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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, Tunis.


3 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 International Expert Panel

4 Why Pre-operative Chemotherapy?
Downstage: Increase operability Facilitate breast conservation Earlier treatment of micrometastases Assess chemotherapy sensitivity

5 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 ?

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

7 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.

8 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.


10 B-18 Pathologic 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

11 40 32 32 60 68 P < 0.01 68 B-18 Surgery Performed 100 80 Mast 60
Lump 60 % 40 60 68 P < 0.01 20 68 Postop Chemo Preop Chemo

12 Era of pre-taxanes : NSABP B-18 trial Overall 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:

13 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

14 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 , T1-3, N0-1, M * * * % versus 60% P=0.002 Gianni, ECTO T1-3, N0-1, M NA NA NA % versus 35% P < Van der Hage, T1c-4d, N0-1, M * * * % versus 21% Eortc NA Jakesz, ABCSG T1-3, N0-2, M NA ‡ * * *NA Scholl, S T2-3, N0-2, M * * * % versus 77% Overview of Randomized Trials of NACT vs ACT(adjuvant chemotherapy) in Breast Cancer *No Statistical difference

15 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 ???

16 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.

17 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.

18 Role of Docetaxel in neo-adjuvant therapy for breast cancer

19 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

20 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?

21 Neoadjuvant Taxotere The Aberdeen Trial NSABP B27 GEPARDUO

22 Neoadjuvant Taxotere The Aberdeen Trial NSABP B27 GEPAR-DUO

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

24 Aberdeen Tax 301 Objective clinical response rates 1st phase: 4 cycles CVAP
ORR - 67% N=162 patients; 4 cycles of CVAP given to all patients

25 Aberdeen Tax301 Objective clinical response rates 2nd phase: responding patients

26 Aberdeen Tax 301 Objective clinical response rates 2nd phase: non-responding patients
ORR - 47% N=55 patients; additional 4 cycles of Taxotere given

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

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

29 Neoadjuvant Taxotere The Aberdeen Trial NSABP B27 GEPAR-DUO

30 Operable Breast Cancer
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 Surgery Taxotere x 4 Bear et al, J Clin Oncol 2003; 21

31 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. 22

32 NSABP B-27 Clinical Response
cCR cPR cNR 100 80 40% 65% % 60 40 45% 26% 20 14% 9% AC N=1502 AC Taxotere N=687

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

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

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

36 Neoadjuvant Taxotere The Aberdeen Trial NSABP B27 GEPAR-DUO

37 Geparduo GEPARDUO trial AT + Tam AC-T +TAM T  2 cm (stage I,II)
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

38 Adapted from G.Raab – SABCS ’03, Abs#241, Poster
Treatment regimens 4 cycles AC followed by 4 cycles of Taxotere Doxorubicin mg/m² (day 1 q 22) Cyclophosphamide 600 mg/m² (day 1 q 22) Taxotere 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

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

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

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

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

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

44 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 AC x 4, Doc x Von Minckwitz 913 T2-3, N0-2, M0 AT x 4 q2w GABG AC x 4, Doc x Untch, AGO † T2-4d, N0-2, M0 ET x NA Epi x 3, Tax x 3 q2w Von minckwitz 248 T2-3, N0-2 AT x 4 q2w GABG AT x 4 q2w + Tam Penault-Llorca ‡ NA AC NA France AT Buzdar T1-3, N0-1, M0 FAC x Houston Tax x Smith T2-4, N0-2, M0 CVAP x § CVAP x 4, Tax x § Overview of Rand. Trial comparing different Primary Systemic Therapy Regimens in Breast Cancer *No invasive or in situ tumor cells in the removed breast

45 Population Size* All Randomized Trials
Number of studies meeting criteria: Number of patients enrolled in non-TAX: 1443 Number of patients enrolled in TAX: Overall Number of patients: * All Randomized Trials * Updated after abstract submission

