Reduction in breast cancer recurrence upon treatment with aromatase inhibitors in premenopausal ER+ breast cancer patients

A recent meta-analysis of four large trials that compared the use of aromatase inhibitors with tamoxifen showed that these inhibitors helped to reduce the risk of breast cancer recurrence in premenopausal women with oestrogen receptor-positive breast cancer who were receiving ovarian suppression. The derived benefit from aromatase inhibitors was typically observed in treatment years 0 to 4.

For women with early stage hormone receptor-positive (HR⁺) breast cancer, adjuvant treatment with tamoxifen reduces their 15-year risk of death from breast cancer by about one third. Aromatase inhibitors (AIs) are even more effective than tamoxifen in post-menopausal women but, used alone, are ineffective in pre-menopausal women due to compensatory ovarian oestrogen production. Several trials have assessed whether AIs may also be more effective than tamoxifen at preventing breast cancer recurrence in premenopausal women, if administered together with ovarian suppression (OFS). However, as trial results have been inconsistent, a patient level meta-analysis of 7,030 women in four randomised trials was conducted.

Study design

Individual patient data were available from four randomised controlled trials, including 7,030 pre-menopausal women with oestrogen receptor-positive (ER⁺) breast cancer. All women received ovarian suppression or ablation and were randomised to receive either an AI or tamoxifen for 3 years (ABCSG XII study) or 5 years (SOFT, TEXT and HOBOE trials). Primary outcomes for the meta-analysis were time to invasive breast cancer recurrence (distant, loco-regional, or new contralateral breast primary) and breast cancer mortality. Of note, the four trials had different chemotherapy administrations. In ABCSG 12, only neoadjuvant chemotherapy was permitted, and 5% of women received this treatment. In the TEXT trial, chemotherapy was optional, and was administered concurrently with ovarian suppression to 60% of participants. In SOFT, chemotherapy was given before randomisation so long as patients remained premenopausal after completion; 54% of women received this treatment. Lastly, in HOBOE, chemotherapy was given before randomisation to 63% of enrolled patients.

Results

Overall, the annual rate of recurrence was 21% lower for women who received an AI as compared to those receiving tamoxifen (relative risk [RR]: 0.79 [95%CI: 0.69-0.90], p=0.0005). The 10-year absolute risk of breast cancer recurrence was 2.8% lower in the AI group than the tamoxifen group (14.7% versus 17.5%). At a 5-year follow-up, the rate of recurrence was 10.1% with AI compared to 6.9%. The main benefit from AI on recurrence was seen in years 0-4, the period when treatments differed, with no further benefit or loss of benefit in years 5-9.  Limited follow-up data was available beyond year 10. Although distant recurrence was significantly reduced with AI (RR [95%CI]: 0.83 [0.71-0.97]; p=0.02), breast cancer mortality was similar between the two groups (RR [95%CI]: 1.01 [0.82-1.24]; p=0.94).  However, longer follow up is needed to reliably assess the effects of AI on breast cancer mortality.

Furthermore, thirteen analyses investigated possible variabilities in the recurrence rate reduction across the difference subgroups. The proportional reduction in recurrence during the period when treatments differed did not vary by age, body mass index, tumour size, tumour grade, histological subtype, or the presence or absence of chemotherapy. Despite the overall findings from the meta-analysis, there was a trend for diminished efficacy with increased lymph node involvement, with no apparent benefit from AI in N4+ disease (RR: 0.71 in N0, RR: 0.71 in N1-3, RR: 1.03 in N4+; p-value for trend was 0.05). This finding was unanticipated and there seems to be no good reason for a lesser benefit in N4+ disease. There were more bone fractures in women receiving AI as compared to those receiving tamoxifen (5.0% versus 3.8%, p=0.02). Finally, among these relatively young women enrolled in this meta-analysis, few non-breast cancer deaths occurred (0.5% versus 0.2%; RR [95%CI]: 1.29 [0.75-2.24]).

Conclusion

Using AI rather than tamoxifen in pre-menopausal women receiving ovarian function suppression reduces the risk of breast cancer recurrence by approximately 21%. In addition, a reduction in distant recurrence of 17% was observed. However, there was no effect on breast cancer mortality or overall survival and longer follow-up is needed. Finally, there was no increase in non-breast cancer deaths but there were more bone fractures in women receiving AI.

Reference

Bradley R, et al. Aromatase inhibitors vs tamoxifen in pre-menopausal women with estrogen receptor positive early stage breast cancer treated with ovarian suppression: a patient level meta-analysis of 7030 women in four randomised trials. Presented at SABCS 2021; abstract GS2-04.