- Email: [email protected]
Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients
original articles
Annals of Oncology 25. Simon R, Wittes RE, Ellenberg SS.Randomized phase II clinical trials. Cancer Treat Rep 1985; 69(12): 1375–1381. 26. Cannistra S, Matulonis UA, Penson RT et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer. J Clin Oncol 2007; 25(33): 5180–5186. 27. Gordon AN, Fleagle JT, Guthrie D et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 2001; 19(14): 3312–3322. 28. Taran A, Ignatov A, Smith B et al. Acute hepatic failure following monotherapy with sunitinib for ovarian cancer. Cancer Chemother Pharmacol 2009; 63(5): 971–972.
29. Tillmanns TD, Lowe MP, Schwartzberg LS et al. A phase II study of bevacizumab with nab-paclitaxel in patients with recurrent, platinum-resistant primary epithelial ovarian or primary peritoneal carcinoma. J Clin Oncol 2010; 28: 15s. (Abstr 5009). 30. Sweeney C, Chiorean EG, Verschraegen CF et al. A phase I study of sunitinib plus capecitabine in patients with advanced solid. J Clin Oncol 2010; 28(29): 4513–4520. 31. Robert F, Sandler A, Schiller JH et al. Sunitinib in combination with docetaxel in patients with advanced solid tumors: a phase I dose-escalation study. Cancer Chemother Pharmacol 2009; 66(4): 669–680.
Annals of Oncology 23: 2271–2277, 2012 doi:10.1093/annonc/mdr612 Published online 1 March 2012
E.-F. Solomayer1*, G. Gebauer2, P. Hirnle3, W. Janni4, H.-J. Lück5, S. Becker1, J. Huober6, B. Krämer1, B. Wackwitz7, D. Wallwiener8 & T. Fehm1 1 Department of Obstetrics, Gynecology, and Reproductive Medicine, University of Saarland, Homburg; 2Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg; 3Department of Radiation Oncology, Central Academic Hospital, Bielefeld; 4Department of Gynecology and Obstetrics, Heinrich-Heine University, Düsseldorf; 5Department of Gynecologic Oncology, Hannover Medical School, Hannover, Germany; 6Breast Center, Department of Senologie, Kantonsspital St. Gallen, St. Gallen, Switzerland; 7Norvartis Oncology, Department of Medical Affairs, Nuremberg; 8Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany
Received 10 August 2011; revised 5 December 2011; accepted 12 December 2011
Background: The presence of disseminated tumor cells (DTCs) in bone marrow of patients with early breast cancer (EBC) has been correlated with increased risk of metastatic disease or locoregional relapse. Zoledronic acid (ZOL) treatment has reduced DTCs in the bone marrow of patients with EBC in several studies. This controlled study sought to confirm these observations. Patients and methods: Patients with EBC and DTC-positive bone marrow were randomized (N = 96) to treatment with ZOL plus adjuvant systemic therapy or adjuvant systemic therapy alone. The change in DTC numbers at 12 months versus baseline was measured. Results: DTC-positive patients treated with ZOL were more likely to become DTC-negative after 12 months of treatment compared with the controls (67% versus 35%; P = 0.009). At 12 months, DTC counts decreased to a mean of 0.5 ± 0.8 DTCs in the ZOL group and to 0.9 ± 0.8 DTCs in the control group. In addition, ZOL was generally well tolerated. Conclusions: Treatment with ZOL improves elimination of DTCs. Further studies are needed to determine whether the reduction in DTCs by ZOL provides clinical benefit. Key words: breast cancer, disseminated tumor cells, metastasis, recurrence, zoledronic acid
introduction Breast cancer (BC) is the most common solid tumor in women [1]. Metastatic disease is the predominant cause of death in the ∼465 000 patients who succumb to this disease [1]. Despite therapeutic interventions, ∼15% develop distant metastases within 3 years [2]. Furthermore, patients may have late
*Correspondence to: Prof. Dr E.-F. Solomayer, Department of Obstetrics, Gynecology, and Reproductive Medicine, University of Saarland, Kirrberger Strasse, 66421 Homburg/Saar, Germany. Tel: + 49-6841-162-8100; Fax: + 49-6841-162-8110; E-mail: [email protected]
recurrence (‘metastatic dormancy’) ≥10 years after initial diagnosis [2]. Common sites of BC metastasis include bone, lung, and brain [2, 3], of which bone is the most common site (∼75% of cases) [4]. Distant metastasis is associated with poor prognosis [4, 5]. The hypothesis that recurrent/metastatic disease is initiated by micrometastases has gained wide acceptance. Disseminated tumor cells (DTCs) can be sequestered in a dormant state in the bone marrow for several years before reactivating to cause disease recurrence [6]. The most compelling clinical evidence comes from a retrospective pooled analysis of patients with BC (N = 4703) wherein patients with DTC-positive bone marrow
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Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients
original articles
patients and methods patients Eligible patients were female, ≥18 years of age, with primary BC ( pT1-4, N1-2, M0) and initiated study treatment within 42 days of completing primary tumor resection and axillary lymph node dissection. All enrolled patients had minimal residual disease composed of DTC in bone marrow, per the ‘Clinical Assessments’ section below, and were to receive adjuvant therapy (hormonal, cytotoxic, or both). All patients provided written informed consent before initiation of any study-specific procedures. The study was approved by the Ethics Committee at all participating institutions. Patients were excluded if they had inflammatory, metastatic, or recurrent BC or a history of BC before the most recent BC diagnosis, creatinine clearance < 30 ml/min, current active dental problems or trauma, or a current or prior diagnosis of
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osteonecrosis of the jaw (ONJ). Neoadjuvant chemotherapy was not permitted.
study design and treatment In this parallel-group, open-label, multicenter study patients were prospectively stratified on the basis of six predefined strata: two nodal-status categories ( positive, negative) by three adjuvant-treatment categories (chemotherapy, hormonal therapy, chemotherapy plus hormonal therapy). Patients were then randomized 1 : 1 to adjuvant therapy alone (control) or with intravenous ZOL every 4 weeks for 24 months (Figure 1), the dose and schedule approved for the prevention of skeletal-related events in patients with bone metastases [16]. Per the approved label, ZOL dosing was guided by creatinine clearance [16]. The primary end point was the effect of ZOL on DTC counts after 12 months. Secondary end points at 24 months included safety; changes in DTC counts versus baseline; bone metastasis-free survival, which included death from any cause or bone metastasis; and DFS, which included death from any cause or disease recurrence at any site. Correlative analyses of change in DTC counts with tumor–node–metastasis stage, estrogen- and progesterone-receptor status, and menopause status were planned. This clinical study was designed, implemented, and reported in accordance with the International Good Clinical Practice Guidelines, with applicable local regulations [17, 18] and with the ethical principles in the Declaration of Helsinki.
clinical assessments Bone marrow aspirates for DTC assessment were obtained at baseline, 12 months, and 24 months after initiating study. After baseline and treatment initiation (month 0) visits, eight additional study visits at 3-month intervals were planned. Clinical assessments at each visit included serum biochemistry, hematology, Eastern Cooperative Oncology Group performance status, and physical examination. There was continuous adverse event (AE) monitoring and follow-up scans for skeletal and nonskeletal lesions as clinically indicated. Patients were assessed using X-rays, magnetic resonance imaging, or computed tomography scans for suspected bone metastases. Serum creatinine was monitored before each ZOL infusion. Assessments of DTCs were conducted as previously described [19]. For the quantitation of DTCs, 2 × 106 cells were analyzed on two slides per patient. Slides were automatically scanned using the ACIS™ imaging system (ChromaVision, Medical Systems Inc., San Juan Capistrano, CA), as described elsewhere [20]. Criteria for detection of DTCs were based on European ISHAGE Working Group recommendations [19]. Slides were centrally evaluated by two independent blinded observers. Nonconcordant results were evaluated by a third investigator.
