Early Systemic Treatment            Aron Goldhirsch, MD            Department of Medicine      European Institute of Oncol...
Adjuvant Therapies  for Women with Breast Cancer:        Present and FutureAdjuvant Therapies are the most important field...
Adjuvant Treatments ...         Why are they special?•   Patient is free of overt disease•   Assumption is that:      res...
Preoperative (Neo-Adjuvant)                Treatments• Treating more efficiently patients with locally  advanced disease• ...
Adjuvant Treatments• Historically, the first adjuvant treatments were  ovarian function suppression (OFS) and  chemotherap...
Relapse-Free Survival (A) and Overall Survival (B)         According to Treatment Group                       Bonadonna G....
RFS and OS According to Treatment Group               N-All 90 pts had endocrine non responsive disease!                  ...
CALGB/CTSU – 49907                                                             RFS by ER status                           ...
…understanding the    Need for Tailored Treatments for          Individual Patients• Times of «one therapy fits all» are  ...
Tailored Treatments for          Individual Patients…• Understanding the target – should have  been particularly easy in b...
Breast Cancer
Thresholds for Treatment ModalitiesTreatment Modality               Indication                         CommentsEndocrine t...
Thresholds for Treatment ModalitiesTreatment           Indication        CommentsModalityEndocrine therapy   Any ER staini...
Thresholds for Treatment ModalitiesTreatment           Indication           CommentsModalityAnti HER2 therapy   ASCO/CAP  ...
Thresholds for Treatment ModalitiesTreatment Modality    Indication                  CommentsChemotherapyA. With anti HER2...
Chemotherapy in ER+ve HER2-veRelative Indications for          Factors not useful in decision*   Relative Indications for ...
Treatment Modalities 2009                 Endocrine              Endocrine                 Responsive           Non-Respon...
Treatment Selection Flowchart 2009           Estrogen Receptor ≥ 1% stained cells                 Yes               No  HE...
Central Pathology Review at IEO(ALTTO Trial of anti-HER2 Therapy – 30nov08)   ER          CENTRAL REVIEW (IEO)            ...
BIG 1-98 Postm., HR-posFalse Positive Receptor Status        94/3610 (2.6%) false positive
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
Adjuvant Therapy for PremenopausalWomen with Endocrine-Responsive Disease • Standard: Tamoxifen • Standard: Ovarian Functi...
IBCSG Trial 11-93Prem. with N+, ER+ Disease             1993-1998    174 patients; 97% had 1-3 N+RAN     OFS→AC/EC x 4→Tam...
IBCSG 11-93                   n=174 (1993-1998)Premenopausal, node-positive disease (97% had 1-3 N+)     10-year med fu; T...
Aol analysis conducted on trial 11 IBCSG Trial 11-93 and Adjuvant! Online      RFS for AOL control (OFS+Tam)         may b...
IBCSG Trial 15-95 Design  n = 344 (1995-2000)RA   Standard Dose Chemotherapy (SD-CT)ND   AC/EC x 4 → CMF x 3OM    Dose Int...
IBCSG Trial 15-95SD-CT = ACx4 -> CMFx3 + tamoxifenDI-EC = E(200 mg/m2)+C(4 gm/m2)x3      + PBPC support + tamoxifen       ...
IBCSG Trial 15-95ER-positive cohort (n=149)     ER-negative cohort (n=193) Interaction p-value = 0.21  DI-EC useful for all
Trial 13-93Chemotherapy-Induced Amenorrhea  ER Positive     ER Positive Tamoxifen
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
Adjuvant Therapy for Postmenopausal Women     with Endocrine-Responsive Disease• Standard: should include Aromatase    Inh...
Trials III+IV         (1978-1981)Postmenopausal, node-positive diseasen=463                          n=320         All tre...
Trial III DFSER+                   ER-
Trials III+IV         (1978-1981)Postmenopausal, node-positive diseasen=463                          n=320         All tre...
IBCSG Trial IV
BIG 1-98 Sequential Therapy          2-Arm Option A       Tamoxifen B        Letrozole         4-Arm Option A       Tamoxi...
