Quantitation of p95HER2 in Paraffin Sections by Using a p95-Specific Antibody and Correlation with Outcome in a Cohort of Trastuzumab-Treated Breast Cancer Patients

Sperinde, Jeff; Xiao, Jin; Banerjee, Jayee; Penuel, Elicia; Saha, Anasuya; Diedrich, Gundo; Huang, Weidong; Leitzel, Kim; Weidler, Jodi; Ali, Suhail M.; Fuchs, Eva-Maria; Singer, Christian F.; Köstler, Wolfgang J.; Bates, Michael; Parry, Gordon; Winslow, John; Lipton, Allan

doi:10.1158/1078-0432.ccr-10-0410

Cited by 124 publications

(145 citation statements)

References 27 publications

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“…Interestingly, the HCC-1954 model, which is innately resistant to trastuzumab, expresses high levels of P95HER2, a truncated form of HER2 that lacks the extracellular ligand-binding domain. The presence of this truncated form of HER2 has been reported to correlate with trastuzumab resistance and poor prognosis; however, these tumor types may benefit from treatment with an AKT inhibitor such as AZD5363 (43,44).…”

Section: Discussionmentioning

confidence: 99%

Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background

Davies

Greenwood

Dudley

et al. 2012

Molecular Cancer Therapeutics

355

345

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AKT is a key node in the most frequently deregulated signaling network in human cancer. AZD5363, a novel pyrrolopyrimidine-derived compound, inhibited all AKT isoforms with a potency of 10 nmol/L or less and inhibited phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 mmol/L. AZD5363 monotherapy inhibited the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of 3 mmol/L or less. Cell lines derived from breast cancers showed the highest frequency of sensitivity. There was a significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD5363 and between RAS mutations and resistance. Oral dosing of AZD5363 to nude mice caused doseand time-dependent reduction of PRAS40, GSK3b, and S6 phosphorylation in BT474c xenografts (PRAS40 phosphorylation EC 50 $ 0.1 mmol/L total plasma exposure), reversible increases in blood glucose concentrations, and dose-dependent decreases in 2[18F]fluoro-2-deoxy-D-glucose ( 18 F-FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 caused dose-dependent growth inhibition of xenografts derived from various tumor types, including HER2þ breast cancer models that are resistant to trastuzumab. AZD5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib, and trastuzumab in breast cancer xenografts. It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic activity in vivo, has potential to treat a range of solid and hematologic tumors as monotherapy or a combinatorial agent, and has potential for personalized medicine based on the genetic status of PIK3CA, PTEN, and RAS. AZD5363 is currently in phase I clinical trials. Mol Cancer Ther; 11(4); 873-87. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 99%

Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background

Davies

Greenwood

Dudley

et al. 2012

Molecular Cancer Therapeutics

355

345

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“…Based on these studies, it is expected that differences in prognosis despite treatment programs directed with molecular indicators that provide data on tumor molecular identity, prognosis, and individualized treatment will be an even more pronounced subject in the near future. For example, based on HER-2 patients who were resistant to treatment with monoclonal antibodies (Herceptin) targeting the extracellular domain or those who relapsed after treatment, possible causative mechanisms were investigated (28)(29)(30). It was reported that a portion of HER-2 positive breast cancer patients with poor prognosis express a heterogeneous group of HER2 carboxy-terminal fragments known as p95HER2 (29).…”

Section: What Are the Molecular Subgroups?mentioning

confidence: 99%

Molecular Classification of Breast Carcinoma: From Traditional, Old-Fashioned Way to A New Age, and A New Way

et al. 2015

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Breast carcinoma comprises a group of diseases with specific clinical, histopathologic and molecular properties. Traditional classification use morphology to divide tumors into separate categories with differing behavior and prognosis. However, there are limitations of traditional classification systems, and new molecular methods are expected to improve classification systems. Molecular subtypes of breast carcinomas have been characterized in the last 11 years, and have been studied extensively. Much of the information accumulated in recent years, and molecular taxonomy seems to be still developing and undergoing change. The main question is whether new molecular techniques such as gene expression profiling will be accepted as gold standard in determining breast cancer subtypes, and whether molecular classification is useful in specific subtypes of breast cancer as it is in ductal carcinoma (nonspecific type). In addition, critical review of the literature reveals major problems such as poor definition, lack of reproducibility and lack of quality control in current molecular techniques and classifications. Therefore, current molecular approaches are not yet used in routine clinical practice and treatment guidance since they are immature and can even lead to incorrect assessment.

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“…28 A short form of HER2 missing the extracellular domain, so-called p95, is constitutively active and unresponsive to trastuzumab because it lacks the trastuzumab-binding domain. [29][30][31] Upregulation of receptor ligands or the receptors themselves has also been proposed as a mechanism of acquired resistance. 32,33 Escape pathways such as ER or insulin-like growth factor receptor signaling have also been implicated in resistance.…”

Section: Journal Of Clinical Oncology O R I G I N a L R E P O R T V Omentioning

confidence: 99%

Multicenter Phase II Study of Neoadjuvant Lapatinib and Trastuzumab With Hormonal Therapy and Without Chemotherapy in Patients With Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer: TBCRC 006

Rimawi

Mayer

Forero

et al. 2013

JCO

230

162

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Purpose We previously reported the eradication of human epidermal growth factor receptor 2 (HER2)– amplified human xenografts in mice by inhibition of the HER2 pathway with lapatinib and trastuzumab to block all homo- and heterodimer signaling as well as by blockade of estrogen receptor (ER) when expressed. In this clinical trial, we sought to translate these findings to patients using targeted therapy without chemotherapy. Patients and Methods Women with stages II to III HER2-positive breast cancers were eligible. They received trastuzumab once per week (4 mg/kg loading, then 2 mg/kg) and lapatinib 1000 mg once per day for 12 weeks. Women with ER-positive tumors also received letrozole (plus a luteinizing hormone–releasing hormone [LHRH] agonist if premenopausal). Pathologic response was assessed by ER status. Biopsies were obtained at baseline, weeks 2 and 8, and time of surgery. Results Sixty-six patients were enrolled, and 64 were eligible and evaluable for response. Median tumor size was 6 cm (range, 1.5 to 30 cm). Adverse events were mainly grades 1 to 2 (GI, 63%; skin, 46%). Grade 3 metabolic, GI, and liver (18%; 12 patients) and grade 4 liver toxicities (one patient) were also observed. Overall, in-breast pathologic complete response (pCR; ypT0-is) was 27% (ER positive, 21%; ER negative, 36%). The rate of low-volume residual disease (ypT1a-b) was 22% (ER positive, 33%; ER negative, 4%). Conclusion In patients with locally advanced HER2-positive breast cancer, our approach of targeted therapy only resulted in a high pCR rate without chemotherapy. Our data support the hypothesis that selected patients with HER2-positive tumors may not need chemotherapy, and more-complete blockade of HER receptors and ER is an effective strategy worthy of further study.

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Quantitation of p95HER2 in Paraffin Sections by Using a p95-Specific Antibody and Correlation with Outcome in a Cohort of Trastuzumab-Treated Breast Cancer Patients

Cited by 124 publications

References 27 publications

Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background

Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background

Molecular Classification of Breast Carcinoma: From Traditional, Old-Fashioned Way to A New Age, and A New Way

Multicenter Phase II Study of Neoadjuvant Lapatinib and Trastuzumab With Hormonal Therapy and Without Chemotherapy in Patients With Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer: TBCRC 006

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