Treatment of Breast Cancer in 2013 Where are we now?

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1 Treatment of Breast Cancer in 2013 Where are we now? Evangelia Razis MD, PhD Director. 3rd Oncology Dept Hygeia Hospital Athens Greece

2 Projected number of Breast Cancers to new cases per year

3 0% 1% 2% 3% 4% year of death ris k of de at h fro m ca nc er be for e ag e 75 (% ) Deaths from Breast Cancer

4 In the 1970s Black September in the Middle East China Launches Its First Satellite And since we are talking about tailoring..fashion American soldiers found guilty of murdering entire town of Vietnamese civilians World Trade Center is completed Lithium is approved by the FDA The Beatles release Let It Be Floppy disc was invented

5 In 2012 The Middle East is still in upheaval And fashion The World trade center is destroyed Americans are being convicted of war crimes Everyone takes SSRIs China is a superpower We are discussing microarrays and microelectrinics in oncology Most popular music is..rap

6 Are we doing better? And at what cost? From 1991 to 2002, the number of patients receiving chemotherapy for lung, colorectal and breast cancer rose. The increase in chemotherapy, along with the higher costs of new drugs, accounted for much of the increased costs However, hospital costs still made up the largest percentage of the increased costs. The average cost for treating a lung cancer patient went up $7,139, to an average of $39,891. With prostate cancer, the average price tag for treatment went up $5,345, to an average of $41,134. The cost of treating breast cancer went up $4,189, to an average cost of $20,964.

7 Letting the Gen(i)e out of the bottle.. Will we get our wish?... NEJM 10/1/2008

8 Factors Associated with Reduction In Breast Cancer Mortality Early Detection Mammography LR Therapy Surgery XRT Adjuvant Systemic Therapy Hormonal Therapy and Chemotherapy Treatment of Advanced Disease Hormonal Therapy, Chemotherapy, Trastuzumab

9 Tailoring Chemo in the 20th century Or..one size doesn t fit all breast cancer tumors Chemo in the 21st century

10 Challenge of Early-Stage Breast Cancer Despite surgery, cytotoxic chemotherapy, hormonal therapy, and/or regional radiotherapy, ~ 30% of patients will eventually experience disease recurrence The biologic reasons for recurrence and resistance to treatment are poorly understood Recurrent breast cancer is usually lethal

11 Breast Cancer Biology in 2012: A Pragmatic View H E R 2 N e g at iv Pe o si ti v e Positive ENDO CHEMO CHEMO TRAS ENDO ER Negative CHEMO CHEMO TRAS

12 Why This Pragmatic View Fails... Early breast cancer is much more complex than we thought MBC is much more complex than early breast cancer

13 Considering the Use of Adjuvant Therapy in BC Patients Questions: What is the expected benefit (vs. toxicity)? What is the risk for recurrence?

14 Patients 45 yo 3cm tumor 3 positive ALN ER positive Her 2 negative 55yo 1.8 cm tumor LN negative ER/PR negative Her2 positive In 1990 both would have been probably referred for chemotherapy probably the same kind of chemotherapy The first one would have also had the only available type of HT Now: CT vs HT? Anthracyclines? Taxanes? Which dose/schedule? Anti Her 2 therapy? Which Hormonal agent?..and all this will need to be based on more clinical ( ex. LVEF, Fam Hx) and biological information

15 Systemic Therapy Setting & Purpose Early Stage Locally Advanced Metastatic No evidence of disease Reduce risk of recurrence Render inoperable operable Commence systemic therapy Reduce risk metastatic disease Disease control

16 Rationale for Hormone Therapy Prevent breast cancer cells from receiving stimulation from endogenous estrogen Beatson, 1896

17 Estrogen Production in Premenopausal and Postmenopausal Patients Hypothalamus Premenopausal Gonadotropins (FSH + LH) Pituitary gland Premenopausal and Postmenopausal Adrenocorticotropic hormone (ACTH) Ovary Prolactin Growth Hormone Adrenal gland Estrogens Progesterone Corticosteroids Progesterone Androgens Estrogens Aromatase inhibitors

18 Early Breast Cancer Trialists Group Overview: Tamoxifen EBCTCG, Lancet 2005,365: 1687

19 Side Effects of Tamoxifen Common side effects Hot flashes Rare but serious side effects Thromboembolic disease Endometrial cancer Cataracts Issues with SSRIs

