SOLE trial: Intermittent letrozole may provide benefit for some breast cancer patients

CHICAGO – Five years of extended intermittent letrozole provided no overall improvement in disease-free survival (DFS) when compared with continuous treatment with the aromatase inhibitor among postmenopausal women who received 4-6 years of endocrine therapy for hormone receptor–positive, lymph node–positive early breast cancer in the randomized phase III Study of Letrozole Extension (SOLE).

However, the similarities in DFS and adverse events incidence in the intermittent and continuous treatment groups – and improvements in a number of quality of life measures with intermittent treatment – suggest that temporary treatment breaks are acceptable in those who could benefit from them, Marco Colleoni, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The DFS among 2,425 women who received 5 years of intermittent letrozole after completing 4-6 years of adjuvant endocrine therapy was 85.8%, compared with 87.5% among 2,426 women who received 5 years of continuous letrozole after adjuvant therapy (hazard ratio, 1.08) said Dr. Colleoni of the European Institute of Oncology, Milan, Italy.

Similar outcomes were observed for breast cancer–free interval (HR, 0.98), distant recurrence-free interval (HR, 0.88), and overall survival (HR, 0.85), he said.

Of note, trends toward greater improvement on both the primary and secondary endpoints were seen with continuous therapy among those who received prior selective estrogen receptor modulator (SERM) vs. aromatase inhibitor (AI) therapy, but the differences did not reach statistical significance, he said.

Adjuvant extended endocrine therapy with letrozole has been recommended after initial tamoxifen for postmenopausal women with hormone receptor–positive (HR+) breast cancer, but the magnitude of the beneficial effect of extended letrozole in women who previously received an aromatase inhibitor has been limited, Dr. Colleoni said.

“Therefore, based on available data, the use of an AI for 10 years should be discussed on an individualized basis,” he said.

However, there is rationale for the intermittent use of letrozole as a therapeutic option to prolong sensitivity to endocrine therapies,” he noted.

“Breast cancer cells, in fact, can develop resistance following antihormonal therapy. In particular, cells that are maintained estrogen-free for years start to grow spontaneously. It has been shown ... that minimal concentrations of estrogen, similar to those achievable through interruption of treatment with aromatase inhibitors, can produce a cytocidal effect on cells that are deprived of estrogen,” he explained. “Moreover, in breast cancer cells transplanted into animal models, a response to a 6-week withdrawal of letrozole was observed when the treatment was started again.”

Thus, the SOLE study was designed to look at the value of extended adjuvant therapy in patients with HR+ breast cancer, the role of intermittent administration of letrozole in patients previously treated with AIs, the impact of intermittent vs. continuous administration on the side effect profile and quality of life and adherence to intermittent administration, he said.

Study participants were women with a median age of 60 years who were enrolled from 240 centers in 22 countries between November 2007 and July 2012. They had HR+ invasive breast cancer, any HER2 status, and disease confined to the breast and axillary lymph nodes. All had received SERM, AI, or combination SERM and AI treatment for 4-6 years but must have discontinued that therapy within 1 year prior to randomization.

Women in the intermittent treatment group were treated for the first 9 months of years 1-4 and for 12 months in year 5. Those in the continuous treatment group received 2.5 mg of letrozole daily for 5 years.

The adverse events were as expected, with 36.2% and 34.5% of patients in the intermittent and continuous treatment groups experiencing grade 3 or 5 events, respectively, and were similar, Dr. Colleoni said.

Treatment was discontinued for DFS events in 8% of patients and for other reasons in 24% of patients. Treatment was completed by 39% of patients and currently is ongoing in 29%, he said.

“When we designed the SOLE study, we were worried about ... the treatment gap. We’re delighted to observe that more than 90% of the patients regularly resumed [treatment] after interruption, ... reassuring [us of] the feasibility of a treatment gap during extended adjuvant letrozole,” he said.

Additionally, a quality of life substudy of 955 patients from the SOLE trial, who were assessed at baseline and at 6, 12, 18, and 24 months, showed a consistent pattern favoring intermittent therapy on patient-reported quality of life measures. Specifically, there was significantly less worsening from baseline with respect to vaginal problems, musculoskeletal pain, sleep disturbance, physical wellbeing, and mood at 12 months in the intermittent vs. continuous letrozole group and significantly greater improvement in hot flashes at 24 months in the intermittent vs. continuous group, he said.

“The results ... provide clinically relevant information on intermittent administration of extended letrozole for patients who could benefit from temporary treatment breaks,” he concluded, noting that translational studies are ongoing, such as measurement of estradiol levels during treatment gaps.

The SOLE trial was supported by Novartis. Dr. Colleoni reported receiving honoraria from Novartis, and serving as a consultant or advisor for AstraZeneca, Celldex, OBI Pharma, Pfizer, Pierre Fabre, and Puma Biotechnology.

