BREAST CANCER TREATMENT IN GERMANY

Screening includes mammography, clinical breast examination by specialists, MRI (for patients in the high-risk group) and monthly self-examination.

Annual mammography screening is recommended for women ≥ 50; it reduces mortality in this age group by 25–35%. Mammography results are more accurate in older women, partly because with age the fibroglandular breast tissue tends to be replaced by fatty tissue, which is easier to distinguish from abnormal tissue. However, screening in women aged 40–50 remains controversial; recommendations include annual mammography (American Cancer Society), mammography every 1–2 years (National Cancer Institute) and mammography with no fixed interval (American College of Physicians). The arguments against performing it too often relate to the increased radiation exposure and to the overdiagnosis of tumours (for example, ductal carcinoma in situ) that may never progress to invasive cancer during the patient's lifetime. Radiation exposure at a young age increases the risk of developing cancer. Overall, most experts recommend mammography screening every 1-2 years for women aged 40 to 50.

Only 10% to 15% of the changes detected by screening mammography turn out to be cancer, and false-negative results may exceed 15%. The accuracy of this examination depends in part on the techniques used and on the radiologist's experience. Some centres perform computer analysis of digitised mammography results  in order to make the diagnosis more accurate. Such systems may be more sensitive for detecting invasive cancer in women < 50 if the results are interpreted by a radiologist, but they are probably not as effective when interpreted by a computer program.

Clinical breast examination is usually part of the routine annual check-up in women > 35; it detects 7–10% of cancers that are not visible on the mammogram. In the USA, clinical breast examination complements but does not replace screening mammography. However, in some countries where mammography is considered too expensive, clinical breast examination is the only diagnostic method; the data on its effectiveness are conflicting.

MRI is considered to be more effective than clinical examination or mammography when examining women at high (i.e. > 15%) risk of breast cancer, for example those carrying a BRCA gene mutation. For these women, examination should include MRI as well as mammography and clinical breast examination. MRI has higher sensitivity but may be less specific. Because of its lower accuracy, it is not recommended for screening women at average or slightly increased risk.

Breast self-examination on its own does not reduce mortality, the data on its effectiveness are contradictory, and it is widely used in practice. Because a negative self-examination result may tempt some patients to skip mammography or clinical breast examination, the importance of these procedures must be explained to patients when they are taught how to perform self-examination. Patients should be advised to carry out self-examination on the same day of each month. Women of reproductive age are advised to do this 2–3 days after the end of menstruation, since the breasts are then less tender and swollen.

Percutaneous core needle biopsy is preferred over surgical biopsy. Imaging or palpation may be used to guide the core needle biopsy. Stereotactic biopsy (needle biopsy under X-ray guidance performed in 2 planes and analysed by computer to produce a three-dimensional image) or ultrasound-guided biopsy is often used to improve accuracy. Clips are placed at the biopsy site so that it can be identified later. If core needle biopsy is not feasible, for example when the lesion lies in the posterior part of the breast, surgical biopsy may be used; a guide wire is inserted under imaging guidance to mark the site from which tissue is to be taken. Areas of skin included in the specimen should also be examined, because this makes it possible to detect cancer cells in the dermal lymphatics.

The excised specimen is examined by radiography; the findings are compared with the mammogram taken before the biopsy in order to confirm that the abnormal area has been removed completely. The X-ray examination of the breast is repeated once the breast pain has stopped, usually 6–12 weeks after the tissue sample was taken as a double-check. 

Staging is based on the results of histological examination of the biopsy specimen.

Stages are classified using the TNM system (tumour, nodes, metastases). Because clinical examination and imaging are not sensitive enough to detect lymph node involvement, staging of the disease is refined during surgery, when the regional lymph nodes can be assessed. However, if a patient has palpable abnormalities of the axillary lymph nodes, preoperative ultrasound-guided fine-needle aspiration or core needle biopsy may be performed. If the results are positive, axillary lymph node dissection is usually carried out during the definitive operation. If they are negative, sentinel lymph node biopsy, which is a less invasive procedure, may be used instead.

