Adjuvant Therapy With Zoledronic Acid in Patients With Breast Cancer: A Systematic Review and Meta-Analysis

Valachis, Antonis; Polyzos, Nikolaos P.; Coleman, Robert E.; Gnant, Michael; Eidtmann, Holger; Brufsky, Adam; Aft, Rebecca; Tevaarwerk, Amye J.; Swenson, Karen K.; Lind, Pehr; Mauri, Davide

doi:10.1634/theoncologist.2012-0261

Cited by 70 publications

(58 citation statements)

References 44 publications

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“…In a comprehensive meta-analysis of 15 randomized clinical trials on adjuvant therapy for breast cancer patients with zoledronate, the authors identified a significant overall survival benefit with zoledronate treatment, in agreement with one smaller meta-analysis [2] but not another [3] conducted earlier. These new findings support the call for zoledronate to be considered as a new standard of care in adjuvant breast cancer therapy [4].The dilemma remains that the biological mechanism underlying the antitumor role of zoledronate is unclear, as Valachis et al correctly highlight [1]. The clinical benefit may in fact stem, at least in part, from the activity of zoledronate on the patient's immune system by specifically stimulating V␥9/V␦2 T cells, which compose 0.5%-5% of circulating T cells in healthy adults [5].…”

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confidence: 60%

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We read with great interest the article by Valachis et al [1], published in The Oncologist. In a comprehensive meta-analysis of 15 randomized clinical trials on adjuvant therapy for breast cancer patients with zoledronate, the authors identified a significant overall survival benefit with zoledronate treatment, in agreement with one smaller meta-analysis [2] but not another [3] conducted earlier.

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confidence: 99%

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γδ T Cells Predict Outcome in Zoledronate-Treated Breast Cancer Patients

et al. 2013

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We read with great interest the article by Valachis et al. [1], published in The Oncologist. In a comprehensive meta-analysis of 15 randomized clinical trials on adjuvant therapy for breast cancer patients with zoledronate, the authors identified a significant overall survival benefit with zoledronate treatment, in agreement with one smaller meta-analysis [2] but not another [3] conducted earlier. These new findings support the call for zoledronate to be considered as a new standard of care in adjuvant breast cancer therapy [4].The dilemma remains that the biological mechanism underlying the antitumor role of zoledronate is unclear, as Valachis et al. correctly highlight [1]. The clinical benefit may in fact stem, at least in part, from the activity of zoledronate on the patient's immune system by specifically stimulating V␥9/V␦2 T cells, which compose 0.5%-5% of circulating T cells in healthy adults [5]. Targeted immunotherapy studies directly exploiting the potent non-major histocompatibility complexrestricted cytotoxicity of V␥9/V␦2 T cells have shown excellent safety profiles and promising clinical observations in a variety of hematological and solid cancers [6], including metastatic breast cancer [7].Studies by us and others have demonstrated that zoledronate treatment induces a rapid and long-lasting conversion of the peripheral V␥9/V␦2 T-cell phenotype from CD27 ϩ CD45RA Ϫ central memory T (T CM ) cells to CD27 Ϫ CD45RA Ϫ effector memory T (T EM ) cells in many, but not all, individuals [7][8][9]. In Figure 1, zoledronate-treated breast cancer patients with stable disease showed elevated proportions of V␥9/V␦2 T EM cells at the time of blood sampling compared with patients with progressing disease and untreated controls (Fig. 1A). No such differences were observed with regard to patient age, time on treatment, or pretreatment clinical status. We then stratified the same patient cohort according to their follow-up disease status at 3-9 months after blood sampling. This showed successful conversion from T CM to T EM cells (as evident by a lower frequency of T CM cells) in patients who were stable 3-9 months after blood sampling compared with patients who went on to show progressing disease (Fig. 1B).Our analysis illustrates the diagnostic and prognostic potential of a ␥␦ T-cell-based blood test and implies a link between immune responsiveness and positive outcome with zoledronate therapy, thereby contributing to our understanding of the as yet unexplained clinical benefit of adjuvant therapy. These findings are particularly intriguing because new treatments specifically targeting bone resorption, such as denosumab, lack this potential to act on CD45RAϪ centralmemoryTcellsinrelationtosubsequent clinical outcome at 3-9 months after sampling. Patients received at least two cycles of zoledronic acid (Zometa; Novartis International, Basel, Switzerland, http://www.novartis.com) for Ͼ1 monthandϽ8monthsandhadnootheractivemalignancieswithinthe previousyear;noactiveoruncontrolledinfections;noautoimmunedisorders or ...

