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Adjuvant Breast Cancer Therapy An Analysis of Current Treatment Paradigms

Adjuvant Breast Cancer Therapy An Analysis of Current Treatment Paradigms. Mark D. Pegram, MD UCLA/Jonsson Comprehensive Cancer Center. Age 47 Premenopausal breast carcinoma Lumpectomy - 1.3 cm poorly differentiated, high grade infiltrating ductal carcinoma

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Adjuvant Breast Cancer Therapy An Analysis of Current Treatment Paradigms

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  1. Adjuvant Breast Cancer Therapy An Analysis of Current Treatment Paradigms Mark D. Pegram, MDUCLA/Jonsson Comprehensive Cancer Center

  2. Age 47 Premenopausal breast carcinoma Lumpectomy - 1.3 cm poorly differentiated, high grade infiltrating ductal carcinoma HER2 amplified, HER2/Chr17 (FISH) ratio = 8 ER/PR negative SLN Bx – 2 LNs negative Lymphovascular invasion – present SPF – 20%; KI 67 = 30% DNA content - aneuploid Case Study 1: Early Breast CancerHigh-Risk, Node-Negative, HER2+

  3. Case Study 1: Early Breast CancerHigh-Risk, Node-Negative, HER2+ • The patient is referred to you for adjuvant therapy recommendations. In addition to post-lumpectomy radiation, which treatment option would you recommend? • Anthracycline and/or taxane-based adjuvant chemotherapy • Anthracycline and taxane-based adjuvant chemotherapy regimen incorporating trastuzumab for one year • Anthracycline-based adjuvant chemotherapy followed by trastuzumab for one year (no taxane) • Non-anthracycline combination chemotherapy with trastuzumab for one year (e.g. TCH or TC→H) • Combination chemotherapy with trastuzumab for a period of 9 weeks

  4. NSABP B-31: Quality Assurance • Initial protocol • Patients were eligible if tumors were HER2+ by an accredited laboratory (n = 104) • All samples were re-analyzed by a central laboratory • Only 82/104 were found to be HER2+ by HercepTest and PathVysion • 21%false positive (82% of the false-positive results were from smaller laboratories [≤ 99 cases per month]) • Amended protocol • To be eligible, tumors must be HER2+ by a central laboratory (n = 240) • This reduced the number of false positives from 21% to 2% (P = 0.003) Paik S, et al. J Natl Can Inst 2002;94:852–4

  5. n Hazard Ratio All All 3387 3387 0.54 0.54 Nodal Nodal status status Any, neo Any, neo - - adjuvant chemotherapy adjuvant chemotherapy 358 358 0.53 0.53 0 pos, no neo 0 pos, no neo - - adjuvant chemotherapy adjuvant chemotherapy 1100 1100 0.52 0.52 1 1 - - 3 pos, no neo 3 pos, no neo - - adjuvant chemotherapy adjuvant chemotherapy 972 972 0.51 0.51 ³ ³ 4 pos, no neo 4 pos, no neo - - adjuvant chemotherapy adjuvant chemotherapy 953 953 0.53 0.53 Adjuvant chemotherapy regimen Adjuvant chemotherapy regimen No anthracycline or taxane No anthracycline or taxane 203 203 0.64 0.64 Anthracycline, no taxane Anthracycline, no taxane 2307 2307 0.43 0.43 Anthracycline + taxane Anthracycline + taxane 872 872 0.77 0.77 Receptor status/endocrine therapy Receptor status/endocrine therapy Negative Negative 1674 1674 0.51 0.51 Pos + no endocrine therapy Pos + no endocrine therapy 467 467 0.49 0.49 1234 1234 0.68 0.68 Pos + endocrine therapy Pos + endocrine therapy Age group Age group <35 yrs <35 yrs 251 251 0.47 0.47 35 35 - - 49 yrs 49 yrs 1490 1490 0.52 0.52 50 50 - - 59 yrs 59 yrs 1091 1091 0.53 0.53 ³ ³ 60 yrs 60 yrs 549 549 0.70 0.70 Region Region Europe, Nordic, Canada, SA, Aus, NZ Europe, Nordic, Canada, SA, Aus, NZ 2430 2430 0.58 0.58 Asia Pacific, Japan Asia Pacific, Japan 405 405 0.42 0.42 Eastern Europe Eastern Europe 364 364 0.31 0.31 Central + South America Central + South America 188 188 0.90 0.90 Favors Favors Favors Favors 0 0 1 1 2 2 Trastuzumab Observation HERA Trial: DFS Benefit in SubgroupsHR: 1-Year Trastuzumab vs. Observation

