1. Overview of Neoadjuvant Chemotherapy in Breast Cancer
Dr. Vinod Raina MD, FRCP
Professor of Medical Oncology
All India Institute of Medical Sciences
New Delhi
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2. Suggest a new term: Primary Systemic Therapy (PST)
Refers to post diagnosis systemic therapy
Takes into account order of administration, intended 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

3. Clinical rationale for increasing use of neoadjuvant chemotherapy
Studies in experimental tumour models
Excellent clinical response rates in locally advanced breast cancer (T3,T4 or TxN2)
Pathological CRs of up to 15%
Adjuvant chemotherapy has survival benefit in node positive and negative breast cancer
Breast-conservation possible

4. 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.
stages IIIA-B or T3-4 disease ?

5. Locally advanced breast cancer
In India it forms 30 % of all breast cancers at some centers.
Our own data at AIIMS 1998

6. 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 who are deemed 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.

7. 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.

8. NSABP B-18 Clinical and Pathological Responses
Clinical responses 9%
p Complete
(n=63)
36%
cCR
(249 patients) 4%
p Non-Invasive
(n=26)
23%
p Invasive
(n=160)
cPR
(296 patients)
43%
cSD + cPD
(140 patients)
20%
(number of patients=658)

9. NSABP B18 Overall survival and response to chemotherapy
5yr survival
Path CR = 87%
Clin PR = 68%
Clin NR = 64%
p<0.0001
Data from: Fisher et al, J Clin Oncol 1988; 16:

10. 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

11. 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 Comparing Primary Systemic Therapy and Adjuvant Systemic Therapy in the Breast Cancer
*No Statistical difference

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

13. 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.

14. 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.

15. PST: Rate of successful breast –conservation surgery
It correlates with clinical response and size of the primary tumor
Patients with a complete clinical response may have a successful breast conservation rate of 90 %.
In the largest trial so far no statistically significant difference was found in local recurrence free survival between patients treated with PST (4 cycles of AC) and those treated with AST (4 cycles of AC)

16. 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

17. 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.

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

19. 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.

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

21. 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

22. 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 .

23. 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.

24. 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

25. 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.

26. PST: Unresolved issues.
New compounds that are directed against specific molecular targets need to be tested in this setting.
Axillary nodal issue still not convincingly resolved
But it is here to stay

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

28. 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

29. 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?

30. Neoadjuvant Taxotere The Aberdeen Trial NSABP B27 GEPARDUO

31. Neoadjuvant Taxotere The Aberdeen Trial NSABP B27 GEPAR-DUO

32. 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

33. 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

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

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

36. 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)

37. 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)

38. Neoadjuvant Taxotere The Aberdeen Trial NSABP B27 GEPAR-DUO

39. 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

40. 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

41. 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

42. NSABP B-27: Proportion of Patients with negative axillary lymph nodes80 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

43. NSABP B-27: Breast Conservation80 60 % 63 61 40
p = 0.70 20 AC
(N=1492)
AC Taxotere
N=718
Bear et al, J Clin Oncol 2003; 21

44. Neoadjuvant Taxotere The Aberdeen Trial NSABP B27 GEPAR-DUO

45. 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

46. 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

47. 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)

48. 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

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

50. 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)

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

52. 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

53. 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

54. 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

55. 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

56. Thanks

57. 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)

58. 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.

59. 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

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

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

62. 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

63. 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

64. 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

65. 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

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

67. 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.

68. 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

69. 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

70. 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.

71. TAX 301 Study Conclusions 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

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

73. 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% )

74. 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

75. 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.

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