Therapeutics
Bisphosphonates do not reduce breast cancer in postmenopausal women 多多多多多多夞
Clinical impact ratings:
多多多多多夞夞
Hue TF, Cummings SR, Cauley JA, et al. Effect of bisphosphonate use on risk of postmenopausal breast cancer: results from the randomized clinical trials of alendronate and zoledronic acid. JAMA Intern Med. 2014;174:1550-7.
多多多多多夞夞
Question
*See Glossary.
Do bisphosphonates reduce breast cancer in postmenopausal women treated for osteoporosis?
Sources of funding: Merck & Co (FIT) and Novartis, Basel, Switzerland (HORIZON-PFT).
Methods
For correspondence: Dr. T.F. Hue, University of California, San Francisco, CA, USA. E-mail [email protected].
Design: Post hoc secondary analysis of 2 randomized placebocontrolled trials (Fracture Intervention Trial [FIT] and Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly–Pivotal Fracture Trial [HORIZON-PFT]). ClinicalTrials.gov NCT00049829 (HORIZON-PFT). Allocation: Unclear allocation concealment.* Blinding: Blinded* (patients, clinicians, and outcome assessors). Follow-up period: 4 years (FIT) and 3 years (HORIZON-PFT). Setting: 11 academic sites in the USA (FIT); and sites in Asia, the Pacific, Europe, and North and South America (HORIZON-PFT). Patients: 6459 women 55 to 81 years of age (mean age 68 y) who did not have a menstrual period for > 2 years and had a femoral neck bone mineral density (BMD) ≤ 0.68 g/cm2 (T-score ≤⫺1.6) in FIT; and 7765 postmenopausal women 65 to 89 years of age (mean age 73 y) who had a femoral neck T-score ≤⫺2.5, with or without evidence of an existing vertebral fracture, or a T-score ≤⫺1.5, with ≥ 2 mild or ≥ 1 moderate vertebral fractures in HORIZON-PFT. Women with a history of breast cancer were excluded from this post hoc analysis. Intervention: Oral alendronate sodium, 5 mg/d for 2 years and 10 mg/d thereafter (n = 3236), or placebo (n = 3223) in FIT; and yearly IV zoledronic acid, 5 mg (n = 3889), or placebo (n = 3876) in HORIZON-PFT. All women in both trials received daily calcium and vitamin D. Outcomes: Any new breast cancer (excluding ductal carcinoma in situ). Patient follow-up: 96% for FIT and 98% for HORIZON-PFT (modified intention-to-treat analysis).
Main results Groups did not differ for breast cancer (Table).
Conclusion In postmenopausal women treated for osteoporosis, bisphosphonates (alendronate sodium or zoledronic acid) did not reduce breast cancer compared with placebo.
Commentary Observational studies have found a decreased risk for primary breast cancer in patients receiving bisphosphonates, but the association is confounded by indication because bisphosphonates are used in women with low BMD, a group that also has a lower risk for breast cancer (1). Hue and colleagues investigated the effect of bisphosphonates on prevention of postmenopausal breast cancer in a post hoc analysis of 2 well-conducted, randomized, double-blind, placebo-controlled trials (FIT and HORIZON-PFT). The study populations comprised women with low BMD who were randomized to bisphosphonates (alendronate or zoledronic acid) or placebo, effectively negating the indication bias inherent in the observational studies. Pooled analysis of the 2 trials found no difference in risk for invasive breast cancer between the groups, refuting the hypothesized benefit raised by observational studies. These results contrast with evidence favoring adjuvant bisphosphonate use in patients with early-stage breast cancer. A recent meta-analysis of individual patient data from 41 randomized controlled trials found a reduction in breast cancer mortality with adjuvant bisphosphonate therapy (2). However, the metaanalysis found no decrease in risk for local recurrence or contralateral breast cancer (2), a finding that supports the results of Hue and colleagues and suggests that the benefits of bisphosphonates in early breast cancer are due to effects on metastatic disease rather than prevention of new primary cases of cancer. However, extrapolation of the findings from patients with low BMD to adjuvant treatment of early-stage breast cancer may not be prudent since the latter included adjuvant