Breast cancer

Mammary carcinoma is the most frequent of women in Germany. 8-10% of all women get this in their lifetime.

In rare cases, men are as well affected. Average age is between 45 – 50 and then between 60 – 65 years of age.

Risk factors are mainly family burdens, for example, breast in the family, overweight, late or no pregnancies, hormone therapy (isolates estrogens) and proliferative mastopathy. Based on the frequency and significantly better prognosis for early diagnosis early detection of breast is strongly required by intense self-examination, regular check ups at gynecologist, as well as by means of mammography at recommended intervals.

In addition to mammography also other measures are useful to confirm the diagnosis – ultrasound, biopsy (tissue sampling) and MRT.

Possible treatment is surgery or with a passing chemotherapy to reduce the tumor. When possible, the breast-conserving surgery is preferred. In case of an extensive tumour the mastectomy can not be avoided. In any case, the lymph nodes of the axilla are also taken off, to determine the stage of the disease. For this purpose, in addition, the upper abdomen examination by ultrasound and scintigraphy of bones is also carried out. For further treatment also the examination of the tissue is critical (especially the determination of so called hormone receptors).

Postoperative treatment comprises of radiation therapy, chemotherapy and / or hormone therapy, and also from postoperative examinations. Treatment is determined individually, based on the patient’s age, the tumour responsiveness to hormones and disease stage.

DEFINITION AND OCCURRENCE

Under the breast mammary a malignant breast disease is understood. Mammary carcinoma in women in western countries is the most common . is about 18% of all malignant diseases in women. Approximately 1-2 of 1 000 women get sick in Germany every year with this malignant tumour. Of all the women around 10% get sick in Germany from this disease sometime in their lives. Average age is between 45 – 50 and on between 60 – 65 years of age. Expressed in absolute numbers, this means that in Germany per year 48,000 women become ill from breast and about 18,000 die each year because of it.

If we imagine a cross with a breast nipple as the centre, so we can perform spatial frequency distribution into four quadrants. The upper outer quadrant is specially often noticeable, because it contains also the largest part of the mammary gland.

The cause of breast is not yet fully understood. However, it starts from the fact that approximately in 5% of women a genetic cause is jointly responsible. risk increases so, for example, to threefold in people, who have an ill first-degree relative. It seems that some changes in genotype encourage the development of tumours, but it has been proved only in a few types of tumours. First benign proliferation of gland lobules and fibrous tissue, so called proliferative mastopathy, is another risk factor. The breast is encouraged also by a diet rich in fats, radiation by ionizing rays, tobacco and alcohol usage, as well as long-term use of female sex hormones (estrogens). In contrast, the use of birth control pills probably does not increase the risk of .

PREVENTION AND DISEASE RISK

Universal prevention consists of weight reduction, as well as from alcohol and tobacco abstinence. Taking estrogens, for example, to mitigate the difficulties during the menopause should occur only under strict medical supervision and possibly time-limited. The finding that estrogen levels in postmenopausal women can encourage the development of has led to the idea that this level was decreased by medicines. Antiestrogen Tamoxifen, given for many years in the treatment against tumours, actually led to a reduction in the risk of tumours. Tamoxifen, however, is associated with numerous side effects. However, despite several studies, especially in the U.S., there is still insufficient experience on the effect of a long-term use, this method is not generally recommended.

Crucial importance has the further self-examination as a measure of early diagnosis. It includes examination and palpation of the skin of the breast and armpit. Lumps, nodules, non-healing wounds, sunken places in the skin, swelling of the lymph nodes or secretion of the mammary glands are until the proof of the contrary always suspicious and require medical treatment.

Apart from the commendable intense self-examination by palpation, women from 20 year of life have once a year in Germany the opportunity to have a free medical examination to detect . Women between 50 and 70 age should undergo mammography every two years. Risk patients (common in the family, proliferative mastopathy, etc.) should have the mammograms carried out since they are 30.

