Adjuvant Therapy

In many cases additional treatment is required after surgery. This is called adjuvant therapy. The adjuvant treatment for breast cancer may include chemotherapy, hormonal therapy, radiotherapy or immunological therapy. Usually a combination of the above is administered. The objective of adjuvant treatment is to destroy residual cancer cells circulating in the body, preventing them from lodging in organs and giving rise to distant metastases. Currently there are no means to identify these circulating cancer cells, but based on a number of the characteristics of breast cancer the probability of recurrence or metastases can be estimated. From large international clinical studies, we know that chemotherapy and hormonal therapy can reduce the risk of relapse and death from breast cancer by 30-40%.

Chemotherapy

Chemotherapy treatment is recommended in some patients. The individual risk of relapse is taken into account. The higher the chance of relapse, the higher the expected benefits of chemotherapy.

Classical criteria that we use to recommend chemotherapy are: tumor size, involvement of the axillary lymph nodes, hormone sensitivity (ER and PR), HER2 status, ki-67 (a marker of proliferation) and lymphovascular invasion. In addition, the age of the patient and her relevant medical history are taken into account.

Chemotherapy or cytostatics act on the genetic material of the cancer cell and thus prevent cell division and tumor growth. Since chemotherapy mainly works on rapidly dividing cells, it will also affect other rapidly dividing body cells and give rise to a number of side effects. Healthy body cells, however, have a greater capacity to recover and restore than cancer cells, such that the net effect of chemotherapy is a reduction in tumor volume and repair of damaged healthy cells.

Chemotherapy can be given 'adjuvant', which means that this treatment starts after the breast tumor has been surgically removed. On the other hand, chemotherapy can also be given 'neo-adjuvant', which means that one starts chemotherapy first and performs surgery in the second step.

The historical standard is adjuvant administration of chemotherapy. Previously, only patients with large, inoperable breast tumors were treated neoadjuvantly. The goal was to shrink the tumor, making surgery possible.

Today chemotherapy is increasingly being given neoadjuvant. Especially with regard to the triple negative (= hormone receptors negative and HER2 negative) and the HER2 positive tumors. This has a number of advantages, the most important of which are briefly mentioned here:

1. The response to neoadjuvant chemotherapy is of prognostic importance. Patients in whom the tumor shrinks nicely or even disappears completely under chemotherapy have a better prognosis than patients in whom this is not the case. They are less likely to develop distant metastases and have better survival.

2. There is also a therapeutic benefit. In patients who did not have a good response to neoadjuvant treatment, the therapy can be extended / modified, which may mean an additional chance of a cure.

3. Chemotherapy can reduce the size of the tumor, which sometimes requires less extensive surgery, with all the associated benefits.

Several chemotherapy schedules exist. Depending on the type of breast cancer, the stage, the age of the patient and his relevant history, your physician will make a proposal regarding treatment. A classic schedule may look like this: 4 cycles of Epirubicin - Cyclophosphamide (administered once every 2 or 3 weeks) followed by 12 weekly administrations of Paclitaxel.

This treatment is usually administered intravenously (via an IV), although in recent years treatment with tablets has also been possible in some cases. The courses are repeated at regular intervals, eg. every 3-4 weeks, for a certain number of cycles (eg. 6).

The main side effects of chemotherapy are:

• Nausea and vomiting

• Bone marrow suppression and thus increased susceptibility to infection

• Hair loss, nail abnormalities

• Oral and eye mucosal inflammation

• Local reactions at the injection site

• Fatigue

• Influence on fertility and menstruation

• Cystitis and urine discoloration

• Specific organ toxicity in relation to the heart, lungs, liver, kidneys, nervous system. This toxicity is very specific for a limited number of products.

Your doctor will always take this into account in function of your body surface area, your general condition and the underlying suffering. Sometimes it will be necessary to make dose reductions or to omit certain products from the schedule.

Radiotherapy

Radiotherapy will usually be administered after surgery for breast cancer, depending on the type and size of the original tumor. Radiation therapy is a topical treatment that reduces the chance of the tumor returning. The irradiation is done at the level the breast, or in case of mastectomy, at the level of the chest wall. Sometimes an extra dose or boost must be administered on the tumor bed. If the axillary glands are affected, it may be necessary to also irradiate the armpit.

Depending on the proposed treatment schedule, the irradiation session is given either daily or every other day. Where treatment used to last up to 7 weeks, it has now been shortened to a maximum of 2 to 3 weeks. After all, studies have shown that a higher dose can be safely administered at the same time. In addition, the boost can now be done simultaneously with the rest of the irradiation (simultaneously integrated boost), so it no longer needs to be added afterwards.

Due to the improved techniques, side effects such as skin burns are greatly reduced. In less than 10% of the patients, "moist desquamation" or burning is still seen. Moreover, this is often limited to small regions, very different from the extensive burns in the past. General fatigue, redness of the skin and swelling of the chest may still occur. Scarring or fibrosis can occur many years after radiation, causing the breast to feel firmer or to shrink in volume. The skin can also become discolored. Irradiation to the heart and lungs is kept as low as possible, both by radiation techniques and by an adapted radiation position, to avoid damage to these organs.

Just like axillary surgery and chemotherapy, radiation to the armpit can cause lymphedema of the arm. Both for the prevention and treatment of lymphedema you can visit the lymph clinic, a multidisciplinary collaboration between gynecologists, plastic and reconstructive surgeons, vascular surgeons, radiotherapists and physiotherapists.