20 Hormonal Therapy in Postmenopausal Women

21 Aromatase Inhibitors- Mechanism of Action Smith et al., N Engl J Med 348(24):

22 Recurrence Rate for HR+ Patients 25 P A T ati e nt 20 HR s ITT ( % 15 ) Anastrozole (A) Tamoxifen (T) 10 HR % CI ( ) ( ) P-value Absolute difference:1.7% 2.4% 2.8% 3.7% At risk: Follow-up time (years) A T DFS includes all deaths as a first event Howell A, et al. Lancet 2005

23 Aromatase Inhibitors Anastrazole (Arimidex), Femara (Letrozole), Aromasin (Exemestane) Improve outcome in postmenopausal women Side Effects Osteopenia, Osteoporosis, Increased risk of fractures Possible increase in cholesterol

24 Adjuvant Chemotherapy

25 Progress in Chemotherapy for Early Stage Breast Cancer 1970s Combination chemotherapy (CMF) Use of anthracyclines Addition of taxanes Superior taxane containing regimens Addition of trastuzumab 2000s BUT: ALL chemotherapy is associated with toxicities and risks need better ways to identify which patients will benefit from treatment

26 Adjuvant Chemotherapy Degree of benefit varies according to nodal status and patient age Degree of benefit varies according to sensitivity of tumor to hormones (ER+ vs. ER-)

27 Side effects Cardiac toxicity Anthracyclines increase risk of congestive heart failure Arrhythmias increased with taxanes Radiation Neuropathy Taxanes Hypersensitivity Taxanes, require steroids Ovarian ablation Premature menopause

28 SO How can we do better? Better selection of patients for treatment with chemotherapy Treat only those patients who are most likely to recur AND who will therefore benefit most from the addition of chemotherapy Take advantage of genomics

29 Oncotype DX or Recurrence Score (RS) Assay for patients with ER + LN- disease 16 Cancer and 5 Reference Genes From 3 Studies PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 INVASION Stromelysin 3 Cathepsin L2 HER2 GRB7 HER2 ESTROGEN ER PR Bcl2 SCUBE2 GSTM1 CD68 BAG1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC RS = x HER2 Group Score x ER Group Score x Proliferation Group Score x Invasion Group Score x CD x GSTM x BAG1 Category RS (0 100) Low risk RS < 18 Int risk RS 18 and < 31 High risk RS 31

30 Recurrence Score as a Continuous Predictor Distant Recurrence at 10 Years 40% 35% 30% 25% 20% 15% 10% 5% 0% Low Risk Group Intermediate Risk Group My RS is 30, What is the chance of recurrence within 10 yrs? 95% CI Recurrence Score High Risk Group

31 Oncotype DX Clinical Validation: B-14 Results DRFS DRFS for the three distinct cohorts identified D R F S 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Low Risk (RS <18) n = 338 Intermediate Risk (RS 18-30) n = 149 High Risk (RS 31) n = 181 P < Years Paik et al. N Engl J Med. 2004;351:

32 B-14 Benefit of Tamoxifen By Recurrence Score Risk Category D R F S Low Risk (RS<18) N Years D R F S Int Risk (RS 18-30) Placebo Placebo Tamoxifen Tamoxifen N Years D R F S High Risk (RS 31)1 Placebo Tamoxifen N Years Interaction P = The results should not be used to indicate that tamoxifen should not be given to the high-risk group Paik et al. ASCO Abstract #510.

33 Oncotype Dx: Chemotherapy benefit RS < 18 RS RS DRFS Low Risk Patients (RS < 18) Tam + Chemo Tam Years DRFS Int Risk (RS 18-30) 0.1 Tam + Chemo Tam Patients with tumors that have high Recurrence Scores have a large absolute benefit of chemotherapy (similar results with CMF and MF) Patients with tumors that have low Recurrence Scores derive minimal, if any, benefit from chemotherapy Years DRFS High Risk Patients (RS!31) 0.1 Tam + Chemo Tam Years Paik et al, J Clin Oncol. 2006

34 Biological or Targeted Therapy

35 Targeted therapies for Early Stage Breast Cancer Treatments that target specific proteins or receptors expressed by tumor Hormonal therapy was the first targeted therapy for breast cancer Monoclonal antibodies Trastuzumab (Herceptin)

36 HER-2 Positivity in Breast Cancer OVEREXPRESSION: marked increase in number of HER2 receptors on the cell surface AMPLIFICATION: increase in number of HER2/neu gene copies in the nucleus HER2-normal (HER2-) breast epithelium cell (~20,000 receptors) HER2-positive breast cancer cell (up to 1-2 million receptors) Courtesy of Jeffrey Ross, Albany Medical College, Albany, NY.

