- Email: [email protected]
IN15 RANKL signalling: bone metastasis and beyond
Invited Speakers’ Abstracts / The Breast 21S1 (2012) S1–S9
breast cancer. In the adjuvant setting, early trials published around 10 years ago showed conflicting results but the largest (Clodroplac) involving over 1,000 patients treated with oral clodronate for 2 years showed a significant reduction in the incidence of bone metastases and a significant survival improvement. One of the largest modern adjuvant bisphosphonate trials, AZURE, involved 3,360 patients randomized to treatment with Zoledronic acid or not for 5 years showed no significant overall benefit in terms of disease-free survival. Sub-group analysis however showed a significant disease-free and overall survival benefit for women with a low oestrogen environment (menopausal) but no benefit for premenopausal women in a high oestrogen environment. The Austrian ABCSG-12 trial found that Zoledronic acid given 6 monthly to premenopausal women on Goserelin (ie low oestrogen environment) achieved a significant reduction in disease-free survival and overall survival and similar significant gains were seen for post-menopausal women randomized to immediate 6 monthly zoledronic acid compared with delayed until bone-related events occurred. Finally, the large NSABPB-34 trial randomized over 3,300 patients to oral Clodronate for 3 years versus placebo. As in the AZURE trial no overall significant benefit in disease-free survival was seen but there was a significant benefit for those over the age of 50, most of whom would have been postmenopausal. In conclusion the evidence from all these trial suggests that there is indeed a benefit from adjuvant bisphosphonate therapy in early breast cancer in reducing the risk of recurrence and improving survival, but only in women in a low oestrogen environment. IN15 RANKL signalling: bone metastasis and beyond R. Coleman *. Weston Park Hospital, CR-UK/YCR Sheffield Cancer Research Centre, Sheffield, UK Bone metastases result from the interactions between cancer cells in the bone marrow microenvironment and normal bone cells. RANKL is a key mediator in this process. Within the bone microenvironment, tumour derived factors stimulate stromal cells and osteoblasts to secrete RANKL, which binds to its receptor RANK on precursor and mature osteoclasts. Release of RANKL leads to stimulation of osteoclastic bone resorption, and provides the rationale for bone-targeted therapies as an adjunct to traditional anticancer agents in the management of advanced malignancy. Modern multi-disciplinary care has transformed the clinical course of metastatic bone disease. Until recently, bisphosphonates (BPs) were the treatment of choice but recent data has resulted in the emergence of a new, targeted therapeutic strategy. Denosumab is a fully human monoclonal antibody that inhibits RANKL with high affinity and specificity. Preclinical data show that denosumab is a more complete inhibitor of osteoclast function than the BPs. In a randomised phase II study in patients with increased bone resorption despite IV BP treatment, rapid and sustained biochemical response was seen in >80% of patients switched to denosumab compared with <30% for those continuing on BPs. In a phase III trial of double-blind, active-controlled trial comparing denosumab 120 mg SC to zoledronic acid 4 mg IV (both given 4 weekly) in 2046 breast cancer patients with bone metastases, denosumab was statistically superior to zoledronic acid in delaying the first SRE (HR 0.82, 95% CI 0.71–0.95, P = 0.01). Denosumab was easier to administer and had safety advantages with fewer acute phase reactions than zoledronic acid and no need for renal monitoring. Both agents were associated with a low risk (0.5–1% per year) of osteonecrosis of the jaw. Denosumab is also being studied in the prevention of metastasis setting. The D-CARE trial is designed to assess if denosumab treatment prolongs bone metastasis-free survival (BMFS) and
S5
disease-free survival (DFS) in the adjuvant breast cancer setting. Secondary endpoints include overall survival, safety, incidence of SREs (following the development of bone metastasis) patient reported outcomes, and biomarkers. It will be interesting to see whether this adjuvant strategy can improve the outcome for younger premenopausal women who do not seem to benefit from adjuvant BPs.