For some time, due to family illness occurrence frequency a genetic cause is presumed. Recently, three genes could have been discovered BRCA-1, 2 and 3. BRCA yet is short for Breast . The mutation carriers in the BRCA-1 have an increased risk of breast by 85%. We remember that in men with this gene defect, the risk of prostate is increased three times more and four times more the risk of colon . BRCA-2 mutation is also associated with an increased risk of breast by 85%. Increased risk of BRCA-3 has not been sufficiently explored yet.

Because the gene test is costly and expensive, only certain patients after a thorough examination and counseling are tested. Therefore, certain criteria were determined for this test:

• two women in one family with mammary or ovarian , of whom at least one fell ill before they were 50
• a first-degree relative with unilateral mammary before 30th year of life;
• a first-degree relative with bilateral mammary before 40th year of life;
• a first-degree relative with ovarian before 40th year of life;
• a male relative with breast mammary .

However, as for the bearers of such mutations there is no specific treatment option so far, measures are restricted to a monthly self-examination and half-annual preventive examination from the 25th year of life.

Most tumours, however, occur by spontaneous mutation and also at the existence of the above criteria maybe only in 15% of these individuals demonstrate gene mutation BRCA-1. A negative test result, moreover, does not exclude that maybe there are other mutation points of genes that have not been identified yet and have the relevance for the development of tumours. The final evaluation of genetic test is therefore still missing.

DIAGNOSIS AND DIVISION OF STAGES

At the slightest suspicion of mammary carcinoma a thorough medical examination should be done. In addition to a detailed history and palpation of both breasts, armpits and collarbone holes examination of the breasts and ultrasound examination is made by X-ray. Mammography, i.e. breast x-ray, allows for a microscopic evidence of hardening, of the size and number of tumours and distinguishing it from non-malignant changes. Microscopic calcium, which builds up in the ducts under the affected breast tissue is an indirect evidence – under the circumstances – of even very small tumour.

Ultrasound examination, along with mammography, significantly increases the certainty in diagnosis. In case of dispute, during ultrasound check up, a tissue sample (biopsy) may be removed by microscopic examination by fine needle. Mammography and ultrasound are also, in addition, needed immediately before surgery in to accurately identify the operated area. Computed tomography, bone scans by open emitters (bone scintigraphy) and ultrasound examination of the liver provide data on eventually existing metastases. Before surgery tumor markers CEA and CA 15-5 can be determined, which in the context of malignancies appear increasingly in the blood.

After surgery the re-increased of such tumour markers to highlight the occurrence of new tumours. The result of microscopic examination of the tissue (histology) gives an explanation of the type of tumour and its degree of aggressiveness (grading). Examination of the tumour and lymph nodes acquired by surgery, enables to report on the extent and spread of the tumour, or metastasis. Independently, on one sample of the tumour, it is examined whether it contains receptors for the female sex hormone estrogen. Estrogen can stimulate the tumour’s growth. On the contrary – his “removal” may hinder tumour’s growth. Examination results can be grouped into so-called scheme TNM (tumour, lymph nodes, metastasis). This again results into the division of stages. This division of stages determines, together with histology, the prognosis and treatment strategy. Because the histology is carried out already during the operative procedure (rapid histological examination), the scope of surgery may be heavily influenced.

All breast tumours can be divided roughly into the duct , also called ductal carcinoma, and mammary carcinomas also called lobular carcinoma.

Type of breast	Frequency in %
invasive ductal carcinoma	75
colloid carcinoma	15
lobular invasive carcinoma	10
tubular carcinoma	rarely
adenocystic carcinoma	rarely
papilar carcinoma	rarely
The most common forms of tumours

MAMMARY IN MEN

The disease is rare in men. It is, however, generally not discovered until an advanced stage. Because the pectoral muscle fascia has often been exceeded, this muscle must be then removed. As with women, a decisive role for the prognosis plays the infestation extent of axillary lymph nodes. Treatment and postoperative care does not differ from that in ill women. However, the prognosis is often, due to the advanced stage of the tumour, at discovery usually less favourable than that in a woman.

