P95 HER2 fragments and breast cancer outcome

Abstract

HER2 is a 185-kDa transmembrane oncoprotein encoded by the HER2 gene. It is located on chromosome 17q21 and is overexpressed in approximately 15% of invasive breast cancers. In addition, it is a poor prognostic factor for survival and disease progression. Approximately 30% of HER2-positive tumors also express a series of carboxy-terminal HER2 fragments known as p95HER2, in addition to the full-length HER receptor. Previous studies have found that p95HER2 represents an independent prognostic marker in patients with HER2-positive disease. Moreover, p95HER2 status might be a decisive factor when choosing between different therapies because p95HER2 fragment-positive tumors are resistant to trastuzumab but respond to tyrosine kinase inhibitors, such as lapatinib, as do p95HER2-negative tumors. p95HER2 fragments arise through at least two different mechanisms: proteolytic shedding of the full-length p185HER2 receptor extracellular domain and translation of HER2 mRNA from internal initiation codons. The present review is based primarily on recent studies suggesting p95HER2 constitutes a new surrogate marker for an aggressive HER2-positive breast cancer subtype with distinct clinical and biological features.

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

“…2). This CTF are yielded through at least two different mechanisms: proteolytic shedding of the extracellular domain of the full-length HER-2 receptor or translation of HER-2 mRNA from alternate internal initiation codons (positions 611 and 678, respectively) [65,66]. Strikingly, in vitro studies of 611-CTF (100-115 kD) revealed more rapid activation of multiple signalling pathways to promote tumour progression when compared with the full length receptor and 648-CTF [67].…”

“…p95HER-2 is hyperactive and has been demonstrated to play a role in cancer progression, increased metastasis, poor prognosis and disease-free survival when compared with patients that express the wild full-length HER-2 [65,68]. Approximately 30% of HER-2-positive tumours express this HER-2 fragment [66]. The specific characteristic of p95HER-2 is still unclear, but the overexpression of p95HER-2 can promote the growth of tumour via forming homodimers by intermolecular disulfide bonds in subdomain IV, similar to dimers formed in extracellular domain mutations [69,70].…”

Role of HER2-Related Biomarkers (HER2, p95HER2, HER3, PTEN, and PIK3CA) in the Efficacy of Lapatinib plus Capecitabine in HER2-Positive Advanced Breast Cancer Refractory to Trastuzumab

“…P95HER2 is expressed in up to 30% of HER2-positive breast cancers and is correlated with increased nodal metastasis and shorter DFS [20,21,22]. In our study cohort, more than half (56.3%) of the tumors refractory to Tmab therapy showed a high expression of p95 VeraTag assay.…”

Clinical Implications of Compounds Designed to Inhibit ECM‐Modifying Metalloproteinases

“…The p95 fragment is also an indicator of poor prognosis and survival. [106] INCB7839 in combination with trastuzumab improved the response rate and overcame trastuzumab resistance in the p95 positive HER2 positive subpatient population. The combination has been generally safe and well tolerated with deep vein thrombosis occurring in a significant number of patients.…”

“…The p95 fragment is a constitutively active portion of HER2 left behind on cells once HER2 is cleaved, and its presence leads to trastuzumab resistance. The p95 fragment is also an indicator of poor prognosis and survival . INCB7839 in combination with trastuzumab improved the response rate and overcame trastuzumab resistance in the p95 positive HER2 positive sub‐patient population.…”