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SERMs New data & The Future

SERMs New data & The Future. P. Neven, M.D., Ph.D. Dept. Obstetrics and Gynaecol Gyn Oncol and Multidisciplinary Breast Centre UZ Leuven. Outline. SERMs: Mechanism of Action Oestrogenic or anti-oestrogenic ? Major publications in past few years RCT and peer-reviewed data Future

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SERMs New data & The Future

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  1. SERMsNew data & The Future P. Neven, M.D., Ph.D. Dept. Obstetrics and Gynaecol Gyn Oncol and Multidisciplinary Breast Centre UZ Leuven

  2. Outline • SERMs: Mechanism of Action • Oestrogenic or anti-oestrogenic ? • Major publications in past few years • RCT and peer-reviewed data • Future • New SERMs Tamoxifen, Raloxifene, Lasofoxifene More evidence than before Time is ripe for reassessment of the rapidly changing SERM concept

  3. Estrogen-Receptor Action SERM-ER interactions: Complex and Ligand Dependent Breast tamoxifen oestradiol Target genes SERMs initiate or suppress target genes leading them to their actions SERM activity ~ relative levels or coregulators in target cells Riggs BL and Hartmann LC in N Engl J Med 2003;348:1192

  4. Endometrium Target genes differ for oestradiol and tamoxifen They bind to the same ER In Vitro Signalling Different ligands bind to different parts of the ER or different subtypes with different affinities, recruiting different co-activators/repressors resulting in differential gene regulation Shang Y et al. Science 2002 & Nat Cancer Rev 2006 In Vivo signalling > 3X down-regulated >3X up-regulated RNA-extraction: gene-expression profiling Tamoxifen-treatment results in modulation of expression of specific genes (370 genes) Tamoxifen-treatment results in modulation of genes also regulated by estrogens (142 genes) Gielen S. et al. Signaling by estrogens and tamoxifen in the human endometrium in J Steroid Biochem Mol Biol 2008

  5. Evolution of the SERM-Concept • A compound that binds with a high affinity to the ER and not to another nuclear receptor • It should induce an oestrogenic activity in some tissues and oestrogenic antagonistic activity in others • Each SERM induces a unique set of clinical responses which frequently differs from another SERM and can not be compared to oestrogen or anti-oestrogen

  6. SERM Development Timeline Fulvestranta DT56a HMR 3339 *Lasofoxifene +Arzoxifene +Raloxifenea *Tamoxifena +Bazedoxifene *Toremifene *Droloxifene *Ospemifene *Clomiphene DES *Idoxifene 1990 1930 1940 1980 2000 2010 1950 1960 1970 *Tamoxifen-Like +Raloxifene-Like aFDA-approved. Graphic courtesy of William H. Catherino, MD, PhD.

  7. Tamoxifen • 1962: Oral Contraceptive • 1973: Metastatische ER+ borstkanker • 1980: Adjuvante behandeling van ER+ borstkanker • 1995: Behandeling van ER+ DCIS • 2000: Preventie van borstkanker bij risico ≥1.67% volgens GAIL-model (NNT: 1/100 – 1/25) • 2002-8: EBCC Shall we abandon tamoxifen? No • 2010: Longer against shorter (10 years) • ?: Low dose (5 mg) • ?: Gel (mastodynia) • ?: By CYP2D6 status D. Hayes JNCI 2008

  8. Adjuvant Tamoxifen Therapy Pre- and Postmenopausal Women ABSOLUTE 15 YEAR SURVIVAL IMPROVEMENT BY NODAL STATUS Node +ve pts Node -ve pts lives saved/100 women + 11% + 6% 5 years tamoxifen EBCTG 2005 AIs ATLAS and aTTom trial only preliminary results

  9. Chemoprevention with tamoxifenOnly if high risk…FDA Carry over effect Cumulative rates per 1000 women of invasive and noninvasive breast cancers in NSABP P-1 participants by treatment group JNCI 1998 and Update JNCI 2005

  10. Risks Balancing Risks and Benefits Benefits EMEA: No indication Vascular events! Premenopausals Similar efficacy Less toxicity DVT Stroke Cataracts No Carry Over

  11. Raloxifene • 1980: A failed breast cancer drug • 1990: Preclinical uterine data • 1998: Osteoporosis drug • 2008: Prevention and therapy of postmenopausal osteoporosis and prevention of breast cancer if osteoporosis or high breast cancer risk Premenopausals: Fibroids, Endometriosis

