HER2-neu status en adjuvante chemotherapie bij het mammacarcinoom M. Bontenbal Erasmus MC - Daniel den Hoed Kliniek 19 november 2004.

HER2-neu status en adjuvante HER2-neu status en adjuvante chemotherapie bij het mammacarcinoomchemotherapie bij het mammacarcinoom

M. Bontenbal

Erasmus MC - Daniel den Hoed Kliniek

19 november 2004

Chemotherapy in breast cancer

Emperical, based on conclusions of studies

Extrapolated for the individual patiënt

Leads to inefficient and potentially toxic treatment for

many to benefit a few

Cardoso, Int J Oncol 2004, 24, 201

Challenge

Select the best drug(s)

for a particular patiënt

with a biologically specific tumor

Cardoso, Int J Oncol 2004, 24, 201

16-10-2001

HER2 in breast cancer

Slamon D et al. Science 1987

HER2 oncoprotein overexpression

HER2 oncogeneamplification Shortened median survival

HER2 overexpressing 3 yearsHER2 normal 6–7 years

Method Target FDA-approved Silde-based

IHC Protein Yesa Yes

FISH Gene Yesa Yes

CISH Gene No Yes

Southern blot Gene No No

RT-PCR mRNA No No

Microarray TPb mRNA No No

Tumor ELISA Protein No No

Serum ELISA Protein Yesc No

a For prognosis and prediction of response and eligibility to receive trastuzumab therapy. b TP, transcriptional profiling. c For monitoring response of breast cancer to treatment.

Ross, Molecular and Cellular Proteomics 2004, 3, 379

Methods of detection of HER-2/neu status in breast cancer

HER2-neu gene and protein and the prognosis in breast cancer

Correlation status Number of Number of

studies (%) cases (%)

All cases

None 8 (10%) 1995 (8%)

Univariate or 73 (90%) 25.166 (92%)

multivariate significance

Independent on 52 (71%) NA

multivariate analysis

Totals 81 (%) 27.161 (100%)

Ross, The Oncologist 2003, 8, 307

HER2-neu gene and protein and the prognosis in breast cancer

Cases with no correlation: Number of Number of

studies (%) cases (%)

Immunohistochemistry 5 (63%)

Southern blot 2 (25%)

RT-PCR 1 (12%)

Totals 8 (100%) 1995 (100%)

Ross, The Oncologist 2003, 8, 307

HER2 positivity correlates with:

a poor prognosis

HER2 as a predictor of response to chemotherapy in MBC

Author Pt. HER2+ Test Therapy Outcome

(n) (%) HER2+ HER2-

Stender ‘97 319 23 EIA A+P;P equal

Gianni ‘97 (49) 35 FISH A+P CR: 50% vs 17%

Niskanen ‘97 173 31 IHC FEC q 1 equal

or 4 wk

Sjöström ‘02 283 42 IHC MF vs D equal

Poznak ‘02 188 25/15 IHC Phase II equal

P or D

P, paclitaxel; D, docetaxel

HER2 as a predictor of response to chemotherapy in MBC

Author Pt. HER2+ Test Therapy Outcome (RR)

(n) (%) HER2+ HER2-

Kònecny ‘04 275 35 FISH EP 76%* 50%

vs

EC 46% 33%

Di Leo ‘04 176 20 FISH A 27% 35%

vs

D 67% 40%

D, docetaxel; P, paclitaxel; *difference significant

HER2 as a predictor of response to neo-adjuvant chemotherapy

Author Pt. HER2+ Test Therapy Outcome

(n) (%)

Rozan ‘98 329 19 IHC FAC cCR 20% HER-

31% HER+

S (5yr) : equal

Colleoni ‘99 73 10 IHC FUFAv RR 56% HER-

86% HER+

Zhang ‘03 79 28 IHC/ FAC RR, DFS (3yr): equal

FISH

Gonzalez ‘04 71 28 FISH P/D pCR 10% HER-

16% HER+

OS (5yr): equal

HER2 as a predictor of response to adjuvant CMF

Author Pt HER2+ Therapy Conclusions(n) (%) DFS and OS

Allred ‘92 613 14 CMFp Adv. better in HER2--

Gusterson ‘93 1506 16-19 CMF (1) Adv. better in HER2-CMFp (6)

Miles ‘99 274 30 CMF Adv. better in HER2- -

Menard ‘01 386 16 CMF Adv. “equal” -

Adv.: advantage

HER2 positivity correlates with:

a poor prognosis

relative resistance to alkylating agents

HER2 as a predictor of response to adjuvant anthracyclinesAuthor Pt HER2+ Therapy Conclusions

(n) (%) Anthra in HER2+

Paik ‘98 638 38 PF DFS, RFS, OS better*PAF

Ravdin ‘98 595 16 CAFT DFS better*T

Paik ‘00 2034 29 AC DFS, RFS, OS betterCMF

Pritchard ‘02 602 20 (IHC) CMF DFS, OS better24 (FISH) CEF

Di Leo ‘02 354 21 (FISH) CMF EFS better EChEC

Moliterni ‘03 506 19 CMF+A DFS, OS* better CMF

* significant

Dose-response effect of (neo-)adjuvant anthracyclines in HER2 positive tumors

Author Pt. HER2+ Therapy Conclusion

(n) (%) HER2+

Thor ‘98 992 27 FISH CAF PFS, OS related

(3 dose levels) to dose

Petit ‘01 79 26/30 FEC 50 or OR HER2-: equal

FEC 100 OR HER2+:

FEC 50: 12%

FEC 100: 100%

HER2 positivity correlates with:

a poor prognosis

relative resistance to alkylating agents

slightly higher anthracycline sensitivity

BCIRG 001 - Design

Docetaxel 75 mg/m2 Doxorubicin 50 mg/m2

Cyclophosphamide 500 mg/m2

5-FU 500 mg/m2

Doxorubicin 50 mg/m2

Cyclophosphamide 500 mg/m2

FAC

TAC

R

Dexamethasone premedication, 8 mg bid, 3 days Prophylactic Cipro 500 mg bid, day 5-14

Every 3 weeks x 6 cycles

Stratification:• Nodes:

1-3 4+

• Center

N= 1491

BCIRG 001 - Disease-Free Survival (ITT)

75%

N Events HR P-value

Stratified Log Rank

TAC 745 172 0.72 .0010

FAC 746 227

1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30 36 42 48 54 60 66

FAC

TAC

Cu

mu

lati

ve p

rob

abil

ity

68%

DFS Time(months)

BCIRG 001 - Overall Survival (ITT)

1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30 36 42 48 54 60 66

FAC

TAC

Cu

mu

lati

ve P

rob

abil

ity

87%

81%

N Events HR P-value

Stratified Log-Rank

TAC 745 91 0.70 .0080

FAC 746 130

Survival Time (months)

HR = 0.60 P = 0.0088

Positive

0 6 12 18 24 30 36 42 48 54 60 66

90

80

70

60

50

FAC

TAC

Time to First Event

100

BCIRG 001 - DFS by HER2 Status

0 6 12 18 24 30 36 42 48 54 60 66

100

90

80

70

60

50

FAC

TAC

HR = 0.76 P = 0.046

Negative

Time to First Event

% A

live

and

Dis

ease

-Fre

e

(FISH performed centrally)

Ratio of HRs 0.85 P = 0.4122

HER2 positivity correlates with:

a poor prognosis

relative resistance to alkylating agents

slightly higher anthracycline sensitivity

probably slightly higher taxane sensitivity

Author N Scheme RR TTP OS (%) (mo) (mo)

Lück ‘00 541 EP 60/175 46 9.4 NS

EC 60/600 40 7.4

Carmichel ‘01 705 EP 75/200 40 6.5 NS

EC 75/600 37 6.8

Jassem ‘01 267 AP 50/220 68 8.3 23.3

FAC 500/50/500 55 6.2 18.3

Biganzoli ‘02 271 AP 60/175 58 5.9 20.6

AC 60/600 54 6.0 20.5

First-line Anthracycline + Paclitaxel in MBCPhase III studies

First-line Anthracycline + Docetaxel in MBC Phase III studies

22.6

16.1

8.1

6.6

64

41

AT 50/75

FAC 500/50/500

216Bontenbal ‘03

34

28

7.8

5.9

63

34

ET 75/75

FEC 500/75/500

142Tubiana ‘03

21

22

7.1

6.7

55

44

TAC 75/50/500

FAC 500/50/500

484Mackey ‘02

22.5

21.7

8.6

7.3

59

47

AT 50/75

AC 60/600

429Nabholtz ‘03

OS

(mo)

TTP

(mo)

RR

(%)

SchemeNAuthor

Taxane-based adjuvant therapy Phase III studies

Med.

Trial Design Nodes Pt FU Outcome

(n) (mo) (of taxane)

CALGB 4AC4P N+ 3170 69 DFS and OS

9344 4AC better

NSABP 4AC4P N+ 3060 64 DFS better,

B28 4AC OS equal

BCIRG 6TAC N+ 1491 55 DFS and OS

001 6FAC better

HormoonReceptoren

ER+ en/ofPgR+

ER- en PgR-

Leeftijd / Menopauzale status / Aantal positieve klieren (N)PostmenopauzaalPremenopauzaal

50-59 jaar 60-69 jaar > 70 jaarN > 1: 6 TAC + 5 jrtam. of LHRH oftam. + LHRH

N > 1: 6 TAC

N > 1: 5 FEC + 5 jraromataseremmer

N > 1: 5 FEC

N1-3: 5 jr aromatase-remmer

N 4: 5 FEC + 5 jraromataseremmerN > 1: 5 FEC

N > 1: 5 jraromataseremmer

N > 1: Geen adviesmogelijk

Tabel II: Richtlijn adjuvante systemische therapie bij een N+ mammacarcinoom met HER2-neu overexpressie

Incidence of neutropenic complications Geicam-9805 study (adjuvant TAC for N0)

No. of patients %

TAC FAC

pre- post- pre- post- amendm. amendm. amendm. amendm. (n=109) (n=115) (n=111) (n=113)

Neutropenia (all grades) 105 (96.3) 86 (74.8) 86 (86.5) 88(77.9)

Neutropenia (grade 3-4) 102 (93.6) 47 (40.9) 47 (42.3) 44(38.9)

Febrile neutropenia* 26 (23.9) 4 (3.5) 1 (0.9) 2 (1.8)

Fever during 39 (35.8) 12 (10.4) 3 (2.7) 4 (3.5)

* grade 2 fever (>38.5ºC) with grade 4 neutropenia and requiering I.V. antibiotics and/or hospitalisation in the some cycle