Background

Cancer, the most common disease, and the second leading cause of mortality globally refer to several diseases characterized by the progress of unusual cells that grow uncontrollably [1]. Breast cancer (BC) is the fifth foremost reason of cancer-related mortality worldwide [2]. According to statistics, in 2022, after lung cancer, BC is the second main reason of cancer-related death among women globally [3]. The American Cancer Society provides its update for BC where it declares BC alone accounts for 30% of newly diagnosed women in US. In addition, 290, 560 women were diagnosed with BC in 2022. Incidence rates have amplified slightly—by about 0.5% per year on typical—since the mid-2000s [3]. Around 43,250 women will die from BC in 2022 [3]. In the United States, at the beginning of 2022, about 4.1 million women with a history of BC living have been reported. Around 4% of these women are alive with metastatic BC, more than half of whom were initially detected with early-stage (I-III) BC [4]. Overall, in developed countries, the BC incidence is higher than that of in developing countries, however, it has been increasing in developing countries as well [5]. This may be due to a higher prevalence of the known risk factors, lifestyle factors, behavior, late age at any birth, socioeconomic, early age at menarche, low parity, late age at first birth, and late menopause [6,7,8]. Therefore, genomic alterations are a significant issue that significantly changes the risk profile of BC [9]. BC is a highly heterogeneous cancer that comprises four subtypes including, HER2-positive, triple-negative, luminal A, and luminal B [10, 11]. About 20% of all BC belongs to Triple-negative BC (TNBC) which is most common among women under 40 years of age [10]. TNBC is an aggressive tumor with early relapse and a trend to become in progressive stages [10]. The mortality effects, the economic burden, and social effects of BC are key factors for human society [12, 13]. For example, it was reported that the economic burden for lung cancer, colon/rectal cancer, and BC was $188 billion, $99 billion, and $88 billion in the world, respectively [14]. Consequently, the economic burden of cancers is vital due to the increasing costs of cancer diagnosis and therapy. Compared to patients with non-TNBC, patients with TNBC have advanced cancer stages with a low prognosis. These patients experience a higher hospital resource use and cost of care [15]. As TNBC usually occurs at a younger age, therefore patients with TNBC bear a greater economic burden. Because of the growing incidence rate and extended patient being with the higher management costs of BC care, the economic burden of it has possibly elevated ultimately [16]. The costs of TNBC include direct and indirect costs that mainly driven by hospitalization, emergency department visits, reduction of work productivity or loss of job, and outpatient [17, 18] [19].Patients with TNBC receive common chemotherapies. The effects of novel therapies like immunotherapies on total costs of cancer care are unclear. Furthermore, disability and loss of income, mainly among working-age individuals, increase extra burden to young patients, which known indirect costs [20]. For economic assessment (direct and indirect costs), the approaches used for the quantity of efficiency costs may impact the outcomes of the experiments [21]. Variability in methodology used for the productivity costs could hinder the evaluation of results between different countries. Inconsistency results may arise from the value of local efficiency, patient and type of diseases, social security programs, and epidemiologic situations [22]. Due to the high economic burden (direct and indirect costs) of TNBC, the essential to progress the managing patients with TNBC, especially in developing countries is of excessive standing [23]. Cost of cancer investigations are very useful in defining the cost efficacy of diagnosis and therapies of the cancer and accordingly the optimum use of resources. Patients with TNBC bear several direct and indirect costs. In this study, we aimed to prepare a systematic literature review to summarize the published studies and evaluate the several different types of studies included direct and indirect costs of TNBC.

Methods

In the present study, we used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendation to identify, select, and critically evaluate all relevant research published between the years of January 2010 and January 2023 [24].

Literature search

In this systematic literature review, we searched articles from established literature search electronic databases like, PubMed, ISI Web of Science, Scopus, and Google Scholar from January 2010 and January 2023 (Supplementary table S1). No limitations on publication status were enacted. The keywords used were “Breast cancer”, “economic burden”, " TNBC “, " TNBC burden”, and’’ triple-negative breast neoplasms”. The primary exclusion criteria were: (i) publications that were not peer-reviewed, (ii) publications that lack methodological information, (iii) studies not written in English and (iv) publications that did not primarily focus on BC economic burden. The eligibility criteria for study inclusion are presented in Table 1.

Table 1 The eligibility criteria for study inclusion
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Table 2 Relevant studies involved in the systematic review
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Data extraction

After a full literature search, a reference manager tool (EndNote) was used to identify and remove potential duplicate articles. Data were extracted from relevant studies, economic evaluations, and clinical trials. For the direct and indirect costs of patients with TNBC, data were extracted from relevant articles. Direct costs are costs that are related to patient care directly, for example: drugs, nursing services, diagnostic imaging, medical supplies, and rehabilitation. Indirect costs - are costs that are not directly attributable to patient care. For instance: reduction of work productivity or loss of job, information technology, general administration, human resources, health records, physical plant and maintenance, and other local facilities. The eligibility criteria inclusion was presented in Fig. 1.

