The choice of endocrine treatment (ET) for estrogen receptor-positive (ER+) perimenopausal patients has been met with controversy in recent years. Tamoxifen has traditionally been preferred over the use of aromatase inhibitors (AIs) in this group. This is because AIs only decrease extraovarian estrogen production. They do this via a negative feedback loop involving the hypothalamus and pituitary gland but they do not affect ovarian estrogen production. As a result, ovarian stimulation increases in perimenopausal women via subsequent gonadotropic secretion.

When used in perimenopausal women, AIs are combined with LHRH analogues to provide complete blockade of estrogen production in both the ovaries and the periphery, which reduces estrogen levels to postmenopausal levels.

Chemotherapy-induced amenorrhea occurs in about 77% of women. When present in women aged 40 years or older, it is often irreversible and results in chemotherapy-induced menopause. However, if ovarian function returns, AI treatment would be ineffective, but tamoxifen would retain its efficacy.

The purpose of this prospective, population-based cohort study was to determine the optimal ET for chemotherapy-treated ER+ women who were aged 45 to 50 years at BC diagnosis.

This cohort study gathered data from the Netherlands Cancer Registry of all Dutch women aged 45 to 50 years who were diagnosed with ER+ BC between 2004 and 2007. To be included in the study, women were to have no history of prior malignancy, nor were they to have received adjuvant chemotherapy or endocrine therapy.

The investigators calculated the AI-ET ratio, which was the AI treatment duration divided by the combination of AI and tamoxifen treatment duration multiplied by 100. This ratio more adequately reflects ET usage since there are frequent treatment switches between AIs and tamoxifen. The AI-ET ratio was presented in time-dependent intervals. Study endpoints included recurrence-free survival (RFS) and overall survival (OS).

A total of 2,295 women aged 45 to 50 years with ER+ invasive BC were enrolled in the study. Approximately 83% of women were initially started on tamoxifen. The average duration of ET was 5.5 years, and 65.5% received treatment beyond 5 years, with the average duration of 6.5 years in the latter group.

Patients often switched between ET, with only 35% of patients receiving just one type of treatment. Of these nonswitchers, 56.3% received tamoxifen while 43.7% received an AI.

AIs were administered the following percentage of the time: 47.5% for AI duration of 25% to 75%, 27.2% for AI <25% of the time, and 25.3% for AI >75% of the ET duration. Slightly over half were pT2, and over 85% were grade II to III. About 72% of women had metastases to one or more lymph nodes. Of the ER+ BCs, 87.3% were also progesterone receptor-positive (PR+) and about 7% were HER2-positive; AI >75% was used by 38.2% of this latter group. A total of 97% of women had received an anthracycline.

After a 7.6-year follow-up period, 377 RFS events were observed. Almost three-quarters (71%) of these events involved distant metastases.  

Correlating RFS with ET status, about 30% of those on AI <25% of the time experienced a disease recurrence compared with a disease recurrence of 10.8% and 12.8% in those who received 25% <AI, <75%, and AI >75%, respectively. A total of 236 deaths occurred during an average follow-up period of 7.7 years. Use of AI >75% was associated with better OS compared with AI <25% (adjusted 5-year OS was 97.3% vs. 94.6%, respectively).

At 5 years, the risk of dying was decreased by about 70% in those receiving 25% <AI, <75% versus AI <25% (adjusted 5-year HR = 0.32, 95% CI, 0.21-0.49). After 5 years, the relative risk of dying increased for each additional 1-year increment in follow-up time. On the other hand, the risk of dying was reduced by 10% for each additional 10% increase in AI-ET ratio.

The authors concluded that the use of predominantly an AI regimen following chemotherapy in ER+ perimenopausal BC patients aged 45 to 50 years offered significant RFS and OS benefit compared with tamoxifen. They advised that AIs can be considered for all women in this age group with chemotherapy-induced amenorrhea.

Pharmacists can play a major role in the educating perimenopausal ER+ BC patients on the signs of ovarian recovery. If this occurs, pharmacists would need to alert prescribers that ovarian suppression or ablation should be added to AI therapy or that the patient should be switched to tamoxifen.

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