Advanced breast cancer remains

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1 PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM Updates in the Treatment of Advanced Breast Cancer CHRISTINA I. HEROLD, MD Division of Hematology/Oncology Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School Boston, Massachusetts Advanced breast cancer remains challenging, with the major goals of treatment being prolongation of life and preservation of patient-defined quality of life. The treatment of advanced breast cancer has become increasingly guided by molecular tumor markers, including the presence or absence of hormone receptors (HRs) and amplification or over-expression of human epidermal growth factor receptor (ErbB2 or HER2/neu). The past few years have brought significant improvements in the treatment of subtypes of breast cancer, including HR-positive disease, HER2-positive disease, disease associated with BRCA mutations, triple-negative (estrogen receptor [ER]-, progesterone receptor [PR]-, and HER2-negative) disease, and treatment of patients with bony metastases. This review explores the recent data on treatment of various breast cancer subtypes, the role of metastatic tumor biopsies, and prevention of skeletal-related complications in patients with advanced breast disease. Evolving Role for Metastatic Tumor Biopsies In the past year, multiple studies have sought to evaluate the frequency with which metastatic tumor biopsies display transitions in tumor markers when compared with the characteristics of the original primary tumor. Of these, perhaps Amir et al presented the most informative study at the American Society of Clinical Oncology (ASCO) 2010 annual meeting. In a combined analysis of the DESTINY and BRITS studies involving 271 patients, the investigators prospectively analyzed changes in marker status. 1 The primary objective of this study was to ascertain the frequency with which medical oncologists changed their treatment plan based on the results of the metastatic biopsy. To this end, oncologists were asked to record their treatment plan both before and after the result of the metastatic biopsy was known. Analysis of these plans revealed that, based on the results of the metastatic biopsy, 15.1% of patients received a CLINICAL ONCOLOGY NEWS SPECIAL EDITION

2 different treatment than originally had been planned. As secondary objectives, the researchers investigated the frequency of discordant results and reported an overall discordance of 39%, including 5.4% for HER2 status, 12.6% for ER status, and 34% for PR status. These results highlight the frequency with which tumor markers may change during the evolution of disease and suggest that metastatic tumor biopsies likely have an important role in targeting therapies to the most current profile of a patient s disease. Endocrine Therapy for HR-Positive Disease At the 2010 San Antonio Breast Cancer Symposium, several important studies were presented on the management of HR-positive disease. One of these studies, FIRST (Fulvestrant First-Line Study Comparing Endocrine Treatments), examined the first-line treatment of advanced breast cancer, whereas the other 2 studies used novel therapeutics the mammalian target of rapamycin (mtor) inhibitor everolimus (Afinitor, Novartis) and AMG 479 (Amgen) to overcome endocrine resistance. FIRST During the randomized Phase II FIRST study, investigators compared high-dose (500 mg intramuscularly on days 0, 14, and 28, and monthly thereafter) fulvestrant (Faslodex, AstraZeneca) with anastrozole (1 mg per day) as first-line therapy for advanced breast cancer. 2 The primary outcome was time to progression (TTP); median TTP was significantly improved for the fulvestrant group (23.4 months) compared with the anastrozole group (13.1 months); this corresponds to a 35% reduced risk for progression for the fulvestrant group (hazard ratio [HR], 0.66; 95% confidence interval [CI], ; P=0.01). Additionally, fulvestrant was well tolerated, and there were no new safety concerns. Although FIRST is a Phase II study, these results have the potential to influence clinical care, given the significant improvement in TTP associated with this treatment. Of note, the results from FIRST differ from those reported from EFECT (Evaluation of Fulvestrant versus Exemestane Clinical Trial), a Phase III randomized, double-blind, placebo-controlled study enrolling women with HR-positive advanced breast cancer who had demonstrated disease progression while taking a nonsteroidal aromatase inhibitor (AI). 