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SAN FRANCISCO -- Older patients with advanced, relapsed, estrogen receptor-positive breast cancer had significant improvement in progression-free survival with no increased toxicity when the mTOR inhibitor everolimus (Afinitor) was added to exemestane (Aromasin), a new analysis of a randomized trial showed.

Patients 65 and older had a 41% reduction in the hazard for progression when treated with everolimus as compared with patients who received exemestane and placebo.

Adverse events occurred more often in those who received the everolimus-exemestane combination, but grade 3-4 adverse events were uncommon, as reported here at the Breast Cancer Symposium.

"The safety profile of everolimus and exemestane in elderly patients with advanced breast cancer was consistent with the known overall profiles of each agent," Hope Rugo, MD, of the University of California San Francisco, and colleagues concluded in a poster presentation. "Compared with younger patients, there were few differences in the incidence of adverse events."

"The addition of everolimus to exemestane can provide an effective new option for patients with advanced breast cancer, especially in elderly patients who may not tolerate toxic treatments."

The findings came from a subgroup analysis of the multicenter BOLERO-2 trial, which compared everolimus-exemestane and exemestane-placebo in 724 women with hormone receptor-positive breast cancer that had progressed on treatment with a nonsteroidal aromatase inhibitor.

The primary results of the trial showed a 57% reduction in the risk of progression in women treated with the everolimus-exemestane combination. Rugo reported findings from a comparison of outcomes in patients younger than 65 and those 65 and older.

More than 40% of patients with breast cancer are in that older age bracket and tend to have reduced physiologic function and increased comorbidity, both of which can adversely affect response to therapy.

Moreover, older patients have a greater tendency toward noncompliance because they often take multiple medications for various conditions. Additionally, the risk of adverse events increases with number of medications, Rugo and colleagues noted in the introduction to their presentation.

The BOLERO-2 study population included 275 patients 65 and older, 195 of whom received the everolimus-exemestane combination. Two-thirds of patients in the younger and older subgroups required dose reductions or interruptions as a result of everolimus-related toxicity.

After a median follow-up of 18 months, progression events (including death) had occurred in 60% of everolimus-treated patients 65 and older compared with 70% of patients in the placebo group. Median progression-free survival -- the primary outcome -- was 6.83 months with everolimus and 4.01 months with placebo.

Older patients treated with everolimus had a hazard ratio for progression of 0.59 versus the same age group treated with exemestane and placebo (95% CI 0.43 to 0.80). Stratification of patients into age groups younger than 70 and 70 and older produced similar results (HR 0.44 versus HR 0.45, respectively, in favor of everolimus).

The clinical benefit rate (response plus stable disease ≥24 weeks) was 58% in younger patients treated with everolimus and 41% in older patients. That compared with 24% and 31% of younger and older patients treated with exemestane and placebo.

Younger patients had a longer treatment duration with everolimus (34 versus 27 weeks for older patients) and a slightly higher dose intensity (7.9 versus 7.1 mg/day).

The most common adverse events among patients 65 and older were stomatitis (53%), fatigue (37%), decreased appetite (35%), and diarrhea (37%).

Adverse events of special interest occurred in a similar proportion of older and younger patients: pneumonitis (15% versus 17%), hyperglycemia (13% versus 15%), and hypercholesterolemia (6% versus 13%). Patients in both age groups had a mean weight loss of about 11 pounds from baseline when treated with everolimus.

Results of BOLERO-2 probably represent only the beginning of a new phase of treatment leading to better outcomes in patients with estrogen receptor-positive, HER2-negative breast cancer, said invited discussant Matthew Ellis, MD. Future therapies will build on evidence of better outcomes with endocrine agents combined with inhibitors of the PI3-kinase pathway.

"Use everolimus with caution -- fatalities are rare but patients can be very uncomfortable if side effects are not well managed," said Ellis, of Duke University. "Use in an older patient population is reasonable but, again, caution is needed regarding side effects."

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