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ORLANDO – Cumulative evidence over the years has shown that bisphosphonates reduce distant metastases in postmenopausal women with early-stage breast cancer but that effect does not seem to extend to younger, premenopausal women who may experience adverse effects with bisphosphonates, nor has it been replicated in other types of cancer, such as lung or prostate, Robert Coleman MBBS, MD, said in a presentation marking the 50th anniversary of the publication of the first papers describing the then-new class of drugs.
“We have some science – at least in postmenopausal breast cancer – [showing] that we’re really making a difference, but we don’t understand why it’s not working in the other patients or in the other diseases,” said Dr. Coleman of the University of Sheffield (England) at the annual meeting of the American Society for Bone and Mineral Research.
Mixed findings in early studies
Early studies showing the metastases-prevention effects of bisphosphonates were with clodronate. In one study, Dr. Coleman said, researchers found that oral clodronate at a dose of 1,600 mg/day as a supplementary treatment to standard treatment for primary, operable breast cancer reduced the risk of bone metastases in a cohort of 1,069 patients with stage 1-3 breast cancer (hazard ratio, 0.692; P = .043) over 5 years (Breast Cancer Res. 2006 Mar 15. doi: 10.1186/bcr1384). Another trial, of 302 patients with breast cancer who received oral clodronate at 1,600 mg/day for 2 years, found that 20.4% of patients who received oral clodronate had died by 8.5 years of follow-up, compared with 40.7% of those who did not receive the intervention (Ann Oncol. 2008;19[12]:2007-11).
However, those results were in conflict with findings from an earlier study in which researchers followed patients with breast cancer who received 1,600 mg/day of oral clodronate or placebo for 3 years. They found a similar number of bone metastases in the clodronate and placebo groups (32% and 29%, respectively), as well as a lower overall disease-free survival rate at 10 years for the clodronate group, compared with the placebo group (45% vs. 58%; Acta Oncol. 2004;43[7]:650-6).“For various other reasons, clodronate did not gain traction as a therapeutic strategy in early-stage breast cancer,” said Dr. Coleman, although emerging evidence showed that other bisphosphonate agents were effective in some patients with breast cancer.
In a 2009 article, Gnant et al. reported that premenopausal patients, who underwent primary surgery for stage 1 or stage 2 breast cancer and received standard goserelin therapy for induced menopause and endocrine therapy (either tamoxifen or anastrozole) in addition to treatment with zoledronic acid, had a disease-free survival rate of 94.0% at a median 47.8 months of follow-up (N Eng J Med. 2009;360:679-91). After a median 94.4 months of follow-up, the investigators reported a lower risk of disease progression (HR, 0.77; 95% confidence interval, 0.60-0.99; P = .042) and death (HR, 0.66; 95% CI, 0.43-1.02; P = .064; Ann Oncol. 2015;26[2]:313-20).
In his own group, Dr. Coleman and colleagues recruited patients with early-stage breast cancer in the AZURE trial, a phase 3 study of 3,360 patients who received standard therapy with or without zoledronic acid 4 mg every 3-4 weeks for 6 doses, followed by 8 doses every 3 months then 5 doses every 6 months (N Eng J Med. 2011;365:1396-405). “We saw no effect,” said Dr. Coleman. “[That was] very different from what was shown by [Dr.] Gnant.”
For a subgroup of postmenopausal patients, Dr. Coleman and colleagues found that the adjusted HR for disease-free survival was 0.82 for women who were more than 5 years postmenopausal (95% CI, 0.67-1.00) at the time of breast cancer and bisphosphonate treatment, but women younger than 40 years had worse survival outcomes at 10 years (HR, 1.56; 95% CI, 1.09-2.22) and had a significantly higher risk of death from breast cancer (HR, 1.67; 95% CI, 1.16-2.40; J Bone Oncol. 2018 Sep 27. doi: 10.1016/j.jbo.2018.09.008).