Breast Cancer Events                     TamLet vs. Let          Overall                 By Nodal Status**42% of the popu...
Breast Cancer Events                   LetTam vs. Let           Overall                 By Nodal Status**42% of the popul...
BIG 1-98 Overall Design                      R                      A                                       2-Arm Option  ...
Contributions to Composite RiskPoints:       0     ~0.25     ~0.5   ~0.75   ~1.5Lymph nodes    0              1-3     4-9 ...
STEPP 5-year DFS by Composite Risk    Node neg    Node 3+     T 1.5cm    T 1.9cm     Her2 neg               Node neg      ...
STEPP 5-year DFS by Composite Risk       Increasing Composite Risk
STEPP 5-year DFS by Composite Risk       Low Risk       Intermediate Risk         High Risk     All treatments    All letr...
DFS by Increasing Composite Risk:              High
DFS by Increasing Composite Risk:          Intermediate
DFS by Increasing Composite Risk:              Low
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
Adjuvant Chemotherapy• No standard regimen• No predictive test for use of individual  components• Choose efficient treatme...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
Genomic Profiles Determine WhichPatients Receive Adjuvant Chemotherapy?• «The Panel accepts molecularly-based tools  (such...
Trastuzumab• Adjuvant Trastuzumab x 1 year with CT is  standard of care for women with high risk  HER2+ve breast cancer• S...
Trastuzumab:        Open Questions• Trastuzumab for small (<1cm)  HER2+ve cancers• Trastuzumab alone v. plus CT in  lower ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center                      ...
Current & Future Trials• Chemotherapy: still looking at the risk of relapse• Endocrine therapies: looking at the sequence•...
Oncotype DX 21 Gene           Recurrence Score (RS) Assay   16 Cancer and 5 Reference Genes From 3 StudiesPROLIFERATION   ...
Expression Data Matrix of 70 Prognostic Markers Genes from Tumorsof 78 Breast Cancer Patients Hybridized Using the Custom ...
Current & Future Trials• Chemotherapy: still looking at the risk of relapse• Endocrine therapies: looking at the sequence•...
S LEStudy Of Letrozole Extension  IBCSG 35-07 / BIG 1-07Coordinating Group: IBCSG
S LEAfter 4 to 6 Years of Prior Adjuvant Endocrine Therapy     Postmenopausal, HR-Positive, Node-Positive               R ...
Effect of Intermittent Letrozole Treatment in                                                         MCF-7Ca Xenografts  ...
Current & Future Trials• Chemotherapy: still looking at the risk of relapse• Endocrine therapies: looking at the sequence•...
HER2 Targeted Trial: ALTTORA                  TrastuzumabND                   LapatinibOM          T            LapatinibI...
Current & Future Trials• Chemotherapy: still looking at the risk of relapse• Endocrine therapies: looking at the sequence•...
Metronomic Therapy (CM) Following Standard Adjuvant             Chemotherapy for Patients With       ER-Negative and PgR-N...
DF/PCC Breast Cancer SPORERandomized Phase II Trial of Metronomic    Chemotherapy ± Bevacizumab CM + bevacizumab       CM ...
BEX Regimen in Advanced BC  Bevacizumab       10 mg/kg iv every 2 weeks  Cyclophosphamide       50 mg/day orally @ 9 a.m. ...
BEX ResultsBest response                                        n             %Assessable patients                        ...
Selected Triple                     negativeTAILORED              HER2+CLINICAL TRIALS                     Endocrine      ...
Thanks topatients,investigators,nurses,data managers, sponsors, andall who are committed to clinicaltrialsfor progress inc...
