- Email: [email protected]
Adjuvant zoledronic acid for breast cancer: mechanism of action?
Correspondence
5
Faerden AE, Sjo O, Andersen SN, et al. Sentinel node mapping does not improve staging of lymph node metastasis in colonic cancer. Dis Colon Rectum 2008; 51: 891–96. Mulsow J, Winter DC, O’Keane JC, et al. Sentinel lymph node mapping in colorectal cancer. Br J Surg 2003; 90: 659–67.
Zoledronic acid in earlystage breast cancer Michael Gnant and co-workers1 reported an update of the ABCSG-12 randomised trial of adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer. At a median follow-up of 62 months, addition of zoledronic acid improved disease-free survival in patients taking anastrozole or tamoxifen. Although zoledronic acid did not significantly affect risk of death, these data suggest an antitumour activity of zoledronic acid. As discussed by the investigators, zoledronic acid probably acts on the bone microenvironment. After intravenous administration, bisphosphonates decrease quickly in non-calcified tissues, proportionate to the decrease of plasma concentration, with a half-life of about 15 min. Bisphosphonates accumulate in the bone, where their half-life is proportional to the rate of bone resorption and can last several months. Gnant and collaborators postulated that zoledronic acid might modify the bone microenvironment surrounding cancer cells, impeding cancer-cell survival and seeding of disease recurrence. In particular, zoledronic acid might reduce the occurrence of disseminated tumour cells. The formation of metastases is complex and several non-transformed cell types contribute. Mesenchymal stem cells (MSCs) reside predominantly in the bone marrow, where they give rise to specialised connective tissue cells.2 MSCs can contribute to the formation of metastases through different mechanisms: (1) MSCs are recruited to developing breast tumours where they can enhance the metastatic potential of www.thelancet.com/oncology Vol 12 October 2011
weakly tumorigenic breast cancer cells;3 (2) MSCs and other cells derived from bone marrow can form a premetastatic niche within specific tissues to which tumour cells metastasise;4 and (3) MSCs might sustain the growth and survival of cancer cells within the bone microenvironment where they can contribute to form niches for dormant micrometastases that might later seed distant metastases. We have shown that zoledronic acid significantly reduced the ability of MSCs to migrate.5 Additionally, treatment with zoledronic acid reduced the secretion of factors, such as RANTES/chemokine (C–C motif) ligand 5 (CCL5) and interleukin 6, which induce breast cancer cell migration. Therefore, we postulate that the effects of zoledronic acid on MSCs within the bone-marrow microenvironment contribute to its antitumour activity by affecting the ability of MSCs to migrate to developing tumours or premetastatic niches; reducing the secretion of factors that sustain breast cancer cell metastasis in MSCs that migrate to metastatic sites; and disturbing the interaction between MSCs and breast cancer cells within the bone-marrow microenvironment (during which zoledronic acid might also directly inhibit breast cancer cell growth). Because we reported that zoledronic acid significantly affects the secretion of RANTES/CCL5 and interleukin 6 in MSCs and that these factors cooperate to induce the migration of breast cancer cells, we are investigating whether plasma concentrations of RANTES/CCL5 and interleukin 6 represent biomarkers of activity of adjuvant zoledronic acid in the HOBOE trial (NCT00412022). We declare that we have no conflicts of interest. This work was supported by a grant from the non-profit organisation Associazione Italiana per la Ricerca sul Cancro.
*Nicola Normanno, Antonella De Luca, Marianna Gallo, Luana Lamura, Francesco Perrone [email protected]
Cell Biology and Biotherapy Unit (NN, ADL, MG, LL) and Clinical Trials Unit (FP), INT-Fondazione Pascale, Naples, Italy 1
2
3
4
5
Gnant M, Mlineritsch B, Stoeger H, et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol 2011; 12: 631–41. Deans RJ, Moseley AB. Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 2000; 28: 875–84. Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449: 557–63. Psaila B, Lyden D. The metastatic niche: adapting the foreign soil. Nat Rev Cancer 2009; 9: 285–93. Gallo M, De Luca A, Lamura L, Normanno N. Zoledronic acid blocks the interaction between mesenchymal stem cells and breast cancer cells: implications for adjuvant therapy of breast cancer. Ann Oncol 2011; published online May 6, 2011. DOI:10.1093/annonc/mdr159.