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γδ T Cells Predict Outcome in Zoledronate-Treated Breast Cancer Patients

et al. 2013

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“…The only two phase iii trials that considered cancer-specific primary endpoints and compared adjuvant therapy with and without za (abcsg-12 and azure) independently suggested that adjuvant za improves breast cancer outcomes in patients with low circulating estrogen levels secondary to induced or natural menopause 13,14 . Meta-analyses of adjuvant za and adjuvant bisphosphonate trials as a whole appear to confirm the benefit in that subgroup of patients 6,[15][16][17] .…”

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confidence: 86%

Cost–Utility of Adjuvant Zoledronic Acid in Patients with Breast Cancer and Low Estrogen Levels

et al. 2015

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“…Many prospective studies have been performed and several systematic reviews and meta-analyses have been published [14,15,16]. Hypotheses from early BP trials include that antitumor effects are mainly due to a reduction in bone metastases and that distant recurrence is predominantly reduced as compared to local or contralateral recurrence.…”

Section: Bps As Anticancer Agentsmentioning

confidence: 99%

“…In the first systematic review by Mauri et al in 2010 [14], ZA was not associated with a significant reduction in bone metastases or death. In the latest peer-reviewed meta-analysis by Valachis et al from 2013 [16] including 15 eligible trials, a significant improvement for overall survival and fracture rates but not for disease-free survival or incidence of bone metastasis was shown for the overall study population (table 1), a finding that cannot be interpreted easily.…”

Section: Bps As Anticancer Agentsmentioning

confidence: 99%

Adjuvant Bisphosphonates in Breast Cancer Treatment

Knauer

Thürlimann

2014

Breast Care

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Several solid tumors like breast cancer tend to spread to the bone, where the microenvironment is especially receptive to the tumor by special interactions between bone cells and tumor cells. Bone metastases often lead to skeletal-related events with significant morbidity and mortality. The therapy of bone metastases and osteoporosis with bisphosphonates (BPs) has been established many years ago as a standard treatment. In the adjuvant setting, cancer treatment-induced bone loss is a frequent cause of morbidity, and prevention and treatment of this condition with BPs and the monoclonal antibody denosumab are also well established. Besides postmenopausal patients, several studies including 2 larger studies by the Austrian Breast and Colorectal Cancer Study Group (ABCSG) and the Cancer and Leukemia Group B (CALGB) have shown an increase in bone mineral density in premenopausal women. BPs as anticancer treatment are, however, still controversial because several studies yielded conflicting results, with beneficial effects only in subgroups of patients. The publication of the latest Oxford overview of prospective trials is being awaited; at the presentation of the results, a 34% relative reduction of bone metastasis and a 17% improvement in overall survival was demonstrated in the subgroup of postmenopausal patients. These results will likely lead to an incorporation of the use of BPs into routine adjuvant breast cancer treatment.

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Adjuvant Therapy With Zoledronic Acid in Patients With Breast Cancer: A Systematic Review and Meta-Analysis

Cited by 70 publications

References 44 publications

γδ T Cells Predict Outcome in Zoledronate-Treated Breast Cancer Patients

γδ T Cells Predict Outcome in Zoledronate-Treated Breast Cancer Patients

Cost–Utility of Adjuvant Zoledronic Acid in Patients with Breast Cancer and Low Estrogen Levels

Adjuvant Bisphosphonates in Breast Cancer Treatment

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