Adjuvant Treatment of Early-Stage Breast Cancer: Meta-analyses Provide More Clarity

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Aju Mathew, MD, MPhil

Adam Brufsky, MD, PhD

Regardless of the several unanswered questions, one thing is certain—aromatase inhibitors and bisphosphonates continue to prove their mettle.

—Aju Mathew, MD, MPhil (top), and Adam Brufsky, MD, PhD

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) continues its practice of being a lighthouse, shedding its beacon of light on the vast ocean of breast cancer research through the publication of two large, individual patient level–data meta-analyses on the management of women with early-stage breast cancer.1,2 The first publication described the effects of aromatase inhibitors compared with tamoxifen in postmenopausal women, and the second article investigated the antitumor role of bisphosphonates. The analyses are summarized in this issue of The ASCO Post.

Aromatase Inhibitors Impress Again

Aromatase inhibitors reduced both breast cancer and all-cause mortality compared with tamoxifen.1 Although patients were on an aromatase inhibitor vs tamoxifen, a 30% proportional reduction in risk for recurrence was observed. As expected, all three aromatase inhibitors (anastrozole, letrozole, and exemestane) produced similar outcomes. There was a carry-over effect for up to 5 years from stopping the medication, similar to that with tamoxifen.

None of the traditionally known prognostic markers (age, body mass index, nodal status, grade, progesterone receptor status, HER2 status) had a predictive effect. However, a greater absolute risk reduction was seen in patients with at least four positive nodes or one to three positive nodes compared with node-negative disease (number needed to treat to prevent one recurrence was 15, 27, and 83, respectively).

Although the meta-analysis noted no increased cardiovascular risk and found significantly fewer uterine cancers compared with tamoxifen use, there were more bone fractures in patients on aromatase inhibitors, both during the treatment period and for 5 years after stopping the medication. Concurrent use of bone-modifying agents may help prevent bone loss due to aromatase inhibitor therapy and may decrease the incidence of fractures.

The recently published results from the ABCSG-18 trial are especially important in the context of bone health.3 In this trial, postmenopausal women on adjuvant aromatase inhibitor therapy were randomized to receive either denosumab (60-mg dose given subcutaneously once every 6 months) or placebo. Denosumab (Xgeva) decreased the incidence of clinical fractures (hazard ratio = 0.50, 95% confidence interval [CI] = 0.39–0.65, P < .0001). Upfront use of zoledronic acid may be another option, especially for women who have baseline osteopenia or osteoporosis.4,5

Therefore, we recommend obtaining a bone density scan at baseline and at 2-year intervals while a patient is on aromatase inhibitor therapy. There may be more than just a bone-protective effect for such a strategy, as the EBCTCG bisphosphonate meta-analysis demonstrates.

In light of the meta-analysis, aromatase inhibitor treatment for 5 years should be the preferred adjuvant endocrine treatment strategy for postmenopausal women. For those who cannot tolerate such a therapy, a switch strategy with sequential use of tamoxifen and aromatase inhibitors for up to 5 years is a reasonable option. Clearly, adjuvant tamoxifen therapy is suboptimal in postmenopausal women, unless they cannot tolerate aromatase inhibitors, in which case tamoxifen is better than nothing at all. Therefore, careful assessment for tolerability and compliance is of crucial importance.

The Final Whistle for Bisphosphonates?

Over the years, bisphosphonates have moved from being used in metastatic disease to the adjuvant setting, primarily as a means of protecting bones from aromatase inhibitor–induced bone loss.6 However, does it also have an effect on breast cancer recurrences and maybe even mortality? The AZURE (zoledronic acid) and NSABP B-34 (clodronate) trials suggested a beneficial effect on breast cancer recurrences in postmenopausal women.7,8 In the ZO-FAST trial, postmenopausal women treated with an aromatase inhibitor had improved disease-free survival with the upfront use of zoledronic acid compared with its use in a delayed manner.5 However, several other studies have failed to show any effect on recurrence.6

To investigate a putative antitumor effect for bisphosphonates, a large, patient level–data meta-analysis of 26 trials was conducted by the EBCTCG—providing greater power to perform subgroup analysis (especially as to the intriguing question on the role of menopausal status) and also investigate overall survival.2 For the sake of analysis, postmenopausal status was defined as those who were at least 55 years old or who reported postmenopausal status at study entry and also included younger women who underwent suppression of ovarian function.

