About HER2 and lung cancer
If you have non-small cell lung cancer (NSCLC) and your doctor told you that you have the HER-2 biomarker, this site will help you understand what your diagnosis means and how it impacts your treatment options. Use this information to help you talk with your doctor to decide the best treatment options for you.

What is a biomarker?
A biomarker is a substance that doctors can measure in tissue, blood, or other body fluids like spit. Biomarkers can be a sign that there are changes (mutations) in a cell’s genes (building blocks of a cell’s DNA) that are causing the cancer to grow. These mutations are called “driver mutations” because they cause (or “drive”) cancer to grow. Other types of lung cancer biomarkers include gene amplifications (too many copies of a gene) and gene overexpressions (too much protein on the cell). Changes in the DNA that affect how the cell behaves are sometimes called “alterations”.

What is HER2?
HER2 (also known as ERBB2) stands for Human Epidermal Growth Factor Receptor 2. HER2 is a gene that builds proteins that live on the surface of a cell. It acts as a signaling receptor in the cell, which means it joins with certain molecules and sends messages to the cell. It belongs to the “tyrosine kinase" family of signaling receptors. This is a large group of proteins that help control cell growth. Another biomarker called EGFR is in the same family of signaling receptors.

What causes HER2 alterations in NSCLC?
The HER2 gene naturally occurs in the body and helps control cell growth. However, some people “acquire” HER2 errors. That means you are not born with or inherit HER2 abnormalities. Researchers are investigating what causes some people to develop problems with HER2—right now it is not entirely clear. More research is needed.

How do problems with HER2 turn into lung cancer?
There are a few ways errors in the HER2 gene can lead to uncontrolled cell growth and cause cancer. If you have one of the errors listed below, you have what is referred to as “HER2-altered lung cancer.”

  1. Mutations or errors in the HER2 gene can change the genetic information (like introducing spelling mistakes into a sentence). The most common type of mutation in HER2-altered NSCLC is a type of insertion in the exon 20 region of the gene. 
  2. There can be an increase in the amount of HER2 protein on the cell surface (called “overexpression”). In lung cancer, HER2 overexpression is usually caused by polysomy, which is too many copies of a chromosome (chromosome 17, specifically). 
  3. There can be too many copies of the HER2 gene (called “amplification”). This can lead to overexpression in some cases.

Can I have HER2 and other gene mutations like EGFR or ALK?
HER2 mutations are usually mutually exclusive with other driver mutations like EGFR, ALK, or ROS1. This means if you have one type of gene mutation that is causing lung cancer, you probably do not have another.

But, you can have another mutation and HER2 protein overexpression. Patients with other types of gene mutations may be tested for HER2 protein overexpression, especially if their cancer continues to grow despite treatment.

Who gets HER2-altered NSCLC?
HER2 lung cancer mutations tend to occur in the adenocarcinoma subtype of lung cancer. They are more common in people who have never-smoked, and the majority of patients are female. About 2-4% of all lung cancer patients have HER2 mutations.  

HER2 overexpression in NSCLC is fairly common, affecting between 2% to 38% of lung cancer patients. This wide range is likely due to pathologists using different ways to measure the amount of HER2 protein present. There have been recent efforts to make HER2 overexpression more standardized.

In NSCLC, about 2-4% of patients have a HER2 amplification. These patients usually have the adenocarcinoma subtype of lung cancer, are male, and have a smoking history.

It is possible for patients to have HER2 mutations, overexpressions, and amplifications at the same time. But having a HER2 mutation doesn’t make you more or less likely to have an overexpression or amplification. Researchers are continuing to explore the role of HER2 in lung cancer.

How do I know if I have HER2-NSCLC? 
There are several techniques doctors use to test for errors in the HER2 gene.

HER2 Gene Mutations
HER2 gene mutations can be found by looking for a large number of gene errors all at once from a tissue sample taken during a biopsy. This is called next-generation sequencing (NGS).

In some cases, physicians may want to search for a specific mutation and use a different laboratory technique like allele-specific PCR (AS-PCR).

NGS is the gold standard and considered “comprehensive biomarker testing.” Talk with your doctor to make sure you’ve received NGS before beginning treatment.

HER2 Protein Overexpression
A laboratory test called immunohistochemistry (IHC) uses staining to detect antibodies (proteins made by the immune system) and find overexpression of HER2. A score is given to the results to show how much of the biomarker is present in the tumor cell. This impacts treatment options.

Possible IHC scores for HER2 NSCLC3:
0 or 1+: Negative, regardless of the number of cells staining,
2+: Equivocal if ≥5 tumor cells exhibit staining; otherwise, negative,
3+: Positive if ≥5 tumor cells exhibit staining; otherwise, negative.

Right now, an IHC score of 3+ has the most bearing on treatment for HER2 overexpression.

HER2 Amplifications
HER2 amplifications are generally detected using a laboratory test called fluorescence in situ hybridization (FISH). Next-generation sequencing can detect HER2 amplifications, but testing is not always routine. Researchers are still exploring the role of HER2 amplifications in treatment decision-making. Right now, testing for HER2 amplifications is usually done for research purposes like clinical trials.


