The government of Serbia commitment in fighting malignant diseases is evident through collaboration with the World Bank. The Ministry of Health (MOH) invested almost 70% of additional financing from the World Bank's Second Health Project ($ 21 million) in radiology infrastructure for improving cancer diagnosis and treatment in 2018. Oncology is the second largest disease expenditure ($ 222 million), just following cardiovascular diseases which consumed $301 million in 2017 (14).

According to NHIF, the average public expenditure for an oncology patient is $ 860 per year, 58% of which covers health services, and 42% covers drugs and medical supplies. Due to the inefficiencies in the provision of care, such as long time on waiting lists, patients who can afford it often turn to the private health sector, mainly for diagnosis and follow-up screening. Key informant estimates suggest that this oncology related OOP spending averages approximately $20 per month per patient (15, 16).

The market for oncology drugs represents only 10% of the whole pharmaceutical market in Serbia, by far the lowest share in the region, in comparison to Bulgaria, Slovenia, Italy and Croatia. Serbia also had the lowest per capita expenditure on oncology drugs ($13) among its neighbors and was far behind European countries in adoption of innovative therapies, such as bio-, immuno-, and hormone-therapies (14). The analysis of adoption of the latest 43 innovative drugs in Europe for oncology ranks Serbia as the last one with only one innovative therapy on the reimbursement list while the average in EU is 24 (17).

Late diagnosis is one of the key challenges of the Serbian oncology program. In 52.5% of cases, the malignant disease in Serbia is diagnosed in an advanced stage (III-b or IV) with regional and distant metastases (18). Since the costs of breast cancer treatment is progressively increasing with new expensive therapy options and better progression free survivals and overall survivals, there is an exponential increase in treatment costs, especially for later stages of illness (19).

Serbia had one the lowest number of computed tomography (CT) scanners per 100,000 inhabitants in 2016 along with Hungary (0.9) and the lowest number of magnetic resonance imaging (MRIs) per 100,000 people (0.3), after Hungary (0.4) (20). Serbia moves toward the EU standard concerning radiotherapy. Between 2016 and 2019, the MOH invested in 15 linear accelerators for radiotherapy treatment, significantly reducing time on waiting lists, therefore increment in patient survival rate are expected to take place by 2022 (14).

A low- and middle-income country have higher rates of breast cancer mortality in comparison to high-income countries and with it comes the higher costs which affects the cancer care delivery, policy and strategies of countries which are crucial components for accessing the good health care (13). Focusing on the EU-27, breast cancer is the most diagnosed cancer with over 360,000 new female cases (13.3% of all cancer diagnoses), followed by colorectal and prostate, and third overall when considering the most common cause of death (21). The total costs of healthcare provided for breast cancer patients in Serbia was found to be between 34.53 million € in 2010 and 25.58 million € in 2019, and these concern only direct costs (Table 1). Data concerning Vojvodina, northern region in Serbia, for 2019 indicated that the total costs for breast cancer were 15 million €, but direct costs accounted for 5 million €, i.e., 34% (23). It is estimated that in 2019 Serbia had 6,963,764 inhabitants, while Vojvodina had 1,852,093 inhabitants. Therefore, breast cancer was also great financial burden for health system in Vojvodina, like in Serbia, as a whole.

In highly developed countries like US, projections of the cost of cancer care pointed to rose from $26.8 billion in 2015 to $29.8 billion in 2020, as a 11.2% increase (24, 25). Although the United States (US) is considered a very developed country, it is also considered one of the countries whose healthcare system is one of the least effective—the COVID-19 pandemic has made this very evident. Countries like Serbia where the Unified Health System (SUS) exists had more effective results, even with a lower per capita value during the pandemic compared to the United States (US). This is justified because in countries like Serbia, the Health System is universal and comprehensive (26), therefore in crisis situations they tend to respond better and be more resilient and responsive.

Breast cancer has the highest treatment cost of any cancer, accounting for 14% of all cancer treatment costs (27). The costs for medical services and prescription drugs in breast cancer patients was $26.2 billion and $3.5 billion, respectively in 2020 in US. The average per-patient costs for medical services were highest for the end-of-life phase (year before death from cancer, $76,100), followed by the initial care phase (first year after diagnosis, $35,000), and continuing care phase (the time in between these two phases, $3,500) (27).

Cancer costs the EU €126 billion in 2009. Lung cancer had the highest economic costs (€18.8 billion, 15% of overall cancer costs), followed by breast cancer (€15.0 billion, 12%) (28). Considering healthcare costs only, breast cancer came in the first place. Newly diagnosed cancer patients from the Central Serbian region, regarded as representative of national cancer incidence and prevalence rates, were included in retrospective data-based analysis regarding two-year period (2010–2011) (29). This investigation of end-of-life costs of medical care for advanced stage cancer patients indicated that the average costs per patient were highest (13,114.10 €) and lowest (4.00 €) in breast cancer and melanoma.

We further analyzed the expenditures associated with the diagnosis, therapy, inpatient/outpatient care, physician examination, drug preparation/administration, nursing care, and other breast cancer patient services. The NHIF database breaks down diagnostic services into the laboratory, radiology services (classic ones, magnetic resonance imaging, computed tomography scan, ultrasound imaging, interventional services), nuclear medicine services, endoscopic services (examinations and treatments), biopsy (including surgery), and other.

Diagnostics of breast cancer in our research increased from 2.83 million € in 2010 to 4.5 million € in 2019. We found different trends regarding the costs of these services—radiology, nuclear medicine, biopsy, endoscopy and other ones, with relatively steady cost of laboratory (Table 1).

