BALKAN MCO 2011 - T. Cufer - Chemotherapy: when, why, prognostic factors, regiments, doses


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BALKAN MCO 2011 - T. Cufer - Chemotherapy: when, why, prognostic factors, regiments, doses

  1. 1. Adjuvant Chemotherapy of Early Breast Cancer: When, Why, Prognostic factors, Regimens<br />Tanja Cufer, MD, PhD<br />University Clinic Golnik<br />Medical Faculty, Ljubljana<br />ESO Masterclass; Dubrovnik 2011<br />
  2. 2. Cancer Mortality Rates in EU Member States<br />Levi F et al.,Ann Oncol2007;18.<br />
  3. 3. Adjuvant Therapy Help Reduce Breast Cancer Deaths<br /><ul><li>Breast cancer mortality decreased by 21.3% from 1975-2000 in USA
  4. 4. 7 independent meta-analysis showed median decline in mortality of 30% (range: 25%-38%)
  5. 5. Due to screening: 15% (range: 7%-23%)
  6. 6. Due to adjuvant therapy: 19%(range: 12%-21%)</li></ul>Berry DA et al. NEJM 2005<br />
  7. 7. Effects of Endocrine Therapy and of Chemotherapy in Early Breast cancer EBCTCG Overview, Lancet 2005<br /><ul><li>Adjuvant HT with Tam (in ER-positive pts)
  8. 8. 40% ↓ risk of recurrence
  9. 9. 32 % ↓ risk of breast cancer mortality
  10. 10. Polychemotherapy
  11. 11. 33% ↓ risk of recurrence
  12. 12. 17% ↓ risk of breast cancer mortality</li></li></ul><li>5<br />10<br />5<br />10<br />5<br />10<br />Chemotherapy Update: EBCTCG Overview Data<br />Taxanes > Anthra > CMF > No Chemo<br />50<br />Control36.4%<br />Anthra<br />31.0%<br />CMF31.3%<br />40<br />4.2%<br />4.3%<br />5.1%<br />30<br />CMF32.2%<br />20.5<br />19.9<br />Anthra27.0%<br />20<br />15.3<br />Taxane25.9%<br />%+ SE<br />17.8<br />16.5<br />12.8<br />10<br />Years<br />Years<br />Years<br />0<br />0<br />0<br />0<br />EBCTCG 2005-06 Overview Peto SABCS 2007 <br />
  13. 13. 2010 EBCTCG Overview: Anthracyclinevs CMF<br />Recurrence<br />BC mortality<br />Any death<br />A C <br />X<br />4<br />ANTHRAC<br />YCLINE<br />M<br />O<br />R<br />E<br />
  14. 14. 2010 EBCTCG Overview: Taxane+anthracycline(A) vs A<br />Recurrence<br />BC mortality<br />Any death<br />T<br />+<br />A<br />vs<br />S<br />a<br />m<br />e<br />A<br />T<br />+<br />A<br />vs.<br />M<br />o<br />r<br />e<br />A<br />
  15. 15. Poly-chemotherapy: Impact on Recurrence <br />Anthracycline (A) + <br />Taxanevs A<br />Anthracyclinevs CMF<br />Early benefit of anthracycline<br />Taxane benefit is durable<br />EBCTCG 2010 (unpublished overview)<br />
  16. 16. Benefit from Chemotherapy According to Subgroups<br />Taxane + Anthracycline (A) vs A <br />AnthracyclinevsNoCTX<br />All subgroups benefit from CT<br />EBCTCG 2010 (unpublished overview)<br />
  17. 17. ER-<br />ER+<br />Genotype <br />Luminal-like A, B<br />HER-like<br />Basal-like<br />Phenotype <br />Triple negative ER-neg PR-neg HER2-neg <br />HER2-pos ER-neg PR-neg<br />ER-pos <br />HER2-neg (mostly)<br />A: low proliferation rate B: high proliferation rate<br />A variety of disease types: <br />should all respond to the same therapy?<br />Adapted from Sotiriou et al,.PNAS, 2003.<br />
  18. 18. How to Select Adjuvant Systemic Therapy for Each Individual patient? <br />A major determinant is a Target not a Risk<br />Molecular targets in breast cancer:<br />Endocrine receptors (ER)<br />HER2 receptor<br />St.Gallen recommendations 2007<br />
  19. 19. Adjuvant systemic therapy is recommended if a relevant absolute risk reduction of recurrence and can can be expected with an acceptable level of treatment –related adverse effects ! <br />EFFICACY<br />TOXICITY<br />
