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A Report from SABCS Up-to-Date Review of the Treatment of Early Breast Cancer. Maura N. Dickler, MD Assistant Attending Physician Breast Cancer Medicine Service Memorial Sloan-Kettering Cancer Center New York, NY. Up-to-Date Review of the Treatment of Early Breast Cancer Overview.

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A Report from SABCS Up-to-Date Review of the Treatment of Early Breast Cancer


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  1. A Report from SABCSUp-to-Date Review of the Treatment of Early Breast Cancer Maura N. Dickler, MD Assistant Attending Physician Breast Cancer Medicine Service Memorial Sloan-Kettering Cancer Center New York, NY

  2. Up-to-Date Review of the Treatment of Early Breast CancerOverview • Chemotherapy • Genomic profiling using the 21-Gene Recurrence Score Assay in postmenopausal, ER+, LN+ patients • Update of AC vs. TC • Trastuzumab for HER2+ Early Breast Cancer: PACS04 Trial • Endocrine Therapy: 100 month update of ATAC • Symptom Management/Supportive Care • Effects of endocrine therapy on bone health and arthralgias • Prevention of AI-induced bone loss • Bisphosphonates • Denosumab

  3. Chemotherapy

  4. SABCS Abstract 10 Prognostic and Predictive Value of the 21-Gene Recurrence Score Assay in Postmenopausal, Node-Positive (N+), ER-Positive (ER+) Breast Cancer SWOG 8814, TBCI 0100 K. Albain, W. Barlow, S. Shak, G. Hortobagyi, R. Livingston, I. Yeh, P. Ravdin, C. Yoshizawa, F. Baehner, N. Davidson, G. Sledge, E. Winer, C. Hudis, J. Ingle, E. Perez, K. Pritchard, L. Shepherd, C. Allred, K. Osborne, and D. Hayes for The Breast Cancer Intergroup of North America

  5. SWOG 8814/TBCI 0100 Correlative Science Study Rationale • The 21-gene Recurrence Score assay (RS) is prognostic for women with node(-), ER+ breast cancer on 5 years of tamoxifen* • A high RS predicts large benefit from chemotherapy in node(-) disease, but no improvement if the RS is low** • There are no RS data in a N+ population with a tamoxifen-alone control • SWOG 8814 is an ideal trial to explore this question *Paik, et al. NEJM, 2004 **Paik, et al. J Clin Oncol, 2006 Albain K, et al. SABCS 2007. Abstract 10.

  6. RANDOMIZE Phase III SWOG 8814 (TBCI 0100) Postmenopausal, N+, ER+ (N = 1477) Tamoxifen x 5 yrs CAF x 6, then tamoxifen CAF x 6, with concurrent tam (N = 361) (N = 550) (N = 566) Superior Disease-Free Survival (DFS) and Overall Survival (OS) over 10 Years Albain K, et al. SABCS 2007. Abstract 10.

  7. SWOG 8814/TBCI 0100 Correlative Science Study • Two co-primary objectives were to determine if the RS: • Provides prognostic information for women with N+ disease treated only with tamoxifen, and • Allows prediction of a N+ group that does not derive benefit from chemotherapy Albain K, et al. SABCS 2007. Abstract 10.

  8. SWOG 8814/TBCI 0100 Correlative Science StudyMethods - I • NCI correlative science project (#8814A-ICSC) used paraffin-embedded specimens from optional central banking protocol • Conducted RT-PCR for 16 genes + 5 reference genes by Genomic Health, Inc; blinded to outcomes • Calculated RS according to published criteria • Assessed same endpoints from main trial: DFS and OS (DRFI not available) • Performed analysis at SWOG Statistical Center using plan finalized before data received Paik, et al. NEJM 2004. Albain K, et al. SABCS 2007. Abstract 10.

