Updates on HER2-low breast cancer

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Published: 2 Feb 2023
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Prof Sana Al Sukhun - University of Jordan, Amman, Jordan

Prof Sana Al Sukhun speaks to ecancer about the latest in HER2-low breast cancer. She discusses the latest in HER2-low BC treatment with trastuzumab and the explores the survival outcomes.

Prof Al Sukhun also speaks about antibody-drug conjugates (ADCs) technologies for management of metastatic breast cancer.

Today I will be bringing good news for patients with metastatic breast cancer worldwide. Through understanding the biology of breast cancer, more and more use of molecular oncology, precision oncology, we learned that we can exploit our knowledge of the HER2 receptor, which is a growth factor receptor, it makes tumours grow faster. It used to be a really tough type to tackle until we learned how to use a targeted therapy called Herceptin, more than a couple of decades so far. The history of HER2 positive tumours, indeed, was transformed. Right now we manage to cure patients, hopefully, or at least put them into remission, when they have HER2 positive early breast cancer – not the story more than a couple of decades ago. 

Also, patients with metastatic breast cancer right now survive for years on treatment with anti-HER2 therapy. We have different types that target that subtype. The problem is patients with HER2 positive tumours to benefit from the current treatment armamentarium targeting this subtype, they have to have strong expression of the HER2 receptor, of this growth factor receptor. We used to rely on a methodologic approach or histologic approach to assess the intensity of those receptors on tumour cells using something called immunohistochemistry. Simply put, we looked at the intensity of staining and we graded; only tumours with +3 would benefit from these options. Tumours which scored +2 by the pathologist we go for more sophisticated assessment and look for amplification by a molecular oncology approach called FISH – fluorescent in-situ hybridisation – to look for amplification and increase the copy number of these genes so that we can use targeted therapy. If they have it we can use it, if they don’t we cannot.

The good news we learned right now, we can use a recently developed anti-HER2 therapy that is so good it is engineered not only to tackle the HER2 receptor but also to carry a chemotherapeutic payload which goes directly to the cell that carries the growth factor receptor. Not only does it stay there but it leaks to the surrounding cells so that it, indeed, induces a much better response as compared to targeted therapy that goes only to the tumour cell that carries the HER2 receptor.

Why is that? Because we know that the tumours are not that classic, they are not all carrying the same intensity of growth factor receptor expression. That, indeed, led to resistance because if you only abolish those tumour cells that carry the HER2 receptor, the tumour cells that do not carry enough growth factor receptor, they will not die, they will stay and they will be a source for resistance and recurrence of the tumour. So, by leakage of that chemotherapeutic payload to the surrounding cells you tackle the tumour cells much better than just targeting the tumour cell with the highest intensity of the growth factor receptor expression.

That created a new description of tumour cells in different subtypes. We used to call breast cancer subtypes in the clinic HER2 positive for those with the highest intensity of HER2 receptor expression, triple negative for those that do not have any expression of hormone receptors or HER2 receptors, and hormone receptor positive for those that carry the oestrogen receptor or progesterone receptor. Right now we added another description called HER2-low, meaning that tumour cells that carry a growth factor receptor at an intensity of +1 or +2. Regardless of the subtype – triple negative or hormone receptor positive – they can benefit from the new treatment that targets the HER2 receptor. It’s called in HER2 or scientifically it’s called trastuzumab deruxtecan. It belongs to a new family being widely used right now in oncology called antibody-drug conjugates. The antibody goes directly, it’s a very specific targeted therapy, it goes directly to the cell that carries the HER2 receptor, regardless of the intensity of expression. The conjugate is a chemotherapeutic agent that is carried by the antibody to the target cell and leaks to the surrounding cells, helping to control tumour cells that are, indeed, heterogeneous. Tumour cells are not a copy of each other, that’s why this kind of approach right now is getting more and more favour among oncologists because it ensures better adaptation to the tumour biology. Good news for our patients – we have a new option to target those tumours, including the triple negative breast cancer tumours, including the hormone receptor positive tumours with HER2 low expression. 

Better news is that even those patients who are unfortunate to have brain metastases do benefit from this new approach. All the best for our patients and hopefully every single meeting we can update you about new options to improve outcomes. One more last addition is that it is being used or tested in earlier settings. Right now, it’s only available for patients with metastatic breast cancer. Soon, hopefully, it will transform the approach to patients with earlier stages of breast cancer.