Abstract

Background

Previous studies have suggested a correlation between the occurrence of vasomotor or joint symptoms during tamoxifen or aromatase inhibitor treatment and improved clinical response.

Patients and methods

A retrospective analysis of the German cohort of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial was carried out to assess disease-free survival (DFS) and overall survival (OS) in patients with and without arthralgia/myalgia and/or menopausal symptoms during adjuvant endocrine treatment.

Results

A total of 1502 patients were included; 739 patients received tamoxifen followed by exemestane and 763 received exemestane. Patients reporting arthralgia/myalgia and patients reporting menopausal symptoms during endocrine treatment had significantly longer OS and DFS than those not reporting these events. The effect on OS was irrespective of treatment. DFS was significantly improved in exemestane-treated patients reporting arthralgia/myalgia or those reporting menopausal symptoms versus those not reporting these events. This effect on DFS was not observed in patients receiving sequential treatment. A combined analysis of patients reporting either menopausal symptoms or arthralgia/myalgia showed that OS and DFS were significantly improved in patients reporting one of these symptoms versus those not reporting either symptom.

Conclusion

The occurrence of arthralgia/myalgia or menopausal symptoms during endocrine treatment is associated with significantly improved OS.

introduction

Endocrine therapy is recommended as adjuvant treatment for postmenopausal patients with hormone receptor-positive early breast cancer [1, 2]. Tamoxifen has been the standard adjuvant endocrine treatment for many years; however, in recent years, aromatase inhibitors (AIs) have demonstrated equivalent or superior efficacy to tamoxifen in several trials [3–5]. Treatment guidelines now recommend that adjuvant endocrine treatment includes an AI [1].

Commonly reported adverse events (AEs) associated with AIs and tamoxifen include those related to estrogen deprivation, such as hot flushes, night sweats, arthralgia and myalgia [3–7]. While tamoxifen is a selective estrogen receptor modulator and interferes with the binding of estrogen to its receptor [8], AIs inhibit the conversion of androgens to estrogen [9]. As a result of these differences in their mechanisms of action, tamoxifen and AIs are associated with distinct AE profiles. Treatment with tamoxifen has been associated with gynecological AEs, including vaginal bleeding and endometrial cancer. Furthermore, thromboembolic events have been associated with tamoxifen treatment [3–7]. In contrast, patients receiving AIs are more likely to suffer from musculoskeletal AEs, including arthralgia and myalgia [10]. AI treatment has also been associated with an accelerated rate of bone loss [11, 12] and the incidence of fractures is increased with AI versus tamoxifen treatment [3–7]. Furthermore, AI treatment has been associated with an increase in cardiovascular AEs versus tamoxifen treatment [13].

With some drugs, the occurrence of specific AEs has been shown to predict treatment response. For example, in patients treated with epidermal growth factor receptor agents, the incidence and severity of rash have been shown to be associated with improved clinical outcomes [14, 15]. Previous studies have suggested that the occurrence of hot flashes during tamoxifen treatment may be associated with reduced recurrence of breast cancer [16].

The Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial was a phase III randomized open-label trial which compared 5 years' exemestane with 2.5–3 years' tamoxifen followed by 2–2.5 years' exemestane in postmenopausal women with hormone receptor-positive early breast cancer [17]. TEAM was initially designed to assess 5 years' exemestane versus 5 years' tamoxifen. However, results from the Intergroup Exemestane Study showed that switching to exemestane following 2–3 years of tamoxifen significantly improved disease-free survival (DFS) compared with continuing tamoxifen. As such, the study design was amended [17]. The final analysis of TEAM, at a median follow-up of 5 years, demonstrated that there were no significant differences in efficacy between 5 years' exemestane and the sequence of tamoxifen followed by exemestane [17]. The authors concluded that exemestane monotherapy or sequential therapy were appropriate treatment options and that consideration of safety profiles would be important when making treatment decisions. We performed a retrospective analysis of the German cohort of the TEAM trial to investigate if the occurrence of specific treatment-emergent AEs was associated with clinical response to treatment with either sequential treatment or exemestane.

