Agenda. Adjuvant Bisphosphonates: Ready For Prime Time? The Osteoporosis Equation. Risk Factors for Osteoporosis. Charles L.

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1 Adjuvant Bisphosphonates: eady For Prime Time? The Osteoporosis Equation Aging, family history, race, menopause [estrogen deficiency] diet, exercise, smoking, alcohol, meds Charles L. Shapiro, MD Director of Breast Medical Oncology Peak bone mass Genetics Exposures Bone Loss Ohio State University Medical Center and Comprehensive Cancer Center March 29 amaswamy and Shapiro Semin Oncol 3:763, 23 Agenda Prevention of bone loss Chemotherapy-induced and GnHinduced ovarian failure isk Factors for Osteoporosis isk factor With BMD 95% CI Body Mass Index* Prior fracture after age 5* Parental history of fracture Aromatase-inhibitor-induced bone loss Prevention of metastasis Current smoking Ever use of steroids* Alcohol intake > 2/day heumatoid Arthritis *isk factor also in men Kanis et al Osteoporosis Int 16:581-9, 25 1

2 Fractures Increase Morbidity and Mortality Prior vertebral fracture associated with: Five-fold increase in future vertebral fracture Increase in hip fracture nearly double Hip fracture: Disability: 5% (many permanently) Long-term nursing home care 25% One year mortality up to 24% Lifetime risk of death=breast cancer Multiple vertebral fractures: Increased mortality rate, particularly from pulmonary disease Non-traumatic fractures are preventable 1. oss PD et al. Ann Intern Med. 1991;114: Cummings S et al. N Engl J Med. 1995;332: iggs BL et al. Bone. 1995;17:55S-511S. 4. ay NF. J Bone Miner es. 1997;12: Cummings S et al. Arch Intern Med. 1989;149: Kado DM et al. Arch Internal Med. 1999;159: Fracture isk Increases with Lower T-scores 5-Year Fracture isk (%) Vertebral Fractures Age (years) Adapted with permission from Cummings S et al. JAMA. 22;288: Hip Fractures T-score Measuring BMD Central DEXA Gold standard Measures spine, hip, or total body BMD T-score The number of SDs by which bone mass falls above or below the mean peak bone mass for a healthy 3- year-old females For every 1 SD decrease in T-score, relative risk of fracture increases ~1.5- to 2.5-fold Causes of Bone Loss Chemo-induced ovarian failure Glucocorticoids Bilateral oophorectomy Hypogonadism Elevated bone turnover Bilateral orchiectomy Aromatase inhibitors GnH agonists T-score Normal > -1 Osteopenia -1 to -2.5 Osteoporosis < -2.5 Bone loss Fracture Pfeilschifter J et al. J Clin Oncol. 2;18:

3 Sources of Estrogen in Post vs Pre Androgens Aromatase (CYP19) Chemotherapy-Induced Ovarian Failure causes Bone Loss at 1 Year 24 month data Shapiro Fuleilhan Saarto Hershman premenopausal Estrogens % BMD -2-4 postmenopausal -6 Lumbar spine Hip Aromatase -8-1 Women with ovarian failure Adipose tissue; ovary; brain 1.Shapiro CL et al. J Clin Oncol. 21;19: Fuleihan G J Clin Endocrinol Metab 9:329-14;25 3. Saarto T et al. J Clin Oncol. 1997;15: Hershman DL et al J Clin Oncol 28: ; 28 Ovarian failure after chemotherapy Fig 1. Probability of menopause during the first year after diagnosis (from model shown in Table 3) Bone loss at 12 mos in Lumbar Spine 4 Normal menopausal Aromatase inhibitor Tamoxifen Chemo-induced OF GnH agonist % Goodwin, P. J. et al. J Clin Oncol; 17: Copyright American Society of Clinical Oncology 1) Warming et al Osteoporosis Int 13:15-12, 22; 2) Eastell et al J Bone Min es 21: , 26; 3) Shapiro et al J Clin Oncol 14:336-11, 21; 4) Fogelman et al Osteoporosis Int 14:11-6, 23 3

4 Bisphosphonates CALGB 7989 esults ** ** ** ** ** Osteoclast inhibitors Inhibit Activation Differentiation Binding to bone matrix Secretion H FDA-approved** Side Effects of zoledronic acid enal toxicity, fevers, pain Osteonecrosis % (5.3) -6.6 (6.9) % ZA control Trial Design: 7989 Stratifications Stage Tamoxifen ZA q3 mo Calcium/ Vit D Adj Chemo /- tamoxifen Calcium/ Vit D 12mo 24mo 36 mo andomized Bisphosphonate Trials Delmas Saarto Powles Fuleihan N Bisphosphonate isedronate vs. placebo Clodronate vs. control Clodronate vs. placebo Pamidronate vs. placebo Effect N=439 Calcium/ Vit D ZA q3 mo Calcium/ Vit D Hershman Shapiro Gnant Zoledronic acid vs. placebo Zoledronic acid vs. control Zoledronic acid vs. placebo 4

