ABCSG-12 Shows Benefit for Zoledronic Acid in Early Breast Cancer

SAN ANTONIO – Despite the negative results overall of the AZURE trial, it may not be time to put the final nail in coffin of adjuvant zoledronic acid for the treatment of hormone-positive breast cancer.

[Zoledronic Acid Sinks as Breast Cancer Therapy in AZURE Trial]

Updated results for the ABCSG (Austrian Breast and Colorectal Cancer Study Group) Trial 12 continue to show disease-free and overall survival benefits 2 years after stopping adjuvant endocrine treatment with zoledronic acid (Zometa), according to an update presented at the annual San Antonio Breast Cancer Symposium.

The positive Austrian trial randomized 899 premenopausal women on goserelin (Zoladex) to 3 years of zoledronic acid with either tamoxifen or anastrozole (Arimidex) and 904 comparators to endocrine therapy alone (N. Engl. J. Med. 2009;360:679-91).

At a median follow-up of 62 months (2 years after treatment completion), zoledronic acid reduced the risk of disease-free survival events by 32%, compared with endocrine therapy alone (hazard ratio, 0.68; P = .008). Better disease-free survival was seen whether the women were on tamoxifen (HR, 0.67) or anastrozole (HR, 0.68). A trend toward reduced risk of death with zoledronic acid also endured (HR, 0.67; P = .09).

"We observed persistence of benefit with adjuvant zoledronic acid in the ABCSG-12 trial," said Dr. Michael Gnant, president of the ABCSG, at the press briefing where Dr. Robert Coleman reported no disease-free survival benefit overall (adjusted HR, 0.98; P = .79) from adjuvant zoledronic acid in the AZURE (Adjuvant Treatment With Zoledronic Acid in Stage II/III Breast Cancer) trial.

"Why are the ABCSG-12 results so different from the premenopausal [women] in AZURE?" asked Dr. Gnant, professor of surgery at the Medical University of Vienna. "I believe that when you look closely, there is minimal overlap in patient selection and treatment," he said.

"All of them [in the ABCSG-12 trial] were put into artificial menopause for 3 years with the use of goserelin. None of these patients had adjuvant chemotherapy. I think that’s an important difference from the AZURE trial," said Dr. Gnant.

In the AZURE trial, 96% of patients had adjuvant chemotherapy, and none got ovarian function-suppression treatment. Also, in the ABCSG-12 trial, about 70% of patients had low-risk, stage I breast cancer. Patients in the AZURE trial had stage II or III breast cancer.

Patients in the ABCSG-12 trial were randomized to one of four treatment groups: 20 mg/day tamoxifen; 20 mg/day tamoxifen plus 4 mg zoledronic acid every 6 months; 1 mg/day anastrozole; or 1 mg/day anastrozole plus 4 mg zoledronic acid every 6 months. Treatment lasted for 3 years. All patients received 3.6-mg subcutaneous goserelin every 28 days.

In all, 1,803 patients were enrolled between 1999 and 2006. As of May 18, 2010, 186 disease-free survival events and 73 deaths were recorded: 45 locoregional relapse events, 100 distant relapse events (including 53 bone metastasis events), and 14 contralateral breast cancer events. Adding zoledronic acid to endocrine therapy was associated with a continued reduction in recurrences inside and outside bone.

[FDA: Bevacizumab Should No Longer Be Indicated for Breast Cancer]

Adverse events associated with zoledronic acid treatment (arthralgia, bone pain, and pyrexia) were generally mild and consistent with the established safety profile. Zoledronic acid did not increase the occurrence of serious adverse events, compared with endocrine therapy alone. Importantly, there was no significant renal toxicity and no confirmed cases of osteonecrosis of the jaw.

"I find it quite intriguing and actually reassuring that with this therapeutic intervention that lasted 3 years – just an infusion every 6 months – you can change something in the long-term outcome of these patients," said Dr. Gnant. "When we break it down according to additional preplanned subgroups, actually we see that ... adjuvant bisphosphonate treatment works in every subgroup, at least if you look at the tumor-derived parameters."

The addition of adjuvant zoledronic acid may not make much difference in patients younger than 40 years, he suggested: "It’s exactly that group of patients where we cannot assume that the goserelin treatment will lead to full suppression of ovarian function and to very low estrogen levels," he said.

Among patients aged 40 years or older in ABCSG-12, however, there was a roughly 40% difference in disease-free survival, which translated into a 40% reduction in the risk of dying from breast cancer, although this did not reach statistical significance.