Session VI. Advanced breast cancer IN16 Advanced breast cancer: Advances in targeted therapy N. Harbeck *. Breast Center, Dept. OB&GYN, University of Munich, Germany In advanced breast cancer, targeted therapy options are becoming increasingly important. Thus, biopsy of the first metastasis is recommended in order to confirm the breast cancer origin as well as to assess hormone receptors (ER, PR) and HER2 status again. If a discrepancy with the primary lesion is found, targeted therapy should be considered if one of the lesions expresses the target. Endocrine therapy is the oldest targeted therapy in breast cancer. Here, young women, i.e. premenopausal patients, have the same endocrine options as postmenopausal patients with ovarian suppression being a necessary prerequisite. With regard to novel targeted agents such as bevacizumab or anti HER2 agents, there is no evidence that the benefit is agedependent, and in particular no evidence of a lower benefit in younger patients. Unfortunately, in some trials, subgroup analysis does not specifically address premenopausal patients or even young women under 40 years. In HER2-negative disease, bevacizumab is a registered option for first line metastatic disease together with paclitaxel or capecitabine in several countries including Europe. In the E2100 study, young patients (27–49 y) derive substantial benefit (HR 0.5) from bevacizumab + paclitaxel compared to paclitaxel alone. In HER2-positive disease, trastuzumab and lapatinib are registered options for advanced disease. Recently, two new agents have been shown to prolong progression-free (PFS) and even overall survival substantially in patients with HER2-positive disease. The monoclonal antibody pertuzumab inhibits dimerization of HER2 with other HER receptors and adds to the efficacy of trastuzumab. The registration study, CLEOPATRA, showed that first line docetaxel + trastuzumab + pertuzumab significantly increases PFS and OS in first line HER2 positive disease compared to the standard of docetaxel + trastuzumab (Baselga et al, 2012). There is no difference in efficacy between patients younger or older than 65 years. In the EMILIA study (Blackwell et al, 2012), the novel antibody-drug conjugate T-DM1 was superior to lapatinib + capecitabine in patients who progressed after taxane + trastuzumab therapy. Again, the data suggests that patients under 65 years derive a substantial benefit from this agent (HR for PFS: 0.62; 95CI 0.52, 0.74). Whereas pertuzumab is already registered by the FDA, registration for T-DM1 is still pending. In conclusion, substantial progress in the area of targeted therapy has recently been made. In particular in the HER2 positive setting, two new substances, pertuzumab and T-DM1, are very promising. No specific interaction of efficacy with young age has yet been observed. Yet, caution needs to be taken with these new substances in pregnancy. Trastuzumab causes placental insufficiency (Gottschalk et al, 2011) and thus needs to be avoided in pregnant patients. Until further data is available, the same caution needs to be taken with the upcoming novel antibodies as well. A summary of the available evidence as well as clinical therapy recommendations addressing targeted therapy options in young
breast cancer. In the adjuvant setting, early trials published around 10 years ago showed conflicting results but the largest (Clodroplac) involving over 1,000 patients treated with oral clodronate for 2 years showed a significant reduction in the incidence of bone metastases and a significant survival improvement. One of the largest modern adjuvant bisphosphonate trials, AZURE, involved 3,360 patients randomized to treatment with Zoledronic acid or not for 5 years showed no significant overall benefit in terms of disease-free survival. Sub-group analysis however showed a significant disease-free and overall survival benefit for women with a low oestrogen environment (menopausal) but no benefit for premenopausal women in a high oestrogen environment. The Austrian ABCSG-12 trial found that Zoledronic acid given 6 monthly to premenopausal women on Goserelin (ie low oestrogen environment) achieved a significant reduction in disease-free survival and overall survival and similar significant gains were seen for post-menopausal women randomized to immediate 6 monthly zoledronic acid compared with delayed until bone-related events occurred. Finally, the large NSABPB-34 trial randomized over 3,300 patients to oral Clodronate for 3 years versus placebo. As in the AZURE trial no overall significant benefit in disease-free survival was seen but there was a significant benefit for those over the age of 50, most of whom would have been postmenopausal. In conclusion the evidence from all these trial suggests that there is indeed a benefit from adjuvant bisphosphonate therapy in early breast cancer in reducing the risk of recurrence and improving survival, but only in women in a low oestrogen environment. IN15 RANKL signalling: bone metastasis and beyond R. Coleman *. Weston Park Hospital, CR-UK/YCR Sheffield Cancer Research Centre, Sheffield, UK Bone metastases result from the interactions between cancer cells in the bone marrow microenvironment and normal bone cells. RANKL is a key mediator in this process. Within the bone microenvironment, tumour derived factors stimulate stromal cells and osteoblasts to