  12. The Ideal Serm? Raloxifene Agonist Antagonist Bone CVS Breast Uterus

  13. Large-Scale Raloxifene Clinical Trials Source: Review: 19,747 20000 15000 10,101 Reviewer Memo: Number of Enrolled Women 7,705 10000 4,011 5000 1,400 1,764 0 Osteoporosis Prevention MORE CORE RUTH STAR EVA MORE, Multiple Outcomes of Raloxifene Evaluation; CORE, Continuing Outcomes Relevant to EVISTA; RUTH, Raloxifene Use for The Heart; STAR, Study of Tamoxifen and Raloxifene; EVA, EVISTA-Alendronate Comparison Slide Modified: Memo:

  14. Breast Cancer PreventionMultiple Outcomes of Raloxifene Evaluation (MORE) TrialRecruitment Postmenopausal Women With Osteoporosis (n=7,705) Raloxifene 120 mg/d (n=2,572) Raloxifene 60 mg/d (n=2,557) Placebo (n=2,576) 3-Year Intervention Primary Endpoint: Fractures Secondary Endpoint: Breast Cancer Cummings et al., 1999

  15. Source: MORE plus CORE Study Design Review: Gap MORE Conclusion CORE Screening MORE (N=7705) CORE (n=4011) Three Treatment Two Treatment Groups Groups Placebo Placebo Reviewer Memo: Raloxifene HCl 60 mg/day Raloxifene HCl 60 mg/day Raloxifene HCl 120 mg/day Year 0 1 2 3 4 5 6 7 8 8 Years Total Follow-up Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761 Slide Modified: Memo:

  16. Raloxifene Is Approved for the Preventionand Treatment of Osteoporosis (MORE) 43% less vertebral fractures No effect against non-vertebral fractures No risk/effect on CHD or stroke Less endometrial cancer/ vaginal bleeding HR = 0.57 (95% CI, 0.42-0.78) 43% decreased risk 5.2 fewer fractures per 1000/yr Clinical vertebral fracturesper 1000 woman-yrs DVT: RR X2!

  17. Source: Source: Invasive Breast CancerMORE Review: Review: Reviewer Memo: Reviewer Memo: 3.1 fewer cases per 1000/yr Slide Modified: Slide Modified: Memo: Memo:

  18. Source: Invasive Breast Cancer 8 Years of MORE plus CORE (N=7705) Review: 4.0 Placebo 4.2 per 1000 Women-Yrs HR 0.34 (95% CI = 0.22-0.50) 3.0 -2.8 per 1000/y Reviewer Memo: p <0.001 66% Cumulative Incidence (%) 2.0 1.0 Raloxifene 1.4 per 1000 Women-Yrs 0.0 0 1 2 3 4 5 6 7 8 Sustained DVT risk: 2.17 Years in Study Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761 Slide Modified: Memo:

  19. Balance of Efficacy and Safety OutcomesMORE FAVORS RALOXIFENE FAVORS PLACEBO Opgepast!

  20. Endometrial Cancer Risk • All EnCa in Philadelphia 07-1999 & 06-2002 • 547 cases versus 1410 controls • Raloxifene users had significantly lower odds of endometrial cancer compared with both tamoxifen users and SERM nonusers, suggesting a role for raloxifene in endometrial cancer prevention and individualization of SERM therapy. J Clin Oncol: 2008 Sep 1;26(25):4151-9 angela.demichele@uphs.upenn.edu

  21. Source: Very recent breast cancer data! Effects of Raloxifeneon Cardiovascular Events and Breast Cancer in Postmenopausal WomenAt high risk for cardiac problemsElizabeth Barrett-Connor1 MD et al. for the Raloxifene Use for The Heart (RUTH) Trial Investigators Review: Reviewer Memo: Barrett-Connor E et al. N Engl J Med 2006: 355; 125-37 Slide Modified: Memo:

  22. Source: RUTH: Baseline Characteristics Review: Reviewer Memo: *P<0.05 Barrett-Connor E et al. N Engl J Med 2006: 355; 125-37 Slide Modified: Memo:

  23. RUTH: Cumulative Incidence Rate for Primary Coronary Endpoint* for All Randomized Women (N=10,101) Source: Review: Reviewer Memo: *First occurrence of coronary death, non-fatal MI, or hospitalized acute coronary syndrome Barrett-Connor E et al. N Engl J Med 2006: 355; 125-37 Slide Modified: Memo:

  24. RUTH: Breast Cancer results from a normal breast cancer risk population Based on the Gail model1, the mean estimated 5-year risk of developing invasive breast cancer in both treatment groups was 1.7% Median duration of follow-up was 5.6 years in both groups During follow-up, 92% of women had a mammogram at 2 years, 88% at 4 years, and 80% at 6 years Clinical breast examination was performed for 91% of participants at 2 years, 88% at 4 years, and 86% at 6 years of follow-up During follow-up, 76 women in the placebo group were diagnosed with breast cancer (annualized rate, 0.29%) compared with 52 in the raloxifene group (annualized rate, 0.20%)2 Grady D, et al. J Natl Cancer Inst 2008;100: 854-61

  25. Cumulative Incidence of Invasive ER+ and ER- Breast Cancers Invasive ER+ Invasive ER- 55% HR = 1.44; 95% CI 0.61-3.36 HR = 0.45, 95% CI 0.28-0.72 • Raloxifene reduced absolute risk by 1.2 cases of invasive ER-positive breast cancer per 1000 women treated over 1 year • Raloxifene had no effect on the incidence of invasive ER-negative cancer Grady D, et al. J Natl Cancer Inst 2008;100: 854-61

  26. Source: Conclusions Review: • In postmenopausal women with or at increased risk for CHD, treatment with raloxifene for more than 5 years • No effect on risk of coronary events or mortality • Reduced risk of invasive breast cancer • Reduced risk of clinical vertebral fractures • Had no effect on all strokes • Increased risk of fatal stroke • Increased risk of VTE • When considering raloxifene treatment in postmenopausal women, potential benefits should be weighed against risks and against alternate interventions Reviewer Memo: Barrett-Connor E et al. N Engl J Med 2006: 355; 125-37 Slide Modified: Memo:

  27. Raloxifene and ER+Breast Cancer 56% 71% 44%

  28. Tamoxifen or RaloxifeneBreast Cancer Prevention 1st Obj. : Efficacy 2nd Obj.: Safety profile DVT Stroke Endometrial Cancer Hysterectomy Rate Cataract Fractures Myocardial Infarction Vogel VG et al. JAMA2006;295:2727-41

  29. NSABP P2 Breast Cancer PreventionSTAR Schema • Age 35 + • No history of: • Cancer • Clotting • DM & HTN Risk-Eligible Post-Menopausal Women • STRATIFICATION • Age • Relative Risk • Race • History of LCIS TAMOXIFEN 20 mg/day x 5 years RALOXIFENE 60 mg/day x 5 years

  30. P-2 STAR: raloxifene vs tamoxifenPrimary endpoint: Breast cancer preventionBaseline Characteristics 19474 women randomized 47.3 months follow-up Mean age, 58.5 years Mean 5-year predicted risk of breast cancer, 4.03% History of lobular carcinoma in situ (LCIS)* Tamoxifen: 9.2% Raloxifene: 9.2% History of breast atypical hyperplasia Tamoxifen: 22.5% Raloxifene: 23.0% 55% hysterectomy *Women with history of ductal carcinoma in situ (DCIS) were excluded Vogel VG et al. JAMA2006;295:2727-41

  31. P-2 STARAge Distribution of Participants 9% 9% <49 70+ 60-69 32% 50-59 50% Vogel VG et al. JAMA2006;295:2727-41

  32. P-2 STARFirst-Degree Relatives with Breast Cancer None 29% 3+ 3% 1 52% 2 16% Vogel VG et al. JAMA2006;295:2727-41

  33. 10 8 6 Av Ann Rate per 1000 4 2 0 Gail Model TAM N= 9726 Raloxifene N= 9745 Projection STAR Average Annual Rate & Number of Invasive Breast Cancers 312* 163* 168* * # of events Populatie: 4 % over 5 jaar zal borstkanker krijgen (normaal: 2%)

  34. 77 70 61 47 44 32† P-2 STARAnnual Rate and Number of Invasive Breast Cancers by 5-year Predicted Risk* *Determined using Gail Model †No. of events Vogel VG et al. JAMA2006;295:2727-41

  35. 3 2 Av Ann Rate per 1000 1 0 TAM Raloxifene STAR: Average Annual Rate and # of In Situ (DCIS & LCIS) Cancers RR = 1.40 95% CI: 0.98 to 2.00 80* 57* * # of events N = 9726 N= 9745

  36. 3 2 Av Ann Rate per 1000 1 0 TAM Raloxifene STAR: Average Annual Rate and# of Uterine Cancers RR = 0.62, 95% CI: 0.35 to 1.08 36* 23 * # of events