MON 2011 - Slide 3 - A. Goldhirsch - Early systemic treatment
MON 2011 - Slide 3 - A. Goldhirsch - Early systemic treatment
MON 2011 - Slide 3 - A. Goldhirsch - Early systemic treatment
MON 2011 - Slide 3 - A. Goldhirsch - Early systemic treatment
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Transcript of "MON 2011 - Slide 3 - A. Goldhirsch - Early systemic treatment"

  1. 1. Early Systemic Treatment Aron Goldhirsch, MD Department of Medicine European Institute of Oncology (EIO)Oncology Institute of Southern Switzerland (IOSI)International Breast Cancer Study Group (IBCSG)
  2. 2. Adjuvant Therapies for Women with Breast Cancer: Present and FutureAdjuvant Therapies are the most important field of medical oncology…because - they lead to CURE saving more lives…
  3. 3. Adjuvant Treatments ... Why are they special?• Patient is free of overt disease• Assumption is that:  residual microscopic disease  same characteristics as primary  similar responsiveness• In case of doubt:  worse scenario  most convenient for the patient• Impossible to check efficacy
  4. 4. Preoperative (Neo-Adjuvant) Treatments• Treating more efficiently patients with locally advanced disease• Information on efficacy & safety of new therapies during the short preoperative exposure• I will not deal with these therapies due to time constraints
  5. 5. Adjuvant Treatments• Historically, the first adjuvant treatments were ovarian function suppression (OFS) and chemotherapies (CTs)• The overwhelming effects of CTs and the lack of clear advantage for OFS signed the misperception about what should be done• Lacking knowledge about the target was the main problem
  6. 6. Relapse-Free Survival (A) and Overall Survival (B) According to Treatment Group Bonadonna G. et al, N Engl J Med 332: 901-906, 1995
  7. 7. RFS and OS According to Treatment Group N-All 90 pts had endocrine non responsive disease! Zambetti M. et al, Ann Oncol 7: 481-485, 1996
  8. 8. CALGB/CTSU – 49907 RFS by ER status Receptor Negative Tumors Receptor-Neg ative Tumors Receptor Positive Tumors Receptor-Positive Tumors Relapse-Free Survival Relapse-Free Survival By Arm Relapse-Free Survival Relapse-Free Survival By Arm 0.8 0.8Proportion Relapse-Free Proportion Relapse-Free 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0 1 2 3 4 5 0 1 2 3 4 5 Years From Study Entry Years From Study Entry CMF/AC N= 106 Events= 14 CMF/AC N= 218 Events= 21 Capecitabine N= 97 Events= 34 Capecitabine N= 209 Events= 26 No Endocrine Therapy Endocrine Therapy
  9. 9. …understanding the Need for Tailored Treatments for Individual Patients• Times of «one therapy fits all» are finished• Maximizing efficacy of treatments means understanding the target
  10. 10. Tailored Treatments for Individual Patients…• Understanding the target – should have been particularly easy in breast cancer • Steroid hormone receptors – the degree of endocrine responsiveness • HER2 positivity – response to trastuzumab (+/- chemotherapy)
  11. 11. Breast Cancer
  12. 12. Thresholds for Treatment ModalitiesTreatment Modality Indication CommentsEndocrine therapy* Any ER staining ER-ve PgR+ve probably artefactualAnti HER2 therapy* ASCO/CAP HER2+ve (30% May use clinical trial strong staining or Fish definitions 2.2+)ChemotherapyA. With anti HER2 Trial evidence limited to use Logical but unproven with or following without chemotherapy in chemotherapy strongly ER+ve HER2+veB. Triple negative Most patients No proven alternative. Most at sufficient riskC. With endocrine therapy Variable according to risk See next tablein ER+ve HER2–ve* Patients with pT1a pN0 and ER-ve disease might be spared adjuvant systemic therapy. Patients with pT1a pN0 and ER+ve disease should be offered endocrine therapy alone at any case, without considering chemotherapy.