46 Pathological Complete Response Rate (pCR)
Method B

47 Randomized controlled trial of TX vs
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 Randomized controlled trial of TX vs. AC as primary (neoadjuvant) therapy in early stage breast cancer. Aims of the study were to evaluate clinical and pathologic responses and compare safety of TX vs. AC. Treatment doses: AC = doxorubicin (60mg/m2 i.v. day 1) + cyclophosphamide (600mg/m2 i.v. day 1). TX = docetaxel (75mg/m2, 1-hour infusion on day 1) + capecitabine (1000mg/m2 twice daily, days 1-14). If no response was obtained prior to surgery, patients crossed over to the other regimen before undergoing surgery. Patient evaluation: Baseline physical exam, PET (to exclude node-negative disease) and ultrasound (to determine tumor size) prior to first cycle of chemotherapy. Repeat ultrasound of affected breast prior to the third cycle of chemotherapy and surgery. Repeat CT or PET performed prior to surgery if indicated. Patients underwent mastectomy or lumpectomy after fourth cycle of primary chemotherapy; patients then crossed over to other treatment arm. For unresponsive tumors (SD or PD), surgery or alternative chemotherapy offered at physicians’ discretion. Patients received radiotherapy  tamoxifen following chemotherapy. Statistical analysis: 209 evaluable patients required to detect 15% difference in pCR rate with 80% power at 5% significance level, (allowing for up to 10% withdrawal rate.). Patients prospectively stratified according to disease status (stage II or III), estrogen receptor status (positive or negative), and age (50 years vs. >50 years). TX x 4 AC x 4 Adjuvant

48 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 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

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

50 Summary neoadjuvant Taxotere
Taxotere offers meaningful benefits to patients: 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

51 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

52 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

53 Adjuvant vs neoadjuvant chemotherapy in breast cancer: randomised studies
Study No. pts Stage DFS(%) OS (%) Ragaz, 1999 204 I,II NR 73 vs 72 Mauriac, 1999 69 T2,T3 same 54 vs 55 Semiglazov, 1994 271 IIb,IIIa 81 vs 72* 86 vs 78 Scholl, 1994 414 IIa - IIIa 59 vs 55 86 vs 78* cCR=clinical complete remission in %, pCR=pathological complete remission in %, BST=breast conserving treatment S=surgery, FECi=5-FU, epirubicin, cisplatin VbEM=vinorelbine,epirubicin,methotrexate FMxC=5-FU, mitoxantrone, cyclophosphamide TAVbCF*=doxorubicin, vinorelbine, cyclosphamide, 5-FU w/wout colony stimulating factor CMF=cyclophosphamide, theotrexate, 5-FU FAC=5-FU, doxorubicin, cyclophosphamide FEC=5-FU, epirubicin, cyclophsphamide A=doxorubicin Makris, 1998 309 T0 - T4 84 vs 82 same Fisher, 1998 1523 T1 - T3 67 vs 67 80 vs 80 (Data from: Wolf and Davidson, J Clin Oncol 2000; *p<0.05)

54 PST: Endocrine therapy remains attractive
When it is desirable to avoid chemotherapy As a second choice for selected patients, elderly women with impaired organ function or low PS, or high surgical risk A positive ER, PgR is a requisite. AI more active and better tolerated, thus preferred in postmenopausal patients. No data in premenopausal patients.

55 Locally advanced breast cancer
Increased public awareness, national breast screening 10-20% of patients - LABC (T3, T4 or N2) Haagensen & Stout, 1943 48% local recurrence 3% 5 year survival } If radical mastectomy performed

56 Alternative treatment strategies for LABC
Radiotherapy Chemotherapy Chemoradiotherapy Clinical responses of 60-70% with various chemotherapies

57 Pathological complete response (pCR) in neoadjuvant Taxotere studies
concurrent sequential single agent * * * * * 13% (B18) *pCR incorporates lymph nodes

58 Pathological Response and Survival (Miller and Payne grading system)
5 1.0 0.9 0.8 0.7 0.6 0.5 0.4 4 3 survival 2 p=0.003* 1 months Ogston et al, 2003

59 Pathological responses Miller & Payne Grade of Pathological Response
Aberdeen Tax301 Pathological responses Miller & Payne Grade of Pathological Response CVAP n = 52 Taxotere n = 52 1 19% 2% pNR 2 19% 17% 3 27% 23% 4 15% 17% pCR 5 15% 31%* *p=0.06 Hutcheon et al, SABCS 2003

60 NSABP B18: Updated results
Still no difference in overall survival Pathological complete response - 85% year survival at 9 years Age DFI Neoadj vs adj OS Neoadj vs adj 49 and under 55% vs 46% 71% vs 65% 50 and over 56% vs 60% 67% vs 75% Wolmark et al, 2001

61 NSABP B-27 trial All patients receive initial AC chemo
Group I; No further treatment Group II: 4 cycles of Docetaxel after surgery Group III: 4 cycles of Docetaxel before surgery

62 NSABP-B27 Clinical complete response rates 36-40% vs 65 %
Path CR 9 % and 18 %

63 PST:Is there a role for endocrine treatment alone
Conventionally response rates with endocrine therapy are far inferior In a largest trial so far of 337 patients, a pCR was observed in only 1.5 % patients. Eiermann et al. Ann Oncol 2001. But things may be changing soon, Aromatase inhibitors have shown better responses in small studies.