The definitive treatment for breast cancer is surgery. The extent of the operation depends directly on the stage of the tumour, its location and the presence of metastases. If the malignant process is detected early, it may be possible to remove only the tumour itself and the tissue surrounding it (sectoral mastectomy). In all other cases the breast is removed completely (radical mastectomy).

• surgery;
• radiotherapy in most cases;
• systemic therapy: hormone therapy and/or chemotherapy.

Surgical treatment includes

• preoperative stereotactic marking of the tumour margins under ultrasound and MRI guidance using isotopes, so that breast-conserving surgery can be performed (a special technique is used during the operation to identify residual cancer cells);
• removal of the tumour (sectoral resection) with sentinel lymph node biopsy (may be combined with intraoperative irradiation of the tumour using Intrabeam).

The standard operation is a radical mastectomy with surgical exploration of the adjacent lymph nodes; If breast removal surgery is performed, the option of simultaneous plastic surgery with the placement of a breast implant is discussed with the patient.

Breast cancer treatment options in Germany besides surgery include conventional chemotherapy, radiotherapy, hormone therapy and targeted chemotherapy. Chemotherapy can be given both before and after surgery. In locally advanced breast cancer, various preoperative chemotherapy regimens are used. Hormone therapy is used to treat hormone receptor-positive breast cancer by lowering estrogen levels or by preventing estrogen from stimulating the growth of cancer cells.

Radiotherapy can be used before and after surgery; its aim is to reduce the size of the tumour before the operation and to destroy any cancer cells that may remain in the body.

Radiotherapy after mastectomy significantly reduces the likelihood of local recurrence in the chest wall and in the regional lymph nodes and may improve overall survival in patients with primary tumours > 5 cm or with ≥ 4 axillary lymph nodes involved. The adverse effects of radiotherapy (for example, fatigue and skin changes) are usually temporary and mild. Long-term side effects (for example, lymphoedema, brachial plexopathy, rib damage, radiation pneumonitis, secondary cancer, cardiotoxicity) are less common.

Reconstructive procedures include:

• the use of a long-term tissue expander filled with physiological (saline) solution or silicone gel;
• transfer of a muscle flap graft (latissimus dorsi or rectus abdominis);
• creation of a free gluteus maximus flap and reconstruction using the internal mammary arteries.

The use of palbociclib has been a breakthrough in the treatment of breast cancer. In 2015 the drug IBRANCE® (palbociclib) was registered in the USA with breakthrough therapy designation, and it was soon given one of the most prestigious awards in the pharmaceutical field — the Prix Galien — as the best drug of 2016 in the USA. In March 2017 IBRANCE® (palbociclib), previously registered in Russia in combination with fulvestrant, received approval for a new indication as first-line therapy in combination with aromatase inhibitors. In the first line of therapy IBRANCE is used in combination with an aromatase inhibitor in postmenopausal women. Previously the drug had been approved for use in combination with fulvestrant after progression on prior therapy. IBRANCE® (palbociclib) is the first drug in a new class of cyclin-dependent kinase (CDK) 4/6 inhibitors and is intended for the treatment of the most common subtype of metastatic breast cancer, HR+/HER2, which occurs in almost 70% of patients. IBRANCE® causes cell cycle arrest and thereby suppresses tumour growth. The discovery of this antitumour mechanism of action, which is fundamentally different from hormone therapy or chemotherapy, was awarded the Nobel Prize in Medicine in 2001. Acting in synergy with hormone therapy, palbociclib is able to block tumour growth for a long time in patients with HR+/HER2- metastatic breast cancer. In the phase III clinical trial PALOMA-2, median progression-free survival in the first line exceeded 2 years for the first time thanks to the combination of palbociclib with an aromatase inhibitor (24.8 months vs. 14.5 months in the comparator group). Clinical benefit in the form of an objective response by RECIST criteria or disease stabilisation was achieved in 85% of cases (as assessed in the group of patients with measurable lesions)5.

IBRANCE® has, on the whole, a favourable safety profile: only 4.1% of patients discontinued therapy because of intolerance according to the clinical trials conducted. The main side effect is haematological toxicity. Adverse events, including neutropenia, are managed by adjusting the dosing schedule with regular monitoring of the complete blood count.