endocrine therapy, which may have contributed to prevention of local recurrences or contralateral breast cancer. Also, bisphosphonate dosages used in adjuvant trials were higher than those used in osteoporosis trials. The study by Hue and colleagues adds to the body of evidence showing that bisphosphonates do not reduce the incidence of primary breast cancer. When discussing the pros and cons of bisphosphonate therapy for postmenopausal women with low BMD, clinicians should clarify that breast cancer prevention is not a potential benefit. Aju Mathew, MD, MPhil Adam Brufsky, MD, PhD University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania, USA
Bisphosphonate (alendronate sodium or zoledronic acid) vs placebo in postmenopausal women† Outcome
Any new breast cancer
Trial
FIT
n
6194
HORIZON-PFT Pooled
Event rates
At 3 to 4 y
Bisphosphonate Placebo
RRI (95% CI)
1.8%
1.5%
24% (⫺16 to 82)
7580
0.9%
0.8%
15% (⫺30 to 88)
13 774
1.3%
1.1%
20% (⫺11 to 62)
†FIT = Fracture Intervention Trial; HORIZON-PFT = Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly–Pivotal Fracture Trial; other abbreviations defined in Glossary. RRI and CI calculated from control event rates and hazard ratios in article.
20 January 2015
Annals of Internal Medicine
ACP Journal Club
References 1. Cauley JA, Lucas FL, Kuller LH, et al. Bone mineral density and risk of breast cancer in older women: the Study of Osteoporotic Fractures. Study of Osteoporotic Fractures Research Group. JAMA. 1996;276:1404-8. 2. Coleman R, Gnant M, Paterson A, et al; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)’s Bisphosphonate Working Group. Abstract S4-07: Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: a meta-analysis of individual patient data from randomised trials. Cancer Res 2013;73:S4-07.
JC5
姝 2015 American College of Physicians
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/931930/ by a Weill Medical College User on 07/16/2017
Bisphosphonates do not reduce breast cancer in postmenopausal women 多多多多多多夞
Clinical impact ratings:
多多多多多夞夞
Hue TF, Cummings SR, Cauley JA, et al. Effect of bisphosphonate use on risk of postmenopausal breast cancer: results from the randomized clinical trials of alendronate and zoledronic acid. JAMA Intern Med. 2014;174:1550-7.
多多多多多夞夞
Question
*See Glossary.
Do bisphosphonates reduce breast cancer in postmenopausal women treated for osteoporosis?
Sources of funding: Merck & Co (FIT) and Novartis, Basel, Switzerland (HORIZON-PFT).
Methods
For correspondence: Dr. T.F. Hue, University of California, San Francisco, CA, USA. E-mail [email protected].
Design: Post hoc secondary analysis of 2 randomized placebocontrolled trials (Fracture Intervention Trial [FIT] and Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly–Pivotal Fracture Trial [HORIZON-PFT]). ClinicalTrials.gov NCT00049829 (HORIZON-PFT). Allocation: Unclear allocation concealment.* Blinding: Blinded* (patients, clinicians, and outcome assessors). Follow-up period: 4 years (FIT) and 3 years (HORIZON-PFT). Setting: 11 academic sites in the USA (FIT); and sites in Asia, the Pacific, Europe, and North and South America (HORIZON-PFT). Patients: 6459 women 55 to 81 years of age (mean age 68 y) who did not have a menstrual period for > 2 years and had a femoral neck bone mineral density (BMD) ≤ 0.68 g/cm2 (T-score ≤⫺1.6) in FIT; and 7765 postmenopausal women 65 to 89 years of age (mean age 73 y) who had a femoral neck T-score ≤⫺2.5, with or without evidence of an existing vertebral fracture, or a T-score ≤⫺1.5, with ≥ 2 mild or ≥ 1 moderate vertebral fractures in HORIZON-PFT. Women with a history of breast cancer were excluded from this post hoc analysis. Intervention: Oral alendronate sodium, 5 mg/d for 2 years and 10 mg/d thereafter (n = 3236), or placebo (n = 3223) in FIT; and yearly IV zoledronic acid, 5 mg (n = 3889), or placebo (n = 3876) in HORIZON-PFT. All women in both trials received daily calcium and vitamin D. Outcomes: Any new breast cancer (excluding ductal carcinoma in situ). Patient follow-up: 96% for FIT and 98% for HORIZON-PFT (modified intention-to-treat analysis).