Hormone treatment

Breast cancer arises from originally normal breast epithelial cells that start to behave abnormally. It is therefore logical that most breast cancer cells still have many properties of the original breast epithelial cells. For example, more than eighty percent of breast cancers have estrogen receptors. This means that if estrogens are present, the breast cancer cells will divide faster.

This is of course something we don't want. Therefore, after surgery and radiotherapy, these estrogen will give sensitive tumors "anti-estrogens". These anti-estrogens are substances that inhibit cell division. Since it is always possible that cancer cells have come loose before the tumor has been discovered and have spread through the lymphatic vessels and blood vessels in the body, we will administer "anti-estrogens" after surgery. For example, we inhibit the growth of small groups of cancer cells in the body. In this way we give the body time to attack and destroy these groups of cells. If we do not do this, these cancer cells will organize into larger groups of cancer cells and we speak of metastases or metastases.

These "anti-estrogens" are called hormone treatment. It would actually be more correct to call it an "anti-hormone" treatment. But because it has become so common, we will now also speak of hormone treatment. This treatment is given as standard five years after surgery.

The best known treatment is tamoxifen (Nolvadex-d®, or a generic product with tamoxifen 20 mg). This material can be compared to a key that fits on the same lock as natural estrogen. As a result, tamoxifen occupies the lock and estrogen can no longer work and the cell division of the cancer cell stops. By default, this substance is given for five years. When the cancer is very aggressive (high degree of division or AI index) or when the tumor is already far advanced when the tumor is discovered (large tumors, or tumors with different glands in the armpit), tamoxifen will be administered for ten years. Tamoxifen is usually well tolerated. Sometimes, as it is an "anti-estrogen", complaints will occur such as: weight gain, joint stiffness, fatigue, swelling of the vagina, dryness.

Another way to counteract the effect of the estrogens is simply to interrupt the production of estrogens. Estrogens are made from their precursor: the male hormone "testosterone". The enzyme that converts male hormone into female hormone is called "aromatase". An aromatase inhibitor counteracts the aromatase enzyme. As a result, no female hormone is produced by the body at all. The substance is only given to menopausal women. Before menopause, the production of estrogens is still too abundant and the aromatase inhibitors are not sufficiently effective. After menopause, there is only local production of estrogen in certain tissues and breast cancer cells. That limited production is completely suppressed by aromatase inhibitors.

Aromatase inhibitors are given five years as standard. As with tamoxifen, the inhibitors are given for more than five years in extensive cancers. And just like tamoxifen, there are also side effects such as: weight gain, stiffness of the joints, fatigue, warmth, vagina dryness, bone loss. Sometimes the side effects are so strong that it is decided to replace aromatase inhibitors with tamoxifen. This is safe if the woman tries to take the aromatase inhibitors for three years. Aromatase inhibitors will also promote bone breakdown, which can lead to osteoporosis. In menopause when taking an aromatase inhibitor or when taking tamoxifen it is recommended to do a bone densitometry. It is also recommended to take bone strengthening agents.

In young women, with extensive tumors, the source of estrogen production, namely the ovaries, will be removed or stopped. Chemical castration can stop the pituitary gland by monthly injections. This stops the ovary from producing female hormone. In addition, an aromatase inhibitor can then also be given. The combination of these two treatments is very stressful.

When the basic treatments such as tamoxifen or aromatase inhibitors no longer work and there is therefore a relapse among these products, other "anti-hormonal" products can be administered. Certain substances will destroy the estrogen lock. On the other hand, certain antibodies or small molecules that act as a cell disruptor will be administered during anti-hormonal treatment. This is still a further line of treatment when there is a relapse.

Immunotherapy: HER2-targeted therapy

About 20% of breast cancer patients have HER2 positive disease. HER2 is a protein expressed on the cell membrane. In patients with HER2 positive breast cancer, much more HER2 is expressed than usual. This ensures that the cancer cells grow and divide quickly. HER2-positive breast cancer is therefore associated with an aggressive course and a poorer prognosis in patients who do not receive (neo-) adjuvant treatment. This means that patients with HER2 positive breast cancer are almost always treated with chemotherapy in combination with HER2-targeted therapy (which significantly improves the prognosis).

Trastuzumab (Herceptine®) is a monoclonal antibody directed against HER2. In HER2 positive breast cancer, it is often associated with chemotherapy treatment. It is administered subcutaneously once every 3 weeks for a total treatment duration of 1 year. Usually it is well tolerated. The main side effect is a decrease in the pumping function of the heart. Usually this is asymptomatic and we see a spontaneous recovery if treatment is interrupted.

Pertuzumab (Perjeta®) is another monoclonal antibody directed against HER2. It can be associated with treatment with trastuzumab in patients, including cancer cells in the axillary glands.

Trastuzumab-Emtansine (Kadcyla®) is a third product. It is an "antibody drug conjugate". This means that it is an antibody (in this case Trastuzumab) which is linked to a certain type of chemotherapy (in this case Emtansine). It is currently used in women in whom tumor cells are found during surgery after neoadjuvant treatment (chemotherapy with trastuzumab and pertuzumab or not). Trastuzumab-Emtansine is administered intravenously every three weeks, usually for 14x in total. It is often well tolerated.

The most common side effects are a decrease in blood platelets, an increase in liver values ​​in the blood, tingling in the fingers and toes, fatigue and gastrointestinal discomfort.