  13. 13. Thresholds for Treatment ModalitiesTreatment Indication CommentsModalityEndocrine therapy Any ER staining ER-ve PgR+ve probably artefactual
  14. 14. Thresholds for Treatment ModalitiesTreatment Indication CommentsModalityAnti HER2 therapy ASCO/CAP May use clinical HER2+ve (30% trial definitions strong staining or Fish 2.2+)
  15. 15. Thresholds for Treatment ModalitiesTreatment Modality Indication CommentsChemotherapyA. With anti HER2 Trial evidence limited to Logical but unproven use with or following without chemotherapy in chemotherapy strongly ER+ve HER2+veB. Triple negative Most patients No proven alternative. Most at sufficient riskC. With endocrine Variable according to See next table therapy in ER+ve risk HER2–ve
  16. 16. Chemotherapy in ER+ve HER2-veRelative Indications for Factors not useful in decision* Relative Indications for endocrinechemotherapy: any of therapy aloneGrade 3 Grade 2 Grade 1High proliferation** Intermediate proliferation Low proliferationLower ER and PgR Higher ER and PgRlevel levelN 4+ N 1-3 Node negativePeritumoral vascular invasion No PVI(PVI)T size > 5cm T size 2 – 5 cm T size <= 2cm***Patient preference to use all Patient preference to avoid sideavailable treatments effects * If most are present, could constitute a relative indication for chemotherapy ** As assessed by conventional or genetic assays *** Patients with pT1a pN0 and ER+ve disease should be offered endocrine therapy alone at any case, without considering chemotherapy
  17. 17. Treatment Modalities 2009 Endocrine Endocrine Responsive Non-Responsive (ER ≥ 1%) (ER = 0%)HER2- neg. ET CT ( CT using criteria listed on next slide)HER2-pos. ET + Trastuzumab Trastuzumab + CT + CT
  18. 18. Treatment Selection Flowchart 2009 Estrogen Receptor ≥ 1% stained cells Yes No HER2-status (CAP/ASCO) HER2-status (CAP/ASCO) Positive Negative Positive Negative ET ET Trastuzumab CT + ( CT using + CTTrastuzumab criteria listed + CT as threshold)
  19. 19. Central Pathology Review at IEO(ALTTO Trial of anti-HER2 Therapy – 30nov08) ER CENTRAL REVIEW (IEO) Positive LOCAL Positive ≥1% and Negative tot LAB ≥10% <10% 113 Positive 2481 54 2648 (4.3%) 388 107 Negative 1788 2283 (16.9%) (4.7%)
  20. 20. BIG 1-98 Postm., HR-posFalse Positive Receptor Status 94/3610 (2.6%) false positive
  21. 21. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 Early Breast Cancer Trialists’ Collaborative Group Eighth Main Meeting Oxford September 2010
  22. 22. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 ER level matters EBCTCG 2010 (unpublished)Clear ―dose-response‖effect for ER level(ligand binding assays)on TAM efficacy
  23. 23. Adjuvant Therapy for PremenopausalWomen with Endocrine-Responsive Disease • Standard: Tamoxifen • Standard: Ovarian Function Suppression Plus Tamoxifen • Role of Aromatase Inhibitors not yet established • Ovarian Function Suppression alone only in extraordinary circumstances • Do all premenopausal women with hormone-responsive breast cancer require chemotherapy? NOT LIKELY
  24. 24. IBCSG Trial 11-93Prem. with N+, ER+ Disease 1993-1998 174 patients; 97% had 1-3 N+RAN OFS→AC/EC x 4→Tam to 5 yrsDOM OFS→Tam to 5 yrsIZE OFS: ovarian function suppression by GnRH analog, oophorectomy, or ovarian RT
  25. 25. IBCSG 11-93 n=174 (1993-1998)Premenopausal, node-positive disease (97% had 1-3 N+) 10-year med fu; Thürlimann et al, BCRT 2009;113,137-144
  26. 26. Aol analysis conducted on trial 11 IBCSG Trial 11-93 and Adjuvant! Online RFS for AOL control (OFS+Tam) may be underestimated 76% 10-yr RFS 64% 10-yr RFS P=0.03
  27. 27. IBCSG Trial 15-95 Design n = 344 (1995-2000)RA Standard Dose Chemotherapy (SD-CT)ND AC/EC x 4 → CMF x 3OM Dose Intensive Chemotherapy (DI-EC)IZ High Dose EC x 3E
  28. 28. IBCSG Trial 15-95SD-CT = ACx4 -> CMFx3 + tamoxifenDI-EC = E(200 mg/m2)+C(4 gm/m2)x3 + PBPC support + tamoxifen 56% ER-neg (≥ 5 N+) 43% ER-pos (≥10 N+) 67% premenopausal
  29. 29. IBCSG Trial 15-95ER-positive cohort (n=149) ER-negative cohort (n=193) Interaction p-value = 0.21  DI-EC useful for all
  30. 30. Trial 13-93Chemotherapy-Induced Amenorrhea ER Positive ER Positive Tamoxifen
  31. 31. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer (NSABP B-30) Swain SM, Jeong JH, Geyer CE Jr et al N Engl J Med. 2010 ;362:2053-65 This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute.
