Overview of Neoadjuvant Chemotherapy in Breast Cancer

Overview of Neoadjuvant Chemotherapy in Breast Cancer

Dr. Vinod Raina MD, FRCPProfessor of Medical Oncology

All India Institute of Medical SciencesNew Delhi

These Power Point presentations are free to download only for academic purposes, with due acknowledgements to authors and this website.

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 2003 International Expert Panel

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

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 ?

Locally advanced breast cancer

In India it forms 30 % of all breast cancers at some centers.

Our own data at AIIMS 1998

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.

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, lesscumbersome than overall survival and less time consuming.

NSABP B-18Clinical and Pathological Responses

36%

20%

43%

cCRcCR(249 patients)(249 patients)

cPRcPR(296 patients)(296 patients)

cSD + cPDcSD + cPD(140 patients)(140 patients)

4%p Non-p Non-

InvasiveInvasive(n=26)(n=26)

9% p Completep Complete(n=63)(n=63)

23%

p Invasivep Invasive(n=160)(n=160)

Clinical responses

(number of patients=658)

NSABP B18Overall survival and response to chemotherapy

5yr survival Path CR = 87% Clin PR = 68% Clin NR = 64%

p<0.0001

0 1 2 3 4 550

60

70

80

90

100

path CR

clin PRclin NR

years

dist

ant d

isea

se-fr

eesu

rviv

al (%

)

Data from: Fisher et al, J Clin Oncol 1988; 16: 2672-2685

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 hadpath neg nodes

More likely to have lumpectomy 68% vs. 59 %,statistically not different

No difference in disease free and overall survival

Author Local Distant BreastAnd No.of Follow-up Failure Failure Survival ConservationGroup 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%

Overview of Randomized Trials Comparing Primary Systemic Therapy and Adjuvant Systemic Therapy in

the Breast Cancer

*No Statistical difference

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.

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.

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.

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)

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 sizeof 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

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.

PST: How should the diagnosis be confirmed before PST

Core biopsy most appropriate Highest diagnostic accuracy by

doing three biopsies, 14 gauge needle

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.

Can breast conservation be increased by PST ?

Study Breast Conservation

(%)

p

Scholl, 1994

82 vs 77

ns

Makris, 1998

89 vs 78

0.004

Fisher, 1998

67 vs 60

0.002

(RCTs of neoadjuvant vs adjuvant chemotherapy)

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

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 .

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.

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

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.

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

Role of Docetaxel in neo-adjuvant therapy for breast cancer

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

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?

Neoadjuvant Taxotere

The Aberdeen TrialNSABP B27GEPARDUO


The Aberdeen TrialNSABP B27GEPAR-DUO

4 cycles of Taxotere

4 cycles of CVAP

No

Response

Response Ra nd omi

se

All Patients4 cycles of CVAP

First Phase

Smith et al, JCO 2002

Tax301 StudyConducted by the Aberdeen Breast

Group

Second phase

4 cycles of Taxotere

Final Assessm

ent / Surgery

Aberdeen Tax 301Objective clinical response rates

1st phase: 4 cycles CVAP

Response % of patients

Complete 15

Partial 52

Stasis 33

Progression 1

ORR - 67%N=162 patients; 4 cycles of CVAP given to all patients

Aberdeen Tax301Objective clinical response rates2nd phase: responding patients

CVAP n=52

Taxotere n=52

Response % %

Complete 33 56

Additional partial 31 29

Maintained partial 29 6

Progression 4 0

ORR 64 85*

* p=0.03

Aberdeen Tax 301Objective clinical response rates

2nd phase: non-responding patients

Response % of patients

Complete 11

Partial 36

Stasis 31

Progression 9

ORR - 47%N=55 patients; additional 4 cycles of Taxotere given

Aberdeen Tax301 Aberdeen Tax301

Type of surgeryType of surgery undertaken

Breast conservation surgeryTaxotere 67%

CVAP 48%

Conservation Mastectomy0

20

40

60

80

100 Taxotere

CVAP

Type of surgery

% o

f pat

ient

s

(p<0.01)

Tax 301 Overall Survival

Time (months)

Median Follow - up: 60 months

Surv

ival

pro

babi

lity

1.0

0.9

0.8

0.7 20

40

60

80

100

Log rank p=0.04TaxotereCVAP

97%

78%



NSABP B-27 Operable Breast CancerOperable Breast Cancer

RandomizationRandomization

AC x 4 AC x 4 Tam X 5 YrsTam X 5 Yrs



SurgerySurgery Taxotere x 4Taxotere x 4 SurgerySurgery

SurgerySurgery Taxotere x 4Taxotere x 4

Bear et al, J Clin Oncol 2003; 21

( 2411 pts )

40%

45%

100100

8080

6060

4040

2020

00

%%

p < 0.001p < 0.001

ACACN=1502N=1502

AC Taxotere AC Taxotere N=687N=687

65%

26%

NSABP B-27 Clinical ResponseNSABP B-27 Clinical Response

cCRcCRcPRcPRcNRcNR

14% 9%

NSABP B-27 Pathological Response (pCR) in Breast

p < 0.001

AC TaxotereN=786

ACN=1567

3.9%

9.8%

7.2%

18.9%20

10

0

30 No TumourNon-Invasive

26.1%13.7%

Adapted from Bear et al, J Clin Oncol 2003; 21

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

nodes

58.2

p < 0.001p < 0.001

ACACN=1534N=1534

AC TaxotereAC TaxotereN=752N=752

8080

6060

4040

2020

00

%%

50.8


NSABP B-27: Breast Conservation: Breast Conservation

p = 0.7061 63

8080

6060

4040

2020

00

%%

ACAC(N=1492)(N=1492)