  9. SWOG 8814/TBCI 0100 Correlative Science StudyMethods - II • Limited to tamoxifen and sequential CAF-T arms (eliminated inferior concurrent CAFT) • Stratified log-rank tests by nodes (1-3 vs. 4+), due to strong prognostic effect in main trial • Conducted Cox regression analyses on continuous RS and its interaction with treatment • Found violation of the proportional hazards assumption (hazard ratio not constant over time) • Therefore, analyses done with a split time axis: ≤ 5 and > 5 years Albain K, et al. SABCS 2007. Abstract 10.

  10. SWOG 8814/TBCI 0100 Correlative Science StudySample Size for Analysis Patients with samples - 666 (45% of parent trial) RT-PCR obtained - 601 (90%) Tamoxifen alone 148 CAFT (concurrent) 234 CAF-T (sequential) 219 Final sample for primary analysis 148 + 219 = 367 (40% of parent trial) Albain K, et al. SABCS 2007. Abstract 10.

  11. Disease-Free Survival 1.00 0.75 Disease-free Survival 0.50 Stratified log-rank P-value = 0.054 at 10 years (adjusted for nodal status) 0.25 Tamoxifen (N=148, 63 events) CAF-T (N=219, 74 events) 0.00 0 2 4 6 8 10 Years Since Registration SWOG 8814/TBCI 0100 Correlative Science Study • Outcomes in RS subset mirror those reported in main trial: superiority of CAF-T Albain K, et al. SABCS 2007. Abstract 10.

  12. SWOG 8814/TBCI 0100 Correlative Science StudyComparative Distribution of RS Albain K, et al. SABCS 2007. Abstract 10.

  13. SWOG 8814/TBCI 0100 Correlative Science Study Results: Prognosis

  14. 21-Gene recurrence score is prognostic for DFS and OS in tamoxifen arm Overall Survival by Risk Group (tamoxifen alone) Disease-Free Survival by Risk Group 1.00 (tamoxifen alone) 1.00 0.75 0.75 Overall Survival 0.50 Disease-free survival Stratified log-rank p = 0.003 at 10 years 0.50 0.25 Stratified log-rank p = 0.017 at 10 years Low RS <18 (N=55) 0.25 Intermediate RS 18-30 (N=46) Low RS <18 (N=55) High RS ≥31 (N=47) 0.00 Intermediate RS 18-30 (N=46) High RS ≥31 (N=47) 0 2 4 6 8 10 0.00 Years since registration 0 2 4 6 8 10 Years since registration • 10-yr: Low RS = 60%, Int. RS = 49%, • High RS = 43% • 10-yr: Low RS = 77%, Int. RS = 68%, • High RS = 51% SWOG 8814/TBCI 0100 Correlative Science Study Albain K, et al. SABCS 2007. Abstract 10.

  15. SWOG 8814/TBCI 0100 Correlative Science Study Results: Prediction

  16. Disease-Free Survival by Treatment • No benefit to CAF over time if low RS • Strong benefit to CAF if high RS 1.00 Low risk (RS < 18) 0.75 0.50 Disease-free survival Stratified log-rank p = 0.97 at 10 years 0.25 Tamoxifen (N=55, 15 events) CAF-T (N=91, 26 events) 0.00 0 2 4 6 8 10 Years since registration Disease-Free Survival by Treatment Disease-Free Survival by Treatment 1.00 1.00 Intermediate risk (RS 18-30) High risk (RS ≥ 31) 0.75 0.75 Disease-free survival Disease-free survival 0.50 0.50 Stratified log-rank p = 0.48 at 10 years Stratified log-rank p = 0.033 at 10 years 0.25 0.25 Tamoxifen (N=46, 22 events) Tamoxifen (N=47, 26 events) CAF-T (N=57, 20 events) CAF-T (N=71, 28 events) 0.00 0.00 0 2 4 6 8 10 0 2 4 6 8 10 Years since registration Years since registration

  17. SWOG 8814/TBCI 0100 Correlative Science StudyTen-Year DFS Point Estimates (95% CI) *40% event rate over 10 years and resistance to CAF Albain K, et al. SABCS 2007. Abstract 10.