The meta-analysis found highly significant reductions in bone recurrence (28%, P = .0002) and breast cancer mortality (18%, P = .002) with the adjuvant use of bisphosphonates in postmenopausal women. At 10 years, the absolute reduction in bone recurrence and breast cancer mortality were 2.2% and 3.3%, respectively (number needed to prevent one death due to breast cancer was 30). Premenopausal women did not benefit from the addition of bisphosphonates to adjuvant therapy.

No other predictive factors were identified in the study. The results were similar regardless of estrogen receptor status, nodal status, type of bisphosphonate, and intensity of therapy. Nonbone recurrences were not reduced, suggesting that the antitumor effect is likely mediated through manipulation of the bone microenvironment. Bisphosphonate therapy did not decrease the incidence of contralateral breast cancers, signifying the absence of a chemopreventive role for it.

With regard to the safety of bisphosphonates, a careful oral examination and regular monitoring will prevent the development of the extremely rare adverse effect of osteonecrosis of the jaw. Otherwise, bisphosphonates are extremely safe and well tolerated.

So, is this the final whistle? Have bisphosphonates won the day? The data are quite compelling to start bisphosphonate therapy in postmenopausal women with early-stage breast cancer. The mortality reduction is similar to that achieved with the use of anthracycline-based chemotherapy over a nonanthracycline-based regimen.9

At the same time, it also warrants an individualized approach. Bisphosphonate therapy should be strongly considered in women with osteopenia or osteoporosis at baseline and in patients with a high risk of recurrence. For all women with early-stage disease, a discussion of the benefits and risks of therapy must ensue, based on the results of this well-conducted meta-analysis. As far as further research is concerned, we may not see any more large clinical trials in this field of research, especially with the drugs going off patent.

What’s Next?

These two large meta-analyses provide much clarity for clinicians. However, they have also expanded the horizons of research to some areas where the beacon does not fall. Will longer follow-up (beyond 10 years) unravel more significant beneficial effects or maybe show increased fracture rates? How do the trials of extended tamoxifen use (ATLAS) fit in with the upfront use of aromatase inhibitors? With around 90% of participants in that trial being postmenopausal at study entry, it can be thought that extended endocrine treatment with aromatase inhibitors could also be efficacious.10

It is hoped that the NSABP B-42 and MA-17R trials will evaluate the efficacy and safety of 10 years of aromatase inhibitors vs 5 years. Similarly, the D-CARE and the ABCSG-18 trials will investigate an antitumor effect for denosumab. Regardless of the several unanswered questions, one thing is certain—aromatase inhibitors and bisphosphonates continue to prove their mettle. ■

Disclosure: Dr. Mathew reported no potential conflicts of interest. Dr. Brufsky has served as a consultant for Novartis.                                                             


1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Aromatase inhibitors versus tamoxifen in early breast cancer. Lancet. July 23, 2015 (early release online).

2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Adjuvant bisphosphonate treatment in early breast cancer. Lancet. July 23, 2015 (early release online).

3. Gnant M, et al: Adjuvant denosumab in breast cancer (ABCSG-18). Lancet 386:433-443, 2015.

4. Brufsky AM, et al: Final 5-year results of Z-FAST trial. Cancer 118:1192-1201, 2012.

5. Coleman R, et al: Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study). Ann Oncol 24:398-405, 2013.

6. Mathew A, Brufsky A: Bisphosphonates in breast cancer. Int J Cancer 137:753-764, 2015.

7. Coleman RE, et al: Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 365:1396-1405, 2011.

8. Paterson AH, et al: Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34). Lancet Oncol 13:734-742, 2012.

9. Peto R, et al: Comparisons between different polychemotherapy regimens for early breast cancer. Lancet 379:432-444, 2012.

10. Davies C, et al: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer. Lancet 381:805-816, 2013.


Dr. Mathew is Assistant Professor of Medicine at Markey Cancer Center, University of Kentucky, Lexington, and Dr. Brufsky is Professor of Medicine and Associate Chief of Hematology and Oncology at Magee-Womens Hospital of the University of Pittsburgh Medical Center and Cancer Institute.

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