statistical assessments No formal hypothesis was tested for statistical significance; thus, the sample size of this trial was determined by feasibility considerations. The safety population included all patients who received at least one dose of study medication and all patients
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(n = 1438) had an approximately twofold increased risk of death versus DTC-negative patients (P < 0.001) [7]. Similarly, a recent study showed that detection of DTCs in patients with early breast cancer (EBC) (N = 655) correlated with reduced distant metastasis-free survival (P = 0.0013) and reduced overall survival (P = 0.005) [8]. Furthermore, at a median follow-up of 56 months in these patients, DTC status was the only significant prognostic factor for locoregional recurrencefree survival in a multivariate analysis (odds ratio = 5.2; P = 0.0005) [9]. These data suggest that DTC status in EBC correlates with risk of distant metastasis, locoregional recurrence, and death [9]. Moreover, in a recent study (N = 120), chemotherapy did not effectively eradicate DTCs in EBC patients [10]. Bone marrow DTCs persisted in ∼36% of patients despite complete response to primary therapy [10]. Therefore, alternative therapeutic options that improve elimination of DTCs may reduce the risk of recurrence and improve survival in EBC. Recently, zoledronic acid (ZOL; 4 mg every 6 months) significantly prolonged disease-free survival (DFS) and relapse-free survival versus no ZOL or delayed use of ZOL in EBC patients undergoing adjuvant hormonal therapy in ABCSG-12 and ZO-FAST (large, randomized, controlled trials) [11, 12]. A possible underlying mechanism of action is that ZOL reduced disease recurrence by suppressing/eliminating DTCs. Indeed, Aft et al. [13] demonstrated that DTC-free BC patients treated with ZOL (4 mg every 3 weeks) were more likely to remain DTC free at 3 months (P = 0.03) and that the subset of patients with estrogen receptor-negative and epidermal growth factor receptor-2-negative disease were more likely to have pathologic complete response with ZOL versus no ZOL. In small studies, ZOL (4 mg/month) increased the proportion of DTC-free patients who remained DTC-free at 6 months versus no ZOL [14] and significantly decreased DTC levels versus baseline at 12 (P < 0.0006) and 24 months (P = 0.0026) [15] in DTC-positive BC patients. Therefore, it is reasonable to hypothesize that ZOL may delay disease recurrence. However, the effects of ZOL on DTCs had not been evaluated in a randomized controlled study.
Annals of Oncology
Annals of Oncology
original articles
in the control group. Efficacy analysis was performed on the modified intent-to-treat (mITT) population composed of all patients in the safety population with at least one post-baseline measurement of DTCs. A per-protocol analysis was performed using all mITT patients who did not have major protocol deviations that might have affected study outcome. These criteria were prospectively defined and documented before analysis. Because of the small sample size and the number of predefined strata, only descriptive analysis was performed. Simple statistics were performed for the number of DTCs and the relative and absolute change from baseline values by treatment group. Significance analysis of categorical variables was done using Fisher’s exact test. Additionally, an analysis of covariance was performed using absolute differences in DTC counts as the dependent variable and baseline DTC number, treatment, center, and stratum as independent variables. Worstcase values for the respective strata were imputed for missing values for baseline DTCs. Missing values at month 12 were imputed with 24-month data, if available. Otherwise, worst-case values for the respective strata were imputed. AEs were coded by MedDRA and analyzed using absolute and relative frequencies.
results patients A total of 96 patients were randomized at four study centers in Germany. Data for the primary end point, DTCs at baseline
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and 12 and/or 24 months, were available for 76 patients (adjuvant therapy plus ZOL, n = 39; control, n = 37) who, by definition, constituted the mITT population (Figure 1). Most patients (59%) had stage I disease, 84% were node negative, 39% had received adjuvant hormonal therapy, and 43% had received adjuvant hormonal therapy plus chemotherapy. Baseline characteristics were well balanced between arms among mITT patients (Table 1). At the time of database closure, 64 (ZOL, 30; control, 34) patients (67%) completed the 24-month study as planned, 4 (ZOL, 3; control, 1) patients (4%) completed 12 months, and 28 (ZOL, 11; control, 17) patients (30%) discontinued before receiving all study medication. The most common reason for discontinuation was withdrawal of consent for the multiple bone marrow biopsies (ZOL, 9; control, 11). As a result, values for the primary variable were available for only 40% of patients.
efficacy assessments Efficacy assessments were conducted in the mITT population as described in the methods. For the control group, the baseline mean DTC count was 2.9 ± 5.5 (median, 2.0; range, 1–35 cells), which decreased to a mean of 0.9 ± 0.8 DTCs (median, 1.0; range, 0–2 cells) at 12 months (Figure 2). For the ZOL group, the baseline mean DTC count was 2.1 ± 1.1 (median, 2.0; range, 1–6 cells), which decreased to a mean of 0.5 ± 0.8 DTCs (median, 0.0; range, 0–2 cells) at 12 months.
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Figure 1. Study design. AEs, adverse events; q, every; ZOL, zoledronic acid.
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Annals of Oncology
Table 1 Patient demographics and baseline characteristics Efficacy evaluable ZOL Control group group (n = 39) (n = 37)
54 (27–77)
54 (36–71)
54 (37–72)
94 (98) 1 (1) 1 (1) 70 (47–105)
38 (97) 0 1 (3) 70 (54–105)
36 (97) 1 (3) 0 69 (50–95)
37 (39) 59 (61)
14 (36) 25 (64)
13 (35) 24 (65)
80 (83) 16 (17) 0 (0–5)
33 (85) 6 (15) 0 (0–5)
33 (89) 4 (11) 0 (0–5)
79 (82) 17 (18) 17 (1–55)
34 (87) 5 (13) 19 (6–50)
30 (81) 7 (19) 20 (2–55)
57 (59) 24 (25) 11 (12) 3 (3) 1 (1)
25 (64) 8 (21) 4 (10) 2 (5) 0
22 (60) 9 (24) 5 (14) 0 1 (3)
1 (1) 6 (6) 74 (77) 15 (16)
1 (3) 3 (8) 28 (72) 7 (18)
0 3 (8) 29 (78) 5 (14)
78 (81) 18 (19)
32 (82) 7 (18)
29 (78) 8 (22)
63 (66) 33 (34)
26 (67) 13 (33)
23 (62) 14 (38)
25 (26) 70 (73) 1 (1) 2 (1–35)
11 (28) 28 (72) 0 2 (1–6)
11 (30) 26 (70) 0 2 (1–35)
Figure 2. Mean DTCs at 0 months (baseline), 12 months, and 24 months in ZOL-treated patients and control patients. DTC, disseminated tumor cell; ZOL, zoledronic acid.
could not be imputed into the model because of missing baseline data. In the per-protocol population (n = 21), all 9 ZOL-treated patients (100%) and 8 of 12 control-group patients (67%) transitioned to DTC-negative status. At the 24-month follow-up, a mean of 0.4 ± 0.8 DTCs (median, 0.0; range, 0–2 cells) were detected in the ZOL group compared with 0.7 ± 0.9 DTCs (median, 0.0; range, 0–2 cells) in the control group. Consistent with the 12-month analysis, ZOL treatment reduced the number of DTCs at 24 months (difference in the least-squares means of − 0.3), although the difference fell short of statistical significance (P = 0.056). No significant differences were detectable in the change in DTC levels among subsets of patients grouped by stratification factors used at enrollment or using other prognostic factors, primarily because of the small sample numbers. However, in an exploratory analysis of DTC change by menopausal status, it was noted that decline in DTCs from baseline was similar in the control and ZOL arms at months 12 and 24 in premenopausal women (13 evaluable patients in each arm). In contrast, the decline in DTC levels in postmenopausal women (24 and 22 evaluable patients for the ZOL and control arms, respectively) receiving ZOL treatment was slightly higher at months 12 and 24 (−73% versus −53% at month 12 and
ECOG PS, Eastern Cooperative Oncology Group performance status; DTC, disseminated tumor cell.
The least-squares means change from baseline to 12 months was −1.9 for the ZOL group and −1.6 for the control group, although the between-group difference (0.3) did not reach statistical significance (P = 0.066). Furthermore, DTC-positive patients treated with ZOL were significantly more likely to become DTC negative at 12 months compared with the control group (P = 0.009; Figure 3). In two patients per group, data
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Figure 3. In patients with DTC-positive bone marrow at baseline, proportion who remained DTC-positive at 12 months. DTC, disseminated tumor cell; ZOL, zoledronic acid.