3 EFECT randomized women to receive loading-dose intramuscular fulvestrant (500 mg on day 0, followed by 250 mg intramuscular fulvestrant on days 14 and 28, and monthly thereafter) or the steroidal AI exemestane (Aromasin, Pfizer). EFECT essentially documented equivalence between the study arms; for example, median TTP was 3.7 months in both treatment groups. It is worth noting that FIRST was conducted using endocrine therapy first-line, whereas EFECT employed it as second-line therapy. Finally, the optimal dosing of fulvestrant has been controversial; the results from FIRST add weight to the recommendation that fulvestrant should be given intramuscularly at 500 mg ( highdose schedule). EVEROLIMUS Based on the hypothesis that endocrine resistance may be associated with activation of the PI3K/AKT pathway, the Phase II TAMRAD (tamoxifen and RAD001- everolimus) study investigated everolimus in postmenopausal women who had demonstrated progression while using an AI. 4 Prior AI use was considered in the adjuvant setting (31% of patients), the metastatic setting (60%), and both settings (9%). However, all patients were deemed poorly hormone-sensitive in that 91% demonstrated progression either during AI use in the metastatic setting or within 6 months of adjuvant AI use. Patients were stratified by TTP after AI therapy and randomized to receive either tamoxifen or the combination of tamoxifen and everolimus. The combination arm demonstrated a statistically significant superior clinical benefit ratio (CBR), the primary study objective: 42.1% in the tamoxifen arm versus 61.1% in the tamoxifen-everolimus arm. Regarding TTP, a secondary study objective, an exploratory analysis showed improved TTP in the combination arm: 4.5 months in the tamoxifen arm versus 8.5 months in the tamoxifen-everolimus arm. Regarding safety, both treatment arms were well tolerated; grade 3/4 stomatitis was more common in the combination arm (11% vs 0%) and grade 3/4 pain was more common in the tamoxifen arm (19% vs 7%). The results from TAMRAD suggest that everolimus can play a therapeutic role in overcoming endocrine resistance, warranting further investigation in a larger Phase III study. AMG 479 Based on the hypothesis that combined inhibition of both ER and type 1 insulin-like growth factor receptor (IGF1R) will impede cell proliferation more than targeting either pathway alone, Kaufman et al conducted a randomized Phase II study involving AMG 479, a fully human monoclonal antibody (mab) that targets IGF1R by inhibiting binding of both IGF-1 and IGF-2. 5 This study included postmenopausal woman with advanced breast cancer who had either progressed during prior endocrine therapy or had experienced disease recurrence within 12 months of completing adjuvant endocrine therapy. Study participants were randomized in a 2-to-1 manner to receive either endocrine therapy (exemestane or fulvestrant per investigator s discretion) with AMG 479 or placebo. The primary study objective was assessment of progression-free survival (PFS). Of the 156 patients enrolled, PFS was 3.9 months in the AMG 479-endocrine therapy arm versus 5.7 months in the placebo-endocrine therapy arm (HR, 1.17; 95% CI, ; P=0.435), demonstrating statistically equivalent results for PFS. Regarding safety, grade 3/4 adverse events (AEs) were more common in the AMG 479-endocrine therapy arm: hyperglycemia (6% vs 0%), neutropenia (6% vs 2%), thrombocytopenia (4% vs 0%), and increased aspartate 30

3 aminotransferase (4% vs 0%). In summary, patients who received AMG 479 with endocrine therapy did not seem to experience clinical benefit beyond that of endocrine therapy alone. Novel Therapies and Combinations For HER2-Positive Disease Over the past several years, many promising new treatments have been developed to treat HER2-positive advanced breast cancer. Many of the research efforts have focused on developing new therapeutics to overcome resistance to trastuzumab (Herceptin, Genentech). PERTUZUMAB In a recent Phase II single-arm study, Baselga et al investigated the combination of trastuzumab, a mab directed against HER2, and pertuzumab (Genentech), a mab that binds to the HER2 dimerization domain and prevents binding of HER2 with associated receptors in the HER family (HER1, HER3, and HER4). 