Utility of Serum HER2 Extracellular Domain Assessment in Clinical Decision Making: Pooled Analysis of Four Trials of Trastuzumab in Metastatic Breast Cancer

Lennon, Siân; Barton, Claire; Banken, Ludger; Gianni, Luca; Marty, Michel; Baselga, José; Leyland‐Jones, Brian

doi:10.1200/jco.2008.16.8351

Cited by 95 publications

(94 citation statements)

References 35 publications

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“…Many other membrane-anchored proteins release their ECD through proteolytic cleavage, such as HER2 and EGFR (28,29). However, clinical significance of such form has been difficult to establish, and effect on response to targeted therapy has not been fully elucidated (30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

Enfortumab Vedotin Antibody–Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models

Challita-Eid¹,

Satpayev²,

Yang³

et al. 2016

Cancer Research

414

386

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The identification of optimal target antigens on tumor cells is central to the advancement of new antibody-based cancer therapies. We performed suppression subtractive hybridization and identified nectin-4 (PVRL4), a type I transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules, as a potential target in epithelial cancers. We conducted immunohistochemical analysis of 2,394 patient specimens from bladder, breast, lung, pancreatic, ovarian, head/neck, and esophageal tumors and found that 69% of all specimens stained positive for nectin-4. Moderate to strong staining was especially observed in 60% of bladder and 53% of breast tumor specimens, whereas the expression of nectin-4 in normal tissue was more limited. We generated a novel antibody-drug conjugate (ADC) enfortumab vedotin comprising the human anti-nectin-4 antibody conjugated to the highly potent microtubule-disrupting agent MMAE. Hybridoma (AGS-22M6E) and CHO (ASG-22CE) versions of enfortumab vedotin (also known as ASG-22ME) ADC were able to bind to cell surface-expressed nectin-4 with high affinity and induced cell death in vitro in a dose-dependent manner. Treatment of mouse xenograft models of human breast, bladder, pancreatic, and lung cancers with enfortumab vedotin significantly inhibited the growth of all four tumor types and resulted in tumor regression of breast and bladder xenografts. Overall, these findings validate nectin-4 as an attractive therapeutic target in multiple solid tumors and support further clinical development, investigation, and application of nectin-4-targeting ADCs. Cancer Res; 76(10); 3003-13. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Enfortumab Vedotin Antibody–Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models

Challita-Eid¹,

Satpayev²,

Yang³

et al. 2016

Cancer Research

414

386

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“…Serum HER2 is the circulating HER2 ECD shed from the surface of tumor cells, and thus it could be used as a diagnostic marker for tissue HER2 status. Numerous studies have investigated the clinical utility of serum HER2 analysis in breast cancer and recent reviews concluded that there is insufficient evidence to support the use of serum HER2 in the clinical management of breast cancer patients [13][14][15]. In contrast, only a small number of retrospective studies have investigated serum HER2 in gastric cancer to date and its clinical significance has not been determined.…”

mentioning

confidence: 99%

Serum HER2 as an adjunct to assess HER2 status for advanced gastric cancer: A prospective multicenter trial (SHERLOCK)

et al. 2016

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Background: Intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity of gastric cancer can be an obstacle to accurate HER2 assessment. Serum HER2, concentrations of the HER2 extracellular domain shed into the bloodstream, has a potential to compensate HER2 immunohistochemistry (IHC) but has not been scrutinized in gastric cancer. This study sought to explore the clinical utility of serum HER2 in gastric cancer. Methods: We performed a prospective multicenter trial (SHERLOCK trial) involving patients with allstage gastric or gastro-esophageal junction cancer. Serum HER2 was measured using direct chemiluminescence while tissue HER2 status was determined using IHC and fluorescent in situ hybridization. For stage IV cases, concordance between local and central laboratories in tissue HER2 assessment was also evaluated. Results: Of 224 patients enrolled, both tissue HER2 status and serum HER2 levels were successfully determined in 212 patients and 21% (45/212) were tissue HER2-positive. Serum HER2 levels, ranged from 4.5 to 148.0 ng/ml (median 10.3), correlated with tissue HER2 status (p ¼ 0.003). At a cut-off level of 28.0 ng/ml determined by receiver operating characteristics analysis, sensitivity, specificity, positive and negative predictive values of serum HER2 were 22.6%, 100%, 100% and 82.3%, respectively. All nine cases with elevated serum HER2 were tissue HER2-positive stage IV cases. Among 61 stage IV cases, the agreement rate for IHC scoring between the local and the central laboratories was 82% and tissue HER2 judgment was conflicting in five (8.2%) cases. Of these five cases, four were confirmed as false-negative and two of these four patients demonstrated elevated serum HER2. Conclusions: Serum HER2 levels correlated with tissue HER2 status in gastric cancer. Although the low sensitivity is a drawback, serum HER2 might be a useful adjunct tool to detect tissue HER2 false-negative gastric cancer.

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“…In patients with breast carcinoma, the overexpression of HER2 is an important predictor for the response of trastuzumab (11). In this study, lung ACs had a significantly higher rate of HER2 IHC staining than LCNEC, with only 2 LCNEC cases showing overexpression of HER2.…”

Section: Discussionmentioning

confidence: 49%

“…Overexpression of the human epidermal growth factor receptor 2 (HER2) tyrosine kinase, usually due to over-amplification, has been linked to poor prognosis in breast cancer (11). Treatment with recombinant monoclonal anti-HER2 antibody (trastuzumab) displays activity in patients with breast cancer, particularly with high HER2 expression.…”

Section: Introductionmentioning

confidence: 99%

Expression profiling and identification of potential molecular targets for therapy in pulmonary large-cell neuroendocrine carcinoma

Iyoda

Travis

Sarkaria

et al. 2011

Experimental and Therapeutic Medicine

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Utility of Serum HER2 Extracellular Domain Assessment in Clinical Decision Making: Pooled Analysis of Four Trials of Trastuzumab in Metastatic Breast Cancer

Abstract: Based on our data, we cannot recommend using serum HER2 ECD levels to make trastuzumab or other treatment decisions for individual patients with advanced/metastatic breast cancer.

Cited by 95 publications

References 35 publications

Enfortumab Vedotin Antibody–Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models

Enfortumab Vedotin Antibody–Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models

Serum HER2 as an adjunct to assess HER2 status for advanced gastric cancer: A prospective multicenter trial (SHERLOCK)

Expression profiling and identification of potential molecular targets for therapy in pulmonary large-cell neuroendocrine carcinoma

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