Highlights in the Management of Breast Cancer July 4-5, 2008 Domus Sessoriana , Rome

1. Highlights in the Management of Breast CancerJuly 4-5, 2008DomusSessoriana, Rome Aromatase inhibitors and bone loss prevention Paola Papaldo Regina Elena Institute, Rome

2. Osteoporosis and risk of fractures Osteoporosis is asymptomatic, and it is associated to an increase in the risk of fractures due to minor traumas (falls from a height which is below one’s stature), but not due to more important traumas (road accidents, falls from heights above one’s stature). Osteoporosis Normal bone density

3. Strategies for the Diagnosis of Osteoporosis The most widely used objective measurement, established by the WHO, is bone mineral density (BMD). Is measured by dual-energy x-ray absorptiometry (DXA)

4. The importance of BMD in evaluating fracture risk 82% of fractures occurred in women with T-scores > 22.5 (i.e. non-osteoporotic women), and 52% of fractures occurred in women with osteopenia (T-score 21.0 to 22.5) (Siris ES, et al. Arch Intern Med 2004) Women with BMD in the osteopenic range (T-score 21.0 to 22.5) are at increased risk of fracture and that treatment may be necessary before women become osteoporotic (T-score < 22.5).

5. Osteoporosi e rischiodifrattura l'osteoporosisi associa ad un aumentato rischio di fratture da trauma minimo (caduta da un altezza inferiore alla propria statura), ma non da traumi importanti (incidenti stradali, caduta da altezza superiore alla propria statura)

6. Risk of osteoporosis before age 65 Screening for osteoporosis before age 65 may also be appropriate on the basis of several risk factors such as: limited physical activity, smoking, thin or petite body habitus, family history of osteoporosis, chronic use of medications associated with impairment of bone metabolism (corticosteroids, many immunosuppressants, chronic heparin therapy, anticonvulsants, proton pump inhibitors, thiazolidinediones, selective serotonin reuptake inhibitors)

7. Menopausal and osteoporosis • With our rapidly aging population, an • osteoporosis epidemic appears inevitable. • Symptomatic osteoporosis in postmenopausal women: nearly 25% meet diagnostic criteria for osteoporosis by age 60, nearly 50% by age 70, and nearly 70% by age 80. • Statistics by World Health Organization (WHO) criteria, the majority of women above age 60 are osteopenic(Melton LJ III. J Bone Miner Res. 1995;10:175-177.) • Increased incidence of osteoporosis is expected in BC pts due to early menopause chemotherapy and hormonal treatment (castration and AIs)

9. Osteoporosi e rischiodifrattura l'osteoporosisi associa ad un aumentato rischio di fratture da trauma minimo (caduta da un altezza inferiore alla propria statura), ma non da traumi importanti (incidenti stradali, caduta da altezza superiore alla propria statura)

10. Osteoporosi e rischiodifrattura l'osteoporosisi associa ad un aumentato rischio di fratture da trauma minimo (caduta da un altezza inferiore alla propria statura), ma non da traumi importanti (incidenti stradali, caduta da altezza superiore alla propria statura)

11. Osteoporosi e rischiodifrattura l'osteoporosisi associa ad un aumentato rischio di fratture da trauma minimo (caduta da un altezza inferiore alla propria statura), ma non da traumi importanti (incidenti stradali, caduta da altezza superiore alla propria statura)

12. Osteoporosi e rischiodifrattura l'osteoporosisi associa ad un aumentato rischio di fratture da trauma minimo (caduta da un altezza inferiore alla propria statura), ma non da traumi importanti (incidenti stradali, caduta da altezza superiore alla propria statura)

13. Fracture incidence in aromatase inhibitor trials {Lipton A,et al. Women’s Health 2007; 3: 441–448)

14. Fractures in aromataseinibitor studies Taken together, the results from large, well-designed, randomized, controlled clinical trials and the associated bone substudies provide strong evidence that both steroid and nonsteroid AI therapy can result in significant bone loss and increased risk of fracture

15. Effect of Anastrozole on Bone Mineral Density: 5-Year Results (ATAC trial) Richard Eastell, Journal of Clinical Oncology, Vol 26, No 7 (March 1), 2008: Mean percentage changes in bone mineral density after 1, 2, and 5 years Lumbar spine Hip

16. Effect of Anastrozole on Bone Mineral Density: 5-Year Results (ATAC trial) Richard Eastell, Journal of Clinical Oncology, Vol 26, No 7 (March 1), 2008: Only those pts with a baseline T-score of less than –1.5 developed osteoporosis on treatment (data within blue circle). Among AI pts, there was a decrease in median BMD in lumbar spine (–6.08%) and total hip (–7.24%)compared with the TAM group (lumbar spine, +2.77%; totalhip, +0.74%).