methods

All patients provided written informed consent. The study was approved by the local ethics committees and was conducted in accordance with the Declaration of Helsinki.

study design and treatment

The TEAM trial was a phase III, randomized open-label trial in which postmenopausal women with hormone receptor-positive early breast cancer were randomly assigned 1:1 to receive 25 mg of exemestane daily for 5 years or tamoxifen 20 mg daily for 2.5–3 years followed by 2–2.5 years of exemestane. The TEAM trial was conducted in nine countries (Belgium, France, Germany, Greece, Ireland, Japan, The Netherlands, the UK and the United States). This was a retrospective analysis of all patients enrolled in the German cohort of the TEAM trial, to assess if there was any correlation between specific AEs and clinical outcome.

Modifications to dose or schedule were not permitted. Patients discontinued study drug if the investigator considered it was medically necessary, unacceptable toxicity was experienced, consent was withdrawn or relapse of disease occurred. All patients were followed up, whether or not they discontinued treatment. Adjuvant hormonal treatment was initiated within 14 weeks after completion of surgery. Patients completed a ‘Drug Administration Record’ at home, which was brought to each clinic visit to document treatment compliance. Further details on the trial design, methods and primary and secondary objectives of the TEAM trial have been published elsewhere [17].

assessments

During the first year of treatment, patients were assessed every 3 months and at least once yearly thereafter; mammography was carried out annually. AEs were recorded at each visit. Data on AEs were obtained using elicited responses and prespecified checklists were not used. Pre-existing AEs were only included if they worsened following the first dose of study drug. Severity was assessed by the investigators, based on the National Cancer Institute—Common Toxicity Criteria, version 2.0. Investigators also assessed the relationship between AEs and treatment.

For this retrospective analysis, AEs of interest included incidence of arthralgia or myalgia, occurrence of fractures and menopausal symptoms. These measured symptoms were defined as of interest before the analysis. In accordance with international guidelines, menopausal symptoms were defined as: hot flashes/flushes; constitutional symptoms, including difficulties sleeping, disorders of sleep, sleeping disturbances, sleeplessness, trouble with sleep, worsening sleep disturbance; insomnia; mood alteration-anxiety, agitation; mood alteration-depression; depressed level of consciousness. All AEs occurring during the 5-year treatment period were included and analysis of DFS and overall survival (OS) were assessed following 5 years of treatment.

end points

The occurrence of arthralgia and myalgia, fractures and menopausal symptoms were assessed. End points for this analysis were DFS and OS in patients with and without arthralgia and myalgia and those with and without menopausal symptoms after 5 years of treatment.

statistical analysis

All randomized patients who started treatment were included in the intention-to-treat population. The intention-to-treat population was used for all efficacy analyses. Kaplan–Meier estimates were used to calculate the occurrence of arthralgia or myalgia, fractures and menopausal symptoms. Kaplan–Meier estimates were also used to calculate OS and DFS in patients with and without arthralgia/myalgia, those with and without menopausal symptoms and those with and without either symptom. Cox regression analyses were carried out to assess the effect of baseline characteristics and these AEs on OS and DFS.

Efficacy and safety end points were compared using log-rank tests and all P values were two-sided. P values < 0.05 were considered statistically significant. All database management and statistical analyses were carried out using the Statistical Analysis System, version 9.1.

results

patient characteristics

A total of 1525 patients were randomized to sequential therapy (n = 752) or exemestane alone (n = 773). A total of 23 patients did not start treatment; therefore, 739 patients and 763 patients were included in this analysis, respectively (supplemental Figure S1, available at Annals of Oncology online). Patients in the sequential arm switched to exemestane after 2.5–3 years of tamoxifen treatment.

Overall, baseline characteristics of patients were similar across treatment groups (Table 1); however, the number of patients with stage 4 disease was significantly higher in the sequential arm. The incidence of arthralgia or myalgia, fracture and menopausal symptoms at baseline was similar between groups (Table 2).

Table 1.