  37. STAR: Endometrial Hyperplasia # Hysterectomies 244 111

  38. 40 35 30 25 20 15 10 5 0 0 6 12 18 24 30 36 42 48 54 60 66 72 STAR: Thromboembolic Events At Risk by Year # of Rate/1000 Treatment 0 3 6 Events at 6 yrs. RR Tamoxifen 9726 6682 814 141 21.0 0.70 Raloxifene 9745 6764 836 100 16.0 P-value= 0.01 Cumulative Incidence (per 1000) Time Since Randomization (months)

  39. STAR: Summary • R is as effective as T in the prevention of primary IBC. • R is less effective than T in the prevention of LCIS & DCIS – (not statistically different). • Compared to T, R use results in: • Fewer thromboembolic events • Fewer endometrial cancers and • Fewer cataracts • No differences in stroke, MI

  40. Raloxifene is an excellent Osteoporosis drug DVT / PE Stroke if CVD! Hot Flashes Raloxifene is an excellent chemopreventive agent for the very high breast cancer risk patient

  41. The Ideal Serm? Lasophoxifene Agonist Antagonist Bone CVS Breast Uterus

  42. Lasofoxifene, a SERM • High affinity for the estrogen receptor • Previous clinical studies • Decreases bone turnover • Decreases bone loss • Decreases LDL-cholesterol • Relieves vulvovaginal atrophy Indication: Treatment of osteoporosis and vaginal atrophy Presented at ASBMR-Canada Sept 2008

  43. The PEARL Trial – 5 year resultsDouble Blind RCT: Plac vs Laso • Randomized placebo-controlled trial • Two daily doses (0.25 mg or 0.5 mg) • All received Vit D3 and calcium daily • 5 year results • 8,556 women 59 to 80 years old • BMD T-score ≤ -2.5 and ≥ -4.5 at the femoral neck or spine • < 4 radiographic vertebral fractures * Postmenopausal Evaluation and Risk-reduction with Lasofoxifene

  44. Endpoint • Adjudication committees (blinded): • Fractures: Vertebral, Non-vertebral, Hip • Breast cancer (ER+ cancer co-1° at 5 yrs) • Gynecologic: endometrial cancer, hyperplasia • Cardiovascular • Stroke, TIA, VTE, major CHD events* • Cause of death *Composite of coronary death, non-fatal MI, new ischemic heart disease, hospitalization for unstable angina, revascularization procedures

  45. Vertebral Fracture at 5 Years 0.58 (0.47, 0.70) 0.69 (0.57, 0.83) 31% (p < 0.001) 42% (p < 0.001) Cumulative % n = 262 n = 189 n = 156 Pbo 0.25 mg 0.5 mg Lasofoxifene

  46. 0.76 (0.64, 0.91) 0.90 (0.76, 1.06) 10% (P = 0.19) 24% (p < 0.01) n = 296 n =269 n = 230 Lasofoxifene Nonvertebral Fracture at 5 Years First SERM with Non-vertebral fracture Risk reduction

  47. ER+ Breast Cancer at 5 years 0.19 (0.07, 0.56) 0.52 (0.25, 1.08) 48% (p = 0.073) n = 21 Incidence Rate per 1000 Patient Years (95% CI) 81% (p < 0.001) n = 11 n = 4 0.25 mg 0.5 mg Placebo Lasofoxifene

  48. Major CHD Events Through 5 Years HR 95% CI p-value Laso 0.25 mg 0.76 (0.56, 1.03) 0.077 Laso 0.5 mg 0.68 (0.50, 0.93) 0.016* Placebo – – 4% 3% Cumulative Incidence 2% 1% 0% 1 2 3 4 5 Baseline Time (years)

  49. Stroke Through 5 Years Excluding TIA Including TIA 0.75 (0.51, 1.10) 0.64 (0.41, 0.99) 0.81 (0.56, 1.18) 0.61 (0.39, 0.96) 19% (p = 0.27) 25% (p = 0.14) 36% (p = 0.04) Incidence Rate per 1000 Patient- Years Incidence Rate per 1000 Patient Years 39% (p = 0.03) 3.9 4.8 3.9 3.6 2.4 2.5 n = 50 n = 31 n = 32 n = 61 n = 50 n = 46 Pbo Pbo 0.25 mg 0.5 mg 0.25 mg 0.5 mg Lasofoxifene Lasofoxifene

  50. Adverse Events: VTE / Flushes 36 (0.3%) 70 (0.5%) 90 (0.7%) Vaginal Bleeding Hot Flushes VTE 158 (1.2) 372 (2.9) 365 (2.8) 18 (0.6%) 48 (1.7%) 37 (1.3%) Endometrial Texture = Tam Like ( 20%) Subepithelial changes and More Atrophic E-Polyps FDA: this is no longer a problem

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