Within the observed 10-year period, the national inflation rate has significantly fluctuated from 2010 to 2013, and in 2011 it amounted 11.14% (Table 1). After that, the national inflation rate has slight fluctuations from 2014 to 2019, in the range from 1.12% to 3.13%. Inflation continues to be a major headline in many countries with each industry branches and sector feeling the repercussions of the nation's economic climate. However, although the inflation rate was the highest in Serbia in 2011, the total costs were not significantly higher compared to other years (Table 1). In the following years, the total healthcare costs of breast cancer in Serbia had more or less decreasing trend. If it is known that, as a rule, inflation or specific price indices are included in the next year's price determination, one could expect the opposite scenario. However, the healthcare industry has traditionally been described as recession-proof, and indeed, from a healthcare perspective, the cost of medical services has lagged slightly compared to other parts of the economy (30). Therefore, it can be considered that inflation in the 10-year follow-up period did not have a significant impact and was not reflected in the growth of the total treatment costs of these patients in our country. This can be explained by the fact that in Serbia, health care is mostly financed from the state budget, so with the intervention of state, health services have a relatively stable price (26).

The costs of breast cancer diagnosis accounted for 8.2% of the total breast cancer costs in 2010 and showed an increment up to 17.6% in 2019 (Table 1). The laboratory services as a part of the diagnostic costs were the most expensive (1.43 million € on average), while the tumor breast markers showed steady percent of costs with roughly 12% of all cost from laboratory analysis during follow-up period. Radiology, nuclear medicine, endoscopy, biopsy, and other services increased from 2010 to 2019 by 1.54 times, 2.5 times, 1.2 times, 5.5 times, and 3.9 times, respectively.

Trend in therapy costs for breast cancer was in contrast with diagnostic costs. A decreasing trend within 10-year period, from 25,24 million € in 2010 to 15,47 million € in 2019 was observed (12.6%), although considering absolute costs in Euros, a larger sum invested in breast cancer patients was used for therapy comparing with the funds invested in diagnostics. Therefore, it appeared that in this period, the focus of the health authorities was on the prevention and early diagnosis of the breast cancer, since it was obviously that there were ineffective preventive programs and premature mortality in our country (5).

Therapy costs were divided into the subgroups in the following order—medication, medical devices, surgery, radiotherapy, interventional radiology, and others (Table 1). All kinds of costs for the breast cancer therapy showed a decreasing trend over the observed period, except for surgery costs which increased by about 42%. Overall, the most expensive was medication, which included all kind of drugs used for breast cancer treatment, but also with continuing decrease over the follow-up period.

We found that the relative costs of inpatient days for breast cancer were on the continuous decline, from 5.8% in 2010 to 3.7% in 2019, as like the costs of outpatient days which roughly decreased double (from 1.1% in 2010 to 0.5% in 2019) (Table 1). The physician examination costs began to rise, from 4.2% in 2010 to 5.9% in 2019, while the relative cost of nursing care was from 1.6% (2010) to 3.2% (2019). Collectively, the costs of inpatient days, outpatients' days, physician examination, and nursing care increased from, 12.67% to 13.26% of the total breast cancer costs from 2010 to 2019.

Total breast cancer therapy costs varied from 25.2 million € in 2010 to 15.5 million € in 2019, of which total chemotherapy accounted for 74.7% to 79.68% of the total therapy costs, respectively (Tables 1, 2).

Costs of anticancer drugs (total chemotherapy) were divided into the subgroups in the following order—biological therapy, hormonal therapy and cytotoxics and antimetabolites (Table 2). During follow-up period, great changes have occurred concerning biological therapy which accounts for 85.8 % of the total chemotherapy costs in 2019, i.e., it increased for 31.3%. However, that large relative increase in costs is largely the result of a decrease in overall costs for anticancer drugs from 2010 to 2019. On the contrary, large decrease of sum invested in hormonal therapy has been noticed, from 25.1% in 2010 to 2.7% in 2019. Costs of cytotoxics and antimetabolites decreased, and it accounted for only 11.6% of all anticancer drug costs in 2019 (Table 2).

Serbia has two health technology assessment (HTA) committees, both with limited capacity to assess population needs and to conduct “tailored” cost effectiveness analyses. One of them is within the MOH and another is housed by the NHIF, that is Central Drug Committee (CDC) (31). The CDC primarily assesses the HTA of pharmaceutical companies, submitted as a part of their application for inclusion of new drugs on the NHIF reimbursement list. After conducting budget impact analysis, the CDC submits recommendations for final approval to the MOH. The ultimate criteria for accepting a drug for national reimbursement list is the budget availability. Serbian GDP per capita and other economic indicators are too low to make innovative therapies appearing cost-effective using the standard National Institute for Health and Care Excellence (NICE) style for HTA assessment (32). Despite the existence of two HTA committees, the introduction of new drugs and medical devices is carried out by ad hoc evaluations that largely take into account the budgetary impact, without sufficient assessment of the optimal cost/benefit ratio (33).

Limitations of the study: The study did not cover the period from 2020 onwards, due to COVID-19 pandemic and, unfortunately, we suppose that there were some changes in making diagnoses and therapy opportunities for these patients. According to Italian researchers' estimates undetected breast cancer cases rate ranges between 5.01 and 11.53% due to the lockdown (34). Therefore, higher health care costs and worsening of long-term outcomes of breast cancer is something that all health systems, including the one in Serbia, would face in the near future. Our study is retrospective observational study. However, we believe that its importance corresponds to the facts that included data relate to the national level and for a whole decade follow-up period.