Baseline characteristics

 Tamoxifen→ exemestane, (n = 739) Exemestane, (n = 763) P value 
Mean age, years (SD) 63.3 (8.2) 63.2 (8.4) 0.7498 
Mean height, cm (SD)a 163.7 (6.0) 163.6 (6.1) 0.8121 
Mean weight, kg (SD)b 71.56 (13.43) 70.93 (12.70) 0.3944 
Mean BMI, kg/m2 (SD)c 26.79 (5.03) 26.38 (4.61) 0.1795 
Mean endometrium thickness, mm (SD)d 3.1 (1.5) 2.7 (1.4) 0.1034 
Adjuvant chemotherapy, n (%) 338 (45.74) 364 (47.71) 0.4448 
Previous radiotherapy, n (%) 563 (76.18) 582 (76.28) 0.9660 
Tumor grade, n (%)    
 Grade 1 26 (3.52) 26 (3.41) 0.9067 
 Grade 2 558 (75.51) 582 (76.28) 0.7273 
 Grade 3 148 (20.03) 152 (19.92) 0.9592 
 Not assigned 7 (0.95) 3 (0.39) 0.1900 
Tumor stage, n (%)    
 Stage 1 444 (60.08) 444 (58.19) 0.4567 
 Stage 2 241 (32.61) 277 (36.30) 0.1325 
 Stage 3 24 (3.25) 25 (3.28) 0.9749 
 Stage 4 30 (4.06) 17 (2.23) 0.0425 
 Tamoxifen→ exemestane, (n = 739) Exemestane, (n = 763) P value 
Mean age, years (SD) 63.3 (8.2) 63.2 (8.4) 0.7498 
Mean height, cm (SD)a 163.7 (6.0) 163.6 (6.1) 0.8121 
Mean weight, kg (SD)b 71.56 (13.43) 70.93 (12.70) 0.3944 
Mean BMI, kg/m2 (SD)c 26.79 (5.03) 26.38 (4.61) 0.1795 
Mean endometrium thickness, mm (SD)d 3.1 (1.5) 2.7 (1.4) 0.1034 
Adjuvant chemotherapy, n (%) 338 (45.74) 364 (47.71) 0.4448 
Previous radiotherapy, n (%) 563 (76.18) 582 (76.28) 0.9660 
Tumor grade, n (%)    
 Grade 1 26 (3.52) 26 (3.41) 0.9067 
 Grade 2 558 (75.51) 582 (76.28) 0.7273 
 Grade 3 148 (20.03) 152 (19.92) 0.9592 
 Not assigned 7 (0.95) 3 (0.39) 0.1900 
Tumor stage, n (%)    
 Stage 1 444 (60.08) 444 (58.19) 0.4567 
 Stage 2 241 (32.61) 277 (36.30) 0.1325 
 Stage 3 24 (3.25) 25 (3.28) 0.9749 
 Stage 4 30 (4.06) 17 (2.23) 0.0425 

aHeight was only measured in 563 patients in the tamoxifen arm and 650 patients in the exemestane arm.

bWeight was only measured in 622 patients in the tamoxifen arm and 640 patients in the exemestane arm.

cBMI could only be calculated in 481 patients in the tamoxifen arm and 551 patients in the exemestane arm.

dOnly 67 patients in the tamoxifen arm and 77 patients in the exemestane arm had a transvaginal ultrasound result.

BMI, body mass index; SD, standard deviation.

Table 2.

Occurrence of arthralgia or myalgia, fractures or menopausal symptoms during treatment with tamoxifen followed by exemestane or exemestane alone for 5 years

  Patients with AEs, n (%)
 
 
  Tamoxifen→ Exemestane (n = 739) Exemestane (n = 763) OR (95% CI) 
Arthralgia or myalgia Baseline 16 (2.2) 28 (3.7) 0.6 (0.3–1.1) 
Months 0–30 116 (15.7) 235 (30.8) 0.4 (0.3–0.5) 
aMonths 30 +  146 (29.6) 176 (27.8) 1.1 (0.8–1.4) 
Fractures Baseline 0 (0) 1 (0.1) NA 
Months 0–30 24 (3.3) 31 (4.1) 0.8 (0.5–1.4) 
aMonths 30 +  6 (1.2) 21 (3.3) 0.4 (0.1–0.9) 
Menopausal symptoms Baseline 88 (11.9) 105 (13.8) 0.8 (0.6–1.1) 
Months 0–30 338 (45.7) 324 (42.5) 1.1 (0.9–1.4) 
aMonths 30 +  214 (43.4) 228 (36.0) 1.4 (1.1–1.7) 
  Patients with AEs, n (%)
 
