Burden of Disease and Cost of Illness of Triple-Negative Breast Cancer in Portugal.

Key Points for Decision Makers

Introduction

Breast cancer (BC) is the second most common neoplasm globally, accounting for 47.1 new cases per 100,000, or 2,310,051 new cases every year [ 1 ]. It is the leading cause of death among women living with cancer, with 12.7 deaths per 100,000. In Portugal, BC is the most common type of cancer, accounting for 11.6 new cases per 100,000 people and 1864 annual deaths [ 1 , 2 ].

Triple-negative breast cancer (TNBC), in which cancer cells do not express hormonal receptors (oestrogen or progesterone) or have human epidermal growth factor receptor-2 (HER-2) amplification, accounts for approximately 15% of all BC cases [ 3 – 5 ].

Among all subtypes of BC, TNBC is typically associated with lower survival rates in the metastatic setting. For TNBC patients presenting with early breast cancer (EBC), a higher incidence of early recurrence is expected, particularly during the first 2–5 years after diagnosis, even though survivors who have been disease free for 5 years have a low probability of experiencing recurrence over the subsequent 10 years [ 6 – 8 ]. Furthermore, since TNBC is noticeably more common in younger women, there are considerable productivity loss costs associated with labour absenteeism and withdrawal from the job market [ 9 , 10 ].

This study aims to estimate the cost and burden of TNBC in the female population, adopting a societal perspective in 2019 in Portugal (using the latest publicly available data on BC epidemiology in Portugal).

Materials and Methods

Cumulative Incidence Model

Cost and burden analysis requires estimating the prevalence and distribution of TNBC cases across all cancer stages (I, II, III and IV). To obtain the most accurate picture of TNBC in Portugal, a cumulative incidence model (CIM) with annual cycles was developed to estimate its prevalence in 2019. The CIM allows the prediction of TNBC evolution in female patients whose diagnosis was made between 2010 and 2019, establishing distinct patient pathways according to cancer stage at diagnosis, namely, locoregional (stages I–III) and metastatic (stage IV) (Fig. 1 ).

The annual probability of death was calculated on the basis of published overall survival (OS) data from the Surveillance, Epidemiology, and End Results (SEER) Program from the United States of America, due to the lack of available Portuguese data [ 11 ]. For patients with locoregional disease at the time of diagnosis, the risk of recurrence estimation was based on progression-free survival (PFS) curves published by Urru et al. (2018) [ 12 ]. Recurrence estimates according to type (locoregional or metastatic recurrence) were based on Steward et al. (2014) [ 12 , 13 ]. The published Kaplan‒Meier (KM) curves allow differentiation between disease stages (I, II, III and IV), which have been extrapolated to the period under analysis through exponential distribution parametric curves. Nonetheless, an adjustment for recurrence and mortality rates was made on the basis of evidence that the risk of recurrence and death is greater in the first 5 years after diagnosis [ 10 ]. Thus, the estimated annual probabilities of death and locoregional and metastatic recurrences, according to cancer stage, are shown in Table 1 .

TNBC incidence estimates in Portugal were based on official data [ 2 , 14 , 15 ]. However, as only data from 2010, 2018 and 2019 were published for the period under analysis, the incidence rates for the remaining years were calculated by linear regression. As stated by the Portuguese Society of Oncology, the TNBC subtype accounts for 15% of all cases of breast cancer (BC) [ 16 ]. The expert panel (EP) (Table 2 ) validated the distribution of cases by each cancer stage.

TNBC-related mortality in 2019 was based on the aforementioned CIM, assuming the average life expectancy loss reported by the Global Burden of Disease (GBD) 2019 for each death occurrence [ 17 ]. Similarly, cancer stage distribution was also calculated with CIM, whose disability weight values were confirmed by the GBD 2019 (Table 3 ) [ 18 ]. To address the impact of each death in terms of years of life lost (YLLs) and to estimate indirect costs, a distribution of new patients diagnosed with TNBC stratified by age group was necessary. Data from van Maaren et al. (2019) were used to estimate the number of TNBC cases [ 10 ].

Burden of Disease

The burden of disease was assessed on the basis of impact in terms of years of healthy life lost due to disease or premature death (DALY), a metric commonly used by the World Health Organization (WHO) [ 19 ]. It includes two time-based indicators, namely, the YLL and the years lost due to disability (YLD). One DALY represents the loss of the equivalent of 1 year living with full health [ 20 ]. The present study adopted the Global Burden of Disease (GBD) methodology of 2010, which considers the following [ 21 ]:

[ c = cost; s = sex; a = age; t = time]

While YLL is calculated as the number of deaths multiplied by the standard life expectancy at the age at which death occurs, YLD is the number of female patients in each cancer stage multiplied by the corresponding disability weight (Table 3 ) [ 18 , 22 ].

