Breast cancer

How breast cancer occurs?

Breast cancer is formation of cells that make up breast tissue (epithelial, connective and fatty tissue). Most often comes from epithelial cells that build canals in the breast structure, which have the role of transferring milk to the nipple and from the group of milk-producing cells. Breast is rich in lymphatic canals, which drain the lymph first into the arterial lymph glands, which is why breast cancer metastases are most commonly seen first on these place.

Malignant tumors-disease rate

According to statistical data from 2015 in Serbia every fifth person dies of malignant tumor. In recent 20 years disease rate of malignant neoplasm are doubled. According to the latest statistics from 2015 in Serbia, every fifth person dies from malignant tumors. Most often seen tumors are breast tumor, cervical cancer, and lung cancer. Annually from breast cancer there are about new 4600 patients, of which 1700 die.

Serbia is ranked second in the number of cancer deaths in Europe. At the moment of diagnosis, almost a quarter of patients are diagnosed in the metastatic phase of the disease.

It is not known exact cause of breast cancer, but risk factors that leads to greater probability of developing breast cancer are known.

Risk factors for developing breast cancer are:

• years of life (advanced age brings more risk)
• early menarche (before age 12)
• obesity
• physical inactivity
• consumption of alcoholic drinks
• hormonal therapy (hormone substitution therapy in menopause longer than 5 years and usage of contraceptive pills)
• chest radiation in childhood/growing
• women that give birth after 30 years of life and women that did not give birth at all are in higher risk to have this malignant disease.
• genetic predisposition is considered to give between 5 – 10% of all number of diseases that are genetically predisposed. If in family there is a person with cancer and is under 40, it is recommended that all family members do genetic testings. Carriers of BRCA1 mutation have high possibility of development breast cancer during their life time.
• women that have breast cancer are in high risk (3 times bigger than general population) to develop cancer of the other breast.

Men also get breast cancer, but much more rarely than women, one in 100 000 get it. It is considered that in men more than 50% cases cancer is genetically predisposed.  

Possibile symptoms and signs that can indicate breast cancer are: 

• nodes in breast
• change in shape and size of the breast
• change in the skin of the breast
• sensitivity and pain in the breast
• redness and swelling of the breast “peau d’orange”
• nipple withdrawal
• nipple discharge

If breast cancer spreads, there are issues in the organs that are infiltrated with metastatic cells: pain in the bones indicates metastatic change in skeletal system, pain in the right ribcage that is accompanied by the yellow skin and mucous membrane tone indicates on metastasis in the liver tissue, cough deposits in lung parenchyma, headache, difficult walk or inability to walk indicates possible metastasis on the brain.

Most often breast cancer is discovered: 

1. by patient herself – by breast self examination (with palpation in the tumor change in the breast tissue, discharge from the nipple, observing of the changed structure of the skin /and shape of the breast)
2. by doctor during clinical examination
3. during mammograph examination

When breast cancer is detected, further diagnostic is needed: 

• clinical examination is the base of the diagnostic and it includes:
• talk with a patient in order to get more information from personal medical history, family medical history, menopausal status, birth, breast feeding
• bimanual breast examination and armpit, supraclavicular and infraclavicular fossa.

After clinical examination it is done additional diagnostics:

radiological examination (mammography, breast ultrasound, lung and heart X ray, abdominal ultrasound, skeleton x ray, scintigraphy, if necessary CT, MRI, PET/CT if there is clinical susceptible change on remote metastases).

laboratory analysis (blood test, biochemistry analysis, tumor markers).

breast biopsy: surgical (“fine or core needle”, with or without ultrasound) or radiological with guidance of mammography or ultrasound. Thus obtained biopsy of clinical and radiological susceptible changes are “gold standard” in multidisciplinary approach of further healing of breast cancer.

A sample of susceptible tumor changes obtained by biopsy, is given to pathologist for pathohistological analysis, based on which the diagnosis of breast cancer is definitely confirmed.

Histopathological type of tumor is estimated by the look of the cells: two main hystological types of breast cancers are: ductal and lobular. Based on the look of the malignant cells and its relation toward tissue structures it is determined invasiveness of the tumor, and further it can be divided on invasive and noninvasive carcinomas (“in situ”).

Based on the number of division of malignant cells, its reciprocal layout and heterogeneity, it is determined level of tumor differentiation. The greater gradus, worse is prognosis. Results of biopsy in skin cancer always contain status of steroid hormonal receptors (ER and PR), her2 status and proliferate index Ki-67.

After all examinations data is gathered when it is estimated tumor widespreadness in the body-determing stadium’s disease. After determing stadium of the cancer, further is determined specific oncological approach by multidisciplinary team (surgeon, oncologist, pathologist, radiotherapist, radiologist).

Surgical treatment of breast carcinomas 

Depending on stadium of disease and decision of multidisciplinary team, it is planned further operative treatment for treating breast cancer. The primary task of surgery is to remove  “up to healthy” tumor in order to allow better local control of tumors and regional lymph nodes.

