adam m. brufsky, md, phd
DESCRIPTION
Improving Bone Health in Patients With Early Breast Cancer: 12-Month Bone Mineral Density Results – The Z-Fast Trial. Adam M. Brufsky, MD, PhD Co-Director, Comprehensive Breast Cancer Center Magee-Women’s Hospital University of Pittsburgh Medical Center Pittsburgh, Pennsylvania. Background. - PowerPoint PPT PresentationTRANSCRIPT
Adam M. Brufsky, MD, PhD Co-Director, Comprehensive Breast Cancer Center
Magee-Women’s HospitalUniversity of Pittsburgh Medical Center
Pittsburgh, Pennsylvania
Improving Bone Health in Patients With EarlyBreast Cancer: 12-Month Bone Mineral
Density Results – The Z-Fast Trial
Background Further reduction or elimination of estrogen activity by AIs in PMW with
BCa may result in bone loss and bone-related complications1,2
– Anastrozole has been associated with greater incidence of fractures vs tamoxifen in PMW with primary BCa (5.9% vs 3.7%; P<0.0001)3
– Exemestane, following 2–3 yrs of tamoxifen therapy, has been associated with greater incidence of osteoporosis vs tamoxifen in PMW with primary BCa (7.4% vs 5.7%)4
– Letrozole has been associated with greater risk of bone fractures vs tamoxifen in PMW with primary BCa (5.8% vs 4.1%, P=0.0006).5
An effective therapy that will prevent bone loss associated with AIs in PMW with BCa is needed
Background (cont’d)
In clinical trials, zoledronic acid (ZA) increased bone mineral density (BMD) vs placebo or no ZA.6,7
– In PMW with low BMD, ZA (4-mg single dose) increased lumbar spine (LS) BMD by 4.3%–5.1% and femoral neck BMD by 3.1%–3.5% compared with placebo at 12 mo (P<0.001 for both).6
– In premenopausal women with BCa receiving anastrozole or tamoxifen with goserelin, LS BMD at 36 mo was higher in patients receiving ZA (4 mg q 6 mo) compared with patients not receiving ZA (P<0.0001).7
ZA = zoledronic acid
Study Design and Objectives
0 5 yrFinal analysis
RRAANNDDOOMMIIZZEEDD
3 yr1 yr
Eligibility:ER+/PgR+ BCaPMW withT score ≥ -2
Stratification:- Adjuvant chemo
(yes or no)- T score (> -1 or
between -1 and -2 )
*Plus daily calcium (1,000–1,200 mg) and vitamin D (400–800 IU).†Initiation determined by a postbaseline T score < -2, any clinical fracture, or an asymptomatic fracture at 36 mo.
Z/ZO-FAST Trial DesignZometa Femara Adjuvant Synergy Trial
+ Letrozole 2.5 mg/d*
UPFRONT Zoledronic acid 4 mg q 6 mo
+ Letrozole 2.5 mg/d*
DELAYED† Zoledronic acid 4 mg q 6 mo
Accrual complete: ZO-FAST: N = 1066; ZFAST: N = 602
Study Objectives
Primary objective
– % change in LS BMD at 12 mo
Secondary objectives
– % change in LS BMD at 2 yr, 3 yr, 5 yr
– % change in total hip (TH) BMD at 12 mo, 2 yr, 3 yr, 5 yr
– Changes in biochemical markers of bone turnover at 12 mo, 2 yr, 3 yr, 5 yr N-telopeptide (NTX) Bone-specific alkaline phosphatase (BSAP)
– Incidence of fractures at 3 yr
– Time to disease progression
– Rate of decrease in LS and TH BMD
Eligibility Criteria
PMW with stage I–IIIa ER+ and/or PgR+ BCa
Baseline LS and TH T score ≥ -2
ECOG PS between 0 to 2
Serum creatinine level < 3 mg/dL
Adjuvant CT, if administered, must have been completed before randomization
No evidence of existing fracture in LS or TH
Prior oral bisphosphonate therapy allowed but must have been discontinued at least 3 weeks before baseline evaluation
Methods
Study Assessments BMD
– DXA used to measure BMD of LS (L1–L4) and TH at baseline, 6, 12, 24, 36, and 48 mo and at final visit
– DXA machines cross-calibrated and films analyzed by central reader
