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HER 2 Positive Mutations Explained

HER 2 is a “Human Epidermal Growth Factor Receptor”

Know your Mutations

Knowing your mutations could save your life. Has your oncologist organised an IHC test and or a Molecular Profile of your tumor? Knowing your exact mutations gives you a road map that will match your tumor type to all available immunotherapy treatments globally.

About this page

This articles content is divided into 3 short sections that will help you gain a better understanding, a patient to patient discussion on what has been learned. It is a very basic starting point for the newly diagnosed patient and their support community.

WHAT | PROBLEM | ANSWER [1/3]

What is HER 2

Human
Epidermal growth factor
Receptor
2

The HER Pathway
Growth Factors are messages, they follow a pathway from the outside of the cell to the inside, this is called the HER Pathway.

About HER

  • Growth factors are messages – proteins secreted by the body’s tissues and sent to the cells with instructions to grow and divide. Growth factor signalling is just one part of the body’s communication system.
  • Receptors are structures on the cell surface that receive the body’s messages. Receptors are responsible for bringing the messages from outside of the cell into the inside of the cell. The message then travels to the nucleus (center) and instructs the cell to grow and divide.
  • HER genes are located within the cells nucleus. These genes are responsible for creating the “HER” receptors on the cell surface.

The HER Family
‘HER 1’, ‘HER 2’, ‘HER 3′ & ,’HER 4’
Two HER Receptors must combine, before a signal can enter the cell.

  • HER receptors must pair or bind with another, ie HER 2 and HER 3 before a growth factor (message) can be received.
  • This pairing/binding is called ‘Dimerization.’
  • Any HER combination is possible – but it has been observed that when HER 2 & HER 3 dimerization occurs, it creates the most powerful pathway.

WHAT | PROBLEM | ANSWER [2/3]

Explaining how HER 2 mutates

It has been observed that some cells can have too many copies of the HER 2 gene within its nucleus, this can cause an over expression of receptors on the cells surface. More receptors on the cell surface, creates more growth factor message /signals passing into the cells nucleus.

  • This increase in messages /signals, cause the Cells to grow and divide to quickly.
  • This creates cell overgrowth and new cells are still immature when they divide – they become mutated.
  • Mutated cells cluster and can become cancerous.

Mutated Cells are now HER Positive

This image outlines it very well

WHAT | PROBLEM | SOLUTION [3/3]

Immunotherapy’s fix for HER 2

  • Immunotherapy drugs are designed in a laboratory.
  • One type of Immunotherapy drug is called monoclonal, meaning it is designed to perform one task only.
  • Laboratories have designed “Monoclonal Antibody drugs (immunotherapies). They extract healthy antibodies from the patient and place them into a petri dish, where they train the antibodies to identify a target.
  • Antibodies are the immune systems scouts who lock onto any foreign threat and signal back to the immune system for destruction.
  • Laboratories have learnt to use antibodies to interfere /block the HER 2 pathway.
  • HER 2  monoclonal antibodies (Y shaped) have been trained to locate and lock onto the HER 2 receptors, thus blocking the pathway.
  • When the antibodies have been trained they are grown in the millions (3 weeks) and reintroduced into the patient intravenously.

The science is that when the monoclonal antibodies attach to the HER 2 receptor, growth factors /signals cannot enter the cell, therefore starving the mutated cell. This treatment has been very successful in Breast Cancer patients but less successful in other cancer types such as Lung or Pancreatic. There are many more ongoing trials to develop this more successfully across a wider range of cancer groups.

Note – Cells have many different types of proteins on their surface, some can be receptors and others will be antigens (the cells ID expression) Antibodies would not normally lock onto a cells receptor.

More HER 2 Specific

The human epidermal growth factor receptor 2. A protein involved in normal cell growth. Human epidermal growth factor receptor 2 may be made in larger than normal amounts by some types of cancer cells, including breast, ovarian, bladder, pancreatic, and stomach cancers. This may cause cancer cells to grow more quickly and spread to other parts of the body. Checking the amount of human epidermal growth factor receptor 2 on some types of cancer cells may help plan treatment. Also called c-erbB-2, HER2, HER2/neu, and human EGF receptor 2.

Source: National Cancer Institute

This section will be updated periodically – Do you know of an article that we should include ?
Please add the link into the comments section of this article.


Chemotherapy, Trastuzumab, and Pertuzumab in Early HER2-Positive, Node-Positive Breast Cancer: Six-Year Follow-up of APHINITY Trial

By The ASCO Post Staff
March 10, 2020 – Supplement: Conference Highlights SABCS 2019
READ MORE 


Phase II DESTINY-Breast01: T-DXd Effective in Pretreated, Metastatic HER2-Positive Breast Cancer

By The ASCO Post Staff
March 10, 2020 – Supplement: Conference Highlights SABCS 2019
READ MORE 


Chemotherapy, Trastuzumab, and Pertuzumab in Early HER2-Positive, Node-Positive Breast Cancer: Six-Year Follow-up of APHINITY Trial

By The ASCO Post Staff
March 10, 2020 – Supplement: Conference Highlights SABCS 2019
Read Article


The art of innovation:
“clinical development of trastuzumab deruxtecan are redefining how antibody-drug conjugates target HER2-positive cancers”Read More


Mayo Clinic Explains 
“HER2-positive breast cancer is a breast cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells”Read More

Pathway

Safety Profile of Durvalumab

More Explantions

Antibodies

Antibodies are large Y-shaped proteins that the immune system produces to stop intruders /threats from harming the body. All cells have different proteins on their surface, which are known as antigens. Antibodies bind (stick) to antigens on cells that don’t belong in your body.

