For those with Inflammatory BC - another reason to love Tykerb

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New Hopes and Directions in IBC Therapy: Part 1: IBC, HER2 and TKIs

Recent Breakthroughs

• From systematic review, it is known that preclinical and clinical studies suggest that the TKI (tyrosine kinase inhibitor) agent lapatinib (Tykerb) is particularly effective against inflammatory breast cancer, as recently found by the independent teams of Spector and colleagues and Burns and colleagues.
  
  In this connection therefore, although formerly often classified as the sphinx of breast cancer types, my systematic review found that IBC is recently becoming both less enigmatic and more effectively treatable with improved survivability. One major clue to optimizing therapies is the discovery of the high incidence of HER2-overexpression in IBC patients: whereas in the general population, HER-2 is over-expressed in around 25% of human breast cancers, more than double (52%) of that number of IBC patients are HER2-positive, suggesting that early HER-2 directed therapy as a part of multimodal IBC treatment may improve outcome.
  
  These findings have been most recently confirmed and extended to apply to a clinical treatment strategy, by Spector and colleagues, as reported at the June 2006 ASCO Annual Meeting, who assessed (in a phase II clinical trial) response rates to lapatinib (Tykerb) monotherapy in patients with relapsed or refractory IBC.

Understanding TKIs (Tyrosine Kinase Inhibitors)

• Lapatinib (Tykerb) is known as a dual EGFR/HER2 TKI, that is a dual action tyrosine kinase inhibitor (TKI). Tyrosine kinases are enzymes within the cell and part of a complex signaling system that transfers information from the outside of the cell into the nucleus, with cells responding to the incoming information in a variety of ways, one of the most basic being to live or die. This is how cells react to molecular cues, such as hormones and growth factors that bind to receptors on the cell surface. The essence of tyrosine kinase is to attach phosphate groups to the well-known and essential amino acid tyrosine, a process known as phosphorylation.
  
  Now, one major means by which cancer cells sustain their excessive proliferation is via to mutations in genes that code for signaling proteins like tyrosine kinase. It's much like that these mutations result in a continual "on" signal for cell proliferation, and when this occurs, the signaling cascade (set of related processes) acts as a survival mechanism for the cancer cell allowing the tumor cells to grow / proliferate out of control, usually resulting in highly aggressive tumor cells often resistant to standard forms of chemotherapy.

Using TKIs to Stop Tumor Cell Proliferation

• Because the phosphorylation of tyrosine process triggers the signaling cascade that provides tumor cells with a survival mechanism, tyrosine kinase inhibitors (TKIs) have been developed to turn the cell growth "on" signal that allows for proliferation to the "off" position. These TKIs cause rapid tumor cell death by virtue of the cancerous survival mechanism being deactivated for tumors that use tyrosine kinase signals to maintain constant proliferation. Evidence has accumulated that certain leukemias, as well as cancer of the breast, prostate, ovary, bladder, liver, and lung are categories of tumors that may be successfully treated with these TKIs.
  
  One of the exciting benefits of using TKIs in cancer therapies is that they can be directed to kill tumor cells while not harming healthy cells, because cancerous cells are dependent on uninterrupted signaling from tyrosine kinases telling them to continue to proliferate rather than die, but non-cancerous cells only use these signals rarely and in highly specialized case, so the normal cells remain unaffected, making TKIs highly "targeted" interventions in breast and other cancers through their ability to interfere with cell communication that would otherwise allow tumor proliferation.

Clinical Findings

• What Spector and colleagues found is that among the women with ErbB2 (aka, HER2) overexpression, 62% experienced a partial response from lapatinib (Tykerb) monotherapy, with a much lower response rate among women without ErbB2 overexpression, but still some response. A 62% response rate is one of the highest ever documented in any cancer therapy and for any kind of cancer. And adverse events were mild, with GI and skin toxicity being the most commonly observed.
  
  And we know from earlier findings of Storniolo and colleagues reported at the 2005 ASCO annual meeting that the combination of lapatinib (Tykerb) + trastuzumab (Herceptin) in Her2 overexpressing MBC (metastatic breast cancer) patients resulted in an impressive 33% (16 patients) experiencing either objective response (8 patients, with one complete response), or disease stabilization (8 patients) lasting at least 6 months.

Clinical Benefit Summary

• The takeaway point therefore is that the TKI agent lapatinib (Tycerb), either as monotherapy or in a combination regimen with trastuzumab (Herceptin) yields extraordinarily high response levels and/or prolonged disease stabilization, all with a highly favorable tolerability profile, even yielding partial responses in patients with trastuzumab-resistant breast cancers.

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Constantine Kaniklidis
Medical Researcher in EBM (Evidence-based Medicine)
European Association for Cancer Research (EACR)
Breast Cancer Watch
Breast Cancer Prevention Watch
IBC Watch
edge@evidencewatch.com