Quantitative Measurements of Tumoral p95HER2 Protein Expression in Metastatic Breast Cancer Patients Treated with Trastuzumab: Independent Validation of the p95HER2 Clinical Cutoff

Duchnowska, Renata; Sperinde, Jeff; Chenna, Ahmed; Haddad, Mojgan; Paquet, Agnès; Yang, Lie; Weidler, Jodi; Huang, Weidong; Winslow, John; Jankowski, Tomasz; Czartoryska-Arłukowicz, Bogumiła; Wysocki, Piotr J.; Foszczyńska-Kłoda, Małgorzata; Radecka, Barbara; Litwiniuk, Maria; Żok, Jolanta; Wiśniewski, Michał; Zuziak, Dorota; Biernat, Wojciech; Jassem, Jacek

doi:10.1158/1078-0432.ccr-13-2782

Cited by 30 publications

(45 citation statements)

References 18 publications

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“…Elevated serum levels of the HER2 ECD in breast cancer patients have been correlated with HER2 gene amplification, metastasis, and poor survival [94][95][96]. Increased levels of the p95HER2 variant have been correlated with poor prognosis and trastuzumab resistance in HER2 positive breast cancer [73,75,[97][98][99]. Preclinical in vitro and in vivo studies demonstrated that p95HER2 exhibited kinase activity that induced tumor proliferation that was resistant to trastuzumab therapy [71,73,75,90].…”

Section: Her2 Structural Alterationmentioning

confidence: 99%

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The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer

et al. 2015

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Endometrial cancer is the most common gynecologic cancer in the United States, diagnosed in more than 50,000 women annually.While the majority of women present with low-grade tumors that are cured with surgery and adjuvant radiotherapy, a significant subset of women experience recurrence and do not survive their disease. A disproportionate number of the more than 8,000 annual deaths attributed to endometrial cancer are due to high-grade uterine cancers, highlighting the need for new therapies that target molecular alterations specific to this subset of tumors. Numerous correlative scientific investigations have demonstrated that the HER2 (ERBB2) gene is amplified in 17%-33% of carcinosarcoma, uterine serous carcinoma, and a subset of high-grade endometrioid endometrial tumors. In breast cancer, this potent signature has directed women to anti-HER2-targeted therapies such as trastuzumab and lapatinib. In contrast to breast cancer, therapy with trastuzumab alone revealed no responses in women with recurrent HER2 overexpressing endometrial cancer, suggesting that these tumors may possess acquired or innate trastuzumab resistance mechanisms. This review explores the literature surrounding HER2 expression in endometrial cancer, focusing on trastuzumab and other anti-HER2 therapy and resistance mechanisms characterized in breast cancer but germane to endometrial tumors. Understanding resistance pathways will suggest combination therapies that target both HER2 and key oncogenic escape pathways in endometrial cancer. The Oncologist 2015; 20:1058-1068Implications for Practice: This review summarizes the role of HER2 in endometrial cancer, with a focus on uterine serous carcinoma. The limitations to date of anti-HER2 therapy in this disease site are examined, and mechanisms of drug resistance are outlined based on the experience in breast cancer. Potential opportunities to overcome inherent resistance to anti-HER2 therapy in endometrial cancer are detailed, offering opportunities for further clinical study with the goal to improve outcomes in this challenging disease.

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Section: Her2 Structural Alterationmentioning

confidence: 99%

“…Some early results have validated specific cutoff levels of expression that can be assayed in a clinical trial setting [97,108]. In contrast to reports showing resistance to trastuzumab as a single agent, early reports from the GeparQuattro and www.TheOncologist.com [109].…”

Section: Her2 Structural Alterationmentioning

confidence: 99%

The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer

et al. 2015

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“…In contrast, in the metastatic setting, p95HER2 has been found to negatively correlate with PFS and OS (23). It is possible that this difference could be due to phenotypic differences in the primary and metastatic tumors, especially under selective pressure of drug treatment.…”

Section: Discussionmentioning

confidence: 99%

“…This C-terminal fragment of HER2, called p95HER2 for its molecular weight by Western blot analysis, is constitutively active, highly tumorigenic, and has been shown to correlate with intrinsic resistance to trastuzumab-based therapy in the metastatic setting (20)(21)(22)(23). Recent data based on p95HER2 evaluation by immunohistochemistry in the neoadjuvant setting, however, showed the opposite trend, correlating the expression of this truncated form with response to trastuzumabbased treatment (24).…”

Section: Introductionmentioning

confidence: 99%

High HER2 Expression Correlates with Response to the Combination of Lapatinib and Trastuzumab

Scaltriti

Nuciforo²,

Bradbury³

et al. 2015

Clinical Cancer Research

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Purpose: Expression of p95HER2 has been associated with resistance to trastuzumab-based therapy in patients with metastatic breast cancer. Conversely, high levels of HER2 have been linked with increased clinical benefit from anti-HER2 therapy. In this work, we aimed to investigate whether the levels of p95HER2 and HER2 can predict response to anti-HER2 therapy in patients with breast cancer.Experimental Design: We measured p95HER2 and HER2 by VeraTag and HERmark, respectively, in primary tumors of patients enrolled in the neoadjuvant phase III study NeoALTTO and correlated these variables with pathologic complete response (pCR) and progression-free survival (PFS) following lapatinib (L), trastuzumab (T), or the combination of both agents (LþT).Results: A positive correlation between p95HER2 and HER2 levels was found in the 274 cases (60%) in which quantification of both markers was possible. High levels of these markers were predictive for pCR, especially in the hormone receptor (HR)-positive subset of patients. High HER2 expression was associated with increased pCR rate upon LþT irrespective of the HR status. To examine whether the levels of either p95HER2 or HER2 could predict for PFS in patients treated with lapatinib, trastuzumab or LþT, we fit to the PFS data in Cox models containing log 2 (p95HER2) or log 2 (HER2). Both variables correlated with longer PFS.Conclusions: Increasing HER2 protein expression correlated with increased benefit of adding lapatinib to trastuzumab. HER2 expression is a stronger predictor of pCR and PFS than p95HER2 for response to lapatinib, trastuzumab and, more significantly, LþT.

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“…Antibodies directed towards HER2, such as trastuzumab, cannot bind in the absence of the ECD. Several retrospective analyses of HER2 positive breast cancer found that increased p95HER2 expression correlated with resistance to trastuzumab therapy and poor survival [19,20]. Preclinical in vitro and in vivo studies demonstrated that p95HER2 exhibited kinase activity that induced tumor proliferation that was resistant to trastuzumab therapy [18,19,21].…”

Section: Introductionmentioning

confidence: 99%

HER2 over-expressing high grade endometrial cancer expresses high levels of p95HER2 variant

Growdon

Byron

DiGloria

et al. 2015

Gynecologic Oncology

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Background-Subsets of high grade endometrial cancer (EnCa) over-express HER2 (ERBB2), yet clinical trials have failed to demonstrate any anti-tumor activity utilizing trastuzumab, an approved platform for HER2 positive breast cancer (BrCa). A truncated p95HER2 variant lacking the trastuzumab binding site may confer resistance. The objective of this investigation was to characterize the expression of the p95HER2 truncated variant in EnCa.

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Quantitative Measurements of Tumoral p95HER2 Protein Expression in Metastatic Breast Cancer Patients Treated with Trastuzumab: Independent Validation of the p95HER2 Clinical Cutoff

Cited by 30 publications

References 18 publications

The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer

The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer

High HER2 Expression Correlates with Response to the Combination of Lapatinib and Trastuzumab

HER2 over-expressing high grade endometrial cancer expresses high levels of p95HER2 variant

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