mAb's cardiotoxicity: why? And who cares?

This study shows that Trastuzumab (Herceptin) raises risk of heart failure.

The risk of either heart failure or cardiomyopathy was highest in those women who received either trastuzumab alone or in combination with anthracycline. Women given trastuzumab alone had a four-fold increased risk of heart failure or cardiomyopathy compared to those who received no chemotherapy (adjusted hazard ratio [HR] of 4.12). Those who were treated with a combination with anthracycline had a seven-fold higher risk of cardiomyopathy or heart failure (adjusted HR of 7.19).

And look: the same sh...t was with another mAb - Avastin! I would like to ask the question once again: how in the world “targeted” monoclonal antibody as Herceptin could be cardiotoxic? Why it is cardiotoxic?  

The mechanism of action of this mAb is following:

Trastuzumab (INN; trade name Herceptin) is a monoclonal antibody that interferes with the HER2/neu receptor. Its main use is to treat certain breast cancers.

The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell to inside the cell, and turn genes on and off. The HER proteins regulate cell growth, survival, adhesion, migration, and differentiation—functions that are amplified or weakened in cancer cells. In some cancers, notably some breast cancers, HER2 is over-expressed, and causes breast cells to reproduce uncontrollably.

Antibodies are molecules from the immune system that bind selectively to different proteins. Trastuzumab is an antibody that binds selectively to the HER2 protein. When it binds to defective HER2 proteins, the HER2 protein no longer causes cells in the breast to reproduce uncontrollably. This increases the survival of people with cancer. However, cancers usually develop resistance to trastuzumab.

The key words here are “Trastuzumab is an antibody that binds selectively to the HER2 protein”. Something is disconnected in this scheme. I would guess that the cardiotoxicity comes from non-selectivity of binding – there are thousands of thousands other different receptors which can be affected by this mAb. Or HER2 protein inhibition by itself is responsible for the toxicity. Who knows? Who cares? The medicine is blockbuster – and this is of the greatest importance!