The disability weight metric is as follows: “diagnosis and primary phase of treatment” are applicable to new TNBC cases; “clinically disease-free” is valid for patients with local and locoregional stages of TNBC, who have undergone conservative surgery or mastectomy (according to EP inputs); “metastatic phase” accounts for the TNBC metastatic stage; and the “terminal phase” applies to female TNBC patients who died during the year of analysis (Table 3 ).

Cost of Illness

The cost of illness was estimated from a societal perspective, considering the prevalence of TNBC and the distribution of patients across all cancer stages (I, II, III and IV) in 2019, including all patients diagnosed over the last 10 years (2010–2019). These estimates were based on inputs from several data sources, such as publicly available data, data from the literature and the EP [ 23 – 30 ]. The EP was conducted to support the cost analysis, both direct and nondirect health care expenditures, and to fill in information gaps regarding standard of care (SoC) approaches. The average calculation was the chosen method to reach consensus in the EP.

Direct medical costs included outpatient and inpatient expenditures and were estimated according to the EP. The outpatient expenditures included outpatient planned and emergency consultations, complementary diagnostic exams (CDE), primary care consultation and pharmacologic therapeutics. Inpatient status considered hospitalizations and outpatient episodes that occurred at the National Healthcare Service (NHS) hospitals, coded according to the 10th Revision of International Classification of Diseases (ICD-10) available from the Hospital Morbidity Database (HMDB). Unit costs were based on official data and remained constant over time [ 23 , 24 , 26 ]. Patient transportation to and from the hospital to attend appointments and treatments/CDE were assessed using the EP input. The cost of each trip was established according to Barros et al. (2015) [ 25 ]. Table 1 (see electronic supplementary material [ESM]) summarizes the unit costs related to direct expenditures, as well as the respective data sources.

The indirect costs, such as early retirement, sick leave and work absences due to TNBC, were established following the human capital approach, according to which the indirect costs are estimated on the basis of the company´s expenditure on each employee lost to adverse health disorders [ 27 ]. Inputs from the EP supported these estimates.

Considering that women’s working age averages 52 years on the basis of the CIM, the average monthly gross wage was estimated, taking into account the wage per level of education completed and the proportion of women employed in Portugal who completed each of these levels [ 28 – 30 ]. On average, the impact of each employed woman on the company, including the social security contribution, adds up to €15,725 per year [ 28 – 30 ].

The impact of the TNBC condition on women’s participation in the job market was obtained from the EP and is summarized in Table 4 . Expert estimates combined with the employer's wage payment per employed woman and estimates of the number of TNBC cases in employed women allowed estimating TNBC indirect costs related to absenteeism or early retirement from work.

In terms of absenteeism, (i) each set of CDEs, with the same nature, represented the loss of a quarter of a full working day, (ii) each consultation represented half a day of work, (iii) each day of a hospital visit or radiotherapy treatment represented a full day of absenteeism, and (iv) TNBC-related hospitalization accounted for the loss of working days equivalent to twice the average hospitalization period (i.e., 9.68 days). The cost of labour absenteeism was estimated as the number of working days lost to medical care services related to the diagnosis and treatment of TNBC multiplied by the mean cost of a full working day lost (i.e., €43).

Results

A total of 1272 newly diagnosed TNBC cases were identified in 2019. The TNBC female population in Portugal is estimated to be 7052 patients. The EP confirmed that, among all patients with TNBC, approximately 24.24%, 29.11%, 27.44% and 19.21% were in Stages I, II, III and IV, respectively (Table 5 ).

The cumulative incidence model allowed estimation of 676 deaths from TNBC in 2019. These deaths resulted in 21,266 YLL, with metastatic disease (IV stage) contributing the most to this result with 15,063 YLL. Figure 2 shows the estimated YLL by age group in 2019 in Portugal. The highest value of YLL is among women aged 45–49 years.

Considering the aforementioned disability weights, the number of YLD due to TNBC was calculated to be 1300. For the locoregional stage (I–III), the YLD yielded was 567. In turn, 733 patients were in the metastatic stage (IV).

Hence, the total burden attributable to TNBC in Portugal in 2019 was 22,566 DALY. These results are summarized in Table 6 .