6 During the study, 66 patients who had received 3 or fewer prior chemotherapy regimens and who had progressed through prior trastuzumab-based therapy were enrolled to receive standard dosing of trastuzumab either weekly (4 mg/kg loading dose, followed by 2 mg/kg) or every 3 weeks (8 mg/kg loading dose, followed by 6 mg/kg) combined with pertuzumab (840 mg loading dose, followed by 420 mg every 3 weeks). In this single-arm study, the overall response rate (ORR) was 24.2%; of the responders, 7.6% experienced complete response and 16.7% had a partial response. An additional 25.8% had stable disease for at least 6 months, corresponding to a CBR of 50%. This combination was generally well tolerated. Cardiac function was monitored rigorously with minimal changes noted; no patients withdrew as a result of cardiac AEs. Further investigation of this combination is under way in the Phase III CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) trial. NERATINIB Neratinib (Pfizer), an orally available irreversible pan- ErbB inhibitor (ErbB 1, 2, and 4), has emerged as another strategy to treat patients whose disease has progressed through prior trastuzumab therapy. In a Phase II trial with a primary objective of 16-week PFS, 2 cohorts of patients, 66 of whom had received prior trastuzumab and 70 of whom had not, were treated with oral neratinib 240 mg daily (Table 1). 7 Gastrointestinal AEs were observed, with diarrhea, the most common grade 3/4 AE, occurring in 30% of patients who had received prior trastuzumab and 13% of patients who were trastuzumab-naïve. Due to the concern for potential cardiac toxicity, serial monitoring was done to assess left ventricular ejection fraction (LVEF). At baseline, the median LVEFs for patients with and without prior trastuzumab were 62% and 60%, respectively, with median LVEF remaining unchanged at the final study visit. No grade 3/4 cardiac toxicities were reported. Table 1. Phase II Neratinib Results Prior Trastuzumab (n=66) 16-wk PFS, % Median PFS, wk ORR, % No Prior Trastuzumab (n=70) ORR, overall response rate; PFS, progression-free survival Based on reference 7. T-DM1 Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that targets delivery of the cytotoxic antimicrotubule agent DM1 (maytansine) to HER2-positive cells. During the 2010 European Society for Medical Oncology (ESMO) Congress, Perez et al reported preliminary results of a Phase II trial that randomized 137 patients with HER2-positive advanced breast cancer to firstline treatment with either T-DM1 (3.6 mg/kg IV every 3 weeks) or trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) with docetaxel (75 or 100 mg/m 2 IV every 3 weeks) (TD). 8 Of note, crossover from the TD arm to the T-DM1 arm was allowed at the time of disease progression. In this preliminary analysis, the authors reported ORR and safety results. Regarding ORR, comparable results were reported, with an ORR of 48% in the T-DM1 arm and 41% in the TD arm. T-DM1 was better tolerated than TD, with rates of grade 3/4 toxicities of 37.3% and 75%, respectively. More complete results, including PFS, CBR, and 1-year overall survival (OS), are expected in the coming year. LAPATINIB WITH TRASTUZUMAB One common clinical scenario occurs in patients with HER2-positive advanced breast cancer who have progressed through multiple lines of therapy. In a Phase III trial, Blackwell et al randomized 296 patients who had received a median of 3 prior trastuzumab-based therapies to receive lapatinib (Tykerb, GlaxoSmithKline), an oral tyrosine kinase inhibitor (TKI) with activity against ErbB1 (EGFR) and ErbB2 (HER2), with or without trastuzumab. 9 For the lapatinib monotherapy arm, the daily dose was 1,500 mg. For the combination arm, the lapatinib dose was 1,000 mg daily and the trastuzumab dose was a 4 mg/kg loading dose, followed by 2 mg/kg weekly. Patients who progressed on the lapatinib-only arm were allowed to cross over to the lapatinib-trastuzumab combination arm. Results were reported based on intention to treat. For the primary objective of this study, PFS, the combination arm was superior; compared with lapatinib alone, there was a 23% relative reduced risk for progression for patients who received combination therapy (HR, 0.75; P=0.008). CBR also was improved in 31