37 Anti-HER2 Antibodies: Mechanism of Action P P P P P P P P Excessive cell proliferation, survival, and angiogenesis Potentiation of chemotherapy Inhibition of tumor cell proliferation Facilitation of immune function Baselga and Albanell. Ann Oncol. 2001;12(suppl 1):S35. Noonberg and Benz. Drugs. 2000;59:753.

38 NSABP B-31/N9831 Joint Analysis: Impact of Adding Trastuzumab to AC Paclitaxel on Disease-Free Survival* % S ur vi vi ng di se as e- fr ee 0 P< HR=0.48 *N9831 arm B (sequential trastuzumab after AC P) not included in joint analysis. 87.1% 85.3% 75.4% 67.1% Years after randomization Trastuzumab (133 events) Median FU 2.0 y Control (261 events) No. at risk Control Trastuzumab Romond et al. N Engl J Med., 2005;353:1673.

39 Adjuvant Trastuzumab: Room to Improve Generally well tolerated Some patients will still recur Intravenous infusion q1-3 wks for one year Serious side effect: cardiotoxicity Study Regimen Symptomatic CHF B31/NCCTG AC TH % NCCTG AC T H 2.5% HERA Chemo H 0.6% BCIRG 006 TCH 0.4% FinHER H chemo 0% Piccart-Gephardt, ASCO 2006

40 Moderate alcohol intake- Lifestyle Modifications Obesity increases risk of postmenopausal breast cancer-maintain a normal Body mass index Evidence suggests that physical activity decreases risk of breast cancer and risk of recurrence- Get Active Low fat diet decreases risk of breast cancer recurrence Balanced Healthy Diet

41 Metastatic disease: Principles of Treatment Hormonal therapy for indolent disease Single agent chemotherapy for aggressive/symptomatic disease or disease not responding to hormonal therapy Polyagent chemotherapy for visceral crisis or disease requiring rapid response IV bisphosphonates or denosumab for bone secondaries

42 Goals of Therapy Prolongation of survival Improvement of quality of life - Improvement of symptoms - Acceptable toxicity

43 Dafni et al. ECCO-ESMO,2009; Abstract O year trends in MBC survival in Greece: meta-analysis of 10 Hellenic Cooperative Oncology Group (HeCOG) clinical trials Kaplan-Meier estimates of survival by time cohort Median survival: : 1.3 years : 1.7 years : 2.2 years : 2.6 years

44 Endocrine Therapy for Metastatic Breast Cancer

45 First-line Letrozole vs Tamoxifen, Then Crossover Median OS Letrozole: 34 mos Tamoxifen: 30 mos Time to Crossover Letrozole: 17 mos Tamoxifen: 14 mos P r o 0.6 p o 0.5 r ti 0.4 o 0.3 n P =.53 (long-rank test) A 0.2 li v 0.1 e Mos Letrozole Tamoxifen 1st Mouridsen H, et al. J Clin Oncol. 2003;21: st

46 CONFIRM: Fulvestrant 500 mg vs 250 mg in Postmenopausal Women With ER+ MBC Postmenopausal women with ER-positive advanced breast cancer (N = 736) Fulvestrant 250 mg* (n = 374) Fulvestrant 500 mg (n = 362) *Fulvestrant 250 mg: 1 injection of fulvestrant 250 mg IM + 1 placebo injection on Day 0; 2 placebo injections on Day 14; 1 injection of fulvestrant 250 IM + 1 placebo injection on Day 28, then every 28 days thereafter. Fulvestrant 500 mg: 2 injections of fulvestrant 250 mg IM on Days 0, 14, 28, then every 28 days thereafter. DiLeo A, et al. SABCS Abstract S1-4.

47 CONFIRM: Effect of Fulvestrant 500 mg vs 250 mg on Survival in Postmenopausal Women Baseline characteristics appeared well balanced between treatment arms Outcome Timing of Analysis Fulvestrant 500 mg Fulvestrant 250 mg HR (95% CI) Median PFS First* 6.5 mos 5.5 mos 0.80 ( ) Median OS First* 25.1 mos 22.8 mos 0.84 ( ) Median OS Final 26.4 mos 22.3 mos 0.81 ( ) *First analysis was performed at 50% maturity. Final analysis was performed at 75% maturity. P =.006 P =.001 P =.016 Subsequent therapies were well balanced between arms, with approximately 60% of patients receiving subsequent chemotherapy and approximately one third receiving other hormonal therapy DiLeo A, et al. SABCS Abstract S1-4.