[Dual Anti-HER2 Blockade Called the Future of Breast Cancer Therapy]

The AZURE researchers also did extensive planned subgroup analyses. "One clearly stands out from all the others. That is the treatment effect on disease-free survival according to menopausal status," observed Dr. Coleman, a professor of medical oncology at the University of Sheffield (England). There was a clear overall survival benefit for women at least 5 years out from menopause on zoledronic acid. These women had a 29% reduction in the risk of death (P = .017).

"While obviously it’s fair to say that the overall result of AZURE is a little bit disappointing, scientifically it makes perfect sense," said Dr. Gnant. "Perfect suppression – or a natural lack of estrogen – in combination with adjuvant zoledronic acid leads to significant disease-free and overall survival benefit."

To put the results in practical terms, Dr. Gnant noted that for the past 2 years, he would have put his 42-year-old wife on zoledronic acid if she developed ER-positive breast cancer, but not his 83-year-old mother. "This has changed this afternoon. Now, my 83-year-old mother would also receive zoledronic acid," he said.

The ABCSG-12 trial was sponsored by Austrian Breast & Colorectal Cancer Study Group, with support from AstraZenaca (which makes Arimedex) and Novartis Pharmaceutical (which makes Zometa). Dr. Gnant disclosed that he has significant financial relationships with several pharmaceutical companies, including Novartis.

[Women's Health Initiative: New Findings on Big-Three Cancer Rates]

The AZURE trial was sponsored by the University of Sheffield. Dr. Coleman disclosed that he receives grant support from Novartis and is a speaker for Novartis and Amgen.

SAN ANTONIO – Despite the negative results overall of the AZURE trial, it may not be time to put the final nail in coffin of adjuvant zoledronic acid for the treatment of hormone-positive breast cancer.

[Zoledronic Acid Sinks as Breast Cancer Therapy in AZURE Trial]

Updated results for the ABCSG (Austrian Breast and Colorectal Cancer Study Group) Trial 12 continue to show disease-free and overall survival benefits 2 years after stopping adjuvant endocrine treatment with zoledronic acid (Zometa), according to an update presented at the annual San Antonio Breast Cancer Symposium.

The positive Austrian trial randomized 899 premenopausal women on goserelin (Zoladex) to 3 years of zoledronic acid with either tamoxifen or anastrozole (Arimidex) and 904 comparators to endocrine therapy alone (N. Engl. J. Med. 2009;360:679-91).

At a median follow-up of 62 months (2 years after treatment completion), zoledronic acid reduced the risk of disease-free survival events by 32%, compared with endocrine therapy alone (hazard ratio, 0.68; P = .008). Better disease-free survival was seen whether the women were on tamoxifen (HR, 0.67) or anastrozole (HR, 0.68). A trend toward reduced risk of death with zoledronic acid also endured (HR, 0.67; P = .09).

"We observed persistence of benefit with adjuvant zoledronic acid in the ABCSG-12 trial," said Dr. Michael Gnant, president of the ABCSG, at the press briefing where Dr. Robert Coleman reported no disease-free survival benefit overall (adjusted HR, 0.98; P = .79) from adjuvant zoledronic acid in the AZURE (Adjuvant Treatment With Zoledronic Acid in Stage II/III Breast Cancer) trial.

"Why are the ABCSG-12 results so different from the premenopausal [women] in AZURE?" asked Dr. Gnant, professor of surgery at the Medical University of Vienna. "I believe that when you look closely, there is minimal overlap in patient selection and treatment," he said.

"All of them [in the ABCSG-12 trial] were put into artificial menopause for 3 years with the use of goserelin. None of these patients had adjuvant chemotherapy. I think that’s an important difference from the AZURE trial," said Dr. Gnant.

In the AZURE trial, 96% of patients had adjuvant chemotherapy, and none got ovarian function-suppression treatment. Also, in the ABCSG-12 trial, about 70% of patients had low-risk, stage I breast cancer. Patients in the AZURE trial had stage II or III breast cancer.

Patients in the ABCSG-12 trial were randomized to one of four treatment groups: 20 mg/day tamoxifen; 20 mg/day tamoxifen plus 4 mg zoledronic acid every 6 months; 1 mg/day anastrozole; or 1 mg/day anastrozole plus 4 mg zoledronic acid every 6 months. Treatment lasted for 3 years. All patients received 3.6-mg subcutaneous goserelin every 28 days.