5 ABCSG Trial 12 Sources of Estrogen in Post Aromatase Inhibitor Zoledronic acid 4 mg Q6 mo x 3 years No Zoledronic acid Control Androgens Aromatase (CYP19) Estrogens Premenopausal, E GnH agonist TAM or Anastrozole Baseline T-score -2. postmenopausal Aromatase Adipose tissue, ovary; brain Brufsky et al J Clin Oncol 25:829-36; 27 ABCSG-12: BMD Fractures with Aromatase Inhibitors Trial N F/U (mo) Treatment Clinical Fracture ate (%) AI vs. TAM ATAC A vs. TAM 11. vs. 7.7 [p<.1] BIG LET vs. TAM 8.6 vs. 5.8 [p<.1] T scores: w/ ZA T AI after 2-3 years of TAM IES EXE vs. TAM 7. vs. 5. [p=.3] T scores: no ZA Tam AI ABCSG8/ ANO 3224 AI after 5 years of TAM 28 A vs. TAM 2. vs. 1. [p=.15] MA LET vs. Placebo 5.3 vs. 4.6 [p=.25] Gnant, M. F.X. et al. J Clin Oncol; 25:

6 Z-Fast /ZO-Fast Trial ZO-FAST Trial: 36 months Postmenopausal Age 6 years Letrozole 2.5 Baseline T-score -2. Zoledronic acid 4 mg Q6 mo Zoledronic acid only if T-score < -2 Upfront ZA (N=524) Delayed ZA (N=536) P-Value % Lumbar Spine <.1 BMD % Total Hip BMD <.1 All Fractures 26 (5%) 32 (6%).52 Brufsky et al J Clin Oncol 25:829-36; 27 Eidtmann, SABCS 28, Abstract 44 esults esults of Delayed Group Baseline BMD 36-month BMD (%) Normal Normal -1 to -2 < -2 Missing Osteopenic Only 15% of Delayed Group received Zoledronic Acid at 36 mo 6

7 SABE Trial: isk Stratification Anastrozole Does Chemotherapy Directly Contribute to Bone Loss? High isk T score -2. (n=38) Moderate isk (n=154) T score -1. to -2. isedronate isedronate Placebo Trial Saarto (1997) Shapiro (21) Fogelman (23) N Ovarian failure or Amenorrhea Mean or median % CI -8.9, -4.7 etained Menstrual Function Mean or median % CI -3., 1.2 Low isk (n=42) T score -1. Observation p=.1 Van Poznak et al, SABCS 27, Abstract 53 Abbreviations: Confidence Interval (CI) p=.1; p>.5; ** p= women anastrazole 1 mg T-score -1 to women Aromatase Inhibitor Mean T score ~1 Ibandronate 15 mg q month Placebo At 2 years LS spine: I vs. P ~6%, p<.2 Denosumab 6 mg sc q 6 month Placebo At 2 years LS spine: D vs. P ~ 8%, p<.1 Treatment of Bone Loss in Cancer Same recommendations as for non-cancer isk factor assessment Physical activity, calcium/vitamin D, stop smoking, reduce alcohol DEXA screening every 2 years Bisphosphonate treatment if indicated by T- score Consider stopping bisphosphonate with normalization of T-score Lester, JE et al; Clin Can es 28; Ellis et al J Clin Oncol 28 7

8 ASCO Approach to Bone Loss Exercise, stop smoking, supplemental calcium/vitamin D isk Factors Ovarian failure AI treatment Low risk High risk BMD of L/S spine and Hip by DEXA scan Healthy Lifestyle Monitor T-score 2. to 1 T score 2.5, or < 2. w/f Monitor BMD Start bisphosphonate DEXA Scans Treatments Bisphosphonates Hillner BE et al. J Clin Oncol. 23;21: When to start a bisphosphonate? ASCO 23: Start bisphosphonate -2.5 or lower New Guidelines being finalized; based NOFG Start bisphosphonate at 2 or lower Use T-score in hip/lumbar or femoral neck Individualize therapy -1.5 to -2 based on risk factors isk Factors: smoking; alcohol; sedentary; family history; chronic corticosteroids; being on AI Vitamin D and Vitamin D Deficiency Calcium and Vitamin D reduces fractures WHI randomized placebo-controlled trial and meta-analysis of trials of vitamin D /- calcium reduces fractures with 8 IU/day Vitamin D deficiency Common, caused by decreased sun exposure, intake, absorption ecent study in breast cancer survivors show low or deficient 25-OH in 76% (Healthy Eating, Eating, Activity and Lifestyle or HEAL study) Overall mean (/- SD) = 25 (1) ng/ml African-American = 18 (9) ng/ml Hispanics = 22 (9) ng/ml No consensus on measuring serum vitamin D Correcting D deficiency improves response to bisphosphonate Bishoff-Ferrari et al JAMA 293: , 25; Jackson et al N Eng J Med 354:669-83, 26; Neuhoser et al Am J Clin Nutrition 88:133-9, 28; Adami et al Osteoporosis Int June on-line; Geller et al Endocr Pract 14:293-7, 28 8