 
  Tamoxifen→ Exemestane (n = 739) Exemestane (n = 763) OR (95% CI) 
Arthralgia or myalgia Baseline 16 (2.2) 28 (3.7) 0.6 (0.3–1.1) 
Months 0–30 116 (15.7) 235 (30.8) 0.4 (0.3–0.5) 
aMonths 30 +  146 (29.6) 176 (27.8) 1.1 (0.8–1.4) 
Fractures Baseline 0 (0) 1 (0.1) NA 
Months 0–30 24 (3.3) 31 (4.1) 0.8 (0.5–1.4) 
aMonths 30 +  6 (1.2) 21 (3.3) 0.4 (0.1–0.9) 
Menopausal symptoms Baseline 88 (11.9) 105 (13.8) 0.8 (0.6–1.1) 
Months 0–30 338 (45.7) 324 (42.5) 1.1 (0.9–1.4) 
aMonths 30 +  214 (43.4) 228 (36.0) 1.4 (1.1–1.7) 

aPatients in the tamoxifen followed by exemestane group switched to exemestane treatment after 2.5–3 years of treatment.

AE, adverse event; CI, confidence interval; OR, odds ratio.

incidence of arthralgia or myalgia, fracture and menopausal symptoms during treatment

Exemestane was associated with significantly more arthralgia or myalgia versus tamoxifen during the first 2.5 years of treatment (P < 0.0001; supplemental Figure S2A, available at Annals of Oncology online). When the occurrence of arthralgia or myalgia was evaluated over time (Table 2), significantly more patients receiving exemestane reported arthralgia or myalgia compared with those receiving tamoxifen between the beginning of treatment and until 30 months of treatment. At the time when patients receiving tamoxifen switched to exemestane (month 30 onwards), there were no significant differences in arthralgia or myalgia between groups.

Overall, the incidence of fracture was not significantly different between treatment groups during the first 2.5 years of treatment (P = 0.4; data not shown). The occurrence of fractures during the 5 years of treatment is shown in Table 2. There were significantly more fractures in the exemestane alone group than the sequential treatment arm during month 30 onwards (Table 2).

Menopausal symptoms were commonly reported during tamoxifen and exemestane treatment (Table 2). During the first 2.5 years' treatment, more patients receiving tamoxifen reported menopausal symptoms than those receiving exemestane; however, this difference was not significant (P = 0.1; supplemental Figure S2B, available at Annals of Oncology online). The incidence of either menopausal symptoms or arthralgia/myalgia was not significantly different between treatment groups (P = 0.3; supplemental Figure S2C, available in Annals of Oncology online).

OS and DFS in patients with and without arthralgia/myalgia

In the total patient population, patients who experienced arthralgia/myalgia had significantly longer OS [hazard ratio (HR) 3.6, 95% CI 2.0–6.6; P < 0.0001; Figure 1A] than those who did not report these symptoms. The improvement in OS was irrespective of treatment, with OS significantly improved in both sequential- and exemestane-treated patients reporting arthralgia/myalgia versus those with no arthralgia/myalgia (HR 4.5, 95% CI 1.6–12.6; P < 0.01 and HR 3.1, 95% CI 1.5–6.7; P < 0.01; Table 3).

Table 3.