  32. 32. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 Overall Survival and Disease-free Survival «Amenorrhea was associated with improved survival regardless of the treatment and estrogen-receptor status.»Swain SM et al. N Engl J Med 2010;362:2053-2065
  33. 33. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010Taxane-Based Chemotherapy for Node-Positive Breast Cancer — Take-Home Lessons «An unexpected finding in this study was that chemotherapy-induced menopause appeared to be associated with increased survival among both ER-positive and ER- negative subgroups. Ovarian suppression has value in the treatment of breast cancer, but the effect was logically thought to be restricted to ER-positive disease.»Ellis, M. NEJM 2010; 362:2122-2124
  34. 34. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 Amenorrhea & ER: NSABP & IBCSGNSABP B-30IBCSG 13-93 This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute.
  35. 35. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 Amenorrhea analysis methodologyNSABPB-30 Anderson JR, Cain KC, Gelber RD: Analysis of survival by tumor response. J Clin Oncol 1:710-719, 1983IBCSG13-93
  36. 36. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 NSABP B-30 Landmark analysis «By contrast, women with HR for amenorrhea (DFS) ER-negative tumors had a similar outcome Study ER pos ER neg regardless of whether NSABP they had amenorrhea, with NEJM a hazard ratio for death of 0.62* 0.71* 2010 1.08 (P = 0.76) and a hazard (Jun) ratio for disease recurrence, a IBCSG second malignant condition, JCO 0.61 1.58 or death of 0.96 (P = 0.85).» 2006 p = 0.004 n.s. NSABP NEJM 0.51 0.96 2010 p < 0.001 n.s. (Dec)Swain SM et al.N Engl J Med 2010;363:2268-2270 (Dec 2)
  37. 37. Adjuvant Therapy for Postmenopausal Women with Endocrine-Responsive Disease• Standard: should include Aromatase Inhibitors (AIs) with some exceptions• Standard: start with AIs if high-risk• Switch to tamoxifen is safe and effective• Check ovarian function if young postmenopausal women with AIs• Use AIs for 2-5 years• Beyond 5 years proceed with caution
  38. 38. Trials III+IV (1978-1981)Postmenopausal, node-positive diseasen=463 n=320 All treatments for 1 year
  39. 39. Trial III DFSER+ ER-
  40. 40. Trials III+IV (1978-1981)Postmenopausal, node-positive diseasen=463 n=320 All treatments for 1 year
  41. 41. IBCSG Trial IV
  42. 42. BIG 1-98 Sequential Therapy 2-Arm Option A Tamoxifen B Letrozole 4-Arm Option A Tamoxifen N=1548* B Letrozole N=1546 N=6,182 Enrolled C Tamoxifen Letrozole N=1548 1999-2003 D Letrozole Tamoxifen N=1540 *612 patients (40%) received 0 2 5 letrozole after the tamoxifen YEARS arm was unblinded.