9 How well are we doing? 259 age < 5; 89 (34%) chemo-induced ovarian failure: ecommendations egular exercise 72% Calcium/vitamin D 57% DEXA scan 4% Conclusions Estrogen deprivation either through chemotherapyinduced ovarian failure, AI Health professionals should be: Familiar with recommendations to maintain bone health DEXA scans to screen for osteoporosis, and criteria for bisphosphonate treatment Generate appropriate referrals ecommendations for bone health (calcium, vitamin D, exercise, reduce smoking and alcohol) promote overall health Many unanswered questions: who needs a bisphosphonate?; what is the optimal timing, dose, and duration? Is ZA new standard for women on AI? Tham, XL et al Abs # 67, SABCS 25 What about Osteonecrosis? eported in 3-11% metastatic pts on IV bisphosphonates: Schedule (monthly), duration (> 2-3 years), drug (zoledronic acid), and dental procedure No effective treatments Prevention: dental exam; oral hygiene, avoid dental work Very rarely observed in adjuvant trials using 4 mg q3 or q6 months Prevention of Distant ecurrence by adjuvant Bisphosphonates Two Hypotheses: Indirect anti-tumor effects Bisphosphonates breaking the Vicious Cycle Direct anti-tumor effects 9

10 ABCSG Trial 12 Zoledronic acid 4 mg Q6 mo x 3 years No Zoledronic acid Control Bone micrometastasis is adverse prognostic factor Factors that regulate normal bone breakdown/ new bone formation are growth factors for tumor cells Premenopausal, E GnH agonist TAM or Anastrozole Baseline T-score -2. Yoneda BBC 25 Brufsky et al J Clin Oncol 25:829-36; 27 Stopping the Vicious Cycle H=.64 ( ) Adjuvant Bisphosphonate 1

11 Preclinical Data using Bisphosphonates In breast cancer cell lines: Inhibits adhesion, invasion Apoptosis Antiangiogenic activity: Synergistic anti-tumor effects: With CMF, taxanes, doxorubicin AZUE Demographics Premenopausal Endocrine Only Chemo Only Endo Chemo Anthracyclines N ZA Dosing ADJ TX (n=1678) ADJ TX ZA (n=1681) Q1 mo x 6; Q3 mo x 8; Q6 mo x 5 = 5 yr ABCSG-12 (n=181) 1 1 ~4 Q6 mo x 3 yr AZUE UK Trial Higher pc with ZA Stage II/III N=336 Closed 1/26 Adjuvant Therapy (Neo, Chemo, Endo) Adjuvant Therapy ZA Subset of 25 (<1%) received neoadjuvant N CT CT ZA P Tumor size mm pc (%) Mastectomy (%) Suggestive, but hardly definitive. Winter, SABCS 28, Abstract 511 Winter, SABCS 28, Abstract

12 Trial Diel 1998; 24 BM mets AZUE Completed Trials Powles 22; 26 Saarto 21, 24 NSAPB 34 N F/U (mo) Treatment Clod 16 mg vs. control x 2 yr Clod 16 mg vs. placebo x 2 yr Clod 16 mg vs. control x 3 yr Clod 166 mg vs. placebo x 3 yr ZA Q1 mo x 6; Q3 mo x 8; Q6 mo x 5 = 5 yr Outcome survival bone mets non-bone mets Is adjuvant ZA ready for prime time? Early Adapters Yes in everyone Yes, but only in premenopausal with endocrine therapy Late Adapters No one, until AZUE and NSAPB are reported Yes, but only in premenopausal with endocrine therapy Trial INTEGOUP BIG 4-4 GAIN Ongoing Trials N F/U (mo) Treatment ZA vs. Clod vs. Ibandronate capectibine /- Ibandronate CEP /- capectibine /- Ibandronate Outcome Conclusions Zoledronic acid has anti-tumor activity in preclinical studies and in the results of one a few clinical trials More information is expected soon with presentations of larger trials My opinion is that we need more data to understand whether zoledronic should be prescribed for its anti-tumor effects in clinic 12