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Does the efficacy of bisphosphonates support the use of extended aromatase inhibitor therapy in women at risk for bone fractures?
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Yes.
The results from the ATLAS trial noted breast cancer mortality benefit for extended tamoxifen use — 10 years vs. 5 years — in patients with early-stage breast cancer. Although we hoped that extended use of aromatase inhibitors would provide greater, if not at least similar, benefit to tamoxifen for preventing breast cancer recurrence, three trials presented at the San Antonio Breast Cancer Symposium (SABCS) disappointed both patients and physicians. This was in contrast to the result of the MA.17R trial, presented at the ASCO Annual Meeting in 2016, which showed benefit for an additional 5 years of letrozole after completing 10 years of antiestrogen therapy. In that trial, most of the DFS benefit came from reduction in incidence of contralateral breast cancer.
The studies from SABCS included the NSABP B-42 trial, which evaluated 10 years of letrozole compared with 5 years of letrozole; the DATA trial, which evaluated 6 years of anastrozole compared with 3 years of anastrozole after 2 to 3 years of tamoxifen; and the IDEAL trial, which evaluated 10 years of letrozole compared with 7.5 years of letrozole. Unfortunately, none of these trials met their primary endpoints. However, there was a statistically insignificant benefit noted in all the three trials. Taken together, all four trials of extended aromatase inhibitors showed lack of a significant DFS benefit.
These trials highlight the extremely important role of an oncologist in individualizing treatment plans for the patient. Those patients with a high risk for distant recurrence may still benefit from extended antiestrogen therapy. In the case of a postmenopausal woman, we know that 5 years of aromatase inhibitor is superior to tamoxifen. In such a setting, the concern for aromatase inhibitor–induced bone loss becomes a significant factor in individualizing care.
Patients who are at risk for bone fractures — including those who have osteopenia or osteoporosis — may have worsening bone mineral density loss while on aromatase inhibitor therapy. However, several trials have shown improvement in bone mineral density with the use of concurrent bisphosphonates — clodronate, ibandronate, risedronate and zoledronate. In the ABCSG-12 trial, the mean difference in lumbar spine bone mineral density at 5 years was 11.3% in women who were receiving zoledronate compared with the control group. Similarly, in the Z-FAST trial, mean difference in lumbar spine bone mineral density at 5 years in those who were on upfront zoledronate therapy vs. delayed use of the drug was 8.9%.
Additionally, bisphosphonates have an adjuvant antitumor role in the treatment of breast cancer. ASCO guidelines endorse the adjuvant use of bisphosphonates in women who are postmenopausal (naturally or induced).
Given such a beneficial effect on both protecting the bones and in reducing distant recurrences, we firmly believe that postmenopausal women who are at high risk for recurrence should receive extended antiestrogen therapy with aromatase inhibitors along with bisphosphonates.
References:
Davies C, et al. Lancet. 2013;381:805-816.
Goss PE, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1604700.
Mathew A and Brufsky A. Int J Cancer. 2015;doi:10.1002/ijc.28965.
The following were presented at San Antonio Breast Cancer Symposium; Dec. 6-10, 2016; San Antonio, Texas:
Blok EJ, et al. Abstract S1-04.
Mamounas P, et al. Abstract S1-05.
Tjan-Heijnen VC, et al. Abstract S1-03.
Aju Mathew, MD, MPhil, FACP, is assistant professor at University of Kentucky Markey Cancer Center. He can be reached at aju.mathew@uky.edu. Disclosure: Mathew reports no relevant financial disclosures.
Adam M. Brufsky, MD, PhD, FACP, is professor at University of Pittsburgh Cancer Institute and a HemOnc Today Editorial Board member. He can be reached at brufskyam@upmc.edu. Disclosure: Brufsky reports no relevant financial disclosures.
No.
Whether to extend aromatase inhibitor therapy beyond 5 years remains a key question for postmenopausal women with hormone receptor–positive breast cancer. Due to the risk for late recurrences after 5 years, multiple studies have examined the extension of endocrine therapy. The MA.17R trial evaluated 5 years of letrozole compared with placebo following completion of 5 years of tamoxifen in postmenopausal women. Letrozole improved DFS (HR = 0.58; 95% CI, 0.45-0.76) after a median follow-up of 30 months. Patients with node-positive disease achieved an OS benefit. Subsequently, results from the ATLAS and aTTom studies — which studied continuing tamoxifen for 10 years — also showed lower risk for recurrence and breast cancer mortality compared with stopping tamoxifen after 5 years. These studies started to support the hypothesis that longer durations of endocrine therapy may be optimal.
However, other data on extending aromatase inhibitor therapy from 5 years to 10 years has been less clearly beneficial. In the MA.17R trial, longer therapy resulted in significantly better 5-year DFS (95% vs 91%; HR = 0.66; P = .01), but the DFS events excluded death from other causes in the primary analysis — usually classified as breast cancer–free interval. Once these events were added, there was no difference in DFS. Further, the difference in the primary DFS outcome was mostly due to a lower incidence of contralateral breast cancer with extended aromatase inhibitor therapy than with placebo. The distant recurrence risks were similar and low (4.4% vs 5.5%), and there was no OS difference. The NSABP B-42 study also evaluated letrozole beyond 5 years and did not meet its predefined DFS endpoint, which included death from other causes. Thus, there is no clear survival benefit from extending aromatase inhibitor therapy beyond 5 years in unselected patients with hormone receptor–positive breast cancer.
Bone health remains an important issue for mortality and morbidity in postmenopausal women. In MA.17R, bone mineral density was monitored every 2 years. Bisphosphonates were used by both groups (46% letrozole; 47% placebo). At the time of treatment discontinuation, the letrozole group had lower bone mineral density. The letrozole group also experienced a higher risk for fractures (14% vs. 9%; P = .001), with 56% of fractures in the letrozole cohort occurring while on a bisphosphonate. Thus, the risk for fracture, despite optimal bone health management, should be considered. Although ASCO guidelines now support adjuvant bisphosphonate treatment with IV zoledronic acid in postmenopausal women to reduce risk for bone metastasis and improve survival, the recommended duration is 3 to 5 years. Therefore, the potential benefits and risks of continuing IV bisphosphonates with extended aromatase inhibitor therapy beyond 5 years is unclear. Ultimately, rather than relying on bisphosphonates to mitigate the risks for fractures from aromatase inhibitor therapy, we need to better identify those patients at risk for late distant recurrence from hormone receptor–positive breast cancer. These are the individuals who would potentially benefit the most from extended endocrine therapy.
References:
Davies C, et al. Lancet. 2013;381:805-816.
Dhesy-Thind S, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2016.70.7257.
Goss PE, et al. J Clin Oncol. 2007;25:2006-2011.
Goss PE, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1604700.
Gray R, et al. J Clin Oncol. 2013;31:(suppl; abstr 5).
Mamounas P, et al. Abstract S1-05. Presented at: San Antonio Breast Cancer Symposium; Dec. 6-10, 2016; San Antonio, Texas.
Kari B. Wisinski, MD, is associate professor of medicine in the division of hematology and medical oncology at University of Wisconsin Carbone Cancer Center. She can be reached at University of Wisconsin Carbone Cancer Center, 1111 Highland Ave., Madison, WI 53705; email: kbwisinski@medicine.wisc.edu. Disclosure: Wisinski reports research funding from or a site principal investigator role for clinical trials sponsored by AstraZeneca, Daiichi Sankyo, Eli Lilly and Novartis.