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Optimizing Treatments for Early-Stage Breast Cancer Hyman B. Muss, MD Professor of Medicine University of Vermont Fletcher Allen Health Care Burlington,

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Presentation on theme: "Optimizing Treatments for Early-Stage Breast Cancer Hyman B. Muss, MD Professor of Medicine University of Vermont Fletcher Allen Health Care Burlington,"— Presentation transcript:

1 Optimizing Treatments for Early-Stage Breast Cancer Hyman B. Muss, MD Professor of Medicine University of Vermont Fletcher Allen Health Care Burlington, VT Experts Review Clinical Application of Evolving Treatment Paradigms

2 Case 1 A 70-year old women in excellent health sees you in consultation for a 1.3 cm, moderately differentiated, infiltrating ductal carcinoma of the right breast Sentinel nodes were negative ER and PR positive HER-2 negative by FISH

3 Which of the following would you use or recommend to help make treatment recommendations?  Adjuvant! Online to estimate the value of endocrine therapy and chemotherapy  Oncotype DX ® testing  All of the above  None of the above Case 1

4 Which of the following would you use or recommend to help make treatment recommendations?  Adjuvant! Online to estimate the value of endocrine therapy and chemotherapy  Oncotype DX ® testing  All of the above  None of the above Recommended Approach:  Calculate treatment benefit from Adjuvant!  Oncotype ® testing unless patient adamantly against chemotherapy  Neither Adjuvant! or Oncotype ® are correct all the time and in 10% to 20% of patients may give opposite estimates Case 1

5 Adjuvant! Online Results 70-Year old with 1.3 cm N-MDIDC, ER+/PR+/HER2- From adjuvantonline.com; excellent health, TC 2 nd gen chemo, OS 12% die of other causes Adjuvantonline.com

6 Oncotype DX ® 21 Gene PCR Assay PROLIFERATION (5) Ki-67, STK15,Survivin Cyclin B1, MYBL2 ESTROGEN (4) ER, PR, Bcl2, SCUBE2 INVASION (2) Stromolysin 3,Cathepsin L2 HER2 (2) GRB7,HER2 OTHER (3) GSTM1, CD68, BAG1 REFERENCE (5) β-actin, GAPDH. RPLPO GUS,TFRC RS = Coefficient x Expression Level + 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68 - 0.08 x GSTM1 - 0.07 x BAG1 CategoryRS (0-100)Mets 10y Low risk<180-11% Int risk≥18 to <3112-21% High risk≥3122%+ Paik S, et al: NEJM 2004

7 Oncotype RS as a Continuous Predictor RS is 30, What is the chance of recurrence within 10 yrs if you take tamoxifen? RS is 30, What is the chance of recurrence within 10 yrs if you take tamoxifen? 95% CI Paik S, et al: NEJM 2004

8 Adjuvant! vs Oncotype DX Correlation of Risk Indices Concordance = 48% Bryant J: St Gallen 2005

9 You present the patient with adjuvant online and oncotype results. She declines chemotherapy or entry into a clinical trial. What endocrine therapy would you suggest for this patient?  Tamoxifen  Aromatase inhibitor  Give patient both options and mutually decide? Case 1 (continued)

10 You present the patient with adjuvant online and oncotype results. She declines chemotherapy or entry into a clinical trial. What endocrine therapy would you suggest for this patient?  Tamoxifen  Aromatase inhibitor  Give patient both options and mutually decide? Recommended Approach:  Offer both options to patient Case 1 (continued)

11 Case 1 Clinical Course The patient elects to take tamoxifen You plan to switch her to an AI in two years –She declines and takes tamoxifen for five years She is now 75-years old, healthy and has no toxicity with endocrine therapy

12 Tamoxifen x 5 Years ↓ Annual Odds Of Recurrence/Death (15-yr Follow-up) EBCTG Lancet 2005

13 AI vs Tamoxifen Initial Rx ATAC [anastrozole vs tamoxifen (T) vs both] –100 month follow BIG (letrozole vs T vs L>T vs T>L) Both show –3-5% improvement in RFS with AI –No improvement OS –No predictive marker for AI vs T