Fig. 1
figure 1

PRISMA flowchart for the systematic literature review on direct and indict costs of triple-negative breast cancer

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The authors independently reviewed the titles and abstracts of the articles and evaluated full texts for eligibility. Irrelevant studies, duplicated articles, and studies that did not cover the inclusion criteria were discarded. Using a conventional data abstraction process, the authors contributed to preparing the following data from each included article: authors and year of publication, population, setting, country, interventions, age, indirect costs, direct costs, and study design. In the next stage of the selection process, for the risk of bias, extracted data were additionally assessed by Dr Sadeq Rezaie independently [25].

Quality investigation

The qualitative investigation was passed by two authors (SR and MB) using a checklist. The qualitative investigation was checked by the authors SR. The following points were checked: study design and analysis, economic burdens, scope, type of costs, full text, and availability of the results.

Cost Adjustment

Because of the diversity in time and place of studies, we adjusted all costs to 2023 (January) USA dollars ($US) for simplifying comparisons between studies as described previously [26]. In articles the cost year was not reported, we considered the publication date as the cost year.

Results

Characterization of published and relevant studies

The search and assortment procedure to identify relevant studies, which investigated the economic burden of TNBC, was provided as a flow diagram (Fig. 1). As shown in Fig. 1, we first identified 881 studies related to the economic burden. Then, after a screening process, we found 19 eligible articles for full-text monitoring, finally, 15 articles were analyzed according to the study design criteria in the present review work. Included articles are presented in Table 2.

Study characteristics

The 15 articles published between 2010 and 2022 assessed TNBC-related direct medical costs and indirect costs (Table 2). The direct costs were assessed in 13 studies [27,28,29,30,31,32,33,34,35,36,37,38]. Two studies estimated both direct and indirect costs [39, 40] (Table 2). As shown in Fig. 2, nine studies were conducted in the USA (60%). The first article was published in 2012, however, almost the studies (n = 7) were done in 2020. In addition, we found that direct costs were the main topic in a total of 15 studies. According to World Bank Classification, all studies were completed in high-income nations (Fig. 2A, B). Five studies investigated the Union’s countries of the European Union. Furthermore, the largest sample size (3271 people) was studied in the article of Brezden-Masley et al. [30], while the smallest sample size (14 people) was studied by Roman et al. [31].

Fig. 2
figure 2

Representative images of study characteristics. Percentage of studies locations (A) and the number of studies conducted in different regions (B)

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Direct and indirect costs

For direct costs, in French, the direct costs for patients with mTNBC who first received chemotherapy were ($33,826) [36]. A work conducted by Aly et al. in the USA estimated that direct costs were $87,682 per mTNBC patient [34]. The authors reported that the monthly direct cost of patients with mTNBC who received chemotherapy was lower than that of those who did not receive chemotherapy. In Canada, the annual per-patient costs for patients with mTNBC and eTNBC were $125,049 and $31,284 respectively [30]. For eTNBC, in Belgium, direct costs for per patient were estimated ($29,571) [31]. In Portuguese, it was reported that direct costs for eTNBC were $14,093 per patient after 3 years of follow-up from the diagnosis period [28]. A study by Skinner et al. estimated the highest annual cost (~ $316,800) for treatment of mTNBC [33]. Furthermore, Skinner et al. reported that per month healthcare costs of mTNBC were increased along with lines of therapy [33]. According to Sieluk et al., compared to patients without recurrence, monthly healthcare costs of patients with TNBC with metastatic recurrence and patients with TNBC with locoregional recurrence were $8575 and $3609 higher than respectively. In other word, patients with TNBC with recurrence, mainly metastatic one, had greater direct healthcare costs against patients with TNBC without recurrence [39]. Hospitalization costs of patients with mTNBC who treated anticancer medication were high at the primary medication and low in continuing care but increase in the final care step [37].

For indirect costs, a work showed that the mean indirect costs were $186,535 for each mTNBC patient after 5 years of follow-up in Spain [40] (Table 3). The authors concluded that the economic burden of mTNBC is substantial, but varies by HER2 and HR subtype of BC. HER2−/HR + patients showed the highest-burden because of the prevalence of this tumor, but then HER2+/HR + patients showed the highest costs per patient. Another study in USA reported that monthly indirect costs of patients with TNBC with locoregional relapse were $498.375 against TNBC without relapse; and those with metastatic relapse were $1060.875. Furthermore, patients with TNBC with recurrence showed a 63% higher rate of work loss [39]. De Las Heras et al. reported that costs for overall TNBC population as percentage of total direct and indirect costs comprise 99.85% and 15% over 5 years, suggesting high level of direct costs for patients with TNBC [40].