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Age, median years (range) Race, n (%) Caucasian Black Oriental Weight, median kg (range) Menopausal status, n (%) Premenopausal Postmenopausal ECOG PS, n (%) 0 1 Time since first diagnosis, median months (range) Most radical type of surgery, n (%) Breast conserving Ablative Tumor size (largest diameter), median mm (range) Disease stage, n (%) Stage I Stage IIA Stage IIB Stage IIIA Stage IIIB Tumor grade, n (%) Grade x Grade 1 Grade 2 Grade 3 Estrogen-receptor status, n (%) Positive Negative Progesterone-receptor status, n (%) Positive Negative HER-2/neu status, n (%) Positive Negative Unknown DTCs in bone marrow, median (range)
Total (N = 96)
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Annals of Oncology Table 2 Most frequently reported treatment-emergent adverse eventsa by MedDRA-preferred term Adverse eventb
Control (N = 52), n (%)
Total (N = 96), n (%)
33 (75) 24 (55) 24 (55) 29 (66) 18 (41) 14 (32) 15 (34) 14 (32) 16 (36) 18 (41) 15 (34) 15 (34) 18 (41) 14 (32) 12 (27) 15 (34) 10 (23) 9 (20) 12 (27) 5 (11) 11 (25) 11 (25) 9 (20) 11 (25) 10 (23)
19 (37) 25 (48) 21 (40) 14 (27) 21 (40) 19 (37) 18 (35) 16 (31) 14 (27) 12 (23) 14 (27) 10 (19) 7 (13) 10 (19) 12 (23) 8 (15) 11 (21) 11 (21) 6 (12) 12 (23) 6 (12) 6 (12) 7 (13) 3 (6) 0
52 (54) 49 (51) 45 (47) 43 (45) 39 (41) 33 (34) 33 (34) 30 (31) 30 (31) 30 (31) 29 (30) 25 (26) 25 (26) 24 (25) 24 (25) 23 (24) 21 (22) 20 (21) 18 (19) 17 (18) 17 (18) 17 (18) 16 (17) 14 (15) 10 (10)
Adverse events with an incidence of ≥20% at preferred term level in either treatment group are displayed. b Adverse events are sorted by frequency. ZOL, zoledronic acid. a
−83% versus −66% at month 24) compared with postmenopausal women in the control arm. At the time of database closure, no patients had died or developed bone metastases, and few patients had discontinued the study for medical reasons. Therefore, the secondary end points of bone metastasis-free survival and DFS and the number and location of bone metastases were not evaluable.
safety Patients in the ZOL group were treated for a mean of 21 ± 6 months (range, 1–26 months), with a mean observation period of 20 ± 9 months (range, 1–29 months) in the control group and 21 ± 6 months (range, 1–26 months) in the ZOL group. Among the most common AEs associated with ZOL were arthralgia, myalgia, and pyrexia, reflecting the known flu-like acute phase reaction that can occur, typically after the first infusion. Fatigue and neutropenia were most common in the control group (Table 2). Most (66%) AEs in the ZOL group were grade 1 or 2. The most frequent grade 3 events were hematologic: grade 3 neutropenia (ZOL, 11%; control, 23%) and grade 3 leukopenia (ZOL, 6%; control, 7%). Only two patients in the ZOL arm [wound infection and bone pain (one
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discussion This was the first prospective, randomized controlled study evaluating the effects of ZOL on DTCs in patients with EBC. Although DTC levels at 12 and 24 months were reduced versus baseline in both treatment groups, patients treated with ZOL trended toward a greater decrease in DTC counts versus control at 12 (P = 0.066) and 24 months (P = 0.056). Moreover, a significantly higher proportion of patients were DTCnegative at 12 months in the ZOL group versus control (P = 0.009), suggesting effective DTC elimination by ZOL, although 24-month data were limited. In the recent report by Aft et al. [13], chemotherapy alone also was not as effective as chemotherapy with concomitant ZOL for maintaining DTCnegative status. Moreover, chemotherapy alone had no discernible effect on DTC status in DTC-positive patients [13]. The enhanced reduction of DTCs with ZOL may be the result of anticancer effects of ZOL or anticancer synergy between ZOL and agents used for adjuvant therapy. Indeed, preclinical and clinical data have provided evidence of antitumor synergy between chemotherapeutic agents and ZOL [21, 22]. Regardless of the mechanistic basis for the reduction/ elimination of DTCs, it may be speculated that the reduction of DTCs by ZOL treatment may, in part, contribute to the significant improvements in DFS with ZOL reported in adjuvant clinical trials in EBC [13–15]. Overall, treatment with ZOL was generally well tolerated, and there were few treatment discontinuations because of AEs (<10% in both groups). The detection of DTCs correlates significantly with increased risks of visceral and bone metastasis, locoregional recurrence, and death in BC patients [7, 9]. Therefore, treatments that eliminate or reduce DTCs in bone marrow may potentially decrease risk of recurrent or metastatic disease and improve survival. Indeed, reduced risks of recurrent disease were reported in clinical trials exploring ZOL as adjuvant therapy in EBC patients. In ABCSG-12, the addition of ZOL to endocrine therapy (goserelin with tamoxifen or anastrozole) for 3 years in younger women with early EBC and treatment-induced menopause (N = 1803) significantly improved DFS by 36% (log-rank P = 0.01) and recurrence-free survival by 35% (logrank P = 0.01 for both) relative to no ZOL [12]. At a median follow-up of 48 months, ZOL also produced a trend toward a 40% lower risk of death versus no ZOL (log-rank P = 0.11) [12]. Moreover, ZOL-treated patients had numerically fewer locoregional (20 versus 10) and distant (41 versus 29) recurrences and contralateral disease events (10 versus 6) versus hormonal therapy alone. Furthermore, at the 36-month analysis of ZO-FAST (N = 1064) in postmenopausal women
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Arthralgia Nausea Alopecia Myalgia Constipation Fatigue Mucosal inflammation Stomach discomfort Anorexia Cough Dyspnea Lacrimation increased Headache Pyrexia Hot flush Nasal dryness Nasopharyngitis Menopausal symptoms Dysesthesia Neutropenia Diarrhea Vomiting Dermatitis Onychoclasis Conjunctivitis
ZOL (N = 44), n (%)
patient each)] and three patients in the control arm [osteopenia, osteoporosis, and metastasis to lymph nodes (one patient each)] discontinued treatment because of an AE. There was one case of ONJ in a patient with completely normal dental health prior to developing ONJ 576 days after the start of study medication and lasting 207 days, necessitating prolonged hospitalization, the administration of concomitant medication, and nondrug therapy. This patient also developed moderate osteomyelitis lasting 27 days, which started 756 days after initiating study medication.
original articles
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Nonetheless, this study provides important insight into the effects of ZOL on DTCs within the bone marrow. In conclusion, the results from the current trial are consistent with the antitumor properties of ZOL demonstrated in numerous preclinical studies [27]. Elimination of DTCs by ZOL, as reported in our study, may have profound implications for long-term disease outcomes and survival by reducing the risk of early or late recurrence in patients with BC. Extended follow-up will provide further insight into the clinical benefit of ZOL treatment in this setting. However, additional studies are needed to investigate the role of DTCs in disease progression.
acknowledgements We thank Jerome F. Sah, PhD, ProEd Communications, Inc.®, for his medical editorial assistance with this manuscript.
funding This work was supported by a research grant from Novartis Pharmaceuticals Corporation (ZOL-MRD 001). Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.
disclosure Dr EFS has received honoraria from Novartis, Roche, and AstraZeneca, and research grants from Roche. Dr WJ has received lecture honoraria and research grants from Novartis. Dr H-JL has received lecture honoraria from Roche, Novartis, Sanofi, GlaxoSmithKline, and Pfizer, and is an advisory board member for Roche, Novartis, Pfizer, Fresenius, and BMS. Dr JH has received lecture honoraria from Novartis, and is an advisory board member for Roche, Novartis, and Amgen. Dr TF has received honoraria from Roche, Novartis, and AstraZeneca, and research grants from Roche. Dr BW is employed by Novartis. Dr DW has received research grants from Novartis and Roche. Drs GG, PH, SB, and BK have declared no conflict of interest.
references 1. Garcia M, Jemal A, Ward EM et al. Global Cancer Facts & Figures 2007. Atlanta, GA: American Cancer Society 2007. 2. Psaila B, Kaplan RN, Port ER, Lyden D. Priming the ‘soil’ for breast cancer metastasis: the pre-metastatic niche. Breast Dis 2006; 26: 65–74. 3. Solomayer EF, Diel IJ, Meyberg GC et al. Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat 2000; 59: 271–278. 4. Coleman RE. Skeletal complications of malignancy. Cancer 1997; 80: 1588–1594. 5. Moreno-Aspitia A, Perez EA. Treatment options for breast cancer resistant to anthracycline and taxane. Mayo Clin Proc 2009; 84: 533–545. 6. Shiozawa Y, Havens AM, Pienta KJ, Taichman RS. The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites. Leukemia 2008; 22: 941–950. 7. Braun S, Vogl FD, Naume B et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 2005; 353: 793–802.
