Head of the Chair of Oncology in the Academy of Postgraduate Studies in Zaporizhia, MD, PhD, professor Alexei Alexeievich Kovaliev

Due to the rapid development of science and technologies applied in public health care practice, the modern national schemes against neoplastic diseases provide solid foundations for development and implementation of the more useful methods for cancer treatment. The final effect of the pursuance of those schemes is the reduction of incidence and death rate due to cancer as well as the improvement in the life quality of patients suffering from malignant neoplasms. In the last decade a significant number of EU member states draw up and/or updated their schemes, plans, national strategies for combating cancers associated with primary prevention (promotion of health and environmental protection), secondary prevention (pre-screening and early diagnosis) as well as comprehensive care services and organisation of medical assistance and palliative care for target population groups.

Breast cancer is a serious medical and social problem. It is at the forefront of the neoplasms in the scope of incidence and death rate. In our articles we frequently referred to the issues associated with the prevention of oncologic pathology and organisation of pre-screenings. This time we offer our readers that they become familiar with the paper that was delivered by the Head of the Chair of Oncology in the Academy of Postgraduate Studies in Zaporizhia, MD, PhD, professor Alexei Alexeievich Kovaliev during the National Scientific and Training Conference on Mammography “Modern aspects of malignant breast cancer treatment. Mammary gland in the multidisciplinary context” (26-27 October 2018, Kiev)..

People associate every century with particular diseases. In Antiquity and Middle Ages, communicable diseases, such as smallpox, malaria and plague, constituted a lethal threat to human health. The 19th century was an epoch of tuberculosis whereas neoplastic diseases come to the fore in the 20th century. In the fight with communicable diseases, the humanity succeeded, in particular, due to preventive actions (vaccinations, improvement in the quality and conditions of life etc.). In the case of cancer, however, the decrease in incidence and death rates associated with oncologic diseases is almost impossible without a change of priorities - from treating diseases to preventing their development.

What do we currently know about breast cancer? In the 20th century, this pathology was treated as monolithic disease with neoplastic changes exceeding 3-4 cm. Renowned American clinical surgeon, William Stewart Halsted (1852-1922), recognised tumours of 3.5 inches (approx. 9 cm) as small, thereby not important. Radical surgeries were the most commonly applied treatment method (mastectomy with 3 levels of lymph glands excision). Empirical chemotherapy in the case of breast cancer with metastases was characterised by high toxicity and low effectiveness. The lack of knowledge on breast cancer was the major cause of depression, fear and adoption of a victim attitude in patients suffering from oncologic diseases.

At the beginning of the 21st century, greater attention was paid to early breast cancer detection. General surgery and aesthetic surgery started to be widely applied as the standard treatment methods whereas the role of radiotherapy, which is characterised by a harmful effect of radiation, decreased. Moreover, the meaning of pharmacological therapy increased in that time. Studies have been carried out on the effectiveness of therapeutical combinations and improvement in pharmacological therapy methods. At the beginning of the 21st century, a personalised approach to treatment based on the biological features of tumours and individual features of patients started to be applied. It provided a significant increase in life expectancy and improvement in life quality in oncological patients. Nevertheless, in many countries death rate is high due to neoplastic diseases in women. Taking into account the incidence in the female population, breast cancer is still on the one of the leaders, second only to lung neoplasm. What is more, approximately 90% of deaths associated with malignant neoplasms, including breast cancers, occur in countries in which there are no pre-screenings or primary prevention (M.P. Coleman et al., 2008). Simultaneously, the standardisation of approach to pre-screening diagnostics plays an important role in the improvement in the rates in the case of breast cancer.

Depending on the level of economic development, the experts of World Health Organisation (WHO) classify countries according to low, average and high levels of health care resources. WHO recommends applying various strategies of combating cancer depending on the level of economic development of a given country. Additionally, 3 scenarios have been prepared: A, B and C – for the countries with low, average and high level of health care resources, respectively.