Hazard ratios for overall survival and disease-free survival for endocrine symptoms reported during treatment according to treatment group

 Treatment group Hazard ratio for no adverse event versus adverse event (95% CI) P value 
Overall survival    
 Arthralgia or myalgia Overall 3.6 (2.0–6.6)  <0.0001 
Sequential 4.5 (1.6–12.6)  <0.01 
Exemestane 3.1 (1.5–6.7)  <0.01 
 Menopausal symptoms Overall 2.5 (1.7–3.9)  <0.0001 
Sequential 2.5 (1.4–4.4)  <0.01 
Exemestane 2.7 (1.4–5.0)  <0.01 
 Either side-effect Overall 3.0 (2.0–4.4)  <0.0001 
Sequential 3.0 (1.7–5.3)  <0.001 
Exemestane 2.9 (1.7–5.2)  <0.001 
Disease-free survival    
 Arthralgia or myalgia Overall 2.0 (1.4–2.9)  <0.001 
Sequential 1.3 (0.8–2.2) 0.3 
Exemestane 2.9 (1.6–5.2)  <0.001 
 Menopausal symptoms Overall 1.5 (1.1–2.0) 0.01 
Sequential 1.2 (0.8–1.9) 0.3 
Exemestane 1.9 (1.2–3.0)  <0.01 
 Either side-effect Overall 2.0 (1.5–2.8)  <0.0001 
Sequential 1.7 (1.1–2.5) 0.02 
Exemestane 2.5 (1.6–3.9)  <0.0001 
 Treatment group Hazard ratio for no adverse event versus adverse event (95% CI) P value 
Overall survival    
 Arthralgia or myalgia Overall 3.6 (2.0–6.6)  <0.0001 
Sequential 4.5 (1.6–12.6)  <0.01 
Exemestane 3.1 (1.5–6.7)  <0.01 
 Menopausal symptoms Overall 2.5 (1.7–3.9)  <0.0001 
Sequential 2.5 (1.4–4.4)  <0.01 
Exemestane 2.7 (1.4–5.0)  <0.01 
 Either side-effect Overall 3.0 (2.0–4.4)  <0.0001 
Sequential 3.0 (1.7–5.3)  <0.001 
Exemestane 2.9 (1.7–5.2)  <0.001 
Disease-free survival    
 Arthralgia or myalgia Overall 2.0 (1.4–2.9)  <0.001 
Sequential 1.3 (0.8–2.2) 0.3 
Exemestane 2.9 (1.6–5.2)  <0.001 
 Menopausal symptoms Overall 1.5 (1.1–2.0) 0.01 
Sequential 1.2 (0.8–1.9) 0.3 
Exemestane 1.9 (1.2–3.0)  <0.01 
 Either side-effect Overall 2.0 (1.5–2.8)  <0.0001 
Sequential 1.7 (1.1–2.5) 0.02 
Exemestane 2.5 (1.6–3.9)  <0.0001 

CI, confidence interval.

Figure 1.

Kaplan–Meier estimates of overall survival (A) and disease-free survival (B) for patients with and without arthralgia/myalgia (overall patient population).

Figure 1.

Kaplan–Meier estimates of overall survival (A) and disease-free survival (B) for patients with and without arthralgia/myalgia (overall patient population).

In the total patient population, patients who experienced arthralgia/myalgia had significantly longer DFS (HR 2.0, 95% CI 1.4–2.9; P < 0.001; Figure 1B) than those who did not report these symptoms. There was no difference in DFS in patients receiving sequential treatment with or without arthralgia/myalgia (HR 1.3, 95% CI 0.8–2.2; P = 0.3). DFS was significantly improved in exemestane-treated patients with arthralgia/myalgia versus those without this AE (HR 2.9, 95% CI 1.6–5.2; P < 0.001; Table 3).

OS and DFS in patients with and without menopausal symptoms

In the total patient population, OS was significantly longer in patients reporting menopausal symptoms compared with those who did not report menopausal symptoms (HR 2.5, 95% CI 1.7–3.9; P < .0001; Figure 2A). OS was significantly improved in both sequential- and exemestane-treated patients who experienced menopausal symptoms versus those who did not report these symptoms (HR 2.5, 95% CI 1.4–4.4; P < 0.01 and HR 2.7, 95% CI 1.4–5.0; P < 0.01, respectively; Table 3).

Figure 2.

Kaplan–Meier estimates of overall survival (A) and disease-free survival (B) for patients with and without menopausal symptoms (overall patient population).

Figure 2.