17. Long-term effects of anastrozole on bone: 7-year results from ATAC Coleman R; ATAC Trialists’ Group ASCO 2008 Increased bone-loss observed during the 5-year treatment period with anastrozole compared with TAM did not persist once treatment had stopped. A partial recovery of bone mineral density (BMD) loss at the lumbar spine and no further loss in BMD at the hip was seen in the anastrozole group during off-treatment follow-up In pts treated with TAM, the bone-sparing effects were lost once treatment had ended No patient with normal BMD at 5 years became osteoporotic during the off-treatment follow-up

18. Monitoring of Bone Mineral • Density • Appropriate Therapeutic • Intervention to Prevent • Fractures • Are of Paramount Importance

19. Treatment / Prevention of osteoporosis Lifestyle modification (increased physical activity, smoking cessation) Calcium and Vitamin D Bisphosphonates

20. Osteoporosi e rischiodifrattura l'osteoporosisi associa ad un aumentato rischio di fratture da trauma minimo (caduta da un altezza inferiore alla propria statura), ma non da traumi importanti (incidenti stradali, caduta da altezza superiore alla propria statura)

21. Lifestyle advice • Regular exercise (aerobic, • weight bearing, and resistance • exercises, walking, jogging) should be performed for at least 30 minutes three times a week. • • Completely immobilized patients may lose up to 40% of their bone mass in 1 year, whereas passive physical exercise for 30 minutes each day may completely prevent such bone loss. • Marcus R. In: Favusetak, Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism.4th ed. 1999:262-264

22. Lifestyle advice Try to eliminate known risk factors for osteoporosis development – Alcohol – Caffeine – High Sodium – Smoking – Low Calcium Intake

23. Calcium supplementation • • Women older than 50 need • 1,200mg/day of calcium (1 liter • of milk = 1.2g/calcium, blue fish, • broccoli, spinach, beans, mineral water) • Most individuals require 500 –1,000mg/day as a supplement to dietary sources to realize these intakes. • The average dietary consumption of calcium is about 600 mg [per day]. It is important not to take more than one needs. • Heaney RP. AmJ Med1991;91:23S-28SHeaney 28S

24. Vitamin D supplementation • Vitamin D is important for: – Facilitating calcium absorbition – Osteoclasticresorption • Serum Vitamin D levels decline with age • Vitamin D supplementation in the elderly reduces fractures of all types ChapuyMC.Osteoporosis Int1997;7:439-443 Heikinheimo RJ. Calcif Tissue Int1992;51:105-110

25. Vitamin D supplementation • 400 – 800 IU/day (eggs, liver, fish) • Depends on solar exposure and food intakes • Best to use in combination with 500 –1,000 mg/day of calcium The serum 25-hydroxyvitamin D levels, which represent the best measurement of vitamin D, can be helpful in assessing the need for supplementation, so that the dose is adequate but not excessive. HillnerBE et al. J ClinOncol. 2003;21:4042-4057.

26. Bisphosphonates • Etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva),zoledronate (Zometa or Reclast), • These agents have similar efficacy profiles for preventing vertebral fractures • Their long-term effects are not well understood (osteonecrosis of the jaw and rare fractures in the subtrochanteric femur)

27. Bisphosphonates • The bisphosphonates are all related to pyrophosphate (PPi), which is a byproduct of cellular metabolism. • Pyrophosphate is a natural circulating inhibtor of mineralization in the blood and urine which can't get inside the bones because alkaline phosphatase destroy it (people with genetic problems of alkallinephosphatase have osteomalacia) • If a carbon is substituted for the oxygen, then a bisphosphonate is formed by pyrophosphate

28. Bisphosphonates • These medications are poorly absorbed and any food in the stomach will reduce the amount absorbed. • They also can cause esophageal erosions so must be "flushed down" with at least 6 oz of water. • Calcium supplementation following the doses of etidronate reduced effectiveness, so you don't give any calcium for at least 4 hours after taking the medicine. • The techniques for taking these oral drugs are similar.  • One needs to take one dose first in the morning, while sitting or standing. With Aledronate (Fosamax) and Risedronate (Actonel) one must then remain with an empty stomach for 30 minutes, and with Ibandronate (Boniva) for 1 hour.