In all, 1,803 patients were enrolled between 1999 and 2006. As of May 18, 2010, 186 disease-free survival events and 73 deaths were recorded: 45 locoregional relapse events, 100 distant relapse events (including 53 bone metastasis events), and 14 contralateral breast cancer events. Adding zoledronic acid to endocrine therapy was associated with a continued reduction in recurrences inside and outside bone.

[FDA: Bevacizumab Should No Longer Be Indicated for Breast Cancer]

Adverse events associated with zoledronic acid treatment (arthralgia, bone pain, and pyrexia) were generally mild and consistent with the established safety profile. Zoledronic acid did not increase the occurrence of serious adverse events, compared with endocrine therapy alone. Importantly, there was no significant renal toxicity and no confirmed cases of osteonecrosis of the jaw.

"I find it quite intriguing and actually reassuring that with this therapeutic intervention that lasted 3 years – just an infusion every 6 months – you can change something in the long-term outcome of these patients," said Dr. Gnant. "When we break it down according to additional preplanned subgroups, actually we see that ... adjuvant bisphosphonate treatment works in every subgroup, at least if you look at the tumor-derived parameters."

The addition of adjuvant zoledronic acid may not make much difference in patients younger than 40 years, he suggested: "It’s exactly that group of patients where we cannot assume that the goserelin treatment will lead to full suppression of ovarian function and to very low estrogen levels," he said.

Among patients aged 40 years or older in ABCSG-12, however, there was a roughly 40% difference in disease-free survival, which translated into a 40% reduction in the risk of dying from breast cancer, although this did not reach statistical significance.

[Dual Anti-HER2 Blockade Called the Future of Breast Cancer Therapy]

The AZURE researchers also did extensive planned subgroup analyses. "One clearly stands out from all the others. That is the treatment effect on disease-free survival according to menopausal status," observed Dr. Coleman, a professor of medical oncology at the University of Sheffield (England). There was a clear overall survival benefit for women at least 5 years out from menopause on zoledronic acid. These women had a 29% reduction in the risk of death (P = .017).

"While obviously it’s fair to say that the overall result of AZURE is a little bit disappointing, scientifically it makes perfect sense," said Dr. Gnant. "Perfect suppression – or a natural lack of estrogen – in combination with adjuvant zoledronic acid leads to significant disease-free and overall survival benefit."

To put the results in practical terms, Dr. Gnant noted that for the past 2 years, he would have put his 42-year-old wife on zoledronic acid if she developed ER-positive breast cancer, but not his 83-year-old mother. "This has changed this afternoon. Now, my 83-year-old mother would also receive zoledronic acid," he said.

The ABCSG-12 trial was sponsored by Austrian Breast & Colorectal Cancer Study Group, with support from AstraZenaca (which makes Arimedex) and Novartis Pharmaceutical (which makes Zometa). Dr. Gnant disclosed that he has significant financial relationships with several pharmaceutical companies, including Novartis.

[Women's Health Initiative: New Findings on Big-Three Cancer Rates]

The AZURE trial was sponsored by the University of Sheffield. Dr. Coleman disclosed that he receives grant support from Novartis and is a speaker for Novartis and Amgen.

SAN ANTONIO – Despite the negative results overall of the AZURE trial, it may not be time to put the final nail in coffin of adjuvant zoledronic acid for the treatment of hormone-positive breast cancer.

[Zoledronic Acid Sinks as Breast Cancer Therapy in AZURE Trial]

Updated results for the ABCSG (Austrian Breast and Colorectal Cancer Study Group) Trial 12 continue to show disease-free and overall survival benefits 2 years after stopping adjuvant endocrine treatment with zoledronic acid (Zometa), according to an update presented at the annual San Antonio Breast Cancer Symposium.

The positive Austrian trial randomized 899 premenopausal women on goserelin (Zoladex) to 3 years of zoledronic acid with either tamoxifen or anastrozole (Arimidex) and 904 comparators to endocrine therapy alone (N. Engl. J. Med. 2009;360:679-91).

At a median follow-up of 62 months (2 years after treatment completion), zoledronic acid reduced the risk of disease-free survival events by 32%, compared with endocrine therapy alone (hazard ratio, 0.68; P = .008). Better disease-free survival was seen whether the women were on tamoxifen (HR, 0.67) or anastrozole (HR, 0.68). A trend toward reduced risk of death with zoledronic acid also endured (HR, 0.67; P = .09).

"We observed persistence of benefit with adjuvant zoledronic acid in the ABCSG-12 trial," said Dr. Michael Gnant, president of the ABCSG, at the press briefing where Dr. Robert Coleman reported no disease-free survival benefit overall (adjusted HR, 0.98; P = .79) from adjuvant zoledronic acid in the AZURE (Adjuvant Treatment With Zoledronic Acid in Stage II/III Breast Cancer) trial.