  18. DFS hazard ratios adjusted for nodal status Overall trial Entire RS sample Low RS Trial Subset Intermediate RS High RS Chemotherapy benefit No chemotherapy benefit 0 .5 1 1.5 2 Hazard Ratio SWOG 8814/TBCI 0100 Correlative Science Study Comparison of CAF-T to Tamoxifen Alone Albain K, et al. SABCS 2007. Abstract 10.

  19. No CAF benefit DFS either early or late in low RS, but stable impact over time if high RS Comparison of CAF-T to Tamoxifen Alone (DFS adjusted for nodal status) Low RS Intermediate RS First 5 years Greater than 5 years High RS Chemotherapy benefit No chemotherapy benefit 0 1 2 3 4 Hazard ratio SWOG 8814/TBCI 0100 Correlative Science Study Albain K, et al. SABCS 2007. Abstract 10.

  20. Overall Survival by Treatment 1.00 High risk (RS ≥31) 0.75 Overall survival 0.50 Stratified log-rank test p = 0.027 at 10 years 0.25 Tamoxifen (N=47, 22 deaths) CAF-T (N=71, 20 deaths) 0.00 0 2 4 6 8 10 Years since registration SWOG 8814/TBCI 0100 Correlative Science StudyThe RS is Predictive for Overall Survival • No benefit to CAF in low RS in first 5-years (HR 1.05) or over entire time period (HR 1.18) • Strong impact of CAF in high RS: • First 5-years HR 0.43 (0.21, 0.90) • Over entire period HR 0.56 (0.31, 1.01) • 10-year estimates: Tamoxifen 51% (35%, 65%) CAF-T 68% (51%, 79%) Albain K, et al. SABCS 2007. Abstract 10.

  21. SWOG 8814/TBCI 0100 Correlative Science StudyConclusions on Primary Analysis • The 21-gene RS is prognostic for tamoxifen-treated patients with positive nodes • Chemotherapy benefit is predicted when the RS is high, dominating in the first 5-years, but carried over long-term • A low RS may define a group of women with positive nodes who do not appear to benefit from anthracycline-based chemotherapy • This analysis of SWOG 8814 is just one study to evaluate the predictive impact of RS in ER+, LN+ postmenopausal patients. • Currently, this data should be used with caution for treatment decisions regarding chemotherapy in LN+ patients. Albain K, et al. SABCS 2007. Abstract 10.

  22. SWOG 8814/TBCI 0100 Correlative Science StudyOther Perspectives • New strategies in endocrine/biologic therapy are needed if low RS, given event rate of 40% over 10-years • Biology (not age) should drive treatment decisions, since for high RS chemotherapy is beneficial regardless of age • These data (both RS and IHC) collectively challenge chemotherapy mandates for patients with N+, ER+ disease: not all benefit from chemotherapy, whereas others derive greater benefit than previously predicted Albain K, et al. SABCS 2007. Abstract 10.

  23. SABCS Abstract 12 Extended Follow-up and Analysis by Age of the US Oncology Adjuvant Trial 9735: Docetaxel/Cyclophosphamide is Associated with an Overall Survival Benefit Compared to Doxorubicin/Cyclophosphamide and is Well-tolerated in Women 65 or Older Jones SE, Holmes FA, O’Shaughnessy JA, Blum JL, Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL, Sandbach J, Hyman WJ, Khandelwal P, Negron AG, Richards DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, Muss HB, Savin MA

  24. Doxorubicin 60 mg/m2 IV Day 1 Cyclophosphamide 600 mg/m2 IV Day 1 Every 21 days X 4 Cycles RANDOMI ZE AC Docetaxel 75 mg/m2 IV Day 1 Cyclophosphamide 600 mg/m2 IV Day 1 Every 21 days X 4 Cycles TC AC vs. TC Adjuvant TrialTrial Design Jones SE, et al. SABCS 2007. Abstract 12.

