Are you aware of HER2-Negative Breast Cancer? Let's talk!

You've probably heard a lot about breast cancer. But do you really know what this type of cancer is called 'HER2-negative'? It behaves a little differently than some other types of breast cancer, and the treatment may be different. Don't worry, today we'll talk about this `HER2-Negative Breast Cancer` in a simple way that you can understand, okay?

What is HER2-Negative Breast Cancer?

Simply put, `HER2-negative breast cancer` means that the cancer cells in your breast do not have too much or too little of a special protein called `human epidermal growth factor 2 (HER2). Did you know that breast cancer usually develops either because of hormones (especially estrogen and progesterone) or because of this `HER2` protein? For example, in `HER2-positive` breast cancer, the `HER2` protein is present on the surface of the cells, which causes the cancer cells to divide rapidly and form tumors.

But in `HER2-negative` cases, the cancer does not develop because there is too much `HER2` protein. That is, other factors are involved.

When your doctor diagnoses you with breast cancer, they will definitely look for your `HER2` status (i.e., positive or negative). These are the special characteristics of cancer cells, which we call `biomarkers` , and when they are understood correctly, doctors can decide what treatment is most suitable and effective for you. Got it?

What are the main types of HER2-negative breast cancer?

The majority of breast cancers currently diagnosed are of the `HER2-negative` type. There are two main types of this, let's take a look at what they are:

1. Hormone receptor-positive and HER2-negative breast cancer (HR+/HER2-) :

This is the most common type of breast cancer, accounting for about 70 percent (70%) of all breast cancers. In this case, the cancer cells have receptors that are sensitive to either the estrogen hormone (ER+), the progesterone hormone (PR+), or both. Simply put, when these hormones bind to these receptors, the cancer cells start to grow. However, these types of cancers do not have high levels of the HER2 protein. That is why they are called HR+/HER2-.

2. Hormone receptor-negative and HER2-negative breast cancer (HR-/HER2-) :

This type accounts for about 11 percent (11%) of all breast cancers. These cancer cells do not have receptors for either estrogen or progesterone. Also, as mentioned earlier, the `HER2` protein is not high. This means that neither hormones nor the `HER2` protein contribute to the growth of this cancer . Another name for this is `Triple-Negative Breast Cancer` . This is because the estrogen receptor, progesterone receptor, and `HER2` protein are all `negative` in this case.

What are the symptoms of HER2-negative breast cancer?

In fact, the symptoms of HER2-negative breast cancer are very similar to those of any other breast cancer. You should be aware of the following:

• If you notice an unusual change in the size or shape of one or both of your breasts.
• If you notice a new lump, lump, or firmness in your breast or armpit, especially if the lump doesn't change with your monthly menstrual cycle.
• Changes in the skin of the breast or nipple. For example:
• Dimpling of the skin, like an orange peel
• Skin wrinkling, puckering
• Scaly skin
• A constant itch
• Skin color changes (red, purple, brown, or unusually dark).
• Nipple discharge . This may be red like blood, a clear liquid, or a milky white color (if you are not pregnant or breastfeeding).
• Nipple inversion (if it wasn't there before).

It is important to note that breast cancer does not always cause obvious changes in the way you look . Also, many of these changes can also be seen in benign, normal conditions (e.g. cysts, fibroadenoma). That is why it is so important to regularly monitor your breasts and get age-appropriate breast cancer screenings . If you have any concerns about a change, be sure to see a doctor to find out if it is a sign of cancer or another condition.

What causes HER2-negative breast cancer?

Simply put, HER2-negative breast cancer is caused by changes in the genes, or DNA, in breast cells, called mutations , that cause those cells to become cancer cells. These cancer cells then divide and multiply rapidly without control, forming tumors.