64 2nd phase: non-responding patients
Aberdeen Tax301 2nd phase: non-responding patients Miller & Payne Grade of Pathological Response Taxotere n = 46 1 15 pNR 2 11 3 13 4 6 pCR 5 1 20 (44%) patients had a grade 3,4 or 5 response

65 Taxotere and paclitaxel
Similar mechanisms of action, but some differences Taxotere has: Greater affinity for tubulin Longer half-life Longer intracellular retention Lower cardio toxicity with doxorubicin

66 PST: scientific basis Pulmonary metastases in animals underwent growth spurt on removal of primary tumor, this can be overcome by prior chemotherapy Growth fractions in cell populations suggest micro metastases might respond differently to preoperative chemotherapy Goldie–Coldman hypothesis suggests that resistance to chemotherapy was a function of time, hence early treatment might be better.

67 TAX 301 Study After 4 cycles of CVAP and Taxotere:
Increased the complete response rate to 62% in initially responsive patients vs. 34% for continued CVAP pCR of 31% (ITT analysis) increased 5 year DFS and Survival Achieve a higher rate of Breast conservation

68 TAX 301 Study Patients unresponsive to primary CVAP chemotherapy receiving further sequential Taxotere achieve : 47% Clinical ORR 1 Complete pathological response

69 NSABP B-27 : Conclusions The addition of preoperative Taxotere to preoperative AC resulted in a significant increase in the rates of: Clinical Complete Response: 40% vs 65% (63% ) Pathologic Complete Response: 13.7% vs 26.1% (91% ) Negative Axillary Nodes: 50.8% vs 58.2% (16% )

70 PST; Early rand. trial Scholl et al from Institut Curie
414 premenopausal women, T2,T3,N0-N1 4 cycles CAF followed by RT (surgery only for those who did not have CR) VS Surgery followed by 4 cycles of same chemo FU 54 months OS better in primary chemo arm, no difference in disease free survival or local recurrence

71 Bordeaux trial 272 women with lesions more than 3 cms rand between mastectomy and chemo if nodes positive VS initial chemotherapy followed by RT/ surgery 34 months FU patients with initial chemo better overall survival, however more isolated recurrence occurred in these patients.

72 Clinical response rates in neoadjuvant Taxotere studies
concurrent sequential single agent 79% (B18) 29% of tumours < 2cm in the B18 study

73 Neoadjuvant therapy Initial concept Evolution of concept
Early Introduction of chemotherapy Unic Clinical situation clinique permitting to analyse tumor response in vivo  Benefit on survival  Increase of breast conservation rate  Reduction of loco-regional sequelae Analysis of response in vivo may be done in sequential (repeated samples) Identification of intermediate markers (« surrogate markers ») Méta analyse neoadjuvant CT vs adjuvant CT, JNCI 97,3, 2005 Identification of factors predicting response  No difference in term of overall and disease-free survival  Higher rate of breast conservation  Morphological Immuno-phenotyping  Genomics

74 Hisotologic response : intermediate marker of a better prognosis ?
Studies Median survival (years) P Value for pCR Bonadonna 1998 Ellis 1998 Fisher NSABP B-18* 1998 Kuerer 1999 Gianni ECTO ASCO 2005 Cleator 2005 Bear 2006 NSABP B27 8 yrs disease-free survival 5 yrs overall survival 5 yrs disease-free survival 10 yrs disease-free survival 10 yrs overall survival 7 yrs disease-free survival 7 yrs overall survival 0,034 0,4 0,0001 0,23 < 0,0001 0,005 0,01 0,03 <0,001

75 Dose-dense Phase III AGO trial : results et 55 months
B: Epi 90 + Taxol 175 q3w x4 A: Epi 150 q2w x3 Taxol 250 q2w x 3 Surgery 3CMF adjuvant pRC 10% 19% I’ pN- 41% 50% DFS 3 68% 76% P<0.05 DFS 5 59% 70% B’ OS 3 85% 90% OS 5 77% 83% Untch M. et al, SABCS 2007, abstract 5052