INFLAMMATORY MAMMARY CARCINOMA

Irrespective of the type of , tumour cells can penetrate into the lymphatic system stored under the skin. This leads to lymphostasis and the swelling of stretched skin areas. The skin then, with its appearance, resembles an orange or shows redness similar to inflammation, hence the name of inflammatory carcinoma. Prognosis is extremely unfavourable and requires an intensive polychemotherapy, followed by surgery and / or radiation therapy.

Therapy

When selecting therapy, the tumour size, histologic characteristics of the tumour, hormone receptor status, metastasis as well as menopausal status are critical. In addition to surgery and radiation therapy adjuvant or non-adjuvant chemotherapy and hormonal therapy are now carried out as well. Adjuvant therapy, or additional therapy is the primary therapy, i.e. therapy immediately followed by surgery and after radiation therapy, non-adjuvant therapy is carried out before surgery.

Primary therapy

Radical surgery

Radical surgery, i.e. the removal of the entire breast must nowadays be done only in about one-third of patients. It must be transferred whenever the tumour is larger than 2 cm, and when there is a negative relationship between the size of the tumour and the rest of the breast tissue, as well as unfavorable histological features, such as, multicentricity, or wide lymphangiosis carcinomatosis.

During the radical surgery the entire body of the breast is removed, thus the entire breast. There are various options, how to, after such a major surgery to “reconstruct” the breast again. The reconstruction can actually be carried out immediately after the radical surgery. However, between the two surgeries weeks or years may go by. Breast reconstruction is, on the one hand, possible using own tissue, for example, muscle tissue or tissue from the abdominal wall, and on the other hand, there are replacement made ​​of plastic available, which are filled with various materials, such as silicone. Because, to this day it is not yet satisfactorily explained, or eventually the exiting silicone at the damaged replacements results in side effects throughout the entire body, also alternative materials such as saline solution are used. A significant disadvantage of replacements lies in forming fibrous capsule around the foreign body. The rough lump caused by this does not only limit the cosmetic result, but also it makes it difficult to diagnose a possible relapse, or recurrence of the disease.

To achieve the best cosmetic results, the reconstruction of the diseased side, and adjustment of the healthy side occur simultaneously.

Plastic surgery that preserves the breast

In approx. 65% of patients there is possible plastic surgery that preserves the breast in combination with radiation therapy. This implies the tumour size of more than 2 cm, whereas at a large breast exceptions to this rule are possible. Tumour however, should be limited only to a single bed.

Depending on the size of the removed tissue due to a better cosmetic result, a small replacement can be inserted into the resulting cavity. The risk of recurrence after plastic surgery preserving the breast is compared with radical surgery increased. Followed by postoperative radiation of remaining tissue, this risk may be reduced by up to 20%. At present, without radiation therapy no surgeries preserving the breast should be performed!

Radiation therapy

Radiation therapy is irreplaceable for the treatment of mammary carcinoma. Plastic surgery after breast preservation must always be followed by radiation therapyof the remaining breast. After radical surgery using histological factors must be individually determined whether the radiation therapy is needed. For example, tumours greater than 5 cm and infiltration of the breast muscle belong here.

Irradiation is now performed by linear accelerators with a maximum energy of 20 MeV. The treatment of each individual patient is determined individually by means of computer-aided planning systems of irradiation on the basis of previously made ​​computerized tomography. Thanks to modern technology not only the effectiveness of treatment was able to be improved, but also the rate of side effects was significantly reduced.

