p95Her2 a (nasty) subgroup of her2

[fullofbeans]

It's not new but I cannot recall hearing about this sub group before.. The variation in the responses to herceptin treatment is dramatic..


Expression of p95HER2, a Truncated Form of the HER2 Receptor, and Response to Anti-HER2 Therapies in Breast Cancer
2007.
Abstract

Background Women with HER2–overexpressing breast cancers have poor prognosis, and many are resistant to the HER2 monoclonal antibody trastuzumab. A subgroup of HER2–overexpressing tumors also express p95HER2, an amino terminally truncated receptor that has kinase activity. Because p95HER2 cannot bind to trastuzumab but should be responsive to the HER2 tyrosine kinase inhibitor lapatinib, we compared the sensitivity of tumors expressing p95HER2 and tumors expressing the full-length HER2 receptor to these agents.

Methods MCF-7 and T47D breast cancer cells were stably transfected with either full-length HER2 or p95HER2. We studied the effects of trastuzumab and lapatinib on receptor signaling, cell proliferation, and the growth of xenograft tumors. A paraffin-based immunofluorescence assay was developed to study the association between p95HER2 expression and sensitivity to trastuzumab in patients with advanced breast cancer. All statistical tests were two-sided.

Results Treatment of p95HER2–expressing cells with lapatinib inhibited p95HER2 phosphorylation, reduced downstream phosphorylation of Akt and mitogen-activated protein kinases, inhibited cell growth (MCF-7p95HER2 clones, lapatinib versus control, mean growth inhibition = 57.6% versus 22.6%, difference = 35%, 95% confidence interval [CI] = 22.5% to 47.3%; P<.001; T47Dp95HER2 clones, lapatinib versus control, mean growth inhibition = 36.8% versus 20%, difference = 16.8%, 95% CI = 11.3% to 22.3%, P<.001), and inhibited growth of MCF-7p95HER2 xenograft tumors (lapatinib versus control, mean = 288.8 versus 435 mm3, difference = 146.2 mm3, CI = 73.8 to 218.5 mm3, P = .002). By contrast, treatment with trastuzumab had no effect on any of these parameters. Of 46 patients with metastatic breast cancer who were treated with trastuzumab, only one of nine patients (11.1%) expressing p95HER2 responded to trastuzumab (with a partial response), whereas 19 of the 37 patients (51.4%) with tumors expressing full-length HER2 achieved either a complete (five patients) or a partial (14 patients) response (P = .029).

Conclusions Breast tumors that express p95HER2 are resistant to trastuzumab and may require alternative or additional anti-HER2–targeting strategies.

[radiant]

Thank-you for posting this. Does anyone know how I, as a bc patient, can get the testing done to determine if I have this expression, p95HER2, and to learn what the condition of my p53 and other very important dna aspects of my cancer are?

I heard someone on TV, during a baseball game (oddly), that somewhere in Santa Clara, CA you can get testing to identify all the dna of your cancer? I don't know how to start this process. It seems REALLY important info, rather than continually getting blasted.

thanks!

Kim

[Rich66]

Access to the tests used tends to be a limiting factor in making use of research like this. In this case, really just one more reason to combine herceptin and Tykerb (and metformin)..until other drugs get approved.

[Jackie07]

Cancer Res. 2011 Mar 1;71(5):1515-9. Epub 2011 Feb 22.
p95HER2 and breast cancer.

Arribas J, Baselga J, Pedersen K, Parra-Palau JL.
Source

Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. jarribas@vhio.net

Abstract

A subtype of HER2-positive tumors with distinct biological and clinical features expresses a series of carboxy-terminal fragments collectively known as p95HER2. One of these fragments, named 100- to 115-kDa p95HER2 or 611-CTF, is hyperactive because of its ability to form homodimers maintained by intermolecular disulfide bonds.

Despite lacking the majority of the extracellular domain, this HER2 fragment drives breast cancer progression in vivo. The recent availability of specific anti-p95 antibodies has confirmed previous results indicating that the expression of p95HER2 is predictive of poor prognosis and correlates with resistance to the treatment with trastuzumab, a therapeutic antibody directed against the extracellular domain of HER2.

ps. Another link listing drugs targeting this expression - not sure if they are in the market yet:
http://www.biocompare.com/ProductLis...557157&sb=true