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receiving letrozole as adjuvant therapy for EBC, upfront use of ZOL (4 mg every 6 months) significantly improved DFS by 41% (P = 0.0314) versus using ZOL only after clinically relevant bone loss was detected (delayed ZOL) [11]. Consistent DFS benefits were reported in an integrated analysis of ZOFAST and a similarly designed trial (Z-FAST; N = 1667) [11, 23]. Consistent with ABCSG-12, the upfront-ZOL group had reduced rates of disease recurrence at both local and distant sites (both within and outside bone) [11]. However, because bone marrow biopsies were not obtained, the effects of ZOL on DTCs in these studies are unknown. Furthermore, multivariate analysis of data from the AZURE study (N = 3360) showed that the addition of monthly ZOL in the subset of patients receiving neoadjuvant chemotherapy for stage II/III BC significantly reduced residual invasive tumor size (43%; P = 0.006) and nearly doubled the rate of pathologic complete responses (P = 0.146) [22]. In the recently reported mature results of the AZURE trial, although no benefit was reported in the overall study population, subset analyses showed that ZOL treatment significantly reduced the absolute risk of recurrent invasive disease by ∼7% [hazard ratio (HR) = 0.75; 95% confidence interval (CI) = 0.59% to 0.96%; P = 0.02] and improved the 5-year survival rate by ∼6% (HR = 0.74; 95% CI = 0.55% to 0.98%; P = 0.04) in patients who had undergone menopause at least 5 years before study entry [24]. These data are consistent with the observation of DTC reduction in postmenopausal women compared with no apparent reduction in mean DTC numbers in premenopausal women in the current study. Thus, it is tempting to speculate that the potential anticancer benefit of ZOL may be mediated through reduction/elimination of DTCs, and ZOL treatment in conjunction with primary therapy may improve clinical benefits. It should be noted, however, that because of the small number of patients in the current study, these data may be considered as hypothesis generating. Improvements in disease outcome with ZOL have been reported in other cancer settings. In patients with bone metastases from lung cancer receiving docetaxel and carboplatin (N = 144), patients who received ZOL (4 mg every 21 days) for bone pain had a statistically significant survival improvement versus no ZOL (medians of 578 and 384 days, respectively; P < 0.001) [25]. Furthermore, the total number of cycles of ZOL also significantly correlated with longer time to progression and overall survival (P < 0.01 for each) [25]. Thus, ZOL can delay or prevent disease recurrence, and its effects on DTCs may contribute to these benefits. In the current study, the decision to measure bone marrow DTCs instead of the more easily measured circulating tumor cells in blood was guided by data suggesting that DTCs correlate strongly with disease outcomes [7–9]. However, the requirement for bone marrow biopsies in patients without clinical evidence of residual disease was a major reason for patient withdrawal. This resulted in major limitations for this study, including a high proportion of missing values for the primary variable (60%), insufficient statistical power, and potentially compromised randomization because of attrition of accrued patients. Additionally, the ACIS automated method utilized in the current study may be less sensitive than the MDS1 or manual methods, as reported by Borgen et al. [26].
Annals of Oncology
original articles
Annals of Oncology
18. Directive 2001/83/EC of The European Parliament and of The Council of 6 November 2001 on the Community Code relating to medicinal products for human use. Official Journal L—311, 28/11/2004, pp. 67–128. http://www. emea.europa.eu/pdfs/human/pmf/2001-83-EC.pdf. (22 December 2010, date last accessed). 19. Fehm T, Braun S, Muller V et al. A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation. Cancer 2006; 107: 885–892. 20. Bauer KD, de la Torre-Bueno J, Diel IJ et al. Reliable and sensitive analysis of occult bone marrow metastases using automated cellular imaging. Clin Cancer Res 2000; 6: 3552–3559. 21. Neville-Webbe HL, Gnant M, Coleman RE. Potential anticancer properties of bisphosphonates. Semin Oncol 2010; 37Suppl 1S53–S65. 22. Coleman RE, Winter MC, Cameron D et al. The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer 2010; 102: 1099–1105. 23. Brufsky A, Bundred N, Coleman R et al. Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Oncologist 2008; 13: 503–514. 24. Coleman RE, Marshall H, Cameron D et al. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 2011; 365: 1396–1405. 25. Zarogoulidis K, Boutsikou E, Zarogoulidis P et al. The impact of zoledronic acid therapy in survival of lung cancer patients with bone metastasis. Int J Cancer 2009; 125: 1705–1709. 26. Borgen E, Pantel K, Schlimok G et al. A European interlaboratory testing of three well-known procedures for immunocytochemical detection of epithelial cells in bone marrow. Results from analysis of normal bone marrow. Cytometry B Clin Cytom 2006; 70B: 400–409. 27. Winter MC, Holen I, Coleman RE. Exploring the anti-tumour activity of bisphosphonates in early breast cancer. Cancer Treat Rev 2008; 34: 453–475.
Annals of Oncology 23: 2277–2282, 2012 doi:10.1093/annonc/mds002 Published online 21 February 2012
Preoperative PET/CT in early-stage breast cancer M. Bernsdorf1*, A. K. Berthelsen2, V. T. Wielenga3, N. Kroman4, D. Teilum4, T. Binderup2,5, U. B. Tange1, M. Andersson1, A. Kjær2,5, A. Loft2 & J. Graff6 Departments of 1Oncology; 2Clinical Physiology, Nuclear Medicine & PET; 3Pathology; 4Breast Surgery, Rigshospitalet, University Hospital of Copenhagen, Copenhagen; 5 Cluster for Molecular imaging, Faculty of Health Sciences, University of Copenhagen, Copenhagen; 6Department of Clinical Physiology and Nuclear Medicine, Hvidovre Hospital, University Hospital of Copenhagen, Copenhagen, Denmark
Received 21 July 2011; revised 28 December 2011; accepted 2 January 2012
Background: The aim of this study was to assess the diagnostic and therapeutic impact of preoperative positron emission tomography and computed tomography (PET/CT) in the initial staging of patients with early-stage breast cancer. Patients and methods: A total of 103 consecutive patients with newly diagnosed operable breast cancer with tumors ≥2 cm were independently examined preoperatively with conventional assessment (mammography, breast/ axillary ultrasound, chest X-ray and blood samples) and PET/CT with no prior knowledge of the other. Results: PET/CT identified a primary tumor in all but three patients (97%). PET/CT solely detected distant metastases (ovary, bones and lung) in 6 patients and new primary cancers (ovary, lung) in another two patients, as well as 12 cases
*Correspondence to: Dr M. Bernsdorf, Department of Oncology, 5073, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen O, Denmark. Tel: + 45-3545-96-93; Fax: + 45-3545-43-91; E-mail: [email protected]
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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8. Bidard FC, Vincent-Salomon A, Gomme S et al. Disseminated tumor cells of breast cancer patients: a strong prognostic factor for distant and local relapse. Clin Cancer Res 2008; 14: 3306–3311. 9. Bidard FC, Kirova YM, Vincent-Salomon A et al. Disseminated tumor cells and the risk of locoregional recurrence in nonmetastatic breast cancer. Ann Oncol 2009; 20: 1836–1841. 10. Becker S, Solomayer E, Becker-Pergola G et al. Primary systemic therapy does not eradicate disseminated tumor cells in breast cancer patients. Breast Cancer Res Treat 2007; 106: 239–243. 11. Eidtmann H, Bundred N, De Boer R et al. The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving letrozole: 36 months follow-up of ZO-FAST. Cancer Res 2009; 69 (Suppl): 74s–75s (Abstr 44). 12. Gnant M, Mlineritsch B, Schippinger W et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009; 360: 679–691. 13. Aft R, Naughton M, Trinkaus K et al. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol 2010; 11: 421–428. 14. Rack B, Juckstock J, Genss EM et al. Effect of zoledronate on persisting isolated tumour cells in patients with early breast cancer. Anticancer Res 2010; 30: 1807–1813. 15. Lin AY, Park JW, Scott J et al. Zoledronic acid as adjuvant therapy for women with early stage breast cancer and disseminated tumor cells in bone marrow. J Clin Oncol 2008; 26 (Suppl): 20s (Abstr 559). 16. Zometa® (zoledronic acid) Injection [Prescribing Information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation 2011. 17. US Food and Drug Administration. CFR—Code of Federal Regulations Title 21: Title 21—Food and Drugs Chapter I—Food and Drug Administration Department of Health and Human Services Subchapter A—General Provisions: Part 50— Protection of Human Subjects. http://www.accessdata.fda.gov/SCRIPTs/cdrh/ cfdocs/cfcfr/CFRSearch.cfm. (22 December 2010, date last accessed).