Irradiation is performed five days a week. Total duration depends on the level of individual and total dose, and on average it is 5-7 weeks. Irradiation itself takes only few minutes and the patient does not feel it, it is not at all painful. To avoid skin irritation, mechanical, thermal and chemical ballasts should be avoided during the radiation therapy. Daily application of powder may cover skin redness, which after the treatment disappears again. At the end of radiation therapy, patients often tend to be quite exhausted and feel tired. These difficulties, however, improve again in a few weeks. Sometimes permanent changes are observed on the irradiated area​​, such as stronger pigmentation of the skin as well as small “spider” advanced blood coils.

Depending on the histology it must be, for each individual patient, decided whether, in addition to irradiation of the remaining breast, respectively, breast wall also the lymphatic drainage routes in the armpits, in the hole of the collarbone or in the middle breast wall must be irradiated.

Adjuvant therapy

Adjuvant, i.e. complementary therapy is a medicinal therapy, following the primary treatment such as hormone therapy, chemotherapy, or a combination of both. Adjuvant therapy should hit metastases that exist at the time of primary therapy. The choice of therapeutic procedure depends primarily on the condition of the lymph nodes. Other factors to be taken into account, are the hormone receptor status of the tumour, as well as menopausal status of the patient.

The following table is used to explain the most important terms:

lymph nodes status
no lymph node metastases in the armpit lymph nodes	nodally negative
lymph node metastases in the armpit lymph nodes	nodally positive
hormone receptor status
tumour tissue does not have hormone receptors	negative
tumour tissue has hormone receptors	positive
menopausal status
before menopause, i.e. the last menstrual bleeding	premenopausal
after menopause, after the last menstrual period	postmenopausal

Whether the patients with nodal negative mammary carcinoma must undergo the adjuvent therapy depends on the individual risk of the patient, whether metastasis can develop at her at a later date. When estimating the risk factors such as tumour size, histological type of the tumour, as well as the degree of aggressiveness are taken into account. Patients are then divided into patients with low, medium or high risk.

In principle, there is a choice – based on the metastases status and hormone receptor status – even at the nodal negative mammary the possible following treatment options corresponding to risk estimation:

	small risk	medium risk	high risk
Premenopausal
In terms of hormone receptors – positive	no adjuvant therapy or Tamoxifen	Tamoxifen ± Chemotherapy	Tamoxifen ± Chemotherapy
In terms of hormone receptors – negative	no adjuvant therapy	no adjuvant therapy	chemotherapy
Postmenopausal
In terms of hormone receptors – positive	no adjuvant therapy or Tamoxifen	no adjuvant therapy or Tamoxifen	Tamoxifen ± Chemotherapy
In terms of hormone receptors – negative	no adjuvant therapy	no adjuvant therapy	chemotherapy
Senium (> 70 years)	no adjuvant therapy or Tamoxifen	no adjuvant therapy or Tamoxifen	if – regarding the hormone receptors – positive: Tamoxifen

In patients with nodal positive breast mammary carcinoma adjuvant therapy always follows, which, however, for patients with nodal negative mammary tumours corresponds to an increased risk. The difference consists of the choice of chemotherapy.

Chemotherapy

Effectivness of the chemotherapy depends on the patient‘s state of menopause. Likelihood of recurrence in premenopausal women may fall by up to 37% in postmenopausal women at approx. 20%.

Classical chemotherapy for breast mammary gland occurs according to the scheme CMF with substances cyclophosphamide + methotrexate + fluorouracil together in more than 6 cycles. This chemotherapy scheme is given mainly in the adjuvant treatment of nodally negative mammary carcinoma respectively to the risk estimation. In recent years, it is given more and more at the nodally positive breast mammary carcinoma – alternatively to CMF scheme also chemotherapy containing anthracycline according to the EC scheme with epirubicin + cyclo phospho-amide, according to AC scheme with adriamycin + cyclo phospho-amide, respectively, according to FEC scheme with 5-fluorouracil + epirubicin + cyclo phospho-amide. 4 cycles are administered here.

