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Neoadjuvant Chemotherapy in Breast Cancer

Neoadjuvant Chemotherapy in Breast Cancer. Pr Hamouda Boussen MD Department of medical oncology Institut Salah Azaiz. Tunis. Post-graduate course of Mediterranean Task Force for Cancer Control and Mediterranean School of Oncology. Hotel El Mechtel. November 14th, 2008. Tunis.

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Neoadjuvant Chemotherapy in Breast Cancer

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  1. Neoadjuvant Chemotherapy in Breast Cancer Pr Hamouda Boussen MD Department of medical oncology Institut Salah Azaiz. Tunis Post-graduate course of Mediterranean Task Force for Cancer Control and Mediterranean School of Oncology. Hotel El Mechtel. November 14th, 2008. Tunis.

  2. Neoadjuvant chemotherapy(NACT)OR Primary Systemic Therapy (PST) ?? • i.e post-diagnosis systemic therapy • Takes into account order of administration, programmation of subsequent treatment and efficacy of systemic intervention • Other terms used are down staging, induction therapy, preoperative systemic therapy, neoadjuvant chemotherapy. Kaufmann JCO 2003 International Expert Panel

  3. PST For whom it is standard of care? • For patients with inoperable breast cancer • Inflammatory breast cancer • involvement of ipsilateral supra or infraclavicular nodes i.e. N3 disease. What about stages IIIA-B or T3-4 disease ?

  4. Locally advanced breast cancer • In Tunisia it forms 30 to 40 % of all breast cancers at some centers*. *Cancer registries(North, Center and South)

  5. For whom can PST be recommended as an alternative to AST ? • Most large randomized trials of PST versus AST indicate that these therapies offer equivalent disease free and overall survival benefits. • For operable breast cancer, PST can be considered as an alternative to AST • For patients appropriate candidates for mastectomy but who desire less extensive surgery (breast conservation surgery). • Success rate 5-36 %. • Also in patients who can technically have a lumpectomy first but whose physical appearance will be less damaged if PST is given first.

  6. PST • May also be advisable in patients who have medical contraindications to surgery or if they simply wish to delay surgery i.e. pregnant patient diagnosed in second and third trimester. • PST offers an optimal test situation for evaluation of new compounds and detection of new biologic or molecular discriminants of either response or resistance • pCR may be used as a surrogate for survival, less cumbersome than overall survival and less time consuming.

  7. NSABP B-18 OPERABLE BREAST CANCER STRATIFICATION • AGE • CLINICAL TUMOR SIZE • CLINICAL NODAL STATUS OPERATION AC x 4 + TAM if >50 yrs. AC x 4 + TAM if >50 yrs. OPERATION

  8. B-18Pathologic Breast Tumor Response in pts with cCR(249 pts) Complete Pathologic Response (63 pts) 9% 36% 4% DCIS only (26 pts) Clinical Complete Response (249 pts) 23% Residual Invasive

  9. B-18Surgery Performed 100 40 32 80 32 Mast Lump 60 % 40 60 68 P < 0.01 20 68 0 Preop Chemo Postop Chemo

  10. Era of pre-taxanes : NSABP B-18 trialOverall survival and response to chemotherapy 5yr survival • Path CR = 87% • Clin PR = 68% • Clin NR = 64% p<0.0001 Fisher et al, J Clin Oncol 1988; 16: 2672-2685

  11. NSABP B-18: updated results. • In pre-op arm 36 % patients had a complete clinical response • Axillary node down staging in preop. patients 59% vs. 42 % path negative nodes • Highly significant correlation between tumor response and path nodal status. • 87 % patients with complete clinical response had path neg nodes • More likely to have lumpectomy 68% vs. 59 %, statistically not different • No difference in disease free and overall survival

  12. Overview of Randomized Trials of NACT vs ACT(adjuvant chemotherapy) in Breast Cancer Author Local Distant Breast And No.of Follow-up Failure Failure Survival Conservation Group Patient Stage (months) Rate Rate Rate (PST vs. AST) Fisher, NASBP 1,523 T1-3, N0-1, M0 96 * * * 67% versus 60% P=0.002 Gianni, ECTO 892 T1-3, N0-1, M0 23 NA NA NA 71% versus 35% P < 0.0001 Van der Hage, 698 T1c-4d, N0-1, M0 56 * * * 37% versus 21% Eortc NA Jakesz, ABCSG 423 T1-3, N0-2, M0 NA ‡ * * *NA Scholl, S6 390 T2-3, N0-2, M0 66 * * * 82% versus 77% *No Statistical difference

  13. B-18 trial: unanswered questions. • Is there a need for further chemotherapy after surgery ??? • Those who show a good response may not require further treatment and those who show a poor response may require different drugs ???