Steve Gschmeissner/Science Photo Library
4
Adjuvant zoledronic acid for breast cancer: mechanism of action? The ABCSG-12 trial1 reported a sustained disease-free survival (DFS) benefit of endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer. Taken together with two other trials of zoledronic acid in premenopausal and postmenopausal patients with breast cancer (webappendix p 1),2,3 this trial raises important questions about which patients might benefit most from adjuvant treatment. By contrast with the positive outcomes of ABCSG-12 and the ZOFAST study,3 investigators reported no DFS benefit with zoledronic acid in the total AZURE trial population.2 On the basis of post-hoc subgroup analyses, the ABCSG-12 investigators proposed that zoledronic acid might be most effective in a low-oestrogenic environment, suggesting that the anticancer effect of bisphosphonates is mediated by age-dependent or oestrogen-dependent changes to the bone microenvironment. However, although subgroup analyses in adjuvant trials seem to support an
See Online for webappendix
991
Correspondence
anticancer effect of zoledronic acid in a low oestrogenic environment (by either natural menopause or ovarian suppression), preclinical data supporting a greater anticancer effect of zoledronic acid in a low oestrogenic environment are lacking. Preclinical studies suggest that nitrogen-containing bisphosphonates such as zoledronic acid might have many anticancer properties including direct induction of tumour-cell apoptosis, synergy with cytotoxic chemotherapy, inhibition of angiogenesis or tumourcell invasion, modification of the cancer-cell microenvironment, effects on disseminated tumour cells, and induction of immunomodulatory effects by selective stimulation of γδ T cells. By contrast with these proposed effects in vitro, only the unique immunomodulatory effect of nitrogencontaining bisphosphonates by selective stimulation of phosphoantigen-reactive γδ T cells has been repeatedly validated in vivo with standard dosing schedules.4–6 Benzaid and colleagues7 provide further evidence for an immunosurveillance function of bisphosphonate-activated γδ T cells against human breast cancer cells by showing that only oestrogenreceptor (ER)-positive and HER2negative breast cancer cells producing high concentrations of intracellular phosphoantigen after zoledronic acid treatment are sensitive to an immunemediated attack by γδ T cells. In view of these data, we propose a different explanation for the conflicting results from the adjuvant trials. Because previous chemotherapy greatly affects the reactivity of bisphosphonateactivated γδ T cells,5 the large proportion of women receiving neoadjuvant or adjuvant chemotherapy in the AZURE trial (95% vs 6% in the ABCSG-12 trial) might also affect DFS by suppressing γδ T-cell-mediated immunomodulatory effects (webappendix p 1). This assumption is strengthened by the fewer acute phase reactions—as assessed by the incidence of pyrexia—which are γδ T-cell-mediated,4 in the AZURE trial than in the ABCSG-12 trial (2·2% vs 992
10%). Additionally, the proportion of ER-positive breast cancers—which are more sensitive to γδ T-cell-mediated cytotoxicity than are ER-negative breast cancers—was smaller in the AZURE trial than in the ABCSG-12 trial (78% vs 94%). The significant DFS and overall survival improvements in the AZURE subset of women who had been postmenopausal for longer than 5 years at study entry (aged >60 years) might be explained by less frequent (or less intensive) previous chemotherapy, or a higher incidence of ER-positive tumours, although this issue has not been reported in detail. On the basis of the interpretation that adjuvant zoledronic acid might be most effective in chemotherapy-naive ER-positive breast cancer, the non-detectable DFS benefit in the ABCSG-12 subset of women younger than 40 years (23% of the overall ABCSG-12 population) might not only be explained by incomplete oestrogen deprivation, but also by more women receiving neoadjuvant chemotherapy and fewer tumours with high ER expression. A reanalysis of completed and ongoing (eg, SWOG 0307) adjuvant trials stratified by previous chemotherapy, rate of acute phase reactions, and ER expression in different age groups would be necessary to clearly define the mechanism of action behind the effects of zoledronic acid, and might help to define the patient subsets who will benefit most. We declare that we have no conflicts of interest.
*Volker Kunzmann, Martin Wilhelm [email protected] Medizinische Klinik und Poliklinik II and Comprehensive Cancer Center Mainfranken, Julius Maximilians University, Würzburg, Germany (VK); and Clinic of Medical Oncology and Hematology, Klinikum Nürnberg, Germany (MW) 1
2
Gnant M, Mlineritsch B, Stoeger H, et al, for the Austrian Breast and Colorectal Cancer Study Group. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol 2011; 12: 631–41. Coleman RE, Thorpe HC, Cameron D, et al. Adjuvant treatment with zoledronic acid in stage II/III breast cancer. The AZURE trial (BIG 01/04). 33rd Annual San Antonio Breast Cancer Symposium; San Antonio, TX, USA; Dec 8–12, 2010. S4–5 (abstr).