4 Viable cell Viable cell Viable cell Cell death Figure 1. The effects of BRCA dysfunction and PARP inhibition of cellular repair. BER, base excision repair; HRR, homologous recombination repair; PARP, poly(adp)-ribose polymerase Adapted from reference 14 with permission UBM Medica. All rights reserved. the combination arm, at 24.7% versus 12.4% (P=0.01). A nonstatistically significant trend for improved OS was observed in the combination arm (HR, 0.75; 95% CI, ; P=0.106). There were no differences in ORR. Analyses of tolerability and safety showed that diarrhea was more common in the combination arm, 60% versus 48% (P=0.03). Common AEs for both arms included diarrhea, nausea, fatigue, and rash. Regarding cardiac safety, the incidence of both symptomatic and asymptomatic cardiac events was low. In summary, the combination of lapatinib and trastuzumab has emerged as a treatment option for patients who have experienced disease progression through multiple lines of prior trastuzumab-based therapies. The combination is generally well tolerated and represents a viable non chemotherapy-based option. PARP Inhibitors for BRCA-Associated And Triple-Negative Disease Poly(ADP)-ribose polymerase (PARP) inhibition recently emerged as a powerful treatment strategy in both BRCA-deficient advanced breast cancer and is being investigated in triple-negative metastatic breast cancer (TNMBC) PARP1 is a critical enzyme in DNA repair. Both BRCA deficiency and PARP inhibition impair the cancer cell s ability to repair DNA; BRCA deficiency impairs homologous recombination, whereas PARP inhibition prevents base excision repair. 13 Exposing BRCA-deficient cells to a PARP inhibitor results in synthetic lethality; the combined losses of homologous recombination and base excision repair leads to cell death because the cell cannot repair DNA damage (Figure 1). 14 In 2009, Tutt et al reported results from a Phase II single-arm study investigating the oral PARP inhibitor olaparib (AstraZeneca) in confirmed BRCA1 or BRCA2 carriers with advanced breast cancer who had progressed through a median of 3 prior lines of chemotherapy. 10 In this heavily pretreated group of patients, the ORR was 38% and the toxicity of olaparib was limited, with grade 3/4 toxicities consisting of fatigue, nausea, and anemia being reported in a minority of patients. As a proof-of-concept study, these results support the premise that PARP inhibitors may have dramatic impact on the treatment of BRCA-associated breast cancer. BRCA-associated breast cancer shares many molecular features with TNMBC: Both typically are classified in the basal-like intrinsic subtype by genomic analysis, and BRCA-associated breast cancers are typically triple-negative. 15 Given these molecular similarities, there has been considerable interest in determining whether the therapeutic benefit of PARP inhibitors in BRCAassociated breast cancer can be translated to TNMBC. In a Phase II trial to test this hypothesis, O Shaughnessy et al enrolled 123 patients with TNMBC who had previously received 2 or fewer prior lines of chemotherapy in the metastatic setting. 11,12 Patients were randomized to receive either gemcitabine 1,000 mg/m 2 and carboplatin (GC) to an area under the curve of 2 on days 1 and 8 of a 21-day cycle, or GC with the IV PARP inhibitor iniparib (BSI-201; Sanofi-aventis) at a dose of 5.6 mg/kg on days 1, 4, 8, and 11, of a 21-day cycle (GCI). End points were ORR, CBR, PFS, and OS. Preliminary results of this trial (86 of planned 120 patients) were presented at ASCO 2009, 11 and final 32

5 results (123 patients) were presented at ESMO Overall, comparing the preliminary results with the final results, the magnitude of difference in the results between the GC and GCI arms is reduced, as reflected by higher but still statistically significant P values. The addition of iniparib to chemotherapy was well tolerated; safety profiles were comparable between the 2 arms. Although these Phase II results were promising, Sanofi-aventis reported in late January that the Phase III randomized trial further investigating this treatment strategy in the same treatment arms failed to meet the prespecified criteria for significance for the primary end points of OS and PFS. 16 The company noted, however, that the results of a prespecified analysis in patients treated in the second- and third-line setting did show improvement in OS and PFS that was consistent with the results of the Phase II study. The full Phase III results are expected to be presented at the 2011 ASCO meeting. Eribulin: A Novel Microtubule Inhibitor Targeting microtubule dynamics of cancer cells is an approach that has been used with many existing cancer therapies, including vinca alkaloids, taxanes, and epothilone B analogs such as ixabepilone (Ixempra, Bristol-Myers Squibb). The newest addition to this general group is eribulin (E7389; Halaven, Eisai), a synthetic analog of the marine sponge halichondrin B (Figure 2). Eribulin inhibits microtubule growth by binding to tubulin and inhibiting microtubule polymerization; this results in cell cycle G2-M arrest. 