Trying to reconcile disparate findings
Those findings left his group with a dilemma, said Dr. Coleman. “Do we start again and run trials, and wait another 10 years, or is there a shortcut to [understanding] what’s going on?” he asked.
In a meta-analysis of all trials from the Early Breast Cancer Trialists’ Collaborative Group in 2015 examining adjuvant bisphosphonate treatment and placebo in patients with early-stage breast cancer, intent-to-treat analyses did not show significant benefit after therapy, but postmenopausal women (11,767 women in 36 trials) saw a clear benefit in all recurrence (rate ratio, 0.86; 95% CI, 0.78-0.94), bone recurrence (RR, 0.72; 95% CI, 0.60-0.86), and breast cancer–related mortality (RR, 0.82; 95% CI, 0.73-0.93; Lancet. 2015 Jul 23. doi: 10.1016/S0140-6736[15]60908-4). The effect seemed to be similar, regardless of bisphosphonate type, with other results seen across trials that used clodronate, zoledronic acid, pamidronate, or ibandronate.
“Although those outcome differences might look quite small for a common disease, that’s a really big effect. Reducing one-sixth of breast cancer deaths at 10 years is the equivalent of saving 10,000 lives across the [European Union], and about half that in the United States,” said Dr. Coleman, noting that guidelines in North America from the American Society of Clinical Oncology and the European Society for Medical Oncology now support adjuvant bisphosphonates in postmenopausal patients with breast cancer.
However, bisphosphonates’ effect on breast cancer does not extend to other cancers, such as non–small cell lung cancer or prostate cancer. In other absorption inhibitors such as denosumab, there also seems to be no benefit for patients with breast cancer, including in postmenopausal patient subgroups, said Dr. Coleman. “In my view, osteoclast inhibition is only part of the story,” he noted.
In the AZURE trial, secondary outcomes examined how the transcription factor MAF interacted with menopausal status and treatment with zoledronic acid. The 79% of patients with tumors that were negative for MAF fluorescence in situ hybridization had improved overall survival (0.69; 95% CI, 0.50-0.94), regardless of menopause status (J Bone Oncol. 2018. doi: 10.1016/j.jbo.2018.09.008). “There’s probably a need to merge the treatment: in this case, the bisphosphonate, the biology of the cancer, and the environment the cancer finds itself in,” noted Dr. Coleman.
“From the cancer perspective, he concluded.
Dr. Coleman reports being a paid employee of prIME Oncology (until March 2019); is a consultant for Amgen, Astellas, Boehringer Ingelheim, Scandell, and Biocon; is on the speakers bureau for Amgen and Eisai; holds intellectual property rights for a biomarker being developed by Inbiomotion; and is on the scientific advisory board for Inbiomotion.
ORLANDO – Cumulative evidence over the years has shown that bisphosphonates reduce distant metastases in postmenopausal women with early-stage breast cancer but that effect does not seem to extend to younger, premenopausal women who may experience adverse effects with bisphosphonates, nor has it been replicated in other types of cancer, such as lung or prostate, Robert Coleman MBBS, MD, said in a presentation marking the 50th anniversary of the publication of the first papers describing the then-new class of drugs.
“We have some science – at least in postmenopausal breast cancer – [showing] that we’re really making a difference, but we don’t understand why it’s not working in the other patients or in the other diseases,” said Dr. Coleman of the University of Sheffield (England) at the annual meeting of the American Society for Bone and Mineral Research.
Mixed findings in early studies
Early studies showing the metastases-prevention effects of bisphosphonates were with clodronate. In one study, Dr. Coleman said, researchers found that oral clodronate at a dose of 1,600 mg/day as a supplementary treatment to standard treatment for primary, operable breast cancer reduced the risk of bone metastases in a cohort of 1,069 patients with stage 1-3 breast cancer (hazard ratio, 0.692; P = .043) over 5 years (Breast Cancer Res. 2006 Mar 15. doi: 10.1186/bcr1384). Another trial, of 302 patients with breast cancer who received oral clodronate at 1,600 mg/day for 2 years, found that 20.4% of patients who received oral clodronate had died by 8.5 years of follow-up, compared with 40.7% of those who did not receive the intervention (Ann Oncol. 2008;19[12]:2007-11).