29. Bisphosphonates - SIDE EFFECTS

30. Bisphosphonates - Incidence of jaw osteonecrosis These charts are from a review of 119 patients The incidence in ordinary osteoporosis is very low.

31. Bisphosphonates Reductions in the bone formation Mineralizing surface as a percentage of the trabecular bone surface The bisphosphonates cause dramatic reductions in the bone formation. It is not clear if this is a direct effect of bisphosphonates or if it is just secondary to the inhibition of bone resorption. With higher doses only 0.16% of the surface is still forming bone. After prolonged usage or with high doses the bone could potentially become more brittle.

32. Bisphosphonates in osteoporosis • The choice of agents is a difficult question to answer due to the inability to compare the different agents across the different clinical trials. • They are NOT APPROVED for prevention of osteoporosis in premenopausal women. • They should not be used in women who got a DEXA and discovered osteopenia. • INDICATIONS - ♦Postmenopausal women with vertebral compression fractures. ♦Postmenopausal women with total hip bone density T-score below -2.5.♦Elderly men with non-traumatic fractures. ♦Some patients with secondary osteoporosis due to corticosteroids. ♦Paget's disease. ♦Cancer metastatic to bone. ♦Other bone diseases with high bone reasorption

33. 29th Annual Meeting of the American Society forBone and MineralResearch (ASBMR). HONOLULU, HAWAII --September 25, 2007 1,292 postmenopausal women with meanlumbar spine BMD T-scorewas -3.2 at baselineand a history of at least one vertebral fracture Women were randomised to risedronate 5 mg daily or to 150 mg monthly. All participants also took calcium 1,000 mg and vitamin D 400 to 1,000 IU supplements daily. At 12 months, there was a 3.54% increase in lumbar spine BMD with monthly risedronateand a 3.43% increase at 12 months with daily risedronate. Fracture rates have not yet been assessed (The Merit-OPStudy. Abstract T382). Another presentation showed that a monthly bisphosphonateregimen results in significantly fewer gastrointestinal (GI) adverse events compared with a weekly regimen. (S. T. Harris. Abstract W353)

34. Oral ibandronate prevents anastrozole-induced bone loss during adjuvant treatment for breast cancer. Two-year results from the ARIBON studyJ. E. Lester, ASCO 2008 131 postmenopausal women receiving adjuvant anastrozole randomized to: oral ibandronate at a dose of 150 mg/month B) or placebo mean percentage BMD lumbar spine hip 1 year 2 years 1 year 2 years

35. Osteoporosis Drug Promotes Atrial Fibrillation in Population-Based Study (Heckbert SR, et al. Arch Intern Med. 2008;168:826-831). AF associated with current or past alendronate (Fosamax, Merck) use among nearly 1700 women in a clinical practice setting: Women who have ever taken alendronate have an increased risk of developing atrial fibrillation (AF), according to a population-based, case-control study

36. ZO-FAST: 1065 pts in 150 centers in rest of world Z-FAST: 602 pts in 93 centers in US and Canada Z-FAST and ZO-FAST: Design Three companion Zometa-Femara Adjuvant Synergy Trials(Z-FAST, N = 602; ZO-FAST, N = 1066; E-ZO-FAST, N = 527) Letrozole +immediate Zoledronic Acid R A N D O M I Z E • Adjuvant BC • ER+ or PgR+ • PM + RP* • No prior HT × 12 mo • No prior bisphos • (12 mo IV, 3 mo PO) • T score ≥-2 SD • Stratification • Adj CT • T score • Established vs recent postmeno* • Delayed ZA • BMD T score ≤2 SD • Or clinical fracture • Or asymptomatic fracture at 36 mo Letrozole ZA: 4 mg IV q6mo Letrozole: 2.5 mg/d ER = estrogen receptor; PgR = progesterone receptor; HT = hormone therapy; SD = standard deviation; CT = chemotherapy; PM = established postmenopausal; RP = recently postmenopausal, *for ZO-FAST only

