were identified and tested for ability to inhibit growth of different HER2-dependent tumor cell lines. An antibody mixture targeting three HER2 subdomains proved to be superior to trastuzumab, pertuzumab, or a combination in vitro and to trastuzumab in two in vivo models. Specifically, the tripartite antibody mixture induced efficient HER2 internalization and degradation demonstrating increased sensitivity in cell lines with HER2 amplification and high EGFR levels. When compared with individual and clinically approved mAbs, the synergistic tripartite antibody targeting HER2 subdomains I, II, and IV demonstrates superior anticancer activity. Mol Cancer Ther; 14(3); 669-80. Ó2015 AACR.

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Section: Introductionmentioning

confidence: 99%

Targeting Three Distinct HER2 Domains with a Recombinant Antibody Mixture Overcomes Trastuzumab Resistance

Pedersen

Jacobsen

Koefoed

et al. 2015

Molecular Cancer Therapeutics

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“…[6][7][8][9][10][11][12] Consequently, treatments that include trastuzumab have become the standard of care for patients with HER2 þ early or metastatic disease. [13][14][15] As the clinical benefits of trastuzumab are highly associated with HER2 positivity, [7][8][9][10][11][12] HER2 testing is recommended at diagnosis of all breast cancers to determine potential eligibility for trastuzumab therapy. 16 Two diagnostic techniques are currently approved for assigning HER2 status in clinical practice: immunohistochemistry (IHC) and in situ hybridization (ISH).…”

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confidence: 99%

HER2 in situ hybridization in breast cancer: clinical implications of polysomy 17 and genetic heterogeneity

Hanna

Rüschoff²,

Bilous³

et al. 2014

Modern Pathology

242

201

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Trastuzumab-containing therapy is a standard of care for patients with HER2 þ breast cancer. HER2 status is routinely assigned using in situ hybridization to assess HER2 gene amplification, but interpretation of in situ hybridization results may be challenging in tumors with chromosome 17 polysomy or intratumoral genetic heterogeneity. Apparent chromosome 17 polysomy, defined by increased chromosome enumeration probe 17 (CEP17) signal number, is a common genetic aberration in breast cancer and represents an alternative mechanism for increasing HER2 copy number. Some studies have linked elevated CEP17 count ('polysomy') with adverse clinicopathologic features and HER2 overexpression, although there are numerous discrepancies in the literature. There is evidence that elevated CEP17 ('polysomy') count might account for trastuzumab response in tumors with normal HER2:CEP17 ratios. Nonetheless, recent studies establish that apparent 'polysomy' (CEP17 increase) is usually related to focal pericentromeric gains rather than true polysomy. Assigning HER2 status may also be complex where multiple cell subclones with distinct HER2 amplification characteristics coexist within the same tumor. Such genetic heterogeneity affects up to 40% of breast cancers when assessed according to a College of American Pathologists guideline, although other definitions have been proposed. Recent data have associated heterogeneity with unfavorable clinicopathologic variables and poor prognosis. Genetically heterogeneous tumors harboring HER2-amplified subclones have the potential to benefit from trastuzumab, but this has yet to be evaluated in clinical studies. In this review, we discuss the implications of apparent polysomy 17 and genetic heterogeneity for assigning HER2 status in clinical practice. Among our recommendations, we support the use of mean HER2 copy number rather than HER2:CEP17 ratio to define HER2 positivity in cases where coamplification of the centromere might mask HER2 amplification. We also highlight a need to harmonize in situ hybridization scoring methodology to support accurate HER2 status determination, particularly where there is evidence of heterogeneity.

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“…Trastuzumab is the current standard of care for the treatment of HER2-positive early and advanced breast cancer (22). In a recent international phase III randomized controlled trial, the addition of trastuzumab to chemotherapy significantly improved overall survival compared with chemotherapy alone in patients with advanced gastric cancer (21).…”

Section: Discussionmentioning

confidence: 99%

Metachronous liver and bone metastasis from small early gastric carcinoma without lymph node involvement: A case report

Namikawa

Shiga

Ichikawa

et al. 2012

Molecular and Clinical Oncology

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Abstract.A 65-year-old man was referred to our Hospital for examination of gastric cancer initially diagnosed by medical check-up. Esophagogastroduodenoscopy demonstrated a superficial depressed-type gastric cancer in the antrum, and abdominal computed tomography showed no evidence of distant metastases. A tumor measuring 11 mm in diameter was removed by endoscopic submucosal dissection (ESD). Since histological examinations of ESD specimens showed a well-differentiated adenocarcinoma invading the submucosal layer with lymphatic invasion, the patient subsequently underwent laparoscopy-assisted distal gastrectomy with regional lymph node dissection, resulting in no residual carcinoma and no lymph node metastasis. The patient developed solitary liver metastasis one year later and was treated with trastuzumab plus capecitabine/cisplatin since results of the immunohistochemical analysis of the resected specimens demonstrated overexpression of the human epidermal growth factor receptor 2 (HER2). The patient was alive 12 months after surgical resection of the liver metastasis and subsequently developed bone metastasis. Controversy remains over the role of HER2 status as a prognostic factor in gastric cancer. However, it has been generally reported that HER2 overexpression correlates with aggressive biological behavior and poor prognosis. HER2 overexpression is a potentially useful predictive factor for tumor recurrence and poor prognosis even in early gastric cancer cases. IntroductionEarly gastric cancer (EGC) is defined as the presence of a lesion confined to the mucosa or submucosa, regardless of the presence of regional lymph node metastasis, and has a good prognosis with appropriate treatment (1). Although the outcome of patients with EGC following curative surgery is excellent, cancer recurrence is a rare event and could occur even after curative gastrectomy with an incidence of 1.4-2.7% (2-5).Endoscopic resection with endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is widely accepted as the standard treatment for EGC without lymph node metastasis and enables a clinician to resect a target lesion en bloc (6,7). Most EGC confined to the mucosa can be curatively treated by endoscopic resection, since lymph node metastasis is rare in such cases. Endoscopic resection is currently considered appropriate for the treatment of intestinaltype gastric cancer cases without central ulceration that are <2 cm in diameter, according to guidelines for EMR/ESD established by the Japanese Gastric Cancer Association (7). However, gastrectomy with lymph node dissection should be performed in patients with submucosal invasion with or without margin involvement following endoscopic resection (8,9).In this study, a case of metachronous liver and bone metastasis after laparoscopy-assisted distal gastrectomy is described, following initial treatment by ESD for small EGC without lymph node metastasis, showing human epidermal growth factor receptor 2 (HER2) overexpression. All diagnostic procedures and therapy...

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Trastuzumab

Cited by 95 publications

References 53 publications

Targeting Three Distinct HER2 Domains with a Recombinant Antibody Mixture Overcomes Trastuzumab Resistance

Targeting Three Distinct HER2 Domains with a Recombinant Antibody Mixture Overcomes Trastuzumab Resistance

HER2 in situ hybridization in breast cancer: clinical implications of polysomy 17 and genetic heterogeneity

Metachronous liver and bone metastasis from small early gastric carcinoma without lymph node involvement: A case report

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