  20. 20. Triple-Negative Early Breast Cancer<br /><ul><li>Chemotherapy remains the mainstay of adjuvant ST in TNBC
  21. 21. The optimal duration of Cht is not known (4-6 cycles)
  22. 22. The addition of taxanes to anthracyclines improves survival rates significantly
  23. 23. Sequential use of taxanes might be beneficial to concurrent use</li></li></ul><li>Triple negative<br />HER2-positive<br />ER-positive<br />HER2- and Ki67 low<br />ER-positive<br />HER2+ or Ki67 high<br />BCIRG001: Benefit of Docetaxel by ER and HER2 Status<br />Hugh J. et al. J Clin Oncol 2009; 27:1168<br />
  24. 24. CALGB 9344: Benefit of Paclitaxel by ER and HER2 Status<br />Hayes DF, et al. N Engl J Med 2007<br />
  25. 25. BIG 2-98: Sequential vs. Concomitant Doxorubicine-Docetaxel<br />Di Leo A, et al. SABCS 2009. Abstract 601.<br />
  26. 26. FinXX: CEF-Docetaxel vs CEX-Docetaxel/Capecitabine: RFS<br />ER+ and/or PR+, HER2+<br />ER+ and/or PR+, HER2-<br />100<br />100<br />80<br />80<br />T/CEF<br />P = 0.845<br />HR = 1.11<br />n = 163<br />P = 0.591<br />HR = 0.91<br />n = 1009<br />60<br />60<br />TX/CEX<br />40<br />40<br />20<br />20<br />0<br />0<br />0<br />1<br />2<br />3<br />4<br />5<br />6<br />7<br />0<br />1<br />2<br />3<br />4<br />5<br />6<br />7<br />ER- and PR-, HER2-<br />ER- and PR-, HER2+<br />100<br />100<br />80<br />80<br />60<br />60<br />P = 0.786<br />HR = 0.91<br />n = 122<br />P = 0.0177<br />HR = 0.48<br />n = 202<br />40<br />40<br />20<br />20<br />0<br />0<br />0<br />1<br />2<br />3<br />4<br />5<br />6<br />7<br />Joensuu et al. SABCS 2010. Abstract S4-1.<br />0<br />1<br />2<br />3<br />4<br />5<br />6<br />7<br />
  27. 27. HER2-positive Early Breast Cancer<br /><ul><li>Adjuvant chemotherapy is recommended for all patients with HER2-positive EBC in which a risk of relapse justifyiesadjuvant systemic therapy
  28. 28. HER2-directed therapy is the mainstay of adjuvant systemic therapy in HER2-positive EBC;5/6 trials have shown substantial DFS and OS benefits of adding trastuzumab to Cht
  29. 29. The optimal chemotherapy to combine with HER2-directed therapy and the optimal schedule of trastuzumab, sequential or concomitant to chemotherapy, still need to be defined. </li></li></ul><li>Standard chemotherapy (CT)<br />Adjuvant Chemotherapy +Trastuzumab: Six Large Adjuvant BC Trials, all N+ or High risk N (>14,000 patients)<br />Paclitaxel<br />AC/FEC<br />Docetaxel<br />Carbo+Doce<br />Trastuzumab (T)<br />FEC or ED<br />Doce/ or Vinorelbine<br />
  30. 30. Adjuvant Chemotherapy ± Trastuzumab Trials: Overall Survival<br />Median<br />FU yrs<br />p<br />Reference<br />Difference at <br />4y/3ya<br />HR<br />Combined US (n=3969)b<br />0.63<br />3.2%<br />3<br />0.0004<br />Perez 2007<br />HERA (n=3401) <br />0.66<br />2.7%*<br />2<br />0.0115<br />Smith 2007<br />BCIRG AC-TH (n=1074)<br />0.59<br />6%<br />3<br />0.004<br />Slamon 2006<br />BCIRG TCarboH (n=1075) <br />3<br />0.017<br />0.66<br />5%<br />Slamon 2006<br />FinHER (n=232) <br />5<br />0.09<br />6.6%*<br />0.55<br />Joensuu 2009<br />n.s.<br />1.27<br />–1.0%<br />4<br />Spielmann 2009<br />PACS-04 (n=528) <br />2<br />1<br />0<br />Favours trastuzumab<br />Favours chemotherapy only<br />*Benefit at 3y<br />a Absolute difference in percentage of patients with OS at 4 or 3 years<br />b Combined US: Joint analysis of NSABP B-31 and NCCTG N9831 <br />