Kaplan–Meier estimates of overall survival (A) and disease-free survival (B) for patients with and without menopausal symptoms (overall patient population).

Similarly, DFS was significantly longer in patients reporting menopausal symptoms compared with those who did not report these symptoms (HR 1.5, 95% CI 1.1–2.0; P = 0.01; Figure 2B). There was no significant difference in DFS between patients receiving sequential therapy with or without menopausal symptoms (HR 1.2, 95% CI 0.8–1.9; P = 0.3). Exemestane-treated patients reporting menopausal symptoms had significantly longer DFS than those not reporting menopausal symptoms (HR 1.9, 95% CI 1.2–3.0; P < 0.01; Table 3).

combined analysis of OS and DFS in patients with and without arthralgia/myalgia or menopausal symptoms

OS and DFS were significantly improved in patients with either arthralgia/myalgia or menopausal symptoms versus patients without these symptoms (HR 3.0, 95% CI 2.0–4.4; P < 0.0001 and HR 2.0, 95% CI 1.5–2.8; P < 0.0001; OS: Figure 3). OS and DFS in sequential- and exemestane-treated patients were significantly improved in patients with arthralgia/myalgia or menopausal symptoms versus those not reporting these AEs (Table 3).

Figure 3.

Kaplan–Meier estimates of overall survival for patients with and without arthralgia/myalgia or menopausal symptoms (overall patient population).

Figure 3.

Kaplan–Meier estimates of overall survival for patients with and without arthralgia/myalgia or menopausal symptoms (overall patient population).

Cox regression analysis

A small but significant correlation between the occurrence of arthralgia/myalgia and age was observed. Age, tumor stage and incidence of arthralgia/myalgia were significantly correlated with OS. Tumor stage and incidence of arthralgia/myalgia were significantly correlated with DFS (data not shown), supporting the results from the Kaplan–Meier analysis.

A significant correlation between age and occurrence of menopausal symptoms was observed. No significant effect of the occurrence of menopausal symptoms and OS or DFS was observed in this analysis (data not shown).

discussion

Our retrospective analysis of the German cohort of the TEAM trial suggested that patients reporting arthralgia/myalgia and those reporting menopausal symptoms had significantly longer DFS and OS than patients who did not report these AEs. The effect on OS was irrespective of treatment. A significant improvement in DFS was observed in exemestane-treated patients reporting arthralgia/myalgia or those reporting menopausal symptoms versus those not reporting these AEs. However, in patients receiving sequential therapy, there was no significant difference in DFS between those reporting arthralgia/myalgia or those reporting menopausal symptoms versus those not reporting these AEs. A combined analysis of patients with either arthralgia/myalgia or menopausal symptoms showed that OS and DFS were significantly improved in patients reporting one of these symptoms versus those not experiencing either symptom. In this analysis, the effect on OS and DFS was irrespective of treatment.

The occurrence of specific AEs has been shown to be associated with improved clinical response with other treatments. For example, the occurrence of hypothyroidism has been shown to be associated with improved clinical outcome in patients with head and neck cancer [18]. Hypertension during sunitinib treatment has also been associated with improved outcome [19].

Similar to our study, a retrospective analysis of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial showed that both anastrozole-, a nonsteroidal AI, and tamoxifen-treated patients who experienced either vasomotor or joint symptoms within the first 3 months of treatment had significantly fewer breast cancer recurrences than those who did not report symptoms [20]. In this analysis, the effect was larger in patients reporting joint symptoms [adjusted HR 0.60 (95% CI 0.50–0.72); P < 0.0001] than those reporting vasomotor symptoms [adjusted HR: 0.84 (95% CI: 0.71–1.00); P = 0.04] [20]. In patients reporting vasomotor symptoms, the effect was mainly observed in patients who had previously received hormone replacement therapy [20].