76 + Herceptin Q3W if HER2 +, follow-up 1 year post surgery
GeparQuattro trial- Phase 3 GBG/AGO Every patient eligible for an adjuvant chemotherapy 4 EC90 4 D 100 4 D75 +X1800 4 D754 X 1800 + Herceptin Q3W if HER2 +, follow-up 1 year post surgery 4 D 100 4 D75 +X1800 4 D754 X 1800 Total HER2+ 147 144 136 427 HER2- 324 327 343 994 I’ No difference in term of cardiac toxicity betw HER2+ and –, More febrile neutropenia in HER2 + A’ Untch M. et al, SABCS 2007, abstract 5053 * Von Minckwitz G. et al, SABCS 2007, abstract 79

77 TPN = unic factor prédictive of CR
Phases II – Neoadjuvant Chemotherapy Protocol Scheme Nb Pts Results comment Roché 5057 R CEX (vs FEC) X 1800 E100 C500 182 RR 58% pCR 13% CEX, 20% FEC safety Lombardi Aviano 5067 DE q3 w x 4 D 75 E 90 45 (23 HER) pRC 20% pRC axil 25% pRC breast +node ? Le Tourneau Curie R 4010 FAC q3w TRIPLE NEG ET HER2+ F 700 J1 J5 A 60 C 700 J1 J8 96 pCR 20% TPN : 47% pCR HER % pRC TPN = unic factor prédictive of CR Alkylants+++ Shen Chine 5070 DxrL + V q3w x6 Caelyx 30 V 25 , J1 J8 61 pRC 3.4% Tox muqueuse ++ And hémato Alvarez Barcelone 5068 Doxo lipos. +D Q2w x 6 M 60 D 60 58 pRC 19.2% ABSTRACT 5073 DE CITY OF HOPE 39 PTES P2 RANDOM REPONSES AFFICHEES NON PRECISEES SI CLINIQUE OU PATHO III’

78 Phase II - Her2+ Protocol Scheme Nb Pts Results comment III’ Tripathy
Roche 5059 DXH D 75 X 1650 H hebdo 34 pRC + quite 52% of pCR Han Miami 5060 DCH q2w Carbo 6 D 70 32 pRC 40% Better for the 14dys scheme Pernas Barcelone 5061 P hebdo puis 4 FEC75 P 80 H x12 4 FEC 75 H hebdo 24w 33 pRC 73% Ki 67> 20 : pRC81% vs 43% si <20 GEICAM 5069 Dxr L + D q3w x6 Myocet 50 D 60 H2 26 pRC 30.8% MD Anderson 5054 FEC + Her then Txt X Hebdo 179 pRC 34% pRC 43% Triple neg Signature prédictive pf pRC? Creighton Houston 82 Lap 6w puis TH q3w x4 Lap 6w then TH q3w x4 25 60% after lap pRC total 63%  of CD44+ CD24- after lap. (10.6 à 4.7%) III’

79 Phase II – Targeted therapies 100% de l’act. Enzymatique FTase
Protocol Scheme Nb Pts Results comment Makhoul 5055 4TCB 4A q3w D75 CPM 500 Avastin 15 Dxr 60 28 pRC 29.3% 1 death ? 1 CaFail clinical Greil 4064 TXB q3w X 1900 18 pRC 22% Ejlertsen R EC +/- Iressa 250 144 RH- pRC 11% Iressa = placebo Sparano 5071 AC +Tipifarnib 46 pRC sein 26% pRC tout 20% 100% de l’act. Enzymatique FTase III’

80 Neoadjuvant chemotherapy and lobular carcinoma
Retrospective study  32 patients Few down staging  pCR 2/4 if HER2 with Herceptin*  Sinon : 0% Conclusion  No neoadjuvant chemotherapy for lobular carcinoma ? Non gradable Vrancken Peeters M-JTFD et al, SABCS 2007, abstract 5074

81 Predictive factors Analysis of responses according to subtypes 48 77
156 pts. Anthracycline taxane herceptin (if HER2+ ) Basal Non basal HER2 3+ RH+/ HER2 nég N 48 77 32 45 pRC% 23 19 31 11 No diff between basal and non basal Signific Diff between HER2 + and RH+/HER2- Allada N. et al, SABCS 2007, abstract 5076

82 Predictive factors of pRC
Question : Does pCR is related to level of hormone receptors ? 185 pts HR+ Neoadjuvant CT 6 FEC 100 Biopsy before chemotherapy RE Total Sc 3-5 Sc 6-7 Sc 8-9 pRC (%) 7 32 9 2 PgR rate didn’t predict response Petit T. et al, SABCS 2007, abstract 4024