According to this classification, Ukraine belongs to the second category. For such countries, WHO recommends the following priority actions in the scope of decreasing the incidence of breast cancer and deaths resulting from this pathology (scenario B): primary prevention, early diagnostics and pre-screening, radical and palliative treatment as well as the improvement in patient rehabilitation conditions.

There are 2 groups of risk factors for breast cancer: uncontrolled (menarche before the age of 12, menopause after the age of 55, ageing, family history of neoplasm, BRCA1 and BRCA2 gene mutations) and controlled (alcohol abuse, obesity, infertility, giving birth to a baby after the age of 30, administration of hormone replacement therapy, application of certain contraception methods, family history of radiotherapy of chest organs).

According to the recommendations of the European Society for Medical Oncology (ESMO), the criteria for genetic studies required for determination of the BRCA status in the case of breast cancer may differ due to various frequency of gene mutations.
Moreover, the following division criteria are applied (S. Paluch-Shimon et al., 2016):

• family history of >3 breast cancers or ovarian cancer;

• medical history of >1 breast cancer or ovarian cancer at the age of 50;

• development of breast cancer and ovarian cancer in the same woman;

• development of breast cancer at a young age.

Moreover, the document also indicates that the frequency of BRCA mutation is 1 in 250 women.

The major methods preventing the development of hereditary breast cancer is active observation, preventive hormonal therapy and preventive surgery.

Morphological classification of neoplasms offered by W. Dupont and D.L. Page includes the following types of precancerous conditions:

• non-proliferative changes;

• proliferative changes without atypia (1.9 times higher risk of breast cancer);

• atypical hyperplasia (5.3 times higher risk of breast cancer);

• lobular carcinoma in situ;

• lobular carcinoma in situ.

In the case of treating women with breast pain, the general recommendations in the scope of dietotherapy include the elimination of products with a significant level of methylxanthines, caffeine and chocolate. It is crucial to decrease the amount of fat and increase the number of complex carbohydrates in the diet. It is recommended to eat products rich in vitamin E. The important preventive actions are strengthening exercises and wearing of a supportive brassiere.

It is crucial to always remember about the neoplastic prevention regardless of the risk level. The risk of breast cancer is known to increase with ageing. Due to this fact women over 50 are recommended to undergo pre-screening (ESMO, 2017). In the case of women in the low-risk group, it is also important to take preventive actions. The risk of breast cancer can be reduced by: several pregnancies, first pregnancy before the age of 30, breastfeeding, high physical activity.

Undoubtedly, participation in pre-screening programmes and routine check-ups in order to detect any hyperplasia of mammary gland are the foundation of any breast cancer prevention schemes regardless of the age category and risk group of the woman.

According to medical pre-screening assumptions, any routine diagnostic scheme that is used in order to detect a particular pathology should fulfil a series of criteria (J. M. G. Willson, Y. G. Jungner, 1968):

• a detected disease should be a serious health and social problem;

• there should be effective and permissible treatment methods for the patients with the diagnosed disease;

• proper diagnostic and treatment services should be accessible;

• detected disease should have a well-identifiable latent stage or early symptomatic stage;

• there should be proper methods of detecting and examining pathology in place;

• examinations should not be excessively inconvenient for the patients;

• it is crucial to understand the course of the natural development of the disease properly (from the latent form to the evident form);

• it must be specified patients who should be classified to the group of patients requiring treatment;

• the costs associated with disease detection (including diagnostics and treatment) should be economically balanced with the potential costs associated with healthcare in general;

• the detection of the disease should be a continuous process, not a single campaign.

The history of breast disease diagnostic technique development, including, in particular, medical imaging, started in 1913 thanks to Albert Solomon and his works (1883-1976). However, due to a low quality of the obtained image and a high level of radiation, the rationality of using this method was recognised as controversial. Moreover, extensive studies in the scope of X-ray had not been conducted long enough.