With this drug, the life expectancy of patients with advanced estrogen-resistant breast cancer has on average doubled, that is, the «quiet» period without clinical symptoms has increased from 10 to 20 months. A significant improvement in quality of life is also seen with the drug. Ibrance is usually used in combination with the estrogen blockers letrozole (Femara) or fulvestrant (Faslodex). Ibrance is contraindicated in pregnancy, during breastfeeding and in case of allergy to the components of the drug.

Patients with lobular carcinoma in situ are often prescribed daily oral tamoxifen. Postmenopausal women are given raloxifene as an alternative.

In invasive cancer, chemotherapy or hormone therapy is usually started soon after surgery and continued for months or years; these forms of therapy help to delay or prevent recurrence in almost all patients, and in some they prolong life. However, some experts believe that these methods are not necessary for many tumours < 1 cm without lymph node involvement (especially in postmenopausal patients), because the prognosis is usually very good. If the tumour is > 5 cm, adjuvant systemic therapy can be started before surgery.

The relative reduction in the risk of recurrence and death with chemotherapy or hormone therapy does not depend on the clinicopathological stage of the cancer. The absolute benefit is therefore greater for patients at higher risk of recurrence or death (a 20% relative risk reduction lowers a 10% probability of recurrence to 8%, but a 50% probability to 40%). Adjuvant chemotherapy reduces annual mortality (relative risk) by an average of 25–35% in premenopausal patients. In postmenopausal patients the reduction is half as large (9–19%), and in terms of 10-year survival the absolute benefit is considerably smaller.

Postmenopausal patients with ER– tumours are the most responsive to adjuvant chemotherapy. For invasive estrogen receptor-positive (ER+) tumours without lymph node involvement, prognostic genomic testing of the primary breast cancer is increasingly used in order to decide whether hormone therapy or combination chemotherapy should be given.

Combination chemotherapy is more effective than monotherapy. Dose-dense therapy lasting 4 to 6 months is preferred; in dose-dense therapy the interval between doses is shorter than in the standard regimen. There are many treatment regimens: a widely used one is ACT (doxorubicin plus cyclophosphamide followed by paclitaxel). Acute side effects depend on the regimen but generally include nausea, vomiting, inflammation of the mucous membranes, fatigue, hair loss, myelosuppression and thrombocytopenia. Bone marrow growth stimulants (for example, filgrastim, pegfilgrastim) are often used to reduce the risk of chemotherapy-related fever and infection. Long-term adverse effects are rare with most treatment regimens; death from infection or bleeding is also rare (< 0.2%).

High-dose chemotherapy combined with bone marrow or stem cell transplantation offers no therapeutic advantage over standard therapy, so its use is not recommended.

Tumours that overexpress HER2 (HER2+) are effectively treated with chemotherapy using the humanised monoclonal antibody – trastuzumab. Trastuzumab is usually continued for a year, although the optimal duration of treatment has not been established. A serious potential side effect is a reduction in cardiac ejection fraction.

Hormone therapy (for example, with tamoxifen, raloxifene or aromatase inhibitors) is most effective when the tumour has both estrogen and progesterone receptors, slightly less effective when only estrogen receptors are present, minimal when only progesterone receptors are present, and has no effect when neither type of receptor is present. For patients with ER+ tumours, especially those at low risk, hormone therapy may be used instead of chemotherapy.