3
4
5
6
7
Eidtmann H, de Boer R, Bundred NJ, et al. Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST study. Ann Oncol 2010; 21: 2188–94. Kunzmann V, Bauer E, Wilhelm M. γδ T-cell stimulation by pamidronate. N Engl J Med 1999; 340: 737–38. Wilhelm M, Kunzmann V, Eckstein S, et al. γδ T cells for immune therapy of patients with lymphoid malignancies. Blood 2003; 102: 200–06. Dieli F, Gebbia N, Poccia F, et al. Induction of γδ T-lymphocyte effector functions by bisphosphonate zoledronic acid in cancer patients in vivo. Blood 2003; 102: 2310–11. Benzaïd I, Mönkkönen H, Stresing V, et al. High phosphoantigen levels in bisphosphonatetreated human breast tumors promote Vγ9Vδ2 T-cell chemotaxis and cytotoxicity in vivo. Cancer Res 2011; 71: 4562–72.
Premature conclusions on HPV-only testing It was with great interest that we read the report by Hormuzd Katki and colleagues,1 which provided strong evidence supporting the co-testing for human papillomavirus (HPV) and cytology for women aged 30 years and older. However, we note several pitfalls in the study design and data interpretation that might affect the conclusion of the study. First, the finding that HPV testing per se was more predictive of the risk for developing clinically significant lesions than Pap cytology might be the result of work-up bias. In other words, women with HPV-positive and Pap-negative test results were less likely to be worked up and treated than women with HPV-negative and Pap-positive test results, therefore the disparity of the management might also contribute to the difference in risk as noted in figure 1. Second, there seems to be several skewed interpretations of data and statistics that favour HPV testing over Pap cytology. For example, figures 1A and 1B were interpreted differently by the researchers even though the data showed very similar trends for both testing modalities. It was stated that for figure 1A, risk for “CIN3 or worse was less in all women negative for HPV than in all women negative by www.thelancet.com/oncology Vol 12 October 2011
5
Faerden AE, Sjo O, Andersen SN, et al. Sentinel node mapping does not improve staging of lymph node metastasis in colonic cancer. Dis Colon Rectum 2008; 51: 891–96. Mulsow J, Winter DC, O’Keane JC, et al. Sentinel lymph node mapping in colorectal cancer. Br J Surg 2003; 90: 659–67.
Zoledronic acid in earlystage breast cancer Michael Gnant and co-workers1 reported an update of the ABCSG-12 randomised trial of adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer. At a median follow-up of 62 months, addition of zoledronic acid improved disease-free survival in patients taking anastrozole or tamoxifen. Although zoledronic acid did not significantly affect risk of death, these data suggest an antitumour activity of zoledronic acid. As discussed by the investigators, zoledronic acid probably acts on the bone microenvironment. After intravenous administration, bisphosphonates decrease quickly in non-calcified tissues, proportionate to the decrease of plasma concentration, with a half-life of about 15 min. Bisphosphonates accumulate in the bone, where their half-life is proportional to the rate of bone resorption and can last several months. Gnant and collaborators postulated that zoledronic acid might modify the bone microenvironment surrounding cancer cells, impeding cancer-cell survival and seeding of disease recurrence. In particular, zoledronic acid might reduce the occurrence of disseminated tumour cells. The formation of metastases is complex and several non-transformed cell types contribute. Mesenchymal stem cells (MSCs) reside predominantly in the bone marrow, where they give rise to specialised connective tissue cells.2 MSCs can contribute to the formation of metastases through different mechanisms: (1) MSCs are recruited to developing breast tumours where they can enhance the metastatic potential of www.thelancet.com/oncology Vol 12 October 2011
weakly tumorigenic breast cancer cells;3 (2) MSCs and other cells derived from bone marrow can form a premetastatic niche within specific tissues to which tumour cells metastasise;4 and (3) MSCs might sustain the growth and survival of cancer cells within the bone microenvironment where they can contribute to form niches for dormant micrometastases that might later seed distant metastases. We have shown that zoledronic acid significantly reduced the ability of MSCs to migrate.5 Additionally, treatment with zoledronic acid reduced the secretion of factors, such as RANTES/chemokine (C–C motif) ligand 5 (CCL5) and interleukin 6, which induce breast cancer cell migration. Therefore, we postulate that the effects of zoledronic acid on MSCs within the bone-marrow microenvironment contribute to its antitumour activity by affecting the ability of MSCs to migrate to developing tumours or premetastatic niches; reducing the secretion of factors that sustain breast cancer cell metastasis in MSCs that migrate to metastatic sites; and disturbing the interaction between MSCs and breast cancer cells within the bone-marrow microenvironment (during which zoledronic acid might also directly inhibit breast cancer cell growth). Because we reported that zoledronic acid significantly affects the secretion of RANTES/CCL5 and interleukin 6 in MSCs and that these factors cooperate to induce the migration of breast cancer cells, we are investigating whether plasma concentrations of RANTES/CCL5 and interleukin 6 represent biomarkers of activity of adjuvant zoledronic acid in the HOBOE trial (NCT00412022). We declare that we have no conflicts of interest. This work was supported by a grant from the non-profit organisation Associazione Italiana per la Ricerca sul Cancro.