The total annual cost associated with TNBC in Portugal was estimated to exceed €50 million in 2019, with an average annual cost of €7140 per patient. This value comprises €28 million in direct costs and €22 million in indirect costs.

The costs related to the treatment and management of the locoregional stage (I–III) accounted for 65% (€18 million) of the total direct costs. Transportation- and screening-related costs are 4-fold higher in earlier stages than in the metastatic stage (€0.87 million vs €0.20 million, respectively). A breakdown of the direct costs for each component is given in Table 7 . More detailed information about healthcare resource utilization is presented in the ESM (Tables 2, 3 and 4).

Total indirect costs of €22 million were estimated considering that 71% of the female population of working age is employed (Table 8 ) [ 28 , 29 , 31 ]. More detailed information about withdrawal from the job market is presented in the ESM (Table 5).

Complementing these data with CIM data, it is estimated that approximately 2914 women living with TNBC (41.3%) are currently employed (Table 9 ), considering the average working age of 52 years. Accordingly, 94% of total indirect costs were allocated to extensive costs due to nonparticipation in the job market, and 6% were allocated to labour absenteeism (Table 8 ).

Discussion

The present study aimed to estimate the costs and burden of TNBC in Portugal in 2019. A CIM of this disease was conducted to estimate the prevalence and mortality attributable to TNBC by age group and cancer stage.

The number of new BC cases among women in Portugal in 2019 was 8482 [ 2 ]. Assuming that TBNC represents 15% of new cases of BC, it is estimated that in Portugal, in 2019, 1272 new cases of TNBC were registered among women [ 16 ]. In terms of age group distribution, the group with the highest number of newly diagnosed TNBC patients is 45–49 years, considerably earlier than the age group of the peak number of new cases of BC (60–64 years) [ 2 ]. With respect to the stage of diagnosis distribution, the highest proportion of new TNBC cases was observed at stage II, similar to what has been reported for BC in Portugal [ 32 ]. Overall, 7052 TNBC cases are estimated.

In 2019, BC was responsible for the death of 1874 women, corresponding to approximately 3% of total female mortality that year [ 33 ]. In the year under analysis, the estimated number of patients who died from TNBC was 676, accounting for 36% of all deaths due to BC. Disability and premature death resulted in a TNBC burden of 22,566 DALY, which corresponds to nearly 46% of the total burden of BC in 2014, adjusted for updated life expectancy [ 34 ]. Considering that only 15% of all BC cases are triple-negative, these results reflect the extreme burden attributable to this cancer subtype. Moreover, a high discrepancy was observed between the two DALY metric components. The total value of YLL far outweighed YLD in TNBC among female patients (21,266 YLL vs 1300 YLD), meaning that this BC subtype is particularly deadly.

The total cost of over €50 million spent in 2019 on TNBC represents 16% of all costs (direct and indirect) estimated for BC, which aligns with the proportion of new TNBC cases compared with new BC cases (16% vs 15%). Stage IV is responsible for one-third of all direct costs attributable to TNBC (€9.8 million), which is substantially higher than the proportion of stage IV costs when all BC cases are considered [19%, according to Sousa et al. (2016)] [ 34 ].

Of the €28 million in direct costs due to TNBC in Portugal in 2019, costs for treatment and follow-up for the locoregional stage accounted for 65%. The per-person cost was €3979, which was 47% greater than that estimated for BC in Portugal (€2705), reflecting a considerable economic burden for TNBC management [ 34 ].

Brandão et al. (2020) estimated the medical direct costs required for BC treatment per cancer stage and subtype [ 35 ]. During the first 3 years after diagnosis, €11,224 were spent per patient with stage I–III TNBC [ 35 ]. Even though this estimation accounts for the first 3 years after diagnosis, the authors claim that nearly all the costs are spent during the first year [ 35 ]. The per-person cost of treatment and follow-up of patients with TNBC stages I–III in 2019 was €10,059 considering all cases and €9132 in the case of only patients in the first year of follow-up. These numbers reported by Brandão et al. (2020) are consistent with the numbers presented in this study. Direct costs of TNBC represent 3% of all direct costs attributable to cancer in Portugal [ 36 ].

As previously described, TNBC is a BC subtype affecting a substantially younger set of female patients [ 10 , 35 ]. In 2019, approximately 57.8% of prevalent cases involved working-aged women; hence, the analysis of indirect costs, such as labour absenteeism and temporary/permanent withdrawal from the job market, is particularly relevant. In 2019, these costs comprised €22 million, with an indirect per-person cost of €3161, which is approximately 5% higher than the cost estimated for BC [ 34 ].