[email protected]

CHICAGO – Five years of extended intermittent letrozole provided no overall improvement in disease-free survival (DFS) when compared with continuous treatment with the aromatase inhibitor among postmenopausal women who received 4-6 years of endocrine therapy for hormone receptor–positive, lymph node–positive early breast cancer in the randomized phase III Study of Letrozole Extension (SOLE).

However, the similarities in DFS and adverse events incidence in the intermittent and continuous treatment groups – and improvements in a number of quality of life measures with intermittent treatment – suggest that temporary treatment breaks are acceptable in those who could benefit from them, Marco Colleoni, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The DFS among 2,425 women who received 5 years of intermittent letrozole after completing 4-6 years of adjuvant endocrine therapy was 85.8%, compared with 87.5% among 2,426 women who received 5 years of continuous letrozole after adjuvant therapy (hazard ratio, 1.08) said Dr. Colleoni of the European Institute of Oncology, Milan, Italy.

Similar outcomes were observed for breast cancer–free interval (HR, 0.98), distant recurrence-free interval (HR, 0.88), and overall survival (HR, 0.85), he said.

Of note, trends toward greater improvement on both the primary and secondary endpoints were seen with continuous therapy among those who received prior selective estrogen receptor modulator (SERM) vs. aromatase inhibitor (AI) therapy, but the differences did not reach statistical significance, he said.

Adjuvant extended endocrine therapy with letrozole has been recommended after initial tamoxifen for postmenopausal women with hormone receptor–positive (HR+) breast cancer, but the magnitude of the beneficial effect of extended letrozole in women who previously received an aromatase inhibitor has been limited, Dr. Colleoni said.

“Therefore, based on available data, the use of an AI for 10 years should be discussed on an individualized basis,” he said.

However, there is rationale for the intermittent use of letrozole as a therapeutic option to prolong sensitivity to endocrine therapies,” he noted.

“Breast cancer cells, in fact, can develop resistance following antihormonal therapy. In particular, cells that are maintained estrogen-free for years start to grow spontaneously. It has been shown ... that minimal concentrations of estrogen, similar to those achievable through interruption of treatment with aromatase inhibitors, can produce a cytocidal effect on cells that are deprived of estrogen,” he explained. “Moreover, in breast cancer cells transplanted into animal models, a response to a 6-week withdrawal of letrozole was observed when the treatment was started again.”

Thus, the SOLE study was designed to look at the value of extended adjuvant therapy in patients with HR+ breast cancer, the role of intermittent administration of letrozole in patients previously treated with AIs, the impact of intermittent vs. continuous administration on the side effect profile and quality of life and adherence to intermittent administration, he said.

Study participants were women with a median age of 60 years who were enrolled from 240 centers in 22 countries between November 2007 and July 2012. They had HR+ invasive breast cancer, any HER2 status, and disease confined to the breast and axillary lymph nodes. All had received SERM, AI, or combination SERM and AI treatment for 4-6 years but must have discontinued that therapy within 1 year prior to randomization.

Women in the intermittent treatment group were treated for the first 9 months of years 1-4 and for 12 months in year 5. Those in the continuous treatment group received 2.5 mg of letrozole daily for 5 years.

The adverse events were as expected, with 36.2% and 34.5% of patients in the intermittent and continuous treatment groups experiencing grade 3 or 5 events, respectively, and were similar, Dr. Colleoni said.

Treatment was discontinued for DFS events in 8% of patients and for other reasons in 24% of patients. Treatment was completed by 39% of patients and currently is ongoing in 29%, he said.

“When we designed the SOLE study, we were worried about ... the treatment gap. We’re delighted to observe that more than 90% of the patients regularly resumed [treatment] after interruption, ... reassuring [us of] the feasibility of a treatment gap during extended adjuvant letrozole,” he said.

Additionally, a quality of life substudy of 955 patients from the SOLE trial, who were assessed at baseline and at 6, 12, 18, and 24 months, showed a consistent pattern favoring intermittent therapy on patient-reported quality of life measures. Specifically, there was significantly less worsening from baseline with respect to vaginal problems, musculoskeletal pain, sleep disturbance, physical wellbeing, and mood at 12 months in the intermittent vs. continuous letrozole group and significantly greater improvement in hot flashes at 24 months in the intermittent vs. continuous group, he said.

“The results ... provide clinically relevant information on intermittent administration of extended letrozole for patients who could benefit from temporary treatment breaks,” he concluded, noting that translational studies are ongoing, such as measurement of estradiol levels during treatment gaps.

The SOLE trial was supported by Novartis. Dr. Colleoni reported receiving honoraria from Novartis, and serving as a consultant or advisor for AstraZeneca, Celldex, OBI Pharma, Pfizer, Pierre Fabre, and Puma Biotechnology.