48 FIRST Study Design Open-label first-line ER+ postmenopausal patients with advanced breast cancer (target, N = 200; actual, N = 205) Endpoints at primary data cutoff Primary endpoint Fulvestrant 500 mg IM on Days 0, 14, 28, and every 28 days thereafter Progression Follow-up Anastrozole 1 mg/day PO Progression Follow-up Clinical benefit rate Secondary endpoints ORR TTP Duration of response Duration of clinical benefit Safety Exploratory endpoint Robertson JF, et al. Clin Oncol. 2009;27: Best response to subsequent therapy

49 FIRST: TTP at Follow-up Analysis Pro port ion of Pati ent s Aliv e and Pro gre ssi on Fre e Pts at Risk, n Fulvestrant 500 mg Anastrozole 1 mg HR: 0.66 (95% CI: ; P =.01) Mos Fulvestrant 500 mg Anastrozole 1 mg Robertson JF, et al. Breast Cancer Res Treat. 2012;136:

50 SWOG S0226: Study Design Primary endpoint: PFS Secondary endpoints: OS, safety Stratified by previous adjuvant tamoxifen Treatment until disease progression Postmenopausal women with hormone receptor positive MBC (N = 707) Anastrozole 1 mg/day PO + Fulvestrant 500 mg on Day 1, 250 mg on Days 14 and 28, 250 mg every 28 days thereafter (n = 355) Anastrozole 1 mg/day PO (n = 352) Women with progression encouraged to cross over to receive fulvestrant Mehta RS, et al. N Engl J Med. 2012;367:

51 SWOG S0226: PFS and OS Overall and by Previous Adjuvant Tamoxifen Endpoint Anastrozole + Fulvestrant Median PFS (n = 694), mos No previous adjuvant tamoxifen (n = 414) Previous adjuvant tamoxifen (n = 280) Anastrozole HR (95% CI) P Value ( ) ( ) ( ) Median OS (n = 694), mos ( ) No previous adjuvant tamoxifen (n = 414) Previous adjuvant tamoxifen (n = 280) Mehta RS, et al. N Engl J Med. 2012;367: ( ) ( )

52 EFFECT: Fulvestrant vs Exemestane After Progression of Nonsteroidal AI Median, mos Fulvestrant 3.7 Exemestane 3.7 HR: (95% CI: ; P =.6531) Cox analysis, P = Fulvestrant Exemestane 0.2 Pts at Risk, n Fulvestrant Exemestane Mos Chia S, et al. J Clin Oncol. 2008;26:

53 Mechanisms of Hormone Resistance VEGF R AI SERD T E2 ER Cytoplas m Plasma membran e P P akt P P P IGF1 R P P PI3- K ERERP p160 CBP ERE Nucle us EGFR/HE R2 P P p90rsk MAPK Basal transcription machinery SOS RAS RAF MEK ER target gene transcription Increased signaling through EGFR and/or IGF1-R Increased signaling through PI3-K pathway Reprinted by permission from the American Association for Cancer Research: Johnston SR. Clin Cancer Res. 2005;11:889s-899s.

54 Crosstalk Between ER and PI3K/AKT/mTOR Signaling: Rationale for Dual Inhibition mtorc1 activates ER in a ligand-independent fashion1 Estradiol suppresses the apoptosis induced by PI3K/AKT/mTOR blockade2 Hyperactivation of the PI3K/AKT/mTOR pathway is observed in endocrine-resistant breast cancer cells3 Adapted from Johnson SR. Clin Breast Cancer. 2009;9(suppl 1):S28-S36. mtor is a rational target to enhance the efficacy of endocrine therapy Abbreviations: AKT, protein kinase B; EGFR, epidermal growth factor receptor; ER, endocrine receptor; ERE, endocrine response element; HER2, human epidermal growth factor receptor-2; IGF-1R, insulin-like growth factor-1 receptor; MAPK, mitogen-activated protein kinase; mtor, mammalian target of rapamycin; mtorc1, mtor complex 1; PI3K, phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin. 1. Yamnik RL, et al. J Biol Chem. 2009;284(10): ; 2. Crowder RJ, et al. Cancer Res. 2009;69(9): ; 3. Miller TW, et al. J Clin Invest. 2010;120(7):