secrete RANKL, which binds to its receptor RANK on precursor and mature osteoclasts. Release of RANKL leads to stimulation of osteoclastic bone resorption, and provides the rationale for bone-targeted therapies as an adjunct to traditional anticancer agents in the management of advanced malignancy. Modern multi-disciplinary care has transformed the clinical course of metastatic bone disease. Until recently, bisphosphonates (BPs) were the treatment of choice but recent data has resulted in the emergence of a new, targeted therapeutic strategy. Denosumab is a fully human monoclonal antibody that inhibits RANKL with high affinity and specificity. Preclinical data show that denosumab is a more complete inhibitor of osteoclast function than the BPs. In a randomised phase II study in patients with increased bone resorption despite IV BP treatment, rapid and sustained biochemical response was seen in >80% of patients switched to denosumab compared with <30% for those continuing on BPs. In a phase III trial of double-blind, active-controlled trial comparing denosumab 120 mg SC to zoledronic acid 4 mg IV (both given 4 weekly) in 2046 breast cancer patients with bone metastases, denosumab was statistically superior to zoledronic acid in delaying the first SRE (HR 0.82, 95% CI 0.71–0.95, P = 0.01). Denosumab was easier to administer and had safety advantages with fewer acute phase reactions than zoledronic acid and no need for renal monitoring. Both agents were associated with a low risk (0.5–1% per year) of osteonecrosis of the jaw. Denosumab is also being studied in the prevention of metastasis setting. The D-CARE trial is designed to assess if denosumab treatment prolongs bone metastasis-free survival (BMFS) and
S5
disease-free survival (DFS) in the adjuvant breast cancer setting. Secondary endpoints include overall survival, safety, incidence of SREs (following the development of bone metastasis) patient reported outcomes, and biomarkers. It will be interesting to see whether this adjuvant strategy can improve the outcome for younger premenopausal women who do not seem to benefit from adjuvant BPs.
Session VI. Advanced breast cancer IN16 Advanced breast cancer: Advances in targeted therapy N. Harbeck *. Breast Center, Dept. OB&GYN, University of Munich, Germany In advanced breast cancer, targeted therapy options are becoming increasingly important. Thus, biopsy of the first metastasis is recommended in order to confirm the breast cancer origin as well as to assess hormone receptors (ER, PR) and HER2 status again. If a discrepancy with the primary lesion is found, targeted therapy should be considered if one of the lesions expresses the target. Endocrine therapy is the oldest targeted therapy in breast cancer. Here, young women, i.e. premenopausal patients, have the same endocrine options as postmenopausal patients with ovarian suppression being a necessary prerequisite. With regard to novel targeted agents such as bevacizumab or anti HER2 agents, there is no evidence that the benefit is agedependent, and in particular no evidence of a lower benefit in younger patients. Unfortunately, in some trials, subgroup analysis does not specifically address premenopausal patients or even young women under 40 years. In HER2-negative disease, bevacizumab is a registered option for first line metastatic disease together with paclitaxel or capecitabine in several countries including Europe. In the E2100 study, young patients (27–49 y) derive substantial benefit (HR 0.5) from bevacizumab + paclitaxel compared to paclitaxel alone. In HER2-positive disease, trastuzumab and lapatinib are registered options for advanced disease. Recently, two new agents have been shown to prolong progression-free (PFS) and even overall survival substantially in patients with HER2-positive disease. The monoclonal antibody pertuzumab inhibits dimerization of HER2 with other HER receptors and adds to the efficacy of trastuzumab. The registration study, CLEOPATRA, showed that first line docetaxel + trastuzumab + pertuzumab significantly increases PFS and OS in first line HER2 positive disease compared to the standard of docetaxel + trastuzumab (Baselga et al, 2012). There is no difference in efficacy between patients younger or older than 65 years. In the EMILIA study (Blackwell et al, 2012), the novel antibody-drug conjugate T-DM1 was superior to lapatinib + capecitabine in patients who progressed after taxane + trastuzumab therapy. Again, the data suggests that patients under 65 years derive a substantial benefit from this agent (HR for PFS: 0.62; 95CI 0.52, 0.74). Whereas pertuzumab is already registered by the FDA, registration for T-DM1 is still pending. In conclusion, substantial progress in the area of targeted therapy has recently been made. In particular in the HER2 positive setting, two new substances, pertuzumab and T-DM1, are very promising. No specific interaction of efficacy with young age has yet been observed. Yet, caution needs to be taken with these new substances in pregnancy. Trastuzumab causes placental insufficiency (Gottschalk et al, 2011) and thus needs to be avoided in pregnant patients. Until further data is available, the same caution needs to be taken with the upcoming novel antibodies as well. A summary of the available evidence as well as clinical therapy recommendations addressing targeted therapy options in young