"Why are the ABCSG-12 results so different from the premenopausal [women] in AZURE?" asked Dr. Gnant, professor of surgery at the Medical University of Vienna. "I believe that when you look closely, there is minimal overlap in patient selection and treatment," he said.

"All of them [in the ABCSG-12 trial] were put into artificial menopause for 3 years with the use of goserelin. None of these patients had adjuvant chemotherapy. I think that’s an important difference from the AZURE trial," said Dr. Gnant.

In the AZURE trial, 96% of patients had adjuvant chemotherapy, and none got ovarian function-suppression treatment. Also, in the ABCSG-12 trial, about 70% of patients had low-risk, stage I breast cancer. Patients in the AZURE trial had stage II or III breast cancer.

Patients in the ABCSG-12 trial were randomized to one of four treatment groups: 20 mg/day tamoxifen; 20 mg/day tamoxifen plus 4 mg zoledronic acid every 6 months; 1 mg/day anastrozole; or 1 mg/day anastrozole plus 4 mg zoledronic acid every 6 months. Treatment lasted for 3 years. All patients received 3.6-mg subcutaneous goserelin every 28 days.

In all, 1,803 patients were enrolled between 1999 and 2006. As of May 18, 2010, 186 disease-free survival events and 73 deaths were recorded: 45 locoregional relapse events, 100 distant relapse events (including 53 bone metastasis events), and 14 contralateral breast cancer events. Adding zoledronic acid to endocrine therapy was associated with a continued reduction in recurrences inside and outside bone.

[FDA: Bevacizumab Should No Longer Be Indicated for Breast Cancer]

Adverse events associated with zoledronic acid treatment (arthralgia, bone pain, and pyrexia) were generally mild and consistent with the established safety profile. Zoledronic acid did not increase the occurrence of serious adverse events, compared with endocrine therapy alone. Importantly, there was no significant renal toxicity and no confirmed cases of osteonecrosis of the jaw.

"I find it quite intriguing and actually reassuring that with this therapeutic intervention that lasted 3 years – just an infusion every 6 months – you can change something in the long-term outcome of these patients," said Dr. Gnant. "When we break it down according to additional preplanned subgroups, actually we see that ... adjuvant bisphosphonate treatment works in every subgroup, at least if you look at the tumor-derived parameters."

The addition of adjuvant zoledronic acid may not make much difference in patients younger than 40 years, he suggested: "It’s exactly that group of patients where we cannot assume that the goserelin treatment will lead to full suppression of ovarian function and to very low estrogen levels," he said.

Among patients aged 40 years or older in ABCSG-12, however, there was a roughly 40% difference in disease-free survival, which translated into a 40% reduction in the risk of dying from breast cancer, although this did not reach statistical significance.

[Dual Anti-HER2 Blockade Called the Future of Breast Cancer Therapy]

The AZURE researchers also did extensive planned subgroup analyses. "One clearly stands out from all the others. That is the treatment effect on disease-free survival according to menopausal status," observed Dr. Coleman, a professor of medical oncology at the University of Sheffield (England). There was a clear overall survival benefit for women at least 5 years out from menopause on zoledronic acid. These women had a 29% reduction in the risk of death (P = .017).

"While obviously it’s fair to say that the overall result of AZURE is a little bit disappointing, scientifically it makes perfect sense," said Dr. Gnant. "Perfect suppression – or a natural lack of estrogen – in combination with adjuvant zoledronic acid leads to significant disease-free and overall survival benefit."

To put the results in practical terms, Dr. Gnant noted that for the past 2 years, he would have put his 42-year-old wife on zoledronic acid if she developed ER-positive breast cancer, but not his 83-year-old mother. "This has changed this afternoon. Now, my 83-year-old mother would also receive zoledronic acid," he said.

The ABCSG-12 trial was sponsored by Austrian Breast & Colorectal Cancer Study Group, with support from AstraZenaca (which makes Arimedex) and Novartis Pharmaceutical (which makes Zometa). Dr. Gnant disclosed that he has significant financial relationships with several pharmaceutical companies, including Novartis.

[Women's Health Initiative: New Findings on Big-Three Cancer Rates]

The AZURE trial was sponsored by the University of Sheffield. Dr. Coleman disclosed that he receives grant support from Novartis and is a speaker for Novartis and Amgen.