However, those results were in conflict with findings from an earlier study in which researchers followed patients with breast cancer who received 1,600 mg/day of oral clodronate or placebo for 3 years. They found a similar number of bone metastases in the clodronate and placebo groups (32% and 29%, respectively), as well as a lower overall disease-free survival rate at 10 years for the clodronate group, compared with the placebo group (45% vs. 58%; Acta Oncol. 2004;43[7]:650-6).“For various other reasons, clodronate did not gain traction as a therapeutic strategy in early-stage breast cancer,” said Dr. Coleman, although emerging evidence showed that other bisphosphonate agents were effective in some patients with breast cancer.
In a 2009 article, Gnant et al. reported that premenopausal patients, who underwent primary surgery for stage 1 or stage 2 breast cancer and received standard goserelin therapy for induced menopause and endocrine therapy (either tamoxifen or anastrozole) in addition to treatment with zoledronic acid, had a disease-free survival rate of 94.0% at a median 47.8 months of follow-up (N Eng J Med. 2009;360:679-91). After a median 94.4 months of follow-up, the investigators reported a lower risk of disease progression (HR, 0.77; 95% confidence interval, 0.60-0.99; P = .042) and death (HR, 0.66; 95% CI, 0.43-1.02; P = .064; Ann Oncol. 2015;26[2]:313-20).
In his own group, Dr. Coleman and colleagues recruited patients with early-stage breast cancer in the AZURE trial, a phase 3 study of 3,360 patients who received standard therapy with or without zoledronic acid 4 mg every 3-4 weeks for 6 doses, followed by 8 doses every 3 months then 5 doses every 6 months (N Eng J Med. 2011;365:1396-405). “We saw no effect,” said Dr. Coleman. “[That was] very different from what was shown by [Dr.] Gnant.”
For a subgroup of postmenopausal patients, Dr. Coleman and colleagues found that the adjusted HR for disease-free survival was 0.82 for women who were more than 5 years postmenopausal (95% CI, 0.67-1.00) at the time of breast cancer and bisphosphonate treatment, but women younger than 40 years had worse survival outcomes at 10 years (HR, 1.56; 95% CI, 1.09-2.22) and had a significantly higher risk of death from breast cancer (HR, 1.67; 95% CI, 1.16-2.40; J Bone Oncol. 2018 Sep 27. doi: 10.1016/j.jbo.2018.09.008).
Trying to reconcile disparate findings
Those findings left his group with a dilemma, said Dr. Coleman. “Do we start again and run trials, and wait another 10 years, or is there a shortcut to [understanding] what’s going on?” he asked.
In a meta-analysis of all trials from the Early Breast Cancer Trialists’ Collaborative Group in 2015 examining adjuvant bisphosphonate treatment and placebo in patients with early-stage breast cancer, intent-to-treat analyses did not show significant benefit after therapy, but postmenopausal women (11,767 women in 36 trials) saw a clear benefit in all recurrence (rate ratio, 0.86; 95% CI, 0.78-0.94), bone recurrence (RR, 0.72; 95% CI, 0.60-0.86), and breast cancer–related mortality (RR, 0.82; 95% CI, 0.73-0.93; Lancet. 2015 Jul 23. doi: 10.1016/S0140-6736[15]60908-4). The effect seemed to be similar, regardless of bisphosphonate type, with other results seen across trials that used clodronate, zoledronic acid, pamidronate, or ibandronate.
“Although those outcome differences might look quite small for a common disease, that’s a really big effect. Reducing one-sixth of breast cancer deaths at 10 years is the equivalent of saving 10,000 lives across the [European Union], and about half that in the United States,” said Dr. Coleman, noting that guidelines in North America from the American Society of Clinical Oncology and the European Society for Medical Oncology now support adjuvant bisphosphonates in postmenopausal patients with breast cancer.
