Commentary by Jon-Emile Kenny MD, PGY- 2
Please also see the clinical vignette presented before last week’s grand rounds.
Medical grand rounds on November 12, 2008 was given by Dr. Jose Baselga, MD. His lecture, ‘Advances in the Therapy of HER2 Positive Breast Cancer’ highlighted the biochemical aspects of HER receptors and the current and future pharmacological implications thereof.
Roughly one in four breast cancers are HER2 receptor positive. Phenotypically, these cancers tend to present as locally advanced tumours at an earlier age. There are 4 subsets of HER receptors that may form homo- or heterodimers on the cell surface, and this is required for cell signaling. HER receptors follow the common biochemical motif whereby receptors on the outer cell surface act as an ‘input layer’ and stimulation conducts as message via a signal cascade within the cytosol; this is the ‘signal processing layer.’ The final result is the regulation of gene transcription within the nucleus.
When HER2 is amplified on the cell surface, a pro-cancerous cellular milieu is established. This is seen with other proteins, typically oncogenes, in other malignancies and it can be detected by fluorescence in situ hydridization (FISH).
About 20 years ago, researches began to target the HER2 receptors with trastuzumab, an antibody that binds to the HER2 receptor near its insertion into the plasma membrane. This resulted in an increase in the median survival of patients with HER2 positive breast CA from 18 to 27 months. Of further note, the NOAH trial showed that trastuzumab can be used effectively as a neo-adjuvant chemotherapy and subgroup analysis of those with inflammatory breast CA found significant response as well.
As cardiac myocytes also express HER2 receptors as a survival pathway, the toxicity imparted by anthracyclines is pronounced when used in conjuntion with anti-HER2 therapies. One potential solution to this side-effect is the use of liposomal doxorubicin.
More recently, novel therapies such as lopatinib which is an oral, small molecule that binds to the intracellular tyrosine kinase aspect of HER2 receptors has shown improved time to progression in HER2 breast cancers and this is true even when a patient has had progression of disease while on trastuzumab.
Another promising HER2 therapy is the antibody pertuzumab which targets the HER2 dimerization site. Pertuzumab is a much more potent HER2 antagonist than trastuzumab in vitro and there is hope that adding the two therapies together will work synergistically.
Cellular chaperones reside within the cytosol and endomembrane system; they aide in protein maturation as they make protein folding more thermodynamically favorable. One such chaperone is Heat Shock Protein 90 (HSP 90) and it helps HER2 take shape within the endoplasmic reticulum. HSP 90 inhibition with 17-AAG, a novel chemotherapeutic, can abolish HER2 expression.
A common concern is that of HER2 resistance after administration of HER2 antagonists. The mechanism of this phenomenon is likely gain of function mutations in down-stream oncogenes within the ‘signal processing layer.’ Two such examples are PTEN and PI3 Kinase. Consequently, compounds directed against these, and other proteins in the transduction cascade are underway.
The lecture was ended with a new way of approaching patients with HER2 positive breast CA. With the aforementioned advances in our understanding of HER2 biochemistry, and clinical trials showing benefit when therapies are started early, it behooves both patients and physicians to move away from the old doctrine of using novel therapies only in those with advanced disease. Instead, Dr. Baselga argues, we should use original chemotherapeutics early and synergistically and that such a ‘neoadjuvant model’ would both enlighten our understanding of the basic sciences and optimize survival in patients with HER2-positive breast cancer.