Biochemical Markers (NTX and BSAP)– Evaluated in subset of ~150 patients– At baseline, every 3 mo for year 1, then every 6 mo up to 48 mo and final visit.– Analyzed by central laboratory
Fractures– X-ray at baseline to exclude patients with existing fractures– Additional x-rays and/or bone scans at discretion of investigator to confirm clinical
fracture throughout study and at 36 mo
Adverse Events (AEs)/Disease Progression– Evaluated every 6 mo– AEs graded using NCI Common Toxicity Criteria, version 2.0
DXA = Dual-energy x-ray absorptiometry
Statistical Analysis ITT population—all randomized pts who received
1 dose of letrozole or ZA and had 1 postbaseline assessment
Safety population—all randomized pts who received 1 dose of letrozole or ZA
Sample size and power considerations
– 250 pts per arm—90% power to detect 3% change in BMD and a common SD of 9% with a significance level of .05 and a 25% dropout rate
Enrollment closed December 2003 with 602 patients accrued at 93 sites in the US and Canada.
Results
DemographicsUpfront Group Delayed Group
No. of patients enrolled 301 301
No. of patients in ITT population 300 300
Median age, yr 60 60
Median age at start of menopause, yr 49 49
Race, no. of patients (%)
White
Black
Other
280 (93)
9 (3)
12 (4)
269 (89.4)
14 (4.7)
18 (5.9)
*One patient each in the upfront and delayed groups were randomized in error.
Demographics (cont’d)Upfront Group Delayed Group
ECOG status, no. of patients (%) 0
1 2 Unknown
253 (84.1)44 (14.6)
1 (0.3)3 (1)
248 (82.4)46 (15.3)
1 (0.3)6 (2)
Stratification factors, no. of patients
Prior adjuvant chemotherapy
No prior adjuvant chemotherapy
T score between -1 and -2
T score > -1
137 (45.7)*
163 (54.3)*
84 (27.9)
217 (72.1)
143 (47.7)*
157 (52.3)*
85 (28.2)
216 (71.8)
*One patient each in the upfront and delayed groups were randomized in error.
ZA Initiation in Delayed GroupNo. of delayed group patients (%) who had initiated ZA
6-mo visit
All patients 29 (9.7)
Per protocol* 12 (4)
12-mo visit
All patients 42 (14)
Per protocol* 24 (8)
Time to initiation of first ZA infusion in delayed group patients, mo
Mean (SD) 8.8 (4.7)
Median 6.3
Range 0.03–24.2
*Because T score decreased to < -2 and/or clinical fracture.
Mean (SD) Percentage Change in BMD (g/cm2)
Lumbar Spine
Total Hip
-8%
-6%
-4%
-2%
0%
2%
4%
6%
% C
han
ge
in B
MD
Upfront Group
Delayed Group
P<0.0001
P<0.0001
Month 6 Month 12 Month 6 Month 12
Mean (-SD) T Scores
-2.0
-1.5
-1.0
-0.5
0.0
0.5
Mea
n T
Sco
re
Upfront Group
Delayed Group
P<0.0001
P<0.0004
Lumbar Spine
Total Hip
Month 6 Month 12Baseline Month 6 Month 12Baseline
Shift in LS T-Score Distribution at 12 Months in Patients With Normal Baseline BMD
At 12 months
0%
20%
40%
60%
80%
100%
Baseline Upfront Delayed
Pa
tie
nts
(%
)
Normal Osteopenic Osteoporotic Missing
Shift in LS T-Score Distribution at 12 Months in Patients With Osteopenic Baseline BMD
At 12 months
0
20
40
60
80
100
Baseline Upfront Delayed
Pa
tien
ts (
%)
Normal Osteopenic Osteoporotic Missing
Mean (SD) Percentage Change in Bone Markers From Baseline
Bone Marker Assessment Upfront Group Delayed Group
NTX, mean (SD)
Baseline, nmol BCE/L
Month 12, nmol BCE/L
% change at month 12
14.2 (6.3)
9.7 (3.6)
-15.1 (70.9)*
13.5 (6)
13.9 (5.2)
19.9 (66.2)
BSAP, mean (SD)
Baseline, µg/L
Month 12, µg/L
% change at month 12
22.1 (7.7)
18.5 (5)
-8.8 (26.5)*
24.4 (9.8)
26.9 (9.6)
24.3 (50.3)
*P<0.0001.BCE=bone collagen equivalent.