• Tamoxifen: Tamoxifen binds effectively to estrogen receptors. Adjuvant tamoxifen taken for 5 years reduces mortality by about 25% in premenopausal and postmenopausal women regardless of axillary lymph node involvement; treatment for 2 years is not as effective. If the tumours carry estrogen receptors, treatment for 10 years prolongs survival and reduces the risk of recurrence compared with 5 years of treatment. Tamoxifen can cause or worsen menopausal symptoms, but it reduces the likelihood of cancer developing in the contralateral breast and lowers serum cholesterol. Tamoxifen increases bone density in postmenopausal women and may reduce the risk of fractures and the risk of coronary heart disease. However, taking tamoxifen significantly increases the risk of endometrial cancer; according to studies, by 1% in postmenopausal women after 5 years of use. Therefore, if a woman has spotting or bleeding, she should be examined for endometrial cancer. Nevertheless, the improvement in survival in women with breast cancer far outweighs the risk of death from endometrial cancer. The risk of thromboembolism is also increased. Raloxifene, which may be prescribed as a preventive agent, is not used for treatment.
• Aromatase inhibitors: These drugs (anastrozole, exemestane, letrozole) block the peripheral production of estrogen in postmenopausal women. Because aromatase inhibitors are more effective than tamoxifen, they are becoming the preferred choice in early-stage receptor-positive breast cancer in postmenopausal women. Letrozole may be used in postmenopausal women who have completed tamoxifen therapy. The optimal duration of aromatase inhibitor therapy has not been established.

The long-term prognosis depends on the stage of the cancer. Lymph node status (the number and location of the affected nodes) correlates with overall disease-free survival more closely than any other prognostic factor.

5-year survival (from the National Cancer Database) depends on the stage of the cancer:

• Stage 0: 93%
• Stages IA and IB: 88%
• Stage IIA: 81%
• Stage IIB: 74%
• Stage IIIA: 67%
• Stage IIIB: 41%
• Stage IIIC: 49%
• Stage IV: 15%

An unfavourable prognosis is associated with the factors listed below:

• Young age: The prognosis is less favourable for patients diagnosed with breast cancer between the ages of 20 and 40 than for those who receive this diagnosis in middle age.
• Larger primary tumours: Larger tumours metastasise to the regional lymph nodes more often and are also associated with a less favourable prognosis regardless of lymph node status.
• Cancer at a late stage: For patients with poorly differentiated cancer the prognosis is less favourable.
• Absence of estrogen and progesterone receptors: For patients with ER+ tumours the prognosis is more favourable and hormone therapy is more effective. For patients whose tumour has progesterone receptors the prognosis may also be more favourable. For patients whose tumour has both estrogen and progesterone receptors the prognosis may be better than for patients with only one type of receptor, but precise data are lacking.
• Presence of the protein HER2:: If the HER2 gene (HER2/neu[erb-b2]) is amplified, overexpression of the HER2 protein begins, which leads to increased cell growth and division and, accordingly, to the appearance of more aggressive tumour cells. Overexpression of the HER2 protein may be associated with more aggressive histological forms, ER- tumours, marked proliferation and larger tumour size, all of which are linked to a poor prognosis.
• Presence of the BRCA genes: At any given stage of cancer, the prognosis for patients with the BRCA1 gene is less favourable than for patients with sporadic tumours, probably because these patients have a greater number of cancer cells at a late stage with no hormone receptors. Patients with the BRCA2 gene may possibly have the same prognosis as patients without these genes if the tumours have similar characteristics. If either of these genes is present, the risk of a second cancer developing in the preserved breast tissue is increased (possibly up to 40%).

• urgent scheduling of an appointment with leading German oncology experts;
• diagnostics and treatment carried out exclusively in certified oncology university centres;
• innovative diagnostic techniques;
• accurate pathological diagnosis in certified institutes of pathology;
• treatment started without delay once the work-up is complete;
• selection of the optimal individual therapy by a multidisciplinary tumour board (surgeons, gynaecological oncologists, radiologists, haematologists, chemotherapists, pathologists, nuclear medicine specialists);
• adherence to international treatment protocols;
• innovative methods of treating cancer;
• use of minimally invasive surgical techniques wherever possible;
• implantation of a port system for chemotherapy to avoid damage to the peripheral veins;
• targeted therapy with tamoxifen and aromatase inhibitors;
• treatment with Herceptin in the presence of the HER2/neu drug resistance gene;
• continuous monitoring of the tumour's response to the drugs, which allows oncologists to change treatment regimens in good time and select more effective agents, ensuring a high survival rate for cancer patients even at an advanced stage;
• supportive therapy to minimise the side effects of chemotherapy and radiotherapy;
• treatment with authentic latest-generation cytostatics;
• an individually tailored radiotherapy plan.