  31. 31. Optimal Chemotherapy to Combine with Trastuzumab<br /><ul><li>Anthracycline-taxane sequences
  32. 32. HER-2 + tumors benefit from anthracycline treatment (Meta-analysis, Gennari et al., 2008; Watanabe T et al. ASCO 2009)
  33. 33. Demonstrated efficacy in randomized clinical trials (NSABP B-31 / NCCTG N9831 and BCIRG 006)
  34. 34. TCH:
  35. 35. Demonstrated effective in one randomized clinical trial (BCIRG 006) and could be considered in patients with risk factors for cardiac toxicity</li></li></ul><li>HER2 status and Anthracyclines in Early Breast Cancer<br />Pooled analysis: Overall survival<br />Non-anthracycline better<br />Anthracycline better<br />Study<br />HR<br />95% CI<br />0.660.90<br />0.821.07<br />0.851.64<br />0.611.26<br />0.730.82<br />0.651.06<br />0.91<br />0.731.03<br />0.47–0.920.69–1.18<br />0.63–1.060.88–1.30<br />0.27–2.690.85–3.15<br />0.32–1.160.89–1.79<br />0.50–1.050.59–1.13<br />0.42–1.010.80–1.40<br />0.83–1.00<br />0.62–0.850.92–1.16<br />NSABP B11<br />NSABP B15<br />GUN3<br />Milan<br />DBCCG-89-D<br />NCIC MA-5<br />Total<br />p=0.056<br />p<0 .0001<br />Overall<br />p=0.86<br />Heterogeneity c25=5.2; p=0.39Heterogeneity c25=5.5; p=0.36<br />0.6<br />1<br />2<br />5<br />0.4<br />0.9<br />ErbB2+ ErbB2–<br />Test for interaction chi2=12.0; p<0.001<br />Gennariet al. J Natl Cancer Inst 2008;100:14.<br />
  36. 36. BCIRG 006: DFS Benefit of Adjuvant Trastuzumab Treatment by TOPO II Coamplification and Treatment Arm<br />(all patients, 2nd interim analysis)<br />% disease free<br />% disease free<br />Slamon. 2006. www.bcirg<br />A, anthracycline; C, cyclophosphamide; D, docetaxel; T, trastuzumab; Carbo, carboplatin<br />
  37. 37. NCCTG N9831: DFS Sequential vs Concurrent Trastuzumab<br />AC -> T + H -> H (138 events)<br />100<br />89.1 %<br />90<br />84.2 %<br />85.7 %<br />80<br />79.8 %<br />AC -> T -> H (174 events)<br />70<br />Alive and Disease Free (%)<br />60<br />Log rank P = .0190<br />HR=0.77<br />50<br />949954<br />837830<br />788766<br />740705<br />676641<br />456418<br />No. at risk<br />40<br />5<br />1<br />2<br />0<br />3<br />4<br />Yrs From Randomization<br />Perez EA, et al. SABCS 2009. Abstract 80.<br />
  38. 38. Endocrine Responsive Early Breast Cancer<br /><ul><li>The absolute benefit of chemotherapy in HR-positive EBC depends on the remaining risk of recurrence and death, after endocrine therapy
  39. 39. A wide spectrum ranging from those at a low risk to those with high risk
  40. 40. Classical clinico-pathological factors
  41. 41. Number of positive nodes
  42. 42. Tumor size
  43. 43. ER/PR expression
  44. 44. Grade
  45. 45. Proliferationindex (Ki- 67)
  46. 46. Novel molecular tools
  47. 47. Multigene microarrays (Genomic signatures, Gene expression grade index)
  48. 48. Levels of uPA, PAI-1 </li></li></ul><li>Benefits of Adjuvant Chemotherapy in Endocrine Responsive Disease<br />Results from two IBCSG Trials (VIII,IX) in Node-negative EBC<br />Cumulative incidence of relapse over time according to treatment group for patients with different molecular subtypes:<br /><ul><li>Triple negative
  49. 49. HER2-positive
  50. 50. ER-positive </li></ul>Colleoni M et al, JCO 2010; 28: 2966<br />
  51. 51. Benefits of Adjuvant Chemotherapy in Endocrine Responsive Disease<br />