  6. In Vitro Drug Interactions With Trastuzumab Pegram et al. J Natl Cancer Inst. 2004;96:739.

  7. ARM C AC AC → P + T P + T → T T 100 100 Events = 53 Events = 53 90 90 80 80 ARM B 70 70 AC AC → P → T T Events = 84 Events = 84 60 60 50 50 Percent Percent 40 40 30 30 HR = 0.64 Stratified log rank P = 0.0114 20 20 10 10 0 0 0 0 1 1 2 2 3 3 4 4 Years Years Number of patients followed: Number of patients followed: B 842 B 842 501 501 285 285 162 162 20 20 C 840 C 840 520 520 285 285 178 178 17 17 N9831: Concurrent vs Sequential Trastuzumab on Disease-Free Survival Perez. Presentation at ASCO 2005 Symposium. http://www.asco.org.

  8. 4 x AC60/600 mg/m2 4 x Docetaxel 100 mg/m2 ACT 4 x AC60/600 mg/m2 4 x Docetaxel 100 mg/m2 HER2+ (Central FISH) N+ or high-risk N– N = 3,222 ACTH 1 Year Trastuzumab 6 xDocetaxel and Carboplatin 75 mg/m2 AUC 6 Stratified by nodes and hormonal status TCH 1 Year Trastuzumab BCIRG 006: Schema

  9. 99% 1.0 95% 94% 97% 94% 93% 0.9 92% 88% 86% 0.8 % Disease Free 0.7 Patients Events 309 35 AC→T 0.6 HR (AC→TH vs AC→T) = 0.32 [0.17;0.62] P = 0.0007 310 12 AC→TH 309 17 TCH HR (TCH vs AC→T) = 0.47 [0.26;0.83] P = 0.0096 0.5 0 1 2 3 4 5 Year from Randomization BCIRG 006DFS Lymph Node Negative: 2nd Interim Analysis

  10. BCIRG 006Cardiac Deaths and CHF(Independent Review Panel) First interim analysis Second interim analysis P = 0.0015 Slamon D. SABCS 2006

  11. 66 65 TCH 64 AC→T 63 62 LVEF points, % AC→TH 61 60 59 58 0 100 200 300 400 500 600 700 800 900 1000 AC→T (N=1014) Time since Randomization (days) AC→TH (N=1042) TCH (N=1030) BCIRG 006Mean LVEF - All Observations2nd Interim Analysis Slamon D. SABCS 2006

  12. Patient Eligibility(Adjuvant Trastuzumab) • Normal left ventricular ejection fraction • No past or active cardiac disease including: • History of myocardial infarction • History of congestive heart failure • Angina pectoris requiring medication • Arrhythmia requiring medication • Clinically significant valvular disease • Uncontrolled hypertension • LVH • Cardiomegaly on CXR Slamon D. SABCS 2006

  13. Asymptomatic PatientsRules for Trastuzumab ContinuationBased on Serial LVEFs • * Repeat LVEF assessment after 4 weeks • If criteria for continuation met – resume trastuzumab • If 2 consecutive holds, or total of 3 holds occur – discontinue trastuzumab Slamon D. SABCS 2006

  14. Arm A Arm B Docetaxel 100 mg/m2 Q3W * 3 Trastuzumab Q1W * 9 Vinorelbine 25 mg/m2 Q1W * 3 FEC 600/60/600 mg/m2 Q3W * 3 Analysis of 4 Treatments of Fin-HerPatients (age ≤65, no HTN) either NP or NN with tumor size > 2 cm and PgR negative. HER2 amplification determined by CISH. n = 1,010; median follow-up 3.2 years All patients were randomized between docetaxel and vinorelbine. HER amplified patients (n = 232) were randomized between additional trastuzumab or not.