Monoclonal Antibodies

Monoclonal Antibodies are clones of the patients antibodies that are grown in the laboratory and trained to recognise a single target of a cancerous cell. These cloned antibodies are then reintroduced into the patients and immediately seek out their target.

Targets can be any protein/antigen on the cell surface, such as foreign unfriendly antigens or a cells growth receptor.


Image Source Lymphoma-action org uk

Cancer Research UK
This video from Cancer Research UK shows how monoclonal antibodies work. Some monoclonal antibodies (MABs) work by seeking out cancer cells that have too many growth factor receptors. The MABs block the receptors so the cancer cell can't receive the signal to grow.

For more information visit https://www.cancerresearchuk.org/abou...

Antigens

Cancer Cells produce Antigen substances on their surface.

Cells present substances on their surface called antigens, if these antigens are foreign or a threat, this will cause an immune response in the body by identifying the substances on cells as friendly or harmful. If it is deemed to be harmful or a foreign threat, the immune system produces and dispatches antibodies (Y shaped proteins) to engage (bind) and mark them for the immune T Cells to locate and destroy.


Image Source:
https://microbenotes.com/introduction-to-antigen/

human epidermal growth factor receptor 2
Source – NCI 
A protein involved in normal cell growth. Human epidermal growth factor receptor 2 may be made in larger than normal amounts by some types of cancer cells, including breast, ovarian, bladder, pancreatic, and stomach cancers. This may cause cancer cells to grow more quickly and spread to other parts of the body. Checking the amount of human epidermal growth factor receptor 2 on some types of cancer cells may help plan treatment. Also called c-erbB-2, HER2, HER2/neu, and human EGF receptor 2.

Test – IHC

Immunohistochemistry Test (IHC)


EVERY PATIENT SHOULD HAVE THIS TEST IMMEDIATELY POST BIOPSY.

This is a quick test on solid tumors if a biopsy / tissue sample is available. 
What the lab are looking for are 2 markers that match current immunotherapy options. 

  1. Does your biopsy finding show PD-L1 on the tumor surface
  2. Does your Biopsy show MSi - High (Microsatellite Instability High) or dMMR

These 2 factors are key ingredients for patient qualification/access to (ICI) Immune Checkpoint Inhibitor Immunotherapy treatments. This treat provides drugs that can interfere with what is going wrong, and unmask the tumor that is hiding behind the PD-L1. MSi-High is a factor because it is more likely that a patient has a higher PD-L1 presence and a higher volume of mutation which makes it more identifiable for the T Cells to locate them.

IHC DETAILS.

  • Cost: Typically Inexpensive <$500.00
  • Time Frame: 3 – 5 Days
  • Biopsy tissue or brushing samples are tested – Brushing’s of a suspected tumour are often obtained in a ECRP investigative procedure.
  • This type of testing is often done “in house” providing valuable efficiency to discover vital information that influences treatment planning.
  • PD-L1 Expression
  • MSI-high which is identified by examining the MMR (Mismatch Repair)
  • MMR or dMMR – Mismatch repair status. “d” means deficient – absent 1 or more of MMR’s proteins.
  • MSI-high means 2 or more of the MMR proteins are absent. If one of those proteins is MLH1 then …
  • MLH1 investigation further establishes if there is a BRAF V600E mutation -This is common and typically confirms mutations origin as “Sporadic”
  • “Germline” is Heriditary or “Sporadic” is Epigentic/environmental, higher chance of Lynch Syndrome This helps your oncologist to know how to proceed.
  • BRAF is a gene that produces the B-Raf protein that sends signals within the cells to direct cell growth.

Next Generation Sequencing


NGS - or Molecular Profiling is both Genetic (Inherited) and Genomic (acquired) profiling of your DNA. You should always include the (IHC) immunohistochemistry test for PD-L1 & MSi-High within this. This often has to be highlighted as required.

Details 

  • Costs: Approximately $ 5000.00
  • Time frame: 3 Weeks
  • Specialised Laboratory
  • Provides a blueprint of what’s going on in a tumor. A Tumor Blueprint, for your Oncologist to help make more informed choices based on the genomic landscape inside the tumor.
  • Definition: Genomic Testing: Is more the epigenetic impact examination of the Genes and DNA mutations that are present and unique in a tumor and driving the growth of the cancer.
  • Definition: Genetic Testing: Examines the hereditary Genes that have been present since birth.

Helpful note:
You may see the term dMMR (deficient MisMatch Repair) when researching MSi-h and become confused.
dMMR creates the MSi environment.
MMR is your bodies DNA repair shop - it fixes the mistakes as they occur. If this does not happen then it is described as dMMR.

MMR has 4 repair worker genes that fix the mistakes. If all 4 repair worker genes are at working correctly, then this is termed MSS (Microsatellite Stable), if one is absent then this is often referred to as MSi-low, if two or more are absent this is referred to as MSi-High.

An MSi-High environment means your body is now producing a high volume of DNA sequence mistakes. If these mistakes go unrepaired they often create a higher volume of tumors. A higher volume is bad but also good with new immunotherapy drugs  - why? because the higher volume is more visible as a target.