  52. 52. p = 0.39<br />Intermediate RS<br />p = 0.61<br />Low RS<br />Proportion without Distant Recurrence<br />High RS<br />p < 0.001<br />High Risk Patients (RS≥31) N Events <br />TAM + Chemo 117 13 TAM 47 18<br />Int Risk Patients (RS 18-30) N Events <br />TAM + Chemo 89 9TAM 45 4<br />Low Risk Patients (RS<18) N Events <br />TAM + Chemo 218 8 TAM 135 4<br />B-20 Results: TAM vs Chemo + TAM<br />Oncotype DX: N0<br />28% absolute benefit from Chemo - TAM<br />Paik et al. J Clin Oncol. 2006<br />
  53. 53. Postmenopausal women with N+<br />HR+ disease<br />(n = 1470)<br />TAM<br />CAF-T<br />CAFT<br />SWOG 8814, INT0100 Trial Disease-Free Survival by Treatment<br />Low risk (21-gene RS < 18)<br />1.00<br />0.75<br />Disease-free survival<br />0.50<br />Stratified log-rank p = 0.97 at 10 years<br />0.25<br />Tamoxifen (n=55, 15 events)<br />CAF-T (n=51, 26 events)<br />0.00<br />0<br />2<br />4<br />6<br />8<br />10<br />Years since registration<br />Intermediate risk (21-gene RS 18- 30)<br />High risk (21-gene RS ≥ 31)<br />1.00<br />1.00<br />0.75<br />0.75<br />Disease-free survival<br />Disease-free survival<br />0.50<br />0.50<br />Stratified log-rank p = 0.033 at 10 years<br />Stratified log-rank p = 0.48 at 10 years<br />0.25<br />0.25<br />Tamoxifen (n=47, 26 events)<br />CAF-T (n=71, 25 events)<br />Tamoxifen (n=46, 22 events)<br />CAF-T (n=57, 20 events)<br />0.00<br />0.00<br />0<br />2<br />4<br />6<br />8<br />10<br />0<br />2<br />4<br />6<br />8<br />10<br />Years since registration<br />Years since registration<br />Albain K, et. al. SABCS 2007.Abstract 10<br />
  54. 54. Prospective Randomized Trials Evaluating Benefit of Chemotherapy in Patients with Good Signature Profiles<br />TAILORx (n = 10,500) and MINDACT (n =6000)<br />Pre- and postmenopausal pts MINDACT: HR-/+ N-/+(1-3)<br />TAILORx: HR+ N-<br />High-risk 21-gene RS<br /> or<br />high-risk 70-gene signature +high-risk Adjuvant! Online<br />Medium-risk 21-gene RS<br />or<br />discordant risk group (mostly low-risk 70-gene signature but high risk adjuvant on line)<br />Low-risk 21-gene RS<br />or<br />low-risk 70-gene signature +low-risk Adjuvant! Online<br />Chemotherapy<br /><ul><li>Randomize chemo: yes or no (TAILORx)
  55. 55. Randomize chemo: yes or no (MiNDACT)</li></ul>Endocrine therapy<br />Potential CT sparing in 10-15% pts<br />
  56. 56. Predicting Sensitivity to Chemotherapy<br />PCR Probability With Neoadjuvant Chemotherapy<br />-<br />33%<br />ER<br />+<br />7%<br />3<br />26%<br />GRADE<br />1 or 2<br />7%<br />20%<br />21%<br />Ki67<br /><20%<br />5%<br />(Colleoni M et al.) <br />
  57. 57. Predicting Sensitivity to Chemotherapy<br /><ul><li>Anthracycline benefit
  58. 58. Chromosome 17 polysomy…
  59. 59. HER2 status
  60. 60. TOPO2A and TIMP-1 ?
  61. 61. Taxane benefit
  62. 62. HER2 ?
  63. 63. P53 ?
  64. 64. Tau protein ?</li></li></ul><li>All patients<br />p53 wild type<br />p53 mutated<br />p=0.27<br />p=0.12<br />p=0.58<br />BIG 01-00/EORTC 10994 p53 Tial : Taxane Benefit in Neoadjuvant Setting<br />All patients<br />Bonnefoi H etal., ASCO 2010<br />
  65. 65. In Conclusion, <br /><ul><li>Chemotherapy remains an important adjuvant breast cancer therapy
  66. 66. Effective biomarkers are needed to optimize chemotherapy in two directions:
  67. 67. To identify patients that can be spared from toxic chemotherapy
  68. 68. To define the optimal Cht regimen for each individual patient
  69. 69. Better understanding of long term side effects of Cht might help us to further refine our strategies. </li>