Annals of Oncology 25. Simon R, Wittes RE, Ellenberg SS.Randomized phase II clinical trials. Cancer Treat Rep 1985; 69(12): 1375–1381. 26. Cannistra S, Matulonis UA, Penson RT et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer. J Clin Oncol 2007; 25(33): 5180–5186. 27. Gordon AN, Fleagle JT, Guthrie D et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 2001; 19(14): 3312–3322. 28. Taran A, Ignatov A, Smith B et al. Acute hepatic failure following monotherapy with sunitinib for ovarian cancer. Cancer Chemother Pharmacol 2009; 63(5): 971–972.
29. Tillmanns TD, Lowe MP, Schwartzberg LS et al. A phase II study of bevacizumab with nab-paclitaxel in patients with recurrent, platinum-resistant primary epithelial ovarian or primary peritoneal carcinoma. J Clin Oncol 2010; 28: 15s. (Abstr 5009). 30. Sweeney C, Chiorean EG, Verschraegen CF et al. A phase I study of sunitinib plus capecitabine in patients with advanced solid. J Clin Oncol 2010; 28(29): 4513–4520. 31. Robert F, Sandler A, Schiller JH et al. Sunitinib in combination with docetaxel in patients with advanced solid tumors: a phase I dose-escalation study. Cancer Chemother Pharmacol 2009; 66(4): 669–680.
Annals of Oncology 23: 2271–2277, 2012 doi:10.1093/annonc/mdr612 Published online 1 March 2012
E.-F. Solomayer1*, G. Gebauer2, P. Hirnle3, W. Janni4, H.-J. Lück5, S. Becker1, J. Huober6, B. Krämer1, B. Wackwitz7, D. Wallwiener8 & T. Fehm1 1 Department of Obstetrics, Gynecology, and Reproductive Medicine, University of Saarland, Homburg; 2Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg; 3Department of Radiation Oncology, Central Academic Hospital, Bielefeld; 4Department of Gynecology and Obstetrics, Heinrich-Heine University, Düsseldorf; 5Department of Gynecologic Oncology, Hannover Medical School, Hannover, Germany; 6Breast Center, Department of Senologie, Kantonsspital St. Gallen, St. Gallen, Switzerland; 7Norvartis Oncology, Department of Medical Affairs, Nuremberg; 8Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany
Received 10 August 2011; revised 5 December 2011; accepted 12 December 2011
Background: The presence of disseminated tumor cells (DTCs) in bone marrow of patients with early breast cancer (EBC) has been correlated with increased risk of metastatic disease or locoregional relapse. Zoledronic acid (ZOL) treatment has reduced DTCs in the bone marrow of patients with EBC in several studies. This controlled study sought to confirm these observations. Patients and methods: Patients with EBC and DTC-positive bone marrow were randomized (N = 96) to treatment with ZOL plus adjuvant systemic therapy or adjuvant systemic therapy alone. The change in DTC numbers at 12 months versus baseline was measured. Results: DTC-positive patients treated with ZOL were more likely to become DTC-negative after 12 months of treatment compared with the controls (67% versus 35%; P = 0.009). At 12 months, DTC counts decreased to a mean of 0.5 ± 0.8 DTCs in the ZOL group and to 0.9 ± 0.8 DTCs in the control group. In addition, ZOL was generally well tolerated. Conclusions: Treatment with ZOL improves elimination of DTCs. Further studies are needed to determine whether the reduction in DTCs by ZOL provides clinical benefit. Key words: breast cancer, disseminated tumor cells, metastasis, recurrence, zoledronic acid
introduction Breast cancer (BC) is the most common solid tumor in women [1]. Metastatic disease is the predominant cause of death in the ∼465 000 patients who succumb to this disease [1]. Despite therapeutic interventions, ∼15% develop distant metastases within 3 years [2]. Furthermore, patients may have late
*Correspondence to: Prof. Dr E.-F. Solomayer, Department of Obstetrics, Gynecology, and Reproductive Medicine, University of Saarland, Kirrberger Strasse, 66421 Homburg/Saar, Germany. Tel: + 49-6841-162-8100; Fax: + 49-6841-162-8110; E-mail: [email protected]
recurrence (‘metastatic dormancy’) ≥10 years after initial diagnosis [2]. Common sites of BC metastasis include bone, lung, and brain [2, 3], of which bone is the most common site (∼75% of cases) [4]. Distant metastasis is associated with poor prognosis [4, 5]. The hypothesis that recurrent/metastatic disease is initiated by micrometastases has gained wide acceptance. Disseminated tumor cells (DTCs) can be sequestered in a dormant state in the bone marrow for several years before reactivating to cause disease recurrence [6]. The most compelling clinical evidence comes from a retrospective pooled analysis of patients with BC (N = 4703) wherein patients with DTC-positive bone marrow
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Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients
original articles
patients and methods patients Eligible patients were female, ≥18 years of age, with primary BC ( pT1-4, N1-2, M0) and initiated study treatment within 42 days of completing primary tumor resection and axillary lymph node dissection. All enrolled patients had minimal residual disease composed of DTC in bone marrow, per the ‘Clinical Assessments’ section below, and were to receive adjuvant therapy (hormonal, cytotoxic, or both). All patients provided written informed consent before initiation of any study-specific procedures. The study was approved by the Ethics Committee at all participating institutions. Patients were excluded if they had inflammatory, metastatic, or recurrent BC or a history of BC before the most recent BC diagnosis, creatinine clearance < 30 ml/min, current active dental problems or trauma, or a current or prior diagnosis of
| Solomayer et al.
osteonecrosis of the jaw (ONJ). Neoadjuvant chemotherapy was not permitted.
study design and treatment In this parallel-group, open-label, multicenter study patients were prospectively stratified on the basis of six predefined strata: two nodal-status categories ( positive, negative) by three adjuvant-treatment categories (chemotherapy, hormonal therapy, chemotherapy plus hormonal therapy). Patients were then randomized 1 : 1 to adjuvant therapy alone (control) or with intravenous ZOL every 4 weeks for 24 months (Figure 1), the dose and schedule approved for the prevention of skeletal-related events in patients with bone metastases [16]. Per the approved label, ZOL dosing was guided by creatinine clearance [16]. The primary end point was the effect of ZOL on DTC counts after 12 months. Secondary end points at 24 months included safety; changes in DTC counts versus baseline; bone metastasis-free survival, which included death from any cause or bone metastasis; and DFS, which included death from any cause or disease recurrence at any site. Correlative analyses of change in DTC counts with tumor–node–metastasis stage, estrogen- and progesterone-receptor status, and menopause status were planned. This clinical study was designed, implemented, and reported in accordance with the International Good Clinical Practice Guidelines, with applicable local regulations [17, 18] and with the ethical principles in the Declaration of Helsinki.
clinical assessments Bone marrow aspirates for DTC assessment were obtained at baseline, 12 months, and 24 months after initiating study. After baseline and treatment initiation (month 0) visits, eight additional study visits at 3-month intervals were planned. Clinical assessments at each visit included serum biochemistry, hematology, Eastern Cooperative Oncology Group performance status, and physical examination. There was continuous adverse event (AE) monitoring and follow-up scans for skeletal and nonskeletal lesions as clinically indicated. Patients were assessed using X-rays, magnetic resonance imaging, or computed tomography scans for suspected bone metastases. Serum creatinine was monitored before each ZOL infusion. Assessments of DTCs were conducted as previously described [19]. For the quantitation of DTCs, 2 × 106 cells were analyzed on two slides per patient. Slides were automatically scanned using the ACIS™ imaging system (ChromaVision, Medical Systems Inc., San Juan Capistrano, CA), as described elsewhere [20]. Criteria for detection of DTCs were based on European ISHAGE Working Group recommendations [19]. Slides were centrally evaluated by two independent blinded observers. Nonconcordant results were evaluated by a third investigator.
