1. Challenging Cases in Cancer: Early Breast Cancer Clifford A. Hudis, MD Chief, Breast Cancer Medicine Service Attending Physician Memorial Sloan-Kettering Cancer Center New York, NY

2. Case 1 57-year old woman with calcifications on her yearly screening mammogram is found to have 1.3 cm of invasive ductal carcinoma The tumor is strongly positive for both the estrogen and progesterone receptors and negative for HER2 After undergoing a lumpectomy with clear margins and a sentinel node procedure yielding negative nodes, she seeks an opinion regarding treatment to improve her overall survival She has already planned radiation therapy

3. Case 1 Which adjuvant therapy has been shown to offer the greatest impact on overall survival for patients with node-negative, hormone-receptor positive invasive breast cancer? 1.Tamoxifen 2.Anastrozole 3.Letrozole 4.Tamoxifen followed by Exemestane 5.Tamoxifen followed by Anastrozole 6.Tamoxifen followed by Letrozole 7.Combination chemotherapy alone 8.Combination chemotherapy AND options 1, 2, 3, 4, 5 or 6 9.Clinical Trial

4. Case 1 Which adjuvant therapy has been shown to offer the greatest impact on overall survival for patients with node-negative, hormone-receptor positive invasive breast cancer? 1.Tamoxifen 2.Anastrozole 3.Letrozole 4.Tamoxifen followed by Exemestane 5.Tamoxifen followed by Anastrozole 6.Tamoxifen followed by Letrozole 7.Combination chemotherapy alone 8.Combination chemotherapy AND options 1, 2, 3, 4, 5 or 6 9.Clinical trial Recommended Approach: Clinical trial

5. Effect of Tamoxifen on Breast Cancer Recurrence Effect of Tamoxifen on Breast Cancer Death Early Breast Cancer Trialists' Collaborative Group. Lancet. 2005; 365:1687-1717

6. Selective vs. Nonselective Aromatase Inhibition Federman, DD: The Adrenal. Dale DC, Federman DD, eds. In: Scientific American Medicine. Section 3. Subsection IV. ©1997 Scientific American Inc. All rights reserved. Multiple steps involving P-450 enzymes and production of steroid intermediates Cholesterol Cortisol Androstenedione Aldosterone Testosterone EstroneEstradiol Selective Inhibitors Nonselective Inhibitors

7. Steroidal and Non-steroidal Aromatase Inhibitors Differences in Structure and Function Androstenedione O NH 2 H C2H5C2H5 O N Aminoglutethimide Steroidal Inactivators Androgen Substrate Non-steroidal Inhibitors CH 3 NC CN AnastrozoleLetrozole N O CH 2 O Exemestane NC CN N N N O O NN Formestane O OH O

8. * Note that some patients from the original newly diagnosed population are lost due to recurrence or adverse events prior to randomization TRIALS ATAC BIG 01-98 TEAM BIG 01-98 IES ITA ARNO95/ABCSG8 * DIRECT COMPARISON SWITCHING * SEQUENCING EXTENDED ADJUVANT MA.17 Adjuvant AI Hormonal Therapy Trial Designs

9. All women were: Postmenopausal 84% HR + 61% node - 21% Rx chemotx Recruitment July 1996-March 2000 Anastrozole + Tamoxifen (N=3,125) Tamoxifen (N=3,116) Surgery ± RT ± chemo Anastrozole (N=3,125) 5 years ATAC Design

10. ATAC: Recurrence (HR +ve) Median follow up 68 months Patients (%) Follow-up time (years) 0 5 10 15 20 25 0126 Absolute difference:1.7%2.4%2.8%3.7% At risk: A261825402448235522682014830 T259825162398230421891932774 Anastrozole (A) Tamoxifen (T) 3 HR 0.74 0.79 HR +ve ITT 95% CI (0.64, 0.87) (0.70, 0.90) P-value 0.0002 0.0005 45 CI = confidence intervals; HR = hazard ratio ITT = intent-to-treat ATAC Trialists’ Group. Lancet 2005;365:60-62

11. ATAC: Overview of Adverse Events* (%) *Adverse events on treatment or within 14 days of discontinuation Drug-related: AEs SAEs AEs leading to withdrawal P-value < 0.0001 0.0001 0.0002 Tamoxifen (N=3,094) 68.4 9.0 14.3 Anastrozole (N=3,092) 60.9 4.7 11.1 ATAC Trialists’ Group. Lancet 2005;365:60-62

12. * Patients  1 fracture occurring before recurrence, including patients no longer on treatment ATAC: Pre-specified Adverse Events (%) T 40.9 10.2 13.2 0.8 2.8 4.5 29.4 7.7 5.1 A 35.7 5.4 3.5 0.2 2.0 2.8 35.6 11.0 1.3 Hot flashes Vaginal bleeding Vaginal discharge Endometrial cancer Ischemic cerebrovascular Venous thromboembolic Joint symptoms Fractures* Hysterectomy P-value < 0.0001 < 0.0001 0.02 0.03 0.0004 < 0.0001 ATAC Trialists’ Group. Lancet 2005;365:60-62

13. ATAC: Overall Survival Curves Shown for HR+ Patients Includes non breast cancer deaths At risk: A261825662505243723772117867 T259825492502243023332080855 Follow-up time (years) 0 5 10 15 20 25 0123456 Patients (%) Anastrozole (A) Tamoxifen (T) HR 0.97 HR+ 95% CI (0.83–1.14) (0.85-1.12) P-value 0.7 ITT A 296 411 T 301 420 ATAC Trialists’ Group. Lancet 2005;365:60-62

14. BIG 01-98 (FEMTA) Tamoxifen Tamoxifen Letrozole Letrozole Letrozole RANDOMIZE Tamoxifen 2 Years 3 Years 5 Years ER+ and/or PgR+ Postmenopausal women s/p surgery ± chemo, ± RT Primary Endpoints: DFS, DDFS, OS

15. BIG 01-98 Primary Core Analysis Compares Letrozole versus Tamoxifen Includes all patients Letrozole: Arms B and D Tamoxifen: Arms A and C Excludes events and FU beyond switch for C & D Tamoxifen Letrozole TamoxifenLetrozole Tamoxifen A B C D 2-Arm Option 4-Arm Option

16. TAM 0 20 40 60 80 100 012345 Percent alive and disease-free Years from randomization 97.7 97.6 Yearly DFS (%) 95.1 93.4 90.5 89.0 86.8 84.6 84.0 81.4 No. at Risk 3892 3896 2964 2926 1261 1238 892 866 4003 4007 567 544 LET NHR (95% CI)P Value 80100.81 (0.70-0.93)0.003 BIG 01-98: Disease-free Survival

17. Updated Safety Analysis of BIG 01-98 Trial: Cardiovascular Adverse Events During Adjuvant Letrozole (Let) vs. Tamoxifen (Tam) Therapy Tamoxifen Letrozole BIG 1-98: N = 7963 Let - HR: 19% lower for DFS, 27% reduced risk for distant recurrence compared to Tam. Grade 3-5 Adverse Event Number of Events With Letrozole (N = 3,975) Number of Events With Tamoxifen (N = 3,988) Relative Risk P Any Cardiac 96571.63.0036 Ischemic Heart Disease 45291.46.12 Hypertension57481.18.40 CVA/TIA47470.98.94 Thromboembolic35920.38 <.0001 Cardiovascular AEs higher for Let, but relatively rare. Patients at risk for thromboembolism should avoid tamoxifen Coates et al, ASCO 2007, Abstract 521

18. ABCSG 8 – ARNO 95: Combined Analysis Trial Structure Primary surgery +/- RTx TAM 3 years N=1,606 Total patients N=3,224 ABCSG 8 N=2,262 + ARNO 95 N=962 ANA 3 years N=1,618 + TAM 2 years 100% HR positive 74% node negative 0% Rx chemotx Jakesz et al, Lancet 2005;366:455–462

19. ABCSG 8 – ARNO 95: Event-free Survival 28 Months Median Follow-up Events = locoregional recurrences, distant metastases, contralateral breast ca Event-free survival (%) At risk: 1606343176 TAM ANA 1618 1217 1243 858 874 593 623 375 178

20. ABCSG 8 – ARNO 95: Overall Survival Number Deaths 3 yrs. OS (%) TAM 1,6065996.4 ANA 1,6184597.1 ANA vs TAM P =0.16 HR 0.76  95% CI 0.52-1.12  Jakesz et al, Lancet 2005;366:455–462

21. IES Trial Design Diagnosis 2-3 years 2-3 years study treatment Total 5 years endocrine therapy Tamoxifen RANDOMIZERANDOMIZE Exemestane 5,162* Tamoxifen 5,294* Post Treatment Follow-up 10335 * Start of study * Total women years Coombes et al, ASCO 2006, # LBA527

22. IES: Disease-free Survivalyear % abs. diff. (95% CI) 2.553.23.4 (1.6 – 4.9) (0.1 – 6.8) End of treatmentER+/Unknown HR = 0.75 (95% CI: 0.65-0.87) Log-rank test: P = 0.0001 E = 339 / 2296 T = 438 / 2306 E = 354 / 2352 End of treatmentITT HR = 0.76 (95% CI: 0.66-0.88) Log-rank test: P = 0.0001 T = 454 / 2372 2.553.43.5 (1.8 – 5.1) (0.1 – 6.9) Coombes et al, Lancet. 2007 Mar 17;369(9565):906.

23. IES: Overall Survivalyear % abs. diff. (95% CI) 2.550.81.2 (-0.4 – 1.9) (-1.5 – 3.9) End of treatment HR = 0.85 (95% CI: 0.71-1.02) Log-rank test: P = 0.08 E = 222 / 2352 T = 261 / 2372 ITT End of treatment HR = 0.83 (95% CI: 0.69-1.00) Log-rank test: P = 0.05 E = 210 / 2296 T = 251 / 2306 ER+/Unknown 2.550.71.6 (-0.4 – 1.9) (-1.2 – 4.3) Coombes et al, Lancet. 2007 Mar 17;369(9565):906.

24. Primary Endpoint: Disease-free Survival n = 2,575 n = 2,582 All Postmenopausal Patients and Disease- free Tamoxifen Placebo Letrozole 4.5 - 6 years initial adjuvant 5 years extended adjuvant 0–3 months NCIC CTG Intergroup Trial MA.17 Design Goss PE, et al, NEJM. 349;19 November 6, 2003.

25. No. at risk (letrozole)257523081327111062490 No. at risk (placebo)258222981295610180110 P <.001 LetrozolePlacebo 0 20 40 60 80 100 Time From Randomization (Months) 0102030405060 Percentage MA.17: Disease-free Survival Goss PE, et al. J NEJM. 349;19 November 6, 2003.

26. Adjuvant Endocrine Trials: EfficacyStrategyRCTsPtsUpdate Median FU (mo.) AI Efficacy [HR, P] DFS/EFSOS Up-Front ATAC6,186 Lancet 2006 68ANA 0.87 (0.01) 0.97 (0.7) BIG-1-984,922 JCO 2007 51LET 0.82 (0.007) 0.91 (>0.05) “Early” Switch ITA-1380 JCO 2001 61AGT NR (0.6) NR (0.005) ITA-2448 Ann Oncol 2006 64ANA 0.57 (0.005) 0.56 (0.1) IES4,742 Lancet 2007 56EXE 0.76 (0.0001) 0.85 (0.08) ABCSG8/ARNO3,224 Lancet 2005 28ANA 0.60 (0.0009) NR (0.16) “Extended” Switch MA.175,157 JNCI 2005 30LET 0.58 (0.001) 0.82 (0.3) ABCSG 6a 856 ASCO 2005 60ANA 0.64 (0.047) NR NSABP B-33 1,598 SABCS 2006 30EXE 0.68 (0.07) 1.20 (0.64)

27. AI’s & Hazard Rate Inflections: Does the Timing of Hormone Therapy Influence the Change in the RATE of Events? 510 YEARS % DFS ATAC/BIG 01-98 MA.17 IES/ARNO 8-ABCSG 95

28. Local/ regional recurrence Distant metastasis Death from any cause Invasive Contra- lateral breast cancer Second primary invasive cancer (non- breast) Ipsi- lateral DCIS Contra- lateral DCIS Ipsi- lateral LCIS Contra- lateral LCIS BIG 1-98XXXXX MA-17XXXXXXX ATACXXXXXX IESXXXX ARNOXXX NOTE: EFS (Event-free Survival) used by ARNO DCIS = Ductal Carcinoma in situ LCIS = Lobular Carcinoma in situ Hudis et al, JCO, Vol 25, No 15 (May 20), 2007: pp. 2127-2132 Example of Inconsistent Definitions of Disease-free Survival

29. Early Breast Cancer Trialists’ Collaborative Group, Sept 2000 (*Lancet 1998) Comparison (N) CMF vs. Nil (12,000) CMF+ vs. Nil (3,200) Other vs. Nil (12,000) *CMF/Tam vs. Tam (640) < 50 *CMF/Tam vs. Tam (9,192) 50+ Anthracyclines+ vs. CMF (13,600) Longer vs. Shorter (6,100) Recurrence +24 ± 3 +20 ± 5 +24 ± 3 + 21 ± 13 +19 ± 3 +11 ± 3 +6 ± 4 Death +15 ± 3 +12 ± 5 +16 ±3 +25 ± 14 + 11 ± 4 +16 ± 3 2 ± 4 PolyChemotherapy: 56/64 Available Trials 10,000 Deaths / 28,000 Enrolled

30. Case 2 45-year old woman with calcifications on her yearly screening mammogram is found to have 1.3 cm of invasive ductal carcinoma (infiltrating carcinoma) metastatic to 3 lymph nodes She has had a lumpectomy and is planning radiation therapy The tumor is weakly positive for both the estrogen and progesterone receptors but also positive by both IHC and FISH for HER2 She seeks an opinion regarding treatment to prevent recurrence and improve her overall survival

31. Case 2 Which adjuvant chemotherapy would you recommend in addition to hormone therapy? 1.CMF x 6 + trastuzumab 2.AC x 4 + trastuzumab 3.FEC/CEF/CAF/FAC + trastuzumab 4.AC x 4 followed by a taxane x 4 + trastuzumab 5.AC x 4 followed by paclitaxel x 4 (all q 2 weeks) + trastuzumab 6.TAC x 6 followed by trastuzumab 7.Carbo/docetaxel + trastuzumab 8.Trastuzumab alone

32. H Trastuz Doxorub Cycloph Paclitax Docetax CBDCA Adjuvant Trastuzumab

33. B-31/N9831 Survival AC  TH 94% 91% 87% 92% AC  T NDeaths AC  T1,67992 AC  TH1,67262 HR = 0.67, 2P = 0.015 Years From Randomization Romond et al, ASCO 2005

34. Disease-free Survival: Adjuvant Trastuzumab Romond EH, et al. N Engl J Med. 2005;353:1673-1684. N9831 Years From Randomization 012345 50 60 70 80 90 100 78% 87% 86% 68% HR: 0.55; 2P =.0005 AC  T 807 90 AC  TH 808 51 012345 50 60 70 80 90 100 B-31 HR: 0.45; 2P = 1x10 -9 74% 87% 85% 66% Patients (%) N EventsTreatment 872171 86483 AC  T AC  TH AC  T AC  TH TreatmentN Events

35. 100 80 60 40 20 0 Patients(%) Months from randomization Observation No. at risk 1703162714981190 794407146 1698160614241042 677354126 1-year trastuzumab 59 90 EventsHR95% CIP value 0.63 0.45, 0.870.0051 3-year OS 92.4 89.2 1236018 6 2430 Smith et al., Proc ASCO 2006 HERA: Overall Survival (censored) Median 2-year FU

36. Disease-free Survival: 2 nd Interim Analysis Absolute DFS benefits (from years 2 to 4): AC  TH vs. AC  T: 6% TCH vs. AC  T: 5% % Disease Free 0.5 0.6 0.7 0.8 0.9 1.0 012345 Patients Events Events 1,073192 AC→T 1,074128 AC → TH 1,075142TCH 81% 87% 86% 77% 83% 82% 87% 93% 92% HR (AC→TH vs. AC→T) = 0.61 [0.48;0.76] P < 0.0001 HR (TCH vs. AC→T) = 0.67 [0.54;0.83] P = 0.0003 Year from randomization

37. Overall Survival: 2 nd Interim Analysis HR (AC→TH vs AC->T) = 0.59 [0.42;0.85] P = 0.004 HR (TCH vs AC→T) = 0.66 [0.47;0.93] P = 0.017 % Survival 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2345 Patients Events Events 1,07380AC→T 1,07449 AC→TH 1,07556TCH 97%99%93% 97% 95% 92% 91% 86% Year from randomization 98%

38. Summary of Results from 5 Adjuvant Trastuzumab Trials Recurrence TrialControlExp ArmConc ? N=; FU= HR, % Mortality TrialControlExp ArmConc ? N=; FU= HR, % Mortality B31+N9831 1 AC + PACSame +Y 3351; 2y4733 all Q3W x 4 Tras 1y all Q3W x 4 Tras 1y N9831AC + PACSame +N3585; 1.5y1315 Post C 1 all Q3W x 4Tras 1y Post C 1 all Q3W x 4Tras 1y HERA 2 Any PriorSame +N3387; 1y4624 adjuvant CTTras 1y adjuvant CTTras 1y BCIRG OO6 3 AC + DSame +Y3222; 2y51--- all Q3W X 4Tras 1y CbD +Y3222; 2y39--- Tras 1y FinHer 4 D or V + Same +Y1010; 3y5859 FEC x 3 Tras 9W 1.Romond EH. N Engl J Med 2005:353:1673-1684 2.Piccart-Gebhart MJ et al. Presented at: ASC0 41 st Annual Meeting; May 13-17, 2005 3.Slamon D et al. Presented at: 28 th Annual San Antonio Breast Cancer Symposium; December 8-11, 2005 4.Joensuu H et al, Breast Cancer Res Treat. 2005;94(suppl 1):S5. Abstract 2. CbD = carbloplatin, docetaxel; CT = chemotherapy; D = docetaxel; HR = hazard ratio; Tras = trastuzumab; V = vinorelbine

39. q 2 wk (w/G-CSF)q 3 wk 7/481 (1.5%) 5/487 (1%)12/488 (2.5%) 12/473 (2.5%)* Grade 3 Post-Rx Cardiac Events: 36/1929 (2%) No association with schedule or regimen ( * plus one cardiac death w/Rx) Hudis et al, SABCS 2005

40. Trastuzumab is Safe With Dose-Dense: AC→ T Preliminary Results Of MSKCC Pilot: 04-126 N = 70 Dang, et al, SABCS. 2006 (abstr 2101). HHHHHHHHHH x 52 doses (weeks)

41. Dose-Dense AC→Paclitaxel (T) + H: Results Multi-gated radionuclide angiography scan (MUGA) obtained at baseline and at months 2, 6, 9, and 18 MUGA at: BaselineMonth 2Month 6Month 9 Month 18 Median LVEF (%) 6867666566 Range55-8158-7952-7553-7555-75 Dang, et al, SABCS. 2006 (abstr 2101). LVEF=left ventricular ejection fraction. CHF in 1 patient of 70

42. Summary Targeting of the estrogen receptor through deprivation of estrogen shows a clear and consistent advantage in post-menopausal women for the use of aromatase inhibitors Role of chemotherapy Targeted therapies can improve survival in early-stage breast cancer Dose-Dense Chemotherapy