  25. AC vs. TC Adjuvant TrialObjectives of this Analysis • Primary Objective: • To compare disease-free survival (DFS) and overall survival (OS) of AC vs. TC in early operable breast cancer at a median followup of 7-years • Secondary Objectives: • To determine outcome by age and treatment regimen • To assess the impact of HER2 status on DFS (limited sample) • To determine toxicity profiles by age and treatment regimen Jones SE, et al. SABCS 2007. Abstract 12.

  26. AC vs. TC Adjuvant TrialInclusion Criteria • Patients with Stage I, II, or operable Stage III invasive breast cancer • Complete surgical excision of the primary tumor • Age >18 years • Adequate renal function • Adequate hematologic function • Adequate hepatic function • Karnofsky PS >80% • Signed informed consent Jones SE, et al. SABCS 2007. Abstract 12.

  27. AC vs. TC Adjuvant TrialDemographics by Treatment and Age Jones SE, et al. SABCS 2007. Abstract 12.

  28. AC vs. TC Adjuvant TrialDFS by Treatment At Risk TC 506 495 473 454 442 434 425 420 418 AC 510 498 477 442 422 412 401 396 392 Jones SE, et al. SABCS 2007. Abstract 12.

  29. AC vs. TC Adjuvant TrialDFS by Treatment and Age Group Jones SE, et al. SABCS 2007. Abstract 12.

  30. AC vs. TC Adjuvant TrialAssessment of HER2 Status by FISH* for 170 Patients *FISH+ = Gene copy ratio of 2.0 or greater Jones SE, et al. SABCS 2007. Abstract 12.

  31. AC vs. TC Adjuvant TrialDFS for HER2 Positive Status At Risk TC 28 27 21 20 17 17 16 16 16 AC 18 17 14 10 9 8 8 8 8 Jones SE, et al. SABCS 2007. Abstract 12.

  32. AC vs. TC Adjuvant TrialDFS for HER2 Negative Status At Risk TC 55 53 49 45 42 42 42 41 40 AC 68 61 51 47 45 44 44 40 38 Jones SE, et al. SABCS 2007. Abstract 12.

  33. Overall HR for DFS = 0.74 AC vs. TC Adjuvant TrialDFS Hazard Ratios (CI) for Key Subgroups Jones SE, et al. SABCS 2007. Abstract 12.

  34. AC vs. TC Adjuvant TrialOverall Survival by Treatment At Risk TC 506 502 495 481 466 461 454 449 448 AC 510 504 493 476 459 448 432 429 427 Jones SE, et al. SABCS 2007. Abstract 12.

  35. AC vs. TC Adjuvant TrialOverall Survival by Treatment and Age Group Insert graphics here Jones SE, et al. SABCS 2007. Abstract 12.

  36. AC vs. TC Adjuvant TrialGrade 3/4 Hematologic Toxicity by Treatment & Age (%) Jones SE, et al. SABCS 2007. Abstract 12.

  37. AC vs. TC Adjuvant TrialGrade 3/4 Nonhematologic Toxicity by Treatment & Age (%) Jones SE, et al. SABCS 2007. Abstract 12.

  38. AC vs. TC Adjuvant TrialLong-term Fatal Toxicities • 3 additional long-term fatal toxicities all on the AC arm • CHF (45 yrs - AC) • Myelodysplastic syndrome (63 yrs - AC) • Myelofibrosis (66 yrs - AC) Jones SE, et al. SABCS 2007. Abstract 12.

  39. AC vs. TC Adjuvant TrialConclusions • At 7 Years, 4 cycles of TC compared to AC was associated with: • Superior DFS (P = 0.033) • Superior Overall Survival (P = 0.032) • Efficacy in HER2+ as well as HER2- disease (limited sample) • TC was effective in older as well as younger patients • Numerically, slightly more febrile neutropenia with TC but more anemia with AC in older patients • Less long-term toxicities (cardiac and bone marrow) with TC Jones SE, et al. SABCS 2007. Abstract 12.