There are two approaches in healing in treatment of breast cancer:

• breast-conserving surgery (quadrantectomy- tumor excision with surrounding breast tissue with dissection of axilla)
• mutilative surgery-total surgery, radical and modified radical mastectomy (removal of the entire breast and lymph glands of the armpit).

Approach depends on stadium of disease and previous application of chemotherapy/hormonal therapy. Application of preoperative therapy (according to decision of consilium) should reduce primary tumor, so it can be enabled efficient surgery on the breast.

After operation material is sent again on pathohystological analysis according the same principle as biopsy of tumor change on breast.

Breast cancer radiation therapy 

Radiotherapy has important place in treatment of breast cancer, as well as for therapy and palliative purposes. It is indicated after post-surgical operations when tumorectomy and quadrantectomy are performed, and after radical mastectomy, if the primary tumor is larger than 5 cm without regard to nodal status, or if 4 and more metastatic altered lymph nodes have been found on the histopathological material after surgery. Radiotherapy is used to irradiate ovaries in premenopausal patients where castration is necessary, since the breast tumor is an endocrine-sensitive tumor.

For palliative purposes, the most common are:

• Bone metastases leading to compressive fractures of spinal vertebrae, elongated fractures or pain that can not be prevented by painkiller therapy
• metastasis in central nervous system, retrobulbar and choroidal metastasis
• local recidive, lenticular skin changes and supraclavicular metastases
• enlarged metastases in mediastinum joint with superior vena cava syndrome
• ulcerated bleeding breast tumors

Medical treatment of breast cancer

Medical treatment of breast cancer implies application of hormonal, cytotoxic and biologic therapy and have role during all phases of the treatment (neoadjuvant, adjuvant, systemic, palliative therapy).

Progress in adjuvant breast cancer treatment (hormonal, cytotoxic, biologic-trastuzumab) has led to a reduction in the risk of relapse of the disease, with a significant reduction in mortality and an increase in the percentage of cured patients.

When selecting optimal medical therapy in the adjuvant approach, a combination of prognostic factors is used to assign patients for appropriate prognostic-therapeutic groups. Recently, genetic profiling of tumors has been investigated for the purpose of assessing relapse risk and improving patient selection for available therapeutic options.

Prognostic factors for breast cancer:

• pathological size of tumor
• status of axillary lymph nodes
• histological grades of tumors
• lymphovascular invasion
• marker of proliferation K1 67
• status of receptors ER and PR
• HER2/neu (c-erb B2)
• age of the patient
• menstrual status

There are three grades of risk for the relapse of the disease:

1. Low risk involves the following characteristics of the patient negative finding of lymph glands to metastases, primary tumor less than 2 cm, tumor gradient I, absence of vascular invasion, HER 2 negative status, age over 35 years. The characteristics of middle-risk patients include: negative lymph nodes and one of the following factors, primary tumor 2 cm I, grade II / III, presence of vascular invasion, absence of steroid receptors, positive HER2, age under 35 years.
2. High risk patients have at least one affected lymph node with metastatic deposits, negative steroid receptors, and HER2 positive tumor.
3. Patients with moderate and high risk are candidates for cytotoxic therapy with biological therapy in case of positivity to HER2 (except tumor size less than 10 mm, with favorable other factors of prognosis). All patients with positive steroid receptors are candidates for hormonal therapy (especially in elderly, those with a poor general condition, and in contraindications for cytotoxic therapy). It is estimated that the use of adjuvant therapy reduces the risk of breast cancer mortality by 30%.

Breast carcinomas are hormone dependent tumors. In patients with pathohistological analysis where it is proved existence of positive score of steroid receptors, only hormonal therapy is applied or with other treatment modalities.  It is proved that hormonal depending tumors have more favorable outcome, recidives occurs later, remote metastasis are more easily treated.

There are several types of hormonal therapy:

• ablation therapy (ovaryectomy, ovary radiation, application of application of LHRH agonists )
• competitive therapy with antiestrogens (tamoxifen)
• therapy with inhibitors of aromatise (anastrozole)
• additive therapy (gestagen, androgen, corticosteroid)

Metastatic breast carcinoma belongs to the group of moderately chemosensitive malignant tumors malignant tumors, which means that the response will be moderately good on systemic anti-neoplastic therapy which lasts shorter or longer, and as a rule ends with a relapse. Despite great progress and establishment of strict standards in healing protocols, metastatic breast carcinomas is still incurable illness.

According to definition of WHO curative therapy in oncology means “possibility of the control of primary or  Prema WHO definiciji kuratvina terapija u onkologiji podrazumeva “mogućnost kontrole primarnog ili meastatskog tumora duže od jedne godine sa konvencionalnim terapijama za određeni tip tumora”.

Palliative therapy is given to the patients in terminal phase of the illness if the response to the applicated curative therapy (WHO). It contains pain control and removal of other symptoms, together with psychological, social and emotional aspect. Aim of this palliative therapy is better quality of life for patient and family.

It is advised to avoid state that brings to increased risk of development of malignant neoplasm of breast cancer, regular self examination of the breast, as well as obligatory regular controls, especially if there is a family cancer history.