statistical assessments No formal hypothesis was tested for statistical significance; thus, the sample size of this trial was determined by feasibility considerations. The safety population included all patients who received at least one dose of study medication and all patients
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(n = 1438) had an approximately twofold increased risk of death versus DTC-negative patients (P < 0.001) [7]. Similarly, a recent study showed that detection of DTCs in patients with early breast cancer (EBC) (N = 655) correlated with reduced distant metastasis-free survival (P = 0.0013) and reduced overall survival (P = 0.005) [8]. Furthermore, at a median follow-up of 56 months in these patients, DTC status was the only significant prognostic factor for locoregional recurrencefree survival in a multivariate analysis (odds ratio = 5.2; P = 0.0005) [9]. These data suggest that DTC status in EBC correlates with risk of distant metastasis, locoregional recurrence, and death [9]. Moreover, in a recent study (N = 120), chemotherapy did not effectively eradicate DTCs in EBC patients [10]. Bone marrow DTCs persisted in ∼36% of patients despite complete response to primary therapy [10]. Therefore, alternative therapeutic options that improve elimination of DTCs may reduce the risk of recurrence and improve survival in EBC. Recently, zoledronic acid (ZOL; 4 mg every 6 months) significantly prolonged disease-free survival (DFS) and relapse-free survival versus no ZOL or delayed use of ZOL in EBC patients undergoing adjuvant hormonal therapy in ABCSG-12 and ZO-FAST (large, randomized, controlled trials) [11, 12]. A possible underlying mechanism of action is that ZOL reduced disease recurrence by suppressing/eliminating DTCs. Indeed, Aft et al. [13] demonstrated that DTC-free BC patients treated with ZOL (4 mg every 3 weeks) were more likely to remain DTC free at 3 months (P = 0.03) and that the subset of patients with estrogen receptor-negative and epidermal growth factor receptor-2-negative disease were more likely to have pathologic complete response with ZOL versus no ZOL. In small studies, ZOL (4 mg/month) increased the proportion of DTC-free patients who remained DTC-free at 6 months versus no ZOL [14] and significantly decreased DTC levels versus baseline at 12 (P < 0.0006) and 24 months (P = 0.0026) [15] in DTC-positive BC patients. Therefore, it is reasonable to hypothesize that ZOL may delay disease recurrence. However, the effects of ZOL on DTCs had not been evaluated in a randomized controlled study.
Annals of Oncology
Annals of Oncology
original articles
in the control group. Efficacy analysis was performed on the modified intent-to-treat (mITT) population composed of all patients in the safety population with at least one post-baseline measurement of DTCs. A per-protocol analysis was performed using all mITT patients who did not have major protocol deviations that might have affected study outcome. These criteria were prospectively defined and documented before analysis. Because of the small sample size and the number of predefined strata, only descriptive analysis was performed. Simple statistics were performed for the number of DTCs and the relative and absolute change from baseline values by treatment group. Significance analysis of categorical variables was done using Fisher’s exact test. Additionally, an analysis of covariance was performed using absolute differences in DTC counts as the dependent variable and baseline DTC number, treatment, center, and stratum as independent variables. Worstcase values for the respective strata were imputed for missing values for baseline DTCs. Missing values at month 12 were imputed with 24-month data, if available. Otherwise, worst-case values for the respective strata were imputed. AEs were coded by MedDRA and analyzed using absolute and relative frequencies.
results patients A total of 96 patients were randomized at four study centers in Germany. Data for the primary end point, DTCs at baseline
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and 12 and/or 24 months, were available for 76 patients (adjuvant therapy plus ZOL, n = 39; control, n = 37) who, by definition, constituted the mITT population (Figure 1). Most patients (59%) had stage I disease, 84% were node negative, 39% had received adjuvant hormonal therapy, and 43% had received adjuvant hormonal therapy plus chemotherapy. Baseline characteristics were well balanced between arms among mITT patients (Table 1). At the time of database closure, 64 (ZOL, 30; control, 34) patients (67%) completed the 24-month study as planned, 4 (ZOL, 3; control, 1) patients (4%) completed 12 months, and 28 (ZOL, 11; control, 17) patients (30%) discontinued before receiving all study medication. The most common reason for discontinuation was withdrawal of consent for the multiple bone marrow biopsies (ZOL, 9; control, 11). As a result, values for the primary variable were available for only 40% of patients.
efficacy assessments Efficacy assessments were conducted in the mITT population as described in the methods. For the control group, the baseline mean DTC count was 2.9 ± 5.5 (median, 2.0; range, 1–35 cells), which decreased to a mean of 0.9 ± 0.8 DTCs (median, 1.0; range, 0–2 cells) at 12 months (Figure 2). For the ZOL group, the baseline mean DTC count was 2.1 ± 1.1 (median, 2.0; range, 1–6 cells), which decreased to a mean of 0.5 ± 0.8 DTCs (median, 0.0; range, 0–2 cells) at 12 months.
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Figure 1. Study design. AEs, adverse events; q, every; ZOL, zoledronic acid.
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Annals of Oncology
Table 1 Patient demographics and baseline characteristics Efficacy evaluable ZOL Control group group (n = 39) (n = 37)
54 (27–77)
54 (36–71)
54 (37–72)
94 (98) 1 (1) 1 (1) 70 (47–105)
38 (97) 0 1 (3) 70 (54–105)
36 (97) 1 (3) 0 69 (50–95)
37 (39) 59 (61)
14 (36) 25 (64)
13 (35) 24 (65)
80 (83) 16 (17) 0 (0–5)
33 (85) 6 (15) 0 (0–5)
33 (89) 4 (11) 0 (0–5)
79 (82) 17 (18) 17 (1–55)
34 (87) 5 (13) 19 (6–50)
30 (81) 7 (19) 20 (2–55)
57 (59) 24 (25) 11 (12) 3 (3) 1 (1)
25 (64) 8 (21) 4 (10) 2 (5) 0
22 (60) 9 (24) 5 (14) 0 1 (3)
1 (1) 6 (6) 74 (77) 15 (16)
1 (3) 3 (8) 28 (72) 7 (18)
0 3 (8) 29 (78) 5 (14)
78 (81) 18 (19)
32 (82) 7 (18)
29 (78) 8 (22)
63 (66) 33 (34)
26 (67) 13 (33)
23 (62) 14 (38)
25 (26) 70 (73) 1 (1) 2 (1–35)
11 (28) 28 (72) 0 2 (1–6)
11 (30) 26 (70) 0 2 (1–35)
Figure 2. Mean DTCs at 0 months (baseline), 12 months, and 24 months in ZOL-treated patients and control patients. DTC, disseminated tumor cell; ZOL, zoledronic acid.
could not be imputed into the model because of missing baseline data. In the per-protocol population (n = 21), all 9 ZOL-treated patients (100%) and 8 of 12 control-group patients (67%) transitioned to DTC-negative status. At the 24-month follow-up, a mean of 0.4 ± 0.8 DTCs (median, 0.0; range, 0–2 cells) were detected in the ZOL group compared with 0.7 ± 0.9 DTCs (median, 0.0; range, 0–2 cells) in the control group. Consistent with the 12-month analysis, ZOL treatment reduced the number of DTCs at 24 months (difference in the least-squares means of − 0.3), although the difference fell short of statistical significance (P = 0.056). No significant differences were detectable in the change in DTC levels among subsets of patients grouped by stratification factors used at enrollment or using other prognostic factors, primarily because of the small sample numbers. However, in an exploratory analysis of DTC change by menopausal status, it was noted that decline in DTCs from baseline was similar in the control and ZOL arms at months 12 and 24 in premenopausal women (13 evaluable patients in each arm). In contrast, the decline in DTC levels in postmenopausal women (24 and 22 evaluable patients for the ZOL and control arms, respectively) receiving ZOL treatment was slightly higher at months 12 and 24 (−73% versus −53% at month 12 and
ECOG PS, Eastern Cooperative Oncology Group performance status; DTC, disseminated tumor cell.
The least-squares means change from baseline to 12 months was −1.9 for the ZOL group and −1.6 for the control group, although the between-group difference (0.3) did not reach statistical significance (P = 0.066). Furthermore, DTC-positive patients treated with ZOL were significantly more likely to become DTC negative at 12 months compared with the control group (P = 0.009; Figure 3). In two patients per group, data
| Solomayer et al.
Figure 3. In patients with DTC-positive bone marrow at baseline, proportion who remained DTC-positive at 12 months. DTC, disseminated tumor cell; ZOL, zoledronic acid.