Risk Factors

Experts still don't know for sure what the exact cause of these genetic mutations is in HER2-negative breast cancers. However, they have identified several factors that can increase the risk of developing breast cancer in general. These include:

• Inherited genetic mutations : There is no specific genetic mutation that is associated with HER2-related breast cancer. However, if someone inherits a mutation in genes like BRCA1 or BRCA2, they are at a higher risk of developing breast cancer (and some other cancers) in general.
• You or someone in your family has had breast cancer before : If you have had breast cancer before, you are at a higher risk of developing it again. Also, if your blood relatives (especially your mother, father, siblings, children) have had breast cancer, you are also at a slightly higher risk.
• Long-term exposure to estrogen or progesterone hormones : If you started your first period at a young age (e.g., before age 12), or if you had late menopause (e.g., after age 55), your body has been exposed to these sex hormones for a long time. This can also be a risk factor. Some hormone replacement therapies can also increase your risk when taken long-term.
• Alcohol use : Research has found that drinking more than one standard drink per day also increases the risk of breast cancer.

In addition to this, factors such as increasing age, obesity, and lack of exercise can also increase the risk of breast cancer in general.

How is HER2-negative breast cancer diagnosed?

Doctors usually diagnose HER2-negative breast cancer through a breast biopsy . This involves taking a small sample (piece) of tissue from a suspicious lump or area and sending it to a lab. There, a pathologist examines the sample under a microscope to see if there are cancer cells.

If cancer cells are confirmed, special tests are then performed to see how much of the `HER2` protein is present on the surface of those cancer cells, or how many copies of the `HER2` gene are present.

• If you have normal (low) amounts of the `HER2` protein or gene, you have `HER2-negative` breast cancer.

The two main laboratory tests performed for this purpose are:

1. Immunohistochemistry (IHC) : This test uses specific antibodies and dyes to detect the HER2 protein on the surface of cancer cells. If the IHC result is 0 or 1+, the cancer is considered HER2-negative. If the result is 2+ (sometimes called "equivocal" or "borderline"), a test called FISH is also performed to confirm the HER2 status.

2. Fluorescence in situ hybridization (FISH) : This test looks at how many copies of the HER2 gene, which makes the HER2 protein, are present in cancer cells. This uses a special microscope and fluorescent (light-emitting) markers. In cases where the IHC test result is inconclusive, such as 2+, the FISH test can definitively confirm the HER2 status (negative or positive).

In addition to these `HER2` tests, the pathologist will also examine the biopsy sample and look for the presence of estrogen receptors (ETU) and progesterone receptors (PR) in the cancer.

You may also need to have imaging procedures such as a mammogram, ultrasound, CT scan, or MRI scan to find out the stage of your cancer (that is, to see how large the tumor is and whether it has spread to lymph nodes or other distant parts of the body).

Your doctor will combine all of this information (HER2 status, HR status, cancer stage, and cancer characteristics) to create the most appropriate treatment plan for you.

What are the treatments for HER2-negative breast cancer?

The best treatment for HER2-negative breast cancer can vary from person to person. It depends on many factors, including the stage of your cancer, whether it's hormone receptor-positive or negative (HR+/HER2- or HR-/HER2-), and your overall health.

In general, treatments may include:

• Breast cancer surgery : The removal of the cancerous tumor and possibly some healthy tissue around it. This can be a lumpectomy, which removes part of the breast, or a mastectomy, which removes the entire breast.
• Radiation therapy : High-energy rays are used to destroy any cancer cells that may remain after surgery, or to shrink the tumor before surgery.

In addition to these basic treatments, there are other specific treatments depending on the type of cancer:

Treatment for HR+/HER2- (hormone receptor-positive, HER2-negative) breast cancer

Because this type of cancer is hormone-dependent, these treatments are also important in addition to surgery and/or radiation therapy:

• Hormone therapy : These treatments work by reducing the levels of the hormones estrogen or progesterone that help cancer grow, or by stopping those hormones from binding to cancer cells. For example:
• Aromatase inhibitors (e.g. Anastrozole, Letrozole, Exemestane)
• Gonadotropin-releasing hormone (GnRH) agonists (stop the ovaries from producing hormones)
• `Selective estrogen receptor modulators (SERMs)` (e.g. Tamoxifen, Raloxifene)

In some cases, you may need to have surgery (oophorectomy) to remove your ovaries, which produce estrogen. Hormone therapy can be given alone or in combination with targeted therapy for several years.