  40. HER2+ Early Breast Cancer

  41. SABCS Abstract 72 Trastuzumab Following Adjuvant Chemotherapy in Node-Positive, HER2-Positive Breast Cancer Patients4-Year Follow-Up Results of the PACS-04 Trial M Spielmann, H Roché, JP Machiels, T Delozier, H Bourgeois, D Serin, G Romieu, JL Canon, A Monnier, G Piot, MMaerevoet, H Orfeuvre,JM Extra, AC Hardy, AL Martin, A Kramar, and J Genève

  42. Perez et al, ASCO, 2007: abstr # 512 • Slamon et al, SABCS, 2006: abstr # 1 • Joensuu et al, N Engl J Med, 2006;354:809-20 • Piccart et al, N Engl J Med, 2005;353:1659-72 • Smith et al, Lancet, 2007;369:29-36 • Romond et al, N Engl J Med, 2005;353:1673-84 PACS-04: BackgroundResults of Adjuvant Trastuzumab Trials

  43. PACS-04: Aim of the Study • The PACS-04 trial evaluated the efficacy of a one-year trastuzumab therapy following adjuvant chemotherapy in HER2-overexpressing, node-positive breast cancer patients Spielmann M, et al. SABCS 2007. Abstract 72.

  44. Stratified on: Center N (<4 vs.  4) Trastuzumab (T) Loading dose 8 mg/kg Maintenance 6 mg/kg q3w for 1 year = 18 injections S U R G E R Y RT* HT 6 FEC100 q3w 2nd randomization performed as soon as HER2 expression determined Trastuzumab started after chemotherapy and RT R1 R2 Observation 6 ED75 q3w RT* HT * RT was delivered within 4 weeks after the last chemotherapy cycle PACS-04: Treatment Protocol Spielmann M, et al. SABCS 2007. Abstract 72.

  45. PACS-04: Major Inclusion CriteriaFirst Randomization • Histologically proven unilateral breast cancer with complete resection (T1-T2-T3) • Axillary node-positive • M0 (bone scan, liver ultrasonography, chest X-ray) • Age > 18 years and  65 years • Left ventricular ejection fraction (LVEF)  50% as measured by MUGA scan or echocardiography Spielmann M, et al. SABCS 2007. Abstract 72.

  46. PACS-04: Second Randomization • Performed as soon as results of HER2 assessment available • HER2-positive status defined by following: • HER2 3+ (IHC) i.e. > 10% stained cells • HER2 2+ and FISH positive (cut-off: 2.2 copies) • HER2 status reviewed by central reference centers • The median time between R1 and R2 was 2.6 months Spielmann M, et al. SABCS 2007. Abstract 72.

  47. PACS-04:StatisticsSecond Randomization • Primary endpoint = 3-year DFS • Hypothesis: Trastuzumab decreases by 33% the risk of relapse • Based on an expected 3-year DFS of 70% for the observation arm •  = 5% and 1 -  = 80% • Number of events required = 118 • Number of patients required = 540 • Intent-to-treat analysis • Overall number of patients required at R1 = 3,000 Spielmann M, et al. SABCS 2007. Abstract 72.

  48. R1 = 3,010 R2 = 528 Obs. = 268 T = 260 Not treated with T Treated = 234 PACS-04:Study Flow Chart • Between February 2001 and August 2004, 3,010 patientsfrom 82 French and Belgian institutions were randomized Spielmann M, et al. SABCS 2007. Abstract 72.

  49. PACS-04: Exposition to Trastuzumab 18% Spielmann M, et al. SABCS 2007. Abstract 72.

  50. PACS-04:Cardiac Safety • * Stopping rules of trastuzumab in case of cardiac toxicity were as follows: • LVEF <45% or [45%-50%] + relative decrease 15% • LVEF [50%-55%] or [45%-50%] + relative decrease< 15% → cardiologist decision Spielmann M, et al. SABCS 2007. Abstract 72.