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Age, median years (range) Race, n (%) Caucasian Black Oriental Weight, median kg (range) Menopausal status, n (%) Premenopausal Postmenopausal ECOG PS, n (%) 0 1 Time since first diagnosis, median months (range) Most radical type of surgery, n (%) Breast conserving Ablative Tumor size (largest diameter), median mm (range) Disease stage, n (%) Stage I Stage IIA Stage IIB Stage IIIA Stage IIIB Tumor grade, n (%) Grade x Grade 1 Grade 2 Grade 3 Estrogen-receptor status, n (%) Positive Negative Progesterone-receptor status, n (%) Positive Negative HER-2/neu status, n (%) Positive Negative Unknown DTCs in bone marrow, median (range)
Total (N = 96)
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Annals of Oncology Table 2 Most frequently reported treatment-emergent adverse eventsa by MedDRA-preferred term Adverse eventb
Control (N = 52), n (%)
Total (N = 96), n (%)
33 (75) 24 (55) 24 (55) 29 (66) 18 (41) 14 (32) 15 (34) 14 (32) 16 (36) 18 (41) 15 (34) 15 (34) 18 (41) 14 (32) 12 (27) 15 (34) 10 (23) 9 (20) 12 (27) 5 (11) 11 (25) 11 (25) 9 (20) 11 (25) 10 (23)
19 (37) 25 (48) 21 (40) 14 (27) 21 (40) 19 (37) 18 (35) 16 (31) 14 (27) 12 (23) 14 (27) 10 (19) 7 (13) 10 (19) 12 (23) 8 (15) 11 (21) 11 (21) 6 (12) 12 (23) 6 (12) 6 (12) 7 (13) 3 (6) 0
52 (54) 49 (51) 45 (47) 43 (45) 39 (41) 33 (34) 33 (34) 30 (31) 30 (31) 30 (31) 29 (30) 25 (26) 25 (26) 24 (25) 24 (25) 23 (24) 21 (22) 20 (21) 18 (19) 17 (18) 17 (18) 17 (18) 16 (17) 14 (15) 10 (10)
Adverse events with an incidence of ≥20% at preferred term level in either treatment group are displayed. b Adverse events are sorted by frequency. ZOL, zoledronic acid. a
−83% versus −66% at month 24) compared with postmenopausal women in the control arm. At the time of database closure, no patients had died or developed bone metastases, and few patients had discontinued the study for medical reasons. Therefore, the secondary end points of bone metastasis-free survival and DFS and the number and location of bone metastases were not evaluable.
safety Patients in the ZOL group were treated for a mean of 21 ± 6 months (range, 1–26 months), with a mean observation period of 20 ± 9 months (range, 1–29 months) in the control group and 21 ± 6 months (range, 1–26 months) in the ZOL group. Among the most common AEs associated with ZOL were arthralgia, myalgia, and pyrexia, reflecting the known flu-like acute phase reaction that can occur, typically after the first infusion. Fatigue and neutropenia were most common in the control group (Table 2). Most (66%) AEs in the ZOL group were grade 1 or 2. The most frequent grade 3 events were hematologic: grade 3 neutropenia (ZOL, 11%; control, 23%) and grade 3 leukopenia (ZOL, 6%; control, 7%). Only two patients in the ZOL arm [wound infection and bone pain (one
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discussion This was the first prospective, randomized controlled study evaluating the effects of ZOL on DTCs in patients with EBC. Although DTC levels at 12 and 24 months were reduced versus baseline in both treatment groups, patients treated with ZOL trended toward a greater decrease in DTC counts versus control at 12 (P = 0.066) and 24 months (P = 0.056). Moreover, a significantly higher proportion of patients were DTCnegative at 12 months in the ZOL group versus control (P = 0.009), suggesting effective DTC elimination by ZOL, although 24-month data were limited. In the recent report by Aft et al. [13], chemotherapy alone also was not as effective as chemotherapy with concomitant ZOL for maintaining DTCnegative status. Moreover, chemotherapy alone had no discernible effect on DTC status in DTC-positive patients [13]. The enhanced reduction of DTCs with ZOL may be the result of anticancer effects of ZOL or anticancer synergy between ZOL and agents used for adjuvant therapy. Indeed, preclinical and clinical data have provided evidence of antitumor synergy between chemotherapeutic agents and ZOL [21, 22]. Regardless of the mechanistic basis for the reduction/ elimination of DTCs, it may be speculated that the reduction of DTCs by ZOL treatment may, in part, contribute to the significant improvements in DFS with ZOL reported in adjuvant clinical trials in EBC [13–15]. Overall, treatment with ZOL was generally well tolerated, and there were few treatment discontinuations because of AEs (<10% in both groups). The detection of DTCs correlates significantly with increased risks of visceral and bone metastasis, locoregional recurrence, and death in BC patients [7, 9]. Therefore, treatments that eliminate or reduce DTCs in bone marrow may potentially decrease risk of recurrent or metastatic disease and improve survival. Indeed, reduced risks of recurrent disease were reported in clinical trials exploring ZOL as adjuvant therapy in EBC patients. In ABCSG-12, the addition of ZOL to endocrine therapy (goserelin with tamoxifen or anastrozole) for 3 years in younger women with early EBC and treatment-induced menopause (N = 1803) significantly improved DFS by 36% (log-rank P = 0.01) and recurrence-free survival by 35% (logrank P = 0.01 for both) relative to no ZOL [12]. At a median follow-up of 48 months, ZOL also produced a trend toward a 40% lower risk of death versus no ZOL (log-rank P = 0.11) [12]. Moreover, ZOL-treated patients had numerically fewer locoregional (20 versus 10) and distant (41 versus 29) recurrences and contralateral disease events (10 versus 6) versus hormonal therapy alone. Furthermore, at the 36-month analysis of ZO-FAST (N = 1064) in postmenopausal women
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Arthralgia Nausea Alopecia Myalgia Constipation Fatigue Mucosal inflammation Stomach discomfort Anorexia Cough Dyspnea Lacrimation increased Headache Pyrexia Hot flush Nasal dryness Nasopharyngitis Menopausal symptoms Dysesthesia Neutropenia Diarrhea Vomiting Dermatitis Onychoclasis Conjunctivitis
ZOL (N = 44), n (%)
patient each)] and three patients in the control arm [osteopenia, osteoporosis, and metastasis to lymph nodes (one patient each)] discontinued treatment because of an AE. There was one case of ONJ in a patient with completely normal dental health prior to developing ONJ 576 days after the start of study medication and lasting 207 days, necessitating prolonged hospitalization, the administration of concomitant medication, and nondrug therapy. This patient also developed moderate osteomyelitis lasting 27 days, which started 756 days after initiating study medication.
original articles
| Solomayer et al.
Nonetheless, this study provides important insight into the effects of ZOL on DTCs within the bone marrow. In conclusion, the results from the current trial are consistent with the antitumor properties of ZOL demonstrated in numerous preclinical studies [27]. Elimination of DTCs by ZOL, as reported in our study, may have profound implications for long-term disease outcomes and survival by reducing the risk of early or late recurrence in patients with BC. Extended follow-up will provide further insight into the clinical benefit of ZOL treatment in this setting. However, additional studies are needed to investigate the role of DTCs in disease progression.
acknowledgements We thank Jerome F. Sah, PhD, ProEd Communications, Inc.®, for his medical editorial assistance with this manuscript.
funding This work was supported by a research grant from Novartis Pharmaceuticals Corporation (ZOL-MRD 001). Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.
disclosure Dr EFS has received honoraria from Novartis, Roche, and AstraZeneca, and research grants from Roche. Dr WJ has received lecture honoraria and research grants from Novartis. Dr H-JL has received lecture honoraria from Roche, Novartis, Sanofi, GlaxoSmithKline, and Pfizer, and is an advisory board member for Roche, Novartis, Pfizer, Fresenius, and BMS. Dr JH has received lecture honoraria from Novartis, and is an advisory board member for Roche, Novartis, and Amgen. Dr TF has received honoraria from Roche, Novartis, and AstraZeneca, and research grants from Roche. Dr BW is employed by Novartis. Dr DW has received research grants from Novartis and Roche. Drs GG, PH, SB, and BK have declared no conflict of interest.
references 1. Garcia M, Jemal A, Ward EM et al. Global Cancer Facts & Figures 2007. Atlanta, GA: American Cancer Society 2007. 2. Psaila B, Kaplan RN, Port ER, Lyden D. Priming the ‘soil’ for breast cancer metastasis: the pre-metastatic niche. Breast Dis 2006; 26: 65–74. 3. Solomayer EF, Diel IJ, Meyberg GC et al. Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat 2000; 59: 271–278. 4. Coleman RE. Skeletal complications of malignancy. Cancer 1997; 80: 1588–1594. 5. Moreno-Aspitia A, Perez EA. Treatment options for breast cancer resistant to anthracycline and taxane. Mayo Clin Proc 2009; 84: 533–545. 6. Shiozawa Y, Havens AM, Pienta KJ, Taichman RS. The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites. Leukemia 2008; 22: 941–950. 7. Braun S, Vogl FD, Naume B et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 2005; 353: 793–802.