However, bisphosphonates’ effect on breast cancer does not extend to other cancers, such as non–small cell lung cancer or prostate cancer. In other absorption inhibitors such as denosumab, there also seems to be no benefit for patients with breast cancer, including in postmenopausal patient subgroups, said Dr. Coleman. “In my view, osteoclast inhibition is only part of the story,” he noted.
In the AZURE trial, secondary outcomes examined how the transcription factor MAF interacted with menopausal status and treatment with zoledronic acid. The 79% of patients with tumors that were negative for MAF fluorescence in situ hybridization had improved overall survival (0.69; 95% CI, 0.50-0.94), regardless of menopause status (J Bone Oncol. 2018. doi: 10.1016/j.jbo.2018.09.008). “There’s probably a need to merge the treatment: in this case, the bisphosphonate, the biology of the cancer, and the environment the cancer finds itself in,” noted Dr. Coleman.
“From the cancer perspective, he concluded.
Dr. Coleman reports being a paid employee of prIME Oncology (until March 2019); is a consultant for Amgen, Astellas, Boehringer Ingelheim, Scandell, and Biocon; is on the speakers bureau for Amgen and Eisai; holds intellectual property rights for a biomarker being developed by Inbiomotion; and is on the scientific advisory board for Inbiomotion.
ORLANDO – Cumulative evidence over the years has shown that bisphosphonates reduce distant metastases in postmenopausal women with early-stage breast cancer but that effect does not seem to extend to younger, premenopausal women who may experience adverse effects with bisphosphonates, nor has it been replicated in other types of cancer, such as lung or prostate, Robert Coleman MBBS, MD, said in a presentation marking the 50th anniversary of the publication of the first papers describing the then-new class of drugs.
“We have some science – at least in postmenopausal breast cancer – [showing] that we’re really making a difference, but we don’t understand why it’s not working in the other patients or in the other diseases,” said Dr. Coleman of the University of Sheffield (England) at the annual meeting of the American Society for Bone and Mineral Research.
Mixed findings in early studies
Early studies showing the metastases-prevention effects of bisphosphonates were with clodronate. In one study, Dr. Coleman said, researchers found that oral clodronate at a dose of 1,600 mg/day as a supplementary treatment to standard treatment for primary, operable breast cancer reduced the risk of bone metastases in a cohort of 1,069 patients with stage 1-3 breast cancer (hazard ratio, 0.692; P = .043) over 5 years (Breast Cancer Res. 2006 Mar 15. doi: 10.1186/bcr1384). Another trial, of 302 patients with breast cancer who received oral clodronate at 1,600 mg/day for 2 years, found that 20.4% of patients who received oral clodronate had died by 8.5 years of follow-up, compared with 40.7% of those who did not receive the intervention (Ann Oncol. 2008;19[12]:2007-11).
However, those results were in conflict with findings from an earlier study in which researchers followed patients with breast cancer who received 1,600 mg/day of oral clodronate or placebo for 3 years. They found a similar number of bone metastases in the clodronate and placebo groups (32% and 29%, respectively), as well as a lower overall disease-free survival rate at 10 years for the clodronate group, compared with the placebo group (45% vs. 58%; Acta Oncol. 2004;43[7]:650-6).“For various other reasons, clodronate did not gain traction as a therapeutic strategy in early-stage breast cancer,” said Dr. Coleman, although emerging evidence showed that other bisphosphonate agents were effective in some patients with breast cancer.
In a 2009 article, Gnant et al. reported that premenopausal patients, who underwent primary surgery for stage 1 or stage 2 breast cancer and received standard goserelin therapy for induced menopause and endocrine therapy (either tamoxifen or anastrozole) in addition to treatment with zoledronic acid, had a disease-free survival rate of 94.0% at a median 47.8 months of follow-up (N Eng J Med. 2009;360:679-91). After a median 94.4 months of follow-up, the investigators reported a lower risk of disease progression (HR, 0.77; 95% confidence interval, 0.60-0.99; P = .042) and death (HR, 0.66; 95% CI, 0.43-1.02; P = .064; Ann Oncol. 2015;26[2]:313-20).