17 In EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician s Choice Versus Eribulin E7389), a Phase III open-label study, women with advanced breast cancer who had received 2 to 5 prior chemotherapy regimens (including an anthracycline and a taxane unless contraindicated), with at least 2 of these prior lines of chemotherapy being in the setting of advanced disease, were randomized in a 2-to-1 fashion to receive either eribulin (1.4 mg/m 2 IV on days 1 and 8 of a 21-day cycle) or treatment of physician s choice (TPC). 18 The primary objective of this study was analysis of OS with secondary objectives including ORR, PFS, and safety. Median OS was 13.1 months for patients treated with eribulin versus 10.7 months for patients in the TPC group; this corresponds to an overall improvement in OS of 2.5 months (HR, 0.81; 95% CI, ; P=0.04). Regarding PFS by independent review, the eribulin group had improved PFS, 3.7 months versus 2.3 months, but this difference was not statistically significant (HR, 0.85; 95% CI, ; P=0.09). Grade 3/4 toxicities associated with eribulin use included fatigue (7.6%), neutropenia (44%), and peripheral neuropathy (8.4%). In summary, this study met the primary objective by demonstrating improved OS with eribulin compared with TPC. One caveat to interpretation of EMBRACE is the nonstandard design using TPC as the control arm. An advantage of this design is that there is no customary accepted sequence of chemotherapy agents to use in the advanced setting. Additionally, this design enabled enrollment of variably but heavily pretreated women with advanced breast cancer. A disadvantage of this design is that it is impossible to compare eribulin with one chemotherapy agent or regimen. The only conclusion to be made is that eribulin outperformed TPC; it is unclear how appropriate TPC was on a patient-by-patient basis. Antiangiogenic Therapies SUNITINIB Sunitinib (Sutent, Pfizer), an orally available multitargeted receptor TKI with activity that inhibits vascular endothelial growth factors (VEGFR1, VEGFR2, VEGFR3) and platelet-derived growth factors (PDGFRα, PDGFRβ), was recently investigated as combination therapy for advanced breast cancer in combination with capecitabine (Xeloda, Genentech) in SUN 1099 and with docetaxel (Taxotere, Sanofi-aventis) in SUN ,20 SUN 1099 was a multicenter, randomized Phase III Halichondrin B E7389 Figure 2. Structures of marine sponge halichondrin B and eribulin (E7389). 33

6 trial that enrolled 422 women with heavily pretreated advanced breast cancer (2 or more lines of therapy in the advanced setting), who had received prior therapy with both an anthracycline and a taxane in any setting,to receive either oral capecitabine alone (2,500 mg/ m 2 per day, days 1-14 of a 21-day cycle) or combination therapy consisting of oral capecitabine (2,000 mg/m 2 per day, days 1-14 of a 21-day cycle) plus oral sunitinib (37.5 mg daily). 19 The primary end point of SUN 1099 was PFS, with secondary outcomes of OS and ORR. For all outcomes of interest, the study arms were statistically equivalent; for the capecitabine-alone arm versus the combination therapy arm, the results were as follows: PFS, 5.9 versus 5.5 months; OS, 16.5 versus 16.4 months; ORR, 16.3% versus 18.6%. Regarding safety and tolerability, grade 3/4 AEs (including neutropenia, thrombocytopenia, asthenia, and fatigue) and discontinuation of therapy also were more common in the combination arm. In summary, results from SUN 1099 do not support combined use of capecitabine and sunitinib in the treatment of advanced breast cancer. Whereas SUN 1099 studied women with heavily pretreated advanced breast cancer, SUN 1064 investigated the efficacy of chemotherapy (docetaxel), with or without sunitinib, as first-line therapy for advanced breast cancer. 