  43. 43. Breast Cancer Events TamLet vs. Let Overall By Nodal Status**42% of the population is node positive; 58% node negative
  44. 44. Breast Cancer Events LetTam vs. Let Overall By Nodal Status**42% of the population is node positive; 58% node negative
  45. 45. BIG 1-98 Overall Design R A 2-Arm Option N D A Tamoxifen N=911 N=1,828 O M B Letrozole N=917 EnrolledS Stratify I 1998-2000 ZUR  Institution EG  CT (Adjuvant/ 4-Arm OptionE N=8,010* Neoadjuvant) R A Tamoxifen N=1548R AY -Prior N -None D B Letrozole N=1546 N=6,182 *ITT: excludes -Concurrent O M C Tamoxifen Letrozole N=1548 Enrolled 18 patients who withdrew I 1999-2003 consent and did Z E D Letrozole Tamoxifen N=1540 not receive study treatment 0 2 5 YEARS
  46. 46. Contributions to Composite RiskPoints: 0 ~0.25 ~0.5 ~0.75 ~1.5Lymph nodes 0 1-3 4-9 10+ER % 50+ 30-49 <30%PgR % 20+ <20Ki-67 % <14 14-33 34+HER2 Neg PosPVI No YesGrade 1 2 3T size ≤2 2.1-4.9 5+
  47. 47. STEPP 5-year DFS by Composite Risk Node neg Node 3+ T 1.5cm T 1.9cm Her2 neg Node neg Her2 neg PVI neg T 2.1cm PVI neg Node 12+ ER 90% Her2 pos ER 95% T 2.5cm PgR 80% PVI neg PgR 75% Her2 neg Ki-67 7% ER 75% Ki-67 11% PVI pos PgR 0% ER 80% Ki-67 35% PgR 75% Ki-67 20% Increasing Composite Risk
  48. 48. STEPP 5-year DFS by Composite Risk Increasing Composite Risk
  49. 49. STEPP 5-year DFS by Composite Risk Low Risk Intermediate Risk High Risk All treatments All letrozole arms Letrozole 5yr including TAM appear similar: TAM appears better than appear similar inferior either sequence Increasing Composite Risk
  50. 50. DFS by Increasing Composite Risk: High
  51. 51. DFS by Increasing Composite Risk: Intermediate
  52. 52. DFS by Increasing Composite Risk: Low
  53. 53. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 ACOSOG Z1031: A randomized neoadjuvant comparison between letrozole (LET), anastrozole (ANA) and exemestane (EXE) for Postmenopausal Women with ER Rich Stage 2/3 Breast Cancer: Biomarker outcomes and the predictive value of the baseline PAM50 based intrinsic subtype Ellis M. et al. SABCS 2010 / abst. 794 This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute.
  54. 54. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 Study Design http://clinicaltrials.gov/ct/show/NCT00265759Ellis M. et al. SABCS 2010 / abst. 794
  55. 55. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 Clinical response (%) Ki67 (%)ACOSOG Z1031 Kruskal Wallis A v E v L P= 0.4550
  56. 56. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 Adjuvant versus neoadjuvant endocrine therapyAdjuvant Trial Result based on Neoadjuvant Result for Ki67 events Ki67 study based changesBIG 1-98 2005 L>T P024 2003 L>TThürlimann et al N=8010 Ellis et al N=185ATAC 2002 A>T=C IMPACT 2005 A>T=CBaum et al N=9366 Dowsett et al N=147MA27 2010 A=E Z1031 2010 A=EGoss et al N=approx 9000 Ellis et al N=165FACE Trial A v L? Z1031 2010 A=L N=approx 4000 Ellis et al N=161Ellis M. et al. SABCS 2010 / abst. 794
  57. 57. Adjuvant Chemotherapy• No standard regimen• No predictive test for use of individual components• Choose efficient treatment among many standards, when indicated• ER, HER2, proliferation may predict response to ANY chemotherapy, rather than being agent-specific• Multigene arrays may be useful
  58. 58. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 Adjuvant Docetaxel for High-Risk, Node-Negative Breast Cancer Martin M. et al. N Engl J Med 2010; 363:2200- 2210 This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute.