Furthermore, a previous study with patients receiving tamoxifen suggested that patients who reported hot flashes were significantly less likely to experience breast cancer recurrence than those who did not report hot flashes (P = 0.01) [16]. It was suggested that this may be due to the role of cytochrome P450 (CYP) 2D6 which converts tamoxifen to its active metabolite, endoxifen. Some polymorphisms of CYP2D6 can result in a less active enzyme. Previous studies in breast cancer patients receiving tamoxifen have suggested that women with impaired CYP2D6 metabolism have a higher risk of recurrence than extensive metabolizers [21, 22]. In addition, one study showed that patients who were homozygous for CYP2D6*4 (the most common allele associated with poor metabolism) had a higher risk of breast cancer recurrence and a lower incidence of hot flashes [23]. However, this topic remains a matter of much debate.

In our study, there did appear to be a correlation between patients reporting menopausal symptoms and improved OS for tamoxifen. However, a similar correlation was also observed for the AI, exemestane. Similarly, in the retrospective analysis of the ATAC trial, there was a link between vasomotor symptoms and improved clinical outcome for anastrozole-treated patients [20]. As AIs are not affected by CYP2D6 metabolism, this would suggest that other factors may be involved.

In contrast with our results and those from the ATAC trial, a recent exploratory analysis of the NCIC CTG MA.27 trial, which randomized patients to 5 years' adjuvant therapy with anastrozole or exemestane, reported no significant difference in DFS between patients experiencing or not experiencing vasomotor or joint symptoms, when evaluating the occurrence of symptoms after 3, 6 and 12 months of treatment [24].

Menopausal symptoms and joint symptoms are commonly reported in patients receiving endocrine therapy for breast cancer and are thought to be related to estrogen deprivation. As such, it may be that a greater reduction in estrogen levels offers more effective inhibition of the estrogen receptor-positive breast cancer tumor but also may result in increased menopausal symptoms and joint symptoms due to a near total estrogen deprivation. It is also important to consider that there was no significant correlation between patients reporting arthralgia/myalgia or those reporting menopausal symptoms and improved DFS for the sequential treatment group. The reasons for this disparity between treatment groups are unclear; however, we may hypothesize that this could be caused by the total estrogen suppression observed with exemestane consequently leading to arthralgia/myalgia, as well as menopausal symptoms. In contrast, tamoxifen acts as a partial agonist/antagonist and may not lead to the same of extent of symptoms. As such, further research into the mechanisms behind the correlation of the occurrence of menopausal symptoms and joint symptoms and response to endocrine therapy in patients with hormone receptor-positive breast cancer is required.

It is also important to note that AEs, such as arthralgia/myalgia and menopausal symptoms, may lead patients to discontinue treatment and result in poor adherence to therapy. Indeed, adherence to endocrine therapy has been shown to be suboptimal, potentially reducing the efficacy of therapy [25, 26]. Our results, in addition to those reported by the ATAC trial, may help reassure patients and encourage them to continue therapy, thereby improving adherence [27, 28]. Our results may also raise questions regarding the appropriateness of treating these AEs, as this may also affect the efficacy of endocrine therapy. However, further investigation regarding this is required and currently, it does seem appropriate to treat arthralgias and menopausal symptoms in patients who are suffering from these AEs.

Limitations of our study include the inaccuracy of coding AEs and serious AEs in clinical trials, as well as the small (n = 1502) patient population. Additionally, we have restricted this analysis to the German cohort, due to the different practice of coding AEs within different countries participating in TEAM. In addition, it is important to note that this was a retrospective analysis, and, as such, caution should be applied when interpreting these results. It should also be considered that the occurrence of arthralgia/myalgia was more frequent in the exemestane group compared with the sequential group during the first 30 months of treatment, which may have affected the results.

In conclusion, our results suggest that the occurrence of arthralgia/myalgia or menopausal symptoms during treatment with either tamoxifen followed by an AI or an AI alone is associated with significant improvements in OS.

funding

Pfizer Inc. (KKS 689–KKS 738).

disclosure

PH is currently conducting research sponsored by Pfizer and has given lectures for Pfizer. DGK is currently conducting research sponsored by Pfizer and is a member of Pfizer's speakers bureau. JT, AH and MZ have declared no conflicts of interest.

acknowledgements

Medical writing assistance was provided by Caroline Masterman at ACUMED (Tytherington, UK) and was funded by Pfizer Inc.

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