20 SUN 1064 was a Phase III open-label study that randomized 593 patients to either IV docetaxel alone (100 mg/m 2 every 3 weeks) or combination therapy with IV docetaxel (75 mg/m 2 every 3 weeks) and oral sunitinib (37.5 mg daily on days 2-15 of a 21-day treatment cycle). Of note, if docetaxel was discontinued for any reason other than progressive disease among those in the combination arm, sunitinib could be continued as monotherapy until disease progression. The primary end point, PFS, was not met, with comparable median PFS results of 8.3 months in the docetaxel arm versus 8.6 months in the combination arm. As a secondary end point, OS also was equivalent: 25.5 months in the docetaxel arm versus 24.8 months in the combination arm. However, ORR was significantly improved in the combination arm: 51% versus 39% (P=0.0018). Based on these findings, with superior results seen only for ORR, the authors did not endorse the regimen of docetaxel and sunitinib as a viable option for the first-line treatment of advanced breast cancer. AVASTIN E2100 was a Phase III open-label trial that randomized 722 patients to first-line therapy consisting of either weekly paclitaxel alone (90 mg/m 2 on days 1, 8, and 15 of a 28-day treatment cycle) or paclitaxel plus bevacizumab (Avastin, Genentech; 10 mg/kg on days 1 and 15). 21 E2100 reported significantly improved PFS and ORR in the combination arm: 11.8 versus 5.9 months and 36.9% versus 21.2%, respectively. However, OS was similar between the 2 groups: 26.7 months for the combination and 25.2 months for paclitaxel alone. Based on the results from E2100, specifically a doubling of PFS, bevacizumab was granted accelerated approval in February 2008 for combination use with paclitaxel in the treatment of patients with advanced breast cancer. At the time, this original decision had been controversial, with opponents of the approval stating that no improvement in OS was seen with the addition of the drug. Later trials using bevacizumab with chemotherapy in the treatment of advanced breast cancer, including AVADO (AVastin plus Docetaxel) and RIBBON-1 (Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Chemotherapy With or Without Bevacizumab for First-Line Treatment of HER2-Negative Locally Recurrent or Metastatic Breast Cancer), did not replicate the impressive improvement in PFS seen in E2100 and also did not show any improvement in OS. 22,23 Based on analysis of these trials, suggesting limited benefit of bevacizumab as well as significant risks associated with its use, such as hypertension, bleeding, perforations, and heart disease, in December 2010 the FDA recommended removing the drug s breast cancer indication. Of note, the FDA does endorse ongoing research to attempt to identify a possible subset of breast cancer patients who may derive more significant benefit from bevacizumab. Ongoing trials examining the use of bevacizumab for breast cancer patients in the neoadjuvant and adjuvant settings will continue. Treatment for Bony Metastases The most common site of metastasis in advanced breast cancer is bone, with the most serious complications being skeletal-related events (SREs). SREs are defined to include pathologic fracture, the need for radiation or surgery to bone, and spinal cord compression. The most common treatment to prevent complications of bone metastases, including SREs, pain, and hypercalcemia, consists of either oral or IV bisphosphonates, a class of drugs that function by inhibiting osteoclast activity, thereby slowing bone loss. Denosumab (Xgeva, Amgen), a fully human mab against the receptor activator of nuclear factor-κb ligand (RANKL), uses a completely separate mechanism of action. Tumor cells in the bone release growth factors that activate osteoblasts to release RANKL. Meanwhile, RANKL stimulates osteoclasts to break down bone, and in this destructive process more growth factors are released that promote tumor cell growth. By inhibiting RANKL, denosumab breaks this vicious cycle of bone destruction and tumor cell proliferation (Figure 3). 24 In a recent Phase III double-blind, double-dummy trial, Stopeck et al randomized 2,046 patients to either denosumab at a dose of 120 mg subcutaneously every 4 weeks (with IV placebo) or zoledronic acid (Zometa, Novartis) at a dose of 4 mg IV every 4 weeks (with subcutaneous placebo). 25 The primary study objective was the time to first on-study SRE, with additional study objectives being time to first and subsequent (multiple) on-study SREs, OS, disease progression, and safety. Denosumab significantly increased the time to first on-study SRE (HR, 0.82; 95% CI, ; P=0.01), corresponding to an 18% reduced risk compared with zoledronic acid. The median time to first on-study SRE was 26.4 months in the zoledronic acid 34