In his own group, Dr. Coleman and colleagues recruited patients with early-stage breast cancer in the AZURE trial, a phase 3 study of 3,360 patients who received standard therapy with or without zoledronic acid 4 mg every 3-4 weeks for 6 doses, followed by 8 doses every 3 months then 5 doses every 6 months (N Eng J Med. 2011;365:1396-405). “We saw no effect,” said Dr. Coleman. “[That was] very different from what was shown by [Dr.] Gnant.”
For a subgroup of postmenopausal patients, Dr. Coleman and colleagues found that the adjusted HR for disease-free survival was 0.82 for women who were more than 5 years postmenopausal (95% CI, 0.67-1.00) at the time of breast cancer and bisphosphonate treatment, but women younger than 40 years had worse survival outcomes at 10 years (HR, 1.56; 95% CI, 1.09-2.22) and had a significantly higher risk of death from breast cancer (HR, 1.67; 95% CI, 1.16-2.40; J Bone Oncol. 2018 Sep 27. doi: 10.1016/j.jbo.2018.09.008).
Trying to reconcile disparate findings
Those findings left his group with a dilemma, said Dr. Coleman. “Do we start again and run trials, and wait another 10 years, or is there a shortcut to [understanding] what’s going on?” he asked.
In a meta-analysis of all trials from the Early Breast Cancer Trialists’ Collaborative Group in 2015 examining adjuvant bisphosphonate treatment and placebo in patients with early-stage breast cancer, intent-to-treat analyses did not show significant benefit after therapy, but postmenopausal women (11,767 women in 36 trials) saw a clear benefit in all recurrence (rate ratio, 0.86; 95% CI, 0.78-0.94), bone recurrence (RR, 0.72; 95% CI, 0.60-0.86), and breast cancer–related mortality (RR, 0.82; 95% CI, 0.73-0.93; Lancet. 2015 Jul 23. doi: 10.1016/S0140-6736[15]60908-4). The effect seemed to be similar, regardless of bisphosphonate type, with other results seen across trials that used clodronate, zoledronic acid, pamidronate, or ibandronate.
“Although those outcome differences might look quite small for a common disease, that’s a really big effect. Reducing one-sixth of breast cancer deaths at 10 years is the equivalent of saving 10,000 lives across the [European Union], and about half that in the United States,” said Dr. Coleman, noting that guidelines in North America from the American Society of Clinical Oncology and the European Society for Medical Oncology now support adjuvant bisphosphonates in postmenopausal patients with breast cancer.
However, bisphosphonates’ effect on breast cancer does not extend to other cancers, such as non–small cell lung cancer or prostate cancer. In other absorption inhibitors such as denosumab, there also seems to be no benefit for patients with breast cancer, including in postmenopausal patient subgroups, said Dr. Coleman. “In my view, osteoclast inhibition is only part of the story,” he noted.
In the AZURE trial, secondary outcomes examined how the transcription factor MAF interacted with menopausal status and treatment with zoledronic acid. The 79% of patients with tumors that were negative for MAF fluorescence in situ hybridization had improved overall survival (0.69; 95% CI, 0.50-0.94), regardless of menopause status (J Bone Oncol. 2018. doi: 10.1016/j.jbo.2018.09.008). “There’s probably a need to merge the treatment: in this case, the bisphosphonate, the biology of the cancer, and the environment the cancer finds itself in,” noted Dr. Coleman.
“From the cancer perspective, he concluded.
Dr. Coleman reports being a paid employee of prIME Oncology (until March 2019); is a consultant for Amgen, Astellas, Boehringer Ingelheim, Scandell, and Biocon; is on the speakers bureau for Amgen and Eisai; holds intellectual property rights for a biomarker being developed by Inbiomotion; and is on the scientific advisory board for Inbiomotion.
EXPERT ANALYSIS FROM ASBMR 2019