- Email: [email protected]
Adjuvant zoledronic acid to treat breast cancer: not for all
Comment
Bisphosphonates have been extensively studied in the adjuvant setting as a host-directed therapy to reduce the risk of breast-cancer relapse. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) patientlevel meta-analysis of adjuvant bisphosphonates, which included 18 776 women with breast cancer, showed a reduction in breast-cancer-associated death among postmenopausal women (hazard ratio [HR] 0·82, 95% CI 0·73–0·93). This outcome was mainly due to the reduction in bone recurrence. Thus, several guidelines have included zoledronic acid and clodronic acid as adjuvant treatments for breast cancer in postmenopausal women.1–3 Women’s age and menopausal status are powerful surrogates for oestrogen concentrations and, thereby, for regulation of bone remodelling. Thus, oestrogendriven changes in the bone microenvironment might affect the likelihood of women in different age groups developing bone metastases.4 An important and as yet unresolved subject of scientific debate is how ovarian function regulates host-driven responses to cancer cells and mainly host-directed (and bone-selective) treatments, such as zoledronic acid. Whether premenopausal women with breast cancer should be considered as candidates for adjuvant treatment with bisphosphonates is a relevant question. Adjuvant bisphosphonates have been reserved for use in postmenopausal women, irrespective of the cause of menopause (physiological, surgical, or due to ovarian function suppression [OFS]). Extending these agents to younger women is an attractive strategy because of the inverse association between age at diagnosis and risk of developing bone or visceral distant metastases.5 In this regard, and given concerns about bone health, the growing use of endocrine treatment intensification (eg, OFS plus aromatase inhibitors6) in premenopausal women with high-risk breast cancer, particularly in those younger than 35 years, is expanding the use of bisphosphonates to younger age groups. MAF, a transcription factor implicated in control of expression of several genes associated with bone metastasis from breast cancer, has been studied as a predictor of bone relapse.7 In The Lancet Oncology, Robert Coleman and colleagues8 report a secondary analysis of the phase 3 AZURE study to investigate whether
MAF amplification status, indicated by copy number on fluorescence in-situ hybridisation (FISH), could predict treatment effects with adjuvant zoledronic acid compared with standard care alone. AZURE is the largest trial included in the EBCTCG meta-analysis. Of 1739 patients who contributed primary tumour samples, 865 (50%) had enough tissue to create two cores assessable by FISH. 184 (21%) had MAF-positive tumours (copy number ≥2·5). At median follow-up of 84·6 months (IQR 72·0–95·8), 282 (33%) patients had distant relapse (147 in the control group and 135 in the zoledronic acid group), 60 of which were in bone (39 and 21, respectively). Although the small number of bone relapses limited the analysis of potential associations between MAF status and bone relapse, in patients receiving zoledronic acid, invasive-disease-free survival (the primary endpoint) was longer in patients with MAF-negative tumours than in patients with MAF-positive tumours (HR 0·52, 95% CI 0·36–0·75). Strikingly, MAF positivity seemed to also predict harm with adjuvant zoledronic acid in non-postmenopausal women, particularly for extraskeletal recurrence (zoledronic acid vs control HR 6·92, 95% CI 2·44–19·60). Thus, among premenopausal women with early breast cancer at high risk of bone loss and osteoporotic fractures, selecting patients with MAF-negative tumours for treatment with adjuvant bisphosphonates might be very important. How functional menopause by OFS affects these findings is unclear. Validation in an independent cohort and translational research into the effects of adjuvant bisphosphonates in patients with early breast cancer are needed. Creation of a standard test for MAF amplification status could be clinically helpful to exclude premenopausal patients with early breast cancer from receiving zoledronic acid and potentially other bisphosphonates. How MAF status might inform the use of denosumab in this setting remains uncertain. Data on the use of adjuvant denosumab have so far been derived only from postmenopausal patients and those with hormonereceptor-positive breast cancers who are receiving aromatase inhibitors.9 The role of adjuvant denosumab in premenopausal and postmenopausal women is being investigated in the D-CARE prospective trial (NCT01077154).
www.thelancet.com/oncology Published online October 13, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30695-2
Zephyr/Science Photo Library
Adjuvant zoledronic acid to treat breast cancer: not for all
Lancet Oncol 2017 Published Online October 13, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30695-2 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(17)30603-4
1
Comment
The AZURE trial has prompted other studies looking for correlations between biomarkers and bone relapse. High expression of macrophage-capping protein (CAPG) and PDZ domain-containing protein (GIPC1) in primary breast cancers is associated with an increase in first recurrence in bone,10 which suggests that patients with tumours expressing these biomarkers would benefit from adjuvant treatment with zoledronic acid. The complex interplay between ovarian function and bisphosphonates for prevention of bone metastases also remains unclear. The findings of Coleman and colleagues8 do not provide a definite explanation for this interaction, but, undoubtedly, leave open the question of whether adjuvant zoledronic acid is suitable for all. *Luís Costa, Arlindo R Ferreira Oncology Division, Hospital de Santa Maria, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-035 Lisbon, Portugal [email protected], We declare no competing interests.