• Targeted therapy : These treatments target specific weaknesses in cancer cells and attack them to stop the growth and spread of cancer cells. For HR+/HER2- cancers, drugs called CDK4/6 inhibitors (e.g. Palbociclib, Ribociclib, Abemaciclib) are used in combination with hormone therapy. These block an enzyme that controls the division of cancer cells.
• Chemotherapy : For some HR+/HER2- breast cancers, especially if the cancer has spread or is aggressive, doctors may recommend chemotherapy along with hormone therapy and/or targeted therapy.

Treatment of HR-/HER2- (triple-negative) breast cancer

Because triple-negative breast cancer is not hormone-dependent, hormone therapy is not effective. In addition to surgery and/or radiation therapy, the following treatments are mainly used:

• Chemotherapy : Chemotherapy is a very important treatment for triple-negative cancer. Doctors use different types of chemotherapy drugs. They may give one drug or a combination of several drugs.
• Immunotherapy : This is a relatively new treatment. It works by stimulating your body's own immune system to recognize and destroy cancer cells. Pembrolizumab (Keytruda®) is an immunotherapy drug approved by the Food and Drug Administration (FDA) and is given with chemotherapy for some types of triple-negative breast cancer.
• Targeted therapy : For triple-negative cancers with a BRCA gene mutation, targeted drugs called PARP inhibitors (e.g., Olaparib, Talazoparib) are used. Also, for metastatic disease, new types of targeted therapies (e.g., antibody-drug conjugates) are now available.

What are the side effects of the treatments?

Although cancer treatments can effectively fight cancer, all treatments, including chemotherapy, radiation therapy, hormone therapy, targeted therapy, and immunotherapy, can cause some side effects. These can be temporary or long-term. For example, fatigue, nausea, vomiting, hair loss, loss of appetite, mouth sores, skin changes, diarrhea or constipation, and low blood cell counts.

Be sure to talk to your doctor about what these side effects are, how long they will last, and how to manage them. They may also refer you to palliative care specialists. Palliative care is not just for the final stages of cancer, but also helps you maintain your quality of life by managing symptoms and side effects throughout treatment.

What is the cure rate for HER2-negative breast cancer?

In all cases of `HER2-negative` breast cancer, the cancer is confined to the breast and has not spread (local stage), and the survival rate is much higher than that of cancer that has spread to distant organs in the body (e.g., liver, lungs, brain, bones) (metastatic cancer or distant stage). The survival rate for cancer that has spread only to nearby lymph nodes but has not spread to distant organs (regional stage) is in between.

However, it is important to remember that your chances of recovery, or prognosis, depend on factors specific to your diagnosis. These include how far the cancer has spread (stage), whether the cancer has hormone receptor status (HR+/HER2- or HR-/HER2-), how aggressive the cancer cells are (grade), your age, overall health, and how you respond to treatment. These are things your doctor can talk to you about and explain to you what to expect. Statistics are just averages, and they won't be the same for everyone.

How do I take care of myself? (Self-care)

Whether you're a person with early-stage HER2-negative breast cancer or someone living with advanced cancer, it's important to take time for self-care. This will help you both physically and mentally. Here are some things you can do:

• Rest when you need to : It's normal to feel tired and exhausted, both from cancer and cancer treatments. When you feel tired, take a break and rest. Listen to your body.
• Eat a healthy, nutritious diet : Some cancer treatments can affect your appetite and sense of taste. But try to eat a balanced diet to get the nutrients your body needs. Include fruits, vegetables, fiber, and protein-rich foods. If you're unsure about what foods to eat and what's not, talk to a dietitian for advice.
• Exercise (but don't overdo it) : It's important to do regular exercise at a level that's right for you, as recommended by your doctor. Even light walking or yoga can be good. It can boost your energy, improve your mood, and help reduce side effects. However, ask your doctor what kind of exercise is right for you and how much you should do, based on your diagnosis and treatment.
• Manage stress : It's normal to feel stressed, anxious, and fearful with an illness like this. Find ways to manage it that work for you. While meditation and breathing exercises work for some, others may prefer to engage in creative activities like reading a book, listening to music, drawing, or gardening. Set aside some time each day for whatever activity helps you feel calm and relaxed.
• Get support : It's important to talk about your feelings with family and close friends. It can also be a great source of support for you to connect with others who have been diagnosed with cancer and share their experiences. Ask your doctor about support groups or cancer survivorship programs.

When should I see the doctor?

It is very important to maintain constant contact with your doctor, both during and after treatment.

• If you develop new symptoms (e.g., persistent pain, a new lump, difficulty breathing, unexplained weight loss), or if your current symptoms seem to be getting worse , see or notify your doctor immediately .
• After treatment, your doctor will schedule follow-up appointments at regular intervals . Make sure you keep these appointments. These are to check for recurrence, manage long-term side effects of treatment, and check your overall well-being. These follow-up appointments are especially important during the first five years after treatment . This is when cancer often recurs.

What questions should I ask my doctor?

When talking to your doctor, don't be afraid to ask any questions you have, no matter how small. Here are some questions you can ask to help you:

• Is my cancer hormone receptor-positive or negative?
• What is the specific subtype and stage of my cancer?
• What treatment do you recommend for me? Why?
• What are the short-term and long-term side effects to expect from these treatments? What can be done to minimize them?
• How long does treatment take?
• What can you tell me about my prognosis?
• Can I continue my daily activities (work, household chores) during treatment?
• Are there any special things I need to pay attention to regarding my diet and exercise?
• What can I do to reduce the risk of cancer coming back?
• If I need support services or counseling, can I get a referral for it?

It's a good idea to write down these questions and ask them, so you won't forget anything.

Is it better to be HER2-positive or negative?

This is a question that many people ask. But it's hard to give a simple answer to this, because the truth is that it 'depends' .

For example, HER2-positive breast cancers tend to grow faster and be more aggressive than HER2-negative cancers. However, there is an advantage to this. There are specific therapies that can target HER2 proteins, e.g., Herceptin, Perjeta, and they are very effective for HER2-positive cancers. These treatments do not work for HER2-negative cancers, because those cancers do not have as much HER2 protein to target.

On the other hand, if a `HER2-negative` cancer is `HR+` (hormone receptor-positive), that is, `HR+/HER2-` type, then there are very effective hormonal therapies and targeted therapies such as `CDK4/6 inhibitors`. In fact, `HR+/HER2-` breast cancer is considered to have the best prognosis among the existing breast cancer subtypes.

But if the cancer is `HER2-negative` (HR-) (hormone receptor-negative), that is, triple-negative, it can usually be more aggressive than other types, and treatment can be a little more challenging. But now there are chemotherapy, immunotherapy, and new targeted therapies for that too.

Therefore, it is not possible to say that one is "better" or "worse" than the other. The most important thing is to accurately identify the specific subtype of your cancer and receive the most effective treatment that is appropriate for it.

Finally, I have to tell you... (Take-Home Message)

When you are diagnosed with `HER2-negative` breast cancer, it is normal to feel scared and anxious. But remember, this is not the end of the world. Science and medical technology are very advanced today, and there are many effective treatments for this type of cancer.

The most important thing is:

• Being properly informed about this situation.
• Always be aware of changes in your body, especially your breasts.
• If you have any doubts, see a doctor on time and get checked out.
• Talk openly and honestly with your doctor, ask all your questions, and gain a good understanding of the treatment options.

Remember, you are not alone in this journey. There are talented doctors, nurses, your family, and your closest friends who are there to help and support you. Keep a positive attitude, follow your doctors' instructions exactly, and get the support you need, and you will definitely be able to cope with this situation successfully and recover. May you be strong!

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