*Nicola Normanno, Antonella De Luca, Marianna Gallo, Luana Lamura, Francesco Perrone [email protected]
Cell Biology and Biotherapy Unit (NN, ADL, MG, LL) and Clinical Trials Unit (FP), INT-Fondazione Pascale, Naples, Italy 1
2
3
4
5
Gnant M, Mlineritsch B, Stoeger H, et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol 2011; 12: 631–41. Deans RJ, Moseley AB. Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 2000; 28: 875–84. Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449: 557–63. Psaila B, Lyden D. The metastatic niche: adapting the foreign soil. Nat Rev Cancer 2009; 9: 285–93. Gallo M, De Luca A, Lamura L, Normanno N. Zoledronic acid blocks the interaction between mesenchymal stem cells and breast cancer cells: implications for adjuvant therapy of breast cancer. Ann Oncol 2011; published online May 6, 2011. DOI:10.1093/annonc/mdr159.
Steve Gschmeissner/Science Photo Library
4
Adjuvant zoledronic acid for breast cancer: mechanism of action? The ABCSG-12 trial1 reported a sustained disease-free survival (DFS) benefit of endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer. Taken together with two other trials of zoledronic acid in premenopausal and postmenopausal patients with breast cancer (webappendix p 1),2,3 this trial raises important questions about which patients might benefit most from adjuvant treatment. By contrast with the positive outcomes of ABCSG-12 and the ZOFAST study,3 investigators reported no DFS benefit with zoledronic acid in the total AZURE trial population.2 On the basis of post-hoc subgroup analyses, the ABCSG-12 investigators proposed that zoledronic acid might be most effective in a low-oestrogenic environment, suggesting that the anticancer effect of bisphosphonates is mediated by age-dependent or oestrogen-dependent changes to the bone microenvironment. However, although subgroup analyses in adjuvant trials seem to support an
See Online for webappendix
991
Correspondence
anticancer effect of zoledronic acid in a low oestrogenic environment (by either natural menopause or ovarian suppression), preclinical data supporting a greater anticancer effect of zoledronic acid in a low oestrogenic environment are lacking. Preclinical studies suggest that nitrogen-containing bisphosphonates such as zoledronic acid might have many anticancer properties including direct induction of tumour-cell apoptosis, synergy with cytotoxic chemotherapy, inhibition of angiogenesis or tumourcell invasion, modification of the cancer-cell microenvironment, effects on disseminated tumour cells, and induction of immunomodulatory effects by selective stimulation of γδ T cells. By contrast with these proposed effects in vitro, only the unique immunomodulatory effect of nitrogencontaining bisphosphonates by selective stimulation of phosphoantigen-reactive γδ T cells has been repeatedly validated in vivo with standard dosing schedules.4–6 Benzaid and colleagues7 provide further evidence for an immunosurveillance function of bisphosphonate-activated γδ T cells against human breast cancer cells by showing that only oestrogenreceptor (ER)-positive and HER2negative breast cancer cells producing high concentrations of intracellular phosphoantigen after zoledronic acid treatment are sensitive to an immunemediated attack by γδ T cells. In view of these data, we propose a different explanation for the conflicting results from the adjuvant trials. Because previous chemotherapy greatly affects the reactivity of bisphosphonateactivated γδ T cells,5 the large proportion of women receiving neoadjuvant or adjuvant chemotherapy in the AZURE trial (95% vs 6% in the ABCSG-12 trial) might also affect DFS by suppressing γδ T-cell-mediated immunomodulatory effects (webappendix p 1). This assumption is strengthened by the fewer acute phase reactions—as assessed by the incidence of pyrexia—which are γδ T-cell-mediated,4 in the AZURE trial than in the ABCSG-12 trial (2·2% vs 992