Table 3 Indirect costs of TNBC in two studies
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Discussion

In present systematic review, we performed summarized data from 15 published articles on the direct and indirect costs of patients with TNBC. Although we identified other literature reviews on BC or TNBC, however, we have focused on the direct and indirect costs of TNBC in published papers. In our study, we identified there was important heterogeneity across studies that may arise from the timetable, patient population, and cost components assessed. For example, some studies evaluated the direct costs of patients with TNBC aged younger, while some of them evaluated older ones. Analysis of the direct costs represents that there was a substantial association between economic burden and TNBC as well as the severity and stage of TNBC. Studies indicated that patients with TNBC who did not cure antitumor therapy had more diseases with shorter life prospects. Furthermore, per patient, the monthly direct cost was higher in patients with mTNBC who had chemotherapy compared with patients who had [34]. For patients who had anticancer therapy, costs were usually high in the course of primary therapy after diagnosis and lessened significantly in the course of continuing therapy, but amplified again in the final care step [37]. We found that the majority of studies estimated the costs of funding by healthcare payers, however, patient out-of-pocket costs were estimated in four USA studies, which reported $2112 per eTNBC patient and $528 per mTNBC patient per month [27, 32, 38]. In addition, per month costs of patients with mTNBC were augmented with additional lines of cancer therapy [33]. This was additionally confirmed by a work by Aly et al. conducted in the USA that reported that among the chemotherapy received patients, per patient medical direct costs amplified along with the line of therapy [34]. Systemic anticancer therapy comprised around 50% of the whole cost of patients with mTNBC following first-line therapy in the USA, whereas hospitalization was the second main cost [35]. However, the studies that considered longer time prospects for evaluation reported that anticancer therapy comprised only a small part of the total cost of TNBC treatment. It is worth noting that these studies did not consider costs of other payments like caregiver costs or necessary informal care. Indeed, the out-of-pocket costs impose a substantial economic burden on the patients with TNBC who were previously affected by declined work efficiency, cheap income, weakened life quality, and disability. Baser and co-workers in two studies reported that the health strategies of the USA covered the majority of direct costs for patients with eTNBC and mTNBC. This resulted in annual patient costs of about $24,288 and $5280 in eTNBC and mTNBC, respectively [38]. The results revealed the clinical actuality when traditional chemotherapies were the main therapies for TNBC. With the advent of novel tumor therapies, for example immunotherapies treatments for TNBC, the tumor therapy costs will certainly rise. On the other hand, novel therapies may decrease cancer relapse and development, thus lessening annual direct costs per patient. Additional study is necessary to estimate the cost influence and cost efficacy of the new therapies in the life of patients with TNBC. Indirect costs were assessed in an incident cohort study, which was conducted in Spain reporting the economic burden of mTNBC in Spain was substantial but varies by HER2 and HR status of breast tumors over 5 years [40]. In keeping, authors showed that total direct costs comprise 99.85% overall costs. Another study conducted in USA reporting high indirect costs for mTNBC individuals with a high rate of losing job [39]. Patients with mTNBC may lose occupation and cause workplace absenteeism and disability, proposing these were also significant cost constituents from patient and social outlooks. Although these studies revealed indirect costs associated with productivity loss, costs associated with premature death, caregiver, and comorbidity costs were not involved. Therefore, the general indirect costs of TNBC were probably underestimated [41,42,43]. In this review, most studies included the history of TNBC in diagnosis and therapy, however, it seems that during the pandemic Covid-19, which impact the human societies and governments [44], studies have been done on the alterations during the malignancy and the hamper in the diagnosis and therapy of BC that have also impacted the indirect costs of the disease [45, 46]. Consequently, the characterization of principles and agreement in the methods used to do these studies should be the main concerns for the scientific public [47]. We should note that our review had limitations, for example, we included studies from various regions. Consequently, the evaluations are heterogeneous and the outcomes are not extrapolatable. In addition, we selected studies published in English and omitted non-English articles. We also excluded conference articles. In addition, all costs were adjusted to 2023 $US to simplify comparisons, however, inflation rates and practice designs differ between countries that may affect interpretations.

Conclusion

The present study represents significant proof of direct costs associated with TNBC that may allow the economic burden of TNBC to be predicted, although cost estimates differ broadly across studies and are fairly challenging to compare. TNBC impose a remarkable economic burden on patients and healthcare systems. The economic burden of patients with TNBC recurrence and progression was substantial with high costs and was increased along with increased cancer severity. Patients with TNBC can be suffered from the indirect economic burden, which is poorly studied in the literature. Further study is essential to evaluate the direct and indirect costs of TNBC therapies to support personalized medicine (e.g., goal-oriented) and medical decisions (e.g., target therapies, participation in randomized controlled trials, etc.) for patients and healthcare payers. These studies may cause an advance in cancer prognosis and therapy methods. In addition, the majority of the studies have been accompanied in high income countries, strategy creators of the healthcare in middle and low income nations need urgencies investigation of such situations.