INTRODUCTION

Aromatase inhibitors (AIs) are the recommended adjuvant therapy to treat estrogen receptor-positive breast cancer^1,2. Its effectiveness in reducing the risk of recurrence and mortality is acknowledged³. However, AIs are also associated with various side effects that affect patients’ quality of life and therefore compromise adherence to treatment and associated mortality⁴.

Reportedly, 30% of patients prescribed with AI discontinue their treatment due to adverse events⁵, mainly musculoskeletal^6,7. Among them, the most frequent are arthralgias⁸ and accelerated loss of bone mass⁹ associated with an increase in osteoporotic fracture^10,11. To prevent the loss of bone mass, treating patients with antiresorptives is recommended, with bisphosphonates (BP) being the most used^12-14.

BP use has been associated with improved mortality associated with reduced bone metastases¹³. Similarly, a study published in a Korean population showed the use of BP was associated with improved adherence¹⁵.

Our study’s objective was to evaluate the persistence of AI therapy, the mortality associated with treatment discontinuation, and the influence of oral BPs, in a population-based cohort with data obtained from routine clinical practice.

MATERIAL AND METHODS

RESULTS

18,455 data were collected from women treated with AI. Its baseline characteristics are described in table 1. The persistence [95% CI] to AI treatment was 99.8% [99.7 to 99.9] at 1 year, 98.3% [98.1 to 98 , 5] at 2 years, 95.8% [95.5 to 96.2] at 3 years, 92.9% [92.4 to 93.4] at 4 years, and 87.0% [86.3 to 87.8] after 5 years of treatment (Figure 1).

Table 1.  Baseline characteristics of the participants included in the study 

BP: bisphosphonates; SD: standard deviation; BMI: body mass index; MEDEA: mortality in small Spanish areas and socio-economic and environmental inequalities.

Figure 1.  Persistence to AI treatment. The graph presents a Kaplan-Meyer curve that shows the risk of AI abandonment in cumulative terms. Abbreviations: AI: aromatase inhibitors 

Mortality was quantified by stratifying the patients taking into account those who completed 5 years of treatment, and, on the other hand, those who did not. An overall mortality of 19.75% (3,644/18,455) was observed: with 21.2% (3,165/14,908) in patients who did not complete 5 years of AI treatment, and 13.5% (479/3,547) in those treated for 5 years or more (p<0.001).

Influence of the BP

Of the 18,455 patients included in the study, 21.7% (n=4,009) were treated with oral BP (Table 2). They showed better persistence to AI than those not treated with BP: 99.9% [99.8 to 100] vs. 99.7% [99.6 to 99.8] at 1 year; 99.8% [99.6 to 99.9] vs. 97.8% [97.5 to 98.1] at 2 years; 98.5% [98.1 to 98.9] vs. 94.9% [94.4 to 95.3] at 3 years; 97.2% [96.6 to 97.8] vs. 91.2% [90.5 to 91.8] at 4 years; and 93.3% [92.2 to 94.4] vs. 84.5% [83.5 to 85.5] at 5 years of treatment, respectively (Figure 2). In this way, the risk ratio of abandoning AIs in BP users compared to non-users was as follows: adjusted HR: 0.53 [95% CI: 0.47 to 0.60], and adjusted SHR: 0, 62 [95% CI: 0.55-0.70].

Table 2.  Baseline characteristics of women treated with AI according to their use of BP 

BP: bisphosphonates; SD: standard deviation; BMI: body mass index; MEDEA: mortality in small Spanish areas and socio-economic and environmental inequalities.

Figure 2.  Persistence of AI treatment among users and nonusers of BP. The graph presents a Kaplan-Meyer curve that shows AI drop out risk in cumulative terms between the study groups: users and non-users of BP. Abbreviations: AI: aromatase inhibitors; BP: bisphosphonates 

In contrast, mortality in patients with BP was 14.6% (587/4,009), while in non-users it was 21.2% (3,507/ 14,446) (p<0.001).