At the end of the 1960s, i.e. after Cohen and the co-author offered the concept of the mammographic pre-screening examinations and after 1962, when the results of extensive study of R. Egan were published, the role of mammographic examinations in pre-screening schemes was thoroughly verified. It was proved that the precision of this method of detecting breast cancer amounts to 92-97%. The scheme of pre-screening examinations was implemented for the first time and is still pursued in the USA, Sweden, Canada and Great Britain. Thanks to its implementation, the death rate associated with breast cancer was significantly decreased in various countries.

In Ukraine, the pursuance of the pre-screening scheme is governed by the Regulation of Minister of Health of Ukraine of 30.06.2015 no. 396 “on approval and implementation of medical and technical documents in the scope of healthcare standardisation in the case of breast cancer”, in which a unified clinical protocol of the primary, secondary and tertiary medical healthcare (highly specialised) “Breast Cancer” (hereinafter referred to as the “protocol”). Pursuant to the regulatory documents, there are three elements of pre-screening scheme pursuance in the scope of breast cancer depending on the institution in which it is pursued.

The stages of organisation of mass pre-screening examination in the scope of breast neoplasms include:

• the gathering of full information on the features that contribute to the occurrence of breast cancer;

• performance of the breast condition examination and palpation in order to divide the examined patients preliminary into groups based on the risk level for further detailed examination;

• mammography.

The major tasks of the physician in the healthcare institutions that provide the primary health care (subparagraph 4.2.1-4.2.7 of the protocol):

• maintaining a register of women obtaining medical assistance from general practitioner;

• filling in the “medical history” for all women obtaining medical assistance from general practitioner in order to determine the family history of breast cancer;

• highlighting the necessity of participation in pre-screening examinations in the scope of breast cancer and of performance of mammography among the greatest possible number of women of 50 to 69 years of age without the ailments associated with breast and without a “genetic” risk of breast cancer. It is the age that is the most important risk factor for the majority of women;

• making available information on breast self-examination that should be performed every month, starting from the age of 20 (on the 7-14 day of the cycle);

• clinical breast examination before referring to mammographic examination is performed once every 3 years by a general practitioner, a nursing assistant, a nurse, who completed the special training, in primary health care institutions;

• issuing women a referral for mammographic examinations to regional diagnostics centre or outpatient clinic by a general practitioner (by means of telephone call or personalised invitation). The institution to which a woman is referred for mammographic examinations should be specified in the local protocol;

• entering data in the register of women undergoing mammographic examination by a general practitioner. Specialists in internal medicine and general practitioners play the key role in the pursuance of those tasks in primary health care institutions. The significant assistance in their work is performed by nursing assistants that completed relevant training.

The major task of specialists in oncology and radiology in healthcare facilities providing the medical assistance of the second and third level is the guarantee of performing high quality mammographic examinations along with issuing written opinions to all patients and regularly providing the general practitioner with information about the register of women who underwent mammographic examinations to general practitioner (point 4.2.9 of the protocol).

Recommendations regarding the performance of mammographic examinations (point 4.2.8 of the protocol):

• the referral for mammographic examinations should not be issued to women below the age of 35 if the are no sufficient bases for their performance (ultrasound examination should be prioritised);

• in the case of positive family history in the scope of breast cancer, the mammographic examinations should be performed once every 1-2 year(s), starting from the age of 35 (regular breast self-examination);

• all women between the age of 35 and 40 a one-off single primary mammographic examinations in order to determine the structure of breast tissue;

• between the age of 40 and 49 it is recommended to perform mammographic examinations according to the indications (clinical examination data and the breast self-examination);

• between the age of 50 and 69, the mammographic examinations are performed once every 2 years, taking into consideration the results of the previous examinations, self-examination or the clinical breast examination.

