Aromatase Inhibitors Reduce Recurrence Risk, But Not Death Rates, in Premenopausal Patients With Breast Cancer

Premenopausal women with estrogen receptor (ER) – positive breast cancer who were receiving ovarian suppression experienced a significantly reduced risk of recurrence when given an aromatase inhibitor, compared with those given tamoxifen, research showed.

Researchers analyzed the effectiveness of aromatase inhibitors by looking at the results of four different trials. Their findings were recently presented at the 2021 San Antonio Breast Cancer Symposium.

Specifically, the annual rate of recurrence associated with aromatase inhibitors was 21% lower than that linked with tamoxifen. The derived benefit from aromatase inhibitors was typically observed in treatment years 0 to four. Limited follow-up remains beyond the 10-year mark.

“Using (aromatase inhibitors) rather than tamoxifen in premenopausal women receiving ovarian suppression reduces the risk of breast cancer recurrence by around 21%,” Rosie Bradley, a medical statistician at Oxford Population Health, University of Oxford, said during a presentation of the findings. “The reduction in distant recurrence (is) 17%, but (has) no effect on breast cancer mortality or overall survival; longer-term follow-up is needed to assess this effect. There's been no increase in non-breast cancer deaths and more fractures in women receiving AI.”

Researchers from the Early Breast Cancer Trialists’ Collaborative Group pooled individual data available from 7,030 premenopausal women with ER-positive breast cancer who had participated in one of the following randomized controlled trials:

• ABCSG 12 (NCT00295646)
• TEXT (NCT00066703)
• SOFT (NCT00066690)
• HOBOE (NCT00412022).

Enrolled patients had all received ovarian suppression or ablation.

Trial participants were randomized to receive either an aromatase inhibitor or tamoxifen for a three-year study period (in ABCSG 12) or a five-year period in other trials (SOFT, TEXT, and HOBOE). Measuring time to invasive breast cancer recurrence, including distant, locoregional (near the original site of the cancer), or new cancer in the opposite breast, and breast cancer mortality were the main outcomes of the trials.

Notably, the four trials had different chemotherapy administrations. In ABCSG 12, only preoperative chemotherapy was permitted, and 5% of women received this treatment. In the TEXT trial, chemotherapy was optional, and was administered alongside ovarian suppression to 60% of participants. In SOFT, chemotherapy was given before randomization so long as patients remained premenopausal after completion; 54% of women in the SOFT trial received this treatment. Lastly, in HOBOE, chemotherapy was given before randomization to 63% of enrolled patients.

Overall, the recurrence risk was 14.7% in women treated with an aromatase inhibitor, compared with 17.5% in those given tamoxifen. At a five-year follow-up, the rate of recurrence was 10.1% vs 6.9%, for the aromatase inhibitor and tamoxifen groups, respectively. Despite the distant recurrence reduction, breast cancer mortality was similar between the two groups. Consequently, longer follow-up is needed to properly assess the impact on morbidity, said Bradley.

Moreover, 13 analyses investigated possible variabilities in the recurrence rate reduction across the different subgroups. During the periods where treatment differed and benefit was derived from the aromatase inhibitor, factors including age, body mass index, or by tumor size, tumor grade, histological subtype or presence and absence of chemotherapy were not found to impact reduction in recurrence proportionally.

Furthermore, despite the overall findings from the meta-analysis, women with disease that spread to four or more lymph nodes did not appear to derive benefit from aromatase inhibitor treatment. The risk reduction for individuals who had no disease spread to lymph nodes was 29%, and 28% for disease that spread to one, two or three lymph nodes. An increase in risk of recurrence was associated with breast cancer that had spread to four or more lymph nodes.

“If the proportional reductions are similar in different risk categories, then the absolute benefit from (aromatase inhibitors) over tamoxifen should increase with increasing risk category,” said Bradley. “Here, we are seeing a doubling of absolute gain of (aromatase inhibitors) compared with tamoxifen to mock span from 2.4% in node negative to 4.8% in (one, two or three) positive nodes. The finding we see (in disease with cancer spread to four or more lymph nodes) was unanticipated. (A prior study) that compared aromatase inhibitors and tamoxifen in postmenopausal women published in The Lancet in 2015, showed no suggestion of any lesser benefit in (disease that spread to four or more lymph nodes).”

Besides nodal status, there were clear differences between the four trial results and between HER2-negative and positive disease. The study authors noted that the latter differences may be a chance finding given the borderline statistical significance.

In addition, more women receiving an aromatase inhibitor experienced bone fractures compared with women receiving tamoxifen (5% vs 3.8%, respectively), and few non-breast cancer deaths occurred (0.5% vs 0.2%, respectively).

In a post-presentation discussion of the findings, Bradley explained that individual patient data was not available for this meta-analysis on toxicity and quality of life (QOL), but that researchers looked at individual trials that have reported on QOL and side effects with these agents, and that there are no strong differences in QOL between aromatase inhibitors or tamoxifen plus ovarian suppression.

Side effects associated with AI include bone fractures and endometrial abnormalities. These may require specific management and therefore treatment management discussions are advised for patients and providers. Bisphosphonates may be an effective strategy to preserve bone density and reduce bone fractures, she added.

Moving forward, the QOL associated with endocrine therapy and ovarian suppression need to be considered, Bradley concluded.

A version of this article originally appeared on OncLive as “Aromatase Inhibitors Significantly Reduce Recurrence in Premenopausal ER+ Breast Cancer.”

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