  15. 100 Trastuzumab 89.3% 80 77.6% No Trastuzumab 60 N EventsHR P T 115 12 No T 116 27 0.42 0.01 (0.21-0.83) % Patients 40 20 0 0 1 2 3 4 Years No. at Risk T 115 112 97 64 21 No T 116 109 91 51 18 Recurrence-Free Survival (%)

  16. Case Study 2: Early Breast CancerLN-positive, ER-positive • Age 47 • Premenopausal breast carcinoma • Lumpectomy - 1.3 cm poorly differentiated, high grade infiltrating ductal carcinoma • HER2 non-amplified HER2/Chr17 (FISH) ratio = 1.91 • ER/PR positive • SLN Bx – 2 LNs positive; axillary dissection – one additional positive LN out of 20 examined • Lymphovascular invasion – present • SPF – 20%; KI 67 = 30% • DNA content - aneuploid

  17. Case Study 2: Early Breast CancerLN-positive, ER-positive • The patient is referred to you for adjuvant therapy recommendations. In addition to post-lumpectomy radiation and standard adjuvant endocrine therapy, which treatment option would you recommend? • Dose-dense AC followed by paclitaxel • AC x 4 q 3 weeks followed by weekly paclitaxel x 12 • TAC x 6 • FEC x 3 → docetaxel x 3 • FEC x 6

  18. 1012 1010 108 106 Cell Number 104 102 1 0 1 2 3 4 5 6 7 Months “Normal” Dose Intensity & Increased Dose Density Larry Norton, M.D., MSKCC; Oncologic Drug Advisory Committee

  19. 1012 1010 108 Cell Number 106 104 102 1 2 0 1 3 4 5 6 7 Months Sequential Therapy is Dose Dense Larry Norton, M.D., MSKCC; Oncologic Drug Advisory Committee

  20. Micrometastasis Tumor Volume dL = 1 - 2 (L – L0) dt Lymph Node Time Comparative Analysis of Micrometastasis to the BoneMarrow and Lymph Nodes of Node-Negative Breast CancerPatients Receiving No Adjuvant Therapy Braun, et al., Journal of Clinical Oncology, Vol 19, No 5 (March 1), 2001: pp 1468-1475

  21. Number of Tumor Cells over Time Non-Gompertzian Growth of HumanSolid Tumors “…the hypothesis of uninterrupted constant growth for locally recurring tumors should be rejected.” Demicheli, R. Sem Cancer Biol 2001:11: 297-305

  22. 3-Week Cycles 2-Week Cycles (w/ G-CSF) 24 wks 16 wks 36 wks 24 wks Doxorubicin (A) 60 mg/m2 Paclitaxel (T) 175 mg/m2 Cyclophosphamide (C) 600 mg/m2 Intergroup/CALGB 9741 Node-Positive Stage II-IIIA Citron, et al. JCO 2003, 21:1431-1439

  23. Concurrent Sequential Disease-Free Survival N Events Con 996 252P = 0.65 Seq 976 256 DFS by Sequential vs Concurrent Rx11/30/2005, Median F/U = 6.5 Years Citron, et al. JCO 2003, 21:1431-1439

  24. ER– q2wk ER+ q2wk ER+ q3wk ER– q3wk Overall survival N Events ER+ q2wk 636 81 ER+ q3wk 639 92 ER– q2wk 336 83 ER– q3wk 327 105 P = NS P = 0.039 OS by ER Status & Dose Density(Exploratory Analysis) 11/30/2005 Citron, et al. JCO 2003, 21:1431-1439

  25. Major Toxicities – During Rx Citron, et al. JCO 2003, 21:1431-1439

  26. Dose-dense “Confirmatory” TrialPhase III FEC q2w vs FEC q3w • 1,214 patients (1992 – 1997) • Node positive or high-risk node negative BC • FEC 600/60/600 mg/m2 x 6 q2w G-CSF support • Median age 53 years • 43% premenopausal • 33% hormone receptor negative • 6.7 years median follow up • DFS: Hazard ratio 0.92, P = NS • OS: Hazard ratio 0.82, P = NS Venturini M et al. SABCS 2003

  27. F 5-FU 500 mg/m2 A Doxorubicin 50 mg/m2 C Cyclophosphamide 500 mg/m2 R T Docetaxel 75 mg/m2 A Doxorubicin 50 mg/m2 C Cyclophosphamide 500 mg/m2 • Stratification • Nodes 1-3 4+ • Center Dexamethasone premedication, 8 mg bid, 3 days Prophylactic ciprofloxacin 500 mg bid, day 5-14 TAX 316/BCIRG 001 Trial Design

  28. Disease-Free Survival Overall Survival TAX 316/BCIRG 001DFS and Overall Survival(Median Follow-Up 55 Months)

  29. G-CSF Prophylaxis Reduces Febrile Neutropenia Rate

  30. TAX 316/BCIRG 001 Conclusions • TAC demonstrated significantly improved disease-free survival compared to FAC • Median follow-up 55 months • 26% reduction in the risk of relapse (P = 0.0047) • Disease-free survival improved irrespective of nodal or hormone receptor status • Longer overall survival • Median follow-up 55 months • 31% reduction in the risk of mortality • Further analysis planned at the time survival data mature

