Validation of p95 as a predictive marker for trastuzumab-based therapy in primary HER2-positive breast cancer: A translational investigation from the neoadjuvant GeparQuattro study.

Loibl, Sibylle; Bruey, Jean Marie; Minckwitz, Gϋnter von; Huober, Jens; Press, MF; Darb‐Esfahani, Silvia; Solbach, Christine; Denkert, Carsten; Tesch, Hans; Holms, Frank; Fehm, T; Mehta, Keyur; Untch, Michael

doi:10.1200/jco.2011.29.15_suppl.530

Cited by 36 publications

(30 citation statements)

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“…Recently, a different p95 immunohistochemical assay was assessed in patients administered neoadjuvant trastuzumab in the GeparQuattro study (16). This assay used a different antibody and at a concentration high enough to give 82% p95 positivity, using a cutoff of 20% strong staining, among those that were HER2 positive by silver in situ hybridization.…”

Section: Discussionmentioning

confidence: 99%

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

Duchnowska

Sperinde

Chenna

et al. 2014

Clinical Cancer Research

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Purpose: P95HER2 (p95) is a truncated form of the HER2, which lacks the trastuzumab-binding site and contains a hyperactive kinase domain. Previously, an optimal clinical cutoff of p95 expression for progression-free survival (PFS) and overall survival (OS) was defined using a quantitative VeraTag assay (Monogram Biosciences) in a training set of trastuzumab-treated metastatic breast cancer (MBC) patients.Experimental Design: In the current study, the predictive value of the p95 VeraTag assay cutoff established in the training set was retrospectively validated for PFS and OS in an independent series of 240 trastuzumab-treated MBC patients from multiple institutions.Results: In the subset of 190 tumors assessed as HER2-total (H2T)-positive using the quantitative HERmark assay (Monogram Biosciences), p95 VeraTag values above the predefined cutoff correlated with shorter PFS (HR ¼ 1.43; P ¼ 0.039) and shorter OS (HR ¼ 1.94; P ¼ 0.0055) where both outcomes were stratified by hormone receptor status and tumor grade. High p95 expression correlated with shorter PFS (HR ¼ 2.41; P ¼ 0.0003) and OS (HR ¼ 2.57; P ¼ 0.0025) in the hormone receptor-positive subgroup of patients (N ¼ 78), but not in the hormone receptor-negative group. In contrast with the quantitative p95 VeraTag measurements, p95 immunohistochemical expression using the same antibody was not significantly correlated with outcomes.Conclusions: The consistency in the p95 VeraTag cutoff across different cohorts of patients with MBC treated with trastuzumab justifies additional studies using blinded analyses in larger series of patients. Clin Cancer Res; 20(10); 2805-13. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

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

Duchnowska

Sperinde

Chenna

et al. 2014

Clinical Cancer Research

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“…Looking at the p95HER2-positive rates in these studies, the values were 74% in the GeparQuattro study (23), 30.7% in the CHER-LOB study (24) and 27.5% in the VeraTag™ assay (25). Although a difference was found between the early breast cancer and recurrent patients regarding the p95HER2 assessment, there was no constant trend, and there are a number of questions that remain to be solved.…”

Section: Discussionmentioning

confidence: 84%

“…There were studies on IHC for p95HER2 that were presented at the annual meeting of the American Society of Clinical Oncology held in 2011. Although p95HER2 was suggested to be a marker of resistance to T, in the neoadjuvant study by Loibl et al (23), there was a significantly higher rate of pathological complete response (pCR) by T treatment in cases that expressed p95HER2. In this study, the 611CTF monoclonal antibody (bioMérieux, Inc.) was used.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of PTEN loss and PIK3CA mutations and their correlation with efficacy of trastuzumab treatment in HER2-positive metastatic breast cancer: A retrospective study (KBC-SG 1001)

Nishimura

Arima

Toyoshima

et al. 2012

Molecular and Clinical Oncology

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Abstract. Trastuzumab (T) has contributed to improving the prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Although some patients have been unresponsive or resistant to T. Loss of phosphatase and tensin homolog (PTEN) deleted on chromosome 10, PIK3CA mutation and p95HER2 expression have been reported to potentially be responsible for the poor response to T. This is a small-scale pilot study to be followed by a large-scale investigation examining the association between the biomarkers and clinical response. Based on the response to T, patients were divided into 3 groups in terms of progression-free survival (PFS): PFS >8 months (group A, n=15), 3-8 months (group B, n=7) and PFS <3 months (group C, n=11). PTEN protein expression was detected by immunohistochemistry and PIK3CA mutation by direct sequencing. The median age was 61, 60 and 47 years in groups A, B and C, respectively,

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“…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: 93%

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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Validation of p95 as a predictive marker for trastuzumab-based therapy in primary HER2-positive breast cancer: A translational investigation from the neoadjuvant GeparQuattro study.

Cited by 36 publications

References 0 publications

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

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

Evaluation of PTEN loss and PIK3CA mutations and their correlation with efficacy of trastuzumab treatment in HER2-positive metastatic breast cancer: A retrospective study (KBC-SG 1001)

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

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