Bisphosphonates in Breast Cancer: From Prevention of Bone Loss to Prevention of Recurrence Adam Brufsky, MD, PhD Associate Chief, Hematology/Oncology Director, Breast Cancer Program University of Pittsburgh Aromatase Inhibitors Are Consistently Superior to Tamoxifen (Disease-Free Survival) Absolute Trial (months) Aromatase inhibitor benefit, % Hazard ratio 0.83 ATAC (68)1 Anastrozole up front (5 yr) 2.5 0.81 BIG 1-98 (26)2 Letrozole up front (5 yr) 2.6 0.82 BIG 1-98 (51)3* Letrozole up front (5 yr) 2.9 0.68 IES (30)4 Exemestane (3 yr) 4.7 0.76 IES (56)5 Exemestane (5 yr) 3.4 ARNO/ 0.60 Anastrozole (2 yr) 3.1 ABCSG (28)6 0.58 MA-17 (30)7 Letrozole (5 yr) vs placebo 4.9 0.5 0.6 0.7 0.8 0.9 1.0 *Analysis restricted to monotherapy arm A vs arm B. 1. Howell A, et al. Lancet. 2005;365:60-62; 2. Thurlimann B, et al. New Engl J Med. 2005;353:2747-2757; 3. Coates A, et al. J Clin Oncol. 2007;486:492-494; 4. Coombes RC, et al. New Engl J Med. 2004;350:1081-1092; 5. Coombes RC, et al. Lancet. 2007;369:559-570; 6. Jakesz R, et al. Lancet. 2005;366:455-462; 7. Goss P, et al. J Natl Cancer Inst. 2005;97:1262-1271. MA.17 Post-Unblinding Cohorts Median F/U 30 Months 54 (16 –86) Months Letrozole n= 2593 Letrozole (LET) n = 2457 Tamoxifen n = 5187 Placebo n= 2594 No Letrozole (PLAC) n = 613 5 years 5 years Letrozole (PLAC-LET) n = 1655 1998 2003 2005 Unblinding Ingle et al Goss et al SABCS 2005 Percentage of Patients with Recurrence 2.5 2.4 2 1.5 1.4 1.5 1.3 Percent 1 0.5 0.5 0.4 0.2 0.24 0 New Primary Local- Distant CBC Only regional PLAC PLAC-LET SABCS 2005 Adverse Events After Unblinding P=0.007 P=0.84 4.0% P=0.60 3.5% 3.0% 2.5% 2.0% 1.5% 1.0% 0.5% 0.0% Bone Fracture New Osteoporosis CV Disease PLAC-LET PLAC SABCS 2005 ATAC trial design Postmenopausal women with invasive breast cancer (n = 9366) Surgery radiotherapy chemotherapy Randomisation 1:1:1 for 5 years Anastrozole Tamoxifen DiscontinuedCombination following (n = 3125) (n = 3116) initialn=3125 analysis as no efficacy or tolerability benefit compared with ITT population ITT population tamoxifen arm n = 3125 n = 3116 Safety population Safety population n = 3092 n = 3094 HR+ subpopulation HR+ subpopulation n = 2618 n = 2598 ITT, intent-to-treat; HR+, hormone receptor-positive Disease-free survival HR+ patients 29.9% Patients 30 HR 95% CI p-value 30 (%) 25 HR+ 0.85 (0.76, 0.94) 0.003 25 25.8% 20 Tamoxifen (T) 20 Anastrozole (A) 16.4% 15 15 10 13.9% 10 5 5 Absolute difference 2.5% 4.1% 0 0 0 1 2 3 4 5 6 7 8 9 Follow-up time (years) At risk: A 2618 2541 2453 2361 2278 2159 1995 1801 1492 608 T 2598 2516 2400 2306 2196 2075 1896 1711 1396 547 HR, hazard ratio; CI, confidence interval All AIs Significantly Reduce Estrogen Levels Aromatase AI drug inhibition, % Plasma estradiol 12/12 undetectable 1 Letrozole > 99.1 Mean 2.1 pmol/L 9/12 undetectable 1 Anastrozole 97.3 Mean 2.6 pmol/L 7/9 undetectable Exemestane2 97.9 Mean 2.8 pmol/L AI = Aromatase inhibitor. 1. Geisler J, et al. J Clin Oncol. 2002;20:751-757; 2. Geisler J, et al. Clin Cancer Res. 1998;4:2089-2093. Aromatase Inhibition Is Associated With Higher Rate of Estrogen Depletion Compared With PMW Change in Corresponding estrogen levels bone loss at hip PMW1 BC + AI2 –1 Estrogen Estrogen level Annual Annual BMD loss, % –2 Years PMW1 BC + AI2 PMW = Postmenopausal women; BC = Breast cancer; AI = Aromatase inhibitor. 1. Stone K, et al. J Bone Miner Res. 1998;13:1167-1174; 2. Eastell R, et al. J Bone Miner Res. 2006;21:1215-1223. Bone Architecture is Compromised by Estrogen Deficiency and Increased Bone Turnover Normal Osteoporosis Dempster DW. J Bone Miner Res. 2000;15:20-23. Decrease in Bone Mineral Density (BMD) is Associate with Fracture Risk 16X 8X Fracture risk 4X 2X 1X 1.0 0 -1.0 -2.0 -3.0 -4.0 Normal Osteopenia Osteoporosis BMD T-score (Standard deviation, SD) 80% of Fractures Occur in Women Who Are Not Osteoporotic 50 450 Fracture rate 45 No. of women with fractures 400 of womenwithNumber fractures BMD distribution years - 40 350 35 300 30 250 25 200 20 150 15 10 100 50 5 Fracture rate per 1,000 person per 1,000rate