Mean (SD) Percentage Change in Mean NTX From Baseline
-140
-120
-100
-80
-60
-40
-20
0
20
40
60
80
100
120
140
Ba
seli
ne
Va
lue
(%
)Upfront Group Delayed Group
P<0.0001
Month 3 Month 6 Month 9 Month 12
Mean (SD) Percentage Change in Serum BSAP From Baseline
-140
-120
-100
-80
-60
-40
-20
0
20
40
60
80
100
120
140B
ase
lin
e V
alu
e (
%)
Upfront Group Delayed Group
P<0.0001
Month 3 Month 6 Month 9 Month 12
Adverse Events Occurring in >5% of Patients
Adverse Event
No. of Pts (%)
Upfront Group(n=300)
Delayed Group(n=300)
Arthralgia 90 (30) 87 (29)
Hot flashes 76 (25.3) 77 (25.7)
Fatigue 52 (17.3) 46 (15.3)
Myalgia 38 (12.7) 29 (9.7)
Bone pain 34 (11.3) 12 (4)
Headache 27 (9) 22 (7.3)
Nausea 24 (8) 17 (5.7)
Pain in extremity 24 (8) 13 (4.3)
Insomnia 21 (7) 16 (5.3)
Depression 17 (5.7) 27 (9)
Back pain 18 (6) 17 (5.7)
Additional Safety Results Renal disorders
– No grade 3-4 renal disorders reported
– 1 patient with a grade-1 increase in serum creatinine level in the upfront group
Jaw disorders
– No osteonecrosis of the jaw reported
– 3 patients reported grade 1-2 jaw pain in the upfront group
Cardiac disorders
– Grade 3-4 cardiac disorders reported in < 2.5% of patients
– None were related to study drugs
Serious adverse events (SAEs) reported
– 16.7% of patients (upfront group), 18.7% of patients (delayed group)
Treatment discontinued due to SAEs
– 1.3% of patients (upfront group), 1% of patients (delayed group)
Conclusions Based on 12-mo data, upfront ZA (4 mg IV q 6 mo) prevents CTIBL in
PMW with early-stage BCa receiving adjuvant letrozole
– Primary endpoint of LS BMD was statistically significant in favor of the upfront ZA group
– TH BMD was also statistically significant in favor of the upfront ZA group
– 4% and 8% of patients in the delayed group experienced a decrease in BMD at 6 and 12 months, respectively, and required initiation of ZA
Bone markers were significantly decreased in patients receiving upfront ZA vs delayed ZA
Additional follow-up is needed to fully define the long-term benefit of ZA combined with AIs in PMW with early-stage BCa
References1. Pfeilschifter J, et al. J Clin Oncol. 2000;18:1570-1593.
2. Heshmati HM, et al. J Bone Miner Res. 2002;17:172-178.
3. Baum M, et al. Lancet. 2002;359:2131-2139.
4. Coombes RC, et al. N Engl J Med. 2004;350:1081-1092.
5. BIG 1-98 Collaborative Group. Breast. 2005;14:Suppl 1:S3. Abstract.
6. Reid IR, et al. N Engl J Med. 2002;346:653-661.
7. Gnant M, et al. Presented at: SABCS; December 8-11, 2004; San Antonio, Tex. Abstract 6.
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