  14. Whether favorable prognosis warrants exposure to known toxicity of treatment • B 20 showed that adding adjuvant chemotherapy in node negative women improved disease free survival significantly • NSABP B20 trial removes possible concerns about preoperative chemotherapy in patients with favorable tumor size, receptor status and histology. • General consensus: that there is no group that is not benefited by chemotherapy: very small palpable tumors, node positive and negative, ER positive and negative, all benefit.

  15. PST: Which regimen and how much • Anthracycline based chemo was standard, but changing fast • A minimum of 3-4 cycles, additional cycles may be considered for responding patients to maximize response and to improve chances of breast conservation • Use of Taxanes and sequential therapies can increase rate of pCR / successful breast conservation surgery / node negative patients by 50%. • Trastuzumab and other targeted therapies are under investigation.

  16. Role of Docetaxel in neo-adjuvant therapy for breast cancer

  17. Rationale for the use of Docetaxel in PST • Activity in anthracycline-resistant MBC • Superior activity observed in patients with poor prognosis disease • Most effective drug in first-line MBC (single, combined) • No cardio toxicity as with paclitaxel • More lab & clinical activity in breast cancer than paclitaxel • Longer half life than paclitaxel

  18. Important questions for Docetaxel • Does the addition of Docetaxel to an anthracycline-containing regimen have beneficial effects? • Clinical and pathological responses • Breast conservation • Survival • Should Docetaxel be given concurrently with or following an anthracycline-containing regimen and what is the best schedule? • What about role of trastuzumab in HER2 over-expressing tumors?

  19. Neoadjuvant TaxotereThe Aberdeen TrialNSABP B27GEPARDUO

  20. Neoadjuvant TaxotereThe Aberdeen TrialNSABP B27GEPAR-DUO

  21. Tax301 StudyConducted by the Aberdeen Breast Group First Phase Second phase 4 cycles of Taxotere All Patients No Response Final Assessment / Surgery 4 cycles of CVAP Response 4 cycles of Taxotere Randomise 4 cycles of CVAP Smith et al, JCO 2002

  22. Aberdeen Tax 301Objective clinical response rates1st phase: 4 cycles CVAP ORR - 67% N=162 patients; 4 cycles of CVAP given to all patients

  23. Aberdeen Tax301Objective clinical response rates2nd phase: responding patients * p=0.03

  24. Aberdeen Tax 301Objective clinical response rates2nd phase: non-responding patients ORR - 47% N=55 patients; additional 4 cycles of Taxotere given

  25. 100 Taxotere CVAP 80 60 % of patients 40 20 0 Conservation Mastectomy Type of surgery Aberdeen Tax301 Type of surgery undertaken Breast conservation surgery Taxotere 67% CVAP 48% (p<0.01)

  26. Median Follow - up: 60 months 1.0 97% Survival probability 0.9 78% Taxotere 0.8 CVAP Log rank p=0.04 0.7 20 40 60 80 100 Tax 301 Overall Survival Time (months)

  27. Neoadjuvant TaxotereThe Aberdeen TrialNSABP B27GEPAR-DUO

  28. NSABP B-27 ( 2411 pts ) Operable Breast Cancer Randomization AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs Surgery Taxotere x 4 Surgery Taxotere x 4 Surgery Bear et al, J Clin Oncol 2003; 21

  29. B-27 Eligibility • Operable Breast Carcinoma • Diagnosis by FNA or core biopsy • Palpable on physical exam (T1c-3 N 0, M 0 , / T 1-3, N 1, M 0 ). • NOT locally or regionally advanced • No T4 or N2 disease Bear et al. Breast Cancer Res Treat. 2004;88(suppl 1):S16. Abstract 26.

  30. NSABP B-27 Clinical Response p < 0.001 cCR cPR cNR 100 40% 80 65% % 60 40 45% 26% 20 14% 9% 0 AC N=1502 AC Taxotere N=687

  31. Non-Invasive No Tumour NSABP B-27 Pathological Response (pCR) in Breast 30 p < 0.001 20 18.9% 26.1% 9.8% 10 13.7% 7.2% 3.9% 0 AC N=1567 AC Taxotere N=786 Adapted from Bear et al, J Clin Oncol 2003; 21

  32. NSABP B-27:Proportion of Patients with negative axillary lymph nodes 80 60 % 58.2 40 p < 0.001 50.8 20 0 AC Taxotere N=752 AC N=1534 Bear et al, J Clin Oncol 2003; 21

  33. NSABP B-27: Breast Conservation 80 60 % 63 61 40 p = 0.70 20 0 AC Taxotere N=718 AC (N=1492) Bear et al, J Clin Oncol 2003; 21

  34. Neoadjuvant TaxotereThe Aberdeen TrialNSABP B27GEPAR-DUO

  35. GEPARDUO trial Geparduo AT + Tam Surgery (N=913) T  2 cm (stage I,II) Surgery AC-T +TAM Adriamycin Taxotere Adriamycin Cyclophosphamide von Minckwitz et al., J Clin Oncol 1999 von Minckwitz et al., J Clin Oncol 2001 Taxotere