AC TaxotereAC TaxotereN=718N=718




GEPARDUO trial

von Minckwitz et al., J Clin Oncol 1999von Minckwitz et al., J Clin Oncol 2001

Surg

ery

Surg

ery

GeparduoGeparduo

T T 2 cm 2 cm (stage I,II)(stage I,II)

(N=913) (N=913) AT + Tam

AC-T +TAMAdriamycinAdriamycin

TaxotereTaxotere

AdriamycinAdriamycinCyclophosphamideCyclophosphamide

TaxotereTaxotere

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

0%

20%

40%

60%

80%

100%

AT AC-T

CompletePartialStasisProgress

(n=(n=421421)) (n=(n=425425))

57.4%32.5%

29.4%

44.7%

10.1%21.1%

Clinical responses in the breast

GEPAR-GEPAR-DUODUO Pathologic Complete Remission (pCR)Pathologic Complete Remission (pCR)

P < 0.001

No Tumor In situ residuals only

AC Taxotere(442 pts)

AT(443 pts)

3.8%

7.7%

6.3%

16.1%

11.5%

22.4%

20%20%

10%10%

00

30%30%

Adapted from G.Raab – SABCS ’03, Abs#241, Poster

Effect on tumour in axillary lymph nodes

60.7%55.4%

6060%%

4040%%

2020%%

00 AT(n=443)

8080%%

AC Taxotere(n=442)

80%80%

74.9%

65.5%60%60%

40%40%

20%20%

00AT

(n=443)AC Taxotere

(n=442)

GEPAR-GEPAR-DUODUO Effect on breast conservation surgery

AC->Taxotere :

Increased Complete Clinical response

Increased pCR rates Increased number of patients with no axillary node

involvement

Increased breast conservation

GEPAR-DUO : Conclusions

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

Overview of Rand. Trial comparing different Primary Systemic Therapy Regimens in Breast

Cancer

*No invasive or in situ tumor cells in the removed breast

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

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

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

Thanks

Adjuvant vs neoadjuvant chemotherapy in breast cancer: randomised studies

same84 vs 82T0 - T4309Makris, 1998

86 vs 78*59 vs 55IIa - IIIa414Scholl, 1994

86 vs 7881 vs 72*IIb,IIIa271Semiglazov,1994

54 vs 55sameT2,T369Mauriac, 1999

73 vs 72NRI,II204Ragaz, 1999

OS(%)

DFS(%)

StageNo. pts

Study

Fisher, 1998 1523 T1 - T3 67 vs 67 80 vs 80

(Data from: Wolf and Davidson, J Clin Oncol 2000; *p<0.05)

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.

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 mastectomyperformed

}

Alternative treatment strategies for LABC

Radiotherapy Chemotherapy Chemoradiotherapy Clinical responses of 60-70% with

various chemotherapies

Pathological complete response (pCR) in neoadjuvant Taxotere studies

13% (B18)

* **

**

*pCR incorporates lymph nodes

single

agent

concurrent sequential

Pathological Response and Survival(Miller and Payne grading system)

51.0

0.9

0.8

0.7

0.6

0.5

0.40 20 40 60 80 100 120 months

surv

ival

p=0.003*p=0.003*

43

21

Ogston et al, 2003

Aberdeen Tax301 Aberdeen Tax301 Pathological responses

Hutcheon et al, SABCS 2003

*p=0.06

5

19%pNR

pCR 31%*15%

17%15%4

23%27%3

17%19%2

2%1

Taxoteren = 52

CVAPn = 52

Miller & Payne Grade of Pathological

Response

NSABP B18: Updated results

Still no difference in overall survival Pathological complete response - 85%

year survival at 9 years

67% vs 75%56% vs 60%50 and over

71% vs 65%55% vs 46%49 and under

OSNeoadj vs adj

DFINeoadj vs adj

Age

Wolmark et al, 2001

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

NSABP-B27

Clinical complete response rates 36-40% vs 65 %

Path CR 9 % and 18 %

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.

Aberdeen Tax301Aberdeen Tax3012nd phase: non-responding patients

5

15pNR

pCR 1

64

133

112

1

Taxoteren = 46

Miller & Payne Gradeof Pathological

Response

20 (44%) patients had a grade 3,4 or 5 response

Taxotere and paclitaxel

• Similar mechanisms of action, but some differencesTaxotere has: Greater affinity for tubulin Longer half-life Longer intracellular retention Lower cardio toxicity with doxorubicin

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.

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

• Patients unresponsive to primary CVAP chemotherapy receiving further sequential Taxotere achieve :

– 47% Clinical ORR– 1 Complete pathological response

TAX 301 Study Conclusions

NSABP B-27 : Conclusions

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% )

The addition of preoperative Taxotere to preoperative AC resulted in a significant increase in the rates of:

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

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.

79% (B18)29% of tumours < 2cm in the B18 study

single agent

concurrent sequential

Clinical response rates in neoadjuvant Taxotere studies

Documents

Overview of Neoadjuvant Chemotherapy in Breast Cancer