2
1
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet 2015; 386: 1353–61. 2 Dhesy-Thind S, Fletcher GG, Blanchette PS, et al. Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: a Cancer Care Ontario and American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2017; 35: 2062–81. 3 Hadji P, Coleman RE, Wilson C, et al. Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel. Ann Oncol 2016; 27: 379–90. 4 Hofbauer LC, Rachner TD, Coleman RE, Jakob F. Endocrine aspects of bone metastases. Lancet Diabetes Endocrinol 2014; 2: 500–12. 5 Purushotham A, Shamil E, Cariati M, et al. Age at diagnosis and distant metastasis in breast cancer—a surprising inverse relationship. Eur J Cancer 2014; 50: 1697–705. 6 Pagani O, Regan MM, Walley BA, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 2014; 371: 107–18. 7 Pavlovic M, Arnal-Estapé A, Rojo F, et al. Enhanced MAF oncogene expression and breast cancer bone metastasis. J Natl Cancer Inst 2015; 107: djv256. 8 Coleman R, Hall A, Albanell J, et al. Effect of MAF amplification on treatment outcomes with adjuvant zoledronic acid in early breast cancer: a secondary analysis of the international, open-label, randomised, controlled, phase 3 AZURE (BIG 01/04) trial. Lancet Oncol 2017; published online Oct 13. http://dx.doi.org/10.1016/S1470-2045(17)30603-4. 9 Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2015; 386: 433–43. 10 Westbrook JA, Cairns DA, Peng J, et al. CAPG and GIPC1: breast cancer biomarkers for bone metastasis development and treatment. J Natl Cancer Inst 2016; 108: djv360.
www.thelancet.com/oncology Published online October 13, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30695-2
Bisphosphonates have been extensively studied in the adjuvant setting as a host-directed therapy to reduce the risk of breast-cancer relapse. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) patientlevel meta-analysis of adjuvant bisphosphonates, which included 18 776 women with breast cancer, showed a reduction in breast-cancer-associated death among postmenopausal women (hazard ratio [HR] 0·82, 95% CI 0·73–0·93). This outcome was mainly due to the reduction in bone recurrence. Thus, several guidelines have included zoledronic acid and clodronic acid as adjuvant treatments for breast cancer in postmenopausal women.1–3 Women’s age and menopausal status are powerful surrogates for oestrogen concentrations and, thereby, for regulation of bone remodelling. Thus, oestrogendriven changes in the bone microenvironment might affect the likelihood of women in different age groups developing bone metastases.4 An important and as yet unresolved subject of scientific debate is how ovarian function regulates host-driven responses to cancer cells and mainly host-directed (and bone-selective) treatments, such as zoledronic acid. Whether premenopausal women with breast cancer should be considered as candidates for adjuvant treatment with bisphosphonates is a relevant question. Adjuvant bisphosphonates have been reserved for use in postmenopausal women, irrespective of the cause of menopause (physiological, surgical, or due to ovarian function suppression [OFS]). Extending these agents to younger women is an attractive strategy because of the inverse association between age at diagnosis and risk of developing bone or visceral distant metastases.5 In this regard, and given concerns about bone health, the growing use of endocrine treatment intensification (eg, OFS plus aromatase inhibitors6) in premenopausal women with high-risk breast cancer, particularly in those younger than 35 years, is expanding the use of bisphosphonates to younger age groups. MAF, a transcription factor implicated in control of expression of several genes associated with bone metastasis from breast cancer, has been studied as a predictor of bone relapse.7 In The Lancet Oncology, Robert Coleman and colleagues8 report a secondary analysis of the phase 3 AZURE study to investigate whether
