*3.1. Study Population*

Patients' mean age at diagnosis was 59 years, while the mean age at the administration of the questionnaire was 66 years, on average 5.5 years after the beginning of AET. In our sample, premenopausal patients represented 36%, while postmenopausal ones represented 64%. At the time of the administration of the questionnaire, 292 patients (78.3%) had taken AIs, while 81 patients (21.7%) had taken tamoxifen. In total, 73 patients (19.6%) currently or previously used GnRH-agonists—55 of them in association with tamoxifen (75%) and 18 in association with AIs (25%). Seventy-nine patients had extended therapy—90% of them with AIs and 10% with tamoxifen. At the time of investigation, 178 patients (48%) had

been taking AET for less than 5 years, while 195 patients (52%) had concluded the 5-year standard treatment.

Characteristics of patients included in our sample are reported in Table 1.


**Table 1.** Characteristics of the study population.

#### *3.2. Incidence of Side Effects*

Eighty-one per cent of patients reported at least one side effect, and the majority of them reported more than one. Side effects were reported by 84% of patients taking tamoxifen and 80% of patients taking AI, and they were described as mild in 43% of cases, moderate in 34% and severe in 23% (Figure 1).

**Figure 1.** Incidence of side effects in patients taking tamoxifen and in patients taking aromatase inhibitors.

Overall, the most common side effects were arthralgia, hot flushes and vaginal dryness. The most common side effects among women taking tamoxifen were hot flushes, arthralgia and vaginal dryness, while they were arthralgia and hypercholesterolemia among women taking AI.

Side effects associated with each therapy and their incidence are reported in Table 2.


**Table 2.** Incidence of side effects of adjuvant endocrine therapy (overall, tamoxifen and aromatase inhibitors).

The addition of GnRH agonists to both tamoxifen and AIs significantly increased the incidence of side effects. In particular, patients taking tamoxifen plus GnRH agonists more often reported hot flushes, vaginal dryness, arthralgia and dyspareunia, while patients taking AIs plus GnRH agonists more often reported hot flushes, vaginal dryness, dyspareunia, mood changes, decreased libido and anxiety (Figure 2).

**Figure 2.** Incidence of side effects in: ( **A**) patients taking tamoxifen vs. patients taking tamoxifen + GnRH agonists; (**B**) patients taking aromatase inhibitors alone vs. patients taking aromatase inhibitors + GnRH agonists.

Patients who received adjuvant chemotherapy before starting AET reported a significantly higher incidence of side effects (84.8% vs. 78.6%; *p* < 0.001), while no significant difference emerged between patients who received radiotherapy and those who did not receive it (81.6% vs. 80.3%; *p* = 0.225).

Premenopausal women were more likely to report side effects compared to those who were menopausal at diagnosis (92% vs. 75%; *p* < 0.001). Hot flushes, vaginal dryness, dyspareunia and decreased libido were more frequent and less tolerated by premenopausal

women, while postmenopausal ones reported arthralgia as the most annoying side effect (Figure 3).

In total, 86 of our patients were offered to continue AET for a further 5 years in an extended therapy regimen, and 79 of them (91%) accepted, while 7 refused. Comparing these two groups of women, it emerged that those who refused the extended therapy regimen more often reported moderate and severe side effects during the first 5 years of treatment (*p* < 0.001). Among patients who accepted the extended therapy, 86% had side effects and 16% reported a worsening of them over time.

#### *3.3. Adherence to Treatment and Discontinuation*

Due to side effects, 79 patients (21%) considered discontinuing AET—57 (72%) taking AI and 22 (28%) taking tamoxifen. In addition, 33 patients (8.2%) reported an irregular assumption—23 (70%) taking AI and 10 (30%) taking tamoxifen. Fifty-nine patients (16%) replaced the treatment with another type of endocrine therapy due to intolerance, while forty-five patients (12%) definitively discontinued the treatment for this reason. The discontinuation rate was 6.4% during the first five years of treatment versus 24% during extended therapy, with no significant difference between different types of AET (14.8% among patients taking tamoxifen and 11.3% among patients taking AIs) (Figure 4).

**Figure 4.** Discontinuation rate in patients taking tamoxifen and in patients taking aromatase inhibitors.

Among patients who definitively discontinued the treatment, 24 (53%) did it during the first 5 years, 7 (16%) did not accept extended therapy at the end of the first 5 years of treatment and 14 (31%) discontinued the therapy between the fifth and tenth year, due to intolerance (Figure 5).

**Figure 5.** Time of discontinuation of adjuvant endocrine therapy.

Overall, 7/45 patients (16%) discontinued AET because of the appearance of severe pathologies, such as endometrial cancer, endometrial thickness or neurologic toxicity, while 38 patients (84%) discontinued because of intolerance to side effects, in particular, arthralgia (64%), hot flushes (4%) and mood alterations (2%), while 11% discontinued treatment for general intolerance, without specific symptoms.

Women who discontinued treatment more often reported severe side effects compared to those who did not discontinue it (44% vs. 15%; *p* < 0.001). Arthralgia was the principal side effect that caused patients to discontinue the treatment (64%).

Patients who had previously received adjuvant chemotherapy showed a lower discontinuation rate, despite a higher incidence of side effects. Even the patients who had received radiotherapy had a lower discontinuation rate compared to those who had not received it (Figure 6).

**Figure 6.** Discontinuation rate in patients who have received adjuvant chemotherapy or radiotherapy vs. patients who have not received adjuvant chemotherapy or radiotherapy.

We also stratified our patients by different breast cancer histological subtypes: ductal, lobular and others. The incidence of lobular breast cancer in our population was 10.5%, which is very similar to the incidence in the general population reported in the literature. We did not find any statistically significant difference in the incidence and severity of side effects nor in AET discontinuation rate between the different histological subtypes.

#### *3.4. Patient–Physician Communication and Support Strategies*

Eighty-eight per cent of patients who experienced AET side effects reported talking about it with the gynecologist during follow up visits. Overall, 77% of patients reported that the gynecologist asked them first about side effects and therapy compliance (Figure 7).

**Figure 7.** Patient–physician communication.

Among women who reported side effects, only 44% took medical treatments to overcome them, especially in the case of vaginal dryness (58.8%), arthralgia (26%) and hot flushes (16%), but 41.3% of them did not report any relief.

Only 9% of patients who experienced menopausal symptoms made regular visits to the dedicated menopause service of the Breast Unit.

Fifteen per cent of patients received psychological support from the dedicated psychology service of the Breast Unit, and ninety-four per cent of them reported that it was very useful and that they would have recommended it to other women diagnosed with breast cancer.

Overall, 94% of women felt well supported during follow-up visits and reported being correctly informed by gynecologists about adverse side effects of AET. On the other hand, 12% of patients who discontinued treatment reported that they would have continued it, if they were better informed about side effects and possible therapies to control them.