Main results Groups did not differ for breast cancer (Table).
Conclusion In postmenopausal women treated for osteoporosis, bisphosphonates (alendronate sodium or zoledronic acid) did not reduce breast cancer compared with placebo.
Commentary Observational studies have found a decreased risk for primary breast cancer in patients receiving bisphosphonates, but the association is confounded by indication because bisphosphonates are used in women with low BMD, a group that also has a lower risk for breast cancer (1). Hue and colleagues investigated the effect of bisphosphonates on prevention of postmenopausal breast cancer in a post hoc analysis of 2 well-conducted, randomized, double-blind, placebo-controlled trials (FIT and HORIZON-PFT). The study populations comprised women with low BMD who were randomized to bisphosphonates (alendronate or zoledronic acid) or placebo, effectively negating the indication bias inherent in the observational studies. Pooled analysis of the 2 trials found no difference in risk for invasive breast cancer between the groups, refuting the hypothesized benefit raised by observational studies. These results contrast with evidence favoring adjuvant bisphosphonate use in patients with early-stage breast cancer. A recent meta-analysis of individual patient data from 41 randomized controlled trials found a reduction in breast cancer mortality with adjuvant bisphosphonate therapy (2). However, the metaanalysis found no decrease in risk for local recurrence or contralateral breast cancer (2), a finding that supports the results of Hue and colleagues and suggests that the benefits of bisphosphonates in early breast cancer are due to effects on metastatic disease rather than prevention of new primary cases of cancer. However, extrapolation of the findings from patients with low BMD to adjuvant treatment of early-stage breast cancer may not be prudent since the latter included adjuvant endocrine therapy, which may have contributed to prevention of local recurrences or contralateral breast cancer. Also, bisphosphonate dosages used in adjuvant trials were higher than those used in osteoporosis trials. The study by Hue and colleagues adds to the body of evidence showing that bisphosphonates do not reduce the incidence of primary breast cancer. When discussing the pros and cons of bisphosphonate therapy for postmenopausal women with low BMD, clinicians should clarify that breast cancer prevention is not a potential benefit. Aju Mathew, MD, MPhil Adam Brufsky, MD, PhD University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania, USA
Bisphosphonate (alendronate sodium or zoledronic acid) vs placebo in postmenopausal women† Outcome
Any new breast cancer
Trial
FIT
n
6194
HORIZON-PFT Pooled
Event rates
At 3 to 4 y
Bisphosphonate Placebo
RRI (95% CI)
1.8%
1.5%
24% (⫺16 to 82)
7580
0.9%
0.8%
15% (⫺30 to 88)
13 774
1.3%
1.1%
20% (⫺11 to 62)
†FIT = Fracture Intervention Trial; HORIZON-PFT = Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly–Pivotal Fracture Trial; other abbreviations defined in Glossary. RRI and CI calculated from control event rates and hazard ratios in article.
20 January 2015
Annals of Internal Medicine
ACP Journal Club
References 1. Cauley JA, Lucas FL, Kuller LH, et al. Bone mineral density and risk of breast cancer in older women: the Study of Osteoporotic Fractures. Study of Osteoporotic Fractures Research Group. JAMA. 1996;276:1404-8. 2. Coleman R, Gnant M, Paterson A, et al; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)’s Bisphosphonate Working Group. Abstract S4-07: Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: a meta-analysis of individual patient data from randomised trials. Cancer Res 2013;73:S4-07.
JC5
姝 2015 American College of Physicians
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/931930/ by a Weill Medical College User on 07/16/2017