[email protected]

CHICAGO – Five years of extended intermittent letrozole provided no overall improvement in disease-free survival (DFS) when compared with continuous treatment with the aromatase inhibitor among postmenopausal women who received 4-6 years of endocrine therapy for hormone receptor–positive, lymph node–positive early breast cancer in the randomized phase III Study of Letrozole Extension (SOLE).

However, the similarities in DFS and adverse events incidence in the intermittent and continuous treatment groups – and improvements in a number of quality of life measures with intermittent treatment – suggest that temporary treatment breaks are acceptable in those who could benefit from them, Marco Colleoni, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The DFS among 2,425 women who received 5 years of intermittent letrozole after completing 4-6 years of adjuvant endocrine therapy was 85.8%, compared with 87.5% among 2,426 women who received 5 years of continuous letrozole after adjuvant therapy (hazard ratio, 1.08) said Dr. Colleoni of the European Institute of Oncology, Milan, Italy.

Similar outcomes were observed for breast cancer–free interval (HR, 0.98), distant recurrence-free interval (HR, 0.88), and overall survival (HR, 0.85), he said.

Of note, trends toward greater improvement on both the primary and secondary endpoints were seen with continuous therapy among those who received prior selective estrogen receptor modulator (SERM) vs. aromatase inhibitor (AI) therapy, but the differences did not reach statistical significance, he said.

Adjuvant extended endocrine therapy with letrozole has been recommended after initial tamoxifen for postmenopausal women with hormone receptor–positive (HR+) breast cancer, but the magnitude of the beneficial effect of extended letrozole in women who previously received an aromatase inhibitor has been limited, Dr. Colleoni said.

“Therefore, based on available data, the use of an AI for 10 years should be discussed on an individualized basis,” he said.

However, there is rationale for the intermittent use of letrozole as a therapeutic option to prolong sensitivity to endocrine therapies,” he noted.

“Breast cancer cells, in fact, can develop resistance following antihormonal therapy. In particular, cells that are maintained estrogen-free for years start to grow spontaneously. It has been shown ... that minimal concentrations of estrogen, similar to those achievable through interruption of treatment with aromatase inhibitors, can produce a cytocidal effect on cells that are deprived of estrogen,” he explained. “Moreover, in breast cancer cells transplanted into animal models, a response to a 6-week withdrawal of letrozole was observed when the treatment was started again.”

Thus, the SOLE study was designed to look at the value of extended adjuvant therapy in patients with HR+ breast cancer, the role of intermittent administration of letrozole in patients previously treated with AIs, the impact of intermittent vs. continuous administration on the side effect profile and quality of life and adherence to intermittent administration, he said.

Study participants were women with a median age of 60 years who were enrolled from 240 centers in 22 countries between November 2007 and July 2012. They had HR+ invasive breast cancer, any HER2 status, and disease confined to the breast and axillary lymph nodes. All had received SERM, AI, or combination SERM and AI treatment for 4-6 years but must have discontinued that therapy within 1 year prior to randomization.

Women in the intermittent treatment group were treated for the first 9 months of years 1-4 and for 12 months in year 5. Those in the continuous treatment group received 2.5 mg of letrozole daily for 5 years.

The adverse events were as expected, with 36.2% and 34.5% of patients in the intermittent and continuous treatment groups experiencing grade 3 or 5 events, respectively, and were similar, Dr. Colleoni said.

Treatment was discontinued for DFS events in 8% of patients and for other reasons in 24% of patients. Treatment was completed by 39% of patients and currently is ongoing in 29%, he said.

“When we designed the SOLE study, we were worried about ... the treatment gap. We’re delighted to observe that more than 90% of the patients regularly resumed [treatment] after interruption, ... reassuring [us of] the feasibility of a treatment gap during extended adjuvant letrozole,” he said.

Additionally, a quality of life substudy of 955 patients from the SOLE trial, who were assessed at baseline and at 6, 12, 18, and 24 months, showed a consistent pattern favoring intermittent therapy on patient-reported quality of life measures. Specifically, there was significantly less worsening from baseline with respect to vaginal problems, musculoskeletal pain, sleep disturbance, physical wellbeing, and mood at 12 months in the intermittent vs. continuous letrozole group and significantly greater improvement in hot flashes at 24 months in the intermittent vs. continuous group, he said.

“The results ... provide clinically relevant information on intermittent administration of extended letrozole for patients who could benefit from temporary treatment breaks,” he concluded, noting that translational studies are ongoing, such as measurement of estradiol levels during treatment gaps.

The SOLE trial was supported by Novartis. Dr. Colleoni reported receiving honoraria from Novartis, and serving as a consultant or advisor for AstraZeneca, Celldex, OBI Pharma, Pfizer, Pierre Fabre, and Puma Biotechnology.

[email protected]