55 Everolimus Clinical Trial Program in ER+ Advanced Breast Cancer Rationale Activation of the PI3K/AKT/mTOR pathway is a key mechanism of endocrine resistance in ER+ advanced breast cancer Early phase 2 study with everolimus monotherapy1 Proof-of-concept phase 2 studies Neoadjuvant study (letrozole ± everolimus)2 TAMRAD study (tamoxifen ± everolimus)3 Pivotal BOLERO-2 phase 3 study (exemestane ± everolimus)4-6 0 Abbreviations: AKT, protein kinase B; ER, estrogen receptor; mtor, mammalian target of rapamycin; PI3K, phosphatidylinositol-3-kinase.1. Ellard SL, et al. J Clin Oncol. 2009;27(27): ; 2. Baselga J, et al. J Clin Onco 2009;27(16): ; 3. Bachelot T, et al. SABCS 2010; abstract S1-6; 4 (oral). Baselga J, et al. N Engl J Med. 2012;366(6): ; 5. Hortobagyi G, et al. SABCS 2011; abstract S3-7 (oral);6. Piccart M, et al. ASCO 2012; abstrac

56 Letrozole ± Everolimus in Neoadjuvant Breast Cancer Phase 2 study; N = 270 Postmenopausal women with ER+ breast cancer Measurable disease Biopsy at baseline, 14 days, and surgical specimen Letrozole 2.5 mg/d + Everolimus 10 mg/d Letrozole 2.5 mg/d + Placebo Primary endpoint RR at 16 wk (palpation) Secondary endpoints RR (ultrasound), biomarkers, safety, PK Abbreviations: ER, estrogen receptor; PK, pharmacokinetics; RR, response rate. Baselga J, et al. J Clin Oncol. 2009;27(16):

57 TAMRAD: Primary Endpoint, Clinical Benefit Rate Cl ini cal Be ne fit Ra te, % of pa tie nts Tamoxife n P =.045 (exploratory analysis) 61 Tamoxifen + Everolimus Everolimus increased CBR 45% over tamoxifen alone (absolute difference 19%) Abbreviations: CBR, clinical benefi rate. Bachelot T, et al. J Clin Oncol May 7 [Epub ahead of print].

58 TAMRAD: Tamoxifen ± Everolimus in Aromatase Inhibitor-Refractory Advanced Breast Cancer Phase 2 study; N = 111 Postmenopausal women with ER+ HER2 advanced breast cancer Previously treated with aromatase inhibitor therapy in adjuvant or metastatic setting Tamoxifen 20 mg/d + Everolimus 10 mg/d Tamoxifen 20 mg/d + Placebo Stratification: Primary or secondary hormone resistance Primary endpoint: CBR at 6 mo Secondary endpoints: TTP, OS, ORR, biomarkers, safety Abbreviations: CBR, clinical benefit rate; ER, estrogen receptor; HER2, human epidermal growth factor receptor-2; ORR, overall response rate; OS, overall survival; TTP, time to progression. Bachelot T, et al. J Clin Oncol May 7 [Epub ahead of print]. 0

59 TAMRAD: Time to Progression TT P Pr ob ab ilit y HR = 0.54 (95% CI = 0.36, 0.81) P =.002 (exploratory analysis) Tamoxifen: 4.5 mo Tamoxifen + Everolimus: 8.6 mo Time, mo Abbreviations: CI, confidence interval; HR, hazard ratio; TTP, time to progression. Bachelot T, et al. J Clin Oncol May 7 [Epub ahead of print].

60 TAMRAD: Overall Survivala 1,0 0,9 Probability of Survival 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 HR = 0.45 (95% CI = 0.24, 0.81); Log-rank P =.007 N (%) of events (Tamoxifen vs Tamoxifen + Everolimus): 31 (54%) vs 16 (30%) Time, mo Abbreviations: CI, confidence interval; HR, hazard rat a As of September 201

61 TAMRAD: Adverse Events Tamoxifen n = 57 Tamoxifen + Everolimus n = 54 Adverse Event, n (%) Any Grade Grade 3/4 Any Grade Grade 3/4 Pain 49 (86) 10 (18) 44 (82) 5 (9) Fatigue 30 (53) 6 (11) 39 (72) 3 (6) Nausea 20 (35) 0 19 (35) 2 (4) Stomatitis 4 (7) 0 30 (56) 6 (11) Anorexia 10 (18) 2 (4) 23 (43) 4 (7) Infection 11 (19) 3 (5) 19 (35) 4 (7) Rash 4 (7) 0 24 (44) 2 (4) Diarrhea 6 (11) 0 21 (39) 1 (2) Vomiting 7 (12) 2 (4) 9 (17) 0 Pneumonitis 2 (4) 2 (4) 9 (17) 1 (2) Decreased hemoglobin 20 (35) 2 (4) 37 (69) 1 (2) Decreased leukocyte count 10 (18) 0 29 (54) 1 (2) Decreased lymphocyte count 12 (21) 2 (4) 26 (48) 1 (2) PNNs 11 (19) 3 (5) 26 (48) 1 (2) Dose reduction due to AE 0 11 (20) Treatment discontinuation due to AE 4 (7.0) 12 (22) Abbreviations: AE, adverse event; PNNs, polymorphonuclear neutrophils. Bachelot T, et al. J Clin Oncol May 7 [Epub ahead of print].