Hormone therapy

Hormone therapy has various substances, which differ in their type of effect. So far, the therapy associated with the administration of anti-estrogen Tamoxifen is possible. Tamoxifen prevents estrogen binding to the estrogen receptor, while it binds itself to them and thus occupy them, we are talking about the competitive inhibition. Tamoxifen is equally effective in pre-and postmenopausal women. The standard is to take it more than five years. Evaluation of a number of studies have shown that Tamoxifen should not be given to receptor-negative patients, and vice versa – in the receptor-positive patients is then combined hormonal chemotherapy an advantage. At present, a number of studies are investigating new anti-estrogens, such as, Toremifene, or selective estrogen receptor modulators, such as Raloxifene, because of their efficacy and tolerability.

In addition, nowadays, several internationalist studies are searching for other hormonal therapy as an alternative to Tamoxifen. These include aromatase inhibitors like Exemestane (Aromasin), Letrozole (Femara), Anostrozol (Arimedex). Aromatase inhibitors are substances that suppress certain enzyme, the aromatase, which is important for the formation of estrogen outside ovaries. The effect therefore consists in preventing estrogen production. The deployment of these drugs should therefore make sense only in postmenopausal women, respectively after the removal of the ovaries.

A new treatment option within the hormone therapy consists of ovariectomy, i.e. the removal of the ovaries, respectively of medical therapy with GnRH – Analogues, these are substances that eliminate the production of estrogen and progesterone in the ovaries. This treatment option has been given only under conditions of trials in premenopausal patients, who have positive hormone receptors and high risk.

Therapy of metastatic mammary gland carcinoma

We talk about the metastatic mammary gland carcinoma when distant metastases were formed, for example, in the liver, bones or brain. In patients with distant metastases it should be considered, whether chemotherapy or hormonal therapy, or their combination is given.

Chemotherapy

In tumours, which are negative with regard to the hormone receptors, with the shorter distance between mammary gland therapy and the occurrence of metastases and the rapid growth of metastases, the chemotherapy is generally preferred. For this, on one hand, the above chemotherapy schemes. On the other hand, at metastasis also other substances proved to be effective, such as Taxane Paclitaxel (Taxol) and Docetaxel (Taxotere). The use of other substances, such as Gemcitabine (Gemzar), Capecitabine (Xeloda) or liposomal Doxorubicin (Caelix) is examined by the studies.

Hormone therapy

Patients, who have – with regard to the hormone receptors – positive mammary gland carcinomas with a short interval between therapy and mammary gland carcinoma metastases, with immediately life-threatening metastases or limited general medical condition may receive hormone therapy, which is significantly better tolerated than chemotherapy. Reactions have been reported up to 60%. Even in patients, who have – with regards the hormone receptors – negative mammary gland carcinomas, hormone therapy can achieve an improvement in 25% of cases.

Hormone therapy takes place according to the same principles as those described in adjuvant therapy. In postmenopausal patients receive aromatase inhibitors – due to the new data studies – a major importance, especially in the primary hormonal therapy of metastatic mammary gland carcinoma, and may replace Tamoxifen as first-line agent.

Immunotherapy

There are women, whose mammary carcinoma carries on the surface of the cell specific receptors, which can be proved histologically and labeled as HER2. In recent years, an antibody was developed that can bind to these special receptors HER2, and promotes the destruction of tumour cells. This antibody known as trastuzumab, a drug called Herceptin. So far, the only possible deployment is in patients with metastatic mammary gland carcinoma, as the evidence of HER2, as well as with overcoing at least two chemotherapies. The antibody can be administered on its own, as well as in combination with chemotherapy.

RADIATION THERAPY

Depending on the type of the existing metastasis the radiation therapy makes sense. Irradiation is always necessary where there are locally limited difficulties and metastasis response to irradiation sensitively. These include primarily bone and brain metastases.

In addition to previously presented therapy options for bone metastases may, in addition, with good success to give bisphosphonates, which reduce further degradation of bones, and in addition to pain relief diminish even the risk of fracture, i.e. the risk of bone fractures.