37. Z-FAST: Mean BMD Mean Percentage Change in BMD Total Hip Lumbar Spine P<0.0001 P<0.0001 Mean Percent Change in BMD from Baseline to 12 Months

38. ZO-FAST: Mean BMD Hip Lumbar Spine P<0.0001 P<0.0001 Mean Percent Change in BMD from Baseline to 12 Months

39. Conclusions • Based on 12-mo data from both Z-FAST and ZO-FAST studies, upfront ZA (4 mg IV q 6 mo) prevents AI bone lost in postmenopausal women with early-stage BCa receiving adjuvant letrozole • Results from the 24- and 36-month analyses of the Z-FAST trial indicate that women receiving up-front zoledronic acid continue to gain BMD during the 3 years of therapy (BrufskyA,et al. Breast Cancer Res Treat 2007; Abstr 27). • The recent 12-month results from E-ZO-FAST are consistent with the other 2 studies (Schenk N, et al. Barcelona, ECCO 14 2007; Abstr 2008). • Additional follow-up is needed to fully define the long-term benefit of ZA combined with AIs in postmenopausal women with early-stage BCa

40. Zoledronic acid To date, twice-yearly dosing of zoledronic acid has proven safe. Out of a total of 2195 patients, • 6 cases of osteonecrosis of the jaw (ONJ) have been reported and only 1 (<0.05%) case has been confirmed by the ONJ Adjudication Committee. • Only 3 patients had impaired renal function that was suspected to be related to bisphosphonate treatment

41. Zoledronic Acid Prevents Cancer Treatment–Induced Bone Loss in Premenopausal Austrian Breast and Colorectal Cancer Study Group - JCO 2007 • TAM (20 mg/d orally) and goserelin(3.6 mg every 28 days subcutaneously) ± zoledronic acid (4 mg intravenously every 6 months) • versus • Anastrozole (1 mg/d orally) and goserelin± zoledronicacid for 3 years • 401 pts were included in the BMD subprotocol (patients underwent serial BMD measurements at 0, 6, 12, 24, and 36 months.). • Overall bone loss was significantly more severe in patients receiving anastrozole/goserelin (BMD, 17.3%; mean T score reduction, 2.6) • compared with patients receiving tamoxifen/goserelin (BMD, 11.6%; mean T score reduction, 1.1). • In contrast, BMD remained stable in zoledronic acid–treated patients (P .0001 compared with endocrine therapy alone)

42. Zoledronic Acid Prevents Cancer Treatment–Induced Bone Loss in Premenopausal Austrian Breast and Colorectal Cancer Study Group - JCO 2007 Lumbar spine Trochanter

43. Adjuvant ovarian suppression combined with tamoxifen or anastrozole, ± zoledronic acid, in premenopausal - First efficacy results from ABCSG-12. (Gnant M, et al. ASCO 2008. Ab. LBA4) • 1800 women • no significant difference in DFS, relapse-free survival or overall survival when comparing anastrozole with tamoxifen • DFS events: 54 in zoledronic acid group 83 in placebo group hazard ratio of 0.643 (95% confidence interval: 0.46-0.91), with a p value of 0.011

44. Use of adjuvant bisphosphonate therapy • The benefits of zoledronic acid treatment in the adjuvant setting may extend beyond preserving BMD and preventing fractures. • The effects of Zoledronic acid appeared to occur “ in and outside the bone” , with a decreased risk of contralateral breast cancer, locoregional, and distant recurrence • Ongoing clinical trials will evaluate the potential role of bisphosphonates in extending disease-free survival in women with breast cancer

45. More data from ATAC • Buzdar A; ATAC Trialists’ Group. ASCO 2008 Abstract 552. • As the length of follow-up increases in clinical trials of women with early breast cancer, competing causes of death are a major confounder of survival findings • After a median of 100 months of follow-up: • 10.2% of women enrolled in the trial had died following recurrence, and 8.8% had died without recurrence. • Death from breast cancer was strongly related to nodal status, with node-positive patients having a two-fold greater chance of death than their node-negative counterparts. • Older age and a history of smoking were important predictors of non-breast cancer death.