Liquid Biopsy (Circulating Tumor DNA (ctDNA) Analysis)
Sometimes a physician is unable to get a tissue sample from a patient’s lung. A liquid biopsy can detect HER2 mutations and amplifications with a specimen from a simple blood test. Liquid biopsies are still being researched and may not be the right option for every patient. Talk with your doctor about your biomarker testing options.

Learn more about the different types of biomarker testing.


How is HER2-altered NSCLC treated?
HER2 treatment is typically available to NSCLC patients whose cancer has spread outside the lung and surrounding lymph nodes (metastasized) and whose cancer has continued to grow or spread despite treatment with chemotherapy (with or without immunotherapy).

HER2 Mutations
Right now, there are three approved therapies for patients with NSCLC who have a HER2 exon-20-insertion mutation: 

  1. Fam-trastuzumab deruxtecan-nxki (abbreviated T-DXd) (Enhertu®) 
  2. Zongertinib (Hernexeos®) 
  3. Sevabertinib (Hyrnuo®)


These medications each work slightly differently, but they all target the error in the HER2 mutation. For that reason, a patient can start one of these targeted therapies and then eventually switch to the other if there is disease progression or poor side effects.

T-DXd (Enhertu®) is an antibody-drug conjugate (ADC), which is a combination of targeted therapy and chemotherapy.

Zongertinib (Hernexeos®) is a tyrosine kinase inhibitor (TKI), which is a small molecule that specifically targets mutated HER2. 

Sevabertinib (Hyrnuo®) is also a TKI. It blocks HER2 and EGFR at the same time. Blocking both of these biomarkers at the same time may stop the cancer cells from changing and becoming resistant to the medication. This approach may be more effective, but may also cause more side effects. Work closely with your physician to discuss the right treatment option for you. 

Some patients may receive a different targeted drug called ado-trastuzumab emtansine (Kadcyla®), which is approved for breast cancer but can be used in treating HER2 lung cancer mutations.

Enhertu® and Kadcyla® are given through an IV every 21 days. Hernexeos® is a once-daily pill, and Hyrnuo® is a twice-daily pill.
Sometimes a clinical trial is the most appropriate treatment option. In these cases, patients should speak with their doctor about participating in a trial. 


HER2 protein expression 
T-DXd (Enhertu®) is available for patients with advanced-stage lung cancer who have an immunohistochemical (IHC) staining score of 3+. 


HER2 Amplification
Researchers are still working to understand the role of HER2 amplification and if it can be treated in lung cancer patients. Early research has shown that targeted therapies have no benefit in HER2-amplified NSCLC, but more research is needed.

What are some side effects of treatments for errors in HER2?
Side effects of HER2 NSCLC treatments differ by drug and by patient. While taking a medication to treat HER2 lung cancer, it is likely you may experience:

  • Digestive problems like diarrhea and nausea 
  • Rash
  • Fatigue

Your doctor will also perform blood tests to watch for common side effects like:

  • Decreased red and white blood cell counts
  • Increased liver function tests
  • Decreased potassium levels


Some HER2 medications can cause problems with certain organs, and your doctor will monitor you closely to make sure you are not having a severe reaction. 

  • In particular, patients taking zongertinib (Hernexeos®) or ado-trastuzumab emtansine (Kadcyla®) are at higher risk for liver and heart problems. 
  • Patients taking T-DXd (Enhertu®) are at higher risk for interstitial lung disease (ILD) (a group of lung conditions that cause lung swelling and scarring). 
  • Patients taking Sevabertinib (Hyrnuo®) are at a high risk for liver problems and ILD, as well as severe diarrhea. 
    You may experience other side effects while taking a HER2 medication. Talk with your doctor about what to expect and always report side effects to your physician as soon as you experience them.


How long do people with HER2-altered NSCLC take targeted therapy?
People taking targeted therapy for HER2 will generally stay on the medication as long as it is controlling the cancer and the patient can tolerate the medication.

Unfortunately, after an initial positive response, many people with HER2 gene mutations eventually develop drug resistance to the therapy, meaning the drug stops working and their cancer begins to grow and spread again.

In this case, you will likely try another HER2 drug if it is available, and if not, your physician might recommend a clinical trial. 
 

What are other treatment options for HER2-altered NSCLC?
At this time, patients need to have tried chemotherapy with or without immunotherapy before starting a targeted drug to treat a HER2 abnormality. Patients should discuss their treatment options with their doctors and ask about clinical trials.

In some cases, HER2 NSCLC that is caused by a gene mutation may spread to the brain. This is called brain metastases or brain mets. Patients with brain mets may receive brain radiation (either in a few specific spots or the whole brain) or brain surgery to try and remove or kill cancer cells.


What are the most important questions I should be asking about my lung cancer diagnosis?

  • What type and stage is my lung cancer, and do I have any biomarkers?
  • Did I have comprehensive biomarker testing (which includes NGS among other possible tests)—which biomarkers did you check for?
  • What are my treatment options?
  • Do I qualify for a clinical trial testing a new treatment for a HER2 abnormality?
  • What are the possible side effects of these treatments?
  • What should I do if I experience a side effect?
  • What will we do if my treatment stops working?


Tip: Bring someone with you to your appointment to take notes.