  59. 59. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 GEICAM (Node - ve)Martin M. et al. N Engl J Med 2010; 363:2200-2210
  60. 60. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 Early Breast Cancer Trialists’ Collaborative Group Eighth Main Meeting Oxford September 2010
  61. 61. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 Anthracycline benefit is early Recurrence as first event in trials of anthracycline-containing regimens versus standard CMF regimensEBCTCG 2010(unpublished)
  62. 62. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 Taxane benefit is durable Recurrence as first event in the trials of a taxane-plus- anthracycline-based regimen vs a non-taxane control regimen with the SAME, or HIGHER, total dose of anthracyclineEBCTCG 2010(unpublished)
  63. 63. Genomic Profiles Determine WhichPatients Receive Adjuvant Chemotherapy?• «The Panel accepts molecularly-based tools (such as the 21-gene recurrence score assay) or gene expression profiling (such as by the 70- gene assay) as an adjunct to high-quality standard histopathologic assessment to refine risk categories.• The Panel recognizes in many cases this may provide more optimal individual risk allocation for making a decision to add chemotherapy or not.»
  64. 64. Trastuzumab• Adjuvant Trastuzumab x 1 year with CT is standard of care for women with high risk HER2+ve breast cancer• Standardised HER2 testing: accredited lab. for all invasive breast cancers• Concurrent v. sequential trastuzumab and anthracycline v. other chemotherapy remain uncertain
  65. 65. Trastuzumab: Open Questions• Trastuzumab for small (<1cm) HER2+ve cancers• Trastuzumab alone v. plus CT in lower risk• Duration = high priority• Other anti-HER2 agents
  66. 66. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 First results of the NeoALTTO trial (BIG 01-06 / EGF 106903): A phase III, randomized, open label, neoadjuvant study of lapatinib, trastuzumab, and their combination plus paclitaxel in women with HER2-positive primary breast cancer Baselga J. et al. SABCS 2010 / abst. 291 This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute.
  67. 67. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 lapatinib lapatinibInvasive breast cancerHER2+ R paclitaxelT >2 cm A S(inflammatory excluded)LVEF  50% N u D r FECN=450 O trastuzumab g  trastuzumab M paclitaxel e 3Stratification:—T<5 cm vs. T>5 cm I r— ER or PgR+ vs. both –— N 0-1 vs. N ≥2 Z— Conservative surgery lapatinib y E lapatinib trastuzumab trastuzumab paclitaxel 6 + 12 weeks 9 weeks 34 weeks 52 weeks of anti-ErbB2 therapy Baselga J. et al. SABCS 2010 / abst. 291
  68. 68. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 NeoALTTOBaselga J. et al. SABCS 2010 / abst. 291
  69. 69. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 NeoSPHEREGianni L. et al. SABCS 2010 / abst. 1000
  70. 70. Current & Future Trials• Chemotherapy: still looking at the risk of relapse• Endocrine therapies: looking at the sequence• Targeted biological therapies: looking at the best use (combination or sequence)• Targeting angiogenesis and stroma
  71. 71. Oncotype DX 21 Gene Recurrence Score (RS) Assay 16 Cancer and 5 Reference Genes From 3 StudiesPROLIFERATION ESTROGEN RS = + 0.47 x HER2 Group Score Ki-67 ER - 0.34 x ER Group Score STK15 PR + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score Survivin Bcl2 + 0.05 x CD68 Cyclin B1 SCUBE2 - 0.08 x GSTM1 MYBL2 - 0.07 x BAG1 GSTM1 BAG1 INVASION Stromolysin 3 CD68 Category RS (0 – 100) Cathepsin L2 Low risk RS < 18 REFERENCE Int risk RS ≥ 18 and < 31 Beta-actin HER2 GAPDH High risk RS ≥ 31 GRB7 RPLPO HER2 GUS TFRC