MAF amplification status, indicated by copy number on fluorescence in-situ hybridisation (FISH), could predict treatment effects with adjuvant zoledronic acid compared with standard care alone. AZURE is the largest trial included in the EBCTCG meta-analysis. Of 1739 patients who contributed primary tumour samples, 865 (50%) had enough tissue to create two cores assessable by FISH. 184 (21%) had MAF-positive tumours (copy number ≥2·5). At median follow-up of 84·6 months (IQR 72·0–95·8), 282 (33%) patients had distant relapse (147 in the control group and 135 in the zoledronic acid group), 60 of which were in bone (39 and 21, respectively). Although the small number of bone relapses limited the analysis of potential associations between MAF status and bone relapse, in patients receiving zoledronic acid, invasive-disease-free survival (the primary endpoint) was longer in patients with MAF-negative tumours than in patients with MAF-positive tumours (HR 0·52, 95% CI 0·36–0·75). Strikingly, MAF positivity seemed to also predict harm with adjuvant zoledronic acid in non-postmenopausal women, particularly for extraskeletal recurrence (zoledronic acid vs control HR 6·92, 95% CI 2·44–19·60). Thus, among premenopausal women with early breast cancer at high risk of bone loss and osteoporotic fractures, selecting patients with MAF-negative tumours for treatment with adjuvant bisphosphonates might be very important. How functional menopause by OFS affects these findings is unclear. Validation in an independent cohort and translational research into the effects of adjuvant bisphosphonates in patients with early breast cancer are needed. Creation of a standard test for MAF amplification status could be clinically helpful to exclude premenopausal patients with early breast cancer from receiving zoledronic acid and potentially other bisphosphonates. How MAF status might inform the use of denosumab in this setting remains uncertain. Data on the use of adjuvant denosumab have so far been derived only from postmenopausal patients and those with hormonereceptor-positive breast cancers who are receiving aromatase inhibitors.9 The role of adjuvant denosumab in premenopausal and postmenopausal women is being investigated in the D-CARE prospective trial (NCT01077154).
www.thelancet.com/oncology Published online October 13, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30695-2
Zephyr/Science Photo Library
Adjuvant zoledronic acid to treat breast cancer: not for all
Lancet Oncol 2017 Published Online October 13, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30695-2 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(17)30603-4
1
Comment
The AZURE trial has prompted other studies looking for correlations between biomarkers and bone relapse. High expression of macrophage-capping protein (CAPG) and PDZ domain-containing protein (GIPC1) in primary breast cancers is associated with an increase in first recurrence in bone,10 which suggests that patients with tumours expressing these biomarkers would benefit from adjuvant treatment with zoledronic acid. The complex interplay between ovarian function and bisphosphonates for prevention of bone metastases also remains unclear. The findings of Coleman and colleagues8 do not provide a definite explanation for this interaction, but, undoubtedly, leave open the question of whether adjuvant zoledronic acid is suitable for all. *Luís Costa, Arlindo R Ferreira Oncology Division, Hospital de Santa Maria, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-035 Lisbon, Portugal [email protected], We declare no competing interests.
2
1
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet 2015; 386: 1353–61. 2 Dhesy-Thind S, Fletcher GG, Blanchette PS, et al. Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: a Cancer Care Ontario and American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2017; 35: 2062–81. 3 Hadji P, Coleman RE, Wilson C, et al. Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel. Ann Oncol 2016; 27: 379–90. 4 Hofbauer LC, Rachner TD, Coleman RE, Jakob F. Endocrine aspects of bone metastases. Lancet Diabetes Endocrinol 2014; 2: 500–12. 5 Purushotham A, Shamil E, Cariati M, et al. Age at diagnosis and distant metastasis in breast cancer—a surprising inverse relationship. Eur J Cancer 2014; 50: 1697–705. 6 Pagani O, Regan MM, Walley BA, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 2014; 371: 107–18. 7 Pavlovic M, Arnal-Estapé A, Rojo F, et al. Enhanced MAF oncogene expression and breast cancer bone metastasis. J Natl Cancer Inst 2015; 107: djv256. 8 Coleman R, Hall A, Albanell J, et al. Effect of MAF amplification on treatment outcomes with adjuvant zoledronic acid in early breast cancer: a secondary analysis of the international, open-label, randomised, controlled, phase 3 AZURE (BIG 01/04) trial. Lancet Oncol 2017; published online Oct 13. http://dx.doi.org/10.1016/S1470-2045(17)30603-4. 9 Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2015; 386: 433–43. 10 Westbrook JA, Cairns DA, Peng J, et al. CAPG and GIPC1: breast cancer biomarkers for bone metastasis development and treatment. J Natl Cancer Inst 2016; 108: djv360.
www.thelancet.com/oncology Published online October 13, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30695-2