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receiving letrozole as adjuvant therapy for EBC, upfront use of ZOL (4 mg every 6 months) significantly improved DFS by 41% (P = 0.0314) versus using ZOL only after clinically relevant bone loss was detected (delayed ZOL) [11]. Consistent DFS benefits were reported in an integrated analysis of ZOFAST and a similarly designed trial (Z-FAST; N = 1667) [11, 23]. Consistent with ABCSG-12, the upfront-ZOL group had reduced rates of disease recurrence at both local and distant sites (both within and outside bone) [11]. However, because bone marrow biopsies were not obtained, the effects of ZOL on DTCs in these studies are unknown. Furthermore, multivariate analysis of data from the AZURE study (N = 3360) showed that the addition of monthly ZOL in the subset of patients receiving neoadjuvant chemotherapy for stage II/III BC significantly reduced residual invasive tumor size (43%; P = 0.006) and nearly doubled the rate of pathologic complete responses (P = 0.146) [22]. In the recently reported mature results of the AZURE trial, although no benefit was reported in the overall study population, subset analyses showed that ZOL treatment significantly reduced the absolute risk of recurrent invasive disease by ∼7% [hazard ratio (HR) = 0.75; 95% confidence interval (CI) = 0.59% to 0.96%; P = 0.02] and improved the 5-year survival rate by ∼6% (HR = 0.74; 95% CI = 0.55% to 0.98%; P = 0.04) in patients who had undergone menopause at least 5 years before study entry [24]. These data are consistent with the observation of DTC reduction in postmenopausal women compared with no apparent reduction in mean DTC numbers in premenopausal women in the current study. Thus, it is tempting to speculate that the potential anticancer benefit of ZOL may be mediated through reduction/elimination of DTCs, and ZOL treatment in conjunction with primary therapy may improve clinical benefits. It should be noted, however, that because of the small number of patients in the current study, these data may be considered as hypothesis generating. Improvements in disease outcome with ZOL have been reported in other cancer settings. In patients with bone metastases from lung cancer receiving docetaxel and carboplatin (N = 144), patients who received ZOL (4 mg every 21 days) for bone pain had a statistically significant survival improvement versus no ZOL (medians of 578 and 384 days, respectively; P < 0.001) [25]. Furthermore, the total number of cycles of ZOL also significantly correlated with longer time to progression and overall survival (P < 0.01 for each) [25]. Thus, ZOL can delay or prevent disease recurrence, and its effects on DTCs may contribute to these benefits. In the current study, the decision to measure bone marrow DTCs instead of the more easily measured circulating tumor cells in blood was guided by data suggesting that DTCs correlate strongly with disease outcomes [7–9]. However, the requirement for bone marrow biopsies in patients without clinical evidence of residual disease was a major reason for patient withdrawal. This resulted in major limitations for this study, including a high proportion of missing values for the primary variable (60%), insufficient statistical power, and potentially compromised randomization because of attrition of accrued patients. Additionally, the ACIS automated method utilized in the current study may be less sensitive than the MDS1 or manual methods, as reported by Borgen et al. [26].
Annals of Oncology
original articles
Annals of Oncology
18. Directive 2001/83/EC of The European Parliament and of The Council of 6 November 2001 on the Community Code relating to medicinal products for human use. Official Journal L—311, 28/11/2004, pp. 67–128. http://www. emea.europa.eu/pdfs/human/pmf/2001-83-EC.pdf. (22 December 2010, date last accessed). 19. Fehm T, Braun S, Muller V et al. A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation. Cancer 2006; 107: 885–892. 20. Bauer KD, de la Torre-Bueno J, Diel IJ et al. Reliable and sensitive analysis of occult bone marrow metastases using automated cellular imaging. Clin Cancer Res 2000; 6: 3552–3559. 21. Neville-Webbe HL, Gnant M, Coleman RE. Potential anticancer properties of bisphosphonates. Semin Oncol 2010; 37Suppl 1S53–S65. 22. Coleman RE, Winter MC, Cameron D et al. The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer 2010; 102: 1099–1105. 23. Brufsky A, Bundred N, Coleman R et al. Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Oncologist 2008; 13: 503–514. 24. Coleman RE, Marshall H, Cameron D et al. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 2011; 365: 1396–1405. 25. Zarogoulidis K, Boutsikou E, Zarogoulidis P et al. The impact of zoledronic acid therapy in survival of lung cancer patients with bone metastasis. Int J Cancer 2009; 125: 1705–1709. 26. Borgen E, Pantel K, Schlimok G et al. A European interlaboratory testing of three well-known procedures for immunocytochemical detection of epithelial cells in bone marrow. Results from analysis of normal bone marrow. Cytometry B Clin Cytom 2006; 70B: 400–409. 27. Winter MC, Holen I, Coleman RE. Exploring the anti-tumour activity of bisphosphonates in early breast cancer. Cancer Treat Rev 2008; 34: 453–475.
Annals of Oncology 23: 2277–2282, 2012 doi:10.1093/annonc/mds002 Published online 21 February 2012
Preoperative PET/CT in early-stage breast cancer M. Bernsdorf1*, A. K. Berthelsen2, V. T. Wielenga3, N. Kroman4, D. Teilum4, T. Binderup2,5, U. B. Tange1, M. Andersson1, A. Kjær2,5, A. Loft2 & J. Graff6 Departments of 1Oncology; 2Clinical Physiology, Nuclear Medicine & PET; 3Pathology; 4Breast Surgery, Rigshospitalet, University Hospital of Copenhagen, Copenhagen; 5 Cluster for Molecular imaging, Faculty of Health Sciences, University of Copenhagen, Copenhagen; 6Department of Clinical Physiology and Nuclear Medicine, Hvidovre Hospital, University Hospital of Copenhagen, Copenhagen, Denmark
Received 21 July 2011; revised 28 December 2011; accepted 2 January 2012
Background: The aim of this study was to assess the diagnostic and therapeutic impact of preoperative positron emission tomography and computed tomography (PET/CT) in the initial staging of patients with early-stage breast cancer. Patients and methods: A total of 103 consecutive patients with newly diagnosed operable breast cancer with tumors ≥2 cm were independently examined preoperatively with conventional assessment (mammography, breast/ axillary ultrasound, chest X-ray and blood samples) and PET/CT with no prior knowledge of the other. Results: PET/CT identified a primary tumor in all but three patients (97%). PET/CT solely detected distant metastases (ovary, bones and lung) in 6 patients and new primary cancers (ovary, lung) in another two patients, as well as 12 cases
*Correspondence to: Dr M. Bernsdorf, Department of Oncology, 5073, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen O, Denmark. Tel: + 45-3545-96-93; Fax: + 45-3545-43-91; E-mail: [email protected]
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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8. Bidard FC, Vincent-Salomon A, Gomme S et al. Disseminated tumor cells of breast cancer patients: a strong prognostic factor for distant and local relapse. Clin Cancer Res 2008; 14: 3306–3311. 9. Bidard FC, Kirova YM, Vincent-Salomon A et al. Disseminated tumor cells and the risk of locoregional recurrence in nonmetastatic breast cancer. Ann Oncol 2009; 20: 1836–1841. 10. Becker S, Solomayer E, Becker-Pergola G et al. Primary systemic therapy does not eradicate disseminated tumor cells in breast cancer patients. Breast Cancer Res Treat 2007; 106: 239–243. 11. Eidtmann H, Bundred N, De Boer R et al. The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving letrozole: 36 months follow-up of ZO-FAST. Cancer Res 2009; 69 (Suppl): 74s–75s (Abstr 44). 12. Gnant M, Mlineritsch B, Schippinger W et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009; 360: 679–691. 13. Aft R, Naughton M, Trinkaus K et al. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol 2010; 11: 421–428. 14. Rack B, Juckstock J, Genss EM et al. Effect of zoledronate on persisting isolated tumour cells in patients with early breast cancer. Anticancer Res 2010; 30: 1807–1813. 15. Lin AY, Park JW, Scott J et al. Zoledronic acid as adjuvant therapy for women with early stage breast cancer and disseminated tumor cells in bone marrow. J Clin Oncol 2008; 26 (Suppl): 20s (Abstr 559). 16. Zometa® (zoledronic acid) Injection [Prescribing Information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation 2011. 17. US Food and Drug Administration. CFR—Code of Federal Regulations Title 21: Title 21—Food and Drugs Chapter I—Food and Drug Administration Department of Health and Human Services Subchapter A—General Provisions: Part 50— Protection of Human Subjects. http://www.accessdata.fda.gov/SCRIPTs/cdrh/ cfdocs/cfcfr/CFRSearch.cfm. (22 December 2010, date last accessed).