83 Predictive factors : Remagus
170 pts 4 EC 75 q3w then 4 D 100 q3w HER2 - HER2 + No Ia Celecoxib Ib No IIa Trastuzumab initial IIb pRC G1 11.5 9.4 6.9 16.7 11% G2 1.0 3.8 6.9 13.3 5.5% RE+ RE- RP+ RP- HER2+ without T HER2- with T TPN pRC% 2.4 31 1.7 22.1 13.8 12.7 30 36 p <0.0001 <0.0006 NS Marty M. et al, SABCS 2007, abstract 5058

84 Sentinel node biopsy after NACT
Poster Method Results NP 3004 Classe France GANEA 195 patientes, cancers stade II et III, traitées par CNA, GS et CA. Taux de détection = 90,2% Faux négatifs = 11,5 % 3023 Bauerfeind Allemagne 76 patientes traitées par CNA, GS et CA. Pas toutes repérées au RI et bleu. 3 centres Taux de détection = 95,65% Faux négatifs = 16,6 % III’ III’ Essai SENTINA N- clin N+ clin Ganglion sentinelle GS - GS + Chimiothérapie néoadjuvante Rien Curage G sent Curage N- clin N+ clin

85 Local recurrence after BCT
5-6% in those who achieve CR 9.7% in those who do not achieve CR Local recurrence did not correlate with the size of the primary tumor before treatment Poor response to PST is a predictor of poor prognosis and high risk of recurrence A demonstrable response may have a positive outcome on the psyche

86 PST; poor response Immediate surgical intervention is indicated?
Alternative chemotherapy i.e. non cross resistant agents like Taxanes an obvious choice, about 50 % patients can respond but require close monitoring. Trastuzumab and other new targeted therapies are still under investigation and should not be used outside clinical trials Smith 2002 JCO.

87 Pre-chemo and surgery procedures

88 PST: How should the diagnosis be confirmed before PST
Core biopsy most appropriate Highest diagnostic accuracy by doing three biopsies, 14 gauge needle

89 PST: How should be the initial tumor localized ?
Risk of poor delimitation of primitive breast lesion in case of objective response Interest of clip or harpon delimitation Permit a better carcinologic surgery

90 How should tumor location be documented
Collaboration of surgical, medical oncologist and radiologist Two major problems can occur: Either a very quick and complete response so that the primary lesion cant be identified Or no response, in that case surgeon may have to intervene. Precise documentation of the tumor on sketch, inserting clips or coils in the center of the lesion or placing a tattoo Stereo-tactic localization using mammography is another option Complete pathological CR becoming more common, so it could become a major issue .

91 PST; Should markers be assessed before PST
Typing of tumor and assessment of surgical grade impossible because of changes due to chemo, hence preferably to be done on core tissue . Similarly ER/ PR and Her 2 or Ki67 to be done on core tissue before PST. Pathological nodal status is not available reg. prognosis and radiotherapy (a major drawback) However pathological nodal status after PST of relevant prognostic importance Data not clear reg. need for axillary biopsy or sentinel node before chemotherapy.

92 Can breast conservation be increased by PST ?
(RCTs of neoadjuvant vs adjuvant chemotherapy)

93 How, when and how often should the effect of PST be monitored
Palpation of lump and axillary nodes at the start of each cycle Mammography and ultrasound are additional tools MRI and PET of the breast being studied Dynamic studies(IGR) Importance of morphologic response : Centrifuge, centripete  correlation with pCR

94 Secondary surgery

95 PST; Surgical treatment of the tumor
To obtain clear margins of > 1 mm No compromise should be made on surgical margins to obtain better cosmetic result No difference in PST and AST in 8 year local recurrence rates Patients less than 40 years and those with larger tumors, high rates of tumor proliferation or close or involved margins are at higher risk of local recurrence There is an increased rate of second surgical procedures.

96 Role of Postoperative chemotherapy after PST
Till date no data to support or negate the use of chemotherapy after PST Data may become available from NSABP B 27 or from European Cooperative trial in Operable Breast Cancer

97 PST:When and where should postoperative radiotherapy be administered
Same indications as for adjuvant treatment Decision should be based on pre-PST findings. No definitive data on the importance of nodal status after PST and need for axillary radiotherapy Radiotherapy is not a substitute to surgery, loco-regional control is inadequate when patient is treated with RT alone.

98 Après un FEC100 Après 6 FEC100 Après un FEC100 Après 6 FEC100

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