  72. 72. Expression Data Matrix of 70 Prognostic Markers Genes from Tumorsof 78 Breast Cancer Patients Hybridized Using the Custom Microarray Laura J. Van’t Veer
  73. 73. Current & Future Trials• Chemotherapy: still looking at the risk of relapse• Endocrine therapies: looking at the sequence• Targeted biological therapies: looking at the best use (combination or sequence)• Targeting angiogenesis and stroma
  74. 74. S LEStudy Of Letrozole Extension IBCSG 35-07 / BIG 1-07Coordinating Group: IBCSG
  75. 75. S LEAfter 4 to 6 Years of Prior Adjuvant Endocrine Therapy Postmenopausal, HR-Positive, Node-Positive R Continuous letrozole x 5 yrs AStratify NInstitutionPrior ET: D SERM O Intermittent letrozole over 5 yrs AI M Both I 9 mos. 9 mos. 9 mos. 9 mos. 12 mos. Z E 0 6 12 18 24 30 36 42 48 54 60 Extended Adjuvant Endocrine Therapy A: Continuous letrozole 2.5 mg daily for 5 years B: Intermittent letrozole 2.5 mg daily for the first 9 months of years 1 through 4, followed by 12 months in year 5
  76. 76. Effect of Intermittent Letrozole Treatment in MCF-7Ca Xenografts 2500 Control Off LetrozoleMean Tumor Volume (mm3) 2250 Her-2 2000 1 5.4 6.7 1.99 0.3 1.1 1750 Letrozole p-Her-2 1500 1 3.1 3.7 2.1 1.3 1.7 p-MAPK 1250 1 4.1 5.9 0.9 0.8 1.1 1000 Back on MAPK 750 Letrozole 1 1 1 0.9 0.9 1 500 Aromatase 1 0.2 0 0.9 2.7 0.8 250 ERα 0 1 0.2 0.1 0.9 2.4 1.1 02 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 ß-Actin Weeks Sabnis G.J. et al. Stopping treatment can reverse acquired resistance to letrozole. Cancer Res 68: 4518-4524, 2008
  77. 77. Current & Future Trials• Chemotherapy: still looking at the risk of relapse• Endocrine therapies: looking at the sequence• Targeted biological therapies: looking at the best use (combination or sequence)• Targeting angiogenesis and stroma
  78. 78. HER2 Targeted Trial: ALTTORA TrastuzumabND LapatinibOM T LapatinibIZ Trastuzumab+LapatinibE 0 6 mos 1 year Target accrual: 8000 patients
  79. 79. Current & Future Trials• Chemotherapy: still looking at the risk of relapse• Endocrine therapies: looking at the sequence• Targeted biological therapies: looking at the best use (combination or sequence)• Targeting angiogenesis and stroma
  80. 80. Metronomic Therapy (CM) Following Standard Adjuvant Chemotherapy for Patients With ER-Negative and PgR-Negative Breast Cancer IBCSG 22-00 Strata R A Menopausal NER <10% Status D CT & O Type of CT MPgR <10% Institution I Z CT  CM x 12 mos ETarget 900 ptsAccrual (6/2008) 718 pts
  81. 81. DF/PCC Breast Cancer SPORERandomized Phase II Trial of Metronomic Chemotherapy ± Bevacizumab CM + bevacizumab CM alone 10 (41%) PR 2 (10%) PR Burstein H., SABCS, 2005
  82. 82. BEX Regimen in Advanced BC Bevacizumab 10 mg/kg iv every 2 weeks Cyclophosphamide 50 mg/day orally @ 9 a.m. Capecitabine 500 mg x 3/day orally after meals Dellapasqua S. et al, J Clin Oncol. 26: 4899-4905, 2008
  83. 83. BEX ResultsBest response n %Assessable patients 46 CR 1 3 PR 18 45 SD24 weeks 8 20 SD<24 weeks 8 20 PD 5 13Overall response (CR+PR) 19 48% 95% CI 32 to 64Clinical benefit (CR+PR+SD24 weeks) 27 68% 95% CI 51 to 81 Dellapasqua S. et al, J Clin Oncol. 26: 4899-4905, 2008
  84. 84. Selected Triple negativeTAILORED HER2+CLINICAL TRIALS Endocrine incompletely responsive Endocrine responsive
  85. 85. Thanks topatients,investigators,nurses,data managers, sponsors, andall who are committed to clinicaltrialsfor progress incare & knowledge

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