When considering the differences between methodological procedures and disease characteristics included among similar studies conducted in Portugal, establishing any comparison with the results obtained from this study is challenging. Nonetheless, approximately 8931 DALY were attributable to multiple myeloma in Portugal in 2018, and direct costs added up to €61 million [ 37 ]. Regarding indirect costs, Miguel et al. (2022) estimated that approximately €3.6 million and €11.4 million are spent due to labour absenteeism and early retirement, respectively, due to multiple myeloma in Portugal. These results illustrate a slightly lower burden than that of TNBC [ 38 ]. Furthermore, these estimates do not consider family-related costs, namely partners’ absenteeism from work and children’s poorer academic performance.

Additionally, Magro et al. (2022) estimated approximately 6067 DALY for inflammatory bowel disease (IBD), namely, Crohn´s disease and ulcerative colitis, whose total cost was estimated at €146 million per year [ 39 ]. Considering this, the TNBC burden accounts for an almost 3-fold increase in DALY compared with that of IBD, and its related costs remain substantially lower (34%) [ 39 ]. Moreover, even though atrial fibrillation represents a slightly greater burden than TNBC (23,084 DALY vs 22,566 DALY), its total costs are not proportionate to this difference (€140 million vs €50 million) [ 40 ].

Limitations

A few limitations must be outlined. The lack of published evidence about TNBC in Portugal may have substantially influenced the cost and burden estimation. The TNBC proportion of breast cancer cases and their distribution among cancer stages are key parameters to accurately achieve the aim of this study. An additional limitation of the lack of Portuguese data on OS and PFS among patients living with TNBC must also be documented. The data included are not data about Portuguese populations; however, they are based on recent research studies of large cohorts considered to be solid official references for use in Western populations. The participation of four oncologists on the expert panel to characterize the healthcare resource utilization in Portugal may be considered another limitation. Nonetheless, the implemented options are plausible.

Conclusion

This study provides the first comprehensive insight into all dimensions of the TNBC burden in Portugal. This highlights a substantial economic and clinical burden attributable to TNBC, considering its diagnosis, treatment and follow-up. Additionally, its high prevalence among working-age women may represent greater productivity losses, either due to labour absenteeism or temporary/permanent withdrawal from the job market. The results provide the basis for an accurate assessment of the real burden of TNBC on society and the Portuguese health care system.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 75 KB)

Acknowledgements

We would like to express our gratitude to Maria Mafalda Nogueira for her contribution as a medical reviewer to this manuscript. This study was developed by IQVIA Portugal and supported by MSD Portugal.

Declarations

Funding

This study was developed by IQVIA Portugal and supported by MSD Portugal.

Competing Interests

Gabriela Sousa, Luís Costa, Margarida Brito and Sónia Oliveira received honoraria from MSD Portugal for participation in the expert panel. Bernardo Rodrigues, João Ferreira and Joana Silva are employees of MSD Portugal. Margarida Borges and Luís Silva Miguel are employees of IQVIA Portugal and were contracted by MSD Portugal to conduct this study. Sónia Oliveira has served as a consultant to Novartis, Pfizer, Eli Lilly Nederland, AstraZeneca, Daiichi Sankyo, Gilead, MSD and Seagen; has received research funding from Pfizer; and has received accommodation services from Novartis, Pfizer, Daiichi Sankyo, Astellas, Bristol-Myers Squibb, AstraZeneca and Gilead. Luís Costa has received grants/research support from Eli Lilly Nederland, MSD, Roche and Amgen; has received honoraria from Servier, AstraZeneca and MSD; and has participated in a sponsored speaker bureau of Novartis, Pfizer, Eli Lilly Nederland, MSD and AstraZeneca. None of the other authors have declared any conflicts of interest.

Author Contributions

Gabriela Sousa, Luís Costa, Margarida Brito and Sónia Oliveira participated in the expert panel, provided useful insights for this study and reviewed the final article. Bernardo Rodrigues, João Ferreira and Joana Silva were responsible for the article development and revision. Margarida Borges and Luís Silva Miguel were responsible for model development, expert panel moderation, data collection and analysis, and article development.

Ethics Approval

All the data analysed were anonymous; therefore, the authors declare that no patient data appear in this article.

Consent to Participate

All participants included in the EP provided their informed consent.

Consent for Publication

All participants included in the EP provided their consent for publication.

Availability of Data and Material

All data supporting the findings are available within the article and supplementary material.

Code Availability

Not applicable.

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Associated Data

Supplementary Materials

Supplementary file1 (DOCX 75 KB)