  31. ARM I Paclitaxel 3-h IV infusion q 3 wk x 4 ARM II Paclitaxel 1-h IV infusion weekly x 12 Doxorubicin IV Cyclophosphamide IV q 3 wk x 12 ARM III Docetaxel 1-h IV infusion q 3 wk x 4 N = 4,988 ARM IV Docetaxel 1-h IV infusion weekly x 12 Intergroup E1199: Study DesignRandomized, Multicenter Phase III Study Sparano JA et al. Protocol E-1199

  32. 1.0 0.8 4-Year DFS Rates (%) 0.6 P3: 80.6P1: 83.5D3: 83.1D1: 80.5 DFS Probability Percent at Risk 0.4 P3 95 86 74 33 3 P1 96 90 80 37 4 D3 96 89 77 36 4 D1 95 89 77 35 3 0.2 0.0 0 6 12 18 24 30 36 42 48 54 60 66 Months from Randomization E1199: Efficacy Comparisons Disease-Free Survival Sparano et al. Breast Cancer Res Treat. 2005; Late-Breaking Abstract 48.

  33. NSABP B-38: Schema Group 1 Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2 Docetaxel 75 mg/m2 q3 weeks x 6 cycles Group 2 Doxorubicin 60 mg/m2 Cyclophosphamide 600 mg/m2 q2 weeks x 4 cycles Paclitaxel 175 mg/m2 q2 weeks x 4 cycles Operable Breast Cancer Histologically Positive Nodes R Group 3 Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2 q2 weeks x 4 cycles Paclitaxel 175 mg/m2 Gemcitabine 2000 mg/m2 q2 weeks x 4 cycles

  34. Evidence for Benefit of Taxanesin Early Stage Breast Cancer • CALGB 9344 • AC vs. AC  Paclitaxel • BCIRG 001 • TAC vs. FAC • PACS 01 • FEC X 6 vs. FEC X 3  Docetaxel • TAX 301 (Aberdeen) • Neoadjuvant CVAP X 4 vs. CVAP X 4  Docetaxel X 4 • USON • AC vs. TC

  35. Case Study 3: Early Breast CancerLN-negative, ER-positive • Age 47 • Premenopausal breast carcinoma • Lumpectomy - 1.5cm poorly differentiated, high grade infiltrating ductal carcinoma • HER2 non-amplified HER2/Chr17 (FISH) ratio = 1.91 • ER/PR positive • SLN Bx – 2 LNs negative • Lymphovascular invasion – present • SPF – 20%; KI 67 = 30% • DNA content - aneuploid

  36. Case Study 3: Early Breast CancerLN-negative, ER-positive The patient is referred to you for adjuvant therapy recommendations. In addition to post-lumpectomy radiation and standard adjuvant endocrine therapy, which treatment option would you recommend? • Dose-dense AC followed by paclitaxel • AC x 4 q 3 weeks followed by weekly paclitaxel x 12 • TAC x 6 • FEC x 3 → docetaxel x 3 • FEC x 6 • TC x 6 • Other

  37. Doxorubicin 60 mg/m2 IV Day 1 Cyclophosphamide 600 mg/m2 IV Day 1 Every 21 days x 4 Cycles RANDOMIZE AC Docetaxel 75 mg/m2 IV Day 1 Cyclophosphamide 600 mg/m2 IV Day 1 Every 21 days x 4 Cycles TC Phase III Trial Comparing AC vs. TC as Adjuvant Therapy for Operable Breast Cancer Jones S, et al. JCO 2006; 24:5381-5387

  38. Disease-Free Survival 89% 86% 86% 80% Phase III Trial Comparing AC vs. TC as Adjuvant Therapy for Operable Breast Cancer Jones S, et al. JCO 2006; 24:5381-5387

  39. 94% 90% 93% 87% Phase III Trial Comparing AC vs. TC as Adjuvant Therapy for Operable Breast Cancer Overall Survival Jones S, et al. JCO 2006; 24:5381-5387

  40. Phase III Trial Comparing AC vs. TC as Adjuvant Therapy for Operable Breast Cancer • Conclusions – Toxicity by Regimen TCAC All grades Myalgia Nausea Arthralgia Vomiting Edema Grades 3&4 Febrile neutropenia Nausea Vomiting Jones S, et al. JCO 2006; 24:5381-5387

  41. Adjuvant Breast Cancer Therapy An Analysis of Current Treatment Paradigms Discussion

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