7 Tumor cell Tumor cell Preosteoclast PTHrP IL-1, IL-6, IL-8 PGE 2 TNF M-CSF Denosumab RANKL RANK Differentiation PTHrP BMP PDGF FGFs IGFs TGF-β Osteoblast RANK Osteoclast Osteoclast in apoptosis Tumor cell Denosumab: Binds to RANKL and neutralizes its activity Reduces osteoclast activity and bone resorption Bone Bisphosphonates: Inhibit tumor cell adhesion to bone Inhibit osteoclast activity Induce osteoclast apoptosis Figure 3. Mechanisms of action for denosumab and the bisphosphonates. Tumor cells secrete a number of cytokines and factors that stimulate osteoblast production of RANKL, which binds to RANK on the suface of osteoclasts. This leads to osteoclast differentiation, activation, and survival, creating osteolytic lesions. Bone resorption releases factors such as BMP, PDGF, FGF, IGF, and TGF-β, which, in turn, stimulate production of PTHrP from tumor cells. Agents such as denosumab and bisphosphonates can interrupt this cycle and reduce osteoclast activity. BMP, bone morphogenic protein; FGF, fibroblast growth factors; IGF, insulin-like growth factors; IL, interleukin; M-CSF, macrophage colony-stimulating factor; PGE 2, prostaglandin E2; PTHrP, parathyroid hormone-related peptide; RANK, receptor activator of nuclear factor-κb; RANK-L, receptor activator of nuclear factor κb ligand; TGF, transforming growth factor; TNF, tumor necrosis factor Adapted from reference 24 with permission American Society of Clinical Oncology. All rights reserved. arm, whereas the median time to first on-study SRE has not yet been reached in the denosumab arm. The time to multiple SREs also was superior in the denosumab arm (HR, 0.77; 95% CI, ; P=0.001), corresponding to a 23% risk reduction. There were no differences noted between the arms with respect to OS or disease progression. Regarding safety, renal AEs and acute-phase reactions were more common with zoledronic acid (8.5% vs 4.9% and 27.3% vs 10.4%, respectively), whereas hypocalcemia was more common with denosumab (5.5% vs 3.4%). Of note, the rates of osteonecrosis of the jaw were comparable between the groups (2% for denosumab and 1.4% for zoledronic acid). The authors conclude that improved time to SREs, comparable tolerance, and the ease of subcutaneous injections with no need for renal monitoring makes denosumab another viable option for treatment of women with advanced breast cancer metastatic to bone. Conclusions Treatment of advanced breast cancer increasingly is based on defining subgroups of patients who are more likely to respond to a given therapy. In the clinic, classical markers such as ER, PR, and HER2 status commonly define these subgroups. In the research setting, more advanced genomic techniques, such as intrinsic subtyping, are used to characterize and treat populations of breast cancer patients. 15 In the past few years, advances in clinical research have yielded several significant improvements in the care of patients with advanced breast cancer, including new treatment targets and new therapies. Mature results from several of the Phase II trials reviewed above, as well as follow-up Phase III trials, will help define these benefits in larger populations in more detail. References 1. Amir E, Clemons M, Freedman OC, et al. Tissue confirmation of disease recurrence in patients with breast cancer: pooled analysis of two large prospective studies. J Clin Oncol. 2010:28(15 suppl): Abstract Robertson JFR, Lindemann JPO, Llombart-Cussac A, et al. A comparison of fulvestrant 500 mg with anastrozole as first-line treatment for advanced breast cancer: follow-up analysis from the FIRST study. Presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX. Abstract S

8 3. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008:26(10): , PMID: Bachelot T, Bourgier C, Cropet C, et al. TAMRAD: a GINECO randomized phase II trial of everolimus in combination with tamoxifen versus tamoxifen alone in patients (pts) with hormonereceptor positive, HER2 negative metastatic breast cancer (MBC) with prior exposure to aromatase inhibitors (AI). Presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX. Abstract S Kaufman PA, Ferrero JM, Bourgeois H, et al. A randomized, double-blind, placebo-controlled, phase 2 study of AMG 479 with exemestane (E) or fulvestrant (F) in postmenopausal women with hormone-receptor positive (HR+) metastatic (M) or locally advanced (LA) breast cancer (BC). Presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX. Abstract S Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2 positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 2010:28(7): , PMID: Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible erbb receptor tyrosine kinase inhibitor, in patients with advanced erbb2-positive breast cancer. J Clin Oncol. 2010:28(8): , PMID: Perez EA, Dirix L, Kocsis J, et al. 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