  36. Treatment regimens 4 cycles AC followed by 4 cycles of Taxotere • Doxorubicin 60 mg/m² (day 1 q 22) • Cyclophosphamide 600 mg/m² (day 1 q 22) • Taxotere 100 mg/m² (day 1 q 22) 4 cycles AT • Doxorubicin 50 mg/m² (day 1 q 15) • Taxotere 75 mg/m² (day 1 q 15) • G-CSF (days 5-10) Tamoxifen 20mg /day at same time Adapted from G.Raab – SABCS ’03, Abs#241, Poster

  37. Clinical responses in the breast 100% 32.5% 80% 57.4% Complete 60% Partial 44.7% Stasis 40% Progress 29.4% 20% 10.1% 21.1% 0% AT AC-T (n=425) (n=421)

  38. GEPAR-DUO Pathologic Complete Remission (pCR) No Tumor In situ residuals only 30% P < 0.001 20% 16.1% 22.4% 10% 7.7% 11.5% 6.3% 3.8% 0 AT (443pts) AC Taxotere (442 pts) Adapted from G.Raab – SABCS ’03, Abs#241, Poster

  39. Effect on tumour in axillary lymph nodes 80% 60% 60.7% 55.4% 40% 20% 0 AT (n=443) AC Taxotere (n=442)

  40. GEPAR-DUO Effect on breast conservation surgery 80% 74.9% 60% 65.5% 40% 20% 0 AT (n=443) AC Taxotere (n=442)

  41. GEPAR-DUO: Conclusions AC->Taxotere : • Increased Complete Clinical response • Increased pCR rates • Increased number of patients with no axillary node involvement • Increased breast conservation

  42. Overview of Rand. Trial comparing different Primary Systemic Therapy Regimens in Breast Cancer Author Clinical Pathologic Breast And No.of Complete Response* Conservation Group Patient Stage Regimen Response(%) (%) Rate NSABP 2,411 T1-3, N0-1, M0 AC x 4 40 9.8 61 AC x 4, Doc x 4 65 18.7 63 Von Minckwitz 913 T2-3, N0-2, M0 AT x 4 q2w 32.5 7.7 65 GABG AC x 4, Doc x 4 57.4 16.1 75 Untch, AGO 475† T2-4d, N0-2, M0 ET x 4 NA 10 55 Epi x 3, Tax x 3 q2w 18 66 Von minckwitz 248 T2-3, N0-2 AT x 4 q2w 5.7 10.3 69 GABG AT x 4 q2w + Tam 12.5 9.1 69 Penault-Llorca 200‡ NA AC NA 6 45 France AT 15 56 Buzdar 174 T1-3, N0-1, M0 FAC x 4 24 18 35 Houston Tax x 4 27 6 46 Smith 104 T2-4, N0-2, M0 CVAP x 8 33 15.4§ 48 CVAP x 4, Tax x 4 56 30.8§ 67 *No invasive or in situ tumor cells in the removed breast

  43. Pathological Complete Response Rate (pCR) Method B

  44. Randomized controlled trial of TX vs. AC as primary therapy in early breast cancer Lee et al ESMO 2004 Randomization AC x 4 TX x 4 Primary Surgery Surgery TX x 4 AC x 4 Adjuvant

  45. Taxotere in ESBC: Conclusions • Addition of Taxotere to conventional anthracycline-containing chemo •  DFS and OS in N+ early-stage breast cancer • Sequential use of Taxotere following 3 cycles of an anthracycline-containing regimen •  DFS and OS in N+ early-stage breast cancer • Neoadjuvant chemo can increase operability in operable and locally advanced breast cancer • Clinical and pathologic response predict outcome • Taxotere-containing regimens for ESBC are safe and provide significant clinical benefit • Taxotere-containing combinations and sequences are a valid treatment option for women with early-stage breast cancer

  46. Operable Breast Cancer - Her-2 + Randomization Paclitaxel X 4 Paclitaxel X 4 + H X 12 wkly FEC X 4 FEC X 4 + HX 12 wkly Local Therapy Appropriate Endocrine Therapy for Patients with Hormone Receptor + Disease MD Anderson Neo-Adjuvant Herceptin Trial

  47. Summary neoadjuvant Taxotere • Highly effective in reducing tumour size • Increases clinical responses • Increases complete pathological response • Increases Nodal clearance • Increases breast conservation • Improved survival in Aberdeen trial • Potential for non-anthracycline combinations Taxotere offers meaningful benefits to patients:

  48. Primary Systemic Chemotherapy • It is here to stay • Effective, improved results in combination • Increased rates of breast conservation • Better cosmesis • Surrogate marker of improved survival • Rescue measures can be taken early rather than late

  49. PST; Drawbacks • Pathological staging not available • Improved survival not proven • Whether post operative chemotherapy is beneficial not known • Can create problems in Radiotherapy • Newer options: AI, Trastuzumab

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