Extending Aromatase-Inhibitor Therapy

Posted by • July 21st, 2016

Goss OA 07.21.16The risk of recurrence of hormone-receptor–positive early breast cancer continues indefinitely. The MA.17R trial, conducted by Goss et al., examined the effects of treatment with an aromatase inhibitor for 10 years rather than 5 years after any duration of prior treatment with tamoxifen, in postmenopausal women with hormone-receptor–positive early breast cancer.

An additional 5 years of adjuvant aromatase-inhibitor therapy in women with early hormone-receptor–positive breast cancer resulted in longer disease-free survival and a lower incidence of contralateral breast cancer than placebo, but not in longer overall survival. An Original Article explains.

Clinical Pearl

• What are current strategies to reduce the risk of recurrence in postmenopausal women who receive treatment for hormone-receptor–positive early breast cancer?

Long-term reduction in the risk of recurrence has been achieved with the antiestrogen agent tamoxifen, aromatase inhibitors, or a combination of the two. These treatments are administered in a variety of adjuvant regimens, including tamoxifen for 10 years, tamoxifen for up to 5 years followed by an aromatase inhibitor for 5 years, or an initial aromatase inhibitor for 5 years. Extrapolating from these results, many patients have chosen to continue taking an aromatase inhibitor for more than 5 years (if they do not have unacceptable side effects), despite the lack of specific data on its value and pending the results of clinical trials.

Clinical Pearl

• Does extending aromatase-inhibitor therapy for an additional 5 years prolong disease-free survival in postmenopausal women with hormone-receptor–positive early breast cancer?

The MA.17R trial showed that treatment with an aromatase inhibitor for an additional 5 years after initial treatment for 4.5 to 6 years was beneficial in preventing disease recurrence, independently of nodal status, prior adjuvant chemotherapy, time since the last dose of aromatase inhibitor, and duration of prior therapy with tamoxifen or an aromatase inhibitor. The rate of 5-year disease-free survival was 95% (95% confidence interval [CI], 93 to 96) in the letrozole group and 91% (95% CI, 89 to 93) in the placebo group. The hazard ratio involving disease recurrence or the occurrence of contralateral breast cancer with letrozole versus placebo was 0.66 (95% CI, 0.48 to 0.91; P=0.01). The annual incidence rate of contralateral breast cancer was 0.21% (95% CI, 0.10 to 0.32) in the letrozole group and 0.49% (95% CI, 0.32 to 0.67) in the placebo group (P=0.007), with a hazard ratio of 0.42 (95% CI, 0.22 to 0.81).

Table 2: Recurrence of Breast Cancer or Occurrence of Contralateral Breast Cancer

Morning Report Questions

Q: What is the effect of extended aromatase-inhibitor therapy on overall survival in postmenopausal women with hormone-receptor–positive early breast cancer? 

A: In the MA.17R trial, a total of 200 participants had died by the time of data cutoff (100 in each study group). The major causes of death in the letrozole and placebo groups were breast cancer (31 and 34 deaths, respectively), other primary cancers (26 and 25), and cardiovascular events (14 and 11). The rate of 5-year overall survival was 93% (95% CI, 92 to 95) in the letrozole group and 94% (95% CI, 92 to 95) in the placebo group, with a hazard ratio for death of 0.97 (95% CI, 0.73 to 1.28; P=0.83). No significant difference in overall survival between letrozole and placebo was found in any of the prespecified subgroups.

Figure 1: Kaplan–Meier Curves for Disease-free and Overall Survival

Q: What safety issues were associated with extended aromatase-inhibitor therapy in the MA.17R trial?

A: In the MA.17R trial, bone-related toxic effects occurred more frequently among patients receiving letrozole than among those receiving placebo, including a higher incidence of bone pain, bone fractures, and new-onset osteoporosis. Only a minority of the fractures in both groups were located in the hip, spine, pelvis, or femur, and no significant change in physical health was recorded in either group, perhaps because most of the women in both groups took bone-protecting supplements or medications during the study. Overall, the low incidence of reported toxic effects is probably due to self-selection on the part of study participants who had had few unacceptable side effects through the first 5 years of aromatase-inhibitor therapy and were thus willing to undergo another 5 years of treatment.

Table 3: Adverse Events

 

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