Fracture 0 0 >1.0 1.0 to 0.5 0.5 to 0.0 0.0 to –0.5 –0.5 to –1.0 –1.0 to –1.5 –1.5 to –2.0 –2.0 to –2.5 –2.5 to –3.0 –3.0 to –3.5 < –3.5 BMD • Fracture rate increases ~2-fold in osteopenic women • Majority of fractures occur in osteopenic women (T-Score between -1.0 to -2.5) Reprinted from Siris ES, et al. Arch Intern Med. 2004;164:1108-1112. All AIs Increase Fracture Risk Letrozole Placebo Exemestane 14 Tamoxifen Anastrozole P < .0001 12 11% 10 P = .003 7.7% 8 7.0% P < .001 P = .25 5.7% 5.3% 6 5.0% 4.6% Fractures, % Fractures, 4.0% 4 2 0 ATAC1 IES2 BIG 1-983 MA.174 (68 months) (58 months) (26 months) (30 months) AI = Aromatase inhibitor. 1. Howell A, et al. Lancet. 2005;365:60-62; 2. Coleman RE, et al. Lancet Oncol. 2007;8:119-127; 3. Thurlimann B, et al. N Engl J Med. 2005;353:2747-2757; 4. Goss PE, et al. J Natl Cancer Inst. 2005;97:1262-1271. Fractures (occurring at any time before recurrence) Fractures before recurrence A T A vs T N=3092 N=3094 (%) (%) Odds ratio 95% CI p-value Patients with one or more 421 311 1.41 1.21-1.65 <0.0001 fracture episodes (13.6) (10.1) Hip 49 42 1.17 0.75-1.82 0.46 (1.6) (1.4) Spine 60 37 1.64 1.08-2.48 0.02 (1.9) (1.2) Wrist / colles 94 83 1.14 0.84-1.54 0.4 (3.0) (2.7) All other sites 270 191 1.46 1.20-1.77 0.0001 (8.7) (6.2) A, anastrozole; T, tamoxifen Fracture episode rates throughout the study Annual 4 fracture Tamoxifen (T) episode Anastrozole (A) rates (%) 3 2 1 0 0 1 2 3 4 5 6 7 8 9 Time since randomisation (years) At risk: A 2984 2859 2745 2640 2496 2306 2077 1713 702 T 2976 2824 2699 2572 2419 2208 2000 1645 659 Bone Loss in Breast Cancer and Its Management Different Classes of Bisphosphonates O HO OH OH HO P OH P O P OH CH O OH N 3 OH OH OH HO P OH H2N P OH O O OH O P Etidronate Pamidronate OH OH HO O O Risedronate P P CI OH OH O OH H2N HO N OH OH CI P P N P O OH OH OH O O Alendronate Clodronate P OH HO HO OH HO OH OH O P OH P CH3 OH O OH N P Zoledronic acid P O OH CI S OH O Tiludronate CH3 Ibandronate Thurlimann. Bisphosphonates in Clinical Oncology: The Development of Pamidronate. 1999. Fleisch. Endocr Rev. 1998;19:80. Relative Potency of Bisphosphonates Zoledronic acid 3 10 Ibandronate Risedronate Dimethyl-APD 102 Alendronate 50 IC Clodronate Pamidronate 101 Neridronate 0 Relative potency vitro potency in Relative 10 Etidronate 100 101 102 103 104 105 Relative potency in vivo (rat) ED50 Zoledronic Acid and Bone Health Management- AIBL Zoledronic Acid Increases BMD in Postmenopausal Women With Low BMD Lumbar spine Femoral neck 7 Zoledronic acid 4 mg Zoledronic acid 4 mg 3.0 5 1.5 3 Placebo 1 Placebo 0 Change in in BMD, % Change -1 -1.5 0 3 6 9 12 0 3 6 9 12 Time, months Time, months Reid IR, et al. N Engl J Med. 2002;346:653-661. Ongoing Trials of Zoledronic Acid For Prevention of Aromatase Inhibitor-Induced Bone Loss (AIBL) • Premenopausal ABCSG-12 (n= 401) • Postmenopausal Z-FAST (n= 602) ZO-FAST (n=1,066) E-ZO-FAST (n= 526) Total of patients treated with Zoledronic acid n= 2,595 ABCSG-12: BMD in Premenopausal Women Receiving Adjuvant Hormonal Therapy . Accrual 1999 to 2006 . 1,800 premenopausal ♀ Tamoxifen + . Bone sub-study (n= 401) Zoledronic acid (4 mg)* q 6 mo . Stage I & II, < 10 pos nodes, R ER+ and/or PgR+ A N . Treatment duration: 3 years Tamoxifen D . Preoperative CT allowed O M Anastrozole + I Surgery Goserelin Zoledronic acid (4 mg)* q 6 mo (+XRT) 3.6 mg/28 days Z E Anastrozole Baseline 6-month 3 years, BMD BMD final BMD ABCSG-12 = Austrian Breast and Colorectal Cancer Study Group Trial 12; BMD = Bone mineral density; CT = Chemotherapy; XRT=Preoperative radiotherapy. *8 mg reduced to 4 mg. Gnant MF, et al. J Clin Oncol. 2007;25:820-828. ABCSG-12 (Follow-up 5 years): % BMD change at the LS Gnant MF. Presented at SABCS 2007, Abstract #26 Zoledronic Acid Preserves BMD Over 3 Years of Adjuvant Therapy Goserelin/Anastrozole Goserelin/Anastrozole + ZOL 100 100 80 80 60 60 Patients, % Patients, Patients, % Patients, 40 40 20 20 0 0 0 6 12 36 0 6 12 36 Time, months Osteoporosis Time, months Osteopenia Normal BMD = Bone mineral density; ZOL = Zoledronic acid.