62 BOLERO-2: Exemestane ± Everolimus in Non- Steroidal Aromatase Inhibitor-Refractory Advanced Breast Cancer Phase 3 study; N = 724 Postmenopausal women with ER+ HER2 advanced breast cancer refractory to letrozole or anastrozole Recurrence during or within 12 mo after end of adjuvant treatment or progression during or within 1 mo after end of treatment for advanced disease Everolimus 10 mg/d + Exemestane 25 mg/d (n = 485) Placebo + Exemestane 25 mg/d (n = 239) Stratification Sensitivity to prior hormonal therapy Presence of visceral disease No crossover Primary endpoint: PFS Secondary endpoints: OS, ORR, CBR, safety, QoL, bone markers Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor receptor-2; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; QoL, quality of life. Baselga J, et al. N Engl J Med. 2012;366(6):

63 a All other patients had 1 bone lesion. BOLERO-2: Baseline Characteristics Everolimus + Exemestane Placebo + Exemestane Characteristic (n = 485), % (n = 239), % Median age, years (range) 62 (34, 93) 61 (28, 90) Race Caucasian Asian Performance status Metastatic site Liver Lung Bone Visceral disease Measurable diseasea 70 68

64 BOLERO-2: Primary Endpoint, PFS (Central Assessment) Pr ob ab ilit y ( % ) of Ev en t HR = 0.38 (95% CI = 0.31, 0.48) Log-rank P value: <.0001 Everolimus + Exemestane: 11.0 mo (E/N = 188/485) Placebo + Exemestane: 4.1 mo (E/N = 132/239) Number of patients still at Everolimus risk + Exemestane Placebo + Exemestane Time, 8 wk Abbreviations: CI, confidence interval; E/N, patients with events/total patients; HR, hazard ratio; PFS, progression-free survival. Piccart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster).

65 RESULTS (PFS by Local Assessment ) Patients at risk EVE+E XE PBO+E XE Censoring times EVE+EXE (n/n=310/485) PBO+EXE (n/n=200/239) All groups HR=0.45 (95% CI, ) Log-rank p< Kaplan-Meier medians EVE+EXE: 7.8 mo PBO+EXE: 3.2 mo Time, wk Pr ob abi lity of Ev ent, % Patients at risk EVE+EXE PBO+EXE Censoring times EVE+EXE (n/n=56/100) PBO+EXE (n/n=30/37) Patients Who Recurred After Neoadjuvant/Adjuvant Therapy HR=0.39 (95% CI, ) Kaplan-Meier medians EVE+EXE: mo PBO+EXE: 4.07 mo Time, wk Piccart et al. SABCS Abstract 3P Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio;

66 RESULTS (Kaplan-Meier Curves of PFS in Patients (A) With Visceral Metastases, (B) Without Visceral Metastases, or (C) With Bone-Only Metastases) A B C Pr ob abi lity of Ev ent, % Censoring times EVE+EXE (n/n=188/271) PBO+EXE (n/n=116/135) HR=0.47 (95% CI, ) Kaplan-Meier medians EVE+EXE: 6.83 mo PBO+EXE: 2.76 mo Pr ob abi lity of Ev ent, % Censoring times EVE+EXE (n/n=122/214) PBO+EXE (n/n=84/104) HR=0.41 (95% CI, ) Kaplan-Meier medians EVE+EXE: 9.86 mo PBO+EXE: 4.21 mo Pr og res sio n- Fr ee Su rvi val, % Censoring Times EVE+EXE (n/n=48/105) PBO+EXE (n/n=33/46) HR=0.33 (95% CI, ) Kaplan-Meier EVE+EXE: medians mo PBO+EXE: 5.29 mo Time, wk Time, wk Time, wk Patients at risk Patients at risk Patients at risk EVE+EXE PBO+EXE EVE+EXE PBO+EXE EVE+EXE 10 PBO+EXE Piccart et al. SABCS Abstract 3P

67 P at ie nt s, % BOLERO-2: Overall Response Rate and Clinical Benefit Rate (Local Assessment) ,6% Everolimus + Exemestane Placebo + Exemestane ORR P < ,7% 51,3% CBR P < ,4% Abbreviations: CBR, clinical benefit rate; ORR, overall response rate. Piccart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster).

68 BOLERO-2: PFS in Prespecified Subgroups All N = 724 Age group < Presence of visceral metastasis No 318 Yes 406 Baseline ECOG performance status , Prior chemotherapy No 231 Yes 493 Number of prior therapies Prior use of hormonal therapy other than NSAI No 326 Yes 398 PgR status Negative 184 Positive ,2 0,4 0,6 0,8 1 1,2 1,4 Hazard Ratio Abbreviations: ECOG, Eastern Cooperative Oncology Group; NSAI, nonsteroidal aromatase inhibitor; PgR, progesterone receptor. Piccart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster). Favors Everolimus + Exemestane Favors Placebo + Exemestane

69 BOLERO-2: Overall Survival Interim Analysis (7-mo follow-up)1 Updated Analysis (12.5-mo follow-up)2 Final PFS Analysis (18-mo follow-up)3 Cutoff date 11 Feb Jul Dec 2011 OS events (Everolimus vs Placebo) 83 (10.7% vs 13.0%) 137 (17.3% vs 22.7%) 200 (25.4% vs 32.2%) Δ OS events 2.3% 5.4% 6.8% Abbreviations: OS, overall survival; PFS, progression free survival. 1. Baselga J, et al. N Engl J Med. 2012;366(6): ; 2. Hortobagyi G, et al. SABCS 2011; abstract S3-7 (oral); 3. Piccart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster). 0

70 BOLERO-2: Most Common Adverse Events a Adverse events of special interest. Piccart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster). Everolimus + Exemestane (n = 482), % Placebo + Exemestane (n = 238), % All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Stomatitis < 1 0 Rash Fatigue 37 4 < Diarrhea 34 2 < 1 19 < 1 0 Appetite decreased Nausea 31 < 1 < Noninfectious pneumonitisa Hyperglycemiaa 14 5 < 1 2 < 1 0

71 Everolimus administration Από του στόµατος θεραπεία Ένα δισκίο των 10mg τη µέρα Με ή χωρίς γεύµα 0

72 BOLERO-3: Study Design pts 572 pts Patients with HER2-positive locally advanced or metastatic breast cancer who have received prior taxane therapy and whose disease is resistant to trastuzumab Stratification by prior use of lapatinib (yes or no) SCREEN R A N D O M I Z E Everolimus (5 mg PO daily) + Vinorelbine (25 mg/m2 weekly) + Trastuzumab (2 mg/kg weekly*) (n = 286) Everolimus : Placebo 1 : 1 Placebo (PO daily) + Vinorelbine (25 mg/m2 weekly) + Trastuzumab (2 mg/kg weeklya) (n = 286) Continue treatment until: Disease progression OR Intolerable toxicity Follow-up for survival q3mo until 384 deaths have been recorded afollowing a 4 mg/kg loading dose on day 1 cycle 1.

73 BOLERO-1: Trial Design Randomization Everolimus 10.0 mg PO daily Paclitaxel 80 mg/m2 IV on days 1, 8, 15 Trastuzumab 2 mg/kga IV on days 1, 8, 15, 22 Placebo PO daily Paclitaxel 80 mg/m2 IV on days 1, 8, 15 Trastuzumab 2 mg/kga IV on days 1, 8, 15, 22 Assessment q8wk PFS Response Survival Safety N = 717 2:1 (everolimus:placebo) Patients with HER2-overexpressing, unresectable locally advanced, recurrent, or metastatic breast cancer; no prior therapy for locally advanced or recurrent disease Stratification by prior adjuvant or neoadjuvant trastuzumab and by presence of visceral metastases 0 aafter a loading dose of 4 mg/kg on day 1, cycle 1 (1 cycle = 28 days).

74 Endocrine Therapy Sequencing in MBC: Which Order Is Best? AI or fulvestrant are most effective first-line single agents; fulvestrant ± AI reasonable choice for endocrine therapy naive patients with MBC Continue endocrine therapies until resistance mtor inhibition with everolimus + exemestane is best second-line therapy after progression on nonsteroidal AI After everolimus, back to anti-er therapy alone or enhanced blockade of PI3K pathway Addition of CDK4/6 inhibitor to first-line letrozole may become a new SOC; phase III trial under way

75 Bone Modifying Agents in Breast Cancer Mechanism of Action

76 Bone Modifying Therapy: zoledronic acid Reduces and delays bone complications due to bone metastases Treats hypercalcemia of malignancy Adjuvant use of zoledronate in postmenopausal women

77 Meta-analysis of adjuvant ZA trials Huang W-W, Huang C, Liu J, Zheng H-Y, et al. (2012) Zoledronic Acid as an Adjuvant Therapy in Patients with Breast Cancer: A Systematic Review and Meta-Analysis. PLoS ONE 7(7): e doi: /journal.pone

78 Denosumab Reduces Skeletal Events Fully humanized monoclonal antibody targeting RANKL RANKL activates bone digesting osteoclast cells FDA-approved in 2010 for prevention of skeletal related events in patients with bone metastases from solid tumors Stopeck AT, et al. J Clin Oncol. 2010;28:

79 Denosumab vs Zoledronic Acid in Patients With Advanced Breast Cancer Background Denosumab: fully human monoclonal antibody targeting RANKL FDA approved in 2010 for preventing SREs in patients with solid tumors and bone metastases Study design Extended follow-up of a phase III trial of zoledronic acid vs denosumab in patients with breast cancer and bone metastases Blinded 4-mo extension planned to allow uninterrupted treatment following primary analysis cutoff date Stopeck A, et al. SABCS Abstract P

80 Denosumab vs Zoledronic Acid: Study Design Extended analysis of a randomized, double-blind phase III trial Primary endpoint: time to first on-study SRE Stratified by previous SREs, previous oral bisphosphonate, current chemotherapy, geographic region Patients with advanced breast cancer and bone metastases (N = 2046) Zoledronic acid 4 mg IV* + Placebo SC every 4 wks (n = 1020) Denosumab 120 mg SC + Placebo IV every 4 wks (n = 1026) *Dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine according to product label. All patients encouraged to take supplemental calcium ( 500 mg/day) and vitamin D ( 400 IU/day). Stopeck A, et al. SABCS Abstract P

81 Denosumab Reduced Time to First On- Study SRE S 1.0 u b 0.8 j e 0.6 c t s 0.4 W it 0.2 h o 0.0 u t S Patients at risk, R n Zoledronic E 102 acid Denosuma ( b % 6 Denosuma bzoledronic acid Study Mo HR: 0.82 (95% CI: ; P =.0096, superiority) KM Estimate of Median Mos Other endpoints: ) no difference in OS or time to overall disease progression between denosumab and zoledronic acid arms Stopeck A, et al. SABCS Abstract P

82 Denosumab Reduced SRE Morbidity Rate Outcome Denosumab (n = 1026) Zoledronic Acid (n = 1020) Relative Reduction P Value Skeletal morbidity rate* Patients with 1 SRE, % Mo Mo At extended analysis SREs by type, % Pathologic fracture Radiation to bone *Number of SREs per patient divided by patient s time at risk. Not all patients completed full study duration. Study duration: 38 mos; median time on study: 18 mos. Stopeck A, et al. SABCS Abstract P

83 Adverse Events Adverse Events, % Denosumab (n = 1020) Zoledronic Acid (n = 1013) Any Serious events Renal events Osteonecrosis of the jaw* Hypocalcemia All grades Grade 3/ Acute-phase reactions *P = Occurring within 3 days of treatment initiation. Stopeck A, et al. SABCS Abstract P

84 Should Metastatic Disease Be Confirmed by Biopsy? Biopsy of metastatic disease is recommended Tumor marker testing (ER/PR and HER2) For women with an initial breast cancer diagnosis, tumor markers must be determined Are tumor markers stable with disease progression?

85 Karolinska Cohort: Intra-individual ER Status at Relapse Aim Determine if hormone receptor and HER2 status change between primary breast cancer and relapse Methods N = 1051 breast cancer patients relapsing between at single center in Stockholm, Sweden Hormone receptor and HER2 status gathered from original patient records Lindstrom L, et al. SABCS Abstract S3-5.

86 Karolinska Cohort: Intra-individual ER Status at Relapse ER Status* Patients, % Primary tumor Relapse Sites Positive Positive 33.7 Negative Negative 37.6 Positive Negative 10.9 Negative Positive 11.9 Heterogeneous Heterogeneous 5.9 Lindstrom L, et al. SABCS Abstract S3-5.

87 Issues for the endocrinologist Fertility preservation Pregnancy Menopausal Symptoms HRT Family History of breast cancer and HRT, BCP etc Chemoprevention Osteoporosis Obesity- metabolic Sx Thyroid dysfunction Oophorectomy in the setting of BRCA

88 Navigating Hormonal Therapy: Tomorrow We will use our rapidly increasing knowledge of cancer genomics and cell biology to develop more effective and less toxic treatments We will continue to probe the mechanisms of endocrine resistance to develop better strategies to overcome this problem We will continue to improve our knowledge of metastatic progression and develop improved technologies to identify cancer at its earliest stages

89 Ευχαριστώ! Sri Lanka Jan 2012