Every available and currently used diagnostic methods regarding breast cancer and the preceding breast hyperplasia has advantages as well as disadvantages. During the self-examination, women detect approximately 90% of breast cancer cases; however, almost 50% of them is disease of advanced stage. It should be noted that along with ageing of women, the sensitivity of this method decreases. The influence of regular performance of self-examination on the incidence among women was not proved. Only 8% of patients examine their breasts regularly, 6% do it irregularly and approximately 66% do not do this independently. If the healthcare personnel that underwent a special training performs the examination, the sensitivity of this method is undoubtedly higher, but it depends on the stage of the disease: carcinoma in situ is detected in 48%, I stage in 70%, II stage in 90%, III stage in 89%, and IV stage in 93% of women.

Mammography is the golden standard in the pursuance of pre-screening schemes; however, due to the possibility and availability of its pursuance, it can be used only in the highly developed countries. The sensitivity of this method depends on the quality of diagnostic equipment, radiologist qualifications, density of breast tissue (in the case of elevated density, the accuracy of the method falls to 55%). It should be observed that in 20% of women between the age of 40 and 49 as well as in 10% of women between the age of 50 and 59, the pathology is not detected by the mammographic method and this method is characterised by a high frequency of false positive results.

As a result, pre-screening mammographic examinations have the following disadvantages:

• high costs, including the costs of health care system associated with equipment purchase and handling and special staff training;

• in the distant regions of Ukraine, it is poorly available or not available;

• the probability of occurrence of false positive results in women with high breast tissue density is 50%;

• it requires the application of additional, more detailed diagnostic methods.

The other available diagnostic method in the scope of breast cancer is ultrasound. However, its application is recommended for women above the age of 35.

Due to the fact that the majority of current pre-screening examination methods in the scope of breast cancer, including mammography, have certain disadvantages, there is an urgent need to develop more available informational and, which is primarily significant, safe pre-screening methods for breast hyperplasia.

The rapid development of technology in the scope of medicine contributed to the occurrence of original solutions associated with non-invasive diagnostic methods. As is known, every process of breast hyperplasia is accompanied by active angiogenesis that is reflected in the local increase in temperature. Scientific publications provide the information that local changes in temperature in the focus of malignant neoplasms are registered in the case of the tumours of small dimensions. Braster PRO is an innovative method of breast examination which relies on the detection of temperature changes that are not associated with neoangiogenesis.

The patented liquid-crystal matrix of the device of high sensitivity allows to detect changes in temperature in the breast tissue. Thermograms obtained during the examinations are transferred to the telemedicine centre by means of mobile application and are analysed by artificial intelligence according to the standardised diagnostic algorithm under the supervision of qualified specialists – the third millennium medical case conference.

Matrix of high sensitivity allows to register temperature changes even in the case of a tumour of very small dimensions. The minimum dimension of the neoplasm detected by Braster PRO is 3 mm. The neoplasms of such a dimension cannot be detected on palpation, breast self-examination or on the specialist’s appointment. It is even hard to detect them with instrumental methods.

During performed mammography, selective examination of fragments that show temperature change detected by Braster PRO increase the diagnostic efficiency of pre-screening.

The sensitivity of the method does not rely on tissue density, breast size, age or menstrual cycle phases and allows to examine the patient during a standard medical appointment. The method is easy to apply. It is performed in a room at the temperature of +22-25 °C. It can be performed by mid-level medical staff. It is painless, it does not put at risk of radiation and the time of performing the examination does not exceed 20 min. The sensitivity of this method amounts to 81.5%, specificity – 87%. In the case of breast pre-screening, it is crucial to remember that the negative prognostic meaning of the method (which is the probability that a patient with a negative examination result has in fact no signs of a disease) amounts to 92.2%.

To sum up, it can be stated that Braster PRO is a comfortable, non-invasive and safe pre-screening method in the scope of breast cancer.

The decrease in incidence due to breast cancer depends on encouraging the highest possible number of women to take part in mammographic pre-screening examinations and the development and implementation of new malignant neoplasm diagnostic methods. One of such methods is a scheme of pre-screening examinations for breast cancer that is based on Braster PRO technology.

Braster PRO is a viable alternative to self-examination as well as palpation and visual examination by a specialist.

Drawn up by Anton Wowczek