DISCUSSION

This study evaluates the persistence of AI therapy in a cohort of women diagnosed with hormone receptor-positive breast cancer, as well as mortality and the effect of bisphosphonates, in routine clinical practice. It was observed that the global persistence at 5 years was 87% with an overall mortality of 19.75%. Mortality in those patients who completed 5 years of therapy was 7.7% lower than those who did not. On the other hand, FB users showed better persistence to AI treatment, with a 47% lower risk of discontinuing therapy, and 6.6% lower mortality than non-users.

Reports indicate the side effects of AI negatively influence adherence to treatment⁵. Several randomized controlled trials (RCTs) have published persistence rates that vary between 76-90%^17,18. However, the reliability of these percentages may be questioned by the lack of discontinuity results from some RCTs. Several studies of adherence in population databases show values of around 69-88% in short observation periods (one year of adherence)^19-21, and of 61-79% in longer follow-up periods (3-4,5 years)^20,22. Hershman et al. (2010)²² observed a 30% discontinuation rate in patients with AI at 4.5 years of follow-up, while Hadji et al. (2013)²³ described a discontinuation between 44-55% at 3 years. Among other factors, the age of the patients (younger, less adherence), and the cost of medicines and/or derived medical expenses –especially in private health systems–, have been described as variables associated with greater discontinuity²¹. The high persistence observed in our population could be explained by a high mean age (mean ± SD: 67.6 ± 11.6) compared to that reported in the RCTs (mean ± SD: 64.1 ± 9.0 in the study ATAC²⁴, and 64.3 ± 8.1 in the IES study²⁵; median [range]: 61 [38-89] in the BIG 1-98 study²⁶; and median of 63.9 and 64.3 in patients with exemestane and anastrozole in study MA.27²⁷) and a public health system, where the cost of treatment is practically negligible.

In the case of global mortality, there is a certain diversity of results depending on the design of the RCT. In the BIG 1-98 study, a mortality of 12.3% was observed²⁸. The ATAC safety study detected a mortality of 23.5% in all AI monotherapy users, and 21.5% in the subpopulation of women with known hormone receptor-positive tumor status²⁹. In contrast, study MA.27, published by Goss et al. (2013), showed a mortality of 5.7% at 5 years²⁷. Unlike RCTs, our study uses data from the general population visited in primary care, achieving a more representative population of the usual clinic. Interestingly, the mortality values of our study population are similar to those described in the ATAC study. This fact could be attributed to the fact that both report mortality results of up to 10 years of follow-up.

On the other hand, and in agreement with our results, the use of BP was reported by Lee et al. (2014)¹⁵ as a factor that improves adherence to AI treatment. Likewise, the use of BP was associated with a 34% decrease in the incidence of bone metastases and a 17% reduction in mortality¹³. In general, the use of BP decreases overall mortality, increases life expectancy and prevents the appearance of various cancers in the general population³⁰. This improvement in life expectancy is not only attributed to the decrease in fractures³¹, but also to a possible prevention of frailty and a greater capacity of the individual to cope with different conditions³².

Taking all this into account, the greater adherence to AI in patients treated with BP could be explained by improved treatment of adverse events that would have a positive impact on the patient, while the decrease in overall mortality derived from the use of the BP could be attributed both to a decrease in bone metastases and to greater adherence to AIs.

One limitation of this study is that the SIDIAP database does not have data referring to the cause of mortality or the reason for discontinuation of treatment. Thus, our study only considers overall mortality, but there is a risk of bias in that mortality before 5 years is not a consequence of discontinuing therapy. Additional studies are needed to verify that the observed difference in mortality is not due to a bias in the populations studied (between those patients who completed 5 years vs. those who did not, and between users and nonusers of BP). However, our study corroborates the results observed in previous studies.

In conclusion, a 5-year persistence to AI of 87% has been observed in routine clinical practice, which improves with the use of BP. On the other hand, completing 5 years of AI therapy and the use of BP would be associated with a decrease in mortality.