10%). Additionally, the proportion of ER-positive breast cancers—which are more sensitive to γδ T-cell-mediated cytotoxicity than are ER-negative breast cancers—was smaller in the AZURE trial than in the ABCSG-12 trial (78% vs 94%). The significant DFS and overall survival improvements in the AZURE subset of women who had been postmenopausal for longer than 5 years at study entry (aged >60 years) might be explained by less frequent (or less intensive) previous chemotherapy, or a higher incidence of ER-positive tumours, although this issue has not been reported in detail. On the basis of the interpretation that adjuvant zoledronic acid might be most effective in chemotherapy-naive ER-positive breast cancer, the non-detectable DFS benefit in the ABCSG-12 subset of women younger than 40 years (23% of the overall ABCSG-12 population) might not only be explained by incomplete oestrogen deprivation, but also by more women receiving neoadjuvant chemotherapy and fewer tumours with high ER expression. A reanalysis of completed and ongoing (eg, SWOG 0307) adjuvant trials stratified by previous chemotherapy, rate of acute phase reactions, and ER expression in different age groups would be necessary to clearly define the mechanism of action behind the effects of zoledronic acid, and might help to define the patient subsets who will benefit most. We declare that we have no conflicts of interest.
*Volker Kunzmann, Martin Wilhelm [email protected] Medizinische Klinik und Poliklinik II and Comprehensive Cancer Center Mainfranken, Julius Maximilians University, Würzburg, Germany (VK); and Clinic of Medical Oncology and Hematology, Klinikum Nürnberg, Germany (MW) 1
2
Gnant M, Mlineritsch B, Stoeger H, et al, for the Austrian Breast and Colorectal Cancer Study Group. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol 2011; 12: 631–41. Coleman RE, Thorpe HC, Cameron D, et al. Adjuvant treatment with zoledronic acid in stage II/III breast cancer. The AZURE trial (BIG 01/04). 33rd Annual San Antonio Breast Cancer Symposium; San Antonio, TX, USA; Dec 8–12, 2010. S4–5 (abstr).
3
4
5
6
7
Eidtmann H, de Boer R, Bundred NJ, et al. Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST study. Ann Oncol 2010; 21: 2188–94. Kunzmann V, Bauer E, Wilhelm M. γδ T-cell stimulation by pamidronate. N Engl J Med 1999; 340: 737–38. Wilhelm M, Kunzmann V, Eckstein S, et al. γδ T cells for immune therapy of patients with lymphoid malignancies. Blood 2003; 102: 200–06. Dieli F, Gebbia N, Poccia F, et al. Induction of γδ T-lymphocyte effector functions by bisphosphonate zoledronic acid in cancer patients in vivo. Blood 2003; 102: 2310–11. Benzaïd I, Mönkkönen H, Stresing V, et al. High phosphoantigen levels in bisphosphonatetreated human breast tumors promote Vγ9Vδ2 T-cell chemotaxis and cytotoxicity in vivo. Cancer Res 2011; 71: 4562–72.
Premature conclusions on HPV-only testing It was with great interest that we read the report by Hormuzd Katki and colleagues,1 which provided strong evidence supporting the co-testing for human papillomavirus (HPV) and cytology for women aged 30 years and older. However, we note several pitfalls in the study design and data interpretation that might affect the conclusion of the study. First, the finding that HPV testing per se was more predictive of the risk for developing clinically significant lesions than Pap cytology might be the result of work-up bias. In other words, women with HPV-positive and Pap-negative test results were less likely to be worked up and treated than women with HPV-negative and Pap-positive test results, therefore the disparity of the management might also contribute to the difference in risk as noted in figure 1. Second, there seems to be several skewed interpretations of data and statistics that favour HPV testing over Pap cytology. For example, figures 1A and 1B were interpreted differently by the researchers even though the data showed very similar trends for both testing modalities. It was stated that for figure 1A, risk for “CIN3 or worse was less in all women negative for HPV than in all women negative by www.thelancet.com/oncology Vol 12 October 2011