14 ATAC at 100 Months Anastrozole N = 3,125 Tamoxifen N = 3,116 HR/P Disease-Free74.2%70.1%.85/.003 Distant Mets13.2%15.6%.84/.02 Contralateral BC2.5%4.2%.60/.004 Overall Survival79.9%80.0%1.0/.99 There is carryover effect years 5-9 (like tamoxifen) No difference in MI for A vs T Yearly fracture rate: A vs T = 2.9% vs 1.9% (Hip NS) Endometrial cancer rates lower A vs T Forbes et al SABCS 2007; abstract 41(revision to abst); Lancet Oncol. 2008;9:45-53

15 BIG 1-98: Time to Relapse Coates AS et al. J Clin Oncol 2007; 25:486 7.9% 6.0% 10.2% L T 0 10 5 15 20 Proportion Relapse (%) Years From Randomization 0 23451 5-year diff (L-T) = -3.2% (SE = 1.1) Cum. inc. P =.005 13.4%

16 Switch to AI After 2-3 Years of Tamoxifen? IES, BIG, ITA, ARNO/ABCSG

17 Intergroup Exemestane Study (IES) Trial Design Coombes et al. Presented at ASCO 2006 (abstract LBA527); Lancet 2007 Post Treatment Follow-up 10,335 * Diagnosis Tamoxifen RANDOMIZERANDOMIZE Exemestane 2,352 Tamoxifen 2,372 2-3 years 2-3 years study treatment Total 5 years endocrine therapy Start of study

18 IES at 56 Months (Events) Tam N = 2,372 Exemestane N = 2,352 HR P Absolute Difference DFS455354.76 0.0001 3.3% OS261222.85.05 1.6% Coombes et al Lancet 2007

19  Discontinue endocrine therapy  Continue tamoxifen  Suggest consideration of an aromatase inhibitor  Other Case 1 (continued) After 5 years of tamoxifen, what would you do?

20  Discontinue endocrine therapy  Continue tamoxifen  Suggest consideration of an aromatase inhibitor  Other Recommended Approach: She has an estimated survival of 12 years Review tamoxifen and AI data Suggest that patient consider AI therapy for five years –Preventing recurrence improves QOL –Toxicity should be minimal Case 1 (continued) After 5 years of tamoxifen, what would you do?

21 Tamoxifen Duration: ATLAS Adjuvant Tamoxifen, Longer vs Shorter Randomized trial 1996-2005 Tamoxifen 5 vs. 10 yrs 38 countries and 420 hospitals 11,500 patients (~follow-up 4.2 yrs/pt) –Data reasonably complete for first 10 yrs ER+ 59%, others unknown 1,300 recurrences yr 5-9 Peto et al SABCS 2007, Abstract 48 LBA

22 RFS significantly better for longer tam –Recurrence T vs none: 739 vs 835 –12% risk reduction for 5 more yrs (P =.0005) Overall Survival and BC mortality lower but not significant Safe but more endometrial cancer Await 10-14 year data Tamoxifen Duration: ATLAS Adjuvant Tamoxifen, Longer vs Shorter Peto et al SABCS 2007, Abstract 48 LBA

23 NCIC MA.17: Trial Design Goss PE et al: J Natl Cancer Inst 97:1262, 2005 Primary end point: DFS Secondary end points: OS/rate of contralateral breast cancer/safety/QOL Tamoxifen Randomization (all patients disease-free) Placebo daily Letrozole 2.5 mg daily ~ 5 years5 years extended adjuvant 0-3 months N = 2,593 N = 2,594

24 Overall Survival MA-17 (30 Months) P = 0.04 Node PositiveNode Negative P = 0.34 Goss PE et al: J Natl Cancer Inst 97:1262, 2005

25 MA-17 Toxicity Letrozole % Placebo % P Hot Flashes5854.003 Fatigue39 NS Vaginal Bleeding68.005 Arthritis65.07 Arthralgia2521<.001 Myalgia1512.004 High Cholesterol16 NS Fractures5.34.60.25 Cardiac Events5.85.6.76 Goss PE et al: J Natl Cancer Inst 97:1262, 2005

26 Case 2 A 58-year old women with well controlled hypertension sees you in consultation for a 1.8 cm, moderately differentiated, infiltrating ductal carcinoma of the left breast Sentinel nodes were negative ER and PR positive HER-2 negative by FISH

27 You’ve sent her tumor for Oncotype testing and are awaiting results. What is her estimated 10-year overall survival if you treated her with endocrine therapy alone?  85%  75%  65%  55% Case 2

28 You’ve sent her tumor for Oncotype testing and are awaiting results. What is her estimated 10-year overall survival if you treated her with endocrine therapy alone?  85%  75%  65%  55% Answer:  85% Case 2

29 Clinical Course She is randomized to chemotherapy You offer her an ongoing clinical trial for patients with node negative tumors and she declines I would offer her a second generation chemotherapy regimen as per Dr. Ravdin (adjuvantonline.com)

30 Adjuvant! Online Results 58-year old with 1.8 cm N-MDIDC, ER+/PR+/HER2- From Adjuvantonline; minor problems, TC 2 nd gen chemo, OS 8% die of other causes

31 Intergroup – PACCT TAILORx Trial (Randomization ~ 4,390) RS < 11 Hormone Therapy Risk < 6% RS 11-25 Randomize Hormone Rx vs. Chemotherapy + Hormone Rx Risk 6-17% RS > 25 Chemotherapy + Hormone Rx Risk 18+% Node Negative ER+ Oncotype DX ® Assay

32 Adjuvant! Online Dr. Ravdin CT*4 1 st 2 nd 3 rd

33 AC vs TC: US Oncology 9735 Are Anthracyclines Essential? Doxorubicin 60 mg/m 2 IV Day 1 Cyclophosphamide 600 mg/m 2 IV Day 1 Every 21 days X 4 Cycles Docetaxel 75 mg/m 2 IV Day 1 Cyclophosphamide 600 mg/m 2 IV Day 1 Every 21 days X 4 Cycles AC TC RANDOMIZERANDOMIZE Jones SE, et al. SABCS 2007. Abstract 12.

34 Disease-free Survival by Treatment Jones SE, et al. SABCS 2007. Abstract 12.

35 Overall Survival by Treatment Jones SE, et al. SABCS 2007. Abstract 12.

36 Overall Survival by Treatment and by Age Group Insert graphics here Jones SE, et al. SABCS 2007. Abstract 12.

37 Grade 3-4 Hematologic Toxicity by Treatment and Age (%) < 65 Years≥ 65 Years TCACTCAC Adverse Event428 Pts 78 Pts82 Pts Anemia< 11 5 Neutropenia60545259 Thrombocytopenia< 110 Febrile Neutropenia4284 Jones SE, et al. SABCS 2007. Abstract 12.

38 Case 3 A 47-year old women in otherwise good health sees you in consultation for a 2.1 cm moderately differentiated infiltrating ductal carcinoma of the left breast One of 3 sentinel nodes were positive Axillary dissection revealed 2 other positive nodes of 16 removed ER positive PR negative HER-2 positive (IHC 3+) She declines participation in a clinical trial

39 Which of the following regimens would you recommend?  AC and trastuzumab  TC and trastuzumab  Docetaxel, carboplatin and trastuzumab (TCH)  AC (either q 3 weeks or dose-dense) followed by paclitaxel and trastuzumab (TH)  Other Case 3

40 Which of the following regimens would you recommend?  AC and trastuzumab  TC and trastuzumab  Docetaxel, carboplatin and trastuzumab (TCH)  AC (either q 3 weeks or dose-dense) followed by paclitaxel and trastuzumab (TH)  Other Recommended Approach:  AC → TH (but TCH is a reasonable alternative)  Monitor cardiac function every 3 months  Add endocrine therapy after completion of chemotherapy/RT Case 3

41 Telli, M. L. et al. J Clin Oncol; 25:3525-3533 2007 Efficacy: Adjuvant Trastuzumab One Year Duration 9 weeks

42 Romond, E. H. et al. N Engl J Med 2005;353:1673-1684 Kaplan-Meier Estimates of Disease-free Survival (Panel A) and Overall Survival (Panel B)

43 Joensuu H et al. N Engl J Med 2006;354:809-820 Effects of Single-Agent Docetaxel or Vinorelbine and Trastuzumab on the Kaplan-Meier Estimates of Recurrence-free Survival (Panels A and C) and Overall Survival (Panels B and D) Among Women with Breast Cancer “Finnish Trial” 9 wks of trastuzumab Only 39 recurred or died (small #) of 232 HER2+ randomized

44 BCIRG: Disease-Free Survival (2 nd Interim Analysis) % Disease Free 0.5 0.6 0.7 0.8 0.9 1.0 012345 Patients Events 1073192 AC  T 1074128 AC  TH 1075142TCH 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 Absolute DFS benefit (from years 2 to 4): AC  TH vs AC  T: 6% TCH vs AC  T: 5%

45 Baseline 10 Year OS With Tam and Chemo Added Herceptin Benefit Due to Herceptin NP (1-3) T245 %64 %72 %8 % NN T259 %74 %79 %5 % NN T1c81 %86 %88 %2 % NN T1ab88 %90 %91 %1 % Is Adjuvant Herceptin Needed For All Breast Cancer Patients? Speculation ! (Ravdin) 60-Year Old Women. ER+, Her2+, average comorbidity. Competeing mortality about 8%. To Get Tam + CA * 4, T * 4q3w HER2 FISH+; Additional RR conferred by HER2: 1.5 Risk of developing CHF 5%, 2/3 have symptoms resolve in 6 months. Cardiac status at 10 years??

46 Issues for HER2+ Disease Optimal duration Role of anthracyclines (TCH) Role of trastuzumab (Topo 2 ↑) Cardiac Protection and monitoring –ACE inhibitors/beta-blockers up front? Role of lapatinib New agents

47 Case 4 A 67-year old women with well controlled adult onset diabetes sees you in for a 1.8 cm poorly differentiated infiltrating ductal carcinoma of the left breast One of 2 sentinel nodes were positive (2.1 mm metastatic deposit) Subsequent axillary dissection revealed 8 other negative nodes ER negative PR negative HER2 negative She declines participation in a clinical trial

48 Which of the following regimens would you recommend?  AC  TC  Docetaxel, doxorubicin and cyclophosphamide  AC followed by paclitaxel (dose dense)  AC (dose-dense or q 3 weeks) followed by weekly paclitaxel x 12  Other Case 4

49 Which of the following regimens would you recommend?  AC  TC  Docetaxel, doxorubicin and cyclophosphamide  AC followed by paclitaxel (dose dense)  AC (dose-dense or q 3 weeks) followed by weekly paclitaxel x 12  Other Recommended Approach:  Chemotherapy regimen consisting of an anthracycline and taxane  Although she is older, she is in good health and should get similar benefits from these more intensive regimens as younger patients Case 4

50 ER Poor Chemo vs Not RFSOS All HR Absolute benefit HR Absolute benefit <50 15% N+.7312%.758% 50-69 58% N+.8210%.876% All P-values <.01 Lancet 371;29 January 2008

51 Berry, D. A. et al. JAMA 2006;295:1658-1667. Kaplan-Meier Curves for Disease-free Survival According to Estrogen-Receptor (ER) Status in the 3 Studies CAF 3 Doses AC ± T DD v Q3wk ER-ER+

52 Overall Survival for All Patients by Chemotherapy Intensity and Age Group Muss HB et al. JAMA 2005;293:1073-1081.

53 Classification of Breast Cancer for Clinical Trials Node − Node + ER and PR HER2 Old New

54 Sorlie, et al. PNAS 2001 ER neg ER pos

55 Overall and Relapse Free Survival by Tumor Types Defined with Gene Expression Patterns Sorlie, et al. PNAS 2001.

56 Divide by ER and HER-2 and Conquer! (from Winer) ER+/HER2- (low grade; luminal A) ER+/HER2- (high grade; luminal B) HER2- / ER- (Triple Negative) HER2+ ER+/ER- Adapted with permission from E. Winer.

57 Optimizing Treatments for Early-Stage